Histopathology Specimens - Clinical, Pathological and Laboratory Aspects (PDFDrive)

Derek C.
Allen
R. Iain Cameron
Editors
Histopathology
Specimens
Clinical, Pathological
and Laboratory Aspects
Third Edition
123
Histopathology Specimens
Derek C. Allen • R. Iain Cameron
Editors
Histopathology
Specimens
Clinical, Pathological and
Laboratory Aspects
Third Edition
Editors
Derek C. Allen R. Iain Cameron
Belfast City Hospital Altnagelvin Hospital
Belfast Londonderry
UK UK
ISBN 978-3-319-57359-5 ISBN 978-3-319-57360-1 (eBook)

DOI 10.1007/978-3-319-57360-1
Library of Congress Control Number: 2017950223
© Springer International Publishing AG 2017

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To Alison, Katie, Rebecca, and Amy
Preface
Since the publication of the second edition of Histopathology Specimens:

Clinical, Pathological, and Laboratory Aspects, pathology has further con-
solidated its position at the core of clinical multidisciplinary teams and their
attendant meetings. These forums are pivotal nodal discussion points in
patient investigation, treatment planning, and prognostication. Pathologists
are required to produce and comment on reports that are timely, accurate, and
relevant. To this end, the UK Royal College of Pathologists and other organ-
isations (International Collaboration on Cancer Reporting (ICCR)) continue
to publish standards of professional practice such as the Cancer Datasets and
Tissue Pathways for the handling and reporting of cancer and non-cancer
specimens, respectively. Indeed, the UK Royal College of Pathologists has
established key performance indicators incorporated into UKAS accredita-
tion standards aimed at ensuring laboratory processes and outcomes are ben-
eficial to patients. These include >90% targets for attendance at
multidisciplinary team meetings, coding and use of proforma histopathology
reports, and 80–90% report turnaround times of 7–10 days, respectively. The
College has also produced a standardised user satisfaction survey in metric
form that should allow assessment of measureable pathology performance
and team communication. This may also potentially be considered alongside
colleague and user multisource feedback as part of annual appraisal and med-
ical revalidation.
One other standard is that laboratories should aim to have a significant
minority (15–30%) of their medical and scientific staff in training grades. The
structure and content of this book not only facilitates delivery of high perfor-
mance standards but also reflects the clinically integrated approach to the
teaching of pathology as determined by the Royal College postgraduate train-
ing curriculum and the General Medical Council medical student undergrad-
uate curriculum. Its content is also directly relevant to Biomedical Scientists
in their devolved role of consultant supervised specimen dissection as evi-
denced by the collaborative IBMS/RCPath diploma of extended practice and
advanced specialist diplomas in histological dissection.
Belfast, UK Derek C. Allen

Londonderry, UK R. Iain Cameron
vii
Acknowledgements
The authors gratefully acknowledge the use of illustrations from Wittekind

C., Greene L., Hutter R.V.P., Klimfinger M., and Sobin L.H. TNM Atlas:
Illustrated Guide to the TNM/pTNM Classification of Malignant Tumours.
5th edition. Berlin, Heidelberg: Springer-Verlag, 2005.
Grateful appreciation is expressed to Joanna Renwick (Editor, Clinical
Medicine), Andre Tournois, and the staff at Springer.
ix
Contents
Part I Gastrointestinal Specimens
1 Gastrointestinal Specimens: General Comments�� 3

Derek C. Allen and R. Iain Cameron
2 Oesophagus�� 13
Damian T. McManus, Derek C. Allen, and R. Iain Cameron
3 Stomach�� 25
Damian T. McManus, Derek C. Allen, and R. Iain Cameron
4 Pancreas, Duodenum, Ampulla of Vater and Extrahepatic
Bile Ducts�� 37
Paul J. Kelly, Derek C. Allen, R. Iain Cameron,
and Maurice B. Loughrey
5 Small Intestine�� 55
Derek C. Allen, R. Iain Cameron, and Maurice B. Loughrey
6 Colorectum �� 67
7 Appendix �� 87
8 Anus�� 95
9 Gallbladder�� 103
10 Liver�� 111
11 Abdominal Wall, Umbilicus, Hernias, Omentum,
and Peritoneum�� 125
xi
xii Contents
Part II Breast Specimens
12 Breast�� 133
Shauna Casey and R. Iain Cameron
Part III Head and Neck Specimens
13 Nasal Cavities and Paranasal Sinuses�� 149

Seamus S. Napier and Ramzan M. Ullah
14 Lips, Mouth, and Tongue�� 157
Seamus S. Napier and Derek J. Gordon
15 Maxilla, Mandible, and Teeth �� 169
Seamus S. Napier and with clinical comments
by John J. Marley
16 Pharynx and Larynx�� 179
by Barry Devlin
17 Salivary Glands�� 193
by John J. Marley
18 Thyroid Gland�� 203
Caroline L. Coghlin and Seamus S. Napier
19 Parathyroid Glands�� 213
20 Neck: Cysts, Tumours, and Dissections �� 219
by Derek J. Gordon
Part IV Eye
21 Eye �� 231

Roy W. Lyness
Part V Gynaecological Specimens
22 Ovary�� 243
Oisin P. Houghton and W. Glenn McCluggage
23 Fallopian Tube�� 255
24 Uterus�� 261
25 Cervix�� 273
Contents xiii
26 Vagina�� 283
27 Vulva�� 289
28 Placenta�� 295
Oisin P. Houghton
Part VI Urological Specimens
29 Kidney, Renal Pelvis, and Ureter�� 301

Declan M. O’Rourke and Derek C. Allen
30 Bladder�� 321
31 Prostate �� 337
32 Urethra�� 353
33 Testis, Epididymis, and Vas�� 363
34 Penis�� 379
Part VII Pelvic and Retroperitoneal Specimens
35 Pelvic Exenteration Specimens �� 393

Damian T. McManus and Derek C. Allen
36 Retroperitoneum�� 399
Oisin P. Houghton and Damian T. McManus
37 Adrenal Gland�� 405
Maurice B. Loughrey and Caroline L. Coghlin
Part VIII Skin Specimens
38 Skin�� 415
Maureen Y. Walsh
Part IX Cardiothoracic Specimens and Vessels
39 Lung�� 435
Kathleen M. Mulholland
40 Pleura�� 447
xiv Contents
41 Mediastinum�� 453
42 Heart�� 461
43 Vessels�� 469
Part X Osteoarticular and Soft Tissue Specimens
44 Joint Space, Bone, Soft Tissues,

and Special Techniques�� 477
Oisin P. Houghton
Part XI Haemopoietic Specimens
45 Lymph Nodes, Spleen, and Bone Marrow �� 495

Lakshmi Venkatraman and Damian T. McManus
Part XII Miscellaneous Specimens and Ancillary Techniques
46 Miscellaneous Specimens and Ancillary Techniques�� 519

Damian T. McManus
Clinical Request Form Abbreviations�� 533
Resection Specimen Blocking Summary�� 543
Index�� 547
Contributors
Derek C. Allen Histopathology Laboratory, Belfast City Hospital, Belfast

Health and Social Care Trust, Belfast, UK
R. Iain Cameron Histopathology Laboratory, Altnagelvin Hospital,
Western Health and Social Care Trust, Londonderry, UK
Shauna Casey Histopathology Laboratory, Belfast City Hospital, Belfast
Caroline L. Coghlin Histopathology Laboratory, Belfast City Hospital,
Belfast Health and Social Care Trust, Belfast, UK
Barry Devlin ENT Surgery, Royal Victoria Hospital, Belfast Health and
Social Care Trust, Belfast, UK
Derek J. Gordon Regional Plastics and Maxillofacial Unit, Ulster
Hospital, Southeastern Health and Social Care Trust, Dundonald, UK
Oisin P. Houghton Histopathology Laboratory, Institute of Pathology,
Royal Victoria Hospital, Belfast Health and Social Care Trust, Belfast, UK
Paul J. Kelly Histopathology Laboratory, Institute of Pathology, Royal
Victoria Hospital, Belfast Health and Social Care Trust, Belfast, UK
Maurice B. Loughrey Histopathology Laboratory, Institute of Pathology,
Roy W. Lyness Histopathology Laboratory, Belfast City Hospital, Belfast
John J. Marley Department of Oral Surgery, School of Dentistry, Royal
Victoria Hospital, Belfast Health and Social Care Trust, Belfast, UK
W. Glenn McCluggage Histopathology Laboratory, Institute of Pathology,
Damian T. McManus Histopathology Laboratory, Belfast City Hospital,
Kathleen M. Mulholland Histopathology Laboratory, Altnagelvin
Hospital, Western Health and Social Care Trust, Londonderry, UK
Seamus S. Napier Histopathology Laboratory, Institute of Pathology,
xv
xvi Contributors
Declan M. O’Rourke Histopathology Laboratory, Belfast City Hospital,

Ramzan M. Ullah Directorate of ENT Surgery, Royal Victoria Hospital,
Lakshmi Venkatraman Histopathology Laboratory, Institute of Pathology,
Maureen Y. Walsh Histopathology Laboratory, Institute of Pathology,
Introduction
The Role of Histopathology Specimens
Histopathology specimens are a vital cornerstone in patient care. They not

only establish a tissue diagnosis but are crucial in clinical management
decisions and provide important prognostic data. They are nodal events in
a patient’s illness shaping the choice of relevant medical and surgical ther-
apies and determining follow-up strategy. The data they provide are used
to assess the efficiency of current and new investigation and treatment
regimes and to monitor the impact of population screening programmes.
Clinical governance has recognised their key role in auditing not only indi-
vidual clinicians but also the patterns and quality of overall health care
provision. Biomedical research with advances in investigations and ther-
apy would flounder without them. They are therefore a precious resource
to be handled with great care by sufficient numbers of appropriately trained
and experienced personnel. The data generated are of a confidential nature
privy to the patient, consultant clinician or general practitioner, and the
reporting pathologist. This information may be shared as appropriate with
other directly involved health care professionals, for example, in the con-
text of multidisciplinary team meetings, but laboratory practice (e.g., tele-
phoned results and report authorisation) must be geared to protect patient
confidentiality at all times. The patient not only has a right to see and have
explained the information in his/her specimen but must undergo a process
of informed consent prior to the clinical procedure. Thus the nature, pur-
pose, extent, and side effects of the procedure are explained in understand-
able terms. This process extends to the laboratory as patients can express
their wish for disposal and use of the tissue not only for diagnosis but also
for educative, audit, and research purposes. Additionally research projects
should be verified by an appropriate research ethics committee. Patient
denial of any of these uses must then be communicated to the laboratory
and incorporated into the handling and disposal procedures. The histopa-
thology specimen report forms a permanent part of the patient’s medical
record and as such may be used as medico-legal evidence in negligence
and compensation cases. These various factors serve to emphasise the
importance of the care that should be taken with these specimens by histo-
pathology laboratory personnel.
xvii
xviii Introduction
The Handling of Histopathology Specimens
Specimen transportation, accession, clinical prioritisation, dissection, audit,

and reporting are considered.
Specimen Transportation
There must be close liaison between pathology and clinical staff to ensure appro-
priate transportation of specimens between the outpatient department, operating
theatre, and the laboratory, for example, prompt transport of fresh specimens or
the provision of special fixatives. This must be reflected in shared protocols, a
user information manual, and education of the clinical and portering staff.
Specimen Accession
Allocation of a unique laboratory number and accurate computer registration

of patient details are fundamental to maintenance of a meaningful and practi-
cable histopathology database. This is important not only to individual patient
care (e.g., a sequence of biopsies) but also for provision of statistics, for
example, download to cancer registries.
Specimen Prioritisation
With ever increasing workload and limited staffing resources, pathologists

may find it necessary to put in place a specimen pull-through protocol related
to clinical need to ensure that diagnostic results are available within an appro-
priate time frame. This can be based on various criteria such as specimen type
and request form information (Appendix A). Suggested overall turnaround
times for histopathology specimens are 80% and 90% of cases reported
within 7 and 10 working days, respectively, subject to individual case needs
and in agreement with local clinical teams.
Specimen Dissection
Traditionally the role of a medical pathologist specimen dissection is now also

being performed by an increasing number of biomedical scientists (BMSs) as
has been the situation for several decades in some laboratories in America
(Pathologist Assistants) and the UK. BMSs, trainee, and consultant pathologists
are all appropriate to the task provided that several principles are adhered to:
• The histopathology specimen and its report remain the overall responsibil-
ity of the reporting consultant pathologist.
• There is close proximity and ready availability of active consultant pathol-
ogist supervision before, during, and after handling of the specimen.
Introduction xix
• There is workforce stability and staff are prepared to work together as a

team. The working unit comprises a variable combination of two people
(junior/senior, medic/BMS) fulfilling the roles of dissector/writer/supervi-
sor with active overarching consultant pathologist supervision.
• Staff recognise that acquisition of dissection skills is an at-the-bench appren-
ticeship based on sufficient knowledge, time, experience, and supervision.
This knowledge base requires insight into normal anatomy, clinical presen-
tation, and investigations relevant to request form information, common
pathological conditions, and their effect on specimens, surgical consider-
ations in production of the specimen, and core report data tailored to patient
management and prognostic information. Consequently the chapters in this
book are structured accordingly under these headings. The cut-up supervisor
plays a vital role in passing on verbal knowledge but this is supplemented by
various means, for example, publications (in-house protocols, ACP broad-
sheets, College datasets, and textbooks) or training courses. A structured
training programme facilitates learning and progression.
Staff must also be familiar with the laboratory process of checking patient
details, specimen labelling, and past history (cytology, biopsy, and treat-
ment), the importance of specimen opening for adequate fixation, demonstra-
tion of resection margins, and use of macroscopic and microscopic digital
photography. Knife etiquette and sampling blocks of appropriate thickness
and fixation are crucial. The supervising pathologist must provide active
feedback as to the significance and adequacy of these blocks. Line diagrams
are an invaluable communication tool between dissector and reporters.
Specimens not infrequently need to be revisited prior to report authorisation
or following new information gained from the multidisciplinary team meet-
ing. Retention of “wet” specimens must be sufficiently long (minimum 4
weeks) to allow this process to happen.
• Dissectors should only work to their individual level of experience and

competence—this is determined by the structured training programme,
audit process (see below), and categorisation of specimens according to
their complexity.
• Dissectors should actively seek supervisor input if a specimen is complex,
novel, shows an unusual variation on a usual theme, or if they have any
doubt.
• The principles and a working practice of surgical cut-up are referred to in
Appendices B and C.
Specimen Dissection Audit
The quality of specimen dissection must be meaningfully monitored, and the

majority of this is done actively at the laboratory bench by the consultant
pathologist/BMS supervisor team as part of the specimen dissection pre-/
peri-/post-view and reporting feedback procedures. In addition, this team
should carry out formal periodic audit and assessment of dissectors’ skills.
xx Introduction
This combination of approaches forms the basis for an individual dissector’s

continued practice and progression between specimen categories (see
Appendix D). It also identifies the areas of subspecialist expertise or in need
of further training. It must be recognised that category progression cannot be
proscribed by rigid time frames but rather related to the aptitude of the indi-
vidual dissector and spectrum of workload that is encountered.
Specimen Reporting
Histopathology specimen reports remain the responsibility of an appropri-

ately trained and experienced medical pathologist. Increasingly Royal
College of Pathologist Cancer Datasets are mandating key audit data to assess
the standards of specimen dissection and reporting, for example, colorectal
cancer mean lymph node harvest and the reported percentages of serosal and
extramural vascular involvement by tumour. Other key service quality indica-
tors include pathologist participation in relevant interpretive histopathology
external quality assurance (EQA) schemes and appropriate continuing pro-
fessional development (CPD) activity. These issues are discussed at annual
appraisal and are foundational to medical revalidation. The overall quality of
a surgical pathology service depends on a number of key performance indica-
tors summarised in a Royal College of Pathologists document (Key perfor-
mance indicators—proposals for implementation. http://www.rcpath.org/).
They include availability and timeliness of clinical advice, participation at
multidisciplinary meetings, coding of histopathology reports, use of cancer
resection report proformas, documentation of second opinions, results trans-
mission, communication of critical and unexpected results, report turnaround
times, monitoring of outstanding reports, appraisal, CPD, participation in
appropriate EQA schemes, user satisfaction surveys, staff qualification,
teaching, training, supervision, and succession planning (Appendix E).
The principles and practice of surgical cut-up and sample protocols for
general specimen handling, categorisation, and laboratory abbreviations
(Appendices F and G) are included in the appendices to this section.
Other aspects of service quality and safety are also actively addressed by
appropriate guidance documents available on the Royal College of
Pathologists website (Appendix H).
The Core Data in Histopathology Specimens
Specimen dissection must be geared to provide information relevant to the

clinician who is managing the patient. Reports must be timely, that is, prompt,
but in the context of an adequate period of fixation so that acquisition of accu-
rate data is not compromised. The report content must not only come to an
interpretationally accurate diagnosis but also be qualified by assessment of
various evidence-based prognostic indicators. In the field of surgical cancer
pathology, this is reflected by the trend towards set format reports or datasets
for the common cancers. Thus the core content should include gross specimen
Introduction xxi
description, tumour histological type and grade, extent of local tumour spread,
lymphovascular invasion, lymph node involvement, relationship to primary
excision margins, and any associated pathology.
Gross Description
Clear distinction should be made between biopsy and resection specimens as

they are handled differently and represent different nodal points in a patient’s
illness. This should be reflected in use of appropriate SNOMED T (topogra-
phy) and P (procedure) codes—this also facilitates audit of biopsy and resec-
tion—proven cancer numbers and correlation with other techniques such as
cytology, radiology, and serum markers. The site, distribution, size, edge, and
appearance of a tumour within an organ greatly influence the specimen han-
dling and creation of a diagnostic shortlist for microscopy. For example, a
gastrointestinal malignant lymphoma may be multifocal, pale, and fleshy
with prominent mesenteric lymphadenopathy, whereas a carcinoma is more
usually ulcerated and annular, firm and irregular with more localised lymph
node disease and vascular involvement.
Histological Tumour Type
There are marked prognostic and therapeutic differences between the diagno-
ses of carcinoma, sarcoma, germ cell tumour, and malignant lymphoma. This
is further highlighted within a given anatomical site, for example, lung, where
a diagnosis of carcinoma can be of various subtypes requiring either primary
surgical (squamous cell carcinoma) or chemo-/radiotherapeutic (small cell
carcinoma) approaches and with very different biological outcomes.
Histological Tumour Differentiation or Grade
Tumour differentiation or grade reflects the similarity to the ancestral tissue of

origin and degree of cellular pleomorphism, mitoses, and necrosis. It too greatly
influences choice of therapy and prognosis, for example, low-grade versus high-
grade gastric lymphoma (antibiotics versus chemotherapy/surgery) or grade I
(surgery alone) versus grade III (surgery and chemotherapy) breast cancer.
An accurate histological tumour type and grade cannot be ascertained
unless there is appropriate specimen handling with adequate fixation.
Extent of Local Tumour Spread
Prognosis of a given cancer may be influenced by the character of its invasive

margin (circumscribed/infiltrative) but is largely determined by its pathologi-
cal stage, that is, the depth or extent of spread in the organ and degree of
lymph node involvement. This is then updated by other information, for
xxii Introduction
example, evidence of distant metastases, to formulate a clinical stage upon

which management is based. The TNM (Tumour Nodes Metastases) classifi-
cation is the international gold standard for the assessment of spread of can-
cer and translates into hard data some of the descriptive language used in
histopathology reports facilitating communication within the multidisci-
plinary team. The post-surgical histopathological classification is designated
pTNM and is based on pre-treatment, surgical, and pathological information.
The staging is formalised and agreed at the relevant multidisciplinary team
meeting thereupon forming a permanent part of the patient’s medical record.
pT Requires resection of the primary tumour or biopsy adequate for

evaluation of the highest pT category or extent of local tumour spread.
Due to tumour heterogeneity, this is contingent upon adequate numbers of
well-orientated blocks. Where possible multiple tumours are individually
staged and the highest pT category used for management decisions
pT0 No histological evidence of primary tumour
pTis Carcinoma in situ
pT1-4 Increasing size and/or local extent of the primary tumour histologically
pN Requires removal of nodes sufficient to evaluate the absence of regional
node metastasis and also the highest pN category. Where possible all
regional nodes in a resection specimen should be sought and harvested
for histology
pN0 No regional lymph node metastasis histologically
pN1-3 Increasing involvement of regional lymph nodes histologically
pM Requires microscopic examination of positive body cavity fluid cytology
or distant metastases—the latter may not be available to the pathologist
and therefore designated on clinical or radiological grounds
Other descriptors include unifocality (pT1a) versus multifocality (pT1b), lym-

phatic invasion (L), venous invasion (V), perineural invasion (Pn), classification
during or after multimodality therapy (ypT), recurrent tumour (rpT), residual
tumour (R0/R1/R2), and multiple primary tumours (pTm). Subdivisions of some
categories exist to allow for greater specificity, for example, pN2a and pN2b.
The post-surgical pathological stage not only gives an estimate of disease
prognosis but is also used to guide adjuvant therapy. Other prognostic and
predictive factors are also taken into account on an individual basis, e.g., the
hormonal expression, molecular features, or gene expression of the tumour in
question. Qualifying tumours in the TNM system are carcinoma, malignant
mesothelioma, malignant melanoma, gastrointestinal neuroendocrine and
stromal tumours, gestational trophoblastic tumours, germ cell tumours, and
retinoblastoma. The 8th edition TNM classification published in December
2016 (and subject to ongoing review - herein referred to as TNM 8) is used
throughout this book unless otherwise stated.
Lymphovascular Invasion
Usually defined histologically in blocks from the tumour edge or slightly

away from it and more likely to be associated with cancers that show
local recurrence, lymph node involvement, submucosal spread, and
Introduction xxiii
s atellite lesions. This has implications for blocking of resection speci-

mens and their margins. Some cancers (hepatocellular carcinoma and
renal cell carcinoma) have a propensity for vascular involvement and care
should be taken to identify this on gross specimen dissection and micros-
copy as it alters the tumour stage and is a marker for distant haematoge-
nous spread.
Lymph Nodes
The pN category relates to the total node yield and the number that are
involved. Nodal yields are used to audit the care of dissection by the
pathologist, adequacy of resection by the surgeon, and the choice of opera-
tion, for example, axillary node sampling versus clearance in breast can-
cer. All regional nodes should be sampled and although ancillary techniques
(xylene clearance and revealing solutions) can play a useful supplemen-
tary role, there is no substitute for time spent on careful dissection. The
TNM system makes a numerical recommendation for what is considered
an appropriate regional lymphadenectomy for each type of cancer resec-
tion. Care should be taken not to double count the same node, and those
small nodes (>1 mm with an identifiable subcapsular sinus) in the histo-
logical slides immediately adjacent to the tumour should not be ignored.
TNM rules state that direct extension of primary tumour into a regional
node is counted as a nodal metastasis as is a tumour nodule with the form
and smooth contour of a lymph node in the connective tissue of a lymph
drainage area (e.g., mesorectum) even if there is no histological evidence
of residual lymphoid tissue. This probably represents a totally replaced
lymph node, provided it is not recognisable as tumour in a vascular struc-
ture or perineural space. A tumour nodule with an irregular contour could
be classified in the pT category, that is, as discontinuous extension, or is
designated as a soft tissue tumour deposit or satellite. Dissection and sub-
mission of separate deposits is therefore important. When size is a crite-
rion for pN classification, for example, vulval carcinoma, measurement is
made of the metastasis, not of the entire node and will usually be made
from the histological slides. Micrometastases (≤2 mm) are designated pN1
(mi) and isolated tumour cells (≤0.2 mm) pN0(i+) as they are not regarded
as having metastatic potential. Most busy general laboratories submit
small nodes (<5 mm) intact or bisected and a mid-slice of larger ones.
Additional slices are processed pending microscopy. Alternatively lymph
nodes are serially sliced at 2–3 mm intervals and allocated a specific cas-
sette. Sentinel nodes are handled in this way supplemented by use of block
levels and immunohistochemistry. The limit node is the nearest node to the
longitudinal and/or apical resection limits and suture ties. Some speci-
mens, for example, transverse colectomy, will have more than one and they
should be identified as such. Extracapsular spread is an adverse indicator
more usually recognised histologically but should be noted on gross
inspection if near to or impinging upon a resection margin, for example,
axillary clearance in breast carcinoma. Non-regional lymph node involve-
ment represents metastatic disease (pM).
xxiv Introduction
Excision Margins
The clearance of excision margins has important implications for patient

follow-up, adjuvant therapy, and local recurrence of tumour. Measurements
should be made on the gross specimen and checked against the histological
slide. Painting of the margins by ink supplemented by labelling of the blocks
is important. Paint adheres well to fresh specimens but also works on
formalin-fixed tissue. India ink or alcian blue is commonly used. Commercially
available multicoloured inks are helpful particularly if there are multiple mar-
gins as in breast carcinoma. If the intensity of the colour on the slide is low,
it can be easily checked against the paraffin block. Paint is usually applied to
margins prior to dissection but can be re-applied for further emphasis after
obtaining the block along its edge. The relevance of particular margins (lon-
gitudinal, quadrant, transverse, circumferential, and anatomical) varies
according to specimen and cancer type and is further discussed in their
respective organ systems. In general terms, involvement of longitudinal mar-
gins can be by direct, discontinuous, or multifocal spread, for example,
oesophageal carcinoma. Positive circumferential radial margins are an indi-
cator of potential local recurrence and a gauge of cancer spread, local anat-
omy, and the extent of surgical excision. Peritoneal or pleural serosal disease
allows potential trans-coelomic spread to other abdominopelvic organs or
transpleural spread to the chest wall.
TNM classifies local resection as:
R0 No residual tumour
R1 Microscopic residual tumour (tumour transection or proven by tumour bed
biopsy or cytology)
R2 Macroscopic residual tumour
Other Pathology
Predisposing, concurrent, and associated conditions should be noted, blocked,

and documented, for example, colorectal carcinoma and adenomatous pol-
yps, gastric carcinoma and gastric atrophy or synchronous malignant lym-
phoma (MALToma).
Ancillary Techniques in Histopathology Specimens
The vast majority of histopathology specimens can be adequately reported by

close attention to careful gross description, dissection and block selection and
microscopy of good quality formalin-fixed paraffin sections stained with hae-
matoxylin and eosin. However, key ancillary techniques are required in a
proportion of cases (see Chap. 46). Some examples are
Introduction xxv
Frozen sections: confirmation of parathyroidectomy, assessment of opera-

tive resection margins in cancer surgery, and cancer versus inflammatory
lesions at laparotomy or thoracotomy.
Histochemical stains: demonstration of mucin in adenocarcinoma, congo-
philia in amyloid, iron in haemochromatosis, and organisms (pyogenic bacte-
ria, tubercle, and fungus) in infection.
Immunofluorescence: glomerular deposits in renal biopsies, deposition of
immunoglobulin, and complement in blistering skin disorders.
Immunohistochemistry: the surgical pathologist’s “second H and E” and
invaluable in assessing tumour type, prognosis, and predictive factors in treat-
ment, for example, carcinoma (cytokeratins) versus malignant lymphoma
(CD45) and malignant melanoma (S100), or better prognostic and hormone
responsive breast cancer (oestrogen receptor positive). Tumour antigenic pro-
file is often crucial in specifying the site of origin for a metastasis, for exam-
ple, prostate carcinoma (PSA/PSAP positive).
Electron microscopy: valuable in medical renal biopsy diagnosis, and
tumours where morphology and immunohistochemistry are inconclusive, for
example, malignant melanoma (pre-/melanosomes) and neuroendocrine car-
cinoma (neurosecretory granules).
Molecular and chromosomal studies: immunoglobulin heavy chain and
T cell receptor gene rearrangements in the confirmation of malignant
lymphoma and the characterisation of various cancers (malignant lym-
phoma, sarcoma, and some carcinomas, e.g., renal) by specific chromo-
somal changes. Distinctive molecular findings in a wide range of solid
tumours are being increasingly used with regard to diagnosis, prognosis,
and predicting response to specific targeted therapies. This trend towards
personalised oncological medicine also requires consideration of the
pre-analytical phase with regard to optimal tissue preservation, fixation,
and processing.
Quantitative methods: prognostic indicators include the Breslow depth of
invasion in malignant melanoma, muscle fibre typing and diameter in myopa-
thies, and the mitotic activity index in breast carcinoma.
Diagnostic Cytology
Fine needle aspiration, exfoliative and body cavity fluid cytology all provide
valuable complementary information in diagnosis and staging (see Chap. 46).
The direct smear/cytospin/liquid based preparations are supplemented by
formalin-fixed paraffin processed cell blocks of cell sediments and needle
core fragments (mini-biopsies) which can combine good morphology and
robust immunohistochemistry. Correlation between the cytology and histo-
pathological findings is pivotal to accurate diagnosis (e.g., lung cancer) and
staging (e.g., pelvic washings in gynaecological cancer). Cytology may also
provide a diagnosis where biopsy fails due to sampling error, inaccessibility
of the lesion, or biopsy crush artefact.
xxvi Introduction
Appendices
Appendix A
Histopathology Specimen Pull-Through Protocol

Specimen Type
• Urgent
• Frozen section
• Cell block—to correlate with corresponding cytology preparations
• Needle core biopsy
• Lymph node (diagnostic/sentinel)
• Bronchial/transbronchial/lung/pleural/mediastinal biopsy
• Temporal artery
• Cancer resection, wide local excision (WLE), endoscopic mucosal resec-
tion (EMR), GI polypectomy, TURBT, trachelectomy, microdochectomy,
nipple biopsy
• Multidisciplinary Team Meeting (MDM/MDTM) cases
• Extras on cases pending (levels, blocks, stains)
ANY endoscopic or diagnostic biopsy specimen marked Red Flag/fast

track or with the following clinical or symptom terminology:
Clinical Terminology (Abbreviations in Brackets)
* Mass * Tumour * Neoplasm (NG)

* Suspicious * Malignant * Carcinoma (Ca)
* Primary (1o)/Secondary (2o) * Lymphoma * Leukaemia
(HD/NHL)
* Melanoma (MM) * Sarcoma * Mesothelioma
* Myeloma * Seminoma/teratoma * Stricture/
ulcer(ation)/
obstruction/
perforation
* SCC, TCC, AdCa, GCT, * Paget’s disease * Severe/high grade
NSCLC, (P)NET, Carcinoid dysplasia/carcinoma
in situ
* Vasculitis/arteritis/ * Ectopic/molar * GvsHD/BMT
Wegener’s gestation
* ARF (acute renal failure) * SLE/PAN * Pneumonia/
consolidation
* Pyrexia
Symptom Terminology
* Dysphagia * Melaena * Haematemesis

* PR bleed * PMB * Haemoptysis
* Haematuria * Jaundice
Introduction xxvii
Footnotes:
TURBT Transurethral resection bladder tumour

NG New growth
MM Malignant melanoma
HD Hodgkin’s disease
NHL Non-Hodgkin’s lymphoma
SCC Squamous cell carcinoma or small cell carcinoma
TCC Transitional cell carcinoma
AdCa Adenocarcinoma
GCT Germ cell tumour
NSCLC Non-small cell lung cancer
(P)NET Primitive neuroectodermal tumour
SLE Systemic lupus erythematosus
PAN Polyarteritis nodosa
GvsHD Graft versus host disease
BMT Bone marrow transplant
Dysphagia: difficulty in swallowing

Melaena: altered blood in the faeces
Haematemesis: vomiting blood
PR bleed: passage of blood per rectum
PMB: post-menopausal bleed
Haemoptysis: coughing up blood
Haematuria: blood in the urine
Jaundice: elevated bilirubin levels due to red blood cell destruction (hae-
molysis), hepatic damage, or bile duct obstruction
Appendix B
Surgical Cut-Up: Principles and Practice
Apprenticeship Attitude/application/accountability
Look/listen/lifelong learning—team work
Do—focus/organisation
Patient details Name/date of birth/health care number
Specimen details Number of specimens/site/laterality/type
Form details Clinical information/abbreviations
Clinical priority Frozen/urgent/treatment decision/MDM case
Past and present History/history/history
Knowledge base Context/context/context
Anatomy/clinical investigations/surgical procedures/
pathology
Targeted dissection Tumour: type/grade/stage/margins
Fixation/sampling
pT/pN/LVI
Longitudinal, circumferential margins
Diagrams and photographs
xxviii Introduction
Resources
1. Pull-through protocols
2. Specimen dissection laboratory procedures/blocking summary sheets
3. RCPath Tissue Pathways/Cancer Dataset documents (audit standards)
4. TNM8
5. Local tissue pathology cancer report protocols
6. Texts—Lester/Westra/Rosai/Allen
Reassess in light of further clinical information (MDM)/audit
Appendix C
Specimen dissection—a working practice
1. Log the specimen into the computer and allocate a laboratory number.
2. Point out any urgent, fresh, or inadequately fixed specimens to a supervi-
sory BMS so that appropriate action can be taken. Record on the request
form.
3. With a supervisory BMS categorise the specimens (see Appendix D) and
make a provisional allocation of work.
4. Send the request form of specimen categories C, D, and E to the secre-
tarial office for registration and attachment of any computer back history.
Return the forms to the laboratory staff so that specimen dissection can
proceed. Categories A and B are usually loaded into the processing cas-
settes before registration.
5. Preview—consult with the supervisory medical pathologist about the
more complex specimens (mainly categories C, D, and E) to confirm
categorisation, reassign categorisation, or to discuss the special needs/
work allocation of particular specimens. The medical pathologist autho-
rises request forms at this stage.
6. Cut-up
• Work in pairs, one to dissect and describe, the other to write, prepare
cassettes, cross check data, observe, and confirm findings. The second
person can also have a supervisory, training role as appropriate.
• Check and sign off request form and specimen container label details, i.e.,
–– Patient name
–– Patient date of birth
–– Patient unit number
–– Specimen type, parts, and numbering
–– Laboratory reference number and cassette labels.
• Dissect to your level of experience and competence to obtain an accu-
rate description and relevant blocks and also to allow a subsequent
meaningful review process.
• Float out the cassettes with their blocks in formalin.
• Set the specimens (mainly categories C, D, and E) aside on and cov-
ered by appropriately numbered wet paper towels with the corre-
sponding request form beside them.
Introduction xxix
7. Review—consult with the supervisory medical pathologist about the

more complex specimens (mainly categories C, D, and E). He/she will
carry out a review with direct feedback to the dissector regarding the
quality of macroscopic descriptions, diagrams, and appropriateness of
blocks. At this stage, the cut-up of individual specimens will either be
confirmed and the request form authorised, or further description, diag-
nostic possibilities, or supplementary blocks indicated. The supervisory
pathologist will mark certain cases for subsequent reporting because of
either a subspecialty interest or unusual/complex features to the case.
8. Enclose the specimens in moist numbered paper towels in correspondingly
numbered plastic bags and store in that day’s plastic tray in the ventilated
cupboard. Small specimens (mainly categories A and B) are individually
wrapped in their numbered paper towels along with any spare cassette
labels and enclosed in a plastic bag marked with the dissector’s initials and
those of his/her working partner. Some individual specimens will be retained
in formalin filled containers, for example, lymph nodes and some complex
cases, as indicated at the review discussion. Specimens are disposed of after
4 weeks once it has been ensured that the surgical histopathology report has
been satisfactorily completed, authorised, and dispatched and the case fully
discussed at the appropriate multidisciplinary team meeting.
9. For specific specimens of interest that they have cut dissectors are to note
the laboratory reference number and to obtain subsequent feedback on the
diagnosis, descriptions, and appropriateness of blocks. Trainee patholo-
gists are encouraged to report and sign out cases that they have cut.
10. Knife etiquette—wipe instruments in between block selection and differ-
ent specimens to avoid tissue carry-in. Use a sharp knife on well-fixed
specimens.
11. Remember—if in doubt—ASK. Problems can be resolved by discussion
and always be prepared to point out potential errors. Work as a team.
Appendix D
Specimen dissection—guidelines for categorisation of specimens according

to complexity (RCPath., recommendations)
These are intended to be broad guideline definitions to act as a baseline
which departments and individual consultants may see fit to modify. The
review system will permit the recognition of situations in which clinical or
anatomical circumstances indicate the category as per protocol is
inappropriate.
Basic Definitions
( A) Specimens only requiring transfer from container to tissue cassette.

(B) Specimens requiring transfer, but with standard sampling, counting,
weighing, or slicing.
xxx Introduction
(C) Simple dissection required with sampling needing a low level of diag-
nostic assessment and/or preparation.
(D) Dissection and sampling required needing a moderate level of

assessment.
(E) Specimens requiring complex dissection and sampling methods.
Category A
All small biopsies (endoscopic, synovial, etc.)

Uterine curettings
Simple products of conception
Bone marrow trephines
Testicular biopsies
Cervical punch biopsies
Needle biopsies (excluding those requiring special procedures, e.g., renal,
muscle)
Skin curettings and skin biopsies not requiring dissection
Category B
Vasa deferentia
Fallopian tubes
Sebaceous cysts
Small lipomas
Unremarkable tonsils
Unremarkable nasal polyps
Temporal arteries
Thyroglossal cysts
Molar pregnancy
Transcervical endometrial resection
Prostatic chippings
Lymph nodes
Category C
Appendix
Gall bladder
Large gastrointestinal polyps
Meckel’s diverticulum
Diverticular disease
Ischaemic bowel
Thyroid—non-tumour
Salivary gland—non-tumour
Placenta
Uterus—routine hysterectomy
Cervical cone biopsy
Muscle and cardiac biopsy
Small soft tissue tumours
Introduction xxxi
Femoral head
Renal biopsy
Skin biopsies—benign—requiring dissection
Simple small benign breast biopsies
Category D
Orchidectomy—non-neoplastic
Simple small ovarian cysts and tumours
Salivary gland—tumours
Thyroid—tumours
Pigmented skin lesions
Gastrectomy—benign ulcer
Complex (non-neoplastic) gastrointestinal resections
Category E
Ovarian tumours
Uterine carcinoma (including cervical carcinoma)
Vulvectomy
Gastrointestinal carcinoma
Oesophagectomy
Renal resections
Bladder resections
Prostatectomy
Penile carcinoma
Orchidectomy—neoplastic
Localised wide lump breast excisions
Mastectomy
Bone tumours
Neck dissection
Mandibulectomy
Appendix E
Royal College of Pathologists—Key performance Indicators:
Standard Compliance requirement (%)

1. Consultant level (FRCPath) staff qualifications 100
2. Documented/named staff leave cover 100
3. Annual appraisal of clinical practice 100
4. CPD scheme registration (RCPath/RCP/or 100
equivalent)
5. Percentage staff in training 15–30
6. Incident/error reporting system 100
7. Annual user satisfaction survey 100
xxxii Introduction
Standard Compliance requirement (%)

8. Multidisciplinary Team Meeting
– Pathologist cover 90
– Lead pathologist attendance 66
9. Cancer proforma reports used 95
10. Documentation of second opinions, urgent, 100
critical, or unexpected results
11. Cellular Pathology turnaround time
– 7 days 80
– 10 days 90
– Identify cases delayed >20 days 100
12. External Quality Assurance participation
– Technical 100
– Interpretive: MDTM lead/deputy pathologist 100
Appendix F
Laboratory abbreviations
g (s) Gram(s)
kg Kilogram
mm Millimetre
ml Millilitre
cm Centimetre
F.W.L Fragments with levels
all processed All tissue processed
processed intact Tissue processed intact
fix Undergoing further formalin fixation
retained Tissue retained in formalin
mes Mesentery
ser Serosa
Bisected
Mid-section
Block in three
Multiple serial sections
Quadrants
Introduction xxxiii
Appendix G
Levels and Label Coding
1. Specimens to be cut through three levels with 100 μm between each level are:
Endoscopic Vocal cord

biopsies Bronchial
Oesophageal
Gastric
Duodenal
Jejunal (also require examination under the dissecting microscope)
Colonic
Rectal
Bladder
Needle Liver
biopsies Pancreas
Breast
Prostate
Renal
Miscellaneous Cervical punch biopsies
Small skin biopsies
Temporal artery (embed transversely)
Cell blocks
Alternatively needle core biopsies can have an index section and a deeper
with the rest of the block retained for further morphology or ancillary
techniques.
2. Cassettes are identified either by a microwriter or the use of perforated
paper labels placed perpendicular to and protruding from the end of the
cassette. They may also be colour coded to designate an urgent specimen
or specimen type, for example, gastric biopsy.
Appendix H
Royal College of Pathologists—Service Quality and Safety Guidance

Documents (all available at http://www.rcpath.org)
1. Guidelines on staffing and workload for histopathology and cytopathol-

ogy departments (4th edition).
2. Workload management in laboratory medicine: patient safety and profes-
sional practices.
xxxiv Introduction
3. The retention and storage of pathological records and specimens (5th

edition).
4. ISO 15189: 2012—an approach to the assessment of uncertainty of mea-
surement for cellular pathology laboratories.
5. The role of the lead pathologist and attending pathologists in the multi-
disciplinary team.
6. Demonstrating personal proficiency in pathology—2015.
7. Communication of unexpected findings, urgent reports, delayed reports,
and the use of alert systems in diagnostic cellular pathology.
8. Double reporting in histopathology.
9. Guidance on inter-departmental dispatch of histopathology material for
referral and clinical trials.
10. Telepathology.
11. Guidance for cellular pathologists on reporting at home (3rd edition).
Part I
Gastrointestinal Specimens
Gastrointestinal Specimens:
General Comments 1
Derek C. Allen and R. Iain Cameron
1.1 Anatomy Inflammatory disease can be mucosa confined

(ulcerative colitis), transmural (Crohn’s disease),
The type of histopathology resection specimen or mixed (ischaemic colitis). Tumour growth
received is dictated by the nature of any previous may be predominantly polypoid and intralumi-
operations and the current disease process, its nal, with only a minor mural component and
distribution, and degree of local spread within the variable presentation depending on the organ
organ and to adjacent structures. Resection sur- involved, e.g., symptomatic dysphagia due to
gery must provide adequate clearance of longitu- oesophageal polypoid carcinoma or asymptom-
dinal and deep circumferential radial margins. It atic iron-deficiency anaemia with a caecal carci-
must also take into account the lymphovascular noma. Often cancer ulcerates and deeply invades
supply to achieve satisfactory anastomoses and the wall, stenosing and obstructing the proximal
the regional lymph node drainage for an adequate bowel with early access to mesenteric nodes,
radical cancer operation. Site location within any lymphovascular channels, and peritoneum, and
given organ may influence the nature of the path- potential perforation. Alternatively the tumour
ological abnormality and surgical procedure may be characterised by an intact mucosa and
undertaken, e.g., anterior resection for high rectal incipient thickening of the wall with a tendency
cancer versus abdominoperineal resection for for longitudinal spread and skip lesions (diffuse
low rectal cancer, or mid-oesophagus (squamous gastric carcinoma—linitis plastica). Thus, nor-
carcinoma) versus distal oesophagus (adenocar- mal anatomy is variably distorted by differing
cinoma). Multifocal distribution may be seen in disease processes, and this must be considered in
both inflammatory (Crohn’s disease) and neo- handling the specimen to obtain appropriate
plastic (malignant lymphoma) disorders. management and prognostic data, e.g., depth of
local tumour spread, peritoneal and regional
lymph node involvement, and excision margin
clearance. Allowance must also be made for vari-
D.C. Allen (*) ation in normal anatomy between and within
Histopathology Laboratory, Belfast City Hospital, individuals. For example, harvest of lymph nodes
Belfast Health and Social Care Trust, Belfast, UK from the mesorectum is scanty compared to the
e-mail: derek.allen@belfasttrust.hscni.net
sigmoid mesocolon, and in some patients few
R.I. Cameron mesorectal nodes will be found. This is also
Histopathology Laboratory, Altnagelvin Hospital,
made more difficult by preoperative r adio−/che-
Western Health and Social Care Trust,
Londonderry, UK motherapy, emphasising the importance of taking
e-mail: iain.cameron@westerntrust.hscni.net into account the previous treatment history and
© Springer International Publishing AG 2017 3

D.C. Allen, R.I. Cameron (eds.), Histopathology Specimens, DOI 10.1007/978-3-319-57360-1_1
4 D.C. Allen and R.I. Cameron
request form information. The surgical histopa- and carcinoembryonic antigen (CEA—meta-
thology specimen also acts as an audit tool for static colorectal carcinoma), although sensitivi-
surgical practice and expertise, e.g., rates of ante- ties and specificities are limited.
rior resection versus abdominoperineal resection Various general radiological investigations are
or completeness of mesorectal excision in rectal also helpful in diagnosing gastrointestinal
cancers. Similarly it allows close correlation with disorders:
preoperative clinical and radiological (e.g., MRI)
assessment, and is a gauge of thoroughness of • CXR (chest X-ray)—to detect metastatic
pathological examination. Thus, preoperative deposits in the lung fields or any enlargement
and operative techniques alter the specimen anat- of the lung hilum, heart, or aorta that might
omy, resulting in differing management and compress the oesophagus; also to show air
prognostic implications for an equivalent degree under the diaphragm following perforated
of tumour spread in similar specimens from dif- duodenal ulcer
ferent patients. • AXR (straight erect abdominal X-ray)—to
demonstrate calcification in pancreatitis or
bowel loops distended by fluid levels due to
1.2 Clinical Presentation intestinal obstruction
and Investigations • ELUS (endoluminal ultrasound) and MRI
(magnetic resonance imaging) scans—to
Site-specific symptomatology and investigations gauge the depth of spread of a tumour through
are alluded to in the relevant chapters, but some the gastrointestinal wall into adjacent struc-
general features can be noted. Clinical presenta- tures, assess locoregional lymph node enlarge-
tion can be non-specific, such as weight loss or ment, and soft tissue margin status
anaemia, or focused on either the upper (nausea, • CT (computerised coaxial tomography) scan
dysphagia, vomiting, haematemesis) or lower chest/abdomen/pelvis—to gauge the extent of
(abdominal pain, bleeding per rectum, change in local and metastatic tumour spread
bowel habit) gastrointestinal tract. An iron- • PET (positron emission tomography) scan—
deficiency anaemia as measured by the haemo- to help detect metabolically active distant
globin level, red blood cell indices, and serum metastases in tumour staging and to distin-
iron/ferritin levels often means occult blood loss guish local tumour recurrence from post-
from ingestion of aspirin/NSAIDs or from the radiotherapy fibrosis
surface of an ulcer or polypoid lesion. Serum • USS (ultrasound scan) abdomen/pelvis—to
albumin levels are decreased due to reduced food detect gallstones; biliary tract dilatation; cysts
intake, protein-losing enteropathy, or liver dis- in the liver, pancreas, appendix, or retrorectal
ease. The erythrocyte sedimentation rate (ESR) space; and mixed solid/cystic abdominopelvic
and C-reactive protein (CRP) are increased in tumours
neoplasia, vasculitis, and acute flare-up of chronic • Radioisotope scan—to detect metastatic dis-
inflammatory bowel disease. Peripheral white ease in gastrointestinal endocrine tumour
blood cell counts and body temperature are often (octreotide scan).
elevated in acute infection or neoplasia, e.g., leu-
kaemia. Features of malabsorption can be due to Diagnostic laparoscopy allows inspection and
either small intestinal or pancreatic disease. Liver biopsy of the peritoneal cavity in various disor-
function (LFTs) and coagulation tests are altered ders, e.g., tuberculous peritonitis, or, more usu-
in hepatic and biliary disease. ally, staging of tumour spread from a gastric
Serological markers of use in diagnosing and carcinoma—a finding that would contraindicate
also detecting recurrence of gastrointestinal can- primary surgical resection of the stomach.
cer are CA19-9 (pancreatic carcinoma), alpha- The mainstay of investigation is gastrointesti-
fetoprotein (AFP—hepatocellular carcinoma), nal endoscopy and biopsy.
1 Gastrointestinal Specimens: General Comments 5
1.3 Biopsy Specimens cytology specimens, and there are various acces-
sories designed for this function.
1.3.1 Flexible Endoscopy
• Forceps: these consist of a pair of sharpened
Gastrointestinal mucosal biopsy specimens are cups attached by a metal cable to a control
obtained by flexible endoscopy due to its ease of handle. The forceps are passed down the chan-
operation and relative lack of complications. nel within the endoscope. The cups are opened
Flexible endoscopes are complex pieces of equip- and closed by an assistant pulling and pushing
ment consisting of a flexible shaft with a manoeu- the plastic handle. The site for biopsy is
vrable tip and a control head which the operator approached perpendicularly and firm pressure
holds. The control head is connected to a fibre- applied while the cups are closed. In the
optic light source. Other channels such as air, oesophagus the approach is tangential and so
water, suction, etc. pass through the light source. forceps with a central spike can be used to pre-
A channel for the passage of therapeutic or diag- vent them from “sliding” off the tissue to be
nostic instruments is located in the control head. biopsied. At least six tissue samples should be
The picture from the tip is transmitted to a televi- taken from a lesion. Biopsies of ulcers should
sion screen. Modern endoscopes also incorporate include samples from the four quadrants and
sophisticated magnification capacity to allow the base, although basal specimens may only
close inspection of the topography of mucosal yield necrotic slough. If malignancy is sus-
surfaces and lesions. This can be supplemented pected, it is prudent to take several specimens
by dye-spray techniques. from the same place as this allows the outer
Upper endoscopy involves informed consent, necrotic layer to be penetrated. With polypoid
fasting for 6 h, intravenous sedation, and passage lesions the crown and base of the polyp as
of the endoscope via a mouth guard with direct well as the adjacent flat mucosa should be
inspection of the oesophagus, stomach, and duo- adequately sampled. In some conditions such
denum, which can be biopsied in relevant areas. as Barrett’s metaplasia or chronic ulcerative
Measurements are printed on the shaft of the colitis, segments of mucosa are sequentially
endoscope so that the operator knows the posi- sampled and mapped by multiple serial biop-
tion of the tip relative to the incisor teeth. Lower sies to detect precancerous epithelial dyspla-
endoscopy requires adequate bowel preparation sia. Site distribution of lesions is also helpful
to remove faecal debris and careful insufflation in differential diagnosis, e.g., ulcerative colitis
of air via the endoscope to dilate the bowel and (continuous) versus Crohn’s disease (discon-
allow navigation of the various contours. Due to tinuous). The biopsy forceps are withdrawn
the fragility of the tissues in some conditions, through the endoscope each time and the tis-
e.g., toxic megacolon or ischaemic colitis endos- sue sample removed from them by an assis-
copy may be contraindicated to avoid perfora- tant. A final larger biopsy can be taken if the
tion. A copy of the digital endoscopy report is a tissue sample is held in the cups of the forceps
great aid to the reporting pathologist, and can while the endoscope is removed.
easily be modified to function as the histopathol- • The tissue sample is then either put directly
ogy request form, maximising the clinical infor- into fixative, or after placement onto an orien-
mation provided and removing the issue of tation millipore (cellulose) filter or polycar-
illegibility. bonate strip, preferably mucosal surface
upward to avoid flattening the glandular or vil-
lous architecture.
1.3.2 Specimen Collection • Cytology brushings: small-spiralled brushes
on a metal cable can be used for surface cytol-
In diagnostic endoscopy, tissue biopsies will ogy of a lesion. The brush is retracted into a
usually be taken sometimes supplemented by covering plastic sleeve, which protects the
specimen during withdrawal. It is then either spring-loaded or manually operated with the cut-
promptly made into direct smears or cut off ting edge of the needle delivering a core of tissue
and placed in a suitable transport medium for into its lumen. The needle is then retracted and
laboratory processing. withdrawn with careful removal of its contents
• Fine-needle aspiration cytology (FNAC): and placement into formalin fixative. The proce-
FNAC can sample submucosal, mural, and dure may be done blind, under X-ray control, or at
extrinsic lesions not accessible to mucosal operation direct vision, depending on the individ-
biopsy. The syringe needle contents are gently ual case. A 16G needle provides a much more
expelled into suitable transport medium, substantial specimen than an 18G needle and is
promptly transported to the laboratory, and especially recommended for “medical” liver biop-
cytocentrifuged onto glass slides for staining sies, i.e., evaluation of diffuse liver disease pro-
and interpretation. cesses. The larger needle is, however, associated
with a slightly greater risk of bleeding. Regardless
Mucosal biopsies are generally 2–4 mm diam- of needle size, the patient should have an adequate
eter and 1–2 mm deep, but this varies with patient coagulation status confirmed beforehand and, dur-
anatomy, the success of the endoscopy proce- ing the procedure, vascular structures avoided to
dure, and the nature and configuration of the minimise any risk of bleeding. Endoscopic, percu-
lesion. Biopsy site and technique also influence taneous, or transabdominal FNAC can traverse
specimen size. For example, pinch biopsies abdominal viscera with no detrimental effect to
obtained via the colonoscope are smaller than sample abdominal and retroperitoneal masses not
rectosigmoidoscopy samples using grasp or accessible to usual endoscopic procedures.
jumbo forceps or a strip technique where glucose
solution or saline is injected submucosally. A
wider diameter biopsy channel can accommodate 1.3.3 Specimen Handling
jumbo forceps or a suction capsule, the latter
being of use where mucosal orientation (reflux Fragments, non-orientated
oesophagitis) or deeper tissues (submucosa for
the assessment of Hirschsprung’s disease) are • Usually multiple fragments, free floating in
required. fixative, non-orientated.
Mucosal polyps vary in size and appearance. • Count.
For example, in the colorectum, hyperplastic pol- • Place in cassette between foam insert pads or
yps are often 1–2 mm diameter, while adenomas loosely wrap in moist filter paper.
can be similar but are not infrequently larger • Insert levels label.
(1–2 cm), with a distinct head and stalk or even • Align in the block at the embedding stage as
sessile. Small polyps may be removed in toto by this facilitates microscopic assessment and
usual biopsy forceps, or monopolar hot biopsy fragments are not missed.
forceps, which results in variable diathermy dis- • Separate specimens: use separate cassettes
tortion of the mucosal detail. Stalked adenomas and site identification labels appropriate to the
are suitable for total excision by an electrosurgi- request form information. Alternatively
cal snare. This is facilitated by elevation of the multiwell cassettes may be submitted by the
mucosa after submucosal injection of adrenaline, endoscopist.
glucose, or saline—a technique that is also used • Cut through multiple levels.
for local endoscopic mucosal resection (EMR) or Fragments, orientated
endoscopic submucosal dissection (ESD) of ses- • This allows better assessment of mucosal
sile lesions. architecture and site distribution of lesions,
Needle biopsy cores of liver and pancreas are e.g., colonic strip biopsy in chronic inflamma-
obtained endoscopically, percutaneously, or at tory bowel disease.
operation transabdominally by a variety of nee- • Filter paper: count the fragments and note any
dles of differing lengths and calibre. They can be that have detached. Process intact between
Fig. 1.1 Colonoscopic biopsies mounted on a polycarbonate or Millipore strip (Reproduced, with permission, from
Allen and Cameron (2013))
foam insert pads or covered by moist filter edge is to within 3 mm of the mucosal margin
paper to preserve orientation for embedding sample at right angles to it from a 10 mm slice.
and cutting through multiple levels. Embed the slices face down in the block and
• Polycarbonate strip (Fig. 1.1): the endoscopist cut through multiple levels.
allows a 2–4 min period of air drying prior to Wedge biopsy
formalin fixation, ensuring adherence of the • Usually derived from the edge of a perforated
mucosal fragments to the strip, which is desig- ulcer detected at surgical laparotomy for an
nated according to a pre-agreed protocol, e.g., acute abdomen. Its base is oversewn and a
the cut pointed end is distal or anorectal. Strict biopsy taken if the edges show any unusual
alignment of the fragments on the strip by the features, e.g., rolled margins.
clinician is essential as it is embedded intact • With the mucosal surface upward, bisect or
and on its edge for cutting to allow representa- cut into multiple vertical serial slices. Embed
tion of all the fragments at the same level in the slices face down and cut through multiple
the block. Count the fragments and cut through levels.
multiple levels. Needle core biopsy
Polyps (Fig. 1.2) • Up to 2 cm long and 1–2 mm diameter, core
• Non-orientated fragments: these are handled size is influenced by the patient’s anatomy, the
as indicated above. nature of the lesion being biopsied, the needle
• Snare specimens: that is used, the route of acquisition (e.g., per-
≤0.5 cm diameter—bisect vertically down cutaneous or transjugular), and operator
through the stalk/base and embed both cut sur- expertise. Some scirrhous carcinomas can be
faces face down. Cut through multiple levels. difficult to sample, whereas other disease pro-
>0.5 cm diameter—obtain a central, vertical cesses lead to fragmentation of the core, e.g.,
mid-slice (3 mm thick) down through and to cirrhosis of the liver. Skinny needle cores can
include an intact stalk/base. Embed face down be particularly fine, requiring careful handling
in the block and the lateral trimmings in a sep- and even painting or immersion in dye (e.g.,
arate block—polyps are submitted in toto. Cut alcian blue) prior to embedding so that the
through multiple levels. If there is a long stalk, tissue can be seen when the block is faced at
precluding submission of a central mid-slice cutting.
in one block, an initial transverse section of its • Count and measure the maximum core length
resection margin may be taken. (mm).
• Local mucosal resection: endoscopic or trans- • Place intact in cassette between foam insert
abdominal; this is used for stalked polyps (see pads or loosely wrap in moist filter paper.
above) or sessile lesions. Ideally the latter • Cut through multiple levels.
should be submitted by the surgeon to the lab- Fresh tissue
oratory already carefully pinned out onto a • The vast majority of specimens are submitted
board or piece of card. Remove after fixation in formalin fixative, but some cases require
and paint the deep and lateral mucosal resec- fresh tissue for frozen sections, e.g., acetyl-
tion margins. Obtain multiple vertical trans- cholinesterase staining in Hirschsprung’s dis-
verse serial slices (3 mm thick) to include the ease, or an inflammatory versus malignant
lesion and underlying base. Where the lesion lesion at diagnostic laparotomy.
Polyp £ 0.5cm diameter-bisect vertically

and embed cut surfaces face down
Polyp > 0.5cm diameter-trim off the edges of

the head leaving a vertical mid-slice
including the stalk and base
Sessile lesion/mucosal resection-paint

the deep and lateral resection margins
and obtain multiple vertical transverse
serial slices to include the underlying
base.Where the lesion edge is to within
3 mm of the mucosal margin (a) sample
at right angles to it from a 10 mm slice
(a)
<10 mm>
Fig. 1.2 Gastrointestinal mucosal polyps and local mucosal resections (Reproduced, with permission, from Allen and
Cameron (2013))
1.4 Resection Specimens 2–3 cm in an anterior resection for rectal can-

cer is considered satisfactory, whereas it is not
1.4.1 Fixation for diffuse gastric or oesophageal cancers
where multifocal mucosal and discontinuous
• Ideally specimens are submitted fresh to the submucosal or mural skip lesions can occur.
laboratory to facilitate sampling for research Longitudinal margins should be blocked first
or biobanking and accurate measurement, as prior to dissection of the tumour to avoid knife
fixation results in considerable shrinkage carry-in of tumour fragments.
(15–30% on average) and discrepancy • Circumferential radial margin (CRM): this
between clinical and pathological dimen- gives an assessment of the extent of lateral or
sions, e.g., longitudinal margins of tumour radial spread of a tumour and its adequacy of
clearance. Fresh submission also permits excision, features that are strongly related to
cleaning out of the specimen and either par- subsequent local recurrence and morbidity.
tial or total opening for pinning out and fixa- Prior to dissection, the CRM should be painted
tion. This avoids specimen distortion and and both macroscopic and microscopic mea-
ultimately allows dissection appropriate to surements of tumour clearance are then made.
the specimen and tumour type, e.g., the In the mesorectum, direct tumour spread or
assessment of circumferential resection mar- tumour within a lymph node or lymphatic to
gins. Adequate fixation of a cleaned, opened within ≤1 mm of the CRM is considered
specimen requires 36–48 h immersion in for- involved. CRM involvement may indicate the
malin. Where it is normal practice to submit need for postoperative radiotherapy. The
resection specimens to the laboratory already amount and completeness of excision of cir-
in fixative, the theatre staff should be cumferential tissues depend on the anatomical
instructed on how to partially open and clean site and expertise of the surgeon. For example,
out the specimen but to avoid transecting the adventitial tissues in an oesophagectomy
tumour segment, thereby compromising mar- specimen may be scanty, whereas the poste-
gin assessment. rior and lateral mesorectum is usually 2–3 cm
deep. The success of total mesorectal excision
(TME) relates to surgical training and the
1.4.2 Margins available time resources to carry out an ade-
quate procedure, but TME grading by the
Longitudinal, circumferential, and anatomical pathologist is an important part of auditing
margins are considered. surgical practice. The significance of tumour
at the mesocolic edge or that of the gastric
• Longitudinal margins: circumferential, trans- lesser omentum is less established but should
verse sections are taken in non-neoplastic dis- be reported by the pathologist.
orders such as ischaemia or chronic • Anatomical margins: The serosa or perito-
inflammatory bowel disease to assess involve- neum is a visceral margin and breech of it
ment. In cancer resections, separate anasto- allows tumour to access the abdominal and
motic rings are often submitted and these pelvic cavities with potential for transcoelo-
constitute the longitudinal margins rather than mic spread, e.g., diffuse gastric cancer with
those of the main specimen. In the absence of bilateral ovarian metastases (Krukenberg
an anastomotic ring, the longitudinal margin tumours). Thus, gastrointestinal cancers may
should be circumferentially sampled although present clinically with deposits at another
if the tumour is close (≤0.5–1 cm) to it a lon- abdominopelvic site and this should be borne
gitudinal block may be more practicable. The in mind on assessment of tumour macroscopic
significance of longitudinal margin clearance and microscopic appearances. Tumour at and
varies, e.g., a macrosopic tumour clearance of ulcerating the serosa represents pT4 disease
and is a decision factor in selection for postop- indicator of metastatic involvement and pN
erative chemotherapy. It should be distin- staging relates to total and involved numbers
guished from the more common finding of of nodes. Small nodes seen histologically in
carcinoma in a subserosal inflammatory the tumour blocks are also counted and may
fibrous reaction but not at its free surface only measure ≥1 mm diameter but are recog-
(pT3). nizable by their subcapsular sinus. A limit
node is identified adjacent to a mesenteric
pedicle suture tie—some specimens, e.g.,
1.4.3 Dissection transverse colon, may have more than one.
Dukes staging for colorectal cancer varies
1.4.3.1 Cancer Resections according to whether the limit node is involved
For optimal demonstration of the deepest point of (C2) or not (C1). Supplementary techniques
tumour spread, its relationship to the CRM and such as xylene fat clearance can usefully
correlation with ELUS/CT cross-sectional imag- increase nodal yields, but, in general, there is
ing multiple, serial, 3–4 mm thick slices of the no substitute for experienced, careful dissec-
cancer in the transverse axis are recommended. tion. The TNM system makes a numerical rec-
The slices can then be laid out in sequence and a ommendation for what is considered an
digital photographic record taken. Generally four appropriate regional lymphadenectomy for
or five blocks of the tumour and wall are selected each type of cancer resection. Regular depart-
to adequately define the pT stage, and to search mental audit of median lymph node counts for
for other adverse prognostic criteria, for example, relevant pathology specimen types ensures
extramural venous invasion. Some pathologists standards are met and maintained. Preoperative
leave the tumour segment unopened during fixa- radio−/chemotherapy can lead to marked
tion and transverse slicing to keep the CRM tumour degeneration, mucinous or fibrotic
intact—others open it carefully avoiding suspect reaction compromising nodal yields and iden-
areas of the CRM to ensure adequate tumour fix- tification of residual primary tumour or nodal
ation and ascertain tumour measurements. Either deposits. Most general laboratories submit
approach is justifiable as long as it is done with small nodes (<5 mm) intact, trimmed, or
care and consistency. Sometimes the local anat- bisected, and a mid-slice of larger ones. It is
omy or proximity of the tumour to a longitudinal important that the same node is not counted
margin necessitates dissection in the longitudinal twice. Alternatively nodes are serially sliced
plane. Such a block can be useful in a poorly dif- at 2–3 mm intervals and submitted in their
ferentiated carcinoma when the adjacent mucosa entirety in individual cassettes. Separate soft
may show a point of origin or clue as to its histo- tissue deposits in a lymph node drainage area
logical type. Mucosal blocks away from the are submitted for microscopy so that the
tumour may also demonstrate its histogenesis, pathologist can determine whether they are
e.g., metaplasia/dysplasia/cancer sequence in the lymph nodes replaced by tumour, discontinu-
stomach, or, multifocality. Multiple colonic can- ous tumour extension, tumour in a vascular or
cers are blocked and reported individually. A perineural space, or, tumour satellites.
clear block index within the pathology report
facilitates case review, e.g., for multidisciplinary 1.4.3.2 Non-neoplastic Resections
team meeting discussion, and tumour block An important descriptive feature in differential
selection (without need for slide review) for diagnosis is disease distribution, e.g., diffuse
future immunohistochemical or molecular (continuous), segmental (discontinuous),
assays. mucosal, or transmural. Overt lesions may
show only end-stage, non-specific florid ulcer-
• All regional lymph nodes should be sampled ation and reactive changes—the disease distri-
for histology as size alone is not a reliable bution and changes in the intervening mucosa
give important diagnostic clues. For example, College of American Pathologists. Cancer protocol tem-
plates. http://www.cap.org/.
ulcerative colitis is continuous and mucosal;
Domizio P, Lowe D. Reporting histopathology sections.
Crohn’s disease is discontinuous and transmu- London: Chapman and Hall; 1997.
ral, with intervening aphthous ulcers and sero- Fletcher CDM, editor. Diagnostic histopathology of
sal fat wrapping; chronic ischaemic stricture is tumors. 4th ed. Philadelphia: Elsevier Saunders;
2013.
preferentially located at the splenic flexure;
Horne J, Bateman AC, Carr NJ, Ryder I. Lymph node
and clostridium difficile infection shows muco- revealing solutions in colorectal cancer: should they
sal pseudomembranes. Non-neoplastic colonic be used routinely? J Clin Pathol. 2014;67:383–8.
specimens therefore require sequential labeled Institute of Biomedical Science/The Royal College
of Pathologists. IBMS guidance to candidates and
blocks of abnormal and normal (e.g., every
trainers for advanced specialist diploma in lower GI
10 cm) areas, with a clear block index in the pathology dissection. https:www.ibms.org/. Accessed
report to aid case review. As the mucosa is Oct 2016.
arranged in transverse folds, long axis blocks International Collaboration on Cancer Reporting.
Publications on structured pathology reporting of can-
are taken. Longitudinal limits are transverse
cer. http://www.iccr-cancer.org/.
sectioned to look for disease involvement and Lester SC. Manual of surgical pathology. 3rd ed.
although mesenteric nodes are usually reactive Philadelphia: Elsevier/Saunders; 2010.
only, they may show helpful diagnostic point- Odze RD, Goldblum JR, editors. Odze and Goldblum
surgical pathology of the GI tract, liver, biliary tract,
ers such as granulomas in Crohn’s disease. In
and pancreas. 3rd ed. Philadelphia: Elsevier Saunders;
ischaemic conditions, mesenteric vessels are 2015.
also sampled for signs of vasculitis or embolic Rosai J. Rosai and Ackerman’s surgical pathology. 10th
thrombi. Some vascular anomalies, e.g., angio- ed. Edinburgh: Mosby Elsevier; 2011.
Sanders SA, Smith A, Carr RA, Roberts S, Gurusamy
dysplasia of the colon, may require close liai-
S, Simmons E. Enhanced biomedical scientist cut-
son with the surgical and radiological teams up role in colonic cancer reporting. J Clin Pathol.
necessitating preoperative injection of radio- 2012;65:517–21.
opaque contrast medium. In some cases, e.g., Shepherd NA, Warren BF, Williams GT, Greenson JK,
Lauwers GY, Novelli MR, editors. Morson and
gastric resections, it is not possible to tell mac-
Dawson’s gastrointestinal pathology. 5th ed. Hoboken:
roscopically if the ulcer, adjacent mucosa, or Wiley-Blackwell; 2013.
regional nodes are benign or malignant or to Simmons EJV, Sanders DSA, Carr RA. Current experi-
gauge the extent of mural spread—dissection ence and attitudes to biomedical scientist cut-up:
results of an online survey of UK consultant histopa-
and block selection must be sufficiently com-
thologists. J Clin Pathol. 2011;64:363–6.
prehensive to allow for this. Sturgeon CM, Lai LC, Duffy MJ. Serum tumour
markers: how to order and interpret them. BMJ.
2009;339:852–8.
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Allen DC. The W5, how and what next of BMS specimen publications/cancer-datasets.html.
dissection. Curr Diagn Pathol. 2004;10:429–34. The Royal College of Pathologists. Joint RCPath/IBMS
Allen DC. Histopathology reporting. Guidelines for surgi- Working Group. Implementation of the extended role
cal cancer. 3rd ed. London: Springer; 2013. of biomedical scientists in specimen dissection and
Allen DC, Cameron RI. Histopathology specimens: sampling—final report. 2004. Contact Publications@
clinical, pathological and laboratory aspects. 2nd ed. rcpath.org.
London: Springer; 2013. The Royal College of Pathologists of Australasia. Cancer
American Registry of Pathology. AFIP atlas of tumor protocols. http://rcpa.edu.au.
pathology, Series I-IV. www.acb.org.uk. Vollmer RT. Pathologists’ assistants in surgical pathol-
Association of Clinical Biochemistry, Institute of ogy. The truth is out. Am J Clin Pathol. 1999;112:
Biomedical Science, Royal College of Pathologists. 597–8.
Tumour marker requesting. Guidance for non-specialists. Westra WH, Hruban RH, Phelps TH, Isacson C. Surgical
http://arporg.squarespace.com/arp-press/. pathology dissection: an illustrated guide. 2nd ed.
Brierley JD, Gospodarowicz MK, Wittekind C, editors. New York: Springer; 2003.
TNM classification of malignant tumours. 8th ed. WHO/IARC classification of tumours. Lyon: IARC Press.
Oxford: Wiley-Blackwell; 2017. http://publications.iarc.fr/.
Wick MR, LiVolsi VA, Pfeifer JD, Stelow EB, Wakely pTNM classification of malignant tumours. UICC. 5th
PE. Silverberg’s principles and practices of surgical ed. Berlin: Springer-Verlag; 2004.
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Cambridge Medicine University Press. 2015. trated guide to the TNM classification of malignant
Wittekind C, Greene FL, Hutter RVP, Klimfinger M, tumours. UICC. 6th ed. Hoboken: Wiley Blackwell;
Sobin LH. TNM atlas: illustrated guide to the TNM/ 2014.
Oesophagus
2
Damian T. McManus, Derek C. Allen,
and R. Iain Cameron
2.1 Anatomy the surface landmark of the suprasternal notch

of the sternum (breast bone).
The oesophagus is a tubular structure, approxi- 2. Intrathoracic oesophagus—approximately
mately 25 cm long, extending from the laryngeal 21 cm long and extends from the thoracic inlet
part of the pharynx at the level of the sixth cervi- to the oesophageal hiatus in the diaphragm. At
cal vertebra, passing through the diaphragm at 25 cm from the upper incisor teeth, the
the level of the tenth thoracic vertebra to join the oesophagus is constricted by the aortic arch
stomach at the oesophagogastric (OG) junction and the left main bronchus crossing its ante-
(Fig. 2.1). For purposes of practicality during rior surface.
endoscopic procedures, the site of a lesion in the 3. Abdominal oesophagus—1–1.5 cm long and
oesophagus is given as the distance from the extends from the oesophageal hiatus in the
upper incisor teeth. As it is approximately 16 cm diaphragm to the right side of the stomach. It
from the upper incisor teeth to the proximal is covered anterolaterally by the peritoneum
oesophageal limit, the OG junction is at approxi- and comes into close relationship with the left
mately 40–41 cm. The oesophagus traverses the lobe of liver.
neck, thorax, and enters the abdominal cavity and
so can be anatomically divided into three subsites: An internal landmark of relevance to deter-
mining the site of origin of an OG tumour is the
1. Cervical oesophagus—2–3 cm long and
OG junction where the pale oesophageal squa-
extends from the proximal oesophageal limit mous mucosa meets the glandular mucosa of the
(C6) to the thoracic inlet, which is marked by gastric cardia. The OG junction can be somewhat
irregular in outline (the Z line) and does not nec-
essarily correspond to the lower physiological
valve or sphincter. External landmarks are distal
D.T. McManus (*) • D.C. Allen
Histopathology Laboratory, Belfast City Hospital, oesophagus orientated to adventitial fat while the
Belfast Health and Social Care Trust, Belfast, UK junctional area and proximal stomach relate to a
e-mail: damian.mcmanus@belfasttrust.hscni.net; covering of serosa or peritoneum. Thus, a tumour
derek.allen@belfasttrust.hscni.net of the distal oesophagus or OG junction can
R.I. Cameron spread through the wall either to adventitial fat of
Histopathology Laboratory, Altnagelvin Hospital, the mediastinum or the abdominal peritoneum.
Londonderry, UK Adventitial fat is disposed laterally, but absent
e-mail: iain.cameron@westerntrust.hscni.net anteriorly and posteriorly where the oesophagus

14 D.T. McManus et al.
Fig. 2.1 Oesophagus
(Used with the
permission of the Union
for International Cancer
Control (UICC),
Geneva, Switzerland.
The original source for
this material is from
Wittekind et al. (2005))
Cervical
18 cm Thoracic
inlet
Upper
thoracic
24 cm Tracheal
bifurcation
Mid thoracic
32 cm
Lower
thoracic
40 cm Oesophago-
gastric junction
Oesophagus
is adjacent to the heart and vertebral column, Lymphovascular drainage (Fig. 2.2):

respectively. Note that the adventitia of the mid- Upper third—deep cervical nodes
oesophagus may also relate to a serosal surface— Middle third—superior and posterior medias-
that of resected mediastinal pleura. tinal nodes
As well as determining the position of the Lower third—nodes along the left gastric
lesion within the oesophagus by its anatomical blood vessels and the coeliac nodes
site, it can also be defined by its relative posi- Venous drainage from the middle third (azygos
tion in the upper, middle, or lower third of the vein) into the lower third (gastric vein) leads to the
oesophagus. This is of relevance clinically as formation of a porto-systemic anastomosis and, with
the lymphovascular drainage is considered in raised portal venous pressure (e.g., as in liver cir-
these terms and is therefore important in cancer rhosis), the possibility of the formation of oesopha-
surgery. geal varices (dilatation of oesophageal veins).

2 Oesophagus 15
site of obstruction can be poor. Occult bleeding

can lead to iron-deficiency anaemia, while haem-
Cervical orrhage (haematemesis) can be potentially life
oesophagus
threatening (varices) or self-limiting due to linear
tears of the OG junction mucous membrane after
prolonged vomiting (Mallory-Weiss syndrome).
Intrathoracic
oesophagus
2.3 Clinical Investigations
• Endoscopy and biopsy.

• CXR to detect any enlargement of the heart,
mediastinal lymph nodes, or pulmonary hilum
that might extrinsically press on the oesopha-
gus. Barium swallow to outline the contour of
the oesophageal lumen and wall, and assess
motility/swallowing.
• For biopsy-proven cancer—ELUS and PET
CT scan chest and abdomen to determine the
pretreatment tumour stage directed toward pT/
pN and pM disease, respectively.
• Laparoscopy with peritoneal washings for OG
junctional and select distal oesophageal ade-
nocarcinoma cases.
• Twenty-four hour pH monitoring—has a high
diagnostic sensitivity for reflux oesophagitis.
Oesophageal manometry can assess the effec-
Fig. 2.2 The regional lymph nodes, irrespective of the tiveness of motility, e.g., achalasia, scleroderma.
site of the primary tumour, are those in the oesophageal
drainage area including coeliac axis nodes and parao-
esophageal nodes in the neck, but not supraclavicular
nodes (Used with the permission of the Union for 2.4 Pathological Conditions
International Cancer Control (UICC), Geneva,
Switzerland. The original source for this material is from 2.4.1 Non-neoplastic Conditions
Reflux oesophagitis: usually due to hiatus hernia

(slippage of the OG junction into the thorax)
2.2 Clinical Presentation resulting in gastro-oesophageal reflux (GOR) of
acid and bile; there is poor correlation with symp-
Patients with oesophageal disease may be asymp- toms, endoscopy and biopsy being normal in
tomatic, but usually experience one or more of 20–30% of cases. Otherwise well-orientated
the following: chest pain, heartburn (a retroster- biopsies show basal zone hyperplasia and promi-
nal burning sensation), reflux of acid/food, and nent vascularized connective tissue papillae. This
dysphagia (difficulty swallowing). Dysphagia is superseded by inflammatory infiltrates of neu-
can be painful (odynophagia) and progressive trophils and eosinophils, surface erosion, full
due to benign or malignant strictures, i.e., ini- thickness ulceration, and, ultimately, fibrous
tially for solid foods, e.g., meat, then soft foods, stricture formation (10% of cases). It may require
and ultimately liquids. Patient localization of the operative dilatation (often repeatedly) to relieve
dysphagia and, although it usually has a smooth lesions to oesophageal cancer are squamous cell
outline, it may be difficult to distinguish endo- dysplasia and Barrett’s metaplasia/dysplasia.
scopically from a malignant growth. Prior to this, Squamous cell dysplasia/carcinoma in situ:
treatment of GOR is either medical (weight loss, Macroscopically often inapparent but seen histo-
antacids) or occasionally surgical. This is usually logically adjacent to, overlying or distant from
done laparoscopically by wrapping the fundus of squamous cell carcinoma.
the stomach around the distal oesophagus (Nissen Barrett’s metaplasia or columnar epithelium
fundoplication) to maintain lower oesophageal lined lower oesophagus (CLO): Seen in about
tone and retain it in the abdominal cavity. 10% of patients with hiatus hernia and/or GOR. It
Eosinophilic oesophagitis: may be associated arises from erosion with differentiation of multi-
with trachealization of the oesophagus or a potential stem cells to metaplastic small intestinal
“feline” or striped appearance at endoscopy par- or gastric glandular epithelia. The Barrett’s seg-
ticularly in younger males. It is characterised by ment appears as a velvety area proximal to the OG
increased numbers of eosinophils (>15 per hpf), junction surrounded by pale squamous mucosa. It
transmucosal distribution, eosinophilic microab- can be multifocal or continuous. The segment is
scess formation and involvement of mid oesoph- either classical/long (≥3 cm) or short (<3 cm).
agus on biopsy. Whilst Barrett’s oeosophagus is associated
Infective oesophagitis: may be seen in other- with an increased risk of developing oesophageal
wise healthy individuals but is more commonly adenocarcinoma, population based studies have
encountered where there is alteration of either shown lower rates of progression (0.5% per
local or systemic immunity (e.g., HIV-AIDS). patient per year) than previously suggested.
Underlying ulceration, broad-spectrum antibiot- Surveillance for Barrett’s oeosphagus is currently
ics, diabetes, corticosteroid therapy, and immu- recommended by many groups, despite the lack
nosuppressive drugs can all alter the local gut of formal evidence from randomized controlled
flora resulting in superimposed infection. trials.
Causative agents are candidal fungus, herpes Dysplastic change within Barrett’s mucosa is
simplex virus (HSV 1 and 2), cytomegalovirus associated with an increased risk of progression.
(CMV), and atypical mycobacteria. Higher rates of progression have been reported if
Miscellaneous: Other causes of oesophagitis, the diagnosis of dysplastic change is made infre-
ulceration, and/or stricture are drugs (e.g., quently, is made by a specialist (rather than com-
NSAIDs, aspirin), mediastinal radiotherapy, munity based) pathologist, is confirmed by two
motility disorders (e.g., achalasia), Crohn’s dis- or more independent pathologists, or if accompa-
ease and direct injury (foreign body, prolonged nied by aberrant p53 staining or abnormal DNA
nasogastric intubation, corrosive ingestion). content.
Incidental endoscopic findings are inflamma- Dysplastic Barrett’s mucosa may be treated
tory or fibrovascular polyps of the OG junction. endoscopically by radiofrequency ablation (RFA)
with relatively low complication rates and high
rates of complete eradication reducing the risk of
2.4.2 Neoplastic Conditions disease progression.
The appearances of Barrett’s metaplasia may
Benign tumours: These are rare in surgical mate- be significantly altered by its treatment with ant-
rial, e.g., squamous papilloma, leiomyoma, or acid medication, ablative techniques, or photody-
granular cell tumour. namic therapy.
Oesophageal carcinoma: Predisposing condi- Squamous cell carcinoma: Forms 30–40% of
tions to oesophageal cancer include GOR, obe- oesophageal cancers and is typically seen in the
sity, diverticula, achalasia, and Plummer–Vinson mid-oesophagus of elderly patients. It is usually
syndrome (elderly females, iron-deficiency anae- moderately differentiated and keratinizing, ulcer-
mia, upper oesophageal web). Predisposing ates or strictures with rolled, irregular margins,

2 Oesophagus 17
involves a long segment of oesophagus, and has Clues as to site of origin are both anatomical and
spread through the full thickness of the wall at histological in the adjacent mucosa (oesopha-
presentation. Palliation can be achieved by gus—Barrett’s metaplasia/dysplasia; stomach—
chemoradiation, ablative laser therapy, or the gastritis/intestinal metaplasia/dysplasia). TNM 8
insertion of an expanding metal stent or tube to includes as an oesophageal cancer any tumour of
relieve obstruction. Primary treatment in a medi- the proximal stomach where its epicentre is
cally fit patient with a locally confined lesion within 2 cm of the OG junction and involves the
<5–10 cm in length may entail radical chemora- oesophagus (Siewert 3). Adenocarcinoma is usu-
diotherapy alone or in the UK, neoaduvant che- ally ulcerated with irregular rolled margins or
motherapy with subsequent surgery. Preoperative polypoid, and histologically tubular or papillary
chemoradiotherapy produces signs of tumour with an intestinal glandular pattern but some-
regression (degeneration, necrosis, fibrosis, kera- times of diffuse signet ring cell type.
tin granulomas) in some 50–60% of cases, but Intramucosal adenocarcinoma may be treated
often makes identification of tumour on gross by endoscopic mucosal resection (EMR) of vis-
inspection of the specimen difficult. Perforation ible nodules/plaques and RFA to the remaining
with potentially fatal mediastinitis is a possible flat Barrett’s mucosa. Submucosal invasion
complication of preoperative therapy and endos- (pT1b) is associated with a markedly increased
copy of malignant strictures. Depending on the risk of nodal metastasis and is generally an indi-
CT chest findings, bronchoscopy is sometimes cation for radical surgical resection. More
done to exclude the possibility of a primary lung advanced disease is optimally managed by peri-
cancer invading oesophagus, which would preoperative chemotherapy combined with surgical
clude primary resection as do haematogenous resection.
and distant nodal metastases or invasion of medi- Other features: Oesophageal cancer tends to
astinal vessels and main structures. show multifocality (15–20%). Examination of
Variants of squamous carcinoma are verru- specimen proximal and distal surgical margins is
cous carcinoma (warty, slow growth), basaloid therefore important. “Early” or superficial squa-
carcinoma (aggressive), and spindle cell/polyp- mous carcinoma is confined to the mucosa or sub-
oid carcinoma (carcinosarcoma—intermediate mucosa with or without regional lymph node
prognosis). involvement and is of better prognosis than
Adenocarcinoma: Forms 50–60% of oesopha- “advanced” or deep muscle invasive carcinoma.
geal cancers and arises in the distal oesophagus/ Involvement of the perioesophageal CRM is
OG junction, often secondary to intestinal-type partly dependent on individual patient anatomy
Barrett’s metaplasia and dysplasia. Over 90% of but is also an indicator of extent of tumour spread,
oesophageal adenocarcinoma patients present adequacy of surgical resection, and potential local
symptomatically with established malignancy, recurrence due to residual mediastinal disease.
often late stage disease. Less than 10% of patients Other cancers: Rare but can include small cell
will have had a previous endoscopic biopsy diag- carcinoma, malignant melanoma, leukaemia/
nosis of Barrett’s oesophagus. The incidence of malignant lymphoma, metastatic cancer (e.g.,
this tumour has greatly increased in the last lung or breast), leiomyosarcoma, and Kaposi’s
20 years due in part to antibiotic eradication of sarcoma (HIV-AIDS).
helicobacter pylori with loss of its gastric acid Prognosis: Prognosis of oesophageal cancer is
suppressor effect, resulting in more GOR dis- poor (5-year survival 5–15%) relating mainly to
ease. As well as extensive radial spread through depth of spread and lymph node involvement,
the wall out to the circumferential radial margin i.e., tumour stage, and involvement of longitudi-
(CRM), it can spread upward, undermining the nal and circumferential excision margins. Early
oesophageal squamous mucosa and downward to or superficial carcinoma does significantly bet-
the proximal stomach where clear distinction ter—55% → 88% 5-year survival depending on
from a primary gastric carcinoma can be difficult. the depth of mucous membrane invasion.
2.5 Surgical Pathology Table 2.1 Choice of surgical procedure in oesophageal

neoplasia
Specimens: Clinical Aspects
Proximal 1/3 tumours Pharyngo-oesophagectomy
2.5.1 Biopsy Specimens Middle 1/3 tumours Ivor Lewis technique
Thoracoabdominal
oesophagectomy
Two main types of oesophageal endoscopy exist,
Two-field transhiatal
namely rigid and flexible. Rigid oesophagoscopy
oesophagectomy
is only occasionally used to provide larger biop- Lower 1/3 tumours Ivor Lewis technique
sies when previous flexible endoscopy (OGD— Thoracoabdominal
oesophagogastroduodenoscopy) samples have oesophagectomy
proven non-diagnostic. Specific lesions such as Transhiatal oesophagectomy
polyps or ulcers necessitate multiple targeted Barrett’s Transhiatal oesophagectomy
biopsies that may be supplemented by brush
cytology of the mucosal surface. Mapping and
annual/biennial surveillance of flat mucosa for the size and position of the tumour in the oesophagus
Barrett’s metaplasia and dysplasia is achieved by (see Table 2.1), and the choice of oesophageal sub-
multiple segmental (every 2 cm) and quadrantic stitute, i.e., stomach, jejunum, or colonic interposi-
biopsies. The clinical extent of the Barrett’s is tion. Ideally the surgeon should strive for a 5 cm
described according to its length of circumferen- longitudinal margin of clearance with adenocarci-
tial disposition (cm) and total length (cm) of the noma and 10 cm for squamous carcinoma, with an
metaplastic segment respectively, e.g., C2M6. appropriate lymphadenectomy. There is currently no
The basis of an oesophageal stricture may be evidence-based favoured method of resection.
easier to demonstrate if malignant in nature
because of carcinoma ulcerating the squamous 2.5.3.1 Procedures Employing
epithelium, whereas a benign peptic stricture due a Thoracotomy
to submucosal or mural fibrosis is often not (a) Ivor Lewis technique—in this operation, upper
accessible to mucosal biopsy. Endoscopic biopsy abdominal and right thoracotomy incisions are
of achalasia or oesophageal webs is often unre- made. The proximal stomach is divided and
warding as it provides intact surface mucosa the oesophagus is transected proximal to the
only. tumour. The distal stomach is then raised into
the chest and an OG anastomosis is fashioned.
(b) Thoracoabdominal oesophagectomy—a
2.5.2 EMR Specimens continuous incision extending from the mid-
line of the upper abdomen running obliquely
EMR (“big biopsy”) specimens can be both diag- across the rib margin and posterolateral
nostic, staging and therapeutic, e.g., in dysplastic aspect of the chest wall. The left diaphragm
Barrett’s to diagnose and remove any “early” nod- is divided and this gives access for potential
ular areas of carcinoma confined to the mucosa. en bloc resection of the oesophagus, stom-
ach, gastric nodes and, if required, the spleen
and distal pancreas. An oesophagojejunal or
2.5.3 Resection Specimens OG anastomosis is fashioned in the neck.
The surgical techniques for resecting oesophageal 2.5.3.2 Transhiatal Oesophagectomy

tumours fall into two broad categories—those which Depending on whether a total or distal oesopha-
employ a chest incision (thoracotomy) and those gectomy is to be performed, two variations of this
which do not (transdiaphragmatic hiatal proce- procedure are used.
dures). The type of procedure used depends on the
general level of health of the patient, any previous (a) “Two-field approach”—the entire oesophagus
operations, the preference of the operating surgeon, and stomach is mobilized via upper abdomi-

2 Oesophagus 19
nal and oblique neck incisions. The cervical There are several benefits in performing a total
oesophagus is divided and anastomosed to thoracic oesophagectomy with cervical anasto-
stomach which had been mobilized and raised mosis: maximum clearance of surgical margins is
high into the posterior mediastinum. obtained while the risk of mediastinitis, sepsis,
(b) Distal oesophagectomy with proximal gas- and GOR that can be seen with an intrathoracic
trectomy (for distal oesophageal/junctional anastomosis is diminished.
tumours)—only an upper abdominal incision
is used, with the distal oesophagus being
mobilized and an OG anastomosis fashioned 2.6 Surgical Pathology
in the chest. Specimens: Laboratory
Protocols
Although transhiatal resection for diseases of
the thoracic oesophagus used to be uncommon, it 2.6.1 Biopsy Specimens
is now more commonly used, reducing the physi-
ological insult experienced with a thoracotomy. See Chap. 1.
Minimally invasive oesophagectomy (MIO) pro-
cedures are being developed using combined
laparoscopic and thoracoscopic techniques. 2.6.2 EMR Specimens
Whenever possible the stomach should be
used in the anastomosis and with appropriate The majority of EMR specimens are submitted
mobilization the stomach will reach the neck in “piecemeal” to the laboratory in contrast to
virtually all patients. If the tumour is limited to Endoscopic Submucosal Dissection (ESD) which
the OG junction, the entire greater curvature of is more likely to produce a single disc shaped
the gastric fundus (shaded area in Fig. 2.3), specimen. EMRs should be examined to identify
including the point which usually reaches most the mucosal surface and the cauterised deep mar-
cephalad to the neck (*in Fig. 2.3), may be pre- gin which may be inked. Smaller specimens with-
served while still obtaining a 4–6 cm gastric mar- out a macroscopically visible surface lesion
gin distal to the malignancy. should be serially sectioned and all tissue pro-
cessed for histological examination through lev-
els, with the judicious application of special stains
to facilitate identification of lymphovascular/
* venous invasion. The use of sponges within speci-
men casettes may help prevent artefactual curling
up and twisting of the specimens.
4−6 cm
2.6.3 Resection Specimens
Specimen
• Most oesophageal resections are for neoplas-

tic conditions: partial oesophagectomy, total
thoracic oesophagectomy (TTO), oesopha-
gectomy with limited gastrectomy,
Excision line oesophagogastrectomy
• The oesophagus can easily lose 25–33% of its
Fig. 2.3 Transhiatal oesophagectomy with limited proxi- length after removal from the patient and fixa-
mal gastrectomy (Reproduced, with permission, from tion in formalin. The length of tumour and dis-
Allen and Cameron (2013)) tances from longitudinal resection margins
will be potentially affected and a strong case • Photograph.

can be made for pinning the specimen out • Fixation by immersion in 10% formalin for
fresh onto a board as soon as possible prior to 48 h preferably pinned out on a corkboard in
immersion in formalin. the opened position but not placed under ten-
Initial procedure sion (to avoid splitting).
• By palpation and with the index finger locate Description
the luminal position of the tumour. • Tumour
• Paint the overlying external CRM comprising –– Polypoid: spindle cell carcinoma/
adventitial fatty connective tissue and any carcinosarcoma
related serosa. –– Warty/verrucous: verrucous carcinoma
• Most authorities (and clinical trial protocols) –– Nodular/plaque: superficial carcinoma
recommend leaving the tubular oesophagus –– Fungating/strictured/ulcerated/infiltrative
unopened and serial transverse slicing after the edge: usual carcinoma
painted margin has dried (Fig. 2.4). This method –– Multifocal
facilitates assessment of the CRM in T3 disease –– Regression and scarring
and is also useful where perioperative chemo- • Mucosa
therapy makes the macroscopic identification/ –– Barrett’s mucosa (velvety appearance)
assessment of tumour/tumour bed difficult. • Wall
• Opening the specimen longitudinally (after –– Tumour confined to mucous membrane, in
inking) may be considered in cases of dysplas- the wall or through the wall
tic Barrett’s oesophagus or T1/T2 disease • Other
(e.g., post EMR) where identification of suspi- –– Achalasia, diverticulum, mucosal web,
cious ulcerated or nodular areas of mucosa perforation.
can greatly facilitate appropriate block selec- Blocks for histology (Figs. 2.4 and 2.5)
tion and where the CRM is not likely to be • Sample the proximal and distal limits of
threatened by the primary tumour (Fig. 2.5). surgical resection—complete circumferen-
• Measurements: tial transverse section (oesophagus) or
–– Oesophagus—length (cm), width (cm) multiple circumferential blocks (proximal
–– Proximal stomach—lengths (cm) along stomach).
lesser and greater curvatures • Alternatively, if separate anastomotic dough-
–– Tumour—length × width × depth (cm) or nuts are submitted, take one complete circum-
maximum dimension (cm) ferential transverse section of each.
–– Distances (cm) to the proximal and distal • Serially section the bulk of the tumour trans-
limits of resection versely at 3–4 mm intervals.
–– Distance (cm) to the OG junction if the • Lay the slices out in sequence and
tumour is mid-oesophageal in location photograph.
–– Relationship to the OG junction: distal • Sample a minimum of four blocks of tumour
oesophageal tumour involving the junction and wall to show the deepest point of circum-
(Siewert 1), tumour straddling the junction ferential invasion (Fig. 2.4).
(Siewert 2), proximal gastric tumour • Sample one block of oesophagus proximal to
involving the junction (Siewert 3). the tumour and one block of oesophagus (or
–– Note that the junction may be obscured by proximal stomach) distal to the tumour.
tumour, and external landmarks (oesopha- • Sample any abnormal background mucosa,
gus—adventitia; stomach—serosa) should e.g., multiple sequential blocks may be
also be used in determining the location. required to map the extent of Barrett’s
–– Barrett’s mucosa—location/length (cm). metaplasia.

2 Oesophagus 21
Proximal limit
Right pleura Oesophagus
Horizontal serial
transverse slices
Stomach
Distal limit
Proximal Distal
Right pleura CRM perioesophageal

adventitial fat
Block harvest pT3 disease

for histology
Fig. 2.4 Oesophageal carcinoma: unopened, painted (CRM) oesophagogastrectomy specimen cut into horizontal,
serial transverse slices for histology block harvest
• If tumour is not seen grossly, sequentially rate proximal segment of normal oesophagus
sample and correspondingly label unremark- excised to facilitate pull-through of the OG
able and abnormal areas of mucosa. anastomosis to the neck.
• Count and sample all lymph nodes. • Histopathology report
• Sample the midpoint and proximal surgical • Tumour type—adenocarcinoma/squamous
limit (as marked by the surgeon) of any sepa- carcinoma/other
a pT3 Tumour invades adventitia

pT4 Tumour invades adjacent structures (pT4a:
pleura/pericardium/diaphragm/peritoneum,
pT4b: aorta/vertebral body /trachea)
Note also any invasion of the proximal gastric

serosa.
Siewert 1–3 tumours are staged as oesopha-
geal under TNM 8.
• Lymphovascular invasion—present/not pres-

ent. Note perineural invasion.
• Regional lymph nodes
• Perioesophageal, including coeliac axis nodes
and paraoesophageal nodes in the neck, but
b not supraclavicular nodes. A regional
lymphadenectomy will ordinarily include 7 or
more lymph nodes.
pN0 No regional lymph node metastasis

pN1 Metastasis in 1–2 regional lymph node(s)
pN2 Metastasis in 3–6 regional lymph nodes
pN3 Metastasis in 7 or more regional lymph nodes
• Excision margins
Proximal and distal limits of tumour clearance
(cm)
Fig. 2.5 Oesophageal carcinoma (T1/T2 disease) or Separate proximal oesophageal and distal gastric
Barrett’s dysplasia: opened oesophago-gastrectomy spec-
imen for (a) targeted or (b) sequential grid blocks anastomotic doughnuts—involved/not involved
Deep CRM of clearance (mm)
• Other pathology:
• Tumour differentiation • Squamous dysplasia, Barrett’s metaplasia/
dysplasia, radio−/chemotherapy necrosis and
Adenocarcinoma Squamous carcinoma Tumour Regression Grade (Mandard score:
Well >95% glands Keratinization/ TRG1 no residual tumour—TRG5 absence of
intercellular bridges
regressive changes), perforation, achalasia,
Moderate 50–95% glands
oesophageal web, diverticulum
Poor <50% glands No keratinization/
intercellular bridges
• Tumour edge—pushing/infiltrative/lymphoid Bibliography

response
• Extent of local tumour spread: TNM 8: for Allen DC. Histopathology reporting. Guidelines for surgi-
carcinoma cal cancer. 3rd ed. London: Springer; 2013.
Allen DC, Cameron RI. Histopathology specimens:
clinical, pathological and laboratory aspects. 2nd ed.
pTis Carcinoma in situ/high-grade dysplasia
Berlin: Springer; 2013.
pT1 Tumour invades pT1a. lamina propria or Allum WH, Blazeby JM, Griffin SM, Cunningham D,
muscularis mucosae, or, pT1b. submucosa Jankowski JA, Wong R. On behalf of the Association
pT2 Tumour invades muscularis propria of Upper Gastrointestinal Surgeons of Great

2 Oesophagus 23
Britain and Northern Ireland, the British Society Odze RD, Goldblum JR, editors. Odze and Goldblum
of Gastroenterology and the British Association of Surgical pathology of the GI tract, liver, biliary tract,
Surgical Oncology. Guidelines for the management of and pancreas. 3rd ed. Philadelphia: Elsevier Saunders;
oesophageal and gastric cancer. Gut. 2011;60:1449–72. 2015.
Bejerano PA, Berho M. Examination of surgical speci- Schlemper RJ, Riddell RH, Kato Y. The Vienna classi-
mens of the esophagus. Arch Pathol Lab Med. fication of gastrointestinal epithelial neoplasia. Gut.
2015;139:1446–54. 2000;47:251–5.
Bosman FT, Carneiro F. WHO classification of tumours of Shepherd NA, Warren BF, Williams GT, Greenson JK,
the digestive system. 4th ed. Lyon: IARC Press; 2010. Lauwers GY, Novelli MR, editors. Morson and
Brierley JD, Gospodarowicz MK, Wittekind C, editors. Dawson’s gastrointestinal pathology. 5th ed. Oxford:
TNM classification of malignant tumours. 8th ed. Wiley-Blackwell; 2013.
Oxford: Wiley-Blackwell; 2017. The Royal College of Pathologists. Cancer datasets
Cotton P, Williams C. Practical gastrointestinal endos- (oesophageal carcinoma, gastric carcinoma, carci-
copy. 4th ed. London: Blackwell Science; 1996. nomas of the pancreas, ampulla of vater and com-
Ibrahim NBN. Guidelines for handling oesophageal mon bile duct, colorectal cancer, gastrointestinal
biopsies and resection specimens and their reporting. stromal tumours (GISTs), liver resection specimens
J Clin Pathol. 2000;53:89–94. and liver biopsies for primary and metastatic car-
Lewin KJ, Appelman HD. Tumors of the esophagus and cinoma, endocrine tumours of the gastrointestinal
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Fascicle 18. Washington, DC: AFIP; 1996. trointestinal and pancreatobiliary pathology, liver
Logan RPH, Harris A, Misciewicz JJ, Baron JH, editors. biopsies for the investigation of medical disease and
ABC of the upper gastrointestinal tract. London: BMJ for focal liver lesions). https://www.rcpath.org/pro-
Books; 2002. fession/publications/cancer-datasets.html. Accessed
Mandard AM, Dalibard F, Mandard JC, Marnay J, Henry- Sept 2016.
Amar M, Petiot JF, Roussel A, et al. Pathologic Wittekind C, Greene L, Hutter RVP, Klimfinger M, Sobin
assessment of tumour regression after preoperative LH. TNM atlas: illustrated guide to the TNM/pTNM
chemoradiotherapy of oesophageal carcinoma. Cancer. classification of malignant tumours. 5th ed. Berlin:
1994;73:2680–96. Springer; 2005.
Stomach
3
Damian T. McManus, Derek C. Allen,
and R. Iain Cameron
3.1 Anatomy The incisura is an important endoscopic

landmark.
The stomach is a dilated portion of the gastroin- Antrum—extends from the incisura to the proxi-
testinal tract which has three main functions: mal part of the pylorus.
storage of food, mixing food with gastric secre- Pylorus—the most tubular part of the stomach
tions, and control of the rate of release of food to and its thick muscular wall forms the physio-
the small intestine for further digestion and logical and anatomical pyloric sphincter,
absorption. It is a J-shaped organ and much of it marked by a slight constriction on the surface
lies under the cover of the lower ribs. It has an of the stomach. The pylorus, which is approxi-
anterior and posterior surface, two openings (the mately 2.5 cm long, joins the first part of the
proximal cardiac and the distal pyloric orifices), duodenum.
and two curvatures (greater and lesser) (Fig. 3.1).
Although relatively fixed at both ends, the inter- The cardiac orifice is where the abdominal
vening part is mobile and can undergo consider- part of the oesophagus enters the stomach.
able variation in shape. The stomach is usually Although no anatomical sphincter is present, a
divided into the following parts: physiological mechanism exists, which prevents
gastro-oesophageal regurgitation.
Fundus—dome-shaped and projects upward and The lesser curvature forms the right border of
to the left of the cardiac orifice. the stomach, extending from the cardiac orifice to
Body—extends from the level of the cardiac ori- the pylorus. The greater curvature extends from
fice to the incisura angularis (a constant notch the left of the cardiac orifice, over the fundus to
at the junction of the lesser curve and antrum). the inferior part of the pylorus. Peritoneum com-
pletely surrounds the stomach and leaves its cur-
vatures as double layers called omenta, which
contain fat, lymph nodes, and vessels. The lesser
D.T. McManus (*) • D.C. Allen
Histopathology Laboratory, Belfast City Hospital, omentum extends from the lesser curve to the
Belfast Health and Social Care Trust, Belfast, UK liver. The gastrosplenic omentum extends from
e-mail: damian.mcmanus@belfasttrust.hscni.net; the upper part of the greater curve to the spleen,
derek.allen@belfasttrust.hscni.net while the greater omentum runs to the transverse
R.I. Cameron colon from the lower part.
Histopathology Laboratory, Altnagelvin Hospital, The mucous membrane of the gastric body is
Londonderry, UK thrown into numerous longitudinal folds or rugae.
e-mail: iain.cameron@westerntrust.hscni.net This facilitates flattening of the mucosa when the

Fig. 3.1 Stomach
(Reproduced, with Gastrosplenic
permission, from Allen omentum
and Cameron (2013))
Cardiac
orifice
Lesser Fundus
curvature
Greater
omentum
Lesser
omentum
Body
Incisura Surface
angularis mucus-
foveolar
cells
Antrum
Mucus
neck cells
Pylorus
Parietal
cells
Chief cells
Gastric microanatomy
stomach is distended by food. The mucosal sur- The main nerve supply to the stomach is from
face contains millions of gastric pits or foveolae the anterior and posterior vagal trunks, with the
that lead to mucosal glands. The mucosal surface innervation of the pylorus being mainly derived
is composed of columnar, mucin-secreting epi- from the anterior vagus.
thelium (surface mucus—foveolar cells), while
deeper in the gastric pits are mucus neck cells.
The gastric glands vary depending on their ana- 3.2 Clinical Presentation
tomic region (Fig. 3.1):
Patients with gastroduodenal disease may be
Cardia—mucin-secreting cells asymptomatic or experience one or more of the
Fundus/body—parietal cells (acid), chief cells following: upper abdominal (epigastric) pain;
(pepsin), and scattered endocrine cells dyspepsia (“indigestion”); vomiting, which may
Antrum/pylorus—endocrine (mostly gastrin G be projectile if there is pyloric outflow obstruc-
cells) and mucin-secreting cells. tion; haematemesis (vomiting blood); melaena
(altered blood per rectum); or dysphagia, if there
Lymphovascular drainage: is a proximal gastric lesion.
The entire arterial supply of the stomach is
derived from the coeliac artery which arises from
the aorta. Veins drain into the portal system. The 3.3 Clinical Investigations
lymphatics drain to the coeliac lymph nodes. The
so-called N1 and N2 node groups (12 in total) are • Endoscopy and Biopsy
situated along the arterial supply (Fig. 3.2). N1 • Erect CXR to detect “air under the diaphragm”
nodes are within 3 cm of the primary malignancy in a perforation and also metastatic tumour
and N2 nodes more than 3 cm from the tumour. deposits in the lungs.
3 Stomach 27
• Gastric function tests—peak acid output is

Distant (M) measured by the pentagastrin test and will dif-
2 ferentiate “hypersecretors” from “non-
1 hypersecretors”—important if surgery is to be
considered for duodenal peptic ulcer disease.
Regional (N) 3
5
3.4 Pathological Conditions
4a
3.4.1 Non-neoplastic Conditions
Acute gastritis: Acute haemorrhagic/erosive gas-

tritis is usually antral and drug related (aspirin,
6
4b NSAIDs, alcohol) or, less commonly, in the body
secondary to shock and hypoperfusion, e.g., post-
trauma, sepsis or burns, and, therefore, not biop-
sied. Acute neutrophilic gastritis is seen in food
10
poisoning, sepsis, and helicobacter pylorii (HP)
9
infection.
7
8 Chronic gastritis: With poor correlation
12 between symptoms, endoscopic appearances,
and histology, it is very common in biopsy mate-
11
rial and is autoimmune, bacterial or chemical in
nature (types A, B, and C). The latter is usually
antral, related to drug ingestion or bile reflux, and
Fig. 3.2 Stomach: Regional lymph nodes. The regional comprises a reactive mucosa with a lack of
lymph nodes are the perigastric nodes along the lesser (1,
inflammatory cells. Autoimmune gastritis affects
3, 5) and greater (2, 4a, 4b, 6) curvatures, the nodes
located along the left gastric (7), common hepatic (8), the corpus, resulting in a spectrum of atrophic
splenic (10, 11) and coeliac arteries (9), and the hepato- gastritis and gastric atrophy with hypochlorhy-
duodenal nodes (12). Involvement of other intra- dria, pernicious anaemia, and a predisposition to
abdominal lymph nodes such as the retropancreatic,
gastric cancer. It is associated with other autoim-
mesenteric, and para-aortic is classified as distant metas-
tasis (Used with the permission of the Union for mune diseases, e.g., diabetes and mucosal dam-
International Cancer Control (UICC), Geneva, age is mediated by circulating antibodies to
Switzerland. The original source for this material is from gastrin receptors on the parietal cells. The anae-
mia is due to lack of gastric intrinsic factor with
decreased vitamin B12 absorption in the terminal
• Barium swallow will outline the mucosal sur- ileum. HP infection is the commonest form of
face, demonstrate decreased distensibility and chronic gastritis and increases in incidence with
wall motility due to diffuse carcinoma (linitis age. The Gram-negative, curved bacillus is read-
plastica) and detect delayed emptying caused ily identified (H and E, Cresyl Violet, Giemsa)
by pyloric outflow obstruction. lying under the surface mucous layer, damaging
• For biopsy-proven cancer—ELUS and CT the epithelium and producing a chronic inflam-
scan chest, abdomen, and pelvis to determine matory reaction in the lamina propria with focal
the pretreatment tumour stage. neutrophil polymorph cryptitis. Treatment is by
• Peritoneal aspiration of ascitic fluid for malig- antibiotic eradication.
nant cells and staging laparoscopy with perito- The Sydney System classifies and grades
neal biopsy and cytology washings. Peritoneal chronic gastritis based on an assessment of histo-
disease is a contraindication to radical cura- logical (neutrophils, chronic inflammation, atro-
tive intent therapy. phy, intestinal metaplasia), topographical (antral/
corpus predominant or pangastritis), and aetio- probably represent healing of the mucosa after
logical (HP, drugs) factors. erosion—malignant change is extremely rare,
Chronic gastritis predisposes to peptic ulcer- although there can be cancer elsewhere in the
ation, gastric carcinoma, and malignant lym- stomach.
phoma. Unusual variants such as lymphocytic, Other non-neoplastic polyps: rare, e.g., ham-
granulomatous, or eosinophilic gastritis are occa- artomatous polyps (Peutz Jegher’s/Cronkhite—
sionally seen—infective gastritis occurs in immu- Canada syndromes), inflammatory fibroid polyp,
nosuppressed patients (e.g., CMV) or or common, such as fundic gland cyst polyps—
opportunistically overlying malignant ulceration small, multiple, gastric body, cystic dilatation of
(e.g., candida fungus). specialized glands, incidental or associated with
Peptic ulceration: there are two patient groups. PPI therapy/familial adenomatous polyposis
(FAP).
1. HP antral gastritis → loss of acid regulatory Note that various diseases can present as pol-
feedback → hyperchlorhydria → duodenitis ypoidal gastric folds or hypertrophic gastropathy,
→ duodenal gastric metaplasia with HP colo- e.g., Ménétrier’s disease (hypochlordydria, pro-
nization → further duodenitis and duodenal tein loss from elongated gastric pits), Zollinger–
ulcer (DU) Ellison syndrome (pancreatic/duodenal
2. HP pangastritis → hypoacidity → weakening gastrinomas, hyper-chlorhydria, multiple peptic
of the mucosal mucous barrier → further gas- ulcers), Crohn’s disease, carcinoma, or malignant
tritis → erosion and gastric ulceration (GU) lymphoma.
Further risk factors include smoking, alcohol,

and drugs (NSAIDs, aspirin, steroids). DU out- 3.4.2 Neoplastic Conditions
numbers GU (4:1). Benign gastric ulcers are usu-
ally on the lesser curve in the vicinity of the Predisposing conditions: Predisposition to gas-
incisura. tric neoplasia occurs with HP gastritis, gastric
Complications include acute or chronic bleed- atrophy, and previous partial gastrectomy with
ing from the ulcer base, perforation with peritoni- gastroenterostomy. Antecedent lesions include
tis, penetration and fistula to an adjacent organ incomplete intestinal metaplasia (type IIb/III
(e.g., colon or pancreas), fibrotic repair resulting large intestinal variant) and epithelial dysplasia.
in mechanical obstruction such as pyloric steno- Dysplasia occurs in flat (commonest), sessile, or
sis, and, rarely, cancer. Surgery for peptic ulcer- polypoid mucosa and is categorized as low or
ation has decreased dramatically in the last two high grade, corresponding to categories 3 and 4
decades with the evolution of effective antiulcer of the Vienna Consensus Classification of
treatments based largely on antibiotic eradication Gastrointestinal Epithelial Neoplasia (Table 3.1).
of HP infection and acid suppression (H2 receptor Low-grade dysplasia requires endoscopic follow-
antagonists, proton pump inhibitors (PPIs)). It is up, while high-grade dysplasia should be consid-
now reserved for those peptic ulcers refractory to ered for surgical resection due to the strong
medical treatment, in which complications have
arisen or there is a suspicion of malignancy. Table 3.1 Vienna classification of gastrointestinal epi-
Acute haemorrhage is managed conservatively thelial neoplasia
by laser, electrocoagulation, or injection of Category Neoplasia/dysplasia
sclerosant. 1 Negative
Hyperplastic polyps: Commonest in the 2 Indefinite
antrum and up to 1.5 cm in size, they form 60% 3 Noninvasive low grade
of gastric mucosal polyps and are characterized 4 Noninvasive high grade
by dilated, hyperplastic glands in oedematous, 5 Invasive—either intramucosal,
inflamed lamina propria. Single or multiple they submucosal, or beyond
3 Stomach 29
association (30–80%) with concurrent or subse- called lacy pattern) or specific clinical situations
quent cancer. Polypoid adenomatous dysplasia e.g., adenocarcinoma developing at or close to
comprises 8% of gastric polyps but has a 30–40% the site of gastroenterostomy post Bilroth gas-
risk of malignancy related to size, villous archi- trectomy. The commonest metastases to the
tecture, and grade of dysplasia. Local resection stomach include lobular carcinoma of the breast,
(endoscopic or surgical) and careful background lung small cell carcinoma, renal cell carcinoma,
mucosal sampling are necessary for full histo- and malignant melanoma.
logical assessment. Carcinoid (well-differentiated neuroendo-
Adenocarcinoma: forms the majority of gas- crine) tumour: of gastric endocrine or
tric malignancy and classically antral (50%) or enterochromaffin-like (ECL) cell origin, either
lesser curve (15%) in site but with an increasing related to gastric atrophy (type 1), ZE syndrome
incidence in the proximal stomach and cardia, in (type 2), or sporadic (type 3).
part due to HP eradication and loss of its acid
suppression effect. Histological patterns are • Multiple (benign): atrophic gastritis/gastric
intestinal (50%), diffuse (20%), or mixed/solid atrophy → hypochlorhydria → hypergastri-
(25%), showing correlation with macroscopic naemia → ECL hyperplasia → microcarcinoi-
appearances and behaviour. Intestinal carcino- dosis (multiple, mucosal, <1.5 mm). If <1 cm
mas arise from intestinal metaplasia/dysplasia, endoscopic removal is sufficient: if 1–2 cm in
form ulcerated or polypoid lesions with expansile size, treatment is by polypectomy or local
margins, and show lymphovascular spread to resection as they have uncertain malignant
regional nodes, liver, lung, adrenal gland, and potential.
bone. Diffuse carcinomas (signet ring cells), or • Single or sporadic (aggressive): surgical
poorly cohesive carcinoma in the WHO 2010 resection if >2 cm in size, invasion beyond
classification, form diffusely infiltrating linitis submucosa, angioinvasion, or cellular atypia
plastica (leather bottle stomach) undermining the (including necrosis or mitoses). Functional
mucosa with transmural spread to the peritoneum secreting tumours are also potentially malig-
where seedlings and classical Krukenberg nant. Detection of metastatic disease is by CT
tumours (bilateral ovarian secondaries) occur. and octreotide scintigraphy scan.
The WHO 2010 classification is descriptive and
lists tubular, papillary, mucinous, poorly cohe- Gastrointestinal stromal tumours (GISTs):
sive and mixed patterns. Gastric cancer may be spindle or epithelioid cell in type a minority of
multifocal—resection margins are routinely gastric mesenchymal tumours are leiomyomatous
checked. Distal cancers can involve proximal or neural and a majority stromal (CD117 (c-kit)/
duodenum, and proximal cancers, the distal DOG-1 positive) in character with absent or
oesophagus. Tubule-rich, mucin-poor tumours incomplete myogenic/neural features. Risk of
with a circumscribed edge have a better progno- recurrence/metastasis can be stratified by use of
sis than tubule-poor, mucin-rich tumours or an the modified Miettinen criteria. In general, size
infiltrative edge. Depth of spread is defined as (>5 cm), cellularity and atypia, tumour necrosis
early gastric cancer (EGC) confined to the and haemorrhage, infiltrative margins, and mitotic
mucous membrane ± regional node involvement, activity (>5/50 high power fields) are associated
or advanced muscle coat invasive disease which with an increased risk of recurrence and progres-
has a much worse prognosis. EGC (10% of cases) sive disease. Metastatic spread is typically to peri-
can be multifocal in distribution and raised, flat, toneum and liver. Endoscopic biopsy diagnosis
or ulcerated in morphology. can be problematic as GISTs are submucosal/
Other carcinomas are rare e.g., hepatoid, pari- mural lesions covered by intact mucosa except for
etal cell, medullary. EBV related gastric cancers a classical central area of “apple core” ulceration.
may occur in association with distinctive mor- Malignant lymphoma: primary with disease
phology (lympho-epithelial carcinoma or a so bulk in the stomach and regional nodes, or
secondary to systemic nodal disease. Single, appropriate typing, grading, and staging (CT
multiple, plaque-like, ulcerated, or as thickened scan, bone marrow trephine) include HP eradica-
folds it has a rubbery, fleshy appearance. The tion (low-grade disease), chemotherapy (high-
majority are of B cell MALT (mucosa associated grade disease), and surgery, the latter particularly
lymphoid tissue) type and strongly associated if there are anatomical alterations, e.g., gastric
with HP chronic gastritis. Low or high-grade, the outlet obstruction, or complications of chemo-
former can be difficult to diagnose requiring an therapy, e.g., perforation.
accumulation of histological, immunohistochem- The primary treatment of GISTs is surgical
ical, and molecular evidence over a number of resection. Targeted therapy in the form of small
biopsy episodes. Cardinal features are the density molecule inhibitors such as imatinib (Glivec)
and uniformity of the lymphoid infiltrate, loss may be used for tumours which are unresectable
and destruction of mucosal glands, demonstra- or metastatic and in an adjuvant setting for high
tion of immunoglobulin light chain restriction, risk GISTs. Neoadjuvant therapy can produce
and heavy chain gene rearrangements. High- tumour regression and shrinkage, facilitating suc-
grade lymphoma transforms from a low-grade cess and choice of operative technique. Mutation
lesion or presents de novo and must be distin- testing is recommended when imamtinib therapy
guished immunohistochemically from poorly dif- is contemplated.
ferentiated carcinoma. Rarely there can be an
association between MALToma and concurrent
or subsequent adenocarcinoma. 3.5 Surgical Pathology
Prognosis: The majority of patients with gas- Specimens: Clinical Aspects
tric cancer present with advanced disease, and
prognosis is poor (20–35% 5-year survival) relat- 3.5.1 Biopsy Specimens
ing to histological type, differentiation, excision
margin involvement, and, crucially, stage of dis- Flexible endoscopy is the cornerstone for investi-
ease. Following a positive endoscopic biopsy, the gation and diagnosis of gastric-related symp-
tumour is staged radiologically and laparoscopi- toms. Biopsies for gastritis should be taken
cally to determine suitability for radical surgery. according to the Sydney protocol from antrum,
Current trials indicate a beneficial role for preop- body, and incisura and any abnormal areas.
erative and postoperative chemotherapy, which Specific lesions such as ulcers need multiple (at
traditionally had been limited to palliative treat- least six) biopsies from the base and margin
ment of advanced disease. Patients with Her 2 quadrants as some 10% of endoscopically suspi-
positive recurrent or metastatic disease (20% of cious lesions need rebiopsy. A peptic ulcer has a
cases) potentially respond to trastuzumab mono- classic endoscopic appearance in that it is round/
clonal antibody therapy. EGC has a better prog- oval and sharply “punched out” with straight
nosis (80–95% 5-year survival) and may be walls. Heaping up of mucosal margins is rare in
amenable to local mucosal resection but is con- benign ulcers and should raise the suspicion of
verted to completion gastrectomy if the cancer malignancy. Size does not reliably differentiate
shows unfavorable features such as size >3 cm, between benign and malignant ulcers as 10% of
>50% surface ulceration, poor differentiation, benign ulcers are greater than 4 cm in diameter.
lymphovascular invasion, or involvement of the Tumours covered by intact mucosa such as dif-
submucosa or specimen base. fuse gastric carcinoma or GISTs are often diffi-
Carcinoid tumours are of low-to-intermediate- cult to demonstrate by mucosal biopsy, and
grade malignancy—70–80% 5-year survival. endoscopic FNA may be employed. Localized
Low-grade MALTomas are indolent (65–95% nodular or polypoid lesions, e.g., hyperplastic
5-year survival), whereas high-grade lesions are polyp, adenomatous polyp, carcinoid tumour,
more aggressive (40–55% 5-year survival). EGC can be diagnosed and successfully removed
Treatment options for gastric lymphoma after by EMR.
3 Stomach 31
3.5.2 Resection Specimens tion, negating the need for a drainage procedure.
The now rare Bilroth II gastrectomy for DU com-
3.5.2.1 Benign Conditions prises a distal gastrectomy with oversewing of
As alluded to above, surgery for chronic peptic the duodenal stump and fashioning of a gastroje-
ulceration is now unusual. It aims to remove the junal anastomosis of either Polya or Roux-en-Y
gastric ulcer and the gastrin-producing G cells type. The latter prevents bile reflux as the distal
that drive acid secretion. This is accomplished by duodenum is joined to the jejunum some 50 cm
a Bilroth I distal gastrectomy with a gastroduode- distal to the gastrojejunal anastomosis.
nal anastomosis (Fig. 3.3). Alternatively block-
age of gastric innervation is achieved by 3.5.2.2 Malignant Conditions
transecting the vagus nerve trunks as they emerge Curative gastric surgery should involve removal
through the diaphragmatic hiatus (truncal vagot- of the tumour with a 5 cm rim of “normal” tissue
omy), resulting in reduced gastric secretions and and the related lymph nodes. The surgeon may
motility. Because of the latter, a drainage proce- prefer to perform a partial or total gastrectomy
dure, either pyloroplasty or gastrojejunostomy, depending on the site and type of tumour (e.g.,
must also be done. This approach is used in diffuse carcinoma) and medical fitness of the
elderly frail patients or for refractory DU. Highly patient.
selective vagotomy preserves pyloric innerva- Total gastrectomy: This can be done with or
without radical lymph node dissection. Both pro-
Bilroth I gastrectomy with gastroduodenal anastomosis cedures employ an upper midline abdominal
incision. In a total gastrectomy without radical
lymph node dissection (D1 resection), the stom-
ach is removed with the lesser and greater omenta
(which contain local lymph nodes). In this resec-
tion, nodes may also be found along the greater
curvature and the gastrosplenic omentum. A radi-
Vagotomy with drainage cal gastrectomy (D2 resection) involves removal
of the stomach, lesser omentum with careful dis-
section of nodes along the hepatic artery and
coeliac plexus, greater omentum and gastrosplenic
omentum. Nodes should also be removed from
along the portal vein, splenic artery, and the ret-
ropancreatic area. In Japan, an even more radical
procedure is popular, which involves en bloc
resection of the stomach, spleen, distal pancreas,
Bilroth II gastrectomy with gastrojejunal anastomosis
and associated lymph node groups.
Polya type Roux-en-y type Good margin clearance is crucial and so the
oesophagus is divided as far proximally as is
needed and occasionally this may involve enter-
ing the chest. The distal margin of resection is
formed by division of the first part of the duode-
num. Continuity is restored by an oesophagojeju-
nostomy with a Roux-en-Y diverting limb for the
duodenal stump.
Partial gastrectomy: The type of procedure
employed will depend on the site of the tumour:
Fig. 3.3 Gastric surgery for gastroduodenal peptic ulcer-
ation (Reproduced, with permission, from Allen and Proximal tumours—tumours in the vicinity of
Cameron (2013)) the OG junction may arise in the distal oesophagus
and infiltrate distally, or in the cardia/fundus and regional lymph node groups, with or without
infiltrate proximally. Various procedures may be spleen removed because of either direct
employed (see Chap. 2). involvement by gastric cancer or for technical
reasons, e.g., operative access or capsular tear
• Transhiatal distal oesophagectomy with prox- at surgery.
imal gastrectomy for tumours of the distal • Laparoscopic GIST resections.
oesophagus/OG junction/cardia Initial procedure
• Transhiatal distal oesophagectomy with total • Orientation of subtotal gastrectomy speci-
gastrectomy for tumours of the cardia with mens can occasionally be problematic. If the
extensive distal spread surgeon marks the left gastric artery with a
• A more extensive oesophagectomy (via either suitable tie this can be used in combination
a two-field approach or thoracotomy) with with other landmarks to allow unambiguous
proximal/total gastrectomy for junctional orientation.
tumours with extensive proximal spread. • By palpation and with the index finger locate
Distal tumours—either a Bilroth I or Bilroth II the luminal position of the tumour/ulcer.
procedure with the latter being favoured as the • Open the specimen along the curvature oppo-
anastomosis is wider (important if there is local site to and avoiding the tumour/ulcer.
recurrence) and further away from the likely • Measurements:
site of recurrence. Distal oesophagus, greater curvature, duodenal
cuff—lengths (cm)
Tumour/ulcer
3.6 Surgical Pathology –– Length × width × depth (cm) or maximum
Specimens: Laboratory dimension (cm)
Protocols –– Distances (cm) to the proximal and distal
limits of excision
3.6.1 B
iopsy and Local Mucosal –– Relationship to the OG junction. TNM 8
Resection Specimens includes as an oesophageal cancer any
tumour of the proximal stomach where its
See Chap. 1. epicentre is within 2 cm of the junction and
involves the oesophagus (Siewert 3).
External landmarks may be helpful—
3.6.2 Resection Specimens oesophagus is orientated to adventitia,
stomach to serosa.
Specimen • Photograph.
• Paint any relevant area of serosa and omental
• The majority of gastric resections are for neo- margin suspicious of tumour involvement or
plastic conditions. However, because of the dif- close to its edge.
ficulty in reliably distinguishing between • Fixation by immersion in 10% formalin for
benign and malignant gastric ulcers on gross 48 h either gently packed with formalin-
inspection, it is practical to use the same han- soaked lint or, if suitable, pinned out on a
dling procedures. Irregular elevated mucosal corkboard in the opened position.
margins and absence of radial mucosal folds are Description
possible pointers to malignancy. Benign ulcers • Tumour/ulcer site
usually do not occur on the greater curvature. –– Distal oesophagus/cardia/fundus/corpus/
• Subtotal gastrectomy, total/radical gastrectomy, antrum/pylorus/lesser curve/greater curve/
variable amounts of lesser and greater omental anterior/posterior/multifocal/extension to
fat including unspecified or separately named duodenum or oesophagus
3 Stomach 33
a b c
Fig. 3.4 Distal gastrectomy—serial, transverse slices (a) dinal limit block (c) may be taken if the tumour is close
or quadrant sections (b) may be used according to the (<0.5 cm to it) (Reproduced, with permission, from Allen
anatomy of the lesion and adjacent structures. A longitu- and Cameron (2013))
• Tumour –– Maximum deposit size (cm)

–– Polypoid/ulcerated/scirrhous/mucoid/ –– Distance of tumour from the omental edge
irregular margins: usual carcinoma (mm)
–– Thickened, non-expansile wall/intact gran-
ular mucosa: diffuse gastric carcinoma Blocks for histology (Fig. 3.4)
–– Plaque/granular mucosa/depressed/multi-
focal: EGC • Sample the proximal and distal limits of resec-
–– Plaque/thickened folds/ulcerated/fleshy/ tion—complete circumferential transverse
multifocal: malignant lymphoma sections (duodenum, oesophagus) or multiple
–– Nodular/ulcerated/yellow: carcinoid circumferential blocks (mid-stomach).
tumour • Alternatively, if separate anastomotic dough-
–– Polypoid/mural/dumb-bell shaped/apple nuts are submitted—one complete circumfer-
core ulceration:GIST ential transverse section of each.
• Ulcer • Count and sample all lymph nodes (lesser/
–– Mucosal edges: flat/punched out/elevated greater omenta, splenic hilum) and process
–– Base: blood vessels/perforation/penetra- separately any named lymph nodes.
tion (e.g., pancreas or fistula present) • Sample a minimum of four blocks of tumour
• Mucosa and wall to show any serosal involvement and
–– Oedematous/atrophic/granular/thickened the deepest point of omental invasion. Serial
• Wall transverse slices (3–4 mm thick) or quadrant
–– Tumour: confined to mucous membrane, in sections may be used according to the anat-
the wall or through the wall omy of the lesion and adjacent structures.
–– Ulcer: perforation/penetration
• Serosa Tumour ulcer: four sections to include the ulcer
–– Involved by tumour/coated in exudate base, edge, adjacent mucosa, and wall
• Omenta Tumour polyp: two sections from the body of the
–– Involved by tumour: circumscribed/irregu- polyp and a minimum of two from the under-
lar margin lying base and wall
Linitis plastica: six transmural blocks as a gross tumours of the stomach have separate TNM 8
lesion is often not evident and the extent of staging schemes
local spread may vary
GISTs: roughly one block per centimetre diam- Carcinoma in-situ: intraepithelial tumour without
pTis invasion of the lamina propria
eter to include mucosal, mural, and extramu-
pT1 Tumour invades lamina propria/muscularis
ral components of the tumour; laparoscopic mucosae (pT1a) or submucosa (pT1b)
local resection is increasingly used for low pT2 Tumour invades muscularis propria
risk GISTs. Identify mucosal and serosal pT3 Tumour invades subserosa or lesser/greater
aspects; take sections to demonstrate these omenta
structures and narrow stapled margin where pT4 Tumour perforates serosa (pT4a) or invades
possible adjacent structures (spleen, transverse colon,
liver, diaphragm, pancreas, abdominal wall,
Omental tumour: representative blocks in rela-
adrenal gland, kidney, small intestine,
tion to the nearest omental edge/serosa. retroperitoneum (pT4b))
• Sample any other satellite lesions or abnormal EGC = pT1 ± lymph node involvement.

areas of mucosa. Advanced carcinoma = pT2/pT3/pT4 ± lymph
• Sample non-neoplastic gastric mucosa away node involvement
from the tumour/ulcer (two blocks).
• Serially slice, at 1 cm intervals, spleen and
pancreas (if present) and sample two blocks • Lymphovascular invasion—present/not present
Histopathology report • Regional lymph nodes
• Tumour type Perigastric, hepatoduodenal, nodes along the
–– Adenocarcinoma: intestinal/diffuse/mixed/ left gastric, common hepatic, splenic and
mucin-rich/mucin-poor coeliac arteries. A regional lymphadenec-
–– Malignant lymphoma tomy will ordinarily include 16 or more
–– GIST lymph nodes. Other intra-abdominal lymph
• Tumour differentiation nodes (retropancreatic, mesenteric, para-aor-
–– Adenocarcinoma tic) are distant metastases (pM1).
Well/moderate/poor defined as tubule-rich or

tubule-poor pN0 No regional lymph node metastasis
–– Malignant lymphoma pN1 1–2 involved regional node(s)
pN2 3–6 involved regional nodes
pN3 7 or more involved regional nodes (pN3a:
MALToma/mantle cell/follicle centre cell or
7–15. pN3b: ≥16)
other
Low-grade/high-grade
–– GIST • Excision margins
Proximal and distal limits of tumour clear-
Spindle cell/epithelioid ance (cm)
Cellularity/atypia/mitoses/necrosis/margins/size Separate proximal oesophageal/gastric and
Leiomyomatous/neural/stromal (CD117/DOG-1) distal gastric/duodenal anastomotic dough-
nuts—involved/not involved/presence of
• Tumour edge—Pushing/infiltrative/lymphoid mucosal dysplasia
response Deep circumferential omental margin of clear-
• Extent of local tumour spread: TNM 8: for ance (mm)
carcinoma. Well differentiated neuroendo- Deep margin of clearance (mm) in polypectomy
crine tumours and gastrointestinal stromal and endoscopic mucosal resection specimens
3 Stomach 35
• Other pathology Lewin KJ, Appelman HD. Tumors of the esophagus and

stomach, Atlas of tumor pathology, vol. 3rd series.
Satellite foci, polyps, intestinal metaplasia,
Fascicle 18. Washington, DC: AFIP; 1996.
dysplasia, gastric atrophy, helicobacter gastri- Logan RPH, Harris A, Misciewicz JJ, Baron JH, editors.
tis, MALToma, hypertrophic gastropathy (e.g., ABC of the upper gastrointestinal tract. London: BMJ
Menetrier’s disease, ZE Syndrome), ECL cell Books; 2002.
Odze RD, Goldblum JR, editors. Odze and Goldblum
hyperplasia/microcarcinoidosis, response to
Surgical pathology of the GI tract, liver, biliary tract, and
neoadjuvant chemotherapy pancreas. 3rd ed. Philadelphia: Elsevier Saunders; 2015.
Pritchard SA. ACP best practice. Best practice in macro-
scopic examination of gastric resections. J Clin Pathol.
2008;61:172–8.
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Allen DC, Cameron RI. Histopathology specimens: Lauwers GY, Novelli MR, editors. Morson and
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Allum WH, Blazeby JM, Griffin SM, Cunningham D, The Royal College of Pathologists. Cancer datasets
Jankowski JA, Wong R. On behalf of the Association (oesophageal carcinoma, gastric carcinoma, carcino-
of Upper Gastrointestinal Surgeons of Great mas of the pancreas, ampulla of vater and common
Britain and Northern Ireland, the British Society bile duct, colorectal cancer, gastrointestinal stro-
of Gastroenterology and the British Association mal tumours (GISTs), liver resection specimens and
of Surgical Oncology. Guidelines for the man- liver biopsies for primary and metastatic carcinoma,
agement of oesophageal and gastric cancer. Gut. endocrine tumours of the gastrointestinal tract includ-
2011;60:1449–72. ing pancreas) and tissue pathways (gastrointestinal
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Brierley JD, Gospodarowicz MK, Wittekind C, editors. tions/cancer-datasets.html. Accessed Oct 2016.
TNM classification of malignant tumours. 8th ed. Wittekind C, Greene L, Hutter RVP, Klimfinger M, Sobin
Oxford: Wiley-Blackwell; 2017. LH. TNM atlas: illustrated guide to the TNM/pTNM
Cotton P, Williams C. Practical gastrointestinal endos- classification of malignant tumours. 5th ed. Berlin:
copy. 4th ed. London: Blackwell Science; 1996. Springer; 2005.
Pancreas, Duodenum, Ampulla
of Vater and Extrahepatic Bile 4
Ducts

4.1 Anatomy The mucosa of the duodenum is thick and

thrown into numerous circular folds called plicae
4.1.1 Duodenum circulares. The common bile duct and the major
pancreatic duct pierce the medial wall of D2,
The small intestine is divided into three parts: duo- approximately halfway along its length. At this
denum, jejunum, and ileum. The duodenum is point, there is a small elevation called the major
C-shaped and joins the gastric pylorus to the proxi- duodenal papilla (see below).
mal jejunum by curving around the head of the pan- Lymphovascular drainage:
creas. It is 25 cm long and receives the openings of The arterial supply originates from the coeliac
the common bile and pancreatic ducts. The proximal artery and the superior mesenteric artery (SMA).
2.5 cm is covered on its anterior and posterior sur- Venous drainage is to the portal system. The lym-
faces by peritoneum, the remainder being retroperi- phatics follow the course of the arteries, i.e.,
toneal. The duodenum, for purposes of description, those from the proximal half drain to the coeliac
is divided into four parts (D1–4). At the duodenoje- nodes and those from the distal duodenum drain
junal junction, the intestine turns forward—this to the superior mesenteric nodes via the periduo-
being called the duodenojejunal flexure. denal nodes.
P.J. Kelly (*) • M.B. Loughrey 4.1.2 P

ancreas, Ampulla of Vater,
Histopathology Laboratory, Institute of Pathology, and Extrahepatic Bile Ducts
Royal Victoria Hospital, Belfast Health and Social
Care Trust, Belfast, UK
e-mail: paul.kelly@belfasttrust.hscni.net; maurice. The pancreas is a soft lobulated retroperito-
loughrey@belfasttrust.hscni.net neal organ which is both an endocrine and
D.C. Allen exocrine gland. The exocrine portion produces
Histopathology Laboratory, Belfast City Hospital, enzymes (lipases, proteases) which are con-
Belfast Health and Social Care Trust, Belfast, UK veyed to the duodenum by the pancreatic duct
and are concerned with digestion. The endo-
R.I. Cameron crine portion (including the islets of
Langerhans) produces hormones such as insu-
Londonderry, UK lin and glucagon. The pancreas is subdivided
e-mail: iain.cameron@westerntrust.hscni.net as follows (Fig. 4.1):

38 P.J. Kelly et al.
Fig. 4.1 Pancreas (Used Portal Aorta

with the permission of the vein
Union for International
Cancer Control (UICC), Duodenum
Geneva, Switzerland. The
original source for this
material is from
Uncinate
process
Superior Head Body Tail

mesenteric
vein
Head—that part to the right of the left border of shaped dilated channel situated in the duodenal
the superior mesenteric vein (SMV). It lies wall. The ampulla opens into the duodenal lumen
within the concavity of the duodenum. The by the major duodenal papilla (Fig. 4.2). The dis-
uncinate process, a part of the head, extends to tal part of both ducts and the ampulla are sur-
the left posterior to the superior mesenteric rounded by muscle fibers, this being termed the
vessels. sphincter of Oddi. It is worth noting that the anat-
Body—lies between the left border of the SMV omy of the ampulla of Vater can vary greatly
and the left border of the aorta. between individuals. In some individuals a minor
Tail—lies to the left of the aorta and comes into ampulla can be recognized. This is smaller, con-
contact with the hilum of the spleen. Anteriorly nects Santorini’s duct with the duodenum and is
the pancreas has a thin covering capsule. located approximately 2 cm cranial to the ampulla
of Vater/duodenal papilla.
The extrahepatic bile ducts consist of the right The extrahepatic bile duct system may be sub-
and left hepatic ducts, common hepatic duct, and ject to a number of variations in its anatomy
common bile duct (Fig. 4.2). The hepatic ducts between individuals.
emerge from the porta hepatis of the liver and Lymphovascular drainage:
converge to form the common hepatic duct. This The arterial supply of the pancreas is from the
descends for 4 cm until it is joined from the right same vessels that supply the duodenum, and
side by the cystic duct when it becomes the com- venous drainage is to the portal system. The lym-
mon bile duct. This has an extrapancreatic por- phatics follow the arteries to the peripancreatic,
tion of approximately 2 cm following which it pancreaticoduodenal, and pyloric nodes, and ulti-
enters the pancreas posteriorly, close to the pan- mately to the coeliac and superior mesenteric
creatic neck. The common bile duct then travels nodes (Fig. 4.3).
through the pancreatic head in a curved fashion The arterial supply to the bile ducts is com-
before reaching the ampulla of Vater. The main plex, originating from both the coeliac and
pancreatic duct runs the length of the gland and SMAs. The lymphatics flow to the infrahepatic,
often merges with the common bile duct to form peripancreatic, periduodenal, coeliac, and supe-
the ampulla of Vater, which is a small flask- rior mesenteric nodes.
4 Pancreas, Duodenum, Ampulla of Vater and Extrahepatic Bile Ducts 39
Fig. 4.2 Ampulla of Calot’s triangle

Vater and extrahepatic
bile ducts (Used with the
for International Cancer Liver
Control (UICC),
Left hepatic duct
Right hepatic duct
Common hepatic
duct
Wittekind et al. (2005)) Cystic duct
Common bile duct
(cholecdochus)
Gall bladder
Ampulla of vater
Duodenal
papilla
4.2 Clinical Presentation leads to cholangitis with pain, fever, rigors, and
jaundice. If severe the cholangitis may become
The symptomatology of duodenal peptic ulcer- “ascending” and may cause liver abscesses.
ation has been discussed in Chap. 3. Duodenal Neoplasms of the head of pancreas (excluding
neoplasms, although rare, may lead to epigas- the uncinate process), ampulla of Vater, and
tric pain, gastric outlet obstruction, and obstruc- extrahepatic bile ducts often lead to obstructive
tive jaundice if present in the region of the jaundice. Tumours elsewhere in the pancreas do
ampulla. not and so will present later. Obstructive jaun-
Classically, acute pancreatitis presents with dice, because of a lack of absorption of fat and
severe epigastric pain which radiates to the back. increased excretion of bilirubin in the urine, leads
Chronic pancreatitis produces less acute, but to light-coloured faeces and dark urine. In gen-
often intractable, epigastric pain. Complications eral, pancreatic and bile duct neoplasms result in
of acute pancreatitis such as shock, infection of vague, poorly localized epigastric pain, anorexia,
necrotic tissue, bowel ileus, metabolic distur- and weight loss.
bance, and multiorgan failure produce character- Tumours of the endocrine pancreas may be
istic clinical features. non-functional or functional, the latter resulting
Bacterial infection in the bile ducts is usually in characteristic clinical features because of the
due to secondary infection of obstructed ducts and hormones they produce:
Fig. 4.3 Pancreas
and ampulla of Vater: 1
regional lymph nodes 2
are peripancreatic (1–4,
10
11), pancreaticoduodenal 11
(5–8), splenic hilar (10),
proximal mesenteric
(7), common bile
duct (9), and coeliac
(12) (Used with the 5 8
permission of the 11
Cancer Control (UICC),
4
The original source for 3
12
• Insulinoma—hypoglycaemic episodes, psy- • Urea and electrolytes (U and E)—electrolyte

chiatric/neurological symptoms imbalance may occur in acute pancreatitis and
• Gastrinoma—Zollinger–Ellison syndrome certain endocrine tumours.
• Glucagonoma—diabetes mellitus and skin rash • Serum amylase—elevated in acute
• VIPoma—watery diarrhoea, hypokalaemia, pancreatitis.
and achlorhydria (WDHA) syndrome • Clotting screen—may be deranged in
• Somatostatinoma—diabetes mellitus, hypo- obstructive jaundice because of lack of
chlorhyrdria, gallstones, diarrhoea/ absorption of fat-soluble vitamins which are
steatorrhoea. required in the synthesis of certain clotting
factors.
• Liver function tests—obstructive jaundice
4.3 Clinical Investigations picture (elevated alk phos and α GT—see
Chap. 10).
The investigation of duodenal peptic ulcer dis- • CA19–9—serum marker of pancreatic or bili-
ease is discussed in Chap. 3. ary tract malignancy.
• Serum gut hormone levels and octreotide iso- • Percutaneous FNAC or needle core biopsy—
tope uptake scan—pancreatic and duodenal may provide a preoperative diagnosis.
neuroendocrine tumours. • Staging laparoscopy with biopsy.
• Cyst fluid CEA—usually obtained by endo- • Doppler studies of the portal vein and angiog-
scopic ultrasound (EUS) and can aid in diag- raphy may be used to ensure that the vessels
nosis of mucinous lesions of the pancreas for are not involved by tumour.
example, intraductal papillary mucinous neo-
plasms (IPMNs) or mucinous cystic neo-
plasms (MCNs). 4.4 Pathological Conditions
• CXR—to detect pulmonary metastases.
• AXR—10% of gallstones are radio-opaque. 4.4.1 Non-neoplastic Conditions
Air in the biliary tree may also be seen if there
has been previous surgery or a biliary-intestinal Duodenum: Duodenitis and DU have been previ-
fistula. ously discussed—gastric metaplasia, or nodular
• USS—to diagnose acute pancreatitis and may gastric heterotopia in D1 and Brunner’s gland
detect gallstones in the bile ducts. Tumours hyperplasia are also encountered in biopsies of
less than 1 cm will not be detected. It will also the proximal duodenum. Biopsy for coeliac dis-
confirm the presence of obstructive jaundice ease is considered under small intestine.
by demonstrating dilated intrahepatic ducts. Ampulla of Vater: Inflammatory polyps of the
• CT (chest, abdomen, and pelvis) and MRI duodenal papilla are small, pedunculated, and
scan—will detect primary tumour and any often ulcerated. Partly traumatic in origin due to
metastatic spread. Magnetic resonance chol- passage of calculi from the biliary tree. Distinction
angiopancreatography (MRCP) can be used from neoplasia at OGD/ERCP can be difficult
for non-invasive imaging of the biliary tree. and biopsy is required.
• Percutaneous transhepatic cholangiogram Pancreas: The distal pancreatic duct forms a
(PTC)—another method of visualizing the common channel with the terminal common bile
bile ducts is by injecting contrast into the right duct in 50–60% of patients resulting in a strong
lobe of the liver. Can be used to obtain bile association between pancreatitis and biliary tract
duct cytology specimens, drain obstructed disease.
hepatic and hilar ducts and deploy stents Acute pancreatitis: With an overall mortality of
across central strictures. 10–15%, it is rarely biopsied or resected. The com-
• OGD/endoscopic retrograde cholangiopan- monest causes are gallstones, sphincter spasm, or
creatography (ERCP)—may be used for both incompetence with reflux of duodenal fluid and
diagnostic (biopsy/biliary brushings) and ther- bile, alcohol, trauma, and hypothermia. It is due to
apeutic purposes (see below). release of pancreatic enzymes comprising pancre-
• Cholangiopancreatoscopy (e.g. “Spyglass™”)— atic haemorrhage, necrosis, and inflammation with
allows direct visualization of bile ducts, includ- saponification and chalky c alcification of abdomi-
ing intrahepatic ducts and pancreatic duct. nal fat. It is usually a self-limiting process, but criti-
Has diagnostic and therapeutic applications cal complications include sepsis, shock, bowel
(see below). paralysis, or perforation. Treatment is resuscitative
• Endoscopic ultrasound (EUS)—used to evalu- and supportive—operative intervention can include
ate abnormalties of the pancreas and lower bili- removal of obstructing gallstones (by ERCP) or
ary tree, to evaluate potential resectability of infected necrotic tissue (necrosectomy).
pancreatic tumours and undertake FNA of focal Chronic pancreatitis: Commonly due to excess
lesions. Can be used in palliative setting to per- alcohol intake, there is correlation between radio-
form a coeliac plexus nerve block for pain. logical calcification, pancreatic endocrine and
• Peritoneal aspiration—for malignant cells in exocrine dysfunction, and the severity of histo-
ascitic fluid. logical changes. Complications include abscess,
systemic fat necrosis and pancreatic pseudocyst. Extrahepatic bile ducts: Stricture of the com-
Caused by disruption of the duct system due to mon bile duct may be caused by passage of a cal-
obstruction by calculus or tumour, a pseudocyst culus with or without ascending cholangitis and
has a thick fibrous wall lined by granulation tissue secondary infection, but is more usually after sur-
but no epithelium. It can rupture into the perito- gical trauma due to inadvertent injury to or liga-
neal cavity or splenic artery. Treatment is by tion of the duct. Treatment aims to reestablish
endoscopic or transabdominal drainage either free drainage of bile to the bowel either by a
internally to stomach or duodenum or externally bypass or stenting procedure (see below).
to skin. Surgical excision is used if small and
localized to the body or tail, or if the pseudocyst is
thick-walled and not appropriately sited for 4.4.2 Neoplastic Conditions
drainage.
The commonest biopsy expression of chronic Ampullary adenocarcinoma: Arising from ade-
pancreatitis is that seen adjacent to a pancreatic nomatous dysplasia of either the periampullary
tumour or secondary to an ampullary tumour due duodenal or intra-ampullary duct mucosae, it is
to duct obstruction. The acinar and stromal one of the commonest causes of death in familial
changes can mimic pancreatic carcinoma, mak- adenomatous polyposis (FAP) in patients who
ing interpretation difficult especially on frozen have had a prophylactic colectomy. Adenoma
section. Chronic pancreatitis tends to retain its may be amenable to local excision, but radical
lobular architecture, lacks malignant cytological surgical resection is often required for large
changes, and shows no invasion of nerve sheaths lesions and because a surface biopsy showing
or peripancreatic fat. epithelial dysplasia may harbour underlying
Autoimmune pancreatitis (AIP): This subtype invasive adenocarcinoma. Most cases have a
of chronic pancreatitis can present with abdomi- well-defined intestinal pattern, but in a minority
nal pain or with painless obstructive jaundice and it can be difficult to separate adenocarcinoma of
an apparent pancreatic mass on imaging thereby the duodenal papilla, ampulla, distal pancreatic
mimicking a pancreatic malignancy. Two sub- duct, and distal common bile duct as they can
types are recognized: Type 1 is associated with share similar well-to-moderately differentiated
elevated serum levels IgG4, a prominence of tubular and ductular patterns. Detailed examina-
IgG4 plasma cells in affected tissue, storiform tion of the exact anatomical location in the resec-
fibrosis and obliterative venulitis. It may occur in tion specimen is required and the primary site
association with extrapancreatic IgG4 related should be determined as duodenal, ampulla of
diseases. Type 2 tends to have normal IgG4 Vater (which includes the duodenal papilla), head
serum levels and is rarely associated with sys- of pancreas or distal common bile duct. This dis-
temic IgG4 disease. There is an association with tinction is important as the staging system and
inflammatory bowel disease (IBD). Histology choice of adjuvant therapy differs for each site. In
typically shows lymphoplasmacytic duct-centric practice this can be difficult to establish, espe-
inflammation with granulocytic epithelial lesions, cially if the tumour is large and involves more
or GELs. Both can be treated by steroids but may than one of these sites. In that scenario, the
come to surgery due to mimicry of malignancy. tumour origin can usually be established at gross
Benign pancreatic cysts: retention cysts, lym- examination by determining the epicentre of the
phoepithelial cysts, squamous lined cysts and tumour. Secondary involvement of the ampulla
pseudocysts may be encountered in surgical prac- by pancreatic cancer can occasionally be speci-
tice. These need to be carefully evaluated to fied based on the histological features and pattern
ensure that they are not neoplastic mucinous of mucosal spread. Ampullary adenocarcinomas
cysts (see below). Developmental cysts can also can have intestinal-type or pancreatobiliary-type
occur and include duodenal diverticula and fore- differentiation, the latter of which has a worse
gut cysts. prognosis. Immunohistochemistry can be used to
make the differentiation (intestinal-type: CK20+, form the vast majority of pancreatic tumours,
CDX2+, MUC2+; pancreaticobiliary: MUC1+, 80–90% are adenocarcinomas which are graded
MUC2−, CDX2−). according to the degree of gland formation. Most
Benign pancreatic non-mucinous neoplastic (70–80%) arise in the pancreatic head with a
cysts: serous cystadenoma (elderly, macro−/ minority in the body or tail and occasionally mul-
microcystic, fluid-filled, central scar, clear cuboi- tifocal. Perineural invasion is characteristic and
dal epithelium). Can occur in Von Hippel-Lindau diagnostically helpful in biopsies. There is lim-
syndrome. Acinar cell cystadenoma, lymphangi- ited suitability for resection (10–20% of cases are
oma may also occur. resectable at diagnosis). Resectable disease is
Cystic pancreatic exocrine lesions of malig- locally confined with absence of distant metasta-
nant potential: IPMNs and MCNs can exhibit a ses and clearance of the main surrounding arte-
benign, borderline, and malignant spectrum of rial and venous structures including superior
behaviour related to the degree of epithelial dys- mesenteric artery, vein and portal vein. Partial
plasia and extent of invasion into pancreatic involvement, distortion of or abutment of some of
parenchyma and peripancreatic fat. MCNs arise these vascular structures in the absence of distant
almost exclusively in middle-aged females, typi- metastases suggests borderline resectable dis-
cally in the pancreatic tail and unconnected to the ease. Patients with borderline resectable disease
pancreatic ductal system. They are characterized may undergo a trial resection or neoadjuvant che-
by the presence of mural ovarian-type stroma. motherapy or chemoradiotherapy. The presence
IPMNs are slightly more common in males, aged of distant metastases or encasement of the vessels
usually around 60 years, arise within the ductal renders a tumour unresectable. Pancreatic head
system but predominantly within the pancreatic tumours are removed by a Whipple’s procedure
head or uncinate process. Intra-ampullary IPMNs which results in an average increase in survival of
can also occur. By definition IPMNs communi- 12–18 months. Tumours of the body and tail of
cate with the ductal system. Three types of ductal the pancreas are resected via a distal pancreatec-
involvement are recognized: main, branch duct or tomy+/−splenectomy. Adjuvant chemotherapy
combined/mixed type i.e. involvement of both may be offered post operatively depending on the
the main duct and its branches. Both MCNs and outcome of pathological evaluation. For those
IPMNs typically show indolent growth but they patients with unresectable disease treatment is
may harbour small foci of invasive malignancy mainly palliative—palliative chemotherapy (if
(identified through careful or complete sampling) fit), pain control, nutritional support, and relief of
or show frank malignant transformation. jaundice by open or laparoscopic bypass, or
Resection of MCNs is recommended in fit endoscopic stent insertion to combat biliary
patients whereas IPMNs are managed according obstruction.
to established guidelines (e.g. Revised Sendai Other cancers: Unusual but include undiffer-
Guidelines) and are resected when certain criteria entiated carcinoma, adenosquamous carcinoma,
are met. Solid pseudopapillary neoplasm—low acinar cell carcinoma, small cell neuroendocrine
grade malignant tumour of uncertain cell origin. carcinoma, malignant lymphoma (usually from
An epithelial origin is suspected. Most com- an adjacent nodal lymphoma), and sarcoma,
monly presents in young females as a mixed which often represents spread from a primary
solid/cystic lesion composed of pseudopapillae sarcoma of gut or retroperitoneum. Renal clear
of uniform cells, cystic areas with necrosis and cell carcinomas have a propensity for metastasiz-
blood lakes. ing to the pancreas and may come to resection.
Pancreatic exocrine carcinoma: Arising from Pancreatic neuroendocrine tumours (NET):
dysplastic pancreatic duct epithelium (referred to Single or multiple and forming a minority (3%)
as pancreatic intraepithelial neoplasia—PanIN), of pancreatic tumours, they can be small
or a pre-existing mucinous lesion such as an (<1–2 cm), well circumscribed, and pale or yel-
IPMN or MCN as discussed above. Carcinomas low in colour. Occasionally cystic NETs occur.
Pancreatic NETs are positive for general neuro- Prognosis: Prognosis of pancreatic ductal ade-
endocrine markers (chromogranin, synaptophy- nocarcinoma is poor with an overall 10–20%
sin) and occasionally specific peptides, e.g., 5 year survival rate. Chemotherapy has an adjunc-
insulin, glucagon, gastrin, somatostatin or pan- tive and palliative role for select patients.
creatic polypeptide. Many (60–85%) are associ- Cystadenocarcinomas are relatively rare but
ated with a functional hormonal syndrome, e.g., potentially resectable. Pancreatic neuroendocrine
Zollinger–Ellison syndrome due to pancreatico- tumours have an indolent time course with a 50%
duodenal gastrinomas. The pancreas is also 10-year survival and potential chemoresponsive-
involved in 80–100% of type I multiple endo- ness even in the presence of metastases. Increased
crine neoplasia (MEN) syndrome comprising understanding of the molecular biology of pan-
hyperplasia or tumours of parathyroid, pituitary, creatic NETs has permitted the development of
adrenal glands, and pancreas (usually gastri- newer drugs such as mTOR inhibitors e.g. evero-
noma). Histology does not reliably predict behav- limus, to treat advanced disease. Ampullary carci-
iour and better indicators of potential malignancy noma has a 5 year survival of 25–50%, improving
are functionality and established metastases— to 80–85% if early stage (pT1) disease confined to
insulinoma (85% benign), gastrinoma (60–85% the sphincter of Oddi. Distal bile duct cancers
malignant), size >3 cm, site (e.g., duodenal), may be potentially resected with 25% 5-year sur-
tumour grade, invasion of vessels, nodes, adja- vival. Sclerosing bile duct carcinoma at the hilum
cent organs, and liver. Detection of metastases is (Klatskin tumour) can have an indolent course,
by CT and octreotide scans. Determination of but the majority of bile duct cancers present late
tumour grade on needle core biopsy (mitotic with very limited survival and only palliative bili-
count and Ki-67 index) indicates likely behaviour ary drainage (open bypass or laparoscopic/endo-
and influences their oncological management. scopic/percutaneous stent insertion) is justified.
Extrahepatic bile duct carcinoma: These are
typically adenocarcinomas (often referred to as
cholangiocarcinomas) and show an increased 4.5 Surgical Pathology
incidence in association with various disorders Specimens: Clinical Aspects
including ulcerative colitis, sclerosing cholangi-
tis, gallstones, and congenital bile duct anoma- 4.5.1 Biopsy Specimens
lies. The majority (50–75%) arise in the upper
third (including the hilum) with lesser numbers The endoscopic technique for the diagnosis of
in the middle and distal thirds (10–25% each) or benign lesions of the duodenum has been dis-
even diffuse and multifocal. Extrahepatic bile cussed previously. Endoscopic biopsy of duode-
duct carcinomas are classified and staged as peri- nal and ampullary tumours is by OGD, or
hilar (proximal to the origin of the cystic duct to ERCP. The ERCP scope differs from OGD in that
include the right, left and main hepatic ducts) or the camera views from the side (lateral view) and
distal (distal to the insertion of the cystic duct; not from the end (forward view), as in the gastro-
cystic duct carcinoma is included under gallblad- scope. This allows the major duodenal papilla to
der carcinoma). Sometimes papillary or polypoid be viewed directly. The papilla is then cannulated
but often nodular, ulcerated, sclerotic, or stric- and contrast injected at intervals to outline the
tured, prognosis relates to the stage of disease, duct system and radiographs, which appear on a
location, and histological grade. There is charac- monitor, are taken in real time to check the posi-
teristic perineural invasion often with involve- tion of the catheter. The bile duct (cholangiogra-
ment of regional lymph nodes, peritoneum, or the phy) and the pancreatic duct (pancreatography)
liver (upper third tumours) at presentation. Other are cannulated in turn and radiographs taken,
rare cancers are carcinoid tumour, malignant which may provide clues to the aetiology of the
melanoma, lymphoma/leukaemia, and in child- condition, e.g., stones, stricture, etc. ERCP has
hood embryonal rhabdomyosarcoma. several diagnostic and therapeutic applications:
The following diagnostic specimens can be not involve major vessels, and has not metasta-
taken by ERCP: sized on imaging, then a curative procedure may
be considered.
• Bile and pancreatic juice for cytology. Although the type of operation will depend on
• Brushings from the ducts for cytology. the site and size of tumour, the curative procedure
• Biopsies from the ampulla of choice for duodenal, ampullary, distal com-
ERCP can also be used for therapeutic mon bile duct, and pancreatic head tumours is a
procedures: standard Kausch–Whipple pancreaticoduodenec-
• Sphincterotomy (division of the sphincter of tomy (PD)—Whipple’s procedure.
Oddi) can be performed in patients with a his- This procedure involves a transverse subcos-
tory of common bile duct stones to allow free tal incision and initial exploration to assess oper-
drainage ability. It then involves the en bloc resection of
• Stone extraction can be performed using a bal- the pancreatic head (with a variable amount of
loon catheter or basket body depending on the location and size of the
• Dilatation of stricture using a balloon tumour), distal two-thirds of the stomach, duo-
catheter denum (and proximal 10 cm of jejunum), gall-
• Both benign and malignant biliary strictures bladder, and common bile duct (Fig. 4.4a), which
may be stented (a palliative procedure in the may be extended proximally for distal common
latter) to reduce jaundice. bile duct tumours. There are many methods (up
• ERCP is not without its complications, two of to 70!) of reconstruction after PD. One of the
the most common being acute pancreatitis most popular is the formation of the following
(1–3% of cases) and cholangitis. (Fig. 4.4b):
Cholangiopancreatoscopy is a more modern 1 . Pancreaticojejunostomy (end to end)

technique and allows direct visual diagnostic 2. Hepaticojejunostomy (end to side)—anasto-
evaluation of the pancreatic duct and bile ducts mosis of the hepatic duct to the jejunum
using a fibreoptic camera. This overcomes many 3. Gastrojejunostomy (end to side)
of the limitations of ERCP and permits more 4.
Jejunojejunostomy (side to side)—this
detailed assessment of abnormalties, such as stric- decompresses the proximal jejunal loop and
tures, and targeted sampling of lesions (brushings reduces jejuno-gastric reflux
and direct biopsy using forceps). Similar to ERCP
there are several therapeutic applications includ- If there is involvement by tumour of the body
ing stent insertion and removal, endoscopic resec- and tail, the procedure can be modified to a total
tion of lesions, tumour ablation therapy, and PD which includes resection of the body and tail
biliary drainage. of the pancreas ± the spleen.
For some small ampullary and periampullary
(i.e., head of pancreas, distal common bile duct,
4.5.2 Resection Specimens and duodenum) tumours, a pylorus-preserving
PD is performed. This is essentially identical to a
4.5.2.1 Neoplastic Lesions: Duodenum, standard PD except that the distal stomach and
Ampulla, Distal Common Bile proximal 3 cm of duodenum are left in situ, thus
Duct, and Exocrine Pancreas retaining the food storage and release functions
At the time of presentation, pancreatic carci- of the stomach.
noma is beyond resection in more than 80% of A distal pancreatectomy consists of resection
patients. Also, given the advanced age of presen- of the body and tail of the pancreas, usually
tation in the vast majority of patients, over 95% including the spleen. This procedure may be used
of cases are treated palliatively. However, if the for tumours—many benign—which are located
patient is fit, the tumour locally confined, does in the distal pancreas.
a b
Fig. 4.4 Whipple’s procedure: (a) limits of resection and (b) reconstruction anastomoses (Reproduced, with permis-
sion, from Allen and Cameron (2013))
In all the above procedures, the pancreatic denum-preserving resection of the pancreatic
resection margin may be sent for frozen section head) for proximal tumours. A PD procedure
examination to ensure adequate excision. is only rarely required for large tumours in the
head of pancreas or duodenum.
4.5.2.2 Neoplastic Lesions
of the Endocrine Pancreas 4.5.2.3 Neoplastic Lesions
The goals of surgery for tumours of the endocrine of the Extrahepatic Bile Ducts
pancreas are twofold: Cancer of the bile ducts (cholangiocarcinoma) is
treated palliatively in 80–90% of cases and resec-
• To locate and excise all abnormal tissue tion should only be considered in localized
• To differentiate between benign and malig- tumours without metastatic spread. When surgi-
nant tumours by conducting a search for meta- cal resection is considered, the type of procedure
static deposits will depend on the site of tumour:
Localization of tumours may be carried out
by a combination of preoperative imaging • Tumours in the distal common bile duct (i.e.,
(MRI, octreotide scanning) and intraoperative lying behind the duodenum and pancreas)—
palpation and USS. Once the tumour has been Whipple’s procedure.
localized, there are two main methods of • Tumours proximal to this and distal to the
excision: confluence of the right and left hepatic ducts—
• Enucleation—Excision of the tumour and a wide excision of the supraduodenal biliary
surrounding segment of normal pancreas can tree, gallbladder, and related nodes. A length
be carried out if the tumour is small (<1.5 cm) of jejunum is isolated in a Roux-en-Y loop
and superficial. and an end-to-side hepaticojejunal anastomo-
• Resection—For larger tumours which are sis allows biliary drainage.
deep-seated, a formal pancreatic resection is • Tumours proximal to the hepatic confluence
required, i.e., a distal pancreatectomy for distal require the above plus a relevant liver resec-
tumours or a proximal pancreatectomy (duo- tion (see Chap. 10).
Palliation for distal common bile duct tumours Bile duct stones may be removed laparoscopi-
is most commonly done by ERCP stenting. Other cally or by an open procedure if they cannot be
methods of operative palliation (i.e., “by-pass” removed by ERCP. Strictures may be stented or
techniques) are: bypassed using one of the techniques described
above.
• Choledochoduodenostomy—proximal com-
mon bile duct is anastomosed to D1.
• Hepaticojejunostomy—can be used in more 4.6 Surgical Laboratory
proximal biliary tumours (i.e., common Specimens: Laboratory
hepatic duct/proximal common bile duct). Protocols
For proximal biliary (hilar) tumours, a seg- 4.6.1 B

iopsy and Local Mucosal
ment III hepaticojejunostomy can be used. In this Resection Specimens
the liver is divided to the left of the falciform
ligament until the segment III duct is visualized. See Chap. 1.
An anastomosis is then fashioned between this
and a Roux-en-Y loop of jejunum.
4.5.2.4 Non-neoplastic Lesions
Two of the most common complications of acute Specimen
pancreatitis requiring surgical intervention are:
• Most pancreatic resections are for neoplastic
• Necrotizing pancreatitis—Surgical interven- conditions, although operative intervention may
tion has a mortality rate of 60% and involves be indicated for debridement of necrotic tissue
removal of necrotic tissue from the pancreas in acute pancreatitis, trauma to a major duct, or
and retroperitoneal spaces, and drainage of removal of the pancreatic head or pseudocyst in
fluid collections. chronic pancreatitis. Resections are either local
• Pancreatic pseudocyst—cystogastrostomy—a for pseudocyst or cystic neoplasms, or radical
pseudocyst in the lesser sac is drained into the for ampullary, pancreatic head or bile duct can-
stomach via an opening in the posterior wall cers. Radical excision is also undertaken for
of the stomach. many cystic lesions due to concerns regarding
• In chronic pancreatitis, the following proce- neoplasia. Carcinoma of the body and tail usu-
dures may be employed: ally presents late and is typically irresectable.
• The pain associated with chronic pancreatitis • To demonstrate the lesion and its relationship
is caused by obstruction of the pancreatic duct to the surgical margins, the pancreas is cut
leading to duct hypertension. The Frey opera- into multiple parallel slices, preferably in the
tion (localized resection of the pancreatic head horizontal plane (to allow correlation with CT
and side to side pancreaticojejunostomy) is scan cross-sectional images). In some cases
designed to decompress the duct. vertical or coronal planes can be used.
• When there is disruption of the duct distal to Specimens may be opened longitudinally
the head, a distal pancreatectomy is indicated. through the stomach and duodenum to aid
• Occasionally, when the disease is maximal fixation prior to complete dissection. A small
in the head, a Whipple’s procedure may be number of axial incisions may be made, if
employed, possibly when investigations are required for biobanking etc., taking care to
equivocal regarding malignancy. Another assess for potential margin involvement.
option would be a duodenum-preserving • The presence of any stent or surgically labeled
resection of the pancreatic head or total structures, e.g., portal vein, SMV, should be
pancreatectomy. noted.
4.6.2.1 Local Resection of Cystic 4.6.2.4 Distal Pancreatectomy (Fig. 4.5)

Lesions • Orientate—cut end is proximal, distal end is
• Weight (g) and maximum dimension (cm). uncut ± spleen.
• Capsule: intact/deficient/smooth/nodular/ • Weight (g) and measurements—length ×
adhesions/circumscribed/lobulated. width × depth (cm).
• Cut surface: uni−/multilocular/septate/solid • Paint the proximal cut margin and the external
areas (cm)/contents—fibrin, mucoid, serous surfaces using different colours of ink for the
fluid. various anatomical and surgical aspects—
• Photograph. superior, inferior, anterior capsule, posterior
• Paint the external surface. retroperitoneal.
• Fixation by immersion in 10% formalin for 48 h. • Fixation by immersion in 10% formalin for
• Sample at least one block per centimetre diam- 48 h.
eter of the tumour/cyst to include thin, nodular, • Transverse section the proximal margin to
and solid areas of its wall and internal aspect. include the duct.
If the cystic lesion is suspected to be an IPMN • Serially section the pancreas at 3–4 mm inter-
or MCN and there is no obvious macroscopic vals in a perpendicular plane to its long axis. If
invasive disease it is preferable to submit the a cystic neoplasm is suspected a probe can be
entire lesion for histological evaluation to inserted into and along the main pancreatic
exclude or identify microscopic invasion. duct and the specimen sliced parallel along the
• Sample adjacent tissues to include the resec- probe. This can aid the assessment of the rela-
tion margins and any other structures. tionship of the cystic lesion to the pancreatic
ductal system. It is perfectly acceptable to slice
4.6.2.2 Local Resection of Pancreatic the specimen using the perpendicular slicing
Head in Chronic Pancreatitis method above.
• Weight (g) and dimensions (cm): then fix in • Lay the slices out in sequence and
10% formalin for 48 h. photograph.
• Serially slice perpendicular to the pancreatic • Tumour: size (cm), edge (circumscribed/irreg-
duct. ular), appearances, consistency, relationship
• Inspect and describe, e.g., haemorrhage, to the pancreatic duct, distances (mm) to the
abscess, necrosis, calculi, calcification. specimen edges.
• Select five representative blocks, assuming no • Sample a minimum of five blocks of tumour
suspicion of malignancy on macroscopic in relation to pancreas, pancreatic duct, peri-
examination. pancreatic fat and its margins, and spleen. If a
cystic lesion is identified it is preferable to
4.6.2.3 Necrosectomy Specimen submit the entire lesion as invasive disease
• Number of pieces, total weight (g), and maxi- (early carcinomas) and ovarian–type stroma
mum dimension (cm). (MCNs) may be missed using a limited sam-
• Fix in 10% formalin for 48 h. pling protocol.
• Serially slice, inspect, and describe, e.g. • Sample all regional lymph nodes, non-
haemorrhage, abscess, necrosis, calculi, calci- neoplastic pancreas and spleen (if present).
fication, tissues present.
• Select five representative blocks.
Fig. 4.5 Distal
pancreatectomy Serial section in a plane
(Reproduced, with perpendicular to the long
permission, after axis of pancreas
Allen and Cameron
(2013))
Spleen
PM
PD
PPF
4.6.2.5 Whipple’s Procedure (Figs. 4.6 and inked prior to slicing (see Fig. 4.6). It is
and 4.7) also advisable to sample the bile duct and pan-
Initial procedure: creatic transection margins prior to slicing.
• Sample the following surgical margins: proxi-
• Open with scissors by cutting along the lesser mal gastric, distal duodenal, pancreatic transec-
curvature of the stomach and the free border tion margin taking care to include the pancreatic
of the duodenum. duct, and, proximal common bile duct.
• Measurements: • Trim off the uninvolved, “excess” parts of the
Lengths (cm) of distal sleeve of stomach and duodenal and gastric wall to leave a small cuff
duodenum, and parts present (D1–4). around the pancreas. This renders the speci-
Dimensions (cm) of pancreas, and parts present men more compact and easier to slice and
(head, body, attached named vessel, e.g., SMV). examine. Do not remove duodenal tissue if
Lengths of gallbladder (if attached) and bile involved by tumour (Figs. 4.6 and 4.7).
duct (cm). • Place the specimen flat on the bench and with
• Fixation by immersion in 10% formalin for 24 h. a long, sharp knife horizontally slice the speci-
• Paint the external anatomical and surgical men into parallel slices 4–5 mm thick
margins using different colours of ink and (Fig. 4.7). Lay the slices out in order from
labeled appropriately—anterior, posterior, superior to inferior, number/label and photo-
SMV, SMA and pancreatic transection mar- graph (if possible to aid sign out and tumour
gin. The surgical margins should be identified board/multidisciplinary meeting discussion). It
Fig. 4.6 “Trimmed”
specimen demonstrating
important margins in a
Whipple’s procedure
(Reproduced, with
permission, Royal College
of Pathologists and Paul
Brown, Medical CBD
Illustrator, Leeds Teaching
Hospitals NHS Trust). PM
CBD common bile duct,
PD pancreatic duct, PM
pancreatic transection PD
margin
Posterior
Anterior surface
surface
SMA
surface
SMV
surface
a S
Fig. 4.7 (a, b) Whipple’s

procedure for carcinoma Pylorus
of ampulla of Vater, head
of pancreas or distal CBD
common bile duct. PM
Modified and reproduced
with permission after DP PD
Allen and Cameron
DP duodenal
(2013), Verbeke (2008,
papilla
2013). (b) Serial
horizontal slices and Serial section in
number slices for a horizontal plane
photography, subdivision D
and harvesting of blocks
Fig. 4.7 (continued) Anterior
b
Common
bile duct
SMV
Posterior
Tumour
SMA
is useful to identify the common bile duct and • Sampling is best performed by following the
pancreatic duct in each slide, as appropriate, and numerical or sequential order of the slices (see
assess the relationship of the tumour mass to above under “Initial procedure”). This makes
these structures to determine the tumour origin. it easier to evaluate the 3-dimensional profile
• Further 24 h fixation may be required. and verify the origin of the tumour during
Description: microscopic evaluation.
• Tumour • Tissue samples are best taken to include the
–– Site: duodenum/ampulla/pancreas (duct/ tumour and neighbouring structures such as
parenchyma)/bile duct margins and lymph nodes. In this regard it is
–– Size: length × width × depth (cm) or maxi- often helpful to submit the most representative
mum dimension (cm) slices from the pancreas in their entirety (as
Appearance: composite blocks, or megablocks, if local
Polypoid/diffuse/ulcerated—ampullary/ resources permit). Lymph nodes should not be
bile duct tumours. dissected out from the pancreatic tissue at this
Cystic/papillary/mucoid/scirrhous/thicken- stage but instead sampled along with adjacent
ing—pancreatic exocrine tumours. pancreatic parenchyma. The position of the
–– Circumscribed/pale/homogeneous—pan- node in the specimen i.e. slice number and clos-
creatic neuroendocrine tumours est margin, can also be recorded and will facili-
–– Edge: circumscribed/irregular tate identification of duplicate nodes (which
• Pancreatic and bile ducts: dilatation/stenosis/ may straddle multiple slices) and assignment of
extrinsic or intraduct tumour/stent lymph node station, if required.
• Pancreas: indurated/oedematous/fat necrosis • Perigastric lymph nodes will not be repre-
• Peripancreatic lymph nodes: location/number/size sented in the slices above. The perigastric fat
• Other organs: involvement of SMV, duode- should be separately examined for nodes and
num or stomach etc. those identified submitted.
Blocks for histology (Fig. 4.7): • Sample non-neoplastic pancreas, stomach,
• Resection margins (see above). and duodenum.
• The peripancreatic fat often contains numer- duct limit or the hepatic resection margin (two
ous small lymph nodes that may not be visible or three blocks).
or palpable during macroscopic examination. • Paint the external adventitial CRM.
After sampling all other blocks as outlined • Serially section the specimen transversely at
above it can be useful to submit the remaining 3–4 mm intervals.
peripancreatic fat separately. • Sample five or six blocks to demonstrate the
• If other organs are present (total or regional worst point of tumour invasion in relation to
pancreatectomy—PD, gastrectomy, splenec- the CRM, liver, gallbladder, proximal and dis-
tomy, portal vein, transverse colectomy, meso- tal surgical limits. If liver resection with peri-
colon, omentum, and regional nodes): describe, hilar tumour, identify and sample obvious
weigh, measure, paint, and block according to infiltration of the main portal vein or hepatic
the macroscopic degree of tumour spread. artery branches (Chap. 10).
Label the blocks as to their site of origin. • Sample all lymph nodes.
4.6.2.6 Distal Extrahepatic Bile Duct Histopathology report:

Cancer Resection • Tumour type
• Bile duct segment –– Ampulla/bile duct: adenocarcinoma (sub-
–– Site: common bile duct/common hepatic divide as intestinal-type or pancreatobili-
duct/cystic duct. For main right, main left ary type using immunohistochemistry; see
or common hepatic duct refer to perihilar section “Neoplastic Conditions”).
staging system (Chap. 10). For tumours of –– Pancreas: adenocarcinoma/neuroendocrine
the cystic duct refer to gallbladder staging tumour/other. If other, please specify type
system (Chap. 9). e.g. adenosquamous
–– Length × diameter (cm) • Tumour differentiation/grade:
–– Dilated/ulcerated/strictured/cyst and maxi- –– Ampullary/bile duct adenocarcinoma:
mum dimension (cm) of lesion well/moderate/poor.
–– Calculi –– Pancreatic carcinoma:
• Tumour
–– Maximum dimension (cm) Well/grade 1 >95% glands
–– Site: common bile duct/common hepatic Moderate/grade 2 50–95% glands
Poor/grade 3 5–50% glands
duct/right or left hepatic duct/cystic duct/
Undifferentiated/grade 4 <5% glands
intraduct/mural/extramural/involvement of
liver
–– Appearance: strictured/ulcerated/nodular/ • Tumour edge
polypoid/multifocal • Pushing/infiltrative/lymphoid response.
• Hepatic resection (more commonly encoun- • Assessment of response to neoadjuvant ther-
tered in perihilar bile duct cancers) apy, if relevant.
–– Segment(s) • Extent of local tumour spread: TNM 8 for carcinoma
–– Dimensions (cm) and maximum dimension Ampulla of Vater.
(cm) of tumour present
–– Identify bile duct margins pTis Carcinoma in situ
• Biliary stent pT1 Tumour pT1a. limited to the ampulla or
sphincter of Oddi, or, pT1b. perisphincteric
–– Not present/present/placement (within or invasion and/or into duodenal submucosa
outside the lumen). pT2 Tumour invades muscularis propria of
• Gallbladder duodenum
–– Present/not present/involved by tumour. pT3 Tumour invades pancreas: pT3a. ≤0.5 cm, or,
• Sample the distal bile duct limit (circumferen- pT3b. >0.5 cm or peripancreatic tissue/
duodenal serosa
tial transverse section) and the proximal bile
pTis Carcinoma in situ pN0 No regional lymph node metastasis

pT4 Tumour invades superior mesenteric artery or pN1 Metastasis in 1–3 regional lymph node(s)
coeliac axis, or common hepatic artery pN2 Metastasis in 4 or more regional lymph nodes
Pancreas—carcinoma of exocrine pancreas or

high-grade neuroendocrine carcinoma (well • Ampulla of Vater: pN1 = 1–2nodes,
differentiated neuroendocrine tumours should pN2 ≥ 3nodes
be staged according to ENETS TNM system; • Excision margins
TNM8 staging may be supplied for compari- Proximal gastric and distal duodenal limits of
son. ENETS is European Neuroendocrine tumour clearance (cm).
Tumour Society). Distal pancreatic surgical margin/common
bile duct margin of tumour clearance (mm)—
pTis Carcinoma in situ also comment on pancreatic intraepithelial
pT1 Tumour limited to the pancreas, ≤2 cm neoplasia (PanIN).
maximum dimension
Peripancreatic edge tumour clearance (mm)—
pT2 Tumour limited to the pancreas, >2 cm and
≤4 cm dimension transection margin, superior mesenteric vein,
pT3 Tumour >4 cm dimension superior mesenteric artery/uncinate, anterior
pT4 Tumour involves coeliac axis, SMA and/or capsule, posterior.
common hepatic artery For extrahepatic bile duct cancer—tumour
clearance (mm) of the distal and proximal bile
duct, hepatic and radial resection margins.
Distal extrahepatic bile ducts—(for tumour dis- • Other pathology
tal to the insertion of the cystic duct; perihilar Duodenal adenoma (s), secondary pancreatitis,
tumours are classified separately—chap. 10) fat necrosis, calculi, ulcerative colitis, scleros-
ing cholangitis, choledochal cysts.
pT1 Tumour invades bile duct wall <5 mm depth
pT2 Tumour invades bile duct wall 5–12 mm depth
pT3 Tumour invades bile duct wall >12 mm depth
pT4 Tumour involves the coeliac axis, SMA and/or Bibliography
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Small Intestine
5
Derek C. Allen, R. Iain Cameron,
5.1 Anatomy Duodenum
The small intestine is the longest part of the gas-

trointestinal tract and is divided into the duode-
num (discussed previously), jejunum, and ileum Jejunum
(Fig. 5.1). It is primarily concerned with diges-
tion and absorption of food. Together the jeju-
num and ileum measure approximately 6 m
(jejunum 2.5 m/ileum 3.5 m) in the adult. The
jejunum commences at the duodenojejunal junc-
tion (flexure) and the ileum ends at the ileo-cae-
cal valve (two horizontal folds of mucosa that Ileum
project around the orifice of the ileum as it joins
the caecum). A fan-shaped fold of peritoneum Fig. 5.1 Small intestine (Used with the permission of the
Union for International Cancer Control (UICC), Geneva,
(the small intestinal mesentery) attaches the
Switzerland. The original source for this material is from
small intestine to the posterior abdominal wall. Wittekind et al. (2005))
The long edge of the mesentery completely

D.C. Allen (*) encloses the intestine, allowing it to be mobile,
Histopathology Laboratory, Belfast City Hospital, while the short “root,” which is attached to the
posterior abdominal wall, admits blood vessels,
lymphatics, and nerves which supply the intes-
R.I. Cameron
tine by traversing the mesentery.
Western Health and Social Care Trust, Although there is a gradual change from jeju-
Londonderry, UK num to ileum, in general, the jejunum tends to be
e-mail: iain.cameron@westerntrust.hscni.net located in the upper part of the abdominal cavity,
M.B. Loughrey is thicker walled with more prominent plicae cir-
Histopathology Laboratory, Institute of Pathology, culares (permanent mucosal folds), and has more
numerous Peyer’s patches (aggregations of lym-
e-mail: maurice.loughrey@belfasttrust.hscni.net phoid tissue).

56 D.C. Allen et al.
Histologically the mucosa of the small intes- two epithelial-lined structures) may occur includ-
tine projects into the lumen in the form of finger- ing an enterovesical fistula (between small intes-
like structures covered by absorptive columnar tine and urinary bladder) which leads to gas in
epithelium. These projections are called villi and the urine (pneumaturia) and repeated urinary
increase the surface area for absorption. The cir- tract infections. Enterocolic and enteroenteric
cular and longitudinal muscle layers are (between adjacent small bowel loops) fistulae
continuous. may also occur. Enterocutaneous fistulae usually
Lymphovascular drainage: only happen after previous surgery. One of the
The arterial supply of the jejunum and ileum differential diagnoses of a right iliac fossa mass
is from the superior mesenteric artery. Numerous is Crohn’s disease with a peri-intestinal abscess
intestinal branches run in the mesentery and around the distal ileum.
anastomose with one another to form “arterial Several conditions, including Crohn’s disease,
arcades,” which in turn supply the intestine. may lead to a protein-losing enteropathy, result-
Venous drainage is via the superior mesenteric ing in generalized oedema. Coeliac disease pres-
vein to the portal system. Lymphatics traverse ents in young children as a failure to thrive and in
through a series of mesenteric nodes and ulti- middle-aged adults with unexplained weight loss
mately drain to the superior mesenteric nodes or iron-deficiency anaemia. Melanin spots may
situated at the origin of the superior mesenteric be seen in the buccal mucosa and lips of those
artery. with Peutz–Jegher’s syndrome.
5.2 Clinical Presentation 5.3 Clinical Investigations
Patients with small intestinal disease may present • U&E—electrolyte imbalance due to
with vague symptoms and signs such as poorly malabsorption.
localized dull central (periumbilical) abdominal • LFTs/albumin—liver enzymes may be
pain. If there is full thickness inflammation, the deranged in Crohn’s disease and hypoalbu-
peritoneal somatic pain receptors are stimulated minemia will occur in protein-losing
and the pain becomes more severe and localized. enteropathy.
A patient with an obstructing lesion will classi- • Folate, B12, and iron studies—pernicious
cally present with vomiting, colicky abdominal anemia in Crohn’s disease.
pain (cramps), absolute constipation (i.e., neither • Erect CXR—air under the diaphragm in a
flatulence nor faeces passed per rectum), and perforation.
abdominal distension. • Erect and supine AXR—will detect gas shad-
Bleeding into the lumen of the small intestine ows and fluid levels in distended loops of
may lead to hypovolaemic shock and altered small intestine in obstruction.
blood (melaena) per rectum. Intussusception pro- • Small bowel series—radiological contrast is
duces a mixture of blood and mucus—“redcurrant drunk and abdominal images are taken at reg-
jelly stool,” particularly in infants. Perforation, ular intervals to outline the mucosal surface of
although rare (e.g., trauma, Meckel’s diverticu- the small intestine and to measure the transit
lum), will lead to a generalized peritonitis. A time. This is particularly useful for obstructing
heart murmur or irregular pulse may provide a lesions and Crohn’s disease, and may also
diagnostic clue in embolic small intestinal detect a Meckel’s diverticulum.
infarction. • Barium enema—will demonstrate an ileo-
The presentation of Crohn’s disease may be colic intussusception and may be used as a
insidious or acute, with symptoms including therapeutic procedure (see below).
diarrhoea, anorexia, and weight loss. Various • Sinogram/fistulogram—useful to delineate the
forms of fistulae (abnormal connection between extent of the complications of Crohn’s disease.
5 Small Intestine 57
• CT scan—useful in delineating an abdominal T-cell lymphoma, EATCL) or adenocarcinoma.

(e.g., right iliac fossa) mass. Other conditions can produce similar histological
• Radioisotope scanning—can be used in cases changes, e.g., Giardia lamblia infestation, lac-
of repeated gastrointestinal haemorrhage of tose intolerance, or postinfective enteritis, but are
unknown aetiology and will localize hetero- not gluten sensitive. Giardia is a kite-shaped flag-
topic gastric mucosa in a Meckel’s diverticu- ellate protozoon present in the intervillous
lum. Radiolabeled red blood cells may show a mucus, causing diarrhoea with or without muco-
site of active bleeding. sal inflammation—it typically affects children or
• Selective arteriography (superior mesen- the elderly.
teric)—will aid identification of a site of small Crohn’s disease (regional enteritis): a pan-
intestinal bleeding. This may detect angiodys- gastrointestinal inflammatory condition of uncer-
plasia of the small intestine providing the tain aetiology, lesions can occur anywhere from
bleeding rate is greater than 2 mL/min. the mouth to the anus. It is characterized by seg-
• Enteroscopy—allows direct visualization of mental, transmural chronic inflammation associ-
small intestinal mucosa. ated with linear and fissuring ulceration, and, in
• Distal duodenal biopsy and serology (anti- 40% of cases, non-caseating epithelioid and giant
endomysial (EMA) and tissue transglutamin- cell granulomas present either in the mucous
ase (tTG) antibodies)—in coeliac disease. membrane, bowel wall, or regional lymph nodes.
The terminal ileum, ileum and colon, or colon
alone, are affected in decreasing order of fre-
5.4 Pathological Conditions quency. Macroscopically the classical features
are skip lesions comprising stenotic ring stric-
5.4.1 Non-neoplastic Conditions tures and hosepipe segments, serosal fat
encroachment (fat wrapping), fissure ulcers with
Duodenitis and duodenal ulcer (DU): HP distal fistulae to other organs, and abscess formation,
gastritis leads to hyperchlorhydria, duodenitis and, ulceration that can be pinpoint (aphthous),
with surface gastric metaplasia, colonization by linear, or contiguous. Perianal fissures or fistulae
HP, and further duodenitis and ulceration. are also often present. Due to its segmental distri-
Occurring mainly in the cap and first part of the bution, subsequent recurrence elsewhere in the
duodenum, DU is invariably benign and only gut is not infrequent. Complications can be gas-
rarely biopsied at laparotomy for perforation if trointestinal, e.g., adenocarcinoma or malignant
its mucosal edges are irregular. DU is success- lymphoma, or extraintestinal, such as liver dis-
fully treated by HP eradication—occasionally it ease, amyloidosis, or arthritis.
is due to other causes, e.g., NSAIDs, Crohn’s dis- Other causes of ileitis include backwash ileitis
ease, or Zollinger–Ellison syndrome. in ulcerative colitis, ileo-caecal tuberculosis, or
Coeliac disease: Traditionally investigated by yersinial infection. Viral adenitis of the mesen-
Crosby capsule biopsy of the proximal jejunum, teric lymph nodes can also mimic ileitis or appen-
it is now assessed by a combination of coeliac dicitis. Relatively common viral or bacterial
serology and distal duodenal biopsies taken at gastroenteritis rarely provide histopathology
flexible oesophagogastroduodenoscopy (OGD). material. Immunodeficency, e.g., HIV AIDS
Cardinal features are an excess of surface intraep- predisposes to various opportunistic infections
ithelial lymphocytes, lamina propria inflamma- (Giardia lamblia, mycobacterium avium intra-
tion, villous atrophy, and crypt hyperplasia. cellulare, cytomegalovirus, etc.) and malignan-
Diagnostic proof is by clinical improvement on a cies (malignant lymphoma, Kaposi’s sarcoma)
gluten-free diet and deterioration on subsequent that need to be considered on duodenal or termi-
rechallenge. Coeliac disease involves the entire nal ileal biopsy.
small intestine and can be complicated by malig- Meckel’s diverticulum: In 2% of people, 2 in.
nant lymphoma (usually enteropathy-associated long, 2 ft from the ileo-caecal valve, and, “too”
important to forget, this is a remnant of the fetal Diaphragm disease: Due to chronic ingestion
vitellointestinal duct comprising an outpouching of NSAIDs, it comprises multiple diaphragm-like
of the ileal wall on its antemesenteric border with mucosal ring strictures with variable lumen ste-
or without a fibrous cord attaching it to the umbi- nosis and intervening compartmentalization and
licus. Its wall is continuous with the ileal muscle sacculation. The strictures have a triangular
coat and the small intestinal lining not infre- cross-sectional profile of fibrovascular connec-
quently shows heterotopic gastric or pancreatic tive tissue and are probably partly ischaemic in
tissue. Complications (4% of cases) include peptic nature. Presentation is with subacute obstruction.
diverticulitis with ulceration, haemorrhage or per- Ischaemia: Acute, subacute, or chronic,
foration, intussusception, or rarely malignancy. depending on the nature, severity, and rapidity of
Obstruction: Broadly, small intestinal obstruc- onset of the cause. Acute ischaemia is character-
tion is either due to loss of peristaltic bowel ized by haemorrhagic necrosis of bowel wall that
movement (paralytic ileus), or mechanical in becomes paper-thin and gangrenous with subse-
nature. Ileus is commonly seen in the postopera- quent electrolyte imbalance, sepsis, and shock.
tive period of abdominal surgery and is self- Chronic ischaemia comprises ulcerated segments
limiting, although it is also encountered in or strictures with replacement of bowel wall by
various metabolic disturbances and can be diffi- fibrovascular connective tissue, evidence of sec-
cult to manage—histopathology specimens are ondary vascular thickening, and haemosiderin
rarely provided. Mechanical obstruction is due to deposition. Examination of these specimens must
blockage of the bowel lumen or distortion of its include assessment of resection limit viability
wall. Common causes are primary or secondary and any abnormality of the mesenteric vessels.
malignancy, ulceration with ring stricture/dia- Common causes are arterial, such as mesenteric
phragm formation (Crohn’s disease, NSAIDs), artery embolism or thrombosis (particularly if
incarceration within a hernia, or extrinsic com- superimposed on a low flow state due to mesen-
pression by postoperative adhesions or fibrous teric atheroma or cardiogenic hypotension), or
bands. The proximal bowel dilates, fills with venous thrombosis. The latter is usually due to
fluid, and ultimately becomes atonic—sepsis or obstruction of venous flow by bowel entrapment
ischaemia are possible complications. Particular within a hernia or kinking of its mesentery by a
forms of enteric obstruction are volvulus, where fibrous band or adhesion resulting from previous
a loop of bowel twists around its mesenteric ped- surgery. Less usual causes of ischaemia are sys-
icle and, intussusception, where a lumenal or temic vasculitis (e.g., polyarteritis) or amyloid
mural abnormality (e.g., tumour) acts as a nidus deposition which thickens and occludes mesen-
for peristalsis to propel a proximal segment (the teric and mural vessels. Drugs must always be
intussusceptum) forward and inside a receiving considered as a cause of isolated ulcers or chronic
distal segment (the intussuscipiens). The intus- ischaemic segments, especially NSAIDs.
susception can be benign or malignant in nature Hernia: Herniation of the bowel can be either
and variable in site, e.g., ileal–ileal or ileal–cae- internal or external. Internal hernias are into ana-
cal. Handling of all these specimens is targeted at tomical spaces, e.g., the lesser omental sac or
determining the nature of the obstructing abnor- across fibrous bands, which can be acquired
mality, its distribution and completeness of exci- (postoperative) or congenital (e.g., persistent
sion, and the presence and extent of secondary vitellointestinal duct). External hernias involve
changes such as inflammation or ischaemia. protrusion of the peritoneum ± bowel into the
Inflammatory fibroid polyp: An inflammatory layers of the abdominal wall (particularly at the
mucosal pseudotumour of unknown aetiology site of a previous surgical incision), groin, or
that can form the apex of an intussusception, it femoral canal. They can be intermittent and
comprises oedematous and inflamed fibrovascu- reducible or irreducible with the risk of second-
lar granulation tissue with an infiltrate of ary ischaemic changes. The surgical specimens
eosinophils. are dealt with elsewhere (see Chap. 11).
Non-neoplastic polyps: In the duodenum these tumour is of intermediate grade malignancy met-
include gastric heterotopia, Brunner’s gland astatic potential relating to size (>1–2 cm), angio-
hyperplasia/hamartoma, and pancreatic heteroto- invasion, invasion beyond the submucosa, and
pia. Small intestine is the commonest site for functionality. It produces vasoactive peptides,
Peutz–Jegher’s syndrome, which is autosomal e.g., serotonin, that cause vascular thickening and
dominantly inherited, comprising oral pigmenta- elastotic stromal fibrosis which distorts the bowel
tion and pan-gastrointestinal polyposis—the pol- wall and mesentery with characteristic spiculate
yps have a branching smooth muscle core and CT appearances leading to subacute obstruction
twisting of the polyp can produce glandular her- or intussusception. Metastatic deposits in the
niation into the submucosa and mimicry of ade- liver result in the peptides accessing the systemic
nocarcinoma. The terminal ileum can show venous circulation and carcinoid syndrome—
mucosal nodular lymphoid hyperplasia which is facial flushing, asthma, and thickening of cardiac
usually of unknown aetiology but occasionally valves. Carcinoid tumours can be ulcerated or
linked to immunodeficiency. A protruberant ileo- nodular, and are usually yellow. Other neuroen-
caecal valve or fatty hyperplasia of its submucosa docrine lesions occur in the duodenum and
can simulate a tumour on radiological investiga- include gastrinoma as part of Zollinger–Ellison
tion, and, if not adequately investigated by colo- syndrome, somatostatinoma, and gangliocytic
noscopy and biopsy, can lead to unnecessary paraganglioma, both of which may be associated
right hemicolectomy. with von Recklinghausen’s syndrome
(neurofibromatosis).
Malignant lymphoma: Solitary or multifocal,
5.4.2 Neoplastic Conditions primary or secondary to systemic nodal disease,
the vast majority are non-Hodgkin’s in type.
Forming less than 10% of all bowel tumours, Established disease is ulcerated, segmental, and
duodenal/jejunal lesions tend to be adenomas or rubbery or fleshy in appearance. Many are
adenocarcinoma, whereas carcinoid tumour and MALT-derived of B cell character and variably
malignant lymphoma have a predilection for the low or high grade, prognosis relating to the grade
ileum. and stage of disease. Unusual variants of malig-
Adenoma: Relatively unusual in the small nant lymphoma include multiple lymphomatous
bowel but commoner in D2, particularly in FAP polyposis (ileo-colonic nodular polyps of mantle
where there is a strong association with periam- cell lymphoma), ileo-caecal Burkitt’s lymphoma
pullary adenocarcinoma. Surgical removal is in children and immunosuppressed patients, and
either by endoscopy or duodenotomy with thor- EATCL. EATCL is strongly associated with coe-
ough assessment of the ampullary region to liac disease, either occult or clinically established
exclude underlying tumour that would necessi- of short or long duration. Presentation can be
tate radical resection. Adenomas can also occur with perforated ulcerative jejunitis, a change in
sporadically in the jejunum or ileum giving rise response to the gluten-free diet (“refractory” coe-
to adenocarcinoma. liac disease) or with abdominal pain/mass.
Adenocarcinoma: Duodenal cancers (70% of Gastrointestinal stromal tumours (GISTs):
cases) are often polypoid, while distal lesions are Spindle or epithelioid cell in type, a minority are
ulcerated and napkin-ring-like. Presentation is leiomyomatous or neural, and a majority stromal
late, with regional lymph node metastases and (CD117 (ckit)/DOG-1 positive) in character
serosal involvement due to the fluid content of derived from interstitial cells of Cajal, which
the small bowel and consequent lack of symp- regulate peristalsis. Malignancy cannot be accu-
toms. Prognosis is poor and incidence is increased rately predicted but indicators are size (>2–5 cm),
in Crohn’s disease and coeliac disease. cellularity and atypia, tumour necrosis and haem-
Carcinoid (well-differentiated neuroendo- orrhage, and infiltrative margins and mitotic
crine) tumour: Single or multiple, carcinoid activity (>5/50 high power fields). Small
intestinal GISTs tend to behave more aggres- 5.5 Surgical Pathology

sively than their equivalent gastric counterparts Specimens: Clinical Aspects
with spread to the abdominal peritoneum and
liver. The tumour can be polypoid, mural, or 5.5.1 Biopsy Specimens
dumbbell-shaped with an extramural component.
Occasionally they arise primarily in the small Biopsy specimens can be obtained from the ileo-
bowel mesentery or retroperitoneum with no caecal valve and terminal ileum by colonoscopy,
attachment to gastrointestinal wall. and from the duodenum by flexible OGD. They
Metastases: The small intestine is particularly can also be obtained during laparotomy by either
prone to involvement by metastatic adenocarci- enteroscopy or wedge resection of a serosal lesion.
noma either from other abdominopelvic sites, In enteroscopy, an incision is made in the wall of
e.g., stomach, pancreas, colorectum, and ovary, the small intestine and an endoscope is passed
or due to distant spread, e.g., lung, breast, malig- along the small intestinal lumen to view the region
nant melanoma. Deposits can be nodular, ulcer- of interest. The endoscope can also be introduced
ate or stricture the bowel wall mimicking a orally and the surgeon can guide it through the
primary lesion—designation as a primary small stomach and small intestine during a laparotomy.
intestinal adenocarcinoma therefore necessitates
exclusion of spread from a more common site or
evidence of a point of origin, e.g., an adjacent 5.5.2 Resection Specimens
mucosal adenoma, although colonization of the
mucosal surface by a metastatic adenocarcinoma Although small intestine may be resected as part
deposit may mimic a primary tumour. of another procedure, e.g., right hemicolectomy, in
Alternatively the deposits may be as diffuse peri- primary small bowel resection, the goals of sur-
toneal seedlings detected at CT scan or at lapa- gery are removal of the lesion and restoration of
roscopy. Malignant melanoma can be intestinal continuity. However, the exact procedure
pigmented. will depend on the type of lesion to be dealt with:
Prognosis: Small bowel adenocarcinoma is
unusual being 50 times less common than 5.5.2.1 Neoplastic Conditions
colorectal cancers. Presentation is late, with poor Tumours: The type of resection will depend on
prognosis (10–30% 5-year survival). Carcinoid the site of the tumour, e.g., a distal tumor will
tumour has an overall 5-year survival rate of require a right hemicolectomy. For more proxi-
50–65% with smaller (<1–2 cm), early lesions, mal lesions, the operation of choice is a local
confined to the bowel wall being more favour- resection with en bloc resection of a wedge of
able. Prognosis is better for low-grade B cell mesentery (Fig. 5.2). At least 5 cm of intestine on
lymphomas (44–75% 5-year survival) than high- either side of the tumour should be removed with
grade B or T cell lymphomas (25–35% 5-year an end-to-end anastomosis to reestablish continu-
survival) and is strongly grade and stage depen- ity. Occasionally a hamartomatous polyp may be
dent. GISTs are of intermediate behaviour, and removed by making a longitudinal elliptical inci-
unresectable/metastatic lesions respond to tar- sion in the intestinal wall to include the base of
geted therapy with the tyrosine kinase inhibitors the polyp. Closure should be done transversely to
such as imatinib (Glivec) leading to tumour avoid luminal narrowing.
shrinkage, cystic degeneration, and hyaliniza-
tion. Neoadjuvant treatment may be considered 5.5.2.2 Non-neoplastic Conditions
to downstage a surgically unresectable GIST and Small intestinal resection in non-neoplastic con-
permit resection. ditions is essentially similar to that for neoplastic
< 5cm > < 5cm > Incision line
Stretching/retraction of wall
Suture
line
Small intestinal
mesentery Fig. 5.3 Small-intestinal stricturoplasty (Reproduced,
with permission, from Allen and Cameron (2013))
Fig. 5.2 Resection of tumour in small intestine
(Reproduced, with permission, from Allen and Cameron
(2013))
until there is active bleeding from the ends that
are going to form the anastomosis. A primary
disease in that the affected length of intestine is anastomosis may be fashioned or in cases of
resected with continuity being restored by a extensive intraperitoneal leakage or uncertain
hand-sewn end-to-end anastomosis. Some spe- intestinal viability, an ileostomy (or jejunostomy)
cific conditions are discussed below: and distal mucus fistula can be fashioned.
Crohn’s disease: Small bowel resection is Essentially an ileostomy (or jejunostomy) is pro-
usually reserved for those individuals for whom duced by bringing the cut opened end of the
medical treatment has failed or who are suffering intestine out through an opening in the abdomi-
complications, e.g., obstruction (due to stric- nal wall where it is sutured in place. A special
tures), peri-intestinal abscess, fistula formation, ileostomy bag is then fitted to collect the
or perforation. Essentially the extent of resection effluent.
is limited to the macroscopically involved intes- Meckel’s diverticulum: They are usually only
tine as extensive resection does not reduce the resected if symptomatic or found incidentally
risk of recurrent lesions and may lead to short during another procedure. Essentially the diver-
bowel syndrome if subsequent resections are ticulum is excised with the opening in the intesti-
necessary. nal wall closed in a transverse fashion to avoid
If there are multiple areas of stricturing, these luminal narrowing. If the diverticulum is large or
need not be resected in order to preserve intesti- broad based, a limited ileal resection may be
nal length. Instead, a “widening procedure” required.
called a stricturoplasty may be employed. In this Intussusception: Barium enema can be used
procedure, the strictured region is incised longi- both as a diagnostic procedure, and if the reser-
tudinally, the walls retracted, and the incision voir of barium is elevated 1 m above the abdo-
then sutured transversely (Fig. 5.3). men, hydrostatic reduction under radiological
Infarction: At laparotomy, the infarcted intes- screening can be attempted as a therapeutic pro-
tine will appear dusky and should be resected cedure. Reduction is signified when barium flows
freely to the proximal loops of ileum. If hydro- • Inspect and describe the diverticulum (espe-
static reduction fails, or there is evidence of per- cially its tip), e.g., heterotopic mucosa, ulcer-
foration/peritonitis, operative management is ation, perforation, abscess, fibrous bands, or
indicated. In this reduction may be facilitated by tumour.
squeezing the distal colon and pushing the intus- • Inspect and describe the ileal segment, e.g.,
suscepted intestine proximally. If this is unsuc- inflammation, ischaemia, or signs of
cessful, then resection of the affected segment intussusception.
should be carried out. • Transverse section the proximal and distal
ileal limits of resection or ileal/diverticulum
base.
5.6 Surgical Pathology • Sample normal appearing ileum, diverticu-
Specimens: Laboratory lum, and its tip.
Protocols • Sample additional blocks as indicated by any
macroscopic abnormalities present.
5.6.1 Biopsy Specimens
5.6.2.2 Ischaemia
See Chap. 1. Formal Crosby capsule jejunal biop- • Measurements: Small bowel segment—length
sies are larger than flexible OGD distal duodenal and maximum diameter (cm). Mesentery—
samples. They are usually submitted on filter length × depth (cm).
paper to allow orientation and inspection of the • Inspect and describe: hyperaemia/duskiness
mucosal surface under a dissecting microscope of the serosa, perforation, constriction bands
and correlation with histology. Finger-like, cere- across the bowel or mesentery.
briform, and mosaic patterns correspond to nor- • Open longitudinally with blunt-ended scissors
mal, partially atrophic, and flat mucosae, along the mesenteric border—inspect for
respectively. mucosal thinning, ulceration, haemorrhage,
necrosis, perforation, stricture formation, or
any underlying tumour that might have pre-
5.6.2 Resection Specimens cipitated volvulus or intussusception.
• Fix by immersion in 10% formalin for 36–48 h.
Specimen: • Transverse section the proximal and distal
limits of resection.
• Resection of small intestine can be for specific • Sample (two blocks minimum) representative
conditions such as Meckel’s diverticulum or macroscopically normal and abnormal areas
ischaemia or, for obstruction due to various as indicated (Fig. 5.5).
inflammatory, mechanical and neoplastic • Sample mesentery with constituent vessels.
disorders. • Sample mesenteric lymph nodes.
5.6.2.1 Meckel’s Diverticulum 5.6.2.3 Obstructive Enteropathy

• Measurements: Ileal base or segment— • The resection specimen is dictated by the
length × diameter (cm). Diverticulum— site and nature of the abnormality and extent
length × diameter (cm). of any complications that are present. For
• Open the ileum longitudinally with blunt- example, jejunal ring diaphragm disease
ended scissors along its mesenteric border results in resection of the radiologically and
opposite the diverticulum, and then cut at macroscopically involved segment, whereas
right angles to this along the diverticulum Crohn’s terminal ileitis produces a limited
toward its tip (Fig. 5.4). Photograph before right hemicolectomy. Intussusception com-
and after dissection. plicated by ischaemia needs a more exten-
• Paint the external aspect of the diverticulum and sive resection than would be otherwise
fix by immersion in 10% formalin for 36–48 h. necessary. A cancer operation will necessi-
Fig. 5.4 Meckel’s Tip perforation or heterotopic tissue

diverticulum—
specimens (Reproduced,
with permission, from
Allen and Cameron
(2013))
a
b b
Planes of
opening
a a
Sample the surgical resection margins (a), body (b) and tip (c) of the diverticulum
Ischemic perforation macroscopically to distinguish between

inflammatory and neoplastic ulcers or stric-
tures—handling of the specimen must
therefore cover these v arious options pend-
ing histopathological assessment.
Initial procedure:
• Open longitudinally with blunt-ended scissors
along the mesenteric border, avoiding any
obvious areas of tumour or perforation.
• Measurements:
Transverse section the surgical limits and the Lengths and maximum diameter (cm) of the
bowel to represent normality and any lesion parts present—duodenum, jejunum, ileum,
that is present. Sample the mesenteric vessels
caecum, ascending colon, and appendix.
Fig. 5.5 Small bowel ischemia (Reproduced, with per- Lengths (cm) of ischaemic, strictured, or
mission, from Allen and Cameron (2013)) hosepipe segments, intussusception.
Maximum dimensions (cm) of any
tate more radical dissection of mesentery perforation(s), ulcer(s), polyp(s), and tumour(s).
and regional lymph nodes. In some Distances (cm) of the abnormality from the
instances, it is not possible clinically or proximal and distal resection limits.
• Photograph. –– Adjacent atrophic mucosa—EATCL

• Gently pack the bowel lumen with formalin- –– Edge: circumscribed/irregular.
soaked lint and fix by immersion in 10% for- • Crohn’s disease: cobblestone mucosa/ulcer-
malin for 48 h. ation (aphthous, linear, confluent)/ring stric-
Description: tures/hosepipe segments/fat wrapping/
• Tumour fistula/polyps or tumour/lymphadenopathy/
–– Site: duodenal/jejunal/ileal/ileo-caecal valve. sharp demarcation at the ileo-caecal valve/
–– Lumenal/mural/extramural/mesenteric. caecal or colonic disease/adhesions/abscess
–– Size: length × width × depth (cm) or maxi- formation.
mum dimension (cm). • Diaphragm disease: ring strictures—number,
–– Appearance: Polypoid/nodular—inflam- width, lumen aperture, intervening saccula-
matory fibroid polyp, carcinoid, malignant tion, mucosal ulceration.
melanoma, adenoma, carcinoma, multiple • Extrinsic compression: constriction band/
lymphomatous polyposis, GIST. extrinsic tumour/lumen stenosis/mucosal
–– Ulcerated/stricture—carcinoma, carcinoid, ulceration/proximal dilatation.
malignant lymphoma, metastatic carcinoma. • Intussusception: apex (inflammatory fibroid
–– Fleshy/rubbery—GIST, malignant polyp, tumour, Meckel’s, mesenteric lymph-
lymphoma. adenopathy)/ischaemia/perforation/ileo-ileal/
–– Multifocal—metastases (carcinoma, mela- ileo-caecal.
noma), carcinoid, malignant lymphoma. Blocks for histology (Fig. 5.6):
Mesenteric lymphadenopathy
Taenia coli
Caecum Terminal Serosal fat

ileum wrapping
Appendix
1. Transverse section the surgical limits

Fig. 5.6 Right 2. Process the appendix as usual
hemicolectomy for 3. Sample normal ileum and colon
Crohn’s disease 4. Sample representative blocks of the
hose pipe segment, any ulceration and adjacent mucosa.
(Reproduced, with
5. Sample mesenteric lymph nodes
permission, from Allen
and Cameron (2013))
Non-neoplastic conditions • Intussusception

Apex (tumour)/secondary ulceration, stric-
• Sample by circumferential transverse sections ture, ischaemia or perforation/site (ileo-ileal/
the proximal and distal limits of resection. ileo-caecal).
• Sample macroscopically normal bowel. • Neoplastic conditions
• Sample representative blocks (a minimum of • Tumour type—adenocarcinoma/malignant
five) of any abnormality that is present to lymphoma/GIST
include its edge and junction with the adjacent • Tumour differentiation
mucosa, e.g., ulceration, stricture, fistula, per- –– Adenocarcinoma—well/moderate/poor
foration, serosal adhesions or constriction –– Malignant lymphoma—MALToma/mantle
band, intussusception apex. These can be taken cell/follicular/Burkitt’s/other, low grade/
transversely or longitudinally depending on high grade
the anatomy and the abnormality present. –– GIST—spindle cell/epithelioid cellularity/
• Sample mesenteric lymph nodes and any adja- atypia/necrosis/mitoses/margins/size
cent structures, e.g., caecum, appendix, or • Tumour edge—pushing/infiltrative/lymphoid
ileo-caecal valve. response.
Neoplastic conditions • Extent of local tumour spread: TNM 8: for
• Sample the nearest longitudinal resection mar- carcinoma. Well differentiated neuroendocrine
gin if tumor is present to within <2 cm of it. tumours and gastrointestinal stromal tumours
• Sample macroscopically normal bowel—usu- of the small intestine have separate TNM 8
ally one section but several if a multifocal staging schemes.
condition, e.g., FAP or EATCL, is suspected.
• Serially section the bulk of the tumour trans- pTis Carcinoma in situ
versely at 3–4 mm intervals. pT1 Tumour invades lamina propria/muscularis
• Lay the slices out in sequence and photograph. mucosae (pT1a) or submucosa (pT1b)
• Sample (four blocks minimum) tumour and pT2 Tumour invades muscularis propria
wall to show the deepest point of circumferen- pT3 Tumour invades through the wall into
tial invasion. With tumours <1 cm diameter, subserosa or non-peritonealised perimuscular
connective tissues (mesentery or
fewer blocks will be possible. Include adja-
retroperitoneum)
cent mucosa where feasible. pT4 Tumour perforates the serosa or invades other
• Count and sample all lymph nodes—identify organs/structures, e.g., small bowel loops,
a suture tie limit node. mesentery/retroperitoneum or abdominal wall
• Sample multifocal serosal tumour seedlings as by way of serosa
indicated by inspection and palpation.
• Histopathology report:
• Ischaemia • Lymphovascular invasion—present/not present.
Necrosis—mucosal/transmural/gangrenous • Regional lymph nodes: A regional lymphade-
Resection limits—ischaemic/viable nectomy will ordinarily include 6 or more
Mesenteric vessels—thrombosis/embolism/ lymph nodes.
vasculitis Duodenum: pancreatioduodenal, pyloric,
Miscellaneous—constriction band/volvulus/ hepatic, superior mesenteric nodes.
intussusception/stricture Ileum/jejunum: mesenteric.
• Crohn’s disease Terminal ileum: ileo-colic, posterior caecal.
Chronic transmural inflammation/granulo-
mas/fissures/fistulae/abscess formation/ileal pN0 No regional lymph node metastasis
confined/ileo-caecal/appendiceal or resection pN1 Metastasis in 1–2 regional lymph node(s)
pN2 Metastasis in 3 or more regional lymph nodes
limit disease/malignancy
• Excision margins ogy dissection. Available via http://www.ibms.org.uk/.

Accessed Oct 2016
Proximal, distal, and mesenteric limits of
tumour clearance (cm). surgical pathology of the GI tract, liver, biliary tract,
• Other pathology and pancreas. 3rd ed. Philadelphia: Elsevier Saunders;
• FAP, Peutz-Jegher’s, Crohn’s disease, caeliac 2015.
Riddell RH, Petras RE, Williams GT, Sobin LH. Tumors
disease, EATCL.
of the intestines, Atlas of tumor pathology, vol. 3rd
series. Fascicle 32. AFIP: Washington, DC; 2003.
Shepherd NA, Warren BF, Williams GT, Greenson JK,
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Dawson’s gastrointestinal pathology. 5th ed. Oxford:
Allen DC. Histopathology reporting. Guidelines for surgi- Wiley-Blackwell; 2013.
cal cancer. 3rd ed. London: Springer; 2013. The Royal College of Pathologists. Cancer datasets
Allen DC, Cameron RI. Histopathology specimens: (oesophageal carcinoma, gastric carcinoma, carcino-
clinical, pathological and laboratory aspects. 2nd ed. mas of the pancreas, ampulla of vater and common
Berlin: Springer; 2013. bile duct, colorectal cancer, gastrointestinal stromal
Bosman FT, Carneiro F. WHO classification of tumours of tumours (GISTs), liver resection specimens and liver
the digestive system. 4th ed. Lyon: IARC Press; 2010. biopsies for primary and metastatic carcinoma, endo-
Brierley JD, Gospodarowicz MK, Wittekind C, editors. crine tumours of the gastrointestinal tract including
TNM classification of malignant tumours. 8th ed. pancreas) and tissue pathways (gastrointestinal and
Oxford: Wiley-Blackwell; 2017. pancreatobiliary pathology, liver biopsies for the inves-
Dudley H, Pories W, Carter D, editors. Rob and Smith’s tigation of medical disease and for focal liver lesions).
operative surgery: alimentary tract and abdominal Available via https://www.rcpath.org/profession/publi-
wall. 4th ed. London: Butterworths; 1993. cations/cancer-datasets.html. Accessed Oct 2016
Institute of Biomedical Science/The Royal College of Wittekind C, Greene L, Hutter RVP, Klimfinger M, Sobin LH.
Pathologists. IBMS guidance to candidates and train- TNM atlas: illustrated guide to the TNM/pTNM classifica-
ers for advanced specialist diploma in lower GI pathol- tion of malignant tumours. 5th ed. Berlin: Springer; 2005.
Colorectum
6
6.1 Anatomy right lobe of liver. Here it becomes continuous

with the transverse colon by turning sharply to
The colon and rectum together measure between the left, forming the right colic or hepatic flexure.
125 and 140 cm in the adult. The colon is divided The ascending colon is bound to the posterior
into the caecum (10 cm) and ascending (15 cm), abdominal wall by peritoneum covering its front
transverse (40 cm), descending (25 cm), and sig- and sides. The transverse colon extends from the
moid (25–40 cm) colons. The rectum measures hepatic flexure to the left, hanging downward and
approximately 13–15 cm (Fig. 6.1). The main then ascending to the inferior surface of the
function of the colon is absorption of water and spleen, where it turns sharply downward to form
electrolytes and the storage of faecal material the left colic or splenic flexure. The transverse
until it can be excreted. The caecum is that part colon is completely surrounded by peritoneum
that lies below the ileocaecal valve and receives with the transverse mesocolon being attached to
the opening of the appendix. It is mostly sur- its superior border (the length of the transverse
rounded by peritoneum, allowing it to be mobile mesocolon accounts for the variability in the
in the right iliac fossa. The base of the appendix position of the transverse colon) and the greater
is attached to the posteromedial surface of the omentum to its lower border. The descending
caecum. The ascending colon extends upward colon extends downward from the splenic flexure
from the caecum to the inferior surface of the to the left side of the pelvic brim. It is bound to
the posterior abdominal wall by peritoneum cov-
ering its sides and front. The sigmoid colon is
continuous with the descending colon and hangs
D.C. Allen (*) as a loop into the pelvic cavity. It is completely
Histopathology Laboratory, Belfast City Hospital, surrounded by peritoneum and a fan-shaped
e-mail: derek.allen@belfasttrust.hscni.net piece of mesentery attaches it to the posterior
abdominal wall, thus allowing mobility. The rec-
R.I. Cameron
Histopathology Laboratory, Altnagelvin Hospital, tum begins as a continuation of the sigmoid colon
Western Health and Social Care Trust, in front of the third sacral vertebra and follows
Londonderry, UK the curvature of the sacrum and coccyx to where
e-mail: iain.cameron@westerntrust.hscni.net it pierces the pelvic floor to become continuous
M.B. Loughrey with the anal canal. Peritoneum covers the ante-
Histopathology Laboratory, Institute of Pathology, rior and lateral surfaces of the upper third and the
Care Trust, Belfast, UK anterior surface of the middle third, the lower
e-mail: maurice.loughrey@belfasttrust.hscni.net third being devoid of a peritoneal covering. At

Fig. 6.1 Colorectum Transverse colon

(Used with the
permission of the Union Splenic flexure
Control (UICC),
Geneva, Switzerland. Hepatic flexure
The original source for Descending colon
Wittekind et al. (2005)) Ascending colon
Caecum Sigmoid colon
Appendix Recturn
Fig. 6.2 Rectosigmoid
and peritoneal reflection Peritoneum
(lateral view) (Used Uterus Rectosigmoid junction
with the permission of
the Union for
International Cancer Bladder
Control (UICC),
Geneva, Switzerland. Rectum
Anus
Vagina
the junction of the middle and lower third, the • The wall of the colon is sacculated, whereas
peritoneum is reflected onto the posterior surface the small intestine is smooth.
of the upper vagina in the female to form the rec- • The colon has “fatty tags” called appendices
tovaginal pouch (pouch of Douglas) and onto the epiploicae.
upper part of the posterior bladder in the male, • The permanent mucous membrane folds (pli-
forming the rectovesical pouch (Fig. 6.2). The cae circulares) in the small intestine are not
extent of serosal covering in the colorectum is present in the colon.
illustrated in Fig. 6.3. The rectum is surrounded
by a bilobed encapsulated fatty structure which is Microscopically the colonic mucosa is made
bulkier posterolaterally than anteriorly—the up of tubular crypts lined by columnar epithelium
mesorectum. with mucin-secreting goblet cells and endocrine
The small and large intestines differ in their cells also being present.
appearance in a number of ways: Lymphovascular drainage:
Embryologically the gastrointestinal tract is
• The longitudinal muscle in the small intestine divided into three segments (fore, mid, and hindgut)
forms a continuous layer, whereas in the colon with each region being supplied by its own artery:
it comprises three bands called taeniae coli.
However, in the rectum, the taeniae coli come • Coeliac artery supplies the foregut (distal
together to form a broad band on the anterior oesophagus to the mid-portion of the second
and posterior surfaces. part of the duodenum).
6 Colorectum 69
Retroperitoneal (posterior) surface • Superior mesenteric artery supplies the mid-

a
gut (mid-portion of the second part of the duo-
denum to the junction of the proximal
two-thirds and distal third of the transverse
Peritoneal colon).
* reflection
• Inferior mesenteric artery supplies the hindgut
(distal third of the transverse colon to the
junction of the superior and inferior half of the
anal canal).
The rectum is also supplied by branches of the

Serosal surface
internal iliac artery. The anastomosis of the colic
arteries around the concavity of the colon forms
“Bare” area the marginal artery. The venous drainage of the
b colon is to the portal venous system and the rec-
tum to the inferior mesenteric and internal iliac
Sigmoid veins.
mesentery The lymphatics accompany the colic vessels
draining to the superior and inferior mesenteric
nodes. Those from the rectum drain into nodes
(pararectal nodes) situated in the perirectal con-
nective tissue (mesorectum) and thence to the
superior mesenteric and internal iliac nodes
(Fig. 6.4).
6.2 Clinical Presentation

c
There is considerable variability in the clinical
presentation of colorectal disease.
Angiodysplasia usually presents with persis-
tent occult bleeding or repeated small bleeds. In
colonic ischaemia/infarction there may be a his-
tory of arrhythmia or cardiac failure, and it may
present acutely with abdominal pain and bloody
diarrhoea or less acutely with stricturing and
symptoms of obstruction. Infective conditions
usually lead to diarrhoea, crampy abdominal
pain, and fever. A careful antibiotic drug history
Fig. 6.3 Extent of serosal covering of the large intestine. should be obtained if pseudomembranous colitis
Arrows indicate the “bare” non-peritonealized areas of is suspected. Inflammatory bowel disease may
different levels. (a) The ascending and descending colon
are devoid of peritoneum on their posterior surface. (b) have an indolent presentation with lethargy,
The sigmoid colon is completely covered with perito- anorexia, and weight loss. However, more char-
neum, which extends over the mesentery. (c) The lower acteristic symptoms of ulcerative colitis include
rectum lies beneath the pelvic peritoneal reflection. The bloody diarrhoea (>10 stools/day), urgency, and
asterisks in (a) indicate the sites where serosal involve-
ment by tumour is likely to occur (Reprinted, with permis- abdominal pain. Peritonitis and systemic sepsis
sion, from Burroughs and Williams (2000)) may occur with toxic megacolon and perforation.
rectum (may cause pruritis ani), tenesmus (a sen-

sation of incomplete evacuation), and electrolyte
loss (particularly potassium). Colorectal carci-
noma is usually asymptomatic early in its exis-
tence and later may present with nonspecific
symptomatology such as an alteration in bowel
habit, mucus PR, abdominal mass or discomfort,
and PR bleeding (may be occult and can lead to
iron-deficiency anaemia). As a rule, the more
proximal the tumour, the darker the blood.
Tumours in the right colon are more likely to be
ulcerated and so tend to present with PR bleed-
ing, whereas tumours of the left colon are often
constrictive and present with obstruction—this is
compounded by the fact that the faecal material is
more solid in the distal colon. Perforation may
occur either through the tumour itself or distant
and proximal to it due to obstruction and back
pressure, e.g., in the caecal pouch. Rectal tumours
can lead to tenesmus and local invasion may pro-
Fig. 6.4 Colorectum: regional lymph nodes are the peri- duce back pain and sciatica (involvement of the
colic, perirectal and those along the ileocolic, right colic, sacral plexus), rectovaginal fistula, etc. Liver
middle colic, left colic, inferior mesenteric, superior rectal metastases may cause clinical jaundice.
(haemorrhoidal) and internal iliac arteries. (Used with
permission of the Union for International Cancer Control
(UICC), Geneva, Switzerland. The original source for this
material is from Wittekind et al. (2005)) 6.3 Clinical Investigations
• FBP—iron-deficiency anaemia as a result of

Colorectal Crohn’s disease characteristically PR bleeding.
presents with diarrhoea. Obstruction due to stric- • U&E—electrolyte disturbance in diarrhoea/
turing may occur and fistulae leading to specific mucus PR.
symptoms (e.g., colovesical—pneumaturia and • LFTs—deranged in liver metastases or in the
recurrent urinary infection; rectovaginal—fecal hepatobiliary manifestations of Crohn’s
discharge per vagina). Perianal fissures/fistulae disease.
and anorectal sepsis are relatively common in • C-reactive protein/ESR—allows the activity
Crohn’s disease. Extragastrointestinal manifesta- of inflammatory bowel disease to be
tions of inflammatory bowel disease include fin- monitored.
ger clubbing and erythema nodosum. Diverticular • Stool culture—rule out infective colitis.
disease may present insidiously with lower • Faecal occult blood—will detect occult
abdominal pain or fistula formation (e.g., colo- bleeding.
vesical), or acutely as acute diverticulitis (abdom- • CXR—will detect pulmonary metastases.
inal pain, diarrhoea, and localized peritonitis), • AXR—will show signs of colonic obstruction.
pericolic abscess, obstruction (due to stricturing), Any dilatation of the colon >6 cm in diameter
perforation (generalized peritonitis), or haemor- heralds the onset of toxic megacolon. In isch-
rhage (relatively rare). aemic colitis, there will be dilated colon with
Adenomatous polyps are usually asymptom- characteristic “thumbprinting.” In colovesical
atic, but large villous adenomas in the rectum fistula, gas is present in the bladder. Free intra-
may elicit an alteration in bowel habit, mucus per peritoneal gas will be seen in colonic perfora-
6 Colorectum 71
tion. In patients being investigated for chronic 6.4 Pathological Conditions

constipation, radio-opaque markers are
ingested and an AXR is taken 5 days later with 6.4.1 Non-neoplastic Conditions
passage of <80% of the markers considered
abnormal. These comprise inflammatory (acute or chronic),
• Barium enema—still used in investigation of mechanical, ischaemic, and iatrogenic disorders.
colorectal disease. There will be characteristic
“thumbprint” filling defects caused by oedema- 6.4.1.1 Inflammatory Disorders
tous mucosa in ischaemia/infarction. The extent Acute proctocolitis: Infective or drug-induced,
of ulcerative colitis can be assessed and in e.g., antibiotics, there is preservation of the
Crohn’s disease it will show skip lesions, areas mucosal architecture and acute inflammation
of stricturing, and any fistulae. It will reveal the with biopsies only being submitted if symptoms
presence of diverticula. Barium enema is useful persist beyond several weeks. Infective cases
in the detection of large polyps and carcinomas (campylobacter, shigella, salmonella) are usually
with constricting tumours producing a charac- self-limited and culture positive in only 40% of
teristic “apple core” lesion. However, it will not cases. Drug-induced inflammation often responds
reliably define rectal lesions. to its withdrawal.
• CT scan—will detect a pericolic abscess (can Chronic proctocolitis: Characterized by dis-
be drained under CT guidance) and is useful turbance of the mucosal architecture and a
in showing the site of a tumour and any meta- chronic inflammatory cell infiltrate ± foci of
static spread. CT colonogram and barium active inflammation. Commonly due to idio-
enema can be of use in a medically unfit pathic chronic inflammatory bowel disease
patient or where there is a distal stricture not (CIBD) but also seen overlying diverticulosis and
passable by the colonoscope. pneumatosis coli, in infection (shigella, amoebia-
• MRI scan and ELUS—allow assessment of sis, schistosomiasis), obstructive enterocolitis,
local pelvic tumour spread in rectal carcinoma and with drugs. Microbiological culture and
for staging purposes and selection for neoad- travel and drug history should always be ascer-
juvant therapy. tained in patients with chronic diarrhoea.
• PET CT scan—helps to distinguish recurrent CIBD—ulcerative colitis and Crohn’s dis-
carcinoma from post-radiotherapy fibrosis in ease: The latter has been discussed previously
the pelvis and to detect occult distant (see Chap. 5) but can present either as isolated
metastases. colonic disease or associated with ileitis. It is a
• Angiography—will demonstrate a bleeding segmental, transmural chronic inflammatory con-
point, e.g., in angiodysplasia if there is active dition and there is often rectal sparing but anal
bleeding >2 mL/min. disease (fissure, fistula, abscess) present. The
• Cytology—examination of ascitic fluid or segmental distribution, focality of inflammation,
peritoneal washings. presence of granulomas, and ileal component are
• Endoscopy and biopsy—inspection and all useful diagnostic pointers in colonoscopic
biopsy of the mucosa, determination of dis- biopsy or resection specimens. Recurrence else-
ease distribution, solitary or multiple lesions. where in the gut is not uncommon despite surgi-
Allied to CT imaging if a mass lesion is cal resection, and, because of this, Crohn’s
detected. disease is a contraindication to pouch formation
• Laparoscopy—staging laparoscopy may be in restorative proctocolectomy. Occasionally it
undertaken and any peritoneal deposits presents isolated to the appendix or sigmoid
biopsied. colon coexisting with diverticulitis.
• CEA serum levels—elevated in colorectal In contrast to this ulcerative colitis is a diffuse,
neoplasia particularly in metastatic or recur- chronic active mucosal inflammatory condition
rent disease. involving the rectum and a contiguous length of
large intestine, e.g., left-sided proctocolitis or various reasons, e.g., treated CIBD, postinfec-
pancolitis. It is of variable severity with episodic tion, drug ingestion, uraemia, stercoral trauma,
exacerbations and remissions—acute fulminant etc. However, microscopic colitis which causes
colitis may be complicated by severe haemor- chronic, voluminous watery diarrhea is radiologi-
rhage, toxic dilatation or megacolon, perforation, cally and colonoscopically normal, or near nor-
and peritonitis. Other complications include mal, with recent recognition of subtle endoscopic
mucosal dysplasia and malignancy (usually ade- abnormalities relating to fragility of the colonic
nocarcinoma) in extensive disease of long- mucosa. It occurs in middle-aged to elderly
standing duration (pancolitis >10 years). women and has variable associations with HLA
Villiform or polypoid DALMs (dysplasia- type, autoimmune diseases, and NSAID inges-
associated lesions or masses) can be difficult to tion. Diagnosis is by histology with a normal
distinguish from the much more common inflam- architecture and transmucosal infiltrate of chronic
matory mucosal polyps and may harbour under- inflammatory cells. Its main variants, collage-
lying adenocarcinoma. Alternatively dysplasia nous and lymphocytic colitis, show a thickened
may occur in flat mucosa, and colonoscopic sur- subepithelial collagen band and excess surface
veillance of chronic colitis involves sequential intraepithelial lymphocytes, respectively. Not
mucosal sampling as well as target biopsy of any infrequently there is spontaneous resolution or
macroscopic abnormality. Biopsy orientation response to anti-inflammatory therapy, depend-
onto a polycarbonate strip aids subsequent local- ing on underlying cause.
ization of any histological abnormalities. Infective proctocolitis: Investigation includes
Macroscopically ulcerative colitis shows muco- microbiological culture with microscopy for
sal granularity, linear or confluent ulceration, and cysts (amoebiasis) and ova (schistosomiasis).
polyps of varying size. The terminal ileum is only Infection should be considered particularly where
involved in severe pancolitis over a length of there is a history of travel or immunosuppression,
1–2 cm (backwash ileitis) and although there is e.g., HIV-AIDS, chemotherapy or post-transplant.
usually proctitis, the rectum may be spared due to In immunosuppression, infection with unusual
treatment effects, e.g., predsol enemas. opportunistic organisms can occur, e.g., crypto-
Extraintestinal effects include arthritis, iritis, and, sporidiosis, atypical mycobacteria.
in the liver, primary sclerosing cholangitis which
can lead to cirrhosis and cholangiocarcinoma. 6.4.1.2 Mechanical Disorders
In a minority of cases, clear distinction cannot Melanosis coli: Characterized by pigmented
be made between ulcerative colitis and Crohn’s macrophages in the lamina propria that impart a
disease on macroscopic/colonoscopic and micro- dusky mucosal appearance mimicking ischaemia.
scopic examination—so-called indeterminate The pigment is lipofuscin and degenerative in
colitis (in a resection specimen) or CIBD, unclas- nature thought to relate to cellular apoptosis.
sified (in biopsy material). There is an association with use of laxatives and
Diversion proctocolitis: Follows faecal stream bowel dysmotility.
diversion, e.g., after ileostomy or colostomy for Volvulus: Usually comprises a markedly
tumour, trauma, or CIBD. The defunctioned seg- dilated atonic sigmoid colon in either Africans
ment develops florid reactive lymphoid hyperpla- (due to a high-fibre diet with bulky stools) or
sia which can be mucosal or transmural, constipation-related acquired megacolon in the
mimicking or superimposed on an underlying elderly. The sigmoid loop twists on its mesentery,
inflammatory disorder such as CIBD. Persistent obstructs, and may become secondarily isch-
severe symptoms may necessitate surgical exci- aemic. Resection specimens are often dilated,
sion of the segment, e.g., the rectal stump follow- thinned, and featureless. Melanosis coli may be
ing colectomy for ulcerative colitis. present.
Microscopic colitis: Minimal inflammation Pneumatosis coli: Submucosal gas cysts lined
may be apparent grossly or histologically for by macrophages and giant cells with overlying
6 Colorectum 73
mucosal chronic inflammation or pseudolipoma- and variable surface erosion. It is common to a

tosis. There is an association with volvulus, con- number of situations including solitary rectal
stipation, diverticulosis, and chronic obstructive ulcer syndrome (SRUS), inflammatory cloaco-
airways disease. Pathogenesis relates to retroper- genic polyp, diverticular-related crescentic coli-
itoneal tracking of air into the bowel mesentery, tis, mucosa adjacent to a polyp, stricture or
abnormal luminal gas production linked to the tumour, stercoral trauma, and the mucocutaneous
increased intraluminal pressure seen in the above junction of stomas. In SRUS, there is a history of
disorders, and introduction of gas during endos- abnormal anterior rectal wall descent due to
copy. About 50% of cases resolve, but recurrent straining at defecation. This results in induration
or severe lesions may require colectomy of the of the wall that can mimic a plaque of tumour on
involved segment. palpation and rectoscopy. Biopsy is diagnostic
Obstructive enterocolitis: Continuous or seg- and treatment is usually conservative, related to
mental areas of inflammation or ulceration adja- better stool habit—occasional cases require
cent to or distant from an obstructing distal resection of the involved sleeve of mucous mem-
lesion, e.g., annular carcinoma or diverticulosis. brane (mucosectomy) with apposition and plica-
Small bowel may also be involved with mimicry tion of the intervening muscle (Delorme’s
of Crohn’s disease. A dilated, thinned caecal procedure).
pouch can become ischaemic and perforate.
Diverticulosis: Very common in Western soci- 6.4.1.3 Ischaemic Disorders
ety due to a low-fibre diet, high intraluminal pres- The pathogenesis of intestinal ischaemia has
sure, and subsequent transmural mucosal been previously discussed and in the large intes-
herniation in the sigmoid colon through points of tine is often due to mesenteric vascular insuffi-
vessel entry from the mesentery. Presentation is ciency because of systemic hypotension
with altered bowel habit, per rectum bleeding, (myocardial infarction, cardiac arrhythmia, blood
left iliac fossa pain or a mass. The latter implies loss) or mesenteric atheroma/thrombosis/embo-
diverticulitis with possible perforation and peri- lism. Acute lesions may resolve if mucosa-
colonic reaction/abscess formation. Portal pyae- confined but are potentially fatal if transmural.
mia, liver abscesses, and peritonitis can ensue. Late or chronic ischaemia has a predilection for
The diverticular segment is thickened and con- the splenic flexure and rectosigmoid watershed
tracted with muscle coat hypertrophy and visible areas of vascular supply. This can result in non-
diverticular pouches in the muscularis and mes- specific ulceroinflammatory and stricturing
enteric fat. They may be filled and obstructed lesions—end-stage changes that can be produced
with faecal or vegetable debris, and ulcerated by various other conditions, e.g., CIBD, infection
with a coating of pericolonic exudate and abscess. (E. coli 0157:H7 bacterium), pseudomembra-
The concertina-like redundant mucosal folds can nous colitis due to Clostridium difficle over-
show crescentic colitis due to abrasion of their growth, obstructive enterocolitis, and stercoral
tips by the passing faecal stream. Occasionally trauma. Rare cases are due to vasculitis or
the chronic inflammation may be transmural and amyloid infiltration. Assessment of resection

granulomatous mimicking or coexisting with limit viability and mural/mesenteric vessels is
Crohn’s disease. Treatment is often conservative, necessary in ischaemia.
e.g., by diet alteration, but severe or complicated A vascular abnormality that can present with
cases require colectomy. Co-presentation with an iron-deficiency anaemia in elderly patients is
occult carcinoma within the strictured segment colonic angiodysplasia. Thought to be degenera-
must be excluded by careful pathological tive in nature due to increased intraluminal pres-
examination. sure compressing mural vessels, the commonest
Mucosal prolapse: A mechanism producing site is the caecum. Operative injection of radio-
reactive mucosal changes of crypt hyperplasia, opaque contrast may be needed to demonstrate
smooth muscle thickening of the lamina propria, areas of vascular ectasia so that targeted blocks
can be sampled. The ectatic vessels involve the monly distal and share some morphological fea-
submucosa and lamina propria. tures and cancer risk of conventional adenomas.
Adenoma (conventional): Designated as tubu-
6.4.1.4 Iatrogenic Disorders lar, tubulovillous, or villous, depending on the
These include drugs, radiation therapy, and graft relative proportions of glands and fronds present
versus host disease. and composed of low- or high-grade dysplastic
Drugs: NSAIDs should always be considered epithelium. Increasing in frequency with age, and
in the presence of any unusual colitis, localized in the left colon, the risk of malignancy relates to
ulceration, stricture, perforation, or mucosal dia- the size (>2 cm = 40–50% risk), degree of villous
phragm formation. Antibiotics can commonly morphology, and grade of dysplasia. Tubular ade-
cause dysfunctional diarrhoea, an acute procto- nomas are polypoid and larger tubular adenomas
colitis, or, particularly in the elderly, pseudo- tend to develop a distinct stalk, whereas villous
membranous colitis. The latter is due to the lesions are typically sessile. Stalked adenomas
production of Clostridium difficile toxin leading can twist and prolapse (typically in the sigmoid
to ischaemic-type lesions with yellow surface colon) resulting in glandular herniation (epithe-
plaques of acute inflammatory and fibrinous lial misplacement) into the submucosa that mim-
pseudomembrane. Severe cases result in end- ics invasive carcinoma—the low power lobular
stage ulceration and colectomy may be indicated configuration, the presence of accompanying
although initial treatment is with appropriate lamina propria haemosiderin and lack of stromal
antibiotics. fibrous desmoplasia are useful histological clues
Radiation therapy: Acute and chronic phases to benignity. This differential diagnosis is a par-
with the potential for mucosal healing and usu- ticularly common problem with the introduction
ally produced by radiotherapy for pelvic (uterine of bowel cancer screening programs based on
cervix, rectum, prostate) or retroperitoneal can- detection of faecal occult blood (FOB), as these
cer. Acute radiation proctocolitis is normally large sigmoid polyps often ulcerate and bleed,
self-limited and seldom biopsied. Chronic resulting in a positive FOB test. Invasive carci-
changes result in mucosal atrophy, hyaline fibro- noma is defined by the presence of neoplastic
sis, vascular thickening, and strictures. epithelium infiltrating submucosa, and in stalked
Graft versus host disease: Immunosuppressed adenomas, polypectomy may be considered ther-
bone marrow transplant patients risk developing apeutic if the tumour is well or moderately dif-
a range of acute and chronic changes similar to ferentiated and does not show lymphatic or
those seen in radiation damage. venous invasion, tumour budding or involvement
of the diathermied polyp base. Otherwise colonic
resection may be indicated and, therefore, good
6.4.2 Neoplastic Conditions orientation of the adenoma to its stalk and
assessment of the base are crucial, at polypec-
Serrated polyps: Simple hyperplastic or meta- tomy handling and dissection in the laboratory. In
plastic polyps are benign and more prevalent in contrast, invasion in a sessile adenoma accesses
the left colon/rectum with increasing age. Sessile true mural submucosa, and colonic resection is
serrated lesions (also referred to as sessile ser- usually considered more appropriate based on
rated polyps/adenomas) are typically larger and greater risk of lymph node metastases, unless the
more architecturally complex than hyperplastic patient is very elderly or medically unfit. Local
polyps and predominantly located in the proxi- mucosal resection is an option, but in such cases
mal colon. They are now considered to be precur- further radical surgery is required if the cancer
sors of right-sided microsatellite instability involves muscle coat, the base of the specimen,
pathway carcinomas, typically in elderly females. lymphovascular channels, or is poorly
Traditional serrated adenomas are more com- differentiated.
6 Colorectum 75
It is not unusual for patients to have several sequently (metachronously). Predisposing con-
sporadic adenomas, but in familial adenomatous ditions are chronic ulcerative colitis, FAP, Lynch
polyposis (FAP), there are hundreds or thousands syndrome (formerly known as hereditary non-
with progression to colorectal cancer 20–30 years polyposis colorectal cancer [HNPCC]) and rarer
earlier than average, indicating a need for pro- polyposis syndromes. In Lynch syndrome, there
phylactic colectomy. There is also a strong asso- is a tendency for right-sided cancers, which may
ciation of FAP with duodenal adenomas and be multiple, mucinous, or poorly differentiated
periampullary carcinoma. Attenuated FAP and and with a family history of cancer at a younger
MYH-associated polyposis present with smaller age (<50 years), also involving other sites, e.g.,
numbers of colorectal polyps, but also predispose uterus, stomach, ovary, ureter, and small intes-
to colorectal cancer. tine. Lynch syndrome cancers are genetically
Flat adenomas are less common and difficult different from typical chromosomal instability
to identify macroscopically without the use of pathway sporadic colorectal cancer and are
magnification or dye spray technique. They have caused by a heritable germline mutation result-
proportionately higher grades of dysplasia and ing in deficiency in one of the DNA mismatch
frequency of carcinoma and may account for a repair (MMR) proteins, resulting in microsatel-
proportion of the 30% of carcinomas without an lite instability (MSI). Importantly, sporadic MSI
identifiable adenoma at their edge. pathway colorectal cancers are more common
In the UK, National Bowel Cancer Screening than Lynch syndrome and share similar mor-
Programs in each nation target the detection of phological and immunohistochemical features,
early colorectal cancers and of adenomas in but are almost invariably caused by somatic
asymptomatic patients in an attempt to prevent inactivating promoter hypermethylation of the
cancer formation. These programs invite the pop- MMR gene MLH1, resulting in loss of immuno-
ulations aged 60–74 years to participate in histochemical expression and MSI. Distinction
2-yearly FOB testing. About 2% have a positive from Lynch syndrome may require further
result and are referred for colonoscopy (or CT molecular investigation including germline
colonogram, depending on fitness and availabil- mutation screening.
ity of local resources) and 50% of these will have As previously noted, the cancer site and its
a detectable abnormality (10% cancer, 70% ade- macroscopic growth pattern influence clinical
nomas, 20% other diagnoses, e.g., CIBD). Initial presentation. Important prognostic indicators are
results have shown a significant yield of precan- the extent of local tumour spread, a circum-
cerous adenomas and a shift towards a higher fre- scribed or infiltrative margin, involvement of the
quency of early stage (Dukes’ A) cancers. There serosa, longitudinal or mesocolic/mesorectal
are plans to move from FOB to faecal immuno- resection margins, and tumour perforation.
chemical testing (FIT), which is a more specific Tumour present within ≤1 mm defines involve-
test and the English Bowel Cancer Screening ment of the mesenteric margin irrespective of
Program has added one-off flexible sigmoidos- whether it is nodal, lymphovascular, direct or dis-
copy screening at age 55 years. continuous spread. Generally a macroscopic
Adenocarcinoma: Comprising the vast clearance of 2–3 cm from a longitudinal margin
majority of colorectal malignancies, 80–85% is satisfactory unless histology shows the cancer
are moderately differentiated adenocarcinoma to be unusually infiltrative or poorly differenti-
of no special type. A minority are mucinous, ated. All mesenteric lymph nodes should be iden-
signet ring cell, or poorly differentiated. tified, counted, and sampled (aiming for a
Distribution is throughout the colorectum— departmental median count of at least 12 nodes
although rectosigmoid is the commonest site per specimen) and a suture tie limit node identi-
(50% of cases), 10–15% of sporadic cases are fied—in some colectomy specimens this may
multiple, occurring either synchronously or sub- mean more than one limit node. Involvement of
adjacent organs or structures (e.g., abdominal Sigmoidoscopy can be carried out by using
wall) is documented and predisposing lesions either a rigid or flexible sigmoidoscope. Rigid
such as adenoma(s) or colitis represented. sigmoidoscopy is usually done without bowel
Multiple tumours are dissected and staged indi- preparation at the bedside or in the outpatient
vidually with respect to mural and nodal spread. clinic. A hollow rigid plastic tube measuring
Other cancers: Carcinoid tumours are usually 25 cm in length with an attached light and air sup-
small incidental mucosal rectal polyps, GISTs ply is inserted into the rectum up to the distal sig-
are rare, and malignant lymphoma can compli- moid colon. Forceps can be passed through the
cate ulcerative colitis or HIV-AIDS. tube to biopsy any lesion visualized. The scope is
Prognosis: Relates mainly to the depth of also used to assess tumour fixation and its dis-
tumour spread, lymph node involvement, and tance from the anus. Flexible sigmoidoscopy (and
adequacy of local excision with overall 5-year colonoscopy) involves formal bowel preparation.
survival 35–40%. Cancers confined to the mucous A flexible fibre-optic endoscope is inserted and
membrane or wall do much better than those that works in the same way as an upper GI endoscope,
invade beyond this or show nodal disease. with a controllable tip and ports for inserting
Adverse prognostic indicators also include a instruments, e.g., forceps, snare, etc. This should
mucinous character, poor differentiation, tumour visualize up to the proximal sigmoid colon.
perforation, obstruction, and resection margin Colonoscopy is carried out using a colono-
involvement. It is estimated that about 50% of scope which is essentially a longer sigmoido-
patients are cured, 10% die from local recurrence scope, with scopes of different lengths available
and 40% from lymphatic and vascular spread. (ranging from 140 to 185 cm). An experienced
Treatment is typically surgical excision with endoscopist should be able to pass the endoscope
adjuvant chemotherapy considered for cancers through the ileocaecal valve to visualize the ter-
showing poor differentiation, nodal, peritoneal, minal ileum. Intraoperative endoscopy can be
and/or extramural vascular spread, tumour perfo- used during a laparotomy to, for instance, locate
ration, or resection margin involvement. Rectal lesions, e.g., polyps found by barium enema/CT
cancers often receive 5-day short-course pre- scan that require localized resection and which
operative radiotherapy in an attempt to down- cannot be palpated by the surgeon.
stage the lesion or facilitate resection. This Biopsy specimens can be taken from the
usually does not produce the marked macro- colonic mucosa by forceps passed through the
scopic and histological features of regression that endoscope in much the same way as that used in
can be seen with the alternative 6-week-long upper GI endoscopy. The colonoscopic manage-
course of neoadjuvant chemoradiotherapy. The ment of polyps is important and depends on the
latter is given to patients with clinically fixed size and type of polyp:
tumours that show significant spread on MRI
scan into the mesorectum, its nodes, or near its • Large pedunculated polyps can be removed by
investing fascia (circumferential radial margin: “snaring.” A circular wire is passed over the
CRM). polyp onto its stalk. An electrical current is
passed along the wire to coagulate the vessels
in the base of the stalk, which is then tran-
6.5 Surgical Pathology sected by closing the wire. If the stalk is large,
Specimens: Clinical Aspects adrenaline can be injected into the base to
minimize bleeding. The polyp is retrieved by
6.5.1 Biopsy Specimens using the snare, a Dormia basket or suction.
• Smaller polyps (5–7 mm) can also be snared
A number of procedures can be undertaken to and removed by suction.
obtain biopsy specimens from the colorectal • Polyps <5 mm can be removed by “hot
mucosa: biopsy.” Biopsy forceps grasp the polyp and a
Proctoscopy is used to inspect the distal rec- current is applied to electrocoagulate the base,
tum and anal canal. and then the head of the polyp is pulled off by
6 Colorectum 77
the forceps. This procedure is used less now, adenomatous polyp. Likewise the extent of
especially for right colonic polyps, because of mesenteric resection will depend on the type of
an increased risk of perforation. lesion, i.e., wide mesenteric resection for neo-
• Broad-based sessile polyps can either be plastic lesions and limited resection for non-
removed piecemeal using the snare or by neoplastic conditions. It also depends on the
injection polypectomy. This involves injecting “intention” of the surgery for a malignant condi-
saline or adrenaline solution into the submu- tion, i.e., a wide mesenteric resection with proxi-
cosa around the polyp, raising it, and allowing mal ligation of vessels and, hence, removal of
it to be snared completely. This method can be lymph node groups if the intention is curative, or
used for polyps up to 5 cm in diameter. limited, if the disease is advanced and the inten-
• In patients with multiple small polyps, these tion is palliative. The variety of terms used to
can be highlighted by spraying dye onto the describe the different types of colonic resection
mucosa. This will reveal polyps 0.5 mm and (colectomy) is depicted in Fig. 6.5. Choice is also
larger as pale areas on a blue background. determined by the distribution or multiplicity of
• If the endoscopist is concerned that a polyp lesions detected at preoperative colonoscopy.
may be malignant, the site of polypectomy Planned elective laparoscopic surgery is the pre-
can be marked by tattooing the bowel mucosa ferred option—open abdominal surgery (laparot-
with India ink. This allows the site to be revis-
ited at a later date.
Submucosal lesions can be sampled by endo-
scopic FNA. Colonoscopy may also be used
F G
as a therapeutic tool, e.g., foci of angiodyspla-
sia may be coagulated using hot biopsy E H
forceps.

D
Resection of the colon and rectum is performed
for a wide variety of both non-neoplastic and
neoplastic conditions (Table 6.1), the type of pro- I
cedure depending on the site and nature of the B
lesion, e.g., a malignant tumour, will require a J
A
more extensive resection than that for a large C
Table 6.1 Colorectal resections K

Specific Diverticular disease
Volvulus
Pneumatosis coli L
Colonic angiodysplasia
Rectal stump (CIBD, diversion
proctitis)
Rectal mucosa (prolapse) Fig. 6.5 Types of colonic resection. A → C
Ulceroinflammatory Ulcerative colitis Ileocaecectomy; ±A + B → D Ascending colectomy;
±A + B → F Right hemicolectomy; ±A + B → G Extended
Crohn’s disease right hemicolectomy; ±E + F → G ± H Transverse colec-
Pseudomembranous colitis tomy; G → I Left hemicolectomy; F → I Extended left
Ischaemia hemicolectomy; J + K Sigmoid colectomy; ±A + B → J
Neoplasia Large or multiple adenomas Subtotal colectomy; ±A + B → L Total colectomy;
±A + B → L Total proctocolectomy; L Proctectomy
Carcinoma
(Reprinted, with permission, from Fielding and Goldberg
Malignant lymphoma (2002))
omy) may be necessary for extensive disease, or tomy may be required if the surgeon thinks that
if the patient presents as an acute emergency. primary anastomosis would be compromised
(e.g., if there is extensive intraperitoneal
6.5.2.1 Resection in Neoplastic contamination).
Conditions The curative resection of rectal tumours may
Adenomatous polyps—As discussed above, the be carried out by one of two methods:
majority of adenomatous lesions can be removed
by endoscopic techniques. However, large sessile • Anterior resection of rectum—In this proce-
polyps >5 cm in diameter and occupying more dure, the rectum is mobilized by entering the
than one-third of the colon circumference should fascial plane around the mesorectum. This
be removed by a localized resection. Sessile ade- allows the rectum to be removed en bloc with
nomas in the rectum can be removed by trans- the mesorectum which contains the initial
anal submucosal resection. In this procedure, draining lymphovascular channels and nodes
adrenaline solution is infiltrated into the submu- (low anterior resection and total mesorectal
cosa around the lesion and the mucosa is incised excision—TME) (Fig. 6.6a). Continuity is
by scissors 1 cm from the lesion. This can then be reestablished by a stapling device forming an
easily lifted off the circular muscle in a single end-to-end colorectal anastomosis.
piece and the mucosal defect is closed by sutures. Occasionally, in low anastomoses, a protec-
This “advanced” polypectomy with submucosal tive loop colostomy/ileostomy may be fash-
infiltration is termed endoscopic mucosal resec- ioned to divert the faecal stream. This can be
tion (EMR). Extensions of this are endoscopic closed at a later date. To obtain an adequate
submucosal dissection (ESD) and transanal length of colon to form a safe anastomosis, the
endoscopic microsurgery (TEMS) providing splenic flexure will usually need to be mobi-
complete mucosectomy to full-wall-thickness lized. On occasion, the spleen may be dam-
specimens. Alternative descriptors are transanal aged during this mobilization and a
resection of tumour (TART) or transanal micro- splenectomy would then have to be performed.
surgery (TAMIS). These “big biopsy” specimens In cases where the tumour is in the proximal
are both diagnostic (benign vs. malignant) and rectum, a high anterior resection and mesorec-
potentially therapeutic, allowing assessment of tal division can be employed. This entails divi-
risk factors that might necessitate subsequent sion of the rectum and mesorectum 5 cm distal
radical surgery (substaging of submucosal inva- to the tumour and allows a larger rectal stump
sion, poor differentiation, lymphatic invasion, for anastomosis.
venous invasion or tumour “budding”), or repeat • Abdominoperineal (AP) excision of rectum
endoscopy and possible further local excision (APER)—In this procedure, the rectum is
(margin involvement). Occasionally large rectal mobilized as above and the colon is divided at
polyps may require formal proctectomy or ante- the apex of the sigmoid. The anal canal and
rior resection. distal rectum are then resected from below via
Malignant lesions—The type of resection for the perineal route (Fig. 6.6b). The entire rec-
colonic tumours will depend on the site of the tum (and mesorectum) and anus are then
lesion and the intent of the surgery. As previously removed en bloc. The perineal wound is
stated, the colonic lymphatics accompany the closed and a permanent end colostomy is fash-
main blood vessels and the extent of resection ioned in the left iliac fossa using the transected
depends on the lymphatic clearance required. In end of the sigmoid colon.
cancer operations of curative intent, the affected
colon with its lymphovascular mesenteric pedicle Until the early 1980s, anterior resection was
is resected. Continuity is restored by either an used in less than 50% of patients with rectal
ileocolic or colocolic end-to-end anastomosis. tumours, i.e., those in the proximal rectum.
However, on occasion, an end ileostomy/colos- However, it is now used for approximately 90%
6 Colorectum 79
Fig. 6.6 (a) Resection a

in low anterior resection Spleen
and total mesorectal
excision; (b) resection in Sigmoid
abdominoperineal mesentery
excision (Reproduced,
Allen and Cameron
(2013))
Sigmoid colon
Rectum
Mesorectum
Anus
Sigmoid colon
Rectum
Anus Resection line
of tumours in the rectum. Initially it was feared saving procedure (i.e., anterior resection) should
that because less tissue is excised and the clear- be employed whenever possible. However,
ance of the distal margin is not as great during tumours extending to less than 2 cm from the
anterior resection, there would be increased local anorectal junction (i.e., less than 6 cm from the
recurrence rates if anterior resection was used for anal verge) should be treated by AP resection.
low rectal tumours. However, it appears that the Extra-levator abdominoperineal excision
degree of lateral clearance is similar in the two (ELAPE), performed partially with the patient in
procedures and that a distal clearance of 2 cm is the prone position, is a more radical operation,
adequate to prevent local recurrence. Given the removing a greater bulk of surrounding muscle,
physical and psychological problems associated with the aim of creating a cylindrical specimen
with a permanent colostomy, and the higher inci- without a ‘waist’ in order to minimize the risk of
dence of bladder and sexual problems in patients CRM involvement by tumour and thereby the
undergoing AP resection, it is felt that a sphincter- risk of recurrence.
Occasionally, in a medically unfit patient, management of ulcerative colitis. Emergency

localized resection is used for a well- surgery is needed in cases of acute severe colitis
differentiated, pT1 rectal cancer that is <3 cm in and/or toxic megacolon. The procedure of choice
diameter. Accurate preoperative staging is crucial is a subtotal colectomy and end ileostomy with
in selection of these patients and some may then the proximal end of the rectum brought to the
need to proceed to salvage resection if adverse surface in the form of a mucus fistula. This spares
pathological features are identified in the patho- an already sick patient the added trauma of pelvic
logical specimen, e.g., poor differentiation, lym- surgery and, if ulcerative colitis is confirmed by
phovascular involvement, or invasion of the deep histological examination, allows an ileoanal
margin or muscle coat. Sometimes patients with pouch procedure to be considered in the future.
obstructing cancers undergo piecemeal resection Prior to the mid-1970s, patients with refractory
(essentially palliative and non-curative), partial ulcerative colitis underwent a panproctocolec-
laser ablation, or stenting to restore intestinal tomy (removal of the colon, rectum, and anus)
continuity and avoid the risk of perforation. This with a permanent end ileostomy. However, in
may allow resection to be carried out more safely 1976, the procedure of restorative proctocolec-
at a later date. tomy was introduced and removed the need for a
permanent ileostomy in suitable patients. In this
6.5.2.2 Resection in Non-neoplastic procedure, the entire colon and rectum are
Conditions removed and the mucosa may be stripped from
Hartmann’s procedure—This is one of the most the upper anus above the dentate line (some sur-
commonly used emergency operations for geons prefer to leave this mucosa intact as it is
colorectal disease. Although this was initially thought to improve future continence). An ileal
devised for the elective treatment of proximal reservoir (pouch) is formed (Fig. 6.7) and an ileo-
rectal tumours, it is now usually used in the emer- anal anastomosis is fashioned. A protective loop
gency setting to treat conditions such as perfo- ileostomy is formed as close to the ileal pouch as
rated diverticular disease (most commonly), possible and this can be closed at a later date
perforated tumour, etc. The procedure itself is
defined as resection of the sigmoid colon (and a S pouch J pouch
variable length of proximal rectum if required)
with the fashioning of a terminal-end colostomy
and closure of the rectal stump. The colostomy
may be reversed at a later date by forming an
end-to-end colorectal anastomosis.
Non-acute presenting diverticular disease is
usually treated surgically by either sigmoid col-
ectomy or left hemicolectomy depending on the
extent of the disease.
Surgery in colorectal inflammatory bowel dis-
ease—The surgical management of colorectal
Crohn’s disease is similar to that in the small
intestine (see Chap. 5). Namely surgical interven-
tion is reserved for those in whom medical man-
agement has failed (i.e., minimal resection of the
diseased segment) or who are suffering compli-
cations, e.g., obstruction, pericolic abscess, fis-
tula, etc.
As in Crohn’s disease, close liaison between Fig. 6.7 Two popular designs of ileal pouch (Reproduced,
surgeons and physicians is required in the with permission, from Allen and Cameron (2013))
6 Colorectum 81
(usually 2–3 months) after healing has been com- (but see diverticular disease and tumour) fol-
pleted. A proportion of these patients (approxi- lowing gentle washing out of faecal debris,
mately 10%) may develop “pouchitis”—increased pinning out with avoidance of unnecessary
frequency of stool and feeling generally unwell. traction, and immersion in 10% formalin fixa-
The exact aetiology of this is unknown but some tive for 48 h. Photographs may be taken before
feel it may be due to bacterial overgrowth in the and after dissection.
pouch. • When opening avoid areas of perforation or
Angiodysplasia—If bleeding is severe enough tumour. Tumour segments may either be left
to require surgical intervention, and if conserva- unopened for fixation and subsequent trans-
tive treatment such as endoscopic coagulation verse slicing or carefully opened—the latter
has been unsuccessful, the procedure of choice gives better fixation, but the cut should be
will be dictated by the site of the bleeding guided by palpation with the index finger to
point(s). However, if the site of bleeding cannot avoid disturbing the relationship of the tumour
be discovered, a total colectomy with ileorectal to the circumferential margin.
anastomosis (or end ileostomy, rectal mucus fis-
tula, and reversal at a later date) may be required. 6.6.2.1 Diverticular Disease
• Measurements: length × diameter (cm) of the
thickened colonic segment
6.6 Surgical Pathology • Inspect and describe: perforation, fistula, peri-
Specimens: Laboratory colonic exudate, or abscess
Protocols • Open and fix
• Serially transverse specimen at 5 mm
6.6.1 Biopsy Specimens intervals
• Sample (four blocks minimum) the divertic-
For biopsy specimens and local mucosal resec- ula, any associated inflammation, or thickened
tions see Sect. 1.3.3 and Fig. 1.2. mucosa that might represent segmental colitis,
mucosal prolapse, or tumour
• Sample mesenteric lymph nodes
6.6.2.2 Volvulus, Pneumatosis Coli,
Specimen: Rectal Stump, Rectal Mucosa
in Prolapse
• Colorectal specimens are for a range of either • Measurements: length × maximum diameter
specific, ulceroinflammatory, or neoplastic (cm)
conditions (Table 6.1). These can be compli- • Open and fix
cated by obstruction with or without associ- • Inspect and describe
ated enterocolitis or perforation or show Volvulus—dilatation, thinning, melanosis,
evidence of background disease such as CIBD stercoral ulceration, ischaemia, perforation
or FAP. The resection specimen is dictated by Pneumatosis—mucosal cobbling, blebs or gas
the site and nature of the abnormality and cysts, inflammation, ulceration, perforation
extent of any complications or predisposing Rectal stump—mucosal granularity, ulcer-
lesions that are present. ation, polyps, fistulae, tumour
Rectal mucosal prolapse—mucosal granular-
Initial procedure: ity, thickening, induration, ulceration
• Sample (four blocks minimum) macroscopi-
• In general, specimens are measured, opened cally normal and abnormal areas as
with blunt-ended scissors along the antimesen- indicated
teric border, and then blocked longitudinally • Sample mesenteric lymph nodes
6.6.2.3 Ulceroinflammatory Ulcerated/stricture—carcinoma, malignant

and Neoplastic Conditions lymphoma, metastatic carcinoma
• Open and inspect Fleshy/rubbery—malignant lymphoma,
• Measurements: GIST
Lengths and maximum diameter (cm) of the Multiple—adenomas, carcinoma (primary
parts present—terminal ileum, appendix, or metastatic), malignant lymphoma
colon, rectum, anus –– Edge: Circumscribed/irregular
Lengths (cm) of ischaemic, inflamed, or stric- Perforation
tured segments Adjuvant therapy changes: necrosis, ulcer-
Maximum dimensions (cm) of any ation, fibrosis
perforation(s), ulcer(s), polyp(s) or tumour(s) • CIBD—ulcerative colitis: continuous/diffuse
Distances (cm) of the abnormality from the mucosal distribution, granularity, ulceration (lin-
proximal and distal resection limits ear/confluent), inflammatory polyps, synechiae,
Distances (cm) of the polyp/tumour/ulcer nodular or sessile DALMs, tumour, mucosal
from the anorectal dentate line and relation- reversion with healing and atrophy, backwash
ship to the peritoneal reflection (above/strad- ileitis, treatment-related rectal sparing
dling/below) and colorectal circumference –– Crohn’s disease: discontinuous/segmental
(anterior/posterior/right or left lateral) and transmural distribution, cobblestone
Distances (mm) of tumour from the nearest mucosa, ulceration (aphthous/linear/con-
aspect of the mesocolic/mesorectal CRM fluent), stricture, fat wrapping, fistulae,
• Grade the plane of mesorectal excision (meso- polyps or tumour, lymphadenopathy, adhe-
rectal fascia, intramesorectal, muscularis pro- sions, abscess formation, ileal/anal
pria) for anterior resection and APE specimens. disease
• Grade the plane of excision of the levators/ • Ischaemia—serosal hyperaemia/constriction
sphincters (extralevator, sphincteric, intra- band, mucosal hyperaemia/haemorrhage/
sphincteric) for APE specimens. ulceration/necrosis, wall thinning/perforation/
• Photograph stricture
• Paint any aspect of the mesocolic/mesorectal • Pseudomembranous colitis—pseudomem-
margin adjacent to or overlying tumour branes (adherent/yellow), mucosal granular-
Gently pin out and fix for 48 h ity/erosion/ulceration, stricture
• Obstructive enterocolitis—ulceration or stric-
Description: ture (contiguous or distant, diffuse or segmen-
tal), dilatation, wall thinning, perforation, ileal
• Tumour component
–– Site
Ileocaecal valve/caecum/colon (which seg- Blocks for histology:
ment, flexure)/rectum (above, straddling, Ulceroinflammatory conditions (Fig. 6.8)
or below the peritoneal reflection and
upper, mid, or lower, anterior, posterior, or • Sample by circumferential transverse sections
lateral)/anus the proximal and distal limits of resection
Lumenal/mural/extramural/mesenteric • Sample macroscopically normal bowel
–– Size • Sample representative longitudinal blocks (a
Length × width × depth (cm) or maximum minimum of four) of any focal abnormality
dimension (cm) that is present to include its edge and junction
–– Appearance with the adjacent mucosa, e.g., ulceration,
Polypoid/nodular—adenoma, carcinoma, stricture, fistula, perforation, pseudomem-
carcinoid, multiple lymphomatous polypo- branes, inflammatory polyps, serosal adhe-
sis, GIST sions or constriction bands. Also
6 Colorectum 83
Fig. 6.8 Ulceroinflammatory
colorectal conditions
(Reproduced, with permission,
from Allen and Cameron (2013))
Mesentery and
lymph nodes
1. Sample the ileal and colorectal resection limits

2. Process the appendix as usual
3. Sample representative blocks of any abnormality
including the junction with adjacent mcosa
4. Sequentially sample normal bowel
5. Sample mesenteric lymph nodes
–– CIBD: Sequential labeled samples at 10 cm • Note and measure the relationship of the deep
intervals from caecum to anus and addi- aspect of the tumour to the nearest site-
tional blocks from any unusual nodular or orientated point of the serosa and the
sessile abnormality (DALM) CRM. Note serosal tumour perforation or
–– Ischaemia: Sample the mesenteric vessels CRM involvement (≤1 mm).
• Sample mesenteric lymph nodes and any other • Note that in some resections the CRM may
structures, e.g., appendix or terminal ileum. comprise an adherent or involved adjacent
structure eg a cuff of peritonealised anterior
Neoplastic conditions (Fig. 6.9) abdominal wall soft tissue or posterior vaginal
wall. Its deep aspect should be painted and
• Sample the nearest longitudinal resection mar- sampled appropriately.
gin if tumour is present to within <3 cm of it. • In general, sample (four blocks minimum)
• Sample macroscopically normal bowel and tumour and wall to demonstrate these relation-
representative blocks of other mucosal lesions ships. With bulky mesentery/mesorectum, the
that are present, e.g., adenomatous polyps (if block may have to be split and appropriately
multiple particularly those >1 cm diameter). labeled for loading in the cassettes.
• Serially section the bulk of the tumour trans- • Count and sample all lymph nodes and iden-
versely at 3–4 mm intervals. tify a suture tie limit node. Take care to count
• Lay the slices out in sequence and photograph. the nodes in the tumour slices and also those
Sigmoid colon and mesentery
C
Mesorectum
Peritoneal reflection
D2
D
D1
Multiple serial
tranverse slices
Anterior
Posterior
Anus
Fig. 6.9 Rectal carcinoma. The upper anterior rectum is serosa; tumour, rectal wall, and mesorectum; Below the
invested in peritoneum. The anterior mesorectum is thin- reflection: D tumour, rectal wall, and mesorectum; D1 dis-
ner (0.75–1 cm) than the posterior mesorectum (1.5–3 cm). tance (mm) of the deepest point of continuous tumour
Cut the resection specimen into multiple serial transverse extension to the nearest point of the painted CRM; D2
slices about 3–4 mm thick. Blocks for histology are: distance (mm) of the deepest point of discontinuous
Above the reflection: A tumour, rectal wall, and serosa; B tumour extension (or in a lymphatic, node, or vessel) to
tumour, rectal wall, and serosa; tumour, rectal wall, and the nearest point of the painted CRM (Reproduced, with
mesentery; At the reflection: C tumour, rectal wall, and permission, from Allen (2013))
in the mesentery away from the tumour, e.g., pathologist can determine whether they are
sigmoid mesocolon in a rectal cancer. Separate lymph nodes replaced by tumour, discontinu-
soft tissue deposits in the mesocolon/mesorec- ous tumour extension, tumour in a vascular or
tum are submitted for microscopy so that the perineural space, or, tumour satellites.
6 Colorectum 85
• Sample multifocal serosal seedlings and • Distance of infiltration beyond muscularis

omental deposits (pM disease) as indicated by propria (for sub-staging pT3 cancers)
inspection and palpation. • Venous invasion—present/not present and deep-
Histopathology report: est (extramural, intramuscular or submucosal)
• Ulcerative colitis—site-related disease activ- • Regional lymph nodes
ity (healed/quiescent/mild/moderate/severe), –– Pericolic, perirectal, those located along
rectal sparing, appendiceal and caecal skip the ileocolic, colic, inferior mesenteric,
lesions, backwash ileitis, toxic dilatation, superior rectal and internal iliac arteries; a
superimposed infection (e.g., CMV), DALMs, regional lymphadenectomy will ordinarily
carcinoma, or lymphoma include 12 or more lymph nodes
• Crohn’s disease—chronic transmural inflam-
mation, granulomas, fissures/fistulae, abscess pN0 No regional lymph node metastasis
formation, segmental distribution/appendi- pN1 1–3 involved regional lymph node(s): pN1a =
1node, pN1b = 2–3 nodes, pN1c = soft tissue
ceal/ileal disease, malignancy deposit(s)/satellite(s) with no involved nodes
• Ischaemia—necrosis (mucosal/transmural/ pN2 4 or more involved regional lymph nodes:p
gangrenous), resection limits (ischaemic/via- N2a = 4–6 nodes, pN2b = 7 or more nodes
ble), mesenteric vessels (thrombosis/embo- Dukes’ stage
lism/vasculitis), miscellaneous (constriction A tumour limited to the wall, node negative
band/volvulus/stricture) B tumour beyond the wall, node negative
• Pseudomembranous colitis—pseudomem- C1 nodes positive, apical node negative
branes, ulceration, necrosis, perforation, C2 apical node positive
strictures D distant metastases
• Obstructive enterocolitis—note ulceration/
perforation/stricture/distribution and features • Excision margins
specific to the aetiological abnormality Proximal and distal longitudinal (cm) and
Neoplastic conditions mesocolic/mesorectal circumferential (mm)
• Tumour type—adenocarcinoma/malignant limits of tumour clearance
lymphoma/other Deep and peripheral margin clearance (mm)
• Tumour differentiation assessed in local excision specimens (see sec-
–– Adenocarcinoma tion “Resection in Neoplastic Conditions” for
Well/moderate or poor other adverse factors).
–– Malignant lymphoma • Other pathology
MALT/mantle cell/follicular/Burkitt lym- Tumour regression grade in response to neoad-
phoma/other juvant therapy, adenoma(s), FAP, ulcerative
Low grade/high grade colitis, Crohn’s disease, diverticular disease
• Extent of local tumour spread: TNM 8: for • MMR protein immunohistochemistry (to
carcinoma detect Lynch syndrome or sporadic MSI path-
way colorectal cancer, based on age of diag-
Carcinoma in situ: intraepithelial (within nosis and/or morphological suspicion).
basement membrane) or invasion of lamina
propria (intramucosal) with no extension through • Molecular testing for prediction of response to
pTis muscularis mucosae into submucosa anti-epidermal growth factor receptor (EGFR)
pT1 Tumour invades submucosa therapy, if clinically indicated (K-RAS,
pT2 Tumour invades muscularis propria N-RAS and BRAF mutation status).
pT3 Tumour invades through the wall into • Block index facilitates slide interpretation at
subserosa or non-peritonealized pericolic/ case review (for MDM or any other purpose)
perirectal tissues
and selection of suitable tumour block (with-
pT4 Tumour pT4a. perforates visceral peritoneum,
out need for slide review) for retrospective
or, pT4b. invades other organs or structures
immunohistochemical or molecular testing.
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Appendix
7
7.1 Anatomy devoid of a mesenteric covering. As was stated,

the position of the appendiceal base is constant,
The vermiform (“worm-like”) appendix is a ves- the surface landmark of this being one-third the
tigial organ in the right iliac fossa. Although way along a line drawn from the right anterior
there is considerable variability in its length and superior iliac spine to the umbilicus—McBur-
position, the base of the appendix is always found ney’s point. Internally the base can be found by
attached to the posteromedial surface of the cae- following the taeniae coli of the caecum to the
cum, approximately 2 cm below the ileocaecal base of the appendix where they converge to
valve. The base is the only part of the appendix form a continuous appendiceal longitudinal mus-
which is fixed, the remainder being free, thus cle coat.
accounting for the great variability in the position Histologically the appendiceal lumen is lined
of the body and tip (Fig. 7.1). It is completely by colonic-type columnar epithelium with abun-
surrounded by peritoneum which is continuous dant lymphoid follicles (which decrease with
with the mesentery of the small intestine, this age) in the submucosa. There are continuous cir-
connection being termed the mesoappendix. cular and longitudinal muscle coats.
Again the size of the mesoappendix is variable, Lymphovascular drainage:
and the distal appendix may occasionally be The appendix is supplied by terminal branches
of the superior mesenteric artery and vein.
Lymphatics drain to nodes in the mesoappendix,
ileocolic nodes, and subsequently to superior
D.C. Allen (*) mesenteric nodes.
Histopathology Laboratory, Belfast City Hospital,
R.I. Cameron
Western Health and Social Care Trust, Acute appendicitis (and its complications) is
Londonderry, UK among the most common surgical emergencies
e-mail: iain.cameron@westerntrust.hscni.net encountered. Classically it presents initially with
M.B. Loughrey vague, colicky, central abdominal (periumbilical)
Histopathology Laboratory, Institute of Pathology, pain, which is associated with vomiting and
anorexia. When the inflammation becomes trans-
e-mail: maurice.loughrey@belfasttrust.hscni.net mural, a localized peritonitis is elicited and the

Fig. 7.1 The various

positions of the
appendix
Preileal 1%
Retrocaecal 74%
Postileal 5%
Paracaecal 2%
Pelvic 21%
Subcaecal 1.5%
pain becomes sharp in nature, localized in the 7.3 Clinical Investigations

right iliac fossa, and associated with pyrexia.
Palpation reveals signs of localized peritonitis in • FBP—white cell count will be elevated in
the vicinity of McBurney’s point. >75% of cases of acute appendicitis.
As was stated above, the position of the • Pregnancy test—will be positive in an ectopic
body and tip of the appendix is variable and so pregnancy.
the nature of the symptoms and signs will vary • Urinalysis—to test for a urinary tract
accordingly, e.g., flank pain and tenderness in infection.
retrocaecal appendicitis. Although perforation • USS—can demonstrate a swollen appendix
of the appendix usually remains localized (due and will detect a pelvic mass.
to “walling off” by the greater omentum), • CT scan—can delineate the nature of an
occasionally it may lead to a generalized “appendiceal mass.”
peritonitis. • Laparoscopy—can be used to differentiate
The list of differential diagnoses for acute acute appendicitis from gynaecological condi-
appendicitis is myriad and includes ectopic tions. It will also detect a small mass in the
pregnancy, torsion of an ovarian cyst, Meckel’s appendix, such as a mucocele, and may be
diverticulitis, urinary tract infection, terminal used to biopsy suspected deposits of pseudo-
ileitis, endometriosis, etc. An appendiceal myxoma peritonei.
abscess (which usually develops 3 days after a
bout of acute appendicitis) can usually be pal-
pated by a combination of abdominal and rectal 7.4 Pathological Conditions
examination. Differential diagnoses of an
appendiceal mass also include carcinoma of the The appendix may be resected incidentally as
caecum, Crohn’s terminal ileitis, and ovarian part of a radical cancer operation, e.g., right
carcinoma. hemicolectomy for caecal carcinoma, or, oppor-
7 Appendix 89
tunistically, at laparotomy for other reasons, e.g., ally isolated and idiopathic), measles, CMV, or
Meckel’s diverticulectomy or resection of ovar- secondary to ulcerative colitis. Periappendicitis
ian malignancy (to exclude metastatic spread or serosal inflammation without a mucosal or
from a primary appendiceal neoplasm). However, mural component should be noted as this may
the vast majority of appendices are removed indicate inflammation emanating from another
because of clinically significant primary inflam- abdominopelvic organ, e.g., pelvic inflammatory
mation and a small minority for neoplasia. disease (salpingitis) or colonic diverticulitis. In
the older patient, such an exudate must also be
closely scrutinized for evidence of peritoneal
7.4.1 Non-neoplastic Conditions spread of carcinoma cells.
Fibroneural obliteration of the appendiceal tip
Appendicitis: Caused by epithelial ulceration, and body is now regarded as an age-related phys-
then infection by bowel bacteria, it may be pre- iological phenomenon rather than representing
cipitated by an underlying structural abnormality evidence of previous inflammation.
such as a diverticulum, or, more commonly, by
luminal obstruction for one of various reasons
(Table 7.1). It is characterized by transmural 7.4.2 Neoplastic Conditions
acute neutrophilic inflammation with the serosal
component eliciting signs of peritonism. There is Carcinoid (well-differentiated neuroendocrine)
usually close correlation between the macro- tumour: Forming over 80% of appendiceal
scopic and histological findings with acute tumours, carcinoid tumour of classical type is
appendicitis, resulting in serosal congestion, usually small (<1 cm diameter) and found as an
inflammatory exudate, and adherence of fat. incidental finding at the appendiceal tip with or
Serious complications can arise from the resul- without associated appendicitis. It can be a histo-
tant mural necrosis with wall thinning, gangrene, logical finding only amidst the inflammation, or
and perforation, potentially leading to general- macroscopically discernible as a firm, pale-
ized peritonitis, periappendicular abscess forma- yellow mass replacing the lumen and wall. It has
tion, portal vein pyaemia, and hepatic abscesses. a variable nested and tubular pattern of uniform
In general, the high risk of morbidity and mortal- neuroendocrine cells that are positive with chro-
ity serves to emphasize the crucial importance of mogranin A and synaptophysin antibodies.
early diagnosis and therapeutic appendicectomy. Despite showing transmural, serosal, and lym-
Chronic appendicitis is a more controversial phovascular spread, appendicectomy is usually
entity, but in a minority of cases the inflammation totally therapeutic and recurrence is only seen in
may resolve, leaving only residual thickening of a very small number of cases where the lesion is
the tissues. greater than 2 cm diameter or there is involve-
Other unusual causes of subacute appendicitis ment of the appendiceal base, caecal wall, meso-
are: granulomatous appendicitis (Crohn’s dis- appendix, or local lymph nodes. Conversely the
ease, sarcoidosis, TB, schistosomiasis, but usu- much less common mucin-rich, goblet cell carci-
noid (formerly adenocarcinoid/crypt cell carci-
Table 7.1 Obstructive causes of appendicitis noma) more frequently involves the appendiceal
base with potential for nodal metastases, local
Hardened, impacted faecal
Faecolith debris invasion of the caecal pouch, and transcoelomic
Foreign body Vegetable matter, fruit pips peritoneal spread with ovarian metastases.
Tumour Carcinoid, adenocarcinoma Because of this, goblet cell carcinoid requires
appendix or caecal base consideration for right hemicolectomy. Due to
Mucosal lymphoid Mesenteric adenitis, infectious the difficulties in distinguishing between carci-
hyperplasia monocleosis, yersinia noid tumour and inflammatory fibrotic reaction,
Endometriosis enterocolitica infection
the appendiceal tip and base are sampled and
separately identified as part of the routine adenomatous epithelium that is limited to the
blocking procedure to assess adequacy of tumour appendix more often results in a self-limited
excision if present. localized reaction.
Polyps: Hyperplastic polyps; sessile serrated It is now recognized that there is a strong asso-
lesions; tubular, tubulo-villous or villous adeno- ciation between generalized pseudomyxoma
mas; adenomas are more often sessile than pol- peritonei, appendiceal mucinous tumours, and
ypoid comprising low- or high-grade dysplastic bilateral ovarian mucinous borderline tumours
epithelium. All these lesions may be associated with the latter regarded as either implantation
with synchronous/metachronous polyps or deposits or metastases from the appendiceal
tumours elsewhere in the colorectum, adenomas lesion.
with FAP, mucocele (see below) or adenocarci- Prognosis: Carcinoid tumours less than 2 cm
noma of the appendix or adjacent caecal pouch. diameter are generally adequately treated by
Diagnosis of any appendiceal polyp within an local appendicectomy. Those that are larger,
appendicectomy specimen should therefore trig- involve the base or mesoappendix or are of goblet
ger consideration of follow-up colonoscopy. cell type may require right hemicolectomy.
Adenocarcinoma: A relatively unusual lesion Prognosis of mucocele depends on the nature of
that may be mucinous and cystic, secondary the underlying mucosal epithelium and degree of
involvement of the proximal appendix from the spillage of epithelium into the peritoneal cavity.
caecal pouch is more common than a primary Adenocarcinoma treated by appendicectomy
appendiceal lesion. Signet ring cell variant ade- alone does worse (20% 5-year survival) than
nocarcinomas may arise from underlying goblet when right hemicolectomy is performed (60–
cell carcinoid and demonstrate overt (MANEC, 65% 5-year survival)—outlook is tumour grade
mixed adenoneuroendocrine carcinoma) or only and stage dependent.
subtle neuroendocrine differentiation. Other can-
cers metastatic to the appendix are from ovary,
stomach, breast, and lung. 7.5 Surgical Pathology
Mucocele: Macroscopic distension of the Specimens: Clinical Aspects
appendiceal lumen by abundant mucus often
with marked thinning of the wall. Obstructed or 7.5.1 Biopsy Specimens
non-obstructed in character the former represents
a retention cyst lined by attenuated and atrophic Not applicable.
but non-dysplastic mucosa. Non-obstructed
mucocele is due to oversecretion of mucus by an
abnormal mucosal lining that can be either hyper- 7.5.2 Resection Specimens
plastic, adenomatous (LAMN—low-grade
appendiceal mucinous neoplasm—if there is 7.5.2.1 Appendicectomy
destruction of the muscularis mucosae) or frankly Although the appendix may be removed laparo-
adenocarcinomatous in nature. Extrusion of scopically or in the course of other procedures for
mucus through the wall to the serosa results in diagnostic and/or staging purposes (e.g., sus-
pseudomyxoma peritonei which is localized to pected ovarian malignancy), the operation of
the periappendiceal tissues or generalized in the choice in acute appendicitis is open appendicec-
peritoneal cavity. The latter can be refractory to tomy. In the case of an “uncomplicated appendi-
surgical debridement with reaccumulation over a citis,” a muscle-splitting Gridiron oblique
prolonged time course of months to years result- incision centred over McBurney’s point is used.
ing in bowel obstruction and death. It is due to The caecum is delivered into the wound and the
spillage of either atypical or frankly malignant taeniae coli are followed to the base of the appen-
appendiceal epithelium into the peritoneal cavity, dix. The appendicular vessels in the mesoappen-
whereas mucocele due to benign hyperplastic or dix are divided and ligated. The appendiceal base
7 Appendix 91
is crushed and ligated, and the appendix is Initial procedure:

divided distal to the ligation. • Orientate the tip (rounded end) and the base
If appendiceal perforation with generalized (clamp marked).
peritonitis is present preoperatively, a midline • Measurements:
incision may be employed to facilitate better Appendix—length (cm) × maximum diameter
access to the abdominal cavity. This will allow an (cm).
adequate laparotomy examination and peritoneal Mesoappendix—maximum dimension (cm).
lavage to be carried out and so will lessen the risk Exudate (serofibrinous/mucin)/perforation/
of postoperative abscess formation. mucocele/tumour—maximum dimension
In the case of an appendiceal abscess, the patient (cm) and distances (cm) from the tip and base.
may be initially treated conservatively with antibi- • Photograph before and after blocking as
otics and close clinical supervision, followed by an appropriate.
interval appendicectomy at a later date. However, if • Fix in 10% formalin for 24–36 h.
there is diagnostic doubt or worsening symptom- Description:
atology (e.g., increasing pyrexia), early operative • Tumour
intervention is indicated. Although a simple appen- –– Nodular/yellow: carcinoid
dicectomy may suffice, a right hemicolectomy –– Cystic: cystadenoma/adenocarcinoma
may be needed if a large mass is present. –– Ulcerated/stricture/polypoid: adenocarci-
noma/goblet cell carcinoid
7.5.2.2 Right Hemicolectomy • Wall
The technique of right hemicolectomy (removal –– Tumour confined to mucous membrane, in
of the terminal ileum, caecum, and proximal the wall or through the wall
ascending colon) is described in detail elsewhere • Mesoappendix
(see Chap. 6). –– Maximum dimension (cm) of abscess/
As well as for a large appendiceal mass, other tumour/mucin deposits
lesions of the appendix requiring a right hemico- • Mucocele
lectomy include primary adenocarcinoma and, as –– Maximum diameter (cm)/intact or rup-
previously discussed, a minority of carcinoid tured/mucin coating (location and extent)
tumours. • Diverticulum
–– Maximum diameter (cm) and location
• Appendicitis
7.6 Surgical Pathology –– Exudate/perforation/gangrene: location
Specimens: Laboratory and extent
Protocols
Blocks for histology (Fig. 7.2):
• Trim off any excess mesenteric fat and only
Specimen: process that which appears abnormal.
• Process in one cassette a 1–1.5 cm longitudi-
• Handle similarly whether as part of a radical nal slice from the tip along with a transverse
cancer resection specimen or a simple appen- section from the base.
dicectomy. The former will require sampling • Serially section the rest of the appendix trans-
of adjacent structures and locoregional lymph versely at 3 mm intervals with a sharp scalpel.
nodes (see Chap. 6). • Sample five to six slices, approximately one
• Some appendicectomies are submitted in sev- slice per 1–1.5 cm length and process in a
eral pieces due to difficulties in surgical exci- separate cassette from that of the tip/base.
sion. This precludes assessment of the base • Sample any area of mural thinning or focal
unless a surgical clamp mark is visible. lesion as indicated by gross inspection.
Surgical
clamp mark
Process a bisected
longitudinal slice from
the tip along with the
base block
Transverse section
the base
Serially section the appendix
transversely at 1−1.5cm intervals
Fig. 7.2 Appendicectomy specimen (Reproduced, with permission, from Allen and Cameron (2013))
• If part of a formal cancer resection specimen, pT3 > 4 cm or into subserosa/mesoappen-

e.g., right hemicolectomy, dissect and sample dix, and, pT4 into peritoneum or adjacent
as previously described (see Chap. 6). organs/structures other than by direct mural
Histopathology report: extension e.g. abdominal wall.
• Appendicitis –– pN1 regional lymph node(s) involved.
–– Cause: faecolith, tumour, diverticulum, –– Spread: mesoappendix, peritoneum, appen-
endometriosis diceal base (R0/R1).
–– Type: acute (transmural/gangrenous/perfo- • Adenocarcinoma
ration/abscess), granulomatous, –– See Chap. 6. In TNM 8 appendiceal adeno-
peri-appendicular carcinoma and goblet cell carcinoid are
• Mucocele staged similarly to colorectal carcinoma.
–– Obstructed/non-obstructed Adenocarcinomas are also classified as
–– Intact/ruptured mucinous or non-mucinous for grading
–– Mucosal hyperplasia/adenoma(LAMN)/ purposes.
adenocarcinoma –– pT1 submucosa, pT2 muscularis propria,
–– Pseudomyxoma: localized/generalized/pres- pT3 subserosa/mesoappendix, pT4 visceral
ence and nature of the epithelium present peritoneum (including mucinous peritoneal
• Carcinoid tumour tumour or acellular serosal mucin) or other
–– Type: classical/goblet cell organs/adjacent structures.
–– Size: ≤ or >2 cm: TNM 8 for well differen- –– pN1 1–3 nodes, pN2 ≥ 4 nodes. A regional
tiated neuroendocrine tumours— lymphadenectomy will ordinarily include
pT1 ≤ 2 cm, pT2 > 2 cm and ≤4 cm, 12 or more lymph nodes.
7 Appendix 93
Bibliography Shepherd NA, Warren BF, Williams GT, Greenson JK,

Allen DC, Cameron RI. Histopathology specimens.
Clinical, pathological and laboratory aspects. 2nd ed.
Bosman FT, Carneiro F. WHO classification of tumours of
biopsies for primary and metastatic carcinoma, endo-
crine tumours of the gastrointestinal tract including
pancreas) and tissue pathways (gastrointestinal and
pancreatobiliary pathology, liver biopsies for the
investigation of medical disease and for focal liver
Surgical pathology of the GI tract, liver, biliary tract, and
lesions). Available via https://www.rcpath.org/pro-
pancreas. 3rd ed. Philadelphia: Elsevier Saunders; 2015.
fession/publications/cancer-datasets.html.
of the intestines, Atlas of tumor pathology, vol. 3rd
series. Fascicle 32. AFIP: Washington, DC; 2003.
Anus
8
8.1 Anatomy perianal skin. The circular muscle layer is thick-

ened around the upper anal canal to form the
The anal canal (anus) is 4 cm long and is continu- internal (involuntary) sphincter. A sheath of stri-
ous with the rectum above the pelvic floor. The ated muscle encloses this—the external (volun-
mucous membrane of the upper half of the anal tary) sphincter. The longitudinal muscle coat
canal is lined by columnar epithelium and sup- descends between the internal and external
plied by autonomic nerves, being sensitive only sphincters. The ischiorectal fossa is a fat-filled
to stretch. The lower half is lined by stratified space on either side of the anal canal between it
squamous epithelium and has a somatic nerve and the bony pelvis (Fig. 8.1).
supply, being sensitive to pain, touch, etc. There Lymphovascular drainage:
is a transition zone with a sharp demarcation The upper half is supplied by the superior rec-
between the two types of mucosa, termed the tal artery (a branch of the inferior mesenteric
dentate line. Distally the canal terminates at the artery) and the lower half by the inferior rectal
anal verge merging with the appendage-bearing artery (a branch of the internal iliac artery). The
veins correspond to the arteries and the lymphat-
ics from the upper and lower halves drain to the
perirectal and inferior mesenteric, and internal
D.C. Allen (*) inguinal and superficial inguinal nodes, respec-
tively (Fig. 8.2).
R.I. Cameron
Histopathology Laboratory, Altnagelvin Hospital, 8.2 Clinical Presentation
Londonderry, UK Anorectal conditions are relatively common in
e-mail: iain.cameron@westerntrust.hscni.net
surgical practice and present in a number of ways
M.B. Loughrey including pain, itch, bleeding, discharge, pyrexia,
Histopathology Laboratory, Institute of Pathology,
a mass or inguinal lymphadenopathy. An accu-
Care Trust, Belfast, UK rate diagnosis is crucial to successful treatment
e-mail: maurice.loughrey@belfasttrust.hscni.net of the condition.

Colorectal zone
Anal transitional zone
Dentate line Anal

canal
Anal gland
External sphincter Squamous zone
Internal sphincter
Ischiorectal fossa Anal margin
Perianal skin
Fig. 8.1 The anatomy of the anal canal (Reproduced, with permission, from Williams and Talbot (1994))
Fig. 8.2 Anus: regional

lymph nodes. Perirectal
(1), internal iliac (2),
and inguinal (3) (Used
with the permission of
the Union for
International Cancer
Control (UICC),
8 Anus 97
8.3 Clinical Investigations Fissure-in-ano: A tear at the anal margin that

often follows the passage of a constipated stool, it
• FBP—occasionally chronic bleeding can lead is usually posterior and midline in location. It is
to iron-deficiency anaemia. painful and may be marked by a skin tag at its
• Serology—if a syphilitic ulcer is suspected. distal aspect. Multiple fissures can complicate
• Blood glucose—in those with recurrent ano- Crohn’s disease.
rectal sepsis to rule out diabetes mellitus. Anorectal abscesses: Resulting from infection
• Microbiology—pus from an abscess should of anal submucosal glands, they are perianal,
be cultured and antibiotic sensitivities ischiorectal, submucosal, or pelvirectal in loca-
obtained. tion. Underlying Crohn’s disease or diabetes
• Proctoscopy—used to inspect the anus and must always be excluded.
anorectal ring. Biopsy of lesions above the Fistula-in-ano: An abnormal communication
dentate line can be taken without anaesthesia. between two epithelial surfaces; commonly the
• Sigmoidoscopy/colonoscopy—should be anal canal and perineal skin. The majority arise
undertaken when an anorectal condition is from infection of anal glands resulting in an ano-
thought to be secondary to inflammatory rectal abscess that tracks and opens, discharging
bowel disease. onto the perineum externally and the anal canal
• MRI scan—useful in delineating the course of internally. Associated conditions such as Crohn’s
complicated fistulae and with ELUS, the disease, ulcerative colitis, and low rectal/anal
extent of local tumour spread. CT scan (chest, mucinous adenocarcinoma must be excluded
abdomen, and pelvis) will demonstrate local histologically.
and distant metastases. Prolapse: A consequence of mucosal prolapse
• Trucut needle biopsy—used when there is at this site is the so-called inflammatory cloaco-
suspicion of recurrent or residual tumour in genic polyp. It arises at the internal margin com-
the ischiorectal fossa. prising a mixture of thickened low rectal and
high anal glandular, transitional and squamous
mucosae associated with hypertrophic muscula-
8.4 Pathological Conditions ris mucosae. These polyps are often excised to
exclude the possibility of adenoma or carcinoma
8.4.1 Non-neoplastic Conditions which can share similar clinical appearances and,
importantly, these can co-exist, with prolapse
Haemorrhoids (piles): Comprising engorgement changes evident adjacent to a mass lesion.
of submucosal veins, they are common and pre-
disposed to by increased pelvic pressure, e.g.,
constipation, pregnancy, obesity, pelvic tumour. 8.4.2 Neoplastic Conditions
They bulge into the anal canal and are trauma-
tized by straining at stool and hard faeces. Benign tumours: These are rare, e.g., granular
Complications include bleeding, reversible cell tumour.
prolapse into the anal canal or persistent prolapse Human papilloma virus (HPV): A common
outside the anal margin—these so-called external aetiological agent associated with a spectrum of
haemorrhoids, which are located below the den- anal viral lesions, preneoplasia (anal intraepithe-
tate line and covered by anal skin, are particularly lial neoplasia—AIN) and carcinoma, as well as
prone to painful strangulation and thrombosis, concurrent lesions of the uterine cervix. HPV
which is an indication for surgical excision. subtypes 16/18 are particularly neoplasia pro-
Skin tags: Fibrous skin tags at the anal margin gressive in this viral–AIN–carcinoma sequence.
can indicate various abnormalities, e.g., a previ- Anal margin/perianal skin carcinoma:
ous thrombosed external haemorrhoid, Crohn’s Commonly well-differentiated keratinizing squa-
disease, fissure, or fistula. mous carcinoma with predisposing conditions
being viral warts (condyloma accuminata) and survival. Adverse indicators are advanced stage
perianal squamous intraepithelial neoplasia or depth of spread, inguinal node involvement,
(PSIN—previously known as Bowen’s disease or and post-treatment pelvic and perineal recur-
squamous cell carcinoma in situ of perianal skin). rence. Malignant melanoma is aggressive with
Variants include the exophytic, indolent verru- poor outlook; the prognosis of leiomyosarcoma
cous carcinoma. Treatment is primarily by local is related to tumour grade.
surgical excision as for skin carcinoma.
Anal canal carcinoma: A squamous cell carci-
noma with variable degrees of squamous, basa- 8.5 Surgical Pathology
loid (synonym: cloacogenic/non-keratinizing Specimens: Clinical Aspects
small cell squamous carcinoma) and ductular dif-
ferentiation. Proximal anal canal cancers are 8.5.1 Biopsy Specimens
poorly differentiated and basaloid, whereas distal
anal cancers are well differentiated and more The anal canal is best inspected by proctoscopy.
overtly squamous in character. There are associa- The proctoscope is a rigid disposable tube with a
tions with Crohn’s disease, smoking, immuno- light source attached, which is inserted with the
suppression and sexually transmitted diseases. At patient in the left lateral position. Forceps can be
diagnosis 15–25% have spread through sphinc- passed through the tube to biopsy any visible
teric muscle into adjacent soft tissues (vagina, lesion. Biopsy specimens may also be received
urethra, prostate, bladder, etc.) and 5–10% have from the walls/roof of areas of anorectal sepsis to
haematogenous metastases to liver, lung and rule out granulomatous inflammation.
skin. Small “early” lesions may be locally excised
but otherwise primary therapy is concurrent
radio−/chemotherapy with good preservation of 8.5.2 Resection Specimens
anal sphincter function and tumour response.
Abdominoperineal or exenterative resection is 8.5.2.1 Resection of Neoplastic Disease
rare and reserved for extensive (e.g., vaginal Anal carcinoma—Small lesions (<2 cm) present
involvement), recurrent or non-responsive at the anal verge are usually treated by local exci-
tumours. Inguinal node disease may require sion ideally with a 2 cm margin of skin around
block dissection of the groin and can be deter- the tumour, but trying to preserve the anal sphinc-
mined on fine-needle aspiration cytology. Many ter. The resection should extend down to the peri-
arise in the vicinity of the dentate line from the anal fat. For larger tumours, or extensive tumours
transitional/cloacal zone with upward submuco- of the anal canal that are unresponsive to radio−/
sal spread, presenting as an ulcerated tumour of chemotherapy, abdominoperineal resection is the
the lower rectum from which it must be distin- procedure of choice. A 2 cm margin of perineal
guished by biopsy as rectal cancer requires surgi- skin should be excised around the tumour and
cal resection following neoadjuvant treatment. there should be a radical ischiorectal resection. If
Other cancers: A not uncommon differential there is metastatic spread to superficial inguinal
diagnosis is a low rectal carcinoma with distal nodes, then a radical groin dissection may be
spread into the anal canal. Relatively rare cancers considered.
are mucinous adenocarcinoma in an anal fistula,
primary anal gland adenocarcinoma, extra- 8.5.2.2 Resection of Non-neoplastic
mammary Paget’s disease (associated with low Lesions
rectal adenocarcinoma, anal gland adenocarci- Fissure-in-ano—Acute fissures can usually be
noma, or isolated), malignant melanoma, and treated conservatively by introducing stool-
leiomyosarcoma. softening measures. However, a chronic anal fis-
Prognosis: Perianal carcinoma 85% 5-year sure can be treated by either anal dilatation or
survival, anal canal carcinoma 65–80% 5-year lateral internal sphincterotomy.
8 Anus 99
Haemorrhoids—If haemorrhoids are small ectatic submucosal vessels. Bisect vertically

and asymptomatic, then no treatment is necessary down through the epithelial surface and pro-
except for measures to avoid constipation. Non- cess both halves. With larger or multiple spec-
prolapsing piles are probably best treated by imens, a mid-slice of each is taken.
injection sclerotherapy. Larger prolapsing piles Skin tags: Count and measure, process intact,
above the dentate line are treated by rubber band vertically bisect or take a representative mid-
ligation. Both the above procedures can be per- slice according to size.
formed during routine proctoscopy without Fissure-in-ano: Not usually excised, although
anaesthesia. Piles too large to band and/or which biopsy fragments of granulation tissue from
extend below the dentate line can be treated by its edge may be submitted.
formal haemorrhoidectomy. The procedure most Anorectal abscess: Usually heavily inflamed
commonly used involves excision of the three ellipses of tissue from the covering skin, lat-
main piles, with preservation of the intervening eral or deep aspects of the abscess wall.
anal mucosa. The wounds are left open to heal by Measure, process intact, vertically bisect or
secondary intention. take a representative mid-slice according to
Anorectal abscess/fistula—An abscess is size.
drained under general anaesthetic, after thorough Fistula-in-ano (Fig. 8.3): Rarely resected but
proctoscopic/sigmoidoscopic examination, by typically a small skin ellipse often with a
incision and laying open the abscess cavity. The punctate opening on the surface, minimal sub-
surgical treatment of fistula-in-ano depends on the cutaneous tissue, and a stringy attachment
position of the tracts and is often complicated. which may be up to several centimeters
Essentially the general principle of anorectal fis- long—the fistulous tract. It may also be sub-
tula surgery is to lay open the primary tract and mitted in fragments if excision was difficult.
drain any secondary tracts while maintaining Measure the skin ellipse, its opening, and the
sphincter function. It is crucial to continence to
preserve the function of the upper part of the
external sphincter and so laying open “high” fistu-
lae is not advised. Instead, a permanent seton
suture is passed through the tract and allows drain-
age while the secondary tract heals. The primary Vertically bisect
tract should then heal after removal of the suture. down through the
surface opening
8.6 Surgical Pathology

Specimen: Laboratory
Protocols Multiple transverse
sections of the
8.6.1 Biopsy Specimens fistula
Elliptical incisional and excisional biopsies of

the perineal skin and anal margin are handled
similarly to skin biopsies (see Chap. 38). Anal Transverse section
the fistula limit
canal biopsy fragments are processed as previ-
ously described (see Chap. 1). Specific points of
note are as follows:
Haemorrhoids: Typically nodular and 1–2 cm in Fig. 8.3 Fistula-in-ano (Reproduced, with permission,
diameter with a smooth covering mucosa and from Allen and Cameron (2013))
tract. Take a block vertically through the skin levator musculature which also forms a tight
to include the punctum and represent any sub- neck or constriction at its junction with the
cutaneous abscess. Sample multiple trans- lower edge of the mesorectum.
verse sections of the fistulous tract and label a • Serially section the tumour transversely at
transverse deep resection limit block. 3–4 mm intervals. Sample a minimum of four
Cloacogenic polyp: Measure, vertically bisect or blocks of tumour and wall to show the deepest
take representative slices. Prior to this, paint point of invasion in relation to the painted
the deep and lateral margins in case it turns CRM. Sample a longitudinal block of tumour
out to be polypoid tumour. and proximal/distal limit if close (<0.5–1 cm)
to it.
Histopathology report:
8.6.2 Neoplastic Conditions • Tumour type—anal canal squamous carci-
noma/other
Anal margin/perianal skin lesions such as condy- • Tumour differentiation—basaloid/keratiniz-
loma, PSIN, or carcinoma are handled as for skin ing/non-keratinizing/ductular component
specimens. • Tumour edge—pushing/infiltrative/lymphoid
Anal canal carcinoma if resected will either be response
because of recurrent or extensive disease in the • Extent of local tumour spread: TNM 8: for
context of abdominoperineal resection or pelvic anal canal carcinoma and also includes carci-
exenteration specimens where the tumour spread nomas of anal margin and perianal skin within
may be partially masked by fibrotic radio−/che- 5 cm of the anal margin
motherapy changes. For general comments see
Chaps. 6 and 35. pTis Carcinoma in situ
Specific points of note in abdominoperineal pT1 Tumour ≤2 cm in greatest dimension
resection for anal canal carcinoma are: pT2 2 cm < tumour ≤5 cm in greatest dimension
pT3 Tumour >5 cm in greatest dimension
pT4 Tumour of any size invading adjacent organ(s),
• Open the canal longitudinally with blunt-
e.g., vagina, urethra, bladder
ended scissors on the opposite side of the
tumour having previously painted the external
CRM (circumferential radial margin). • Lymphovascular invasion—present/not present.
• The tumour is frequently submucosal ± over- Anal margin/perianal skin lesions: inguinal
lying mucosal ulceration. Pale and variably nodes—regional lymphadenectomy will ordi-
fleshy to scirrhous in character; pigmenta- narily include 6 or more lymph nodes.
tion and rubbery/fleshy qualities should raise Anal canal lesions: perirectal, internal iliac,
the possibility of malignant melanoma or inguinal nodes in that order—a regional
leiomyosarcoma, respectively. Mucinous lymphadenectomy will ordinarily include 12
carcinoma may occur in a fistula while anal or more lymph nodes.
gland carcinoma is also submucosal and
sclerotic. pN0 No regional lymph node mestastasis
• The relationships and distances (mm) to the anal pN1a Metastasis in inguinal, mesorectal and/or
internal iliac lymph node(s)
margin/perianal skin and anorectal dentate line.
pN1b Metastasis in external iliac lymph node(s)
• Upward or downward spread to the lower rec-
pN1c Metastasis in external iliac and in inguinal,
tum and perianal skin, respectively. mesorectal and/or internal iliac lymph nodes
• The extent of mucosal/mural/extramural
spread and distances (mm) to the nearest lon-
gitudinal and radial margins (perianal skin, • Excision margins
site-orientated aspect of the CRM). Note that Proximal rectal and distal perianal/perineal
the CRM comprises a tube of perianorectal limits of tumour clearance (cm)
8 Anus 101
Deep circumferential radial margin of clear- and pancreas. 3rd ed. Philadelphia: Elsevier Saunders;
2015.
ance (mm)
• Other pathology of the intestines, Atlas of tumor pathology, vol. 3rd
Condylomatous warts, Bowen’s disease series. Fascicle 32. Washington, DC: AFIP; 2003.
(PSIN), anal fistula, Crohn’s disease, AIN, Shepherd NA, Warren BF, Williams GT, Greenson JK,
radio−/chemotherapy necrosis and tumour
regression Wiley-Blackwell; 2013.
Simpson JAD, Scholefield JH. Diagnosis and manage-
ment of anal intraepithelial neoplasia and anal cancer.
BMJ. 2011;343:1004–9.
Bibliography (oesophageal carcinoma, gastric carcinoma, carcino-
Allen DC. Histopathology reporting. Guidelines for surgi- bile duct, colorectal cancer, gastrointestinal stromal
cal cancer. 3rd ed. London: Springer; 2013. tumours (GISTs), liver resection specimens and liver
Allen DC, Cameron RI. Histopathology specimens: clini- biopsies for primary and metastatic carcinoma, endo-
cal, pathological and laboratory aspects. 1st ed. Berlin: crine tumours of the gastrointestinal tract including
Springer; 2013. pancreas) and tissue pathways (gastrointestinal and
Bosman FT, Carneiro F. WHO classification of tumours of pancreatobiliary pathology, liver biopsies for the inves-
the digestive system. 4th ed. Lyon: IARC Press; 2010. tigation of medical disease and for focal liver lesions).
Brierley JD, Gospodarowicz MK, Wittekind C, editors. Available via https://www.rcpath.org/profession/publi-
TNM classification of malignant tumours. 8th ed. cations/cancer-datasets.html. Accessed Oct 2016.
Oxford: Wiley-Blackwell; 2017. Williams GR, Talbot IC. Anal carcinoma: a histological
Fielding LP, Goldberg SM, editors. Rob and Smith’s oper- review. Histopathology. 1994;25:507–16.
ative surgery: surgery of the colon, rectum and anus. Wittekind C, Greene L, Hutter RVP, Klimfinger M, Sobin
5th ed. Oxford: Elsevier Science; 2002. LH. TNM atlas: illustrated guide to the TNM/pTNM
Odze RD, Goldblum JR, editors. Odze and Goldblum classification of malignant tumours. 5th ed. Berlin:
Surgical pathology of the GI tract, liver, biliary tract, Springer; 2005.
Gallbladder
9
9.1 Anatomy right side of the common hepatic duct to form the
common bile duct. The course of the cystic duct
The gallbladder is a sac that lies on the inferopos- shows great variation between individuals. The
terior surface of the liver. It is divided into the gallbladder is concerned with the concentration,
fundus (rounded portion that projects below the storage, and delivery of bile. To aid the concentra-
liver), body (lies in contact with the liver), and tion process the mucous membrane is thrown into
neck (becomes continuous with the cystic duct). permanent folds. The bile salts emulsify fats in
Stones may cause a dilatation at the junction of the duodenum and so facilitate their digestion and
the neck and cystic duct known as Hartmann’s absorption. When fatty food enters the duode-
pouch. The gallbladder is two-thirds surrounded num, endocrine cells release hormones, which
by peritoneum which binds the non-peritonealized lead to contraction of the gallbladder and relax-
adventitial aspect of the body and neck to the ation of the sphincter of Oddi, thus allowing bile
under surface of the liver. The cystic duct is 4 cm to be delivered to the duodenum. The mucous
long and joins the neck of the gallbladder to the membrane of the cystic duct is raised in the form
of a spiral fold. This is thought to assist in keeping
the lumen patent. An important surgical landmark
(where the cystic artery can be found) is Calot’s
triangle which is formed by the common hepatic
P.J. Kelly (*) • M.B. Loughrey duct, the cystic duct, and the liver (see Fig. 4.2).
Histopathology Laboratory, Institute of Pathology, Lymphovascular drainage:
Care Trust, Belfast, UK The main arterial supply to the gallbladder is
e-mail: paul.kelly@belfasttrust.hscni.net; from the right hepatic artery via the cystic artery
maurice.loughrey@belfasttrust.hscni.net that runs through Calot’s triangle. The cystic vein
D.C. Allen drains directly to the portal system. Lymphatics
Histopathology Laboratory, Belfast City Hospital, from the gallbladder and bile ducts pass to the
Belfast Health and Social Care Trust, Belfast, UK cystic node (situated near the gallbladder neck)
and then through the infrahepatic nodes. At the
R.I. Cameron distal end of the common bile duct, they pass into
Western Health and Social Care Trust, the peripancreatic and periduodenal nodes, and
Londonderry, UK ultimately drain to the coeliac and superior mes-
e-mail: iain.cameron@westerntrust.hscni.net enteric nodes (Fig. 9.1).

flow of bile through the adjacent common bile

duct (Mirizzi syndrome). More commonly, a
stone passes through and on into the common
bile duct obstructing it. Gallstone ileus (small
bowel obstruction due to impactation of a stone
at the ileocaecal valve after the formation of a fis-
tula between the gallbladder and duodenum) is a
rare complication of cholecystitis.
Gallbladder carcinoma may present in a simi-
lar manner to gallstone disease, although weight
loss and jaundice are additional features, obstruc-
tive jaundice being caused by metastatic spread
to nodes which compress the bile ducts.
Fig. 9.1 The regional lymph nodes are the hepatic hilus
nodes (including nodes along the common bile duct, com- 9.3 Clinical Investigations
mon hepatic artery, portal vein, and cystic duct), coeliac
and superior mesenteric nodes (Used with the permission There is considerable overlap in the investigation
of the Union for International Cancer Control (UICC),
Geneva, Switzerland. The original source for this material
of gallbladder and extrahepatic bile duct disease.
is from Wittekind et al. (2005))
• Blood tests—FBC—elevated WCC in chole-
cystitis. LFTs may show elevated serum bili-
rubin or alkaline phosphatase, particularly if
9.2 Clinical Presentation there is a stone in the common duct.
• AXR—limited diagnostic use for detecting
There is considerable overlap in the clinical fea- gallstones as only 10–15% of stones are radio-
tures of gallbladder and extrahepatic bile duct opaque; gas in the gallbladder wall (emphyse-
disease. Gallstones are often asymptomatic. matous cholecystitis) is a serious complication
However, if there is gallbladder outlet obstruction of cholecystitis seen most commonly in dia-
by a stone, then progressively severe right upper betics; in gallstone ileus, it will show the clas-
quadrant “colicky” pain (biliary colic), associ- sic triad of small intestinal obstruction,
ated with nausea and vomiting, may be felt. If the gallstone in the right iliac fossa, and gas in the
stone remains impacted, the gallbladder may biliary tree.
become infected and acutely inflamed (acute • USS—sensitive for stones >4 mm. This has
cholecystitis)—this leads to severe constant right supplanted the use of oral cholecystogram.
upper quadrant pain, pyrexia, and signs of local- • Oral cholecystogram—oral contrast is taken
ized peritonitis. This can progress to an empyema and this is absorbed from the gut, bound to
(pus-filled gallbladder). Stone impactation may albumin in the portal vein, and subsequently
also lead to a mucocele, i.e., a dilated gallbladder secreted in bile. Radiological imaging of the
in which the bile has been resorbed but mucus gallbladder is then carried out 10 h after inges-
secretion continues. A mucocele is heralded by a tion. May be indicated when the clinical
palpable gallbladder and dull right upper quad- symptoms are strongly suggestive of gall-
rant pain. Occasionally in the elderly the gallstones but the USS is negative.
bladder may perforate, leading to generalized • Cholangiography—intravenous cholangiogra-
peritonitis. Gallstones localized to the cystic duct phy has been replaced by MRCP (magnetic
will occasionally cause obstructive jaundice, resonance cholangiopancreatography) to
especially if the duct is short. The inflammation assess the biliary tree non-invasively. MRCP
and oedema around the cystic duct impedes the may identify a mass. ERCP (endoscopic
9 Gallbladder 105
retrograde cholangiopancreatography) and abscesses which may only partly resolve leaving
PTC (percutaneous transhepatic cholangiog- a marked xanthogranulomatous histiocytic
raphy) are generally reserved for removing inflammatory reaction that encases the gallblad-
ductal stones but may also define strictures in der. Prominent sinus formation at the fundus can
the ductal system and allow collection of bili- similarly mimic a mucosal polyp or tumour, so-
ary brushings. called cholecystitis glandularis proliferans.
• Percutaneous drainage—under radiological Unusual variants of chronic cholecysitis are fol-
guidance can be used to drain the gallbladder licular (reactive lymphoid aggregates), eosino-
in, e.g., empyema. philic (often acalculous and chemical in nature),
• CT scan (chest, abdomen, and pelvis), may and malakoplakia. Due to the strong association
demonstrate a tumour mass, invasion of the with pancreatitis, fat necrosis and calcification
liver, and compression of bile ducts. may be seen.
Cholesterolosis: A relatively common find-
ing of yellow mucosal flecks (“strawberry”
9.4 Pathological Conditions gallbladder) due to accumulation of choles-
terol-laden macrophages in the lamina propria.
9.4.1 Non-neoplastic Conditions It is usually incidental and not associated with
hypercholesterolaemia.
Cholelithiasis (gallstones): The commonest aeti- Oleogranulomas: The cystic duct lymph node
ological agent in gallbladder pathology and clas- is not infrequently enlarged and submitted along
sically occurring in fair, fat, fertile, females in with the cholecystectomy specimen. It often con-
their 40s. Mixed stones are the most frequent tains oleogranulomas comprising fat spaces sur-
(80%) formed from an amalgam of bile, choles- rounded by histiocytes, presumably representing
terol, and calcium, and comprising biliary sludge, a gallbladder drainage phenomenon.
calculous gravel or multiple, faceted, laminated
stones. Occasionally stones can be pure such as
dark bilirubinate pigment stones in a congenital 9.4.2 Neoplastic Conditions
haemolytic disorder, e.g., spherocytosis, or, soli-
tary, large, yellow, and cholesterol-rich. Dysplasia: This can be flat or raised/papillary.
Acute cholecystitis: 95% of cases are due to Flat dysplasia is often an incidental finding and
impaction of a stone in the cystic duct resulting in may be multifocal. Low grade dysplasia should
stasis, a bile-induced chemical reaction, and then prompt further examination of the gallbladder
secondary infection. The acute inflammation and submission of extra blocks to assess for high
often subsides with conservative medical treat- grade change or invasive malignancy. High grade
ment but can persist producing an empyema— dysplasia, especially if flat, can spread rapidly
perforation and bile peritonitis are unusual. In a through the gallbladder and may require entire
mucocele, the wall may calcify and form a “por- submission of the gallbladder. The cystic duct
celain” gallbladder. should be carefully examined for dysplasia.
Chronic cholecystitis: Invariably associated Raised papillary lesions may be greater than
with calculi, there are varying degrees of mucosal 1 cm and if so are best classified as intracholecys-
and transmural chronic inflammation, thickening tic papillary neoplasms. A spectrum of dysplasia
of the muscularis, perimuscular fibrosis, and may be found within these lesions, as can inva-
adherence to the liver bed. Indicators of chronic- sive malignancy. There may be flat dysplasia in
ity are mucosal pseudopyloric metaplasia and the surrounding mucosa. Papillary neoplasms
transmural mucosal herniation to form include the entity formally referred to as “non-
Rokitansky–Aschoff sinuses. These mucosal invasive papillary carcinomas.” These lesions
pouches can inspissate with bile and mucus, should be carefully examined to exclude invasive
becoming inflamed and forming extramural disease. In general three epithelial subtypes of
dysplasia are recognized in the gallbladder: bili- 9.5 Surgical Pathology

ary, intestinal or gastric. Specimens: Clinical Aspects
Carcinoma: Usually occurs in late middle-
aged females and many (50–75%) present 9.5.1 Resection Specimens
already with regional lymph node metastasis
and involvement of the gallbladder bed, liver, or 9.5.1.1 Benign Conditions
other direct spread to duodenum, stomach, In benign disease, the gallbladder may be
colon, and peritoneum. Calculi (80–90% of removed either laparoscopically or by an open
cases), chronic inflammatory bowel disease, and procedure.
primary sclerosing cholangitis are risk factors. Laparoscopic cholecystectomy is now by far
Often clinically inapparent and found inciden- the most popular method. There are no absolute
tally as diffuse thickening of the wall at chole- contraindications except for those that apply to
cystectomy for gallstones, 10–20% are initially other operative procedures, e.g., poor anaesthetic
diagnosed by histology of routine blocks, there risk. However, previous abdominal surgery with
having been no macroscopic suspicion of resultant fibrous adhesions and obesity may make
tumour. Fundal in location (60%) and grossly a laparoscopic approach difficult. It may have to
diffuse (70%) or polypoid (30%), the vast be abandoned and converted to an open cholecys-
majority (95%) are adenocarcinomas of tubular tectomy. In a laparoscopic cholecystectomy, an
or papillary patterns arising from a sequence of initial small infraumbilical stab wound is made
intestinal metaplasia—dysplasia—carcinoma. and a spring-loaded Veress needle is passed
Adenosquamous, pure squamous carcinomas, through the abdominal wall into the peritoneal
neuroendocrine tumours (well differentiated cavity. A CO2 supply is then connected to the
and poorly differentiated), and gastrointestinal needle and gas is insufflated into the abdomen to
stromal tumours can also occur in the gallblad- produce a pneumoperitoneum. The needle is then
der. Assessment of the depth of invasion can be removed and the incision extended and deepened.
difficult and extension of carcinoma in situ into A sheath is then inserted and the laparoscope is
Rokitansky–Aschoff sinuses must be distin- passed through this to make the optic port. The
guished from true invasion of the wall. image from the laparoscope is transferred to a
Perineural involvement is characteristic. monitor and can be viewed by the surgeon. Three
Gallbladder cancer may, therefore, be encoun- other incisions (ports) are made under direct
tered either in the context of an incidental find- visualization: for retraction and irrigation, for
ing in a simple cholecystectomy, or infrequently, tools such as an electrosurgical hook, scissors,
as an electively planned extended cholecystec- etc., and for grasping forceps. An initial examina-
tomy (+/− segmental resection of liver) with tion of all areas of the abdomen is performed,
radical lymph node dissection. including the pelvis. The fundus of the gallblad-
Other cancers: Rare but can include embryo- der is then grasped, the cystic artery and duct in
nal rhabdomyosarcoma (children), leiomyosar- Calot’s triangle both clipped and divided. If chol-
coma and malignant lymphoma, or metastatic angiography ± exploration of the common bile
carcinoma, especially transcoelomic—stomach, duct is required, a cannula is passed into the com-
pancreas, ovary, bile ducts, colon, and breast. mon bile duct via an opening in the cystic duct
Prognosis: Better if lesions are of papillary before clipping. The gallbladder is then dissected
type, low histological grade, and confined to from the liver bed and the contents removed by
the mucous membrane when resection is poten- suction. It is then placed in a bag and removed
tially curative (90% 5-year survival). However, through the optic port.
many cases present with disease beyond the Open cholecystectomy is used in the few cases
gallbladder, involvement of liver (25% 5-year deemed inappropriate for laparoscopic cholecys-
survival), and overall 5–10% 5-year survival tectomy via a Kocher’s incision parallel to the
figures. right subcostal margin.
9 Gallbladder 107
9.5.1.2 Gallbladder Cancer operative access has been technically difficult.

Careful patient selection for surgery of gallbladder The proximal end comprises a variable length
cancer is essential and only relatively fit patients of cystic duct adjacent to which an enlarged
with localized tumours and no evidence of meta- lymph node may be present.
static spread should be considered. However, Initial procedure:
despite this, the results of surgery remain poor, • Measurements:
with 90% of patients dying within 12 months. –– Gallbladder—length × maximum diameter
A right subcostal incision is used and a com- (cm)
plete examination of the abdomen undertaken. If –– Cystic duct—length × maximum diameter
there is no invasion of the bile ducts and no or (cm)
only superficial liver invasion, an extended chole- –– Lymph node—number and maximum
cystectomy is performed. In this, after determina- diameter (cm)
tion of the depth of liver invasion by intraoperative • Open longitudinally from the fundus toward
USS, the gallbladder and the hepatic gallbladder the cystic duct with blunt-ended scissors
bed are removed in the form of a wedge resec- draining off the bile and noting any contents.
tion. A regional lymph node dissection is carried • Photograph if appropriate.
out by removing the lymph nodes draining the • Paint the external serosal and adventitial
gallbladder as far as the coeliac nodes. aspects if there is any suspicion of tumour.
If the tumour extends more deeply into the • Fixation by immersion in 10% formalin for
liver, then a segmental liver resection (usually IV 36–48 h.
and V or IV, V, and VI) will be required. Very Description:
occasionally, if the tumour has spread to the • Received
extrahepatic bile ducts, a segmental liver resec- –– Opened/unopened/intact/deficient/perfo-
tion and extrahepatic duct resection are required. rated/fragments
Rarely a liver resection and an extended • Adventitia
Whipple’s procedure may be used. Palliation can –– Adhesions/rim of liver/tumour
involve bypass surgery or stenting to relieve gas- • Serosa
tric outlet obstruction or jaundice. –– Adhesions/exudate/perforation/tumour
• Wall
–– Thickness (cm)/fibrosis/tumour/thinning/
9.6 Surgical Pathology necrosis/perforation/sinuses/abscess/
Specimens: Laboratory calcification
Protocols • Mucosa
–– Tumour: polypoid/nodular/ulcerated/dif-
9.6.1 Biopsy Specimens fuse/mucinous
Length × width × depth (cm) or maximum
Not applicable. dimension (cm)
Location (fundus/body/neck/cystic duct)
and distance (mm) to the cystic duct limit
9.6.2 Resection Specimens Confined to mucous membrane, in the wall
or through the wall
Specimen: –– Cholesterolosis/ulceration/haemorrhage/
polyps
• Most cholecystectomy specimens are now • Contents
done laparoscopically rather than by open sur- –– Bile/mucus/stones (size, number, shape,
gery and submitted opened or unopened con- mixed, pigment, cholesterol)/fibrin/pus
taining 5–10 mL of bile fluid. Occasionally, • Cystic duct
specimens are received in several pieces if –– Stone impaction/dilatation/lymph node
Fig. 9.2 Opening and 3. Open with scissors

transverse sectioning of in the long axis
the gallbladder
(Reproduced, with
permission, from Allen 2. Bisect cystic duct node
and Cameron (2013))
4. Plane of transverse sections

for block selection
1. Transerve section the cystic

duct proximal limit
Blocks for histology (Fig. 9.2): • Tumour type

–– Adenocarcinoma/other
• Sample by circumferential transverse section • Tumour differentiation
the proximal cystic duct limit. –– Well/moderate/poor
• Sample the cystic duct lymph node and any • Tumour edge
other separately submitted named nodes. –– Pushing/infiltrative/lymphoid response
• Serially transverse section the gallbladder at • Extent of local tumour spread: TNM 8: for
3–4 mm intervals with either a sharp knife or carcinoma
scissors.
• Usually one broken transverse ring will suf- pTis Carcinoma in situ
fice for histology in the absence of any macro- pT1 Tumour limited to gallbladder wall
scopic abnormality. a Lamina propria
b Muscularis
• Sample gross lesions with multiple transverse
pT2 Tumour invades perimuscular connective
blocks as indicated, e.g., ulceration, perfora-
tissue; no extension beyond serosa or into liver
tion, tumour, abscess, polyps, wall thickening.
pT3 Tumour perforates serosa (visceral peritoneum)
Demonstrate tumour in relation to the serosa and/or directly invades the liver and/or one
and adventitia including its resection margin. other adjacent organ or structure, e.g., stomach,
• If part of a radical cancer resection—describe duodenum, colon, pancreas, omentum,
extrahepatic bile ducts
and measure the attached segments of liver
pT4 Tumour invades main portal vein or hepatic
and bile ducts, and the relationship of any artery, or invades two or more extrahepatic
tumour to them and their resection limits. organs or structures
Sample multiple blocks to demonstrate these
relationships. Sample all regional lymph
nodes. • Lymphovascular invasion
Histopathology report: –– Present/not present. Note perineural invasion
• Non-neoplastic • Regional lymph nodes
–– Inflammation: acute/chronic/xanthogranu- Hepatic hilus nodes (including along common
lomatous bile duct, hepatic artery, portal vein, and cystic
–– Necrosis/perforation/abscess/empyema/ duct), coeliac and superior mesenteric nodes.
fistula A regional lymphadenectomy will ordinarily
–– Mucocele include 6 or more lymph nodes
9 Gallbladder 109
pN0 No regional lymph node mestastasis Bosman FT, Carneiro F. WHO classification of tumours of
pN1 1–3 regional lymph node(s)
pN2 4 or more regional nodes TNM classification of malignant tumours. 8th ed.
Carter D, Russell RCG, Pitt HA, Bismuth H, editors. Rob
and Smith’s operative surgery: hepatobiliary and pan-
• Excision margins
creatic surgery. 5th ed. London: Chapman and Hall;
Cystic duct limit of tumour and mucosal dys- 1996.
plasia clearance (mm) Goldin RD, Roa JC. Gallbladder cancer: a morpho-
Adventitial margin of tumour clearance (mm) logical and molecular update. Histopathology.
2009;55:218–29.
Hepatic and common bile duct margins of
Mann CV, Russell RCG, Williams NS, editors. Bailey
tumour clearance (mm) & love’s short practice of surgery. 22nd ed. London:
• Other pathology Chapman and Hall Medical; 1995.
Calculi, primary sclerosing cholangitis Odze RD, Goldblum JR, editors. Odze and Goldblum
surgical pathology of the GI tract, liver, biliary tract,
and pancreas. 3rd ed. Philadelphia: Saunders/Elsevier;
2015.
Bibliography (oesophageal carcinoma, gastric carcinoma, carcino-
Adsay V, Saka B, Basturk O, Roa JC. Criteria for bile duct, colorectal cancer, gastrointestinal stro-
Pathologic sampling of gallbladder specimens. Am mal tumours (GISTs), liver resection specimens and
J Clin Pathol. 2013;140:278–80. liver biopsies for primary and metastatic carcinoma,
Albores-Saavedra J, Henson DE, Klimstra DS. Tumors endocrine tumours of the gastrointestinal tract includ-
of the gallbladder, extrahepatic bile ducts and ampulla ing pancreas) and tissue pathways (gastrointestinal
of vater, Atlas of tumor pathology, vol. 3rd series. and pancreatobiliary pathology, liver biopsies for the
Fascicle 27. Washington, DC: AFIP; 2000. investigation of medical disease and for focal liver
Allen DC. Histopathology reporting. Guidelines for surgi- lesions). Available via https://www.rcpath.org/profes-
cal cancer. 3rd ed. London: Springer; 2013. sion/publications/cancer-datasets.html. Accessed Oct
Allen DC, Cameron RI. Histopathology specimens: 2016
clinical, pathological and laboratory aspects. 2nd ed. Wittekind C, Greene L, Hutter RVP, Klimfinger M, Sobin
Berlin: Springer; 2013. LH. TNM atlas: illustrated guide to the TNM/pTNM
Beckingham IJ, editor. ABC of liver, pancreas and gall classification of malignant tumours. 5th ed. Berlin:
bladder diseases. London: BMJ Books; 2001. Springer; 2005.
Liver
10
10.1 Anatomy are supplied by the left hepatic artery and left
hepatic duct. This has led to a different division
The liver, the largest gland in the body, is con- of the liver into surgical lobes and segments (see
cerned with the production and secretion of bile below).
and many metabolic functions crucial to normal The hilum of the liver, or porta hepatis, is
homeostasis. The majority of it is surrounded by found on the infero-posterior surface with the
a peritonealized fibrous capsule and it is situated lesser omentum attached to its margin. Emerging
in the right upper quadrant of the abdomen for from and entering the porta hepatis (from poste-
the most part under the cover of the ribs. It is rior to anterior) are the portal vein, right and left
divided into a large right and smaller left lobe by branches of the hepatic artery, the right and left
the attachment of the falciform ligament. The hepatic ducts, and autonomic nerves.
right lobe is further subdivided into the quadrate Histologically the liver is composed of lobules
and caudate lobes by the gallbladder and the liga- (Fig. 10.1). Each lobule comprises a central vein
mentum teres (Fig. 10.1). However, this is a (a tributary of the hepatic veins) with the portal
purely anatomical subdivision as it has been tracts situated at the periphery. The portal tracts
found that the quadrate and caudate lobes are contain a branch of the hepatic artery, portal vein,
actually a functional part of the left lobe, i.e., they and bile duct. Each lobule is divided into
triangular-shaped acini with terminal branches of
the hepatic artery and portal vein at their bases
and the central vein at the apex. The acinus is
P.J. Kelly (*) • M.B. Loughrey divided into three zones (zone 3 being the most
Histopathology Laboratory, Institute of Pathology, remote from the blood supply). The liver cells
(hepatocytes) are arranged in anastomosing
e-mail: paul.kelly@belfasttrust.hscni.net; maurice. cords, with those adjacent to the portal tract
loughrey@belfasttrust.hscni.net forming the limiting plate.
D.C. Allen Between the cords of liver cells are vascular
Histopathology Laboratory, Belfast City Hospital, channels (sinusoids) lined by a discontinuous
Belfast Health and Social Care Trust, Belfast, UK layer of endothelial cells. These sinusoids carry
blood (both arterial and portal) from the portal
R.I. Cameron tract to the central vein. Channels (canaliculi)
formed between adjacent hepatocytes conduct
Londonderry, UK bile to the ducts in the portal tracts and then to the
e-mail: iain.cameron@westerntrust.hscni.net extrahepatic bile ducts and gallbladder.

Fig. 10.1 Liver Inferior

anatomy and histology vena cava
Falciform ligament
(Reproduced, with
and Cameron (2013))
Right lobe Left lobe
Falciform
ligament
Caudate Inferior
lobe vena cava
Left lobe
LV
Right lobe
Gall bladder
LT
Porta
hepaits
Acinus
Quadrate
Portal lobe
tract
Gall bladder
Zones 1 2 3 CV
LV: Ligamentum venosum

LT: Ligamentum teres
CV: Central vein
Lobule
Lymphovascular drainage: 10.2 Clinical Presentation

The liver receives 30% of its blood from the
hepatic artery (oxygenated blood), the remain- Patients with liver disease may be asymptomatic.
ing 70% being supplied by the portal vein The most common clinical sign is jaundice,
(venous blood rich in nutrients absorbed from although other stigmata of chronic liver disease
the gut). The blood is conducted through the such as spider naevi, finger-clubbing, gynaeco-
sinusoids from the portal tracts to the central mastia, etc. may also be present. If the jaundice is
veins, which in turn drain into the hepatic veins obstructive, then the patient will have dark urine
and ultimately the inferior vena cava. Most of and pale faeces. Weight loss, anorexia, anaemia,
the lymphatics drain to nodes in the porta and ascites may suggest cirrhosis and/or an
hepatis (hepatoduodenal ligament) and then underlying malignancy. Fever and rigors may be
pass to the coeliac nodes. A small number pass seen if an abscess is present. Hepatomegaly may
through the diaphragm into the posterior be encountered in numerous conditions including
mediastinum. cirrhosis and malignancy.
10 Liver 113
A careful clinical history including medica- • Computed Tomgraphy (CT)—is considered

tion (prescription and otherwise), alcohol intake, one of the most accurate imaging techniques
foreign travel, and sexual practice is diagnosti- and is commonly used to identify hepatic, bili-
cally invaluable to the pathologist. ary or pancreatic masses as well as screen the
chest and pelvis for metastatic disease. It may
be less helpful than USS for identifying bili-
10.3 Clinical Investigations ary obstruction. Use of IV contrast can
improve the diagnostic utility of CT. Positron
• U&E—electrolyte imbalance may occur and emission tomography (PET) CT has an
hyponatraemia (low sodium) is a poor prog- increasing role in staging malignancy in the
nostic sign in liver failure. liver and pancreaticobiliary tract.
• Liver function tests (LFTs)—these should • Magnetic Resonance Imaging (MRI)—is the
include tests for liver secretory capacity (bili- test of choice for characterizing liver
rubin, alkaline phosphatase, and gamma glu- masses. Liver MRI has improved sensitivity
tamyl transferase (αGT)); synthetic capacity and specificity for diagnosing hepatocellular
(albumin) and inflammation (aspartate amino- carcinoma (HCC) in cirrhotic livers
transferase (AST) and alanine aminotransfer- and is non-ionising. Magnetic Resonance
ase (ALT)). Cholangiopancreatography (MRCP) has
• Coagulation screen—measures clotting poten- largely replaced other forms of invasive radio-
tial and as such is a test of hepatic function logical imaging of the bile ducts and
(synthesis of clotting factors). pancreas.
• Serology—viral titres of hepatitis A–E. • Percutaneous Transhepatic Cholangiography
• Autoimmune screen—including anti- (PTC)—has investigative and therapeutic
mitochondrial, anti-smooth muscle, and anti- functions. PTC can be used to assess obstruc-
nuclear antibodies. tion of the proximal biliary tree, deploy stents,
• Serum immunoglobulins. provide drainage of obstructed liver segments
• Specific tests—serum iron, ferritin, total iron- and obtain biliary brushings for cytological
binding capacity (TIBC), and HFE gene analysis evaluation of strictures.
(genetic haemochromatosis); serum and urinary • Radioisotope scanning—this provides infor-
copper (Wilson’s disease); serum alpha-1 anti- mation on the liver texture and is useful in
trypsin (alpha-1 antitrypsin deficiency). diagnosing cirrhosis or multiple tumours (if
• Tumour markers—alpha fetoprotein (AFP: >2 cm). Tumours will have decreased uptake.
hepatocellular carcinoma); CEA (metastatic This has largely been supplanted by USS and
colorectal carcinoma), CA19.9 (biliary CT scanning.
obstruction, cholangiocarcinoma). • Angiography—hepatic artery angiography
• CXR—may detect primary lung tumour can be used to delineate the vascular anatomy
(which has metastasized to the liver). of a tumour prior to resection although has
• AXR—may show calcification around a hyda- been largely superseded by CT and MRI. It
tid cyst. may be used for planning or performing
• USS—useful for identifying intra-or extrahe- embolization of liver tumours or haemor-
patic bile duct dilatation, gallstones or gall- rhagic complications.
bladder distension due to obstruction for other • Transient elastography e.g. FibroscanR—uses
reasons. USS can also detect space-occupying ultasonography to assess liver stiffness to
lesions in the liver, for example primary or evaluate fibrosis without the need for biopsy.
secondary tumours. Doppler ultrasonography • Peritoneal aspiration—may detect malignant
can be used to assess direction and patency of cells in ascitic fluid.
blood vessels, detect portal hypertension and • FNAC—percutaneous under USS/CT
assess tumour vascularity. guidance.
• Needle core biopsy—Tru-cut needle biopsy tral veins. This micronodular (<0.3 cm diameter)
under USS/CT guidance can be carried out on or macronodular pattern disturbs liver function
focal lesions or to assess the status of back- and also its internal vascular relationships. As a
ground “normal” liver prior to attempting to consequence, liver failure (jaundice, anaemia,
resect liver masses. Diagnosis of hepatocellu- generalized oedema, and ascites due to hypoalbu-
lar carcinoma is often based on a combination minaemia, hepatic encephalopathy) and portal
of serum AFP and appropriate radiological venous hypertension with the risk of catastrophic
features avoiding the need for biopsy. A nee- haemorrhage from oesophagogastric varices can
dle core biopsy may also be performed on a ensue. In neoplasia or hepatic mass lesions, the
suspicious lesion during laparotomy. biopsy may be for diagnostic purposes to distin-
Alternatively diffuse medical liver conditions guish between primary disease, metastatic carci-
can be sampled percutaneously and blind by a noma, malignant lymphoma and abscess, or, for
needle (16–18 G). staging of known primary tumour elsewhere,
• Staging laparoscopy with biopsy. e.g., colorectal carcinoma. Liver biopsy is less
likely to be performed if there is a potentially
resectable liver tumour due to the risks of tumour
10.4 Pathological Conditions seeding along the biopsy tract. The information
accrued is then factored into future management
Patients with liver disease may present with signs decisions.
of liver failure or complications of it, e.g.,
oesophageal varices or because of biochemically
detected abnormal LFTs. The latter can indicate 10.4.1 Non-neoplastic Conditions
whether the pattern of damage is hepatic (paren-
chymal), extrahepatic (obstructive) or mixed in Viral hepatitis: Commonly hepatitis A, B, C, D,
nature. Hepatic assault is typified by viral hepati- or E (hepatotropic viruses). Hepatitis A (faeco-
tis, alcohol or drug damage, and extrahepatic dis- oral transmission) is usually of short duration,
ease by duct obstruction due to stones or tumour, self-limiting without sequelae, and not biopsied.
e.g., head of pancreas. Mixed biochemical pro- Hepatitis B and C (transmission by blood, serum,
files are not infrequently seen in these various secretions—hepatitis D is often a cofactor) are
disorders. Needle core biopsy is interpreted in strongly associated with blood transfusion,
close correlation with full clinical information sharps injuries, and shared needles in drug abus-
that includes a detailed history and wide range of ers. Occasionally there is acute fulminant hepati-
investigations (see above). Its aims are to distin- tis, but a significant minority go on to chronic
guish between a surgical and medical cause for carriage of viral antigen that can lead to chronic
the damage, and, in non-neoplastic conditions, to active hepatitis (>6 months clinical duration)
assess the degree of necro-inflammatory activity with eventually cirrhosis and hepatocellular car-
that is present and the reparative response of the cinoma. Diagnosis is by positive serology
liver to it. It also establishes a baseline against matched to distinctive histological features (e.g.,
which subsequent treatment can be assessed or portal tract lymphoid follicles and bile duct
indicated, e.g., interferon therapy in chronic viral damage in hepatitis C) which are also graded (the
hepatitis. degree of necro-inflammation) and staged (the
Liver damage has potential to resolve, but if it absence or presence of fibrosis/cirrhosis) as a
is unresponsive to treatment or ongoing, a non- gauge of need for treatment, treatment response,
specific, end-stage or cirrhotic pattern may be and/or evolution of disease. Tissue localization of
reached with few histological clues as to its aeti- viral antigens can be demonstrated immunohisto-
ology. It is due to lobular damage and collapse of chemically or by in situ hybridization. Hepatitis
its framework with fibrous repair expanding and E (faeco-oral transmission, epidemic, or spo-
linking portal tracts with each other and the cen- radic) is now becoming the most common cause
10 Liver 115
of hepatitis worldwide and can cause a mild, cho- Primary biliary cirrhosis (may also be referred to
lestatic hepatitis (resembling hepatitis A), classi- as primary biliary sclerosis in more modern
cal non-cholestatic hepatitis or fulminant disease texts), may overlap with autoimmune hepatitis,
with decompensation, particularly in those with affects a similar patient demographic and is a
preexisting liver disease. non-suppurative, destructive, granulomatous dis-
Alcohol (C2H5OH): Chronic excess alcohol order of bile ducts that leads to their disappear-
intake is a common aetiological factor in liver ance (ductopenia), fibrosis and ultimately
disease and is noted for variable individual sus- cirrhosis. Serum IgM anti-mitochondrial anti-
ceptibility to it. Its hepatotoxic effect causes a body is typically elevated and progress can be
spectrum of change from simple steatosis (fatty gradual over a long time period, treatment being
change), alcoholic steatohepatitis (lobular necro- with ursodeoxycholic acid to reduce bile acid
inflammation with ballooning and Mallory’s hya- accumulation and symptomatic to relieve related
line—tufts of intracytoplasmic intermediate itch. Primary sclerosing cholangitis can affect
filaments) to perivenular fibrosis, cirrhosis, and intra- or extrahepatic bile ducts with a chronic
hepatocellular carcinoma. Abstinence short of inflammatory infiltrate and surrounding fibrosis,
the stage of cirrhosis leads to potential reversibil- leading to obstructive tapering of the ducts and
ity of even severe damage. Similar morphologi- their eventual disappearance. Diagnosis is often
cal features are seen in NASH (non-alcoholic by ERCP—there is a strong association with
steatohepatitis) commonly associated with ulcerative colitis and predisposition to cholangio-
hypertension, diabetes mellitus, and obesity carcinoma. IgG4-related disease may also involve
(metabolic syndrome), and also gut bypass pro- the intra-and extrahepatic bile ducts and can
cedures and some drugs. cause a sclerosing cholangiopathy on imaging.
Drugs: The vast majority of drugs are metabo- Liver biopsies will classically show infiltration of
lized in the liver and cause damage either due to IgG4 positive plasma cells with an elevated
excess dosage (actual or apparent due to preexist- IgG4:IgG ratio on immunohistochemistry, oblit-
ing decreased liver function) or individual idio- erative venulitis and storiform fibrous nodules in
syncratic reaction to them. Various effects are affected portal tracts.
seen with different agents: steatosis, cholestasis Systemic diseases: The liver can be involved
(commonest), granulomas, necrosis, hepatitis, in many other generalized conditions, e.g., diabe-
veno-occlusion, and peliosis (dilated blood chan- tes, coeliac disease, Crohn’s disease, systemic
nels). Location of damage varies within the aci- vasculitis, amyloid (primary or secondary, e.g.,
nar zones related to the blood supply and the due to rheumatoid arthritis) and hereditary disor-
particular agent involved. Diagnosis is strongly ders such as glycogen storage diseases, alpha-1
dependent on an appropriate clinical history and antitrypsin deficiency, cystic fibrosis, Wilson’s
chronology of drug usage correlating with the disease (defect of copper metabolism) and hae-
liver dysfunction. Common agents are—tricyclic mochromatosis (defect of iron metabolism).
antidepressants (chlorpromazine), methotrexate, Focal mass lesions: These need to be distin-
NSAIDs, anaesthetic agents (halothane), antibi- guished radiologically and histocytologically
otics (tetracyclines, erythromycin, amoxicillin— from neoplastic conditions (see below) and
clauvanate), and paracetamol. include simple sporadic cysts (often biliary in
Autoimmune and cholangiodestructive dis- origin), multiple simple cysts (polycystic disease
eases: Characteristically in late middle-aged of liver and kidneys), infective cysts, abscess,
females, autoimmune hepatitis is associated with haemangioma, and focal nodular hyperplasia.
a range of autoantibodies, including antinuclear Abscess may arise from septicaemia, acute cho-
and anti-smooth muscle antibodies, and is steroid lecystitis, or portal pyaemia after perforated
responsive. In this respect, it is of paramount appendicitis or diverticulitis. Focal nodular
importance to separate it from an infective hepa- hyperplasia is usually solitary and more com-
titis in which steroids are contraindicated. monly diagnosed in young-to-middle-aged
women. Exogenous oestrogens for example, the sinusoidal comprising variably differentiated
oral contraceptive pill, are thought to exert tro- hepatoid cells.
phic effects on these lesions leading to an appar- A minority are encapsulated, pedunculated,
ent female preponderance. FNHs are or, in a younger patient, fibrolamellar in type,
characterized by a central, branching stellate these variants having a better prognosis than
fibrous scar that separates nodules of liver cells usual hepatocellular carcinoma.
which often show a peripheral proliferation of Hepatic mucinous cystic neoplasms: formerly
bile ductules. It is thought to be due to a localized
referred to as “biliary cystadenomas with ovarian
vascular abnormality. The main differential diag- type stroma”, these lesions represent the hepatic
nosis includes hepatocellular adenoma, fibrola- analogue of the pancreatic lesion of the same
mellar hepatocellular carcinoma and
name. The ovarian type stroma may be only iden-
well-differentiated hepatocellular carcinoma. tified after careful examination. May be misdiag-
Peribiliary hamartomas (formerly referred to as nosed preoperatively as simple cysts and initially
bile duct adenomas) and biliary hamartoma (von de-roofed. Further completion excision is indi-
Meyenberg complex) are usually encountered as cated given their neoplastic nature although
small, pale, subcapsular nodules at laparotomy, malignant transformation appears to be rare.
e.g., at staging of gastric carcinoma and submit- Cholangiocarcinoma: Scirrhous, solitary, or
ted as a wedge biopsy for frozen section to multifocal adenocarcinoma with a ductuloacinar
exclude metastatic cancer deposits. pattern and predisposed to by primary sclerosing
cholangitis, ulcerative colitis, liver fluke, and
biliary tree anomalies. Can be classified accord-
10.4.2 Neoplastic Conditions ing to origin—intrahepatic, extrahepatic—perihi-
lar or extrahepatic—distal, which can have
Adenoma: Rare, causing acute abdominal presen- implications for staging. Peripheral intrahepatic
tation due to lesional haemorrhage in a middle- cholangiocarcinomas tend to form a mass.
aged female with a history of oral contraception. Perihilar bile duct carcinomas, which include
Devoid of portal tracts or central veins within the “Klatskin tumours” originate from the right, left
nodule but there is a lack of cellular atypia with or main hepatic ducts proximal to the insertion of
preservation of the pericellular reticulin pattern the cystic duct. These may show an aggressive
and liver cell plates—these features help distin- periductal growth pattern without forming a dis-
guish it from well-differentiated hepatocellular crete mass. Intraductal tumours, which are usu-
carcinoma. Adenomas can be subclassified into ally perihilar, tend to be papillary and may be
four types based on their molecular biology: non-invasive (i.e. intraductal papillary neo-
HNF1A-mutated, Beta-catenin mutated, inflam- plasms) or invasive. Intraductal papillary neo-
matory (previous classified as telangectatic vari- plasms share similarities with pancreatic papillary
ant of FNH) and hepatic adenoma, not otherwise mucinous neoplasms and may be detected on
specified (NOS). This molecular classification imaging as cystic lesions or cystic dilatation of
has been found to have clinical relevance. the bile ducts. Distal extahepatic bile duct
Macroregenerative or dysplastic nodules: carcinomas arise in the common bile duct, distal
Irregular nodules in background cirrhosis, to the junction of the common hepatic duct and
1–3 cm diameter with cytoarchitectural atypia the cystic duct. These are discussed in more detail
and potentially premalignant. in Chap. 4. The molecular biology and cells of
Hepatocellular carcinoma: Often in back- origin for perihilar, peripheral intrahepatic, and
ground cirrhosis, and serum AFP is elevated in indeed intraductal cholangiocarcinomas are
25–40% of cases. Single, diffuse or multifocal, thought to be different which may explain the
bile stained, and prone to venous invasion with morphological variability between these tumours.
metastases to lung, adrenal gland, and bone. The Mixed cholangiocarcinoma-hepatocellular
commonest patterns are trabecular, plate-like, or carcinoma: encountered more commonly than
10 Liver 117
suggested in older literature. Diagnosis typically cholangiocarcinoma. This will be determined

requires morphological evidence of both compo- by the location of the tumour and potential to
nents and is not made solely on results of immu- achieve a complete resection. Currently trans-
nohistochemistry. Staging and prognosis is plantation for intrahepatic and hilar cholangio-
determined by the cholangiocarcinoma carcinomas is not recommended in UK
component. guidelines. Chemotherapy has a role in inoper-
Metastatic carcinoma: Commonly from gas- able disease. Solitary metastases, e.g., colorec-
trointestinal tract, lung, and breast, there are tal carcinoma or carcinoid tumour can be
some characteristic clues as to origin. resected to good effect. Thermal ablation,
Colorectum—multiple, large nodules with TACE, SIRT and chemotherapy are also be used
central necrosis/umbilication, ± mucin ± to manage metastatic colorectal carcinoma and
calcification may render previously unresectable disease
Gallbladder—bulk of disease centred on the resectable. Metastatic carcinoid tumour can
gallbladder bed show good chemoresponsiveness.
Lung—medium-sized nodules
Stomach, breast—medium-sized nodules or
diffuse cirrhotic-like pattern 10.5 Surgical Pathology
Note that carcinoma rarely metastasizes to a Specimens: Clinical Aspects
cirrhotic liver.
Other cancers: Well differentiated neuroendo- 10.5.1 Biopsy Specimens
crine tumours (“carcinoids”) metastatic from
gastrointestinal tract (particularly ileum), pan- FNAC and needle core biopsy can be carried out
creas or lung, malignant lymphoma (portal infil- percutaneously either blind or preferably under
trates or tumour nodules), leukaemia (sinusoidal radiological guidance, during laparoscopy, lapa-
infiltrate), malignant melanoma, angiosarcoma, rotomy, or as a radiologically guided transvascu-
epithelioid haemangioendothelioma. lar (vena cava) procedure. Coagulation status is
Prognosis: In hepatocellular carcinoma, this checked prior to core biopsy to avoid risk of
relates to size (>5 cm), differentiation, encapsu- haemorrhage.
lation, multifocality, high serum AFP levels,
vascular invasion, and the presence of back-
ground cirrhosis (adverse). The majority of 10.5.2 Resection Specimens
untreated patients will die within several months
of presentation. However depending on the 10.5.2.1 Neoplastic Lesions
stage of disease and treatment modality, the The key to successful hepatic resection of malig-
5-year survival may reach 70–80%. Surgical nant disease is careful patient selection. In
resection and transplantation are considered general:
curative surgical strategies in select patients.
Thermal ablation with or without transarterial • A primary liver tumour may be considered for
chemoembolization (TACE) is also potentially resection if it involves a single lobe and there
curative in patients for whom surgical manage- is no invasion of the portal vein or inferior
ment is not appropriate. Thermal ablation and vena cava. There should be no evidence of cir-
TACE can also be used in the palliative setting. rhosis in the surrounding liver.
Systemic internal radiation therapy (SIRT) may • A solitary metastatic deposit (the vast major-
also be used in select patients. Few patients with ity of which will be from a primary colorectal
cholangiocarcinoma survive longer than carcinoma) localized to a single lobe may be
2–3 years due to late presentation and limited considered for resection. There should be no
resectability. Surgery offers the best option for evidence of metastatic spread elsewhere.
long-term survival in patients with resectable More recently, this criterion has been extended
to include multiple hepatic metastases pro- fied in relatively young and medically fit
vided resection is technically feasible leaving individuals.
sufficient functioning hepatic remnant. Use of As was stated above, the liver is divided into
neoadjuvant chemotherapy, intravascular right and left “surgical lobes,” which are different
embolization, or radiofrequency ablation to the anatomical lobes. The surgical lobes are
facilitates operative resection by downsizing separated along a plane that extends from the
the tumour deposits. gallbladder bed to the inferior vena cava—the
main portal plane. The surgical lobes are then
Obviously the background physiological state subdivided into eight segments—each segment is
of the patient has to be taken into account before supplied by its own portal venous and hepatic
surgery is considered, i.e., resection is only justi- arterial pedicle (Fig. 10.2).
a Surgical Lobes
Right Left
Falciform
ligament
b IVC
RHV LHV
VIII II
VII
III
Fig. 10.2 (a) Surgical lobes

of the liver. The surgical
lobes of the liver compared IV
with the usual anatomical V
division into left and right
lobes by the falciform LT
ligament. (b) Segments of the
liver (after Couinard). IVC VI LT
inferior vena cava, RHV right
hepatic vein, LHV left hepatic
vein, LT ligamentum teres
10 Liver 119
Major Liver Resection If a metastatic deposit is single, small, and

An S-shaped right subcostal incision is used in all superficial, a simple wedge resection (or atypical
cases and once the abdomen is opened an initial resection) using diathermy can be employed.
laparotomy examination is done to ensure no This procedure may be performed during resec-
other metastatic deposits are present. The definition of the primary tumour, e.g., colorectal carci-
tive type of resection will depend on the site and noma, and sent for frozen section.
extent of the tumour. Preoperatively portal vein
embolization to the lobe to be resected may be 10.5.2.2 Non-neoplastic Lesions
used to hypertrophy the remaining liver tissue.
Perihilar cholangiocarcinomas will usually be Liver Cysts
resected by partial hepatectomy but the specimen Liver cysts may be congenital or acquired (e.g.,
will include an extra portion of extrahepatic bili- neoplastic, inflammatory/infective, traumatic,
ary tree (usually down to the common bile duct) etc.). When surgery is to be carried out for a liver
and a margin of the contralateral main hepatic cyst, an extensive preoperative clinical and radio-
duct. Distal extrahepatic cholangiocarcinomas logical workup is required to ascertain, as closely
are usually resected without the need for a as possible, its aetiology. An initial thorough
hepatectomy. laparotomy examination is undertaken. For non-
infective cysts, the cyst is opened and the con-
• Right hepatectomy—Segments V–VIII. tents aspirated and sent for cytological and
• Left hepatectomy—Segments II–IV. microbiological examination. The cyst wall can
• Extended right hepatectomy—Segments IV– then be excised using cautery. In non-neoplastic
VIII. lesions (e.g., simple cyst) complete excision may
• Extended left hepatecomy—Segments I–V & not be necessary and a large opening is made in
VIII the cyst to allow free drainage into the peritoneal
• Left lateral sectionectomy—Segments II–III. cavity. Neoplastic liver cysts, in particular hepatic
mucinous cystic neoplasm (discussed above)
As well as neoplastic conditions, major liver may only be diagnosed after histological evalua-
resection may also be used for other conditions tion of the specimen and so be initially treated by
such as trauma. de-roofing the cyst in vivo. Due to their potential
for malignant transformation complete resection
Segmental Liver Resection is usually indicated if the patient is surgically fit
Although major hepatic resection may be and may lead to a formal liver resection.
employed for large tumours, when a small tumour Hydatid cysts (echinococcus tapeworm) may
(either primary or secondary) occupies one or vary in size and situation within the liver. They
two segments, a segmental resection can be car- may be excised without removing adjacent liver
ried out. This removes a segment(s) of liver, parenchyma (pericystectomy) or if the cysts are
which is supplied by its own vascular pedicle, large or multiple, a segmental or major resection
and is, therefore, an anatomically based proce- may be needed. When a pericystectomy is carried
dure. Whatever the segment to be resected, its out and the cyst is opened, pads soaked in saline
vascular anatomy is delineated by intraoperative are packed around the cyst to prevent spillage of
USS before dissection. its contents into the peritoneal cavity.
Segmental resection has several advantages For pyogenic abscess/cyst there are three main
over major resection; namely as much function- forms of treatment: long-term antibiotics, percu-
ing parenchyma is left as possible and the vascu- taneous drainage under radiological guidance,
lar supply to this is less likely to be compromised, and open surgical drainage. Percutaneous drain-
there is reduced blood loss, and the procedure is age is now by far the most popular method.
less likely to leave residual tumour. However, if surgical drainage is employed, the
abscess is identified and separated from the peri- stains such as Shikata’s orcein or elastic-van
toneal cavity by pads. The abscess contents are Gieson can help distinguish recent collapse (elas-
then aspirated and the cavity washed out. The tin negative) from old fibrosis (elastin positive).
cyst wall is then de-roofed to facilitate resolution. Haemochromatosis is diagnosed using biochemi-
Pyogenic abscesses may also be treated by lapa- cal and genetic investigations and the degree of
roscopic drainage. iron deposition on biopsy is graded by Perl’s
Prussian Blue or the dry weight iron concentra-
Transplantation tion. Other stains are: rhodanine/Shikata’s orcein
The first successful human liver transplant was for copper or copper-associated protein deposi-
carried out in 1967 and today over 80% of recipi- tion in Wilson’s disease, primary biliary cirrho-
ents survive 1 year. Not only can adult livers be sis, or other chronic cholestatic disorders;
transplanted to adult recipients, but the shortage PAS + diastase (positive globules in alpha-1 anti-
of donor organs has led to adult donor organs trypsin deficiency); and Congo Red (amyloid).
being transplanted to children. This is facilitated Needle cores may have an adherent fragment
by resecting and transplanting only part of the of skin if obtained percutaneously. They can also
donor liver, e.g., left liver (segments I–IV). fragment in diseased liver with cirrhosis or
General indications for transplantation are acute tumour. Fatty liver is pale; haemochromatosis
liver failure, end-stage chronic liver disease, and rust-colored. One aspect of a wedge biopsy is
neoplasms. Conditions encountered in the explant covered by peritonealized capsule and its cut
specimen can, therefore, be diverse including margin is often frayed by diathermy. This margin
viral, autoimmune and alcoholic hepatitis, pri- should be painted and the wedge then cut into
mary biliary cirrhosis, primary sclerosing chol- multiple perpendicular serial slices.
angitis, end-stage cirrhosis, and primary
hepatocellular. Current UK guidelines do not rec-
ommend transplant for cholangiocarcinoma. The 10.6.2 Resection Specimens
liver transplant can be subject to various patholo-
gies including rejection, effects of immunosup- Specimen:
pression, and recurrence of the original disease.
• Liver resection is more commonly performed
for a focal mass lesion such as a cyst, ade-
10.6 Surgical Pathology: noma, focal nodular hyperplasia, or metastatic
Laboratory Protocols colorectal carcinoma and is, therefore, limited
in extent, e.g., segmentectomy, lobectomy, or
10.6.1 Biopsy Specimens partial hepatectomy. Other indications are
major trauma and a small minority of resect-
For needle core and wedge biopsy specimens see able primary liver cancers. Specimen handling
Chap. 1. and reporting should document the nature of
Note that viral hepatitis is a category III patho- the abnormality, its extent, completeness of
gen—it should be submitted to the laboratory excision, vascular invasion, and status of the
with an attached “hazard of infection” sticker and background parenchyma. Total hepatectomy
handled appropriately after 24–48 h of thorough is encountered in transplantation surgery—
formalin fixation. aims are to identify the cause of hepatic fail-
Routine histochemical stains that should be ure, and for tumour to determine the stage and
provided to help assess the degree of hepatic assess porta hepatis margins.
parenchymal loss, reticulin collapse/elaboration, Initial procedure:
and fibrous distortion/replacement, respectively, For liver cyst de-roofing
are, PAS (± diastase), silver reticulin, and Masson • Weight (g) and dimensions of the specimen
Trichrome or haematoxylin Van Gieson. Elastin (mm)
10 Liver 121
Fig. 10.3 Partial Painted paraenchymal

hepatectomy specimen resection margin
(Reproduced, with
and Cameron (2013))
Peritonealised
capsule
Plane of serial
sections perpendicular
to the resection margin
Lay the slice flat on Tumour Nonlesional
the bench for selection liver and
of perpendicular blocks capsule
Tumour and
liver capsule
Tumour and Painted parenchymal
surgical margin resection margin
Sample representative blocks of tumour and

its relationships to capsule, surgical margin and veins.
Sample the nonlesional liver.
• Note and record the size of any focal • Paint the surgical margin and any areas of cap-
abnormalities such as solid areas, nodules or sular bulging, retraction, or reaction that might
septa be related to an underlying mass lesion.
• Sample at least one block per cm in addition to • Serially section the liver perpendicular to the
sampling focal abnormalities. Submission of parenchymal resection margin at 0.5 cm inter-
the entire specimen should be considered to vals (Fig. 10.3).
identify or exclude an epithelial lining or pres- • Photograph.
ence of ovarian-type stroma. • Fixation by laying flat and immersion in 10%
For partial resection formalin for 36–48 h.
• Weight (g) and measurements (mm) in each Description:
dimension. • Note the number, size, and distances (mm) to
• Identify the capsular and cut parenchymal sur- the capsule and surgical margin for each lesion.
faces—the latter constitutes the surgical mar- • Specific points are:
gin. Further orientation can only be given if Abscess
marked appropriately by the submitting –– Contents (pus: pyogenic/“anchovy sauce”:
surgeon. amoebiasis), walled-off, capsular reaction
• Identify bile duct margins if cholangiocarci- Cyst
noma suspected. Sample limits prior to slicing –– Contents (fibrin, fluid (serous/mucoid)),
the liver. Record what ducts are involved wall (chitinous-hydatid) and presence of
grossly and identify any non-peritonealised any thickened area, nodules or septa
margin. Trauma
• Identify vascular margins, particularly if there –– Capsular tear, subcapsular haemorrhage,
is tumour nearby. parenchymal laceration
Tumour mass • For cyst consider submitting the entire cyst

–– Edges: circumscribed/irregular/nodular/ wall as discussed above
elevated • For a tumour mass, also sample a minimum of
–– Central scar: focal nodular hyperplasia four or five representative blocks to demonstrate
–– Haemorrhage: haematoma, adenoma the lesion in relation to the capsule, surgical mar-
–– Bile stained: hepatocellular carcinoma gin, uninvolved liver, and any other relevant struc-
–– Central necrosis/umbilication/mucinous/ tures, e.g., veins, bile duct. Where the tumour
peripheral calcification: metastatic carcinoma is close to the hilum this should be sampled to
–– For suspected perihilar cholangiocarcino- include the large vessels and main branches of
mas record if it is mass forming or periduc- the portal and hepatic vein. Additional blocks are
tal, characterized by thickening around the taken as required, e.g., if in close proximity to the
bile ducts, or intraductal. Note if invasion surgical margin. Sections from the periphery of a
of hepatic parenchyma tumour are often more informative than from the
• Look for and record vascular invasion, espe- center as there is less necrosis with preservation
cially within the main branches of the hepatic of tumour tissue, and its interface with the paren-
arteries or portal veins. chyma can be demonstrated.
• Non-lesional liver • Sample non-lesional liver as far away from the
Fatty change/cholestasis/necrosis/cirrhosis/ main lesion as possible and preferably not
haemochromatosis. subcapsular.
• For abscess, or trauma, four or five representa- For total hepatectomy specimens (Fig. 10.4):
tive blocks of the wall, any capsular tear or
haemorrhage, and adjacent hepatic paren- –– Weight (g) and measure (cm) in three
chyma are usually sufficient. dimensions.
Posterior
Parahilar longitudinal
plane of section
Sample transverse sections

of the porta hepatis and
Fig. 10.4 Total represent any mass lesion in
hepatectomy specimen relation to the capsule, porta
(Reproduced, with hepatis and other structures
permission, from Allen e.g veins. Sample nonlesional
and Cameron (2013)) liver of each lobe.
10 Liver 123
–– If there is a previous diagnosis of hepatitis, Extent of local tumour spread: TNM 8: intrahe-
incise deeply at several points to ensure an patic cholangiocarcinoma and combined hepato-
adequate period (48–72 h) of fixation prior to cellular and cholangiocarcinoma
further handling.
–– Identify the porta hepatis and transverse sec- pTis Carcinoma in situ (may be used for non-
invasive papillary neoplasms)
tion its surgical margin to include the distal
pT1 Solitary tumour without vascular invasion:
limit of the bile duct, hepatic artery, and portal pT1a. ≤5 cm, pT1b. >5 cm
vein. Further transverse sections at mid-duct pT2 Solitary tumour with intrahepatic vascular
and hilar levels can be submitted. invasion, or, multiple tumours, ± vascular
–– Count and sample all lymph nodes. invasion
–– Dissect off the gallbladder and routinely pro- pT3 Tumour perforates peritoneum
cess if macroscopically normal. pT4 Tumour involving local extrahepatic structures
by direct hepatic invasion
–– Section the liver in its long axis either side of
the hilum.
–– Sample representative blocks from the ana- • Extent of local tumour spread: TNM 8: perihi-
tomical lobes and additionally as indicated by lar cholangiocarcinoma
any mass lesion to demonstrate its relationship
to the capsule, vessels, and porta hepatis. pTis Carcinoma in situ (may be used for non-
invasive papillary neoplasms)
Careful attention should be paid to involve-
pT1 Tumour confined to bile duct
ment of the main portal and hepatic veins as
pT2a Tumour invades beyond the bile duct wall
well as the right and left main portal branches into fibroadipose tissue
as this may have staging implications. pT2b Tumour invades hepatic parenchyma
–– Serially slice the rest of the liver to detect any pT3 Tumour invades unilateral branches of portal
further lesions and sample accordingly. vein/hepatic artery
pT4 Bilateral main vessel/duct involvement
• Tumour type—hepatocellular carcinoma/ • Lymphovascular invasion—present/not pres-

cholangiocarcinoma/mixed cholangiocarci- ent. Note the propensity for hepatocellular
noma hepatocellular carcinoma/metastatic carcinoma to invade portal tract veins, major
carcinoma. If perihilar cholangiocarcinomas branches of portal and hepatic veins, and infe-
record pattern of invasion as periductal, intra- rior vena cava. Cholangiocarcinoma typically
ductal and if there is a cystic component. shows perineural space invasion with spread
• Tumour differentiation—well/moderate/poor to lymph nodes, lungs, and peritoneum. Note
• Extent of local tumour spread: TNM 8: hepa- invasion of the main portal vein and hepatic
tocellular carcinoma artery branches alters the staging of perihilar
cholangiocarcinomas.
pT1 Solitary tumour pT1a. ≤2 cm ± vascular invasion, • Regional lymph nodes: hilar (hepatoduodenal
or, pT1b. >2 cm without vascular invasion
ligament), hepatic (along the proper hepatic
pT2 Solitary tumour >2 cm with vascular invasion
or multiple tumours, none more than 5 cm in artery), periportal (along the portal vein),
greatest dimension and those along the abdominal inferior vena
pT3 Multiple tumours any more than 5 cm in cava above the renal veins (except the inferior
greatest dimension phrenic nodes). A regional lymphadenectomy
pT4 Tumour(s) involving a major branch of the will ordinarily include 3 (hepatocellular carci-
hepatic or portal vein with direct invasion of
noma), 6 (intrahepatic cholangiocarcinoma),
adjacent organs (including diaphragm) other
than the gallbladder or with perforation of or 15 (perihilar cholangiocarcinoma) or more
visceral peritoneum lymph nodes
pN0 No regional lymph node metastasis Bioulac-Sage P, Cubel G, Balabaud C. Pathologic diagno-
sis hepatocellular adenoma in clinical practice. Diagn
pN1 Metastasis in regional lymph node(s)
Histopathol. 2011;17:521–9.
• Perihilar cholangiocarcinoma: pN1 = 1–3 Oxford: Wiley-Blackwell; 2017.
Brunt EM. Histopathologic features of hepatocellular car-
nodes, pN2 = 4 or more nodes.
cinoma. Clin Liver Dis. 2012;1:194–9.
• Excision margins Burt A. In: Portmann B, Ferrell L, editors. MacSween’s
Distances (mm) to the capsule and limits of pathology of the liver. 6th ed. Churchill Livingstone
excision of the hepatic parenchyma, bile Elsevier: London; 2012.
Carter D, Russell RCG, Pitt HA, Bismuth H, editors. Rob
ducts, and major veins
and Smith’s operative surgery: hepatobiliary and pan-
• Other pathology creatic surgery. 5th ed. London: Chapman and Hall;
Hepatocellular carcinoma—hepatitis, cir- 1996.
rhosis (hepatitis/alcohol/haemochromatosis, Ishak KG, Goodman ZD, Stocker JT. Tumors of the liver
and intrahepatic bile ducts, Atlas of tumor pathology,
etc.), dysplastic nodules, liver cell dysplasia.
vol. 3rd series. Fascicle 31. AFIP: Washington; 2001.
Cholangiocarcinoma—primary sclerosing Kumagi T, Hiasa Y, Hirschfield GM. Hepatocellular carci-
cholangitis, ulcerative colitis, liver fluke, bili- noma for the non-specialist. BMJ. 2009;339:1366–70.
ary tree anomaly. The Royal College of Pathologists. Cancer datasets
Bibliography biopsies for primary and metastatic carcinoma, endo-
crine tumours of the gastrointestinal tract (including
Allen DC. Histopathology reporting. Guidelines for surgi- pancreas) and tissue pathways (gastrointestinal and
cal cancer. 3rd ed. London: Springer; 2013. pancreatobiliary pathology, liver biopsies for the inves-
Allen DC, Cameron RI. Histopathology specimens: tigation of medical disease and for focal liver lesions).
clinical, pathological and laboratory aspects. 2nd ed. Available via https://www.rcpath.org/profession/publi-
Berlin: Springer; 2013. cations/cancer-datasets.html. Accessed Aug 2016.
Beckingham IJ, editor. ABC of liver, pancreas and gall Wyatt JI. Cholangiocarcinoma—new concepts and clas-
bladder diseases. London: BMJ Books; 2001. sifications. Diagn Histopathol. 2011;17:539–47.
Abdominal Wall, Umbilicus,
Hernias, Omentum, 11
and Peritoneum
11.1 Anatomy intestine and anterior abdominal wall. The

omentum contains lymphoid aggregates which
The anterior abdominal wall is formed by skin, are thought to have an immunological function
fascia, and striated muscles including rectus locally in the peritoneal cavity. The omentum
abdominus and the oblique muscles. The inguinal provides a large area for electrolyte/fluid absorp-
canal is an oblique passage through the groin area tion and will also adhere to sites of inflamma-
of the lower abdominal wall, and although pres- tion/bleeding.
ent in both sexes, it is more prominent in the
male, allowing structures to pass to and from the
testis. 11.2 Clinical Presentation
The umbilicus is present in the midline of the
anterior abdominal wall and is a scar caused by Abdominal wall lesions present with a lump that
the attachment of the umbilical cord, allowing may be associated with discomfort or discharge.
blood vessels to pass to and from the fetus. A hernia occurs when part or all of a viscus
The greater omentum is a two-layered fold of protrudes through the confines of the body cavity
visceral peritoneum that is attached to the in which it is normally situated. It presents with a
greater curvature of the stomach and transverse dull “dragging” sensation or palpable lump usu-
colon. It hangs down between the coils of small ally evident on coughing. Severe constant pain is
a sign of impending strangulation and ischaemia
of any omentum or small bowel contents which
may also become obstructed.
D.C. Allen (*) Umbilical disease can present with a lump,
Histopathology Laboratory, Belfast City Hospital, discharge, or inflammation (omphalitis) and
e-mail: derek.allen@belfasttrust.hscni.net infection leading to pain and abscess forma-
tion. Caput medusa results from dilatation of
R.I. Cameron
Histopathology Laboratory, Altnagelvin Hospital, periumbilical veins secondary to increased
Western Health and Social Care Trust, portal venous pressure usually due to liver
Londonderry, UK cirrhosis.
e-mail: iain.cameron@westerntrust.hscni.net Omental disease is usually due to inflamma-
M.B. Loughrey tion or malignancy in adjacent organs but pri-
Histopathology Laboratory, Institute of Pathology, mary disease can also lead to adhesions and small
Care Trust, Belfast, UK bowel obstruction; torsion produces nausea and
e-mail: maurice.loughrey@belfasttrust.hscni.net vomiting, and tumour, an abdominal mass.

11.3 Clinical Investigations an umbilical deposit (Sister Mary Joseph’s

nodule), which is also a site for hernia, endo-
• FBP—elevated WCC in omphalitis metriosis, or fistula due to persistence of an
• LFTs/liver biopsy—in patients with caput embryonic structure, e.g., the vitellointestinal
medusa duct or urachus. These result in umbilical pro-
• Pus swab—umbilical abscess/suppuration trusion, cyclical menstrual haemorrhage, or
• AXR—dilated small bowel loops in obstructed serous discharge, respectively. A persistent
hernia urachal remnant may be attached to the dome
• Fistulogram—contrast may be passed into an of the urinary bladder potentially acting as a
umbilical fistula to show its origins and course source for internal hernia with bowel entrap-
• Herniography—this rarely used investigation ment and ischaemia.
involves injecting contrast into the peritoneal Abdominal fibromatosis (“desmoid tumour”):
cavity. A plain AXR will then reveal the pres- A locally infiltrative and recurrent form of fibro-
ence and position of a hernial sac matosis typically in the anterior abdominal wall
• USS—useful in diagnosing a hernia and in of a woman of child-bearing age with a previous
distinguishing it from other groin conditions history of caesarean section. It has no potential to
and in the investigation of tumours of the metastasize but causes problematic recurrent
abdominal wall intestinal obstruction and may occasionally be
• CT/MRI scan—will outline tumours of the associated with intestinal polyposis (Gardner’s
abdominal wall, and pelvic and abdominal syndrome), a variant of FAP.
tumours involving the omentum Amyloidosis: Involvement of anterior abdomi-
• FNA/needle core biopsy—used in the diagno- nal wall subcutaneous fat in systemic amyloido-
sis of abdominal wall tumours sis allows a diagnosis to be made by needle
• Laparoscopy and biopsy—useful in the inves- aspiration or biopsy with smearing of fat onto
tigation of omental lesions, particularly sec- glass slides for Congo Red staining.
ondary tumours Stomas: Such as ileostomy or colostomy fash-
ioned during a gastrointestinal surgical operation
may subsequently be taken down as part of a
11.4 Pathological Conditions planned procedure, or revised due to dysfunction.
The latter can be due to ischaemia or mucosal
11.4.1 Abdominal Wall prolapse with obstruction. Rarely secondary car-
and Umbilicus cinoma involves the stomal site.
Various conditions can affect the abdominal wall

and result in both FNA and histopathology 11.4.2 Hernias
specimens.
Secondary carcinoma: Commonly due to External hernias involve protrusion of perito-
either gastrointestinal or gynaecological can- neum ± omentum and bowel into the layers of the
cer involvement can be by direct spread at pre- abdominal wall (particularly at the site of a previ-
sentation or because of a subsequent metastatic ous surgical incision), inguinal or femoral canals.
recurrence. The former is not infrequently seen The hernial sac is usually thin walled, comprising
with a perforated bowel cancer and the inner fibrous connective tissue lined by peritoneum. It
layers of the abdominal wall may be dissected may become irreducible and undergo secondary
off separately or in continuity with it. The lat- ischaemia of the contents and with ulceration and
ter tends to be encountered as an intramural infection of the overlying skin. Internal hernias
nodule or deposit with a previous history of into anatomical spaces (e.g., the lesser omental
bowel resection and is often amenable to diag- sac) or across fibrous bands (congenital or
nosis by clinical FNA. Classically secondary acquired) may also obstruct and become
carcinoma (colon, ovary, breast) can present as ischaemic.
11 Abdominal Wall, Umbilicus, Hernias, Omentum, and Peritoneum 127
11.4.3 Omentum and Peritoneum Diffuse malignant mesothelioma—epitheli-

oid/sarcomatoid or mixed in pattern and a strong
The omental fat and peritoneal serosa may be association with occupational asbestos exposure
involved by various inflammatory and neoplastic and spread from a primary pleural mesotheli-
disorders. oma. Prognosis is poor, with the majority of
Inflammation: Acute due to appendicitis or a patients dying from their disease within months
perforated viscus (gastric ulcer, diverticulitis), or, or 1–3 years. Of very limited suitability for
granulomatous, e.g., tuberculosis, fungal perito- resection.
nitis (chronic ambulatory peritoneal dialysis— Peritoneal serous epithelial proliferation:
CAPD) or after previous surgery. CAPD can also Strongly associated with ovarian serous border-
be associated with the rare condition of scleros- line tumours and either regarded as benign (endo-
ing peritonitis. salpingiosis) or potentially progressive (invasive
Infarction: Spontaneous, idiopathic omental proliferating implants). Also frankly malignant—
infarction in the right iliac fossa mimicking acute primary peritoneal carcinoma. The former two
appendicitis (rare), or, more commonly, infarc- conditions are microscopic findings, while the
tion of an appendix epiploica (pericolonic fat latter is an ovarian/tubal serous-type adenocarci-
tag), which may then undergo saponification and noma with extensive peritoneal disease but mini-
calcification. The latter are also seen as a conse- mal ovarian involvement.
quence of acute pancreatitis or abdominal trauma. Pseudomyxoma peritonei: Characterized by
Omentum incarcerated within a hernial sac may filling of the peritoneal cavity with abundant
also undergo ischaemia. mucin, which may contain variably bland, atypi-
Keratin granulomas: An unusual finding most cal, or frankly malignant epithelium. Prognosis is
often related to treatment and follow-up of a pre- poor as it is refractory to treatment, slowly pro-
vious gynaecological cancer, e.g., endometrioid gressive, and leads to bowel obstruction. There is
adenocarcinoma of the uterus or vulval squamous a strong association with appendiceal and ovarian
carcinoma. mucinous tumours and occasionally secondary
Peritoneal inclusion cysts: Relatively common, colorectal or pancreaticobiliary neoplasms.
solitary, or multiple, and should be distinguished Appendicectomy should be considered in the
from lymphangitic cysts (cytokeratin negative, presence of bilateral cystic ovarian tumours asso-
D2-40 positive endothelial lining) and well-differ- ciated with peritoneal disease to rule out a pri-
entiated multicystic peritoneal mesothelioma. The mary appendiceal malignancy.
latter is rare, occurring on the surfaces of the uterus, Secondary adenocarcinoma: Staging and
ovary, bladder, rectum, and pouch of Douglas, with therapy are considered:
potential for recurrence and invasion locally into Staging—diagnosed either by peritoneal aspi-
retroperitoneum, bowel mesentery, and wall. Some ration cytology, laparoscopic biopsy, or open
have a previous history of surgery, endometriosis, biopsy with frozen section at exploratory lapa-
or pelvic inflammatory disease. rotomy as a prequel to consideration of suitabil-
Mesothelial proliferation: Other mesothelial ity for operative resection of an abdominopelvic
proliferations include: cancer. Postoperative pathological staging of
Mesothelial hyperplasia—commonly seen as ovarian carcinoma also partly relates to the size
a reactive phenomenon in omentum adherent to (< or >2 cm) of the peritoneal deposits—it
an inflammatory or neoplastic abdominopelvic requires removal of the primary ovarian lesion,
lesion or within a hernia. Sometimes it is florid, biopsy of the contralateral ovary, omentum, and
and distinction from mesothelioma can be peritoneum, and peritoneal washings for cytol-
difficult. ogy if ascitic fluid is not present.
Well-differentiated papillary peritoneal meso- Therapy—tumour debulking or cytoreductive
thelioma—rare, with most being an incidental surgery of extensive omental disease is an impor-
finding at hysterectomy, usually localized and tant initial step prior to adjuvant chemotherapy in
benign but occasionally diffuse. ovarian and other abdominopelvic cancers.
Other cancers: These are rare, e.g., intra- Omentectomy—This is a relatively straightfor-
abdominal desmoplastic small round-cell ward procedure usually undertaken as part of
tumor—divergent cellular differentiation, aggres- more extensive surgery, e.g., during a gynae-
sive, pelvis and abdomen of young people. cological cancer operation for therapeutic
cytoreduction and staging purposes. It
involves ligation of the vessels along the
11.5 Surgical Pathology greater curvature of the stomach and trans-
Specimens: Clinical Aspects verse colon with division of the omentum in
this area.
Needle core biopsies of abdominal wall and 11.6 Surgical Pathology

umbilical tumours provide a diagnosis and allow Specimens: Laboratory
future management to be planned. Laparoscopy Protocols
and omental biopsy can be used as a staging
investigation, and is particularly useful in gastric 11.6.1 Abdominal Wall
tumours and ovarian tumours/pseudomyxoma
peritoneii. Ranging from biopsy fragments taken at lapa-
rotomy to formal excision of an abnormal seg-
ment of tissue. Specimens from the inner
11.5.2 Resection Specimens aspect of the wall comprise rectus sheath mus-
cle orientated along one edge to peritoneum
Groin hernias—In uncomplicated groin hernias, and with distortion by the relevant pathological
the principle of surgery is to reduce the hernia condition. External specimens are composed
sac and repair the defect in the abdominal of skin, subcutaneous fat ± abdominal wall
wall. This can be done by either suturing or muscle and may also contain the umbilicus, a
introducing a prosthetic mesh. In complicated stoma, or incisional hernia. Biopsy fragments
hernias in which the small bowel may be are processed in the usual manner, but larger
incarcerated, the hernia sac needs to be opened specimens need to be individually described as
and the viability of the intestine assessed. If it to their constituent parts, their respective
is in question, then a small bowel resection dimensions, and the abnormalities that are
may be required. present. These specimens are usually submit-
Abdominal wall tumours—Primary abdominal ted already fixed in formalin.
wall tumours such as desmoid tumours are Mass lesion (tumour, fibromatosis, endome-
treated by wide excision. The excision usually triosis, abscess):
entails excising the skin and rectus sheath, and
may even extend down to the parietal • Maximum dimension (cm), edges (circum-
peritoneum. scribed/irregular), cut surface (mucinous/scir-
Umbilical lesions—Primary tumours of the rhous/fibrotic/haemorrhage/pus), distances
umbilicus, e.g., squamous carcinoma, are (mm) to the skin and nearest resection margin,
treated by excision of the umbilicus involvement of skin (ulceration/tethering),
(omphalectomy), surrounding skin, and full subcutis, muscle, or peritoneum.
thickness of the periumbilical wall. If abscess • Paint the deep and lateral resection margins.
formation occurs following umbilical infec- • Serially section transversely at 3–4 mm intervals
tion, this should be treated by incision and perpendicular to the skin or peritoneal surfaces.
drainage. Omphalectomy may be required if • Sample four or five representative blocks of the
infection is recurrent. lesion showing its relationship to the various
11 Abdominal Wall, Umbilicus, Hernias, Omentum, and Peritoneum 129
anatomical layers and resection margins. If neous, subcutaneous, and proximal bowel resec-
close (≤0.5 cm) to a long axis margin, obtain a tion limits.
longitudinal block to demonstrate this. • Paint the deep and lateral resection margins.
• Stomas: • Transverse section the proximal bowel resec-
• Note any mucosal prolapse, ulceration, isch- tion limit.
aemia, or tumour at the mucocutaneous junction, • Serially section the specimen transversely at
or bowel stricture—record their maximum 3–4 mm intervals perpendicular to the skin
dimensions (cm) and distances (cm) to the cuta- surface (Fig. 11.1a).
a
Stomal opening
Mucocutaneous
junction
Lateral limit of
skin and subcutis
Plane of deep limit

Select blocks from deep limit,
Plane of section junction and any abnormality present
Fig. 11.1 (a) Sectioning of an abdominal wall mass, stoma (illustrated), or hernia; (b) sectioning of omentum
(Reproduced, with permission, from Allen and Cameron (2013))
• Sample four or five representative blocks of with a shaggy, lace-like appearance weights
the stomal junction/opening and any other rel- vary from a few to several hundred grams.
evant macroscopic abnormality. Record the weight (g) and dimensions (cm).
• Serially slice at 0.5 cm intervals and closely
inspect (Fig. 11.1b).
11.6.2 Hernias • Note any macroscopic abnormalities—nature
(abscess/fat necrosis/cysts/tumour), edge (cir-
• Note any surgical scars or ulceration of the cumscribed/irregular), consistency (cystic/
skin, necrosis in the skin, subcutis, abdominal fibrotic/mucoid/scirrhous), contents (serous
muscle, wall of the hernial sac or its contents. fluid/lymph/mucin), number, and the maxi-
• Hernial sac—dimensions and wall thickness mum dimension (cm).
(cm). • Sample three representative blocks of macro-
• Contents—omentum, bowel, and their dimen- scopically abnormal or unremarkable omental
sions (cm). specimens.
• Paint the deep and lateral resection margins.
• Transverse section bowel resection limits, if
present.
• Sample four or five representative blocks of Bibliography
the hernial sac and its contents to demonstrate
its relationship to the various anatomical lay- Allen DC. Histopathology reporting. Guidelines for surgi-
ers and any abnormality that is present. Allen DC, Cameron RI. Histopathology specimens:
11.6.3 Omentum and Peritoneum– Dudley H, Pories W, Carter D, editors. Rob and Smith’s
operative surgery: alimentary tract and abdominal
wall. 4th ed. London: Butterworths; 1993.
• Laparoscopic biopsy fragments are processed Odze RD, Goldblum JR, editors. Odze and Goldblum
in the usual manner and cut through multiple surgical pathology of the GI tract, liver, biliary tract,
levels. and pancreas. 3rd ed. Philadelphia: Elsevier Saunders;
2015.
• Omental specimens vary in size, depending on Shepherd NA, Warren BF, Williams GT, Greenson JK,
whether the investigation is for diagnostic, Lauwers GY, Novelli MR, editors. Morson and
staging, or therapeutic purposes. Typically Dawson’s gastrointestinal pathology. 5th ed. Oxford:
comprising lobulated fat or the omental curtain Wiley-Blackwell; 2013.
Part II
Breast Specimens
Breast
12
Shauna Casey and R. Iain Cameron
12.1 Anatomy the axillary lymph nodes receiving at least 75%

of the lymphatic flow. These are located at ana-
The mature adult breast is composed of fatty tis- tomical levels—Levels I, II, and III (Fig. 12.2).
sue and parenchyma in which terminal ductulo- Drainage via the internal lymphatics into the
lobular units of epithelium are surrounded by internal thoracic nodes comprises 25% or less of
fibrous connective tissue stroma. There are about the lymph flow and the third and least important
15–25 lobes of parenchymatous elements associ- is to the posterior intercostal nodes where the ribs
ated with each of the lactiferous ducts which and vertebrae articulate.
drain into the nipple. The presence of this func-
tional lobar arrangement provides an anatomical 1. Axillary (ipsilateral): interpectoral (Rotter)
framework for some surgical procedures such as nodes and lymph nodes along the axillary vein
major duct excision and quadrantectomy for can- and its tributaries, which may be divided into
cer. The anatomical boundaries of the breast are the following levels:
not well defined except at the deep surface where (a) Level I (low axilla): lymph nodes lateral
the gland overlies the pectoralis fascia. The gen- to the lateral border of pectoralis minor
eral topographical anatomy of the breast is illus- muscle.
trated in Fig. 12.1. (b) Level II (mid-axilla): lymph nodes
Lymphovascular drainage: between the medial and lateral borders of
There are three routes of lymphatic drainage the pectoralis minor muscle and the inter-
in the breast. The most important is to the axilla, pectoral (Rotter) lymph nodes.
(c) Level III (apical axilla): lymph nodes
medial to the medial margin of the pecto-
ralis minor muscle including those desig-
nated as subclavicular or apical. Note:
Intramammary lymph nodes are coded as
axillary lymph nodes.
S. Casey (*)
Histopathology Laboratory, Belfast City Hospital, 2
. Internal mammary (ipsilateral): lymph nodes
Belfast Health and Social Care Trust, Belfast, UK in the intercostal spaces along the edge of the
e-mail: shauna.casey@belfasttrust.hscni.net sternum in the endothoracic fascia (2). Any
R.I. Cameron other lymph node metastasis is coded as a dis-
Histopathology Laboratory, Altnagelvin Hospital, tant metastasis (M1), including contralateral
Western Health and Social Care Trust, supraclavicular, cervical, or contralateral
Londonderry, UK
e-mail: iain.cameron@westerntrust.hscni.net internal mammary lymph nodes

134 S. Casey and R.I. Cameron
Axillary tail
Upper outer quadrant Upper inner

quadrant
Nipple
Areola
Lower outer quadrant

Lower inner
quadrant
Fig. 12.1 Topographical anatomy of the right breast (Used with the permission of the Union for International Cancer
Control (UICC), Geneva, Switzerland. The original source for this material is from Wittekind et al. (2005))
bloody can be due to an intraduct proliferation

Pectoralis which may require surgical excision (microdo-
minor chectomy). Nipple rash may need to be biopsied
muscle
to exclude Paget’s disease. A palpable discrete
lump can be cystic or solid. The majority of cys-
tic lumps are benign simple cysts which can be
drained by needle aspiration. Occasionally can-
2
cerous lumps may have a cystic component
which is usually bloody. Solid lumps are investi-
gated by the triple assessment approach (see
below) to provide a nonoperative diagnosis of
benignity or malignancy.
Screening: At present, all women aged
Level I II III between 50 and 70 are invited to the National
Health Service Breast Screening Programme,
Fig. 12.2 Breast: regional lymph nodes (Used with the
permission of the Union for International Cancer Control which initially involves mammography to
(UICC), Geneva, Switzerland. The original source for this screen out lesions that require further evalua-
material is from Wittekind et al. (2005)) tion by the triple assessment approach such as
a spiculate density or areas of microcalcifica-
tion. Microcalcifications with no associated
12.2 Clinical Presentation soft tissue abnormality may be the only sign of
malignancy and is the mode of presentation of
Symptomatic: Patients commonly present with a up to one third of cancers found at screening.
palpable lump, breast pain, nipple discharge, or Linear branching microcalcifications are usu-
rash. Breast pain is usually not associated with ally associated with comedo ductal carcinoma
any significant pathology. Nipple discharge if in situ (DCIS) and have a higher predictive
12 Breast 135
value for malignancy than nonlinear irregular diagnosis and if so whether the lesion is benign
microcalcifications. Overall the sensitivity of or malignant.
mammography is 85–90%. Needle core biopsy (NCB): This is performed
with a wide-bore spring-loaded device which
requires local anaesthesia prior to the proce-
12.3 Clinical Investigations dure. It can be done either with radiological
guidance or freehand. In some centres, NCB is
Clinical examination: Symptomatic patients are only carried out when the aspirate is non-diag-
referred to a dedicated Breast Clinic, where they nostic. However, in other centres NCB is carried
are assessed by a multidisciplinary team of spe- out on all lesions and may be the only preopera-
cialists. The patient is usually first seen and tive sample. In malignant lesions, in contrast to
examined by a breast surgeon who instigates FNAC, NCB allows the distinction between in
further investigations where appropriate. situ and invasive carcinoma to be made. In con-
Radiological imaging: The patient normally trast to aspirate cytology, which allows immedi-
has standard two-view mammography, i.e., ate reporting, needle cores require overnight
cranio-caudal and medio-lateral oblique views processing before a result is obtainable by
performed. Additional magnification views may histology.
be required to focus on a suspicious area and Vacuum assisted biopsy: In cases where NCB
facilitate more detailed examination. is not diagnostic or there is an area of microcalci-
Tomosynthesis provides higher resolution views fication, vacuum biopsy under stereotactic X-ray
of suspicious lesions. The radiologist then guidance may be carried out. This involves a
decides if the lesion warrants further investiga- wider bore needle (7–10 G) with removal of more
tion by ultrasonography. Younger women with tissue (up to 3 g) for examination.
dense breast tissue are usually investigated by Triple assessment approach: The above tri-
ultrasonography. Suspicious areas of microcal- ple approach, utilizing the combination of clin-
cification and parenchymal deformity are then ical (surgical) examination, radiological
aspirated and/or core biopsied. In cases of sus- imaging by X-ray and/or ultrasound, and cyto-
pected malignancy, ultrasound scanning of the logical assessment of aspirated material along
ipsilateral axilla is undertaken, and if an with NCB, has been shown to be highly accu-
enlarged or abnormal node is found this can be rate in the preoperative diagnosis of breast can-
aspirated or biopsied. In cases of invasive lobu- cer. This has superseded “frozen-section”
lar carcinoma diagnosed by core biopsy and examination of suspected breast cancers.
breast conserving surgery is being considered, Patients proven to have breast cancer by the
MRI scanning of both breasts is carried out. triple assessment can then go on to a one-stage
This modality is more sensitive in picking up therapeutic procedure which is excision of the
small multifocal and contralateral lobular tumour together with an axillary node proce-
carcinomas. dure (see below).
Fine needle aspiration cytology (FNAC): Open excision biopsy: In a small minority of
This involves the insertion of a 23 G needle cases, a nonoperative diagnosis is not conclusive
into the lump. The needle is moved about or malignancy cannot be excluded; hence, an
within the lump and negative pressure is open biopsy is required for histological diagno-
applied with the attached syringe on a holder. sis. Lesions like radial scars or papillary growths
The procedure ideally is performed by the radi- need formal histological assessment to exclude
ologist under ultrasound guidance. The aspi- associated in situ or invasive malignancy.
rated material is then smeared on glass slides, Impalpable lesions and areas of microcalcifica-
air dried, and stained for immediate micro- tion require radiological needle localization to
scopic examination by the cytopathologist who guide the surgeon to the area in question for ade-
will then indicate if the sample is adequate for quate excision.
12.4 Pathological Conditions mild degree of nuclear atypia, but the presence of
bare nuclei should be reassuring. Excision of the
12.4.1 Non-neoplastic Conditions lesion is most likely performed for cosmetic rea-
sons. A small minority of cases is due to an
Fibroadenosis/fibrocystic changes: These are underlying malignancy.
common in the breast and present as ill-defined Reduction mammoplasty: Bilateral reduction
masses or plaques. There is a varying degree of mammoplasty surgery may be performed on
epithelial proliferation and hyperplasia, with or larger breasts for physical or cosmetic reasons.
without cyst formation. There can often be asso- Symmetrical volumes of fatty breast tissue are
ciated apocrine metaplasia or sclerosing adeno- removed with overlying non-nipple-bearing skin.
sis. Excision of these lesions sometimes occurs at There is normally no significant pathology in the
the request of the patient despite a nonoperative tissues.
diagnosis of benignity by triple assessment. Leakage from silicone implants: A fibrous
Cysts: Simple cyst formation is very common capsule usually forms around a silicone implant,
and presents as a firm but fluctuant lump. Needle but silicone may migrate into and through it.
aspiration to dryness is usually all that is required. Rupture of the capsule can occur by accident,
Breast abscess: Most commonly encountered mammography, or closed capsulotomy. Rupture
in non-lactating premenopausal women in a sub- of the silicone implant envelope may occur
areolar location as a result of duct obstruction. It asymptomatically and once outside the envelope,
is usually diagnosed by FNAC and seldom silicone can disperse through soft tissue, lymph
requires surgical intervention unless there is fail- nodes, or the vasculature. Silicone particles are
ure to resolve. detected in the tissue as small round-to-irregular
Fat necrosis: This is most commonly seen fol- translucent droplets of amorphous refractile non-
lowing a history of trauma, needle core biopsy or polarizing material. Silicone leakage into the
surgery. Clinically and radiologically, fat necro- capsule is characterized by a typical microscopi-
sis can mimic a carcinoma but can be distin- cal appearance of oval-to-round holes partly
guished by FNAC. However, an excision biopsy filled with silicone particles. Giant cells of for-
may be required if the lesion persists. eign body type may be found and granulomas as
Duct ectasia: This is due to duct dilatation a reaction to silicone (“siliconomas”) are seen
with filling of the duct lumen by amorphous after extracapsular rupture of an implant and after
material and accompanying chronic inflamma- injection with silicone. Calcification of the cap-
tion in the duct wall and periductal stroma. sule is common around implants which have
Nipple discharge is usually the first symptom, but been in situ for many years. The recently
a worm-like palpable mass may form in the sub- described breast implant associated anaplastic
aerolar region in more advanced cases where large cell lymphoma is discussed below.
there is periductal fibrosis. Excision of the area
may be necessary to exclude DCIS.
Gynaecomastia: This is the most common 12.4.2 Neoplastic Conditions
clinical and pathological abnormality in the male
breast. It is encountered in adolescent or adult 12.4.2.1 Benign Tumours
males and is usually unilateral. In older men, it Fibroadenoma: This is the commonest benign
may be due to certain drug usage such as digoxin, tumour of the breast most often encountered in
spironolactone, and cimetidine. It forms a firm to premenopausal women who present with a pal-
rubbery plaque deep to the nipple. Patients with pable painless and mobile discrete lump.
bilateral involvement tend to have diffuse lesions Nonoperative diagnosis can be confidently made
as compared to unilateral gynaecomastia which by the triple approach except in large lesions
is more discrete. FNAC usually produces a low to where excision may be advised to exclude a low-
moderately cellular specimen which may show a grade phyllodes tumour.
12 Breast 137
Proliferative lesions (radial scar/complex patients with DCIS associated with a mass or in
sclerosing lesion, intraduct papilloma, nipple those with widespread DCIS requiring mastec-
adenoma, myoepithelioma): These lesions are tomy. In cases of wide local excision, the speci-
due to epithelial proliferations of various com- men resection margins are carefully identified
plexities which can present as firm palpable and labeled by an agreed protocol for close histo-
masses. Mammography may show parenchymal logical examination to assess completeness of
deformity and foci of microcalcification, thus surgical removal. Width of the excision margins
necessitating cytological assessment. The latter around the tumour remains the most important
usually shows a highly cellular sample with some factor in terms of risk of local recurrence, and a
degree of nuclear atypia, indicating either a core minimum clearance of 3 mm should be achieved.
biopsy or local excision. Some of these lesions All cases treated by breast conserving surgery
may harbour DCIS, which can only be confirmed should be considered for adjuvant radiotherapy.
or excluded following histological examination. Invasive carcinoma: Breast carcinoma is a
Miscellaneous: Rarely benign lesions such as heterogeneous group of tumours with different
adenomas, hamartomas, fibromatosis, or pseudo- morphological growth patterns which reflect the
angiomatous stromal hyperplasia (PASH) are clinical behaviour and, hence, the prognosis. The
encountered. most common form of invasive breast cancer is
the ductal type, no special type (NST), account-
12.4.2.2 Malignant Tumours ing for 75–80% of all breast cancers. This tumour
Carcinoma in situ: Carcinoma in situ is a prolif- type is diagnosed by exclusion of other special
eration of malignant epithelial cells within the types, viz., lobular, mucinous, tubular, medullary-
ductulo-lobular system of the breast, which on like, and cribriform carcinoma etc. Invasive lobu-
light microscopy shows no evidence of breaching lar carcinoma is the next most common tumour
the basement membrane to invade the adjacent type forming about 10–15% of cases. Tumours of
stroma. There are two forms—ductal (DCIS) and mixed ductal and special types are also encoun-
lobular (LCIS) carcinoma in situ. LCIS may be tered. Some of the special tumour types such as
associated with microcalcification on mammo- mucinous, tubular and medullary-like have a bet-
gram but is usually seen incidentally on excision ter prognosis. Not infrequently, breast cancer
specimens as a marker for increased risk of may be multifocal (within the same quadrant) or
developing malignancy. DCIS, on the other hand, multicentric (involving other quadrants) and, in
is a heterogeneous group of premalignant lesions, some cases, bilateral. Breast cancers are graded
which are usually asymptomatic and impalpable 1, 2, or 3, depending on the degree of diffferentia-
but may be identifiable on mammography as foci tion (see below) which has been shown to corre-
of microcalcification. It can sometimes present as late with biological behaviour. The invasive
a mass lesion. Nonoperative diagnosis of DCIS is tumour size, type, grade, presence or absence of
based on FNAC and core biopsy. DCIS is catego- lymphovascular invasion and nodal status are
rized by the degree of nuclear pleomorphism as pathological prognostic factors determining
low, intermediate, or high grade, and by its archi- adjuvant therapy and outcome for the patient.
tectural patterns—cribriform, solid, or micropap- Certain biological markers such as oestrogen and
illary with or without comedo necrosis. DCIS Her2/neu receptor status can predict tumour
with comedo necrosis is usually associated with response to hormonal or cytotoxic therapy,
dystrophic calcification and has a high nuclear respectively.
grade. This subtype has the highest risk of stro- Paget’s disease of the nipple: Paget’s disease
mal invasion. The treatment of DCIS depends on of the nipple is characterized by infiltration of
the size and distribution of the lesion. Localized malignant ductal epithelial cells into the epider-
DCIS may be amenable to wide local excision, mis of the nipple-areolar complex. Clinically, it
while extensive disease requires a total mastec- presents as an itchy and scaly rash which may be
tomy. Sentinel node biopsy is carried out in those mistaken for eczema but gradually gives rise to
ulceration, crusting, and bloody nipple discharge an effusion surrounded by a fibrous capsule but
in advanced cases; 1–2% of breast cancers have may also present as a mass. Patients suspected of
associated Paget’s disease. In patients presenting having BIA-ALCL undergo removal of the
with features of Paget’s disease without a clini- implant and capsulectomy with adjuvant therapy.
cally palpable mass, high nuclear grade DCIS is Atypical lymphoid cells are seen within the effu-
nearly always detected in the large subareolar sion fluid which are usually CD30 positive and
lactiferous ducts and up to 40% will have an ALK negative. The cases which present with an
occult invasive tumour within the breast. An exci- effusion usually have a indolent course with an
sion biopsy of the nipple is performed to confirm excellent prognosis. Those that present as a mass
Paget’s disease and treatment is usually by have a higher rate of relapse and generally require
mastectomy. more aggressive therapy.
Phyllodes tumour: This is a tumour of fibro- Treatment and prognosis: The mainstay of
epithelial origin usually seen in older women treatment for primary breast cancer is surgery
compared to fibroadenoma. These tumours aver- (with a locally agreed minimum tumour clear-
age 4–5 cm in size and have a history of rapid ance of excision margins: the exact distance is
growth. Radiology reveals a lobulated or rounded controversial—usually 1–5 mm) followed by
solid mass. FNAC usually produces a highly cel- endocrine treatment or chemotherapy where
lular aspirate composed of epithelium and stroma, appropriate. Radiotherapy may be indicated to
features which overlap with a fibroadenoma prevent local recurrence. In a small number of
hence making distinction between the two diffi- cases, neo-adjuvant therapy is instituted if the
cult. However, stromal fragments that are densely cancer is large and advanced or if surgery is con-
cellular may suggest a phyllodes tumour and, traindicated due to poor general health. Endocrine
taking the patient’s age and size of lesion into treatment is determined by oestrogen and proges-
account, an excision biopsy would be indicated togen receptor status as assayed by immunohisto-
in these circumstances. The biological behaviour chemistry. Chemotherapy is usually indicated in
of these neoplasms is unpredictable. Toward the high-grade and node positive cancers, particu-
benign end of the spectrum, they may locally larly in the younger patient. Her2/neu receptor
recur if incompletely excised (a 10 mm margin status is assessed either by immunohistochemis-
should be achieved), but tumours with sarcoma- try or in situ hybridization techniques. Her2 gene
tous transformation will metastasize by the hae- amplification is associated with poor prognosis.
matogenous route. In Her2 positive tumours there is a survival ben-
Mesenchymal tumours: Malignant mesenchy- efit in those treated with the anti-Her2 therapy
mal tumours such as angiosarcoma, malignant Herceptin (trastuzumab). Patients with high
fibrous histiocytoma, leiomyosarcoma, liposar- grade node positive cancer at diagnosis may be
coma are all rare and have to be distinguished considered for neo-adjuvant chemotherapy.
from a metaplastic carcinoma or sarcomatous Radio-opaque maker clips are inserted to delin-
transformation in a phyllodes tumour. eate the tumour prior to commencement of
Metastatic tumours: Occasionally metastases treatment.
from other primary sites may present as breast The single most important prognostic factor in
lumps such as melanoma, lymphoma, small cell breast cancer is nodal involvement at time of
lung carcinoma, ovarian and gastrointestinal ade- diagnosis. However, the 5-year survival rate has
nocarcinoma. Some of these cases may be diag- also been shown to correlate with histological
nosable preoperatively by FNAC/NCB. tumour type and the Nottingham Prognostic
Breast implant associated anaplastic large Index (NPI) (see below).
cell lymphoma (BIA-ALCL): This is a recently Excellent prognosis tumour types with a
described rare non-Hodgkin lymphoma associ- 5-year survival of greater than 80% include
ated with breast implants which often presents as tubular, mucinous, cribriform and tubulolobular
12 Breast 139
carcinoma. Good prognosis types with 60–80% 12.5.2 Resection Specimens

5-year survival include mixed ductal NST/special and the Types of Surgery
type, tubular and the alveolar lobular variant.
Intermediate prognosis (50–60% 5-year survival) Surgical treatment for localized breast cancer:
types include classical lobular, medullary-like, Most patients with breast cancer will have a com-
and invasive papillary. Those with poor prognosis bination of local treatment to control local dis-
(<50% 5-year survival) are high-grade ductal ease and systemic treatment to manage metastatic
NST, mixed ductal and lobular, pleomorphic lob- disease. Local treatment consists of surgery and
ular, and metaplastic carcinoma. radiotherapy. Surgery can be an excision of the
cancer with surrounding normal breast tissue
(breast-conserving surgery) or a mastectomy.
12.5 Surgical Pathology Certain clinicopathological factors influence the
Specimens: Clinical Aspects selection for breast-conserving surgery or mas-
tectomy, depending on the likelihood of local
12.5.1 Biopsy Specimens recurrence after the former. These include the site
and size of tumour, extent of DCIS, multifocal or
Needle core biopsy: Usually up to six cores of multicentric disease and incomplete initial exci-
tissue, particularly for DCIS and microcalcifica- sion. All patients treated with breast-conserving
tions, are taken with a 19 G needle mounted on a surgery should have adjuvant radiotherapy and
spring-loaded gun under radiological guidance to also those with tumour involvement of the deep
yield 2–3 cm long worm-like samples. They are margin following mastectomy.
X-rayed prior to fixing in formalin in cases of Breast-conserving surgery (BCS): BCS may
microcalcification to ascertain that the right area consist of removal of the tumour with a 1 cm
has been sampled. With vacuum assisted biopsy margin of normal tissue (wide local excision) or
up to 3 g of tissue may be obtained using a a more extensive excision of a whole quadrant of
7–10 G needle. the breast (quadrantectomy). This comprises a
Needle localization biopsy: In cases where the cylinder of tissue taken from the skin superfi-
nonoperative diagnosis by FNAC and/or core cially to the pectoralis fascia at the deep aspect. A
biopsy is inconclusive, a diagnostic biopsy is partial mastectomy involves removal of the
required for histological assessment. The major- tumour with surrounding breast tissue and an
ity of these cases are from screening and involve ellipse of non-nipple-bearing skin. Small and
foci of microcalcification of radiological con- impalpable cancers, often detected by screening,
cern. Some cases of stromal or parenchymal are usually localized radiologically by a guide
deformity, even though they have been proven to wire prior to surgery to assist the surgeon in
be malignant by FNAC or core biopsy, also excising the appropriate area. The single most
require needle localization (by stereotaxis or important factor predicting local recurrence fol-
ultrasound) because they are impalpable and this lowing BCS is completeness of excision. Invasive
assists the surgeon in removing the appropriate or in situ disease at the resection margins
area. increases local recurrence by a factor of 3.4. An
Nipple biopsy: This is done either as a small extensive in situ component increases local recur-
wedge or punch biopsy of the nipple skin to con- rence only when margins are involved. The pres-
firm or exclude Paget’s disease. ence of tumour lymphovascular invasion (LVI)
Microdochectomy: Also known as main duct doubles the local recurrence rate. Grade I tumours
excision for cases of persistent nipple discharge are less likely to recur locally compared to
or an intraductal epithelial growth which may higher-grade tumours. Some of these factors are
have been suggested on smear cytology of the only fully appreciated after detailed histological
discharge material. assessment and subsequent re-excision of margins
or mastectomy as a second procedure is not an incision is made in the axilla and a handheld
infrequent occurrence. Clinically breast cancers gamma probe or direct visual inspection used to
that are suitable for treatment by breast conserva- identify the radioactive node or blue-stained lym-
tion include a single clinical and mammographic phatic channels leading to a blue lymph node.
lesion and tumours <3 cm in diameter or >3 cm The average number of sentinel nodes identified
in large breasts. is two. These are excised and immediately sent to
Cavity shavings: These are additional portions the laboratory where intraoperative examination
of breast tissue submitted separately as shavings in the form of imprint cytology and/or frozen sec-
from the cavity after excision of the tumour when tion may be employed (see below). During this
the surgeon assesses that he/she does not have procedure, the surgeon performs the breast oper-
clear margins following the initial excision. They ation. If the node is found to be involved by meta-
are labeled accordingly as to site, viz., medial, static tumour, then immediate ANC can be
lateral, superior, inferior, deep, or superficial. undertaken. Occasionally small metastatic depos-
Mastectomy: About a third of localized breast its are not seen by intraoperative examination and
cancers are unsuitable for BCS and will require a are only seen after histological examination of
total mastectomy. However, some patients who the sections of node. In these cases, the patient
are suitable for BCS )may also choose to have a will require a second stage ANC at a later date. In
mastectomy. Mastectomy removes the breast tis- some centres intraoperative assessment is not
sue with overlying skin including the nipple, undertaken and if required, ANC is done as a sec-
while the chest wall muscles are left intact. ond stage procedure. The metastatic deposit in a
Patients who are best treated by mastectomy sentinel node is classified according to size: mac-
include those with multifocal disease, extensive rometastasis >2.0 mm; micrometastasis
in situ component, centrally situated cancers, ≤2.0 mm; isolated tumour cells ≤0.2 mm. A sen-
tumours >4 cm in diameter or for whom BCS tinel node with isolated tumour cells or a micro-
would produce an unacceptable cosmetic result. metastatic deposit does not require ANC. An
A skin sparing mastectomy involves the removal axillary sampling of 3–4 nodes may be provided
of all breast tissue including the nipple–areolar if operative identification of the sentinel nodes is
complex but retaining the skin usually as part of uncertain.
a breast reconstruction procedure. Axillary node clearance (ANC): The axilla is
Axillary node surgery: Axillary node dissec- formally dissected out and nodes from Levels I,
tion is performed in conjunction with BCS or II, and III are retrieved for histological assess-
mastectomy for prognostic/staging and therapeu- ment and this usually totals between 15 and 30
tic purposes. This can take the form of either sen- nodes. A minimal regional lymphadenectomy for
tinel node biopsy or axillary node clearance. tumour staging will ordinarily include 6 or more
Sentinel node biopsy (SNB): Approximately lymph nodes.
two thirds of symptomatic and the majority of
screening breast cancers are node negative.
Therefore, axillary node clearance (ANC) in 12.6 Surgical Pathology
these cases is not indicated if it could be pre- Specimens: Laboratory
dicted that the nodes are negative and to avoid Protocols
any risk of morbidity such as arm pain and
lymphoedema. Lymphatic mapping and SNB is a 12.6.1 Biopsy Specimens
minimally invasive technique to identify patients
with axillary node involvement. The sentinel node Needle core, vacuum biopsy and nipple biopsies:
is defined as the first node to receive drainage These are counted, measured (mm), weighed
from the tumour and is identified by injecting a (vacuum biopsy), processed whole, and cut
vital blue dye, a radiocolloid, or both around the through multiple levels. Nipple ellipses may need
area of the tumour just prior to surgery. A small initial bisection depending on size.
12 Breast 141
Main duct excision specimens: These are and orientation sutures. Note the laterality
weighed, measured, and externally painted, and (right or left). Comment if the nipple is
then serially and transversely sliced to look for indrawn.
any intraluminal papillary growths. Multiple • Differentially paint all margins using artists’
slices are processed for histology. pigments or similar dyes according to an
Benign biopsies: Excisions of preoperatively agreed protocol.
proven benign lesions such as fibroadenoma are • Serially slice transversely at 5–10 mm inter-
routinely weighed, measured, and painted and vals (Fig. 12.3a) from the deep aspect to the
representative tissue blocks taken for histology. skin using it as a spine to hold the specimen
Needle localization biopsy specimens: These together.
are treated as resection specimens (see below). • Identify invasive tumour or DCIS areas (oozes
toothpaste-like material in comedo-type) and
measure the largest diameter (mm). In neoad-
12.6.2 Resection Specimens juvant chemotherapy specimens the tumour
bed will be delineated by the clips.
Specimen types: • Measure distances (mm) of the tumour edge to
the excision margins.
1 . Total mastectomy, SNB ± ANC
2. Breast conserving surgery—wide local exci- 12.6.2.2 Needle Localization
sion, quadrantectomy, partial mastectomy, and Wide Local Excision
SNB ± ANC Specimens
3. Needle localization biopsy • Obtain all relevant histories of preoperative
(a) For microcalcification investigative procedures, e.g. FNAC, NCB,
(b) For parenchymal deformity etc.
• Weigh (g) and measure (cm) the specimen.
Specimens submitted fresh to the laboratory • Make sure that laterality is stated (left or right)
that have a clearly palpable lesion can be initially and orientation sutures are correctly placed
incised following painting of excision margins before commencing. Note any accompanying
and prior to thorough formalin fixation (24–48 h). specimen radiograph (obligatory for localiza-
This allows sampling for research and optimal tion specimens) and the presence and location
tumour fixation. Impalpable and localization of any guide wire(s).
specimens are not incised prior to fixation as this • Orientate the specimen with sutures or surgi-
may distort the lesion precluding accurate assess- cal clips as per protocol agreed with the sur-
ment of histological appearances and relationship geon (e.g., long suture for lateral margin, dark
to the margins compounded by leaching of the suture for deep).
paint onto the cut surface. • Differentially paint all margins using artists’
Initial procedure: pigments according to an agreed protocol.
• Serially slice the specimen at 0.3 cm intervals
12.6.2.1 Mastectomy (Total/Partial) (Fig. 12.4a), lay out, and number the slices in
and Quadrantectomy sequence. Inspect with reference to the radio-
Specimens graph and guide wire tip (if applicable) and
• Obtain all relevant histories of preoperative note any macroscopic lesion(s).
investigative procedures, e.g. FNAC, NCB, • Needle localization specimens for microcalci-
etc., especially in cases of multifocal fication may show no obvious abnormality
disease. grossly. The laid out and numbered tissue
• Weigh (g) and measure (cm) the specimen. slices should be X-rayed by a Faxitron
Measure any ellipse of skin and note the pres- machine to help locate the area(s) in question
ence or absence of the nipple–areolar complex for block selection. If an X-ray facility is not
Fig. 12.3 Blocking a
mastectomy/
quadrantectomy Orientation sutures
specimens (a). surface Serial slices from
view (b). lateral view of the deep aspect
a serial slice showing to the skin
tumour, nipple, skin and
specimen margins
(Reproduced, with
and Cameron (2013)) Skin ellipse
Fatty breast
tissue
Nipple and
areola
b Nipple
Tumour and skin
Margin block
Breast tissue
Pectoral muscle
Tumour and Tumour and

breast deep limit
a Tumour-measure b
size and distance
from the margins
Blocks of tumour,
Serial slices in tumour edge and
numbered Guide wire margins
sequence
Orientation
sutures
Invasive
tumour
DCIS
Painted margins
Fig. 12.4 Blocking a breast localization/wide local excision specimen (a). surface view (b). lateral view of a serial
slice showing tumour and specimen margins (Reproduced, with permission, from Allen and Cameron (2013))
12 Breast 143
available, block especially fibrous paren- • Sample areas suspicious of DCIS.

chyma rather than fatty tissue. Small speci- • Sample surrounding breast tissue—one to two
mens less than 20 g, however, may be blocks.
processed in their entirety. • Sample nipple skin in mastectomy specimens
• Stromal deformity and mass lesions are iden- and tumour-involved skin or muscle.
tified grossly; the size and distances to the • In completion mastectomy specimens, sample
excision margins are measured. cavity wall—four blocks.
• In neoadjuvant chemotherapy specimens the • Cavity shave margins—sample all of tissue
tumour bed is delineated by clips • One H&E-stained section of each section of
• Cavity shavings from various margins are sentinel node.
weighed, painted, and labeled accordingly • If sentinel node is negative on H&E examina-
before submitting for processing. tion, immunohistochemistry with a cytokera-
tin stain such as MNF 116 (Dako) can be used
Description: to reveal small metastatic deposits.
• Count and sample all axillary lymph nodes
• Measure tumour size (mm) and note multifo- and label separately where indicated (Levels I,
cal disease. II, and III).
• Measure distances (mm) of tumour to the • A representative complete section of any
margins. grossly involved lymph node is adequate.
• Note the tissue block where the guide wire tip • Lymph nodes over 5 mm in maximum size
is in localization specimens, that orientation should be sliced at approximately 3-mm inter-
sutures are in place correctly, or if some vals perpendicular to the long axis.
sutures have fallen out.
• Note the character of tumour (scirrhous, Histopathology report:
mucoid), edge (circumscribed, irregular), etc.
• Note the character of surrounding breast tis- • Type and side of specimen
sue, and presence of skin, nipple, and skeletal • Specimen size: dimensions, weight
muscle at the deep aspect. • Tumour type
• Tumour grade: I, II, III (see Table 12.1 for
Sentinel node biopsy: grading system)
• DCIS present: no, yes (within/around/away
• Cut the node into 2 mm serial sections perpen- from tumour)
dicular to the long axis. • DCIS type
• The cut surface of each section is imprinted • DCIS nuclear grade (low, intermediate,
several times on a glass slide. high)
• Air dry and stain with Rapi-Diff II stain • Size of invasive component (mm)
(MGG). • Size of DCIS (mm)
• If suspicious on imprint cytology, standard • Size of invasive + DCIS (mm)
frozen section procedure of section of node • Nearest margin: medial, lateral, inferior, supe-
can be employed. rior, deep, superficial (skin)
• Sections of node are fixed in formalin for 24 h. • Distance from margin: invasive/DCIS (mm)
• Lymphovascular invasion: not seen/present
Blocks for histology (Figs. 12.3b and 12.4b) within or outside tumour
• Axillary nodal status: sentinel, Levels I, II,
• Sample tumour, tumour edge, and, tumour and and III number of nodes and number involved
nearest margin(s)—minimum three blocks. In by metastases
neoadjuvant chemotherapy specimens the • Extranodal tumour deposit: yes/no
whole tumour bed should be sampled. • Paget’s disease of nipple: yes/no
Table 12.1 Histological grading of invasive breast mdanderson.org/app/medcalc/index.cfm?p

carcinoma
agename=jsconvert3
Three parameters are assessed and scored as follows • Extent of local tumour spread: TNM 8 staging
1. Tubule formation Score for carcinoma of the female and male breast
Majority of tumour (>75%) 1 (stated as ypTNM in neoadjuvant chemother-
Moderate (10–75%) 2 apy patients)
Little or none (<10%) 3
2. Nuclear pleomorphism
pTis Carcinoma in situ, Paget’s with no tumour
Regular, uniform nuclei 1
pT1 Tumour ≤20 mm
Larger irregular nuclei 2
T1 mic ≤1 mm
Marked variation in size and 3
shape (±multiple nucleoli) T1 a 1 mm < tumour ≤ 5 mm
3. Mitotic count (per 10 high-power fields— T1 b 5 mm < tumour ≤ 10 mm
related to the objective field diameter) T1 c 10 mm < tumour ≤ 20 mm
Leitz Leitz Nikon pT2 20 mm < tumour ≤50 mm
Diaplan Ortholux Labophot pT3 Tumour > 50 mm
× 40 obj. × 25 obj. × 40 obj. pT4 Tumour of any size with direct extension
0–11 0–9 0–5 1 to chest wall (ribs, intercostal muscles,
12–22 10–19 6–10 2 serratus anterior but not pectoral muscle)
or skin
>22 >19 >10 3
(a) Chest wall
Total Grade Differentiation
score (b) Oedema including peau d’orange,
skin ulceration, or satellite
3–5 I Well
nodules in the same breast
6–7 II Moderate
(c) a and b
8–9 III Poor
(d) Inflammatory carcinoma—sore
red breast due to tumour
involvement of dermal lymphatics
• Skin involvement by tumour: yes/no
pNx Nodes cannot be assessed (not removed/
• For neoadjuvant chemotherapy specimens the
previously removed)
following should be included in the report pN0 No regional lymph node metastasis
–– post treatment tumour grade pN1 Micrometastasis (>0.2 mm but ≤2 mm in
–– tumour response: complete pathological mi greatest dimension)
response, either (1) no residual carcinoma pN1a Metastasis in 1–3 ipsilateral axillary
or (2) no residual invasive tumour but DCIS lymph node(s) (movable)
present; or partial response, either (1) min- pN1b Internal mammary nodes with
imal residual tumour/near total effect micrometastasis detected by sentinel
node dissection but not clinically
(<10% of tumour remaining in the bed) or apparent
(2) 10–50% of tumour remaining or (3) pN1c a + b
>50% of tumour remaining; or no evidence pN2a Metastasis in 4–9 ipsilateral axillary
of response to therapy nodes (fixed)
–– nodal response: number with no evidence pN2b Metastasis in clinically apparent internal
of metastatic disease or nodal change; mammary nodes in the absence of
axillary node involvement
number with no evidence of metastatic dis-
pN3a Metastasis in ten or more ipsilateral
ease but nodal change; number with meta- axillary nodes, or ipsilateral
static disease present but also evidence of infraclavicular nodes
response (eg fibrosis); number with meta- pN3b Internal mammary with axillary node
static disease with no response involvement
–– residual cancer burden—calculation on pN3c Ipsilateral supraclavicular node
MD Anderson website—http://www3. metastasis
12 Breast 145
• Prognosis Table 12.3 Scoring method for Her2/neu oncogene

overexpression by immunohistochemistry
Nottingham Prognostic Index (NPI)
0− No membrane staining Her2 negative
<3.4 Good prognosis 85% 5-year 1+ Faint/partial membrane Her2 negative
survival staining in >10% of the
3.4– Intermediate prognosis 68% 5-year tumour cells
5.4 survival 2+ Weak-to-moderate complete Her2 status
>5.4 Poor prognosis 21% 5-year membrane staining in >10% equivocal, for
survival of the tumour cells DDISH testing
3+ Strong complete membrane Her2 positive
NPI = 0.2 × invasive tumour size (cm) + tumour staining in >30% of the
tumour cells
grade + nodal score
Gene amplification studies with dual-colour dual-
hapten in situ hybridization (DDISH)
Nodal score Her2 positive cases for anti-Her2 therapy
1 Node negative
2 One to three low axillary nodes involved
3 Four or more nodes/apical node involved Bibliography
• Predictive factors cal cancer. 3rd ed. London: Springer; 2013.
Hormone receptor status—oestrogen (ER) Allen DC, Cameron RI. Histopathology specimens:
and progesterone (PR) receptors
Oncogene receptor status (Her 2/neu)/C-erb B2 Brierley JD, Gospodarowicz MK, Wittekind C, editors.
For scoring methods, see Tables 12.2 and TNM classification of malignant tumours. 8th ed.
12.3. Oxford: Wiley-Blackwell; 2017.
Dixon M. ABC of breast diseases. 2nd ed. London: BMJ
books; 2000.
Table 12.2 Quick score method for immunohistochemi- Elston CW, Ellis IO, editors. The breast, Systemic pathology,
cal detection of ER status. Score for proportion of cells vol. 13. 3rd ed. Edinburgh: Churchill Livingstone; 1998.
staining and score for staining intensity Guidelines for non-operative diagnostic procedures and
reporting in breast cancer screening. Non-operative
0—No nuclear staining 0—No staining diagnosis subgroup of the National Coordinating
1—<1% nuclei staining 1—Weak staining Group for breast screening pathology. NHSBSP pub-
2—1–10% nuclei staining 2—Moderate staining lication no 50; 2001.
3—10–33% nuclei staining 3—Strong staining Institute of Biomedical Science/The Royal College of
Pathologists. IBMS guidance to candidates and train-
4—33–66% nuclei staining
ers for advanced specialist diploma in breast pathology
5—66–100% nuclei staining dissection. http://ibms.org.uk/. Accessed Oct 2016.
Adding the two scores together gives a maximum score Pathology reporting of breast disease: a joint document
of 8. Data so far suggest that with this scoring system, incorporating the third edition of the NHS Breast
response to hormonal therapy correlates with the follow- Screening Programme Guidelines for pathology
ing cutoff values: reporting in breast cancer screening and the second
Score 0 indicates hormonal therapy will definitely not work edition of the Royal College of Pathologists Minimum
Score 2–3 indicates a small (20%) chance of treatment response dataset for breast cancer histopathology. NHSBSP
Score 4–6 indicates an even (50%) chance of response publication No 58; 2005.
Score 7–8 indicates a good (75%) chance of response Pinder SE, Provanzano E, Earl H, Ellis IO. Laboratory
Where PR content has also been determined, hormonal handling and histology reporting of breast specimens
therapy is thought worthwhile in patients with low ER but from patients who have received neoadjuvant chemo-
high PR scores therapy. Histopathology. 2007;50:409–17.
Provenzano E, Pinder SE. Guidelines for the handling of Thompson P, Miles Prince H. Breast implant-associated
benign and malignant surgical breast specimens. Curr anaplastic large cell lymphoma: a systematic review
Diagn Pathol. 2007;13:96–105. of the literature and mini-meta analysis. Curr Hematol
Purdie CA. Sentinel lymph node biopsy. Review of the Malig Rep. 2013;8(3):196–210.
literature and guidelines for pathological handling and The Royal College of Pathologists. Breast cancer dataset
reporting. Curr Diagn Pathol. 2007;13:106–15. and tissue pathways. https://www.rcpath.org/profes-
Rosen PP. Rosen’s breast pathology. 3rd ed. Philadelphia: sion/publications/cancer-datasets.html.
Lippincott, Williams & Wilkins; 2009. Walker RA, Bartlett JMS, Dowsett M, Ellis IO, Hanby
Rosen PP, Obermann HA. Tumors of the mammary AM, Jasani B, Miller K, Pinder SE. Her2 testing in the
gland. Atlas of tumor pathology, 3rd series. Fascicle 7. UK: further update to recommendations. J Clin Pathol.
Washington DC: AFIP; 1993. 2008;61:318–24.
Sainsbury JRC, Anderson TJ, Morgan DAL. ABC of breast Wittekind C, Greene L, Hutter RVP, Klimfinger M, Sobin
diseases. Breast cancer. BMJ. 2000;321:745–50. LH. TNM Atlas: illustrated guide to the TNM/pTNM
Tavassoli F, Devilee P. WHO classification of tumours. classification of malignant tumors. 5th ed. Berlin:
Tumours of the breast and female genital organs. Springer; 2005.
Lyon: IARC Press; 2003.
Part III
Head and Neck Specimens
Nasal Cavities and Paranasal
Sinuses 13
Seamus S. Napier and Ramzan M. Ullah
13.1 Anatomy while the medial wall represents the nasal sep-
tum. The lateral wall of the nose is complex and
The external nose contains the right and left nos- bears three (occasionally four) horizontal projec-
trils (or nares), each communicating with the tions called turbinates or conchae, the superior
nasal cavities via a slight dilation just inside the turbinate being the smallest and the inferior tur-
nostril called the nasal vestibule. Bone from the binate the largest. The passageway of the nasal
frontal, maxillary and nasal bones supports the cavity below and lateral to each of the turbinates
upper one third of the external nose, while carti- is called the superior, middle, and inferior
lage supports the lower two thirds. meatus, respectively; above and behind the supe-
Each nasal cavity extends posteriorly from rior turbinate lies the sphenoethmoidal recess.
just behind the nasal vestibule, through the open- The paranasal sinuses open onto the lateral wall
ing called the anterior choana, to communicate of the nasal cavity, as does the nasolacrimal duct,
with the nasopharynx via the posterior choana. so that disease affecting this region of the nose
They are separated by the nasal septum, which is can obstruct the drainage of secretions and pres-
composed of bone posteriorly and cartilage ante- ent as sinusitis.
riorly. Each nasal cavity has a roof, a floor, a Each nasal cavity is divided into functional
medial (or septal) wall, and a lateral wall areas, reflected in the nature of the epithelial lin-
(Fig. 13.1). The roof of the nose is closely related ing. The nasal vestibule is lined by skin and con-
to the frontal sinuses, the anterior cranial fossa, tains many short hairs that help to filter particles
the ethmoidal sinuses, and the sphenoidal sinus. from the inspired air. The olfactory area, con-
The floor of the nose is closely related to the ante- cerned with the sense of smell, is restricted to the
rior maxillary teeth and the vault of the palate, upper part of the nasal cavity and is centred on
the cribriform plate of the ethmoid bone, the
adjacent part of the nasal septum and the superior
turbinate. The rest of the nasal cavity is lined by
respiratory mucosa, the function of which is to
S.S. Napier (*)
Histopathology Laboratory, Institute of Pathology, warm and humidify the air and to trap particulate
Royal Victoria Hospital, Belfast Health and Social material. The complex architecture of the lateral
Care Trust, Belfast, UK wall of the nasal cavities facilitates this process
e-mail: seamus.napier@belfasttrust.hscni.net by increasing the surface area and the turbulence
R.M. Ullah of the airflow.
Directorate of ENT Surgery, Royal Victoria Hospital, The paranasal sinuses are extensions of the
e-mail: ramzan.ullah@belfasttrust.hscni.net nasal cavities and represent air-filled spaces in

150 S.S. Napier and R.M. Ullah
Fig. 13.1 Right lateral Superior tubinate

wall of nasal cavity and superior meatus
(Reproduced, with
Frontal sinus Sphenoethmoidal recess
and Cameron (2013))
Sella turcica
Middle turbinate
and middle meatus Sphenoidal sinus
Fossa of Rossenmuller
Vestibule of nose
Opening of Eustachian tube
Inferior turbinate
and inferior meatus
Fig. 13.2 Ethmoidal Anterior cranial Ethmoidal

sinuses and maxillary fossa sinuses
sinuses. Coronal view of
nasal cavities at level of
first molar tooth
showing maxillary and
ethmoidal sinuses
(Reproduced, with
permission, from Allen Orbit
and Cameron (2013))
Middle turbinate
Inferior
turbinate Maxillary sinus
Maxillary alveolus
and palate
the skull bones lined by respiratory mucosa n asolacrimal duct opens into the inferior meatus
(Fig. 13.2). They are usually absent or poorly anteriorly.
developed at birth but enlarge most during the The frontal sinuses lie between the outer and
eruption of the permanent teeth and after inner tables of the frontal bone and are closely
puberty. They are located in the frontal, eth- related to the anterior cranial fossa. Disease in
moidal, sphenoidal, and maxillary bones as the frontal sinus can be associated with intracra-
paired structures about the midline but tend to nial complications. The ethmoidal sinuses num-
be considered from a pathophysiological per- ber between 3 and 18, and consist of a labyrinth
spective into anterior and posterior groups. The of thin-walled bony cavities between the upper
anterior group comprises the frontal sinus, the part of the nasal cavity and the orbits. The path-
anterior and middle ethmoidal sinuses, and the way for drainage of the frontal sinus passes
maxillary sinus, all opening into the middle through the anterior ethmoidal sinus group and
meatus, while the posterior ethmoidal sinuses may be impeded by disease in this area. The
and the sphenoidal sinus represent the posterior sphenoidal sinuses lie within the body of the
group and drain into the superior meatus and sphenoid bone posterior to the upper part of the
the sphenoethmoidal recess, respectively. The nasal cavity. Adjacent structures such as the optic
13 Nasal Cavities and Paranasal Sinuses 151
chiasma, pituitary gland, internal carotid artery, called Midline Destructive Diseases, a collec-
and cavernous sinus may be affected by disease tion of diseases characterized by progressive
of the sphenoidal sinuses. The maxillary sinus is destruction of the nose and sinuses. These
the largest of the paranasal sinuses and is closely tests help distinguish principally between
related to the posterior maxillary teeth, the floor granulomatosis with polyangiitis (previously
of the orbit, the inferior portion of the lateral wall known as Wegener’s granulomatosis) and
of the nose, and the pterygoid plates of the sphe- T-cell/natural killer cell lymphoma.
noid bone.
Lymphovascular drainage:
Lymphatics from the external nose and ante- 13.4 Pathological Conditions
rior nasal cavity, together with those from the
skin of the mid-portion of the face, drain to Level 13.4.1 Non-neoplastic Conditions
I lymph nodes in the submandibular region. The
rest of the nasal cavity and the paranasal sinuses Sinusitis: Acute infections are usually bacterial
drain to Level II lymph nodes in the upper part of and often follow the common cold. Empyema or
the deep cervical chain (Fig. 20.1), sometimes mucocele may result if the draining of the secre-
via the retropharyngeal nodes. tions is obstructed. Chronic sinusitis follows
acute sinusitis and may be associated with
obstruction (e.g., by polyp or tumour) or immune
13.2 Clinical Presentation compromise. Maxillary sinusitis may occur alone
or may be associated with involvement of frontal
Disease affecting the nose presents with unilat- and/or ethmoidal sinuses. Most cases respond to
eral or bilateral nasal obstruction, rhinorrhea antibiotics and topical medications to improve
(watering of the nose), epistaxis (bleeding), facial drainage. Functional endoscopic sinus surgery
pain, facial swelling, epiphora (watering of the (FESS) is the commonest surgical management
eye), proptosis (bulging outward of the eye) or of recurrent sinusitis; opening of the osteo-meatal
anosmia (loss of the sense of smell). Deafness or complex under the middle turbinate or partial
otitis media may be due to obstruction of the removal of pneumatized middle turbinates (con-
opening of the Eustachian tube in the nasophar- cha bullosa) or nasal polyps will improve physi-
ynx by extension of a nasal tumour. ological drainage and allow biopsy sampling.
Pain of dental origin can mimic maxillary
sinusitis and vice versa. Extraction of upper pre-
13.3 Clinical Investigations molar or molar teeth may damage the floor of the
maxillary sinus and result in an oroantral fistula
• Direct visualization of the nasal cavities is through the socket.
performed using a speculum for the anterior Inflammatory polyps: A frequent complication
aspect or a postnasal mirror for the posterior of long-standing rhinitis, often but not exclu-
portion. Nasal endoscopy is the preferred sively allergic in origin. Often multiple and bilat-
method of sampling tissue from the nose and eral, they are a cause of sinusitis and nasal
nasal sinuses. obstruction. Histologically, there is abundant
• Plain radiographs of the nose and sinuses may myxoid or oedematous stroma covered by respi-
demonstrate bone destruction, soft tissue mass, ratory epithelium; ulceration and/or squamous
or fluid levels, although these are more accu- metaplasia are common in larger polyps, where
rately determined by CT and MRI scanning. they contact the nasal walls. The antrochoanal
• Markedly elevated erythrocyte sedimentation polyp is an uncommon large single inflammatory
rates (ESR) and titers of “cytoplasmic” anti- polyp that arises in the maxillary sinus and
neutrophil cytoplasmic antibodies (cANCA) extends into the nasal cavity, presenting at the
are helpful adjuncts to diagnosis in the so-
posterior choana. Nasal polyps in children are tum. Cylindrical cell papillomas are rare. They
often associated with cystic fibrosis. are similar in distribution and appearance to
Granulomatosis with polyangiitis: Previously inverted papillomas but are composed of tall
known as Wegener’s granulomatosis, an uncom- columnar (cylindrical) oncocytic cells.
mon systemic disorder characterized by necrotiz- Other benign neoplasms include pleomorphic
ing granulomatous inflammation and vasculitis adenoma, solitary fibrous tumour, glomangio-
that usually presents in the upper respiratory pericytoma (previously haemangiopericytoma),
tract, lungs, and/or kidneys. Symptoms can be nasopharyngeal (juvenile) angiofibroma, sinus
nonspecific (malaise, pyrexia) or related to the osteoma, meningioma, teratoma, and
anatomical sites involved; in the nose it may paraganglioma.
manifest as sinusitis, rhinorrhea, epistaxis, or Sinonasal cancer: The maxillary sinus is the
nasal obstruction. Rarely are the classical fea- commonest site for sinonasal malignancy and is
tures present in nasal biopsies; diagnosis requires usually either squamous cell carcinoma or adeno-
a high index of suspicion and careful clinicopath- carcinoma in type. The nasal cavity is the second
ological correlation. ESR and cANCA titers are commonest site and is affected by a broad spec-
useful at confirming the diagnosis, although a trum of lesions, but tumours of the sphenoidal
negative cANCA does not exclude. A distinctive and frontal sinuses are rare. Risk factors include
form of small multinucleate giant cell with tobacco use, exposure to hard and soft wood
clumped smudged nuclei, foci of granular colla- dusts, nickel, and irradiation.
gen necrosis, and neutrophil microabscesses are Squamous cell carcinoma: The vast majority
characteristic if under-recognized features. of malignant tumours of the mucosal lining of the
Other non-neoplastic conditions that may nasal cavities and sinuses are classified as squa-
affect the nose and sinuses include fungal infec- mous cell carcinoma. The maxillary or ethmoid
tions (chronic noninvasive colonization by sinuses are the commonest sites but the nasal ves-
Aspergillus, acute fulminant or angioinvasive tibule or septum can be affected. Many tumours
aspergillosis, allergic fungal sinusitis), pyogenic have a “transitional cell” pattern, similar to that
granuloma, haemangioma and other vascular seen in inverted papillomas but exhibiting pleo-
malformations, lymphoid hyperplasia, glial het- morphism and necrosis; a broad “pushing” front
erotopia, and hairy polyp. can make diagnosis of invasion difficult on small
biopsy samples. The term “non-keratinizing
squamous cell carcinoma” can be used, but a
13.4.2 Neoplastic Conditions spectrum of changes including the presence of
single cell infiltration and/or abundant keratiniza-
Benign tumours: Sinonasal papillomas are tion may be seen, sometimes making distinction
uncommon but are the most frequent benign neo- from the usual type of squamous cell carcinoma
plasms, subdivided into fungiform, inverted, and impossible.
cylindrical cell types. Occur twice as often in Salivary gland-type adenocarcinoma: The
males as in females and affect adults aged second commonest type of malignant tumour
between 30 years and 60 years. They are usually with adenoid cystic carcinoma as the pattern
unilateral lesions but may be multiple or multifo- most often encountered.
cal. Inverted papillomas are the commonest form, Intestinal-type sinonasal adenocarcinoma:
found on the lateral nasal wall and sinuses. They Adenocarcinoma exhibiting the differentiation
have an endophytic growth pattern and are com- pattern of large or small intestinal mucosa, with
posed of thick non-keratinizing, “transitional” but occasionally without cytological atypia.
epithelium within oedematous stroma. Fungiform Strongly associated with hardwood dusts (males,
papillomas are exophytic lesions composed of ethmoidal sinuses) but may occur sporadically
transitional epithelium supported by fibrovascu- (females, maxillary sinus). Commonest pattern
lar stroma, found exclusively on the nasal sep- mimics colonic adenocarcinoma—metastasis
needs to be excluded. Mucinous tumours with detailed examination and large biopsy samples are
signet ring cells are rare. best obtained with this technique under general
Malignant lymphoma: All types of non- anaesthesia, as it avoids contamination with tumour
Hodgkin’s lymphoma may affect the sinonasal and compromising later definitive surgical proce-
region either as a site of origin or as part of dis- dures. may Benign tumours such as nasal papillo-
seminated disease; diffuse large B-cell lym- mas may be resected using endoscopic laser surgery
phoma is the commonest. T-cell and natural killer but tend to be delivered as small fragments.
cell lymphomas often demonstrate a striking ten-
dency for vascular involvement, sometimes with
bizarre acute ischaemic changes, such as tooth 13.5.2 Resection Specimens
exfoliation and bone necrosis. The tumour cells
may be small, large or intermediate in size; the Endoscopic resection is being used increasingly
admixture of other inflammatory cells masks the for the management of localized malignancy and
neoplastic component by mimicking an inflam- can be combined with traditional open surgical
matory condition such as infection or granuloma- approaches in extensive disease. Excision speci-
tosis with polyangiitis (previously known as mens of nasal septum are easily delivered intact
Wegener’s granulomatosis). via a lateral rhinotomy incision. Medial maxillec-
Others: Low-grade sinonasal adenocarcinoma, tomy is the commonest surgical procedure for low-
olfactory neuroblastoma, malignant melanoma, grade tumours of the lateral aspect of the nasal
small cell neuroendocrine carcinoma, sinonasal cavity and/or maxillary, ethmoid, and frontal
undifferentiated carcinoma, rhabdomyosarcoma, sinuses. Resection specimens tend to be frag-
chondrosarcoma and chordoma are all uncommon. mented because of the fragile nature of the bone;
Prognosis: Outcome depends on the histologi- in these cases, precise interpretation of surgical
cal type of tumour as well as the extent of spread. margins requires orientation of the tissue samples
Most lesions are advanced at presentation by the surgeon. Alternatively, separate biopsy
although lymph node metastasis with carcinomas samples of critical or suspicious areas may be
is relatively infrequent. Local recurrence is a taken after clearance of tumour and submitted
common problem in spite of radical surgery and separately. Palatal fenestration is recommended
radiotherapy. Melanomas, small cell neuroendo- for low maxillary sinus tumours involving the oral
crine carcinomas, and sinonasal undifferentiated cavity; definite or possible involvement of the pos-
carcinomas are particularly aggressive but 5-year terior wall of the maxillary sinus requires maxil-
survival is the norm with adenoid cystic carcino- lectomy. Prosthetic rehabilitation with an obturator
mas. In intestinal type sinonasal adenocarcinoma, constructed around an upper denture provides
grading based on the degree of differentiation is optimal functional and aesthetic results and allows
important, in that low-grade lesions do well while good visualization of the wound postoperatively
high-grade lesions do badly. Around 20% 5-year facilitating re-biopsy of suspicious areas.
survival is customary. The usefulness of grading Craniofacial resection describes a surgical
olfactory neuroblastomas is less clear. approach through both the anterior skull and the
mid-face performed for tumours of the frontal or
ethmoid sinus that extend into the anterior cranial
13.5 Surgical Pathology fossa. Total ethmoidectomy, nasal exenteration,
Specimens: Clinical Aspects maxillectomy, and orbital exenteration can be
performed if necessary.
13.5.1 Biopsy Specimens Involvement of the orbital floor or medial wall
is an important nodal point in the management of
Rigid or fibre-optic endoscopy is the usual method sinonasal tumours. Breach of the bony wall or
of sampling lesions in the nose and paranasal involvement of periosteum by tumour may neces-
sinuses. When malignant disease is suspected, sitate clearance or exenteration of the orbit.
Concomitant neck dissections are usually not Initial procedure:

indicated unless there is proven metastatic
disease. If intact, orientate the specimen and ink its
margins.
Otherwise, if a larger specimen is submitted, ink
13.6 Surgical Pathology its margins. A line of ink drawn across
Specimens: Laboratory medium-sized fragments can aid orientation
Aspects after microscopic examination and assist
assessment of margins.
13.6.1 Biopsy Specimens Slice the larger pieces into 0.4 cm thick slices
transversely, using a band saw or
Usually as small samples from open biopsies or equivalent.
core needle specimens, free-floating in formalin.
Measure in three dimensions or length of core Measurements:
and submit in total. Specimens containing bone
require decalcification and can be recognized by If intact, dimensions (cm)
their tendency to sink rapidly in the fixative. If fragmented, number of fragments, total weight
(g), and dimensions of largest specimen (cm)
• Tumour
13.6.2 Resection Specimens • Size (cm)
• Number of fragments consisting of tumour
13.6.2.1 S eptal Excision, Medial • Distance to closest surgical margins (cm)
Maxillectomy,
and Craniofacial Resection Description:
Specimens
Most septal excision and medial maxillectomy • Tumour
specimens are for the less extensive or less locally Size, shape, and colour
aggressive neoplastic diseases, such as inverted Presence of necrosis
nasal papilloma, olfactory neuroblastoma, and If fragmented, number of fragments contain-
even malignant melanoma. They are usually ing tumour
received as multiple fragments of mucosa with • Adjacent mucosa
underlying bone and/or cartilage. In medial max- Colour and consistency
illectomy specimens, at least the inferior turbi- Presence of other lesions
nate is included, but, depending on tumour Other
location, all turbinates may be represented. • Lymph nodes, neck dissection
Most craniofacial resection specimens are for Maxillectomy specimens
extensive or locally aggressive neoplastic diseases See Maxilla, Mandible, and Teeth (Chap. 15).
of the frontal or ethmoid sinuses, where a curative
outcome is expected. As such, they will represent Blocks for histology:
composites of septal excision, medial maxillec-
tomy, maxillectomy, and skull-base excisions. In cases of neoplastic disease, the histology
They are usually received intact or as two or three should represent the tumour, its relationship to
large fragments. They are handled as if they rep- the adjacent mucosa, and underlying bone or
resented an extended medial maxillectomy speci- cartilage. Focal abnormalities of mucosa need to
men. Invasion into dura is an ominous finding. be sampled.
Samples of critical or clinically suspicious mar- Three blocks of tumour to illustrate the inter-
gins taken at clearance of tumour should be submit- face with adjacent normal tissues.
ted separately and handled as biopsy specimens. Three blocks of adjacent mucosa.
Closest deep surgical margin. Samples of pT4a Anterior orbit, cheek skin, pterygoid plates,
other lesions, e.g., nodules or polyps. infratemporal fossa, cribriform plate,
sphenoid/frontal sinus
In intact specimens, sample the mucosal mar-
pT4b Orbital apex, dura, brain, middle cranial
gins before sawing the bone and submit sepa-
fossa, cranial nerves other than V2,
rately (reduces contamination of the margins). nasopharynx, clivus
Cut with a sharp blade firmly down to bone and
use a flat blunt instrument to dissect mucosa free Nasal cavity and ethmoid sinus
from the bone. pT1 One subsite
In intact specimens, saw the bone into 0.5 cm pT2 Two subsites or adjacent nasoethmoidal site
slices in the transverse plane (vertical plane in vivo). pT3 Medial wall/floor orbit, maxillary sinus,
If fragmented, bread-slice larger specimens palate, cribriform plate
and submit as labeled blocks. Microscopic analy- pT4a Anterior orbit, skin of nose/cheek, anterior
cranial fossa (minimal), infratemporal fossa,
sis may allow reconstruction and useful assess- pterygoid plates, sphenoid/frontal sinus
ment of margins. pT4b Orbital apex, dura, brain, middle cranial
Histopathology Report: fossa, cranial nerves other than V2,
Final reports of sinonasal specimens should nasopharynx, clivus
include details on: Malignant melanoma
pT3 Involvement of mucosa only
• The specimen type and side pT4a Deep soft tissue/cartilage/bone or overlying
• If fragmented, the number of fragments and skin
the size of the largest pT4b Brain/dura/skull base/lower cranial nerves,
• The type, subtype, and grade of tumour masticator space, prevertebral space, carotid
artery, mediastinal structures
present
Sinonasal papilloma variants
Squamous cell carcinoma and variants As malignant melanomas of the upper aerodi-
Low-grade adenocarcinoma gestive tract are generally aggressive lesions,
Intestinal-type adenocarcinoma Stage I and II disease (i.e., pT1 N0 and pT2 N0)
Lymphoma have been omitted.
• The macroscopic size of tumour All sites except nasopharynx: regional lymph
• The presence or absence of invasion of bone nodes (cervical). Selective and modified/radical
• The distance of tumour from the nearest lymphadenectomy will ordinarily include 10 or
margin 15 or more lymph nodes, respectively.
• The presence or absence of vascular invasion
pN0 No regional node metastasis
• The presence or absence of dural invasion (if
pN1 Metastasis in an ipsilateral single node ≤3 cm
craniofacial resection) without extranodal extension
• Other pathology such as radiation injury pN2 Metastasis in:
(a) Ipsilateral single node ≤3 cm with
Extent of local tumour spread: TNM 8: for extranodal extension, or, >3–6 cm
carcinoma without extranodal extension
Maxillary sinus (b) Ipsilateral multiple nodes ≤6 cm
without extranodal extension
pT1 Mucosa (c) Bilateral or contralateral node(s) ≤6 cm
pT2 Bone erosion/destruction, hard palate, middle without extranodal extension
nasal meatus pN3 (a) Metastasis in a lymph node >6 cm, or
pT3 Posterior bony wall maxillary sinus, (b) Extranodal extension with any of;
subcutaneous tissues, floor/medial wall of >3 cm, multiple ipsilateral, contralateral,
orbit, pterygoid fossa, ethmoid sinus bilateral
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Lips, Mouth, and Tongue
14
Seamus S. Napier and Derek J. Gordon
14.1 Anatomy nective tissue (Figs. 14.1 and 14.2). “Specialized

mucosa” refers to the taste buds.
The mouth extends from the lips and cheeks to The lips are composed of skin and mucosa
the oropharyngeal isthmus at the palatoglossal around the opening to the mouth. They contain
fold. It comprises a number of subsites, which the orbicularis oris, fibrofatty tissue, and many
can be divided into three functional types, minor salivary glands. Upper and lower lips join
although the microscopic structure of each varies at the buccal commissure (angle of the mouth).
subtly from one region to the next. “Masticatory The mucosa of the lips begins at the vermilion
mucosa” is found on the maxillary and mandibu- border with skin and extends across the free sur-
lar gingivae, the hard palate, and on the dorsum face into the oral cavity proper. The cheeks are
of the tongue. It is bound tightly to underlying continuations of the lips; the skin forms most of
tissue and covered by keratotic relatively thick the facial skin, while the buccal mucosa is con-
stratified squamous epithelium to withstand the tinuous through the upper and lower sulci with
trauma of chewing. In contrast, “lining mucosa” the gingivae and with the soft palate/oropharynx.
is elastic and is present on the inner aspect of the Buccinator is the principal muscle of the cheek; it
lips, on the buccal mucosae and their respective is perforated opposite the upper second molar
upper and lower sulci, the ventral surface of the tooth by the parotid duct. Many minor salivary
tongue, and the floor of mouth. It is covered by glands lie between the muscle layer and the
relatively thin stratified squamous epithelium mucosa, while the facial (or buccal) lymph node
supported by loosely textured fibrovascular con- lies external to buccinator below the level of the
occlusal plane.
The gingival margin has a scalloped outline as
it encircles the teeth, forming the interdental
S.S. Napier (*)
papilla between adjacent teeth. Behind the last
Histopathology Laboratory, Institute of Pathology, molar tooth on each side of the mandible, the gin-
Royal Victoria Hospital, Belfast Health and Social giva forms a flat triangular region known as the
Care Trust, Belfast, UK retromolar trigone (or retromolar pad). The hard
e-mail: seamus.napier@belfasttrust.hscni.net
palate is formed mostly by the palatine processes
D.J. Gordon of the maxillary bones and is covered by mucosa
Regional Plastics and Maxillofacial Unit, Ulster
Hospital, Southeastern Health and Social Care Trust,
continuous with the upper gingivae. In the midline
Dundonald, Belfast, UK of the palate anteriorly just behind the incisor
e-mail: derek.gordon@setrust.hscni.net teeth, there is a small mucosal elevation called the

158 S.S. Napier and D.J. Gordon
Fig. 14.1 Mucosal Hard palate + Maxillary gingiva

subsites of lips and oral
cavity (Used with the
Control (UICC),
Geneva, Switzerland. Upper buccal sulcus
Upper lip
this material is from Buccal Soft palate
Wittekind et al. (2005)) mucosa
Lower lip Retomolar trigone
Mandibular gingiva
Lower buccal sulcus
Hard palate
pT4
Oral cavity: tumour Upper buccal sulcus

invades through cortical
bone, deep (extrinsic)
muscle of tongue Dorsum of tongue
maxillary sinus, skin
Lateral border of tongue
Buccal mucosa
Ventral surface of tongue
Lower buccal sulcus
Mandibular gingiva
Floor of mouth
Fig. 14.2 Mucosal subsites of tongue and floor of mouth (UICC), Geneva, Switzerland. The original source for this
demonstrating pT4 tumour of tongue (Used with the per- material is from Wittekind et al. (2005))
mission of the Union for International Cancer Control
incisive papilla. In the anterior palate, the mucosa The floor of mouth is a horseshoe-shaped
forms four or five transverse ridges called rugae region between the tongue, the mandible, and
while posteriorly it is smooth. Small numbers of mylohyoid. It contains the sublingual salivary
minor salivary glands are present in the hard palate glands, the submandibular ducts, the lingual
posteriorly and laterally close to the alveolar pro- nerves, and some of the extrinsic muscles of the
cesses of the maxilla. The hard palate is continu- tongue. Right and left submandibular ducts
ous posteriorly with the soft palate, a mobile flap converge on the lingual frenulum, a midline fold
of mucosa, striated muscle, and fibrofatty tissue running from the ventral surface of the tongue to
separating the nasopharynx from the oropharynx. the gingiva behind the lower central incisor teeth,
14 Lips, Mouth, and Tongue 159
forming a mucosal papilla in the floor of mouth sues of the anterior face and lips drain to lymph
approximately 1 cm posterior to the lingual nodes in the submental and submandibular
gingiva. regions. The tissues of the lateral face, eyelids,
The tongue is divided into two parts by a and anterior portion of the scalp and external ear
V-shaped groove called the sulcus terminalis; the drain to lymph nodes around the parotid region.
anterior two-thirds lies within the oral cavity and The tissues of the posterior scalp and behind the
the posterior one-third (the base) lies within the ear tend to drain to retroauricular and suboccipi-
oropharynx. The anterior two-thirds is divided tal lymph nodes. These superficial lymph node
into: groups ultimately drain to lymph nodes in the
deep cervical chain situated around the internal
• Dorsal surface—the superior surface. It is jugular vein (see Fig. 20.1).
covered by innumerable filiform papillae; Within the oral cavity, the tissues of the palatal
between 30 and 50 dispersed fungiform papil- gingiva, hard palate, and soft palate drain to ret-
lae measuring approximately 1 mm in diame- ropharyngeal lymph nodes or directly to lymph
ter and between 8 and 12 circumvallate nodes in the deep cervical chain. The tissues of
papillae, measuring between 3 and 4 mm in the floor of the mouth and those of the lingual
diameter located in a line just anterior to the gingiva drain to nodes in the submental and sub-
sulcus terminalis. The fungiform and circum- mandibular regions, and ultimately to lymph
vallate papillae bear taste buds. nodes in the deep cervical chain.
• Ventral surface—the inferior aspect. It has a There is much subregional variability in the
smooth surface, merging with the floor of lymphatic drainage of the tongue influenced by
mouth. the presence of the median septum. Malignant
• Lateral border—the side of the tongue. It tumour drains to ipsilateral lymph nodes in the
extends from the tip to the palatoglossal arch deep cervical chain but contralateral node
(anterior pillar of the fauces). involvement should be considered with lesions at
the tip of the tongue, lesions that cross the mid-
The posterior one-third of the tongue has a line or involve the median fibrous septum and
cobblestone surface due to the accumulation of lesions in the posterior one-third.
lymphoid tissue from the lingual tonsil. No papil-
lae are present, although taste buds may be
numerous. The mucosa is contiguous with the 14.2 Clinical Presentation
palatine tonsils laterally and the vallecula of the
epiglottis posteriorly. Disease affecting the mouth and tongue may be
The tongue is divided into right and left halves clinically silent or may present as a mass lesion,
by a median fibrous septum, which is attached an ulcer, a white/red patch, or with a painful/
inferiorly to the hyoid bone. The muscles of the burning sensation often on eating hot or spicy
tongue are divided into the intrinsic group and foods. Pain is a rare presenting feature of malig-
the extrinsic group. The extrinsic group repre- nancy, which is usually asymptomatic until
sents genioglossus, hyoglossus, styloglossus, and advanced.
palatoglossus, having attachments outside the
tongue and considered important in the staging of
malignant tumors; involvement of the extrinsic 14.3 Clinical Investigations
muscles by tumour signifies pT4 staging
(Fig. 14.2). • The ease with which the oral cavity can be
Lymphovascular drainage: examined by direct visualization facilitates
The face, oral tissues, and tongue possess preoperative diagnosis and reduces the need
many lymphatic channels and display a variable for complex investigative procedures. Even
pattern of lymphatic drainage. In general, the tis- so, some areas such as the lingual sulcus or the
posterior tongue can harbour an occult pri- subject of many textbooks. These are divided
mary tumour and the oral cavity must be according to their clinical presentation as either
included in the “triple endoscopy” when plan- lumps, ulcers, or white/red patches.
ning treatment for patients with malignant Lumps: Most discrete mass lesions of the oral
mucosal disease at other sites in the head and mucosa represent forms of fibrous tissue over-
neck. Nevertheless, haematological investiga- growth (fibroepithelial polyp) as a consequence
tions are often useful to determine haemoglo- of low-grade chronic trauma. The term fibrous
bin levels, red blood cell indices, serum epulis is reserved for lesions on the gums, while
ferritin, Vitamin B12, and folate levels. those associated with dentures can be described
• Identification of pathological forms of as denture-induced hyperplasia. Mucous extrav-
Candida species can be achieved by direct asation cysts and mucous retention cysts arise
visualization of periodic acid/Schiff-stained from small salivary glands within the submucosal
smears sampled directly from affected tissues. Vascular anomalies, such as haemangi-
mucosa. Precise subclassification can be per- oma and lymphangioma, can affect any oral site.
formed following culture of swabs or an oral Giant cell epulis (or peripheral giant cell granu-
saline rinse, the latter also providing a quanti- loma) usually arises from the gum anterior to the
tative measure of oral fungal load. premolar region, presumably as a response to
• Biopsy techniques are used frequently to sam- irritational stimuli, but such lesions in older
ple mucosal abnormalities. The value of direct patients may be a manifestation of
and indirect immunofluorescence should not hyperparathyroidism.
be underestimated in blistering and/or ulcerat- Persistent diffuse swellings of the oral mucosa
ing conditions. Endoscopy of the upper are much rarer and most represent vascular
aerodigestive tract is performed prior to sur- anomalies (such as haemangioma or lymphangi-
gery for malignant disease to identify occult oma) present since birth. Causes of intermittent
second primary neoplasms. diffuse swelling of the oral mucosa are orofacial
• Fine-needle aspiration cytology (FNAC) can granulomatosis (sometimes a manifestation of
provide additional information to facilitate the Crohn’s disease) or angioedema, a selective defi-
resolution of a differential diagnosis of sub- ciency of components of the complement
mucosal masses; cytology brushes can be used system.
but interpretation of atypia in mucosal sam- Ulcers: Common on the lining mucosa and
ples can be problematic. tongue and are often due to trauma from teeth,
• Plain radiographs may detect a concurrent dentures, or foodstuffs. Recurrent aphthous
odontogenic or bony lesion and will often ulceration is characterized by crops of ulcers on
identify gross bone destruction by mucosal the lining mucosa of young patients that heal
cancers. CT and MRI scanning are essential in spontaneously over a 2-week period but recur.
planning surgery by indicating the depth of Three clinical subtypes are recognized: minor
the tumour and detecting other changes in the (ulcers 2–4 mm in diameter), major (single ulcer
neck. CT has less motion artifact and is good at least 10 mm in diameter, located posteriorly in
for bone detail, while MRI gives superior soft the mouth that heals slowly), and herpetiform (a
tissue contrast without dental amalgam arti- very rare type, usually close to the front of the
fact or exposure to ionizing radiation. mouth, composed of minute coalescing ulcers).
Around 10% of patients with recurrent aphthous
ulcers may suffer from a haematological defi-
14.4 Pathological Conditions ciency due to a systemic disorder but most
patients are otherwise healthy. Drugs can pro-
14.4.1 Non-neoplastic Conditions duce ulcers through either topical or systemic
effects. Vesiculobullous disorders, such as ery-
The oral mucosa is affected by a bewildering thema multiforme, pemphigus vulgaris, and
number of non-neoplastic conditions that are the mucous membrane pemphigoid, are more likely
to present with ulcers than with intact blisters other laboratory data is required to establish a
because of the relative fragility of the oral mucosa precise diagnosis of oral white/red lesions.
compared to skin. Squamous cell carcinoma may
often present as a non-healing ulcer.
White/red patches: The oral mucosa may 14.4.2 Neoplastic Conditions
become white due to accumulation of keratin or
epithelial hyperplasia and may become red Benign tumours: Squamous cell papilloma com-
because of epithelial atrophy, increased vascular- monly occurs on the lips, cheeks, and tongue, and
ity, or inflammation. Physical stimuli such as is often associated with viral warts on the hands.
friction from teeth or dentures or through the use Neurilemmoma, neurofibroma, and the granular
of tobacco can produce an irritational keratosis cell tumour are not infrequently encountered.
on any part of the oral mucosa, most often lining Lipoma presents as a mucosal polyp, clinically
mucosa. “Chevron” parakeratosis and melanin similar to a fibroepithelial polyp. Benign tumours
incontinence point to tobacco-related lesions. of salivary gland origin arise in the upper lip and
Lichen planus/lichenoid reaction occurs com- in the palate, usually at the junction between the
monly on the lining mucosa and dorsum of the hard and soft palates, the commonest of which is
tongue as white striae or papules against a red the pleomorphic adenoma. Benign salivary
background. Erosive forms are characterized by tumours are rare in the tongue and floor of mouth;
ulceration. Some lesions are a consequence of most salivary tumours in the lower parts of the
systemic drug therapy or as a response to metallic oral cavity are adenocarcinomas.
restorations in adjacent teeth. Geographic tongue Malignant tumours: As at other sites in the
is characterized by irregular areas of mucosal upper aerodigestive tract, tobacco and alcohol
erosion affecting the dorsal surface. Central areas use are the major risk factors for oral cancers.
of atrophy are outlined by a narrow peripheral Their effects are related to dose and duration of
zone of white mucosa and may be accompanied use; together they have a multiplicative rather
by deep fissuring of the tongue. The pattern of than additive effect. Recent interest has focused
atrophic and white areas changes gradually, on the role of viruses in oral malignancy. Human
affected areas returning to normal and new Papillomavirus has been detected in a small pro-
lesions developing. Candida may affect the oral portion of intraoral tumours, but its precise role
mucosa and may present as red or white lesions. in oral oncogenesis is unclear.
Candidal infection is often a marker of underly- Squamous epithelial dysplasia: A rare finding;
ing disease (“disease of the diseased”), although most lesions of the oral mucosa are not dysplas-
a number of local factors can precipitate candidal tic. As with invasive tumours, epithelial dysplasia
infection, particularly smoking, xerostomia, high is strongly associated with tobacco smoking and
carbohydrate diet, and topical steroid application. alcohol use, but, paradoxically, lesions arising in
Furthermore, any mucosal lesion can be second- patients who have never used tobacco are most
arily infected by Candida. A small proportion of likely to develop carcinoma. In contrast to the
white/red lesions of oral mucosa may ultimately cervix with which it has often—probably errone-
develop squamous cell carcinoma, although it is ously—been compared, oral dysplastic lesions
not possible to predict which lesions will develop are frequently hyperkeratotic with varying
malignancy and when such an event might occur. degrees of epithelial hyperplasia and/or atrophy.
Most authorities consider the presence of dyspla- The grade of dysplasia can vary from mild to
sia in these potentially malignant lesions to be a severe. Development of invasive squamous cell
worrying sign, although there are significant carcinoma seems to occur more frequently with
problems with inter- and intra-observer variabil- increasing degrees of cytological disturbance
ity in the assessment of dysplasia. Furthermore, (less than 5% for non-dysplastic lesions and low-
approximately 50% of cases will never develop a grade dysplasia; around 50% for high-grade dys-
tumour within the lifetime of the patient. Careful plasia) but there are no agreed criteria for grading
correlation of clinical, histopathological, and or recognizable features of prognosis. Identifying
high-grade dysplasia highlights the considerable risk of recurrence in the neck and of distant
risk of synchronous or metachronous squamous spread. The size and anatomical site of the tumour
cell carcinoma but other factors such as site and affects the ability to achieve surgical clearance
the clinical appearance of the lesions need to be with the risk of local recurrence but the pattern of
considered. Conservative surgery or ablative tumour invasion is probably the most significant
therapy (e.g., by laser or photodynamic therapy) factor in determining lymph node metastasis. As
will often be attempted, but the effects of treat- with all upper aerodigestive tract malignancies,
ment are difficult to evaluate. The area of abnor- comorbidity from cardiovascular and respiratory
mal mucosa is almost certainly much greater than disease due to the effects of age, tobacco, and
the white or red area detected clinically. Most alcohol use is a major adverse factor in survival.
authorities accept that no form of active treat- Five-year survival with node-negative tongue
ment can predictably ensure that cancer will not carcinomas is approximately 50%, falling to
develop within the patient’s mouth and that care- around 20% for patients with large tumours and
ful clinical follow-up is essential to detect newly positive nodes.
formed tumours at the earliest opportunity. Squamous cell carcinoma of the lip: Arising
Intraoral squamous cell carcinoma: Accounts on the vermilion border of the lower lip, although
for over 85% of primary malignant tumours in the a few are seen on the upper lip. Probably repre-
mouth. Males are affected at least twice as often as sents a cutaneous rather than intraoral malig-
females and most patients are aged between 40 nancy, as it is associated with long solar exposure.
and 60 years. Smoking and alcohol use are the Less than 20% involve lymph nodes. Easily ame-
main risk factors. The commonest intraoral sites nable to early detection and surgical excision, the
are the lateral border/ventral surface of the anterior 5-year survival is in excess of 80%.
two-thirds of tongue (35%) and the floor of mouth Squamous cell carcinoma involving either
(20%), followed by the mandibular gingiva/retro- upper or lower lip but arising within the oral cav-
molar trigone, soft palate, buccal mucosa/buccal ity (e.g., from the buccal commissure) is a true
commissure, and hard palate/maxillary gingiva. intraoral cancer, strongly associated with tobacco
Tumours of the tongue and floor of mouth tend to use. There is a greater likelihood of nodal metas-
metastasize frequently to neck nodes—up to 30% tasis, but the prognosis is still reasonably good in
of patients with carcinoma of the tongue and floor comparison with similar lesions at other intraoral
of mouth who have clinically negative necks will sites.
have metastatic disease. Tumours of the hard pal- Other malignant tumours in the oral cavity
ate rarely involve nodes. include malignant lymphoma (usually a deposit
Histological and reportedly prognostic vari- of disseminated nodal disease), salivary gland
ants of squamous cell carcinoma include verru- types of adenocarcinoma, malignant melanoma
cous carcinoma, papillary squamous cell (palate and maxillary gingiva), rhabdomyosar-
carcinoma (better than usual type), spindle cell coma (around the soft palate), and Kaposi’s sar-
squamous cell carcinoma, adenoid squamous cell coma (junction of hard and soft palate). The oral
carcinoma (same prognosis), basaloid squamous mucosa may be involved by direct spread from a
cell carcinoma, and adenosquamous cell carci- malignant tumour in the minor salivary glands or
noma (worse prognosis). from the nasal cavity/maxillary sinus.
Prognosis: Outcome for patients with intra-
oral squamous cell carcinoma depends on the
precise anatomical site within the mouth (the fur- 14.5 Surgical Pathology
ther back in the mouth, the worse the outcome), Specimens: Clinical Aspects
the size of the tumour and the presence of regional
nodal metastasis. Lymph node metastasis is the 14.5.1 Biopsy Specimens
most significant factor in determining prognosis;
extracapsular spread from affected nodes is also Most oral biopsy specimens represent cold knife
an indicator of limited prognosis, with increased samples of an incisional or excisional nature.
These are usually taken under direct vision and Subtotal or total glossectomy is a very rare proce-
are repaired with either resorbable or non- dure, usually reserved for very large tumours
resorbable sutures. Punch biopsies are being invading widely across the midline fibrous sep-
employed increasingly for mucosal disease, but tum, involving the extrinsic muscles or affecting
they tend to yield less diagnostic tissue than the the posterior one-third that have recurred follow-
traditional “scalpel biopsy” and, in inexperienced ing first-line combined chemotherapy and
hands, carry an increased risk of iatrogenic injury radiotherapy.
to deep structures, such as nerve trunks. The ipsilateral sublingual gland is usually
included with resections of anterior floor of
14.5.1.1 Biopsy Technique mouth mucosa; both sublingual glands are
An ellipse of mucosa is removed with the scalpel included for midline lesions. Partial glossectomy
blade of ideal minimal dimensions of 10 × 6 mm will be included with resections for tumours of
with tissue to a depth of 3 mm. The area sampled the anterior floor of mouth that spread into the
is selected to represent the most significant area tongue. Likewise with tumours encroaching on
of the lesion and to include the interface with the gingiva, compromised mucosa from the lower
adjacent normal tissues. It is a common miscon- alveolus will be resected.
ception that the normal tissue is required to allow Resection may be restricted to the alveolar
comparison with the diseased areas; rather the mucosa for superficial tumours of the upper and
presence of normal tissue facilitates biopsy han- lower gingiva, but larger tumours often require
dling in that a stabilizing suture may be placed extensive resection. For example, a widely infil-
through the normal tissue without distorting the trative carcinoma of the retromolar trigone may
abnormal tissue. The tissue is placed in a fixative require removal of a portion of lower alveolar
or onto orientation filter paper. The wound is mucosa and bone, lingual sulcus, posterior buc-
repaired with sutures. cal mucosa with lower and upper sulci, the poste-
rior portion of the upper alveolar mucosa, the
tonsillar bed, and part of the soft palate. Part of
14.5.2 Resection Specimens the posterior tongue may also be included.
A full-thickness wedge excision of lip
The type of surgical procedure for tumours of the (V-shaped or W-shaped) is the commonest treat-
lips and oral cavity depends on the precise loca- ment for squamous cell carcinoma of the lip. To
tion of the tumour, its T-stage, the presence of limit the development of new lesions, in-
nodal disease, concurrent second primary lesions, continuity mucosal “shave” excision of adjacent
and the health of the patient. mucosal changes on the vermilion border is more
Adequate local clearance with preservation of often than not carried out at the same time.
function is the aim with surgical treatment for When tumour encroaches on the periosteum
intraoral cancers. Very large defects are repaired at any intraoral site, the decision to resect bone
with microvascularized free-tissue flaps, depends on whether or not there has been previ-
although, in the tongue in particular, allowing the ous radiotherapy to the jaw, the precise anatomi-
wound to granulate naturally often results in a cal relationship of tumour and bone, and how
complete return to normal function and speech. A easily the periosteum dissects from the bone.
margin of 10 mm is the ideal but anatomical con- The clinical extent of disease is almost always
straints and the large size of some of the tumours greater than that detected radiographically but
mean that surgical clearance is often restricted to the periosteum offers a considerable barrier to
2 or 3 mm. In addition, extensive areas of abnor- bone invasion and the usual pathway for direct
mal mucosa are often present around the tumours. spread into the jawbone is from the alveolar
Small superficial tumours of the tip or lateral crest rather than through the cortical plate. In
border of the tongue can be treated by local the non-irradiated jawbone with no bone ero-
“wedge” excision, although formal hemiglossec- sion, there is no need to resect bone if tumour-
tomy is preferable for deeply infiltrative lesions. bearing periosteum elevates easily. With
radiographic bone destruction, marginal man- generally easy because specific anatomical
dibulectomy (rim resection) or segmental man- landmarks are discernible, but smaller local
dibulectomy (hemimandibulectomy) is excisions may be difficult.
performed. Where there is radiation injury to Procedure:
the bone, this periosteal barrier is lost and direct
spread through the cortical bone is more likely, • Orientate the specimen(s) using the anatomi-
warranting bone removal. cal or surgeon’s landmarks.
Ideally, where there is proven or a high likeli- • Ink only critical mucosal and deep resection
hood of regional lymph node metastasis, a syn- margins. For glossectomy specimens and
chronous neck dissection is performed. resections of retromolar trigone, the critical
margins are usually the posterior limits with
the lingual sulcus/tonsillar bed. In the tongue,
14.6 Surgical Pathology tumour can unexpectedly involve the deep
Specimens: Laboratory medial margin inferiorly and posteriorly in
Protocols the floor of mouth/oropharynx by sarcolem-
mal spread of tumour along intrinsic muscle
14.6.1 Biopsy Specimens bundles in the tongue. To facilitate assess-
ment of possible bone involvement, the peri-
Usually one fragment is present free-floating in osteal limits of alveolar mucosa not in
formalin, although several specimens may be continuity with the underlying bone should
taken simultaneously. Portions of stabilizing be inked.
sutures may be present, usually located anteri- • With large or complex specimens or those
orly. The surgeon only includes them to reduce with in-continuity resections of bone, e.g.,
artifacts of tissue handling when transferred to resections of the retromolar trigone, sample
the container; rarely are they of significance. the mucosal limits first by taking radial blocks
(Fig. 14.3).
• Measure.
• Place in cassette; if very small wrap in moist 1. Cut the specimen into 4 mm thick slices trans-
filter paper. versely (in the anatomical vertical plane).
• Mark for levels and D/PAS particularly if the 2. Measurements:
sample represents a white/red patch or where • Dimensions of mucosa, deeper tissue, and
a candidal infection is suspected. other components, e.g., bone (cm).
• Orientate the specimen at the embedding stage –– Tumour
to facilitate microscopic assessment. Anteroposterior length × width (cm).
Maximum depth (cm) from reconstructed
mucosal surface.
14.6.2 Resection Specimens Distances to closest mucosal and deep sur-
gical margins (cm).
14.6.2.1 Major Resection Specimens –– Mucosal abnormalities (cm).
The vast majority of lip and oral mucosal
resections are for neoplastic disease, although Description:
some smaller specimens will represent local
excisions of non-healing traumatic ulcers • Tumour
where there is a low index of suspicion. Plaque-like/ulcerated/fungating: usual type
Resections of larger lesions may include squamous cell carcinoma (SCC)
mucosa from adjacent sites as well as bone Warty: well-differentiated SCC, verrucous
from the mandible or maxillary alveolus. carcinoma
Orientation of large resection specimens is Polypoid: spindle cell SCC
a
Posterior end of rim resection
Pterygomandibular rephe (ascending Ramus)
Soft palate
Gingiva from posterior
aspect of upper alveolus
Tonsil
Tumor
Buccal mucosa
Teeth
Buccal gingiva
Lingual gingiva
Posterior end of rim resection
Anterior end of rim resection (ascending ramus of mandible)
(alveolar process of mandible)
b Buccal mucosa
Tonsil
Lingual gingiva
Fig. 14.3 Resection of right retromolar trigone with rim from above; (b) view from lingual aspect (Reproduced,
resection of mandible. Suggested siting and orientation of with permission, from Allen and Cameron (2013))
tissue blocks for resection of retromolar trigone. (a) View
• Mucosa • Deep surgical margins, particularly posterior

White/thickened: in situ lesions and inferomedial margins
• Extent • Proximal lingual nerve, if present
Document local spread, e.g., to salivary gland, • Adjacent uninvolved mucosa and associated
tonsil, bone tissue, e.g., sublingual gland
• Other
Neck dissection, mandibular bone Histopathology report:
Final reports of oral mucosal resection speci-
Blocks for histology: mens should include details on:
The histology should represent the deepest
extent of the tumour, the relationship to the sur- • The specimen type, side, and tissues present
face, mucosal and deep soft tissue margins, and • The type of tumour present
changes in adjacent oral mucosa (Figs. 14.3 and Squamous cell carcinoma NOS
14.4). SCC variants include basaloid, adenosquamous,
spindle cell, verrucous
• At least one block of tumour per centimetre of Adenocarcinoma (salivary gland types)
maximum dimension • The grade of tumour assessed at invasive front
• Mucosal surgical margins, particularly the floor Cohesive or non-cohesive patterns (more
of mouth, retromolar region, and soft palate metastasis with non-cohesive)
where the incidence of dysplasia is highest • The extent of local spread
a Tumour
Sulcus terminalis
Tip of tongue
Anterior ventral tongue limit
Anterior floor of mouth limit
Floor of mouth
Sublingual gland
Medial limit
Floor of mouth limit

Sublingual gland
Fig. 14.4 Right hemiglossectomy specimen. Suggested siting of blocks for hemiglossectomy specimen: (a) Lateral
view; (b) view of transverse slice (Reproduced, with permission, from Allen and Cameron (2013))
• The distance of tumour from the nearest • If the tumour lies within 2 mm of a lateral
mucosal margin limit, take a vertical block through the lateral
• The distance of the tumour from the nearest limit block to illustrate the relationship of
deep margin tumour to the surgical margin.
• Intravascular and/or perineural spread • Measurements:
• If other specimens are attached as an in- –– Length of the lip along the vermilion bor-
continuity dissection (e.g., oropharyngeal der and height (cm)
mucosa, neck dissection, bone), these can be –– Tumour length × width (cm)
cut separately in the usual fashion. Maximum depth from reconstructed muco-
sal surface (cm)
14.6.2.2 Wedge Resection Specimens Distances to closest mucosal and deep sur-
of Lip gical margins (cm)
Procedure: –– Mucosal abnormalities
• Orientate the specimen. Description:

• Ink the deep and lateral resection margins.
• Slice the specimen parasagitally so that the • Tumour
blocks contain both skin and intraoral mucosa, Plaque-like/ulcerated/fungating: usual type
including the lateral shave excisions of ver- SCC
milion border if present. Warty: well-differentiated SCC
• Mucosa • If lateral shave excisions of vermilion border

White/thickened/ulcerated: in situ lesions are present, take one block from the cutaneous
• Extent to mucosal aspects at the junction with the
Spread into muscle wedge and one transverse block of the lateral
limit of each shave. If greater than 2 cm in
Blocks for histology: length, take one additional block for every
The histology should represent the deepest centimetre.
extent of the tumour, the relationship to the cuta- • Cutaneous, mucosal, and deep surgical
neous, mucosal and deep soft tissue margins, and margins
changes in adjacent vermilion border mucosa and • Samples of other lesions not already repre-
skin (Fig. 14.5). sented, e.g., mucosal white areas or ulcers
• At least one block of tumour per centimetre of Final reports of lip resection specimens should
maximum dimension. include details on:
a
Tumour
Vermilion border
Vermilion
Oral mucosa Tumour border
Skin
Minor salivary glands Skin
Oral mucosa
Minor salivary
glands Orbicularis oris
Tumour
b
Labial artery
Tumour
c
Oral mucosa
True surgica
limit
Minor salivary glands Skin
Orbicularis oris
Fig. 14.5 Wedge resection of lower lip. Suggested siting selection of transverse limits if original limit blocks con-
and orientation of blocks for wedge resection of lip: (a) tain tumour (Reproduced, with permission, from Allen
View from in front; (b) outline of central block(s); (c) and Cameron (2013))
• The specimen type, size, and side pN2 Metastasis in:

• The type of tumour present (a) Ipsilateral single node ≤3 cm with
Squamous cell carcinoma NOS extranodal extension, or, >3–6 cm without
extranodal extension
Adenocarcinoma (salivary gland types)
(b) Ipsilateral multiple nodes ≤6 cm without
• The grade of tumour assessed at invasive front
extranodal extension
• The extent of local spread (c) Bilateral or contralateral node(s) ≤6 cm
• The distance of tumour from the nearest lat- without extranodal extension
eral mucosal margin pN3 (a) Metastasis in a lymph node >6 cm, or
• The distance of the tumour from the nearest (b) Extranodal extension with any of; >3 cm,
deep margin multiple ipsilateral, contralateral, bilateral
• Intravascular and/or perineural spread
• Other pathology such as solar damage, dys-
plasia, or radiation injury Bibliography
• Extent of tumour spread: TNM 8—lip and
oral cavity carcinoma Allen DC. Histopathology reporting. Guidelines for surgi-
pTis Carcinoma in situ clinical, pathological and laboratory aspects. 2nd ed.
pT1 Tumour ≤2 cm in greatest dimension and Berlin: Springer; 2013.
≤5 mm depth of invasion Barnest L, Eveson J, Reichart P, Sidransky D. WHO
pT2 Tumour ≤2 cm in greatest dimension and classification of tumours. Pathology and genetics.
6–10 mm depth of invasion, or, tumour >2 cm Tumours of the head and neck. Lyon: IARC Press;
but ≤4 cm in greatest dimension and ≤10 mm 2005.
depth of invasion Brierley JD, Gospodarowicz MK, Wittekind C, editors.
pT3 Tumour >4 cm in greatest dimension or
>10 mm depth of invasion
Gnepp DR, editor. Diagnostic surgical pathology of the
pT4 Lip: Tumour invades adjacent structures, e.g., head and neck. 2nd ed. Philadelphia: WB Saunders;
through cortical bone, inferior alveolar nerve, 2009.
floor of mouth, skin of face Helliwell TR, Giles TE. Pathological aspects of the
Oral cavity: Tumour invades adjacent assessment of head and neck cancer. UK National
structures, e.g., through cortical bone, into Multidisciplinary Guidelines. J Laryngol Otol.
deep (extrinsic) muscle of tongue, maxillary 2016;130(Suppl. S2):S59–65.
sinus, skin of face Kerawala C, Roques T, Jeannon J-P, Bisase B. Oral cav-
pT4b (lip and oral cavity): Tumour invades ity and lip cancer: UK National Multidisciplinary
masticator space, pterygoid plates, skull base, Guidelines. J Laryngol Otol. 2016;130(Suppl.
or encases carotid artery S2):S83–9.
Shah JP, Patel SG. Head and neck surgery and oncology.
3rd ed. Edinburgh: Mosby; 2003.
Regional lymph nodes: cervical—selective and The Royal College of Pathologists. Dataset for histopa-
modified/radical lymphadenectomy will ordinar- thology reporting of nodal excisions and neck dis-
section specimens associated with head and neck
ily include 10 or 15 or more lymph nodes, carcinomas. November 2013. Available via https://
respectively. www.rcpath.org/profession/publications/cancer-
datasets.html. Accessed July 2016.
The Royal College of Pathologists. Tissue pathways for
pN0 No regional node metastasis head and neck pathology. January 2016. Available
via https://www.rcpath.org/profession/publications/
pN1 Metastasis in an ipsilateral single node ≤3 cm cancer-datasets.html. Accessed July 2016.
without extranodal extension
Maxilla, Mandible, and Teeth
15
Seamus S. Napier and with clinical comments by
John J. Marley
15.1 Anatomy from the alveolar process of the upper anterior

teeth below to the infraorbital margin, while the
Detailed consideration of all craniofacial bones is orbital surface forms the floor of the orbit. The
impossible in a text of this sort, but by focusing nasal surface articulates with the ethmoid, lacri-
on the maxilla and mandible alone, this chapter mal, and palatine bones and the inferior turbinate
offers a view of the processes affecting facial to complete the lateral nasal and medial orbital
bones as a whole and how specimens derived walls. The infratemporal surface is convex and
from them might be handled. projects posteriorly and laterally.
The maxilla is the largest bone of the upper The upper alveolar process projects from the
facial skeleton and houses the maxillary sinus. It inferior aspect of the maxilla and contains the
articulates with a large number of other bones, sockets of the maxillary teeth. The roots of teeth
relating to a number of clinically important ana- posterior to the first premolar may be intimately
tomical areas, including the nasal cavity, the pter- related to the maxillary sinus; teeth and sinus
ygomaxillary space, the infratemporal fossa, and may each become involved in diseases originat-
the orbit. It is composed of a body and four pro- ing in the other. The slightly thickened posterior
cesses, namely alveolar, frontal, nasal, and zygo- end of the alveolar process is called the maxillary
matic processes. The body of the maxilla is tuberosity. The frontal process projects superi-
pyramidal in shape with four surfaces, namely orly between the nasal and lacrimal bones, articu-
anterior, nasal, orbital, and posterior (or infra- lating with the frontal bone and contributing to
temporal) surfaces. The anterior surface extends the medial wall of the nasal cavity. The palatine
process projects medially from the inferior aspect
of the maxilla and forms most of the palatal vault
and the nasal floor. The zygomatic process is a
pyramidal projection from the lateral aspect of
the maxilla where anterior, infratemporal, and
S.S. Napier (*) orbital surfaces converge, articulating with the
Royal Hospitals, Belfast Health and Social Care zygomatic bone.
Trust, Belfast, UK The mandible is composed of an arched body,
e-mail: seamus.napier@belfasttrust.hscni.net which runs posteriorly on each side to attach to
J.J. Marley the flat ramus. The body of the mandible has an
Department of Oral Surgery, School of Dentistry, external surface (buccal or labial plate), an inter-
Royal Hospitals, Belfast Health and Social Care nal surface (lingual plate), an upper border, and a
Trust, Belfast, UK
e-mail: john.marley@belfasttrust.hscni.net lower border. The lower border is rounded and

170 S.S. Napier and J.J. Marley
well defined, outlining the profile of the lower the cementum and the bone. At the cervical mar-
jaw. The external surface bears the mental fora- gin, the periodontal ligament merges with the
men between the premolar roots. The internal gingival mucosa; a narrow sleeve of epithelium
surface of the body is indented by the sublingual continuous with the gingiva called the epithelial
and submandibular glands. The superior border, attachment surrounds the cervical margin.
more usually referred to as the lower alveolar The crown of each tooth has five surfaces. The
ridge, contains the sockets of the mandibular biting surface is called the occlusal surface; on
teeth. The posterior aspect of the body joins the incisor teeth, this is termed the incisal edge. The
ramus behind the last molar tooth. The anterior surface closest to the tooth in front is called the
surface of the ramus extending from the abrupt mesial surface; that closest to the tooth behind is
change in angulation of the bone is called the called the distal surface. The surface lying closest
ascending ramus, while the area around the junc- to the cheek is called the buccal surface (or the
tion of the body and ramus is called the angle. labial surface on anterior teeth); the surface lying
The coronoid process extends upward and closest to the tongue is called the lingual surface
slightly forward from the anterosuperior aspect (or the palatal surface on upper teeth). Incisor
of the ramus and bears the attachment of tempo- teeth have a relatively broad crown with a flat-
ralis. The condylar process extends upward and tened edge for cutting food, while canine teeth
posteriorly from the posterior aspect of the ramus have a single point or cusp. Premolar teeth have
and bears the knuckle-shaped articulating condy- two cusps on the occlusal surface, one buccal and
lar head on the narrow condylar neck. The sig- one lingual, while molars have four or five cusps.
moid notch lies between these two processes. There are 20 deciduous (or milk) teeth in the
Near the centre of the medial surface of the ramus primary dentition—two incisors, a canine, and
lies the mandibular foramen, where the inferior two molars in each quadrant of the jaw. The teeth
alveolar branch of the mandibular nerve and its of the primary dentition begin their development
accompanying vessels enter the mandible. The in the first trimester of pregnancy as epithelial
lateral and medial surfaces of the mandible bear ingrowths from the lining of the oral cavity. The
several shallow fossae and roughened elevations epithelial component of the tooth bud forms the
corresponding to the attachments of muscles both enamel while the mesenchymal element gives
of facial expression and of mastication. rise to the remaining parts of the tooth. The crown
Each fully developed tooth is composed pre- of the tooth forms first but the root only forms
dominantly of dentine. The crown, the portion after the crown is complete; root development is
visible within the mouth, is covered by a layer of closely linked with eruption into the mouth. The
hard translucent enamel, while a thin layer of deciduous incisors begin to appear in the mouth
bone-like substance called cementum covers the at around 6 months of age, usually the central
root system, which may be single or multiple. before the lateral, followed by the first deciduous
The crown and root join at a slight narrowing molar at around 12 months. The deciduous canine
called the cervical margin. The dentine encloses appears around 18 months and finally the second
a central cavity called the pulp canal; the portion deciduous molar at around 24 months of age. The
toward the crown is dilated to form the pulp precise timing of eruption into the mouth is vari-
chamber, while the pulp canal narrows at the end able, although the sequence is relatively unchang-
of the root, the apex, into an apical foramen. The ing and lower teeth tend to appear before the
pulp chamber and canal contain the neurovascu- uppers.
lar supply to the tooth, passing through the apical There are 32 teeth in the permanent or second-
foramen. A tooth may have a number of acces- ary dentition—two incisors, a canine, two pre-
sory canals which open just short of the apex. molars, and three molars in each quadrant of the
The tooth is suspended in the alveolar bone by jaw. There is an ordered pattern of replacement of
the periodontal membrane, composed of thick the deciduous dentition by the permanent denti-
bundles of collagenous tissue running between tion. Beginning around 6 years of age, the first
15 Maxilla, Mandible, and Teeth 171
permanent molar erupts distal to the second opmental tooth disorders such as dentinogenesis
deciduous molar, soon followed by shedding and imperfecta or amelogenesis imperfecta; usually
replacement of the incisors. The deciduous all the teeth will be affected.
molars are replaced by the premolars, while the Primary disease of the jawbones, such as
eruption of the permanent canines straddles the fibrous dysplasia or ossifying fibroma, presents
eruption of the second permanent molar with the as bony swellings that may or may not involve
upper canine appearing latest, usually around overlying mucosa or adjacent teeth. Other condi-
13 years of age. The process ends with the erup- tions with a “fibro-osseous” pattern such as
tion of the third permanent molar or wisdom cemento-osseous dysplasia, are seen only in the
tooth around 18 years. tooth-bearing regions.
Lymphovascular drainage: Patients with a history of radiotherapy to the
Lymph drainage of the teeth and jawbones jawbones and bisphosphonate medications are
corresponds to that of the regional cutaneous and prone to developing recalcitrant bone infections
mucosal sites, leading ultimately to the deep cer- (termed osteoradionecrosis and bisphosphonate
vical chain (see Fig. 20.1). related osteonecrosis of the jaws respectively),
particularly following tooth extraction.

The maxilla and mandible are more usually
affected by disease arising from closely related • Vitality testing, using the cooling effect of
structures such as the teeth, oral mucosa, and evaporation of ethyl chloride or small electric
salivary glands, and, in the case of the maxilla, currents, can assess the health of the pulpal
the maxillary sinus, the orbit or the infratemporal tissues. Tenderness to percussion (TTP) indi-
fossa, rather than from primary bone disease. cates involvement of periodontal tissues.
Many of these conditions are described else- Probing the junction between tooth and gum
where; primary diseases of the odontogenic can assess the depth and extent of periodontal
apparatus and jawbones will be considered here. destruction, the presence of bleeding signify-
Disease of the teeth presents as pain, mobility, ing active inflammation. Mobility is assessed
or swelling, although some conditions are in terms of buccolingual and vertical move-
detected as incidental findings at radiographic ment and is due to destruction of periodontal
examination. Caries and periodontal disease are support, perhaps as a result of periodontal dis-
painless until advanced destruction of tissue has ease or because of an adjacent cyst or tumour.
occurred. A draining sinus opening onto mucosa
or facial skin may accompany dental abscesses Plain radiographs are essential for the assess-
but others may present with soft tissue swelling ment of intrabony cystic lesions, particularly to
of the face and other signs of spreading infection. determine the bone–lesion interface (sclerotic
Gingival bleeding is often the only sign of chronic and well-defined implies a slow-growing lesion;
marginal periodontal disease until increased ill-defined suggests a rapidly growing destructive
tooth mobility or the drainage of pus from lesion). Radiographic examination is also vital to
between gingiva and tooth occur. Developmental determine shape, size, and heterogeneity (uni-
cysts, odontogenic hamartomas, and neoplasms locular or multilocular), as these can all be clues
are often painless but may present with bony as to the provenance of the “cyst-like” lesion. CT
swelling, facial asymmetry, or a failure of teeth to scanning particularly with 3D reconstruction is
erupt and normally occur in relationship to the useful for large lesions and assessing relation-
maxillary or mandibular dentoalveolar complex. ships with adjacent anatomical structures; cone
Discolouration of teeth, rapid wear, or abnormal beam CT scanning of jaw bones is widely avail-
morphology are features of the hereditary devel- able in specialist oral surgery practice but have
less utility in large lesions than medical CT. MR pulp canal), or removal of the tooth. Recurrence
imaging has also less utility when investigating is uncommon but relates to a failure to control the
lesions confined to bone, but have a role to play contents of the pulp canal.
in follow-up interval monitoring to reduce expo- Dentigerous cyst (follicular cyst): A develop-
sure to ionizing radiation. mental cyst that surrounds the crown of an
unerupted tooth and is attached at the cervical
region. Common, 15% of jaw cysts; often in
15.4 Pathological Conditions younger patients but not exclusively; usually
seen in the upper canine, lower second premolar
15.4.1 Non-neoplastic Conditions and third molar regions. Well-defined radiolu-
cency, unilocular in form with a sclerotic border
Radicular cyst (also known as apical periodontal surrounding the crown of an unerupted tooth (so-
cyst, dental cyst), apical granuloma, and chronic called dentigerous relationship). May resorb
dental abscess: These inflammatory lesions form roots of adjacent teeth. Develops from the dental
a spectrum of changes related to the apical region follicle surrounding the crown of the unerupted
of a non-vital tooth (usually a consequence of tooth but through an unknown mechanism.
dental caries), with considerable overlap in clini- Enlargement is by hydrostatic mechanisms but
cal, radiological, and pathological findings. what generates the forces is not clear. Has a thin
Granulomas tend to be smaller (<10 mm), are fibrous wall (unless subject to infection), mini-
well defined but do not tend to have a corticated mal inflammatory cell infiltrate (if any), and a
margin. They have a sparser inflammatory cell thin lining of stratified squamous epithelium.
infiltrate, and show less active inflammation than Treatment requires removal of the unerupted
radicular cysts. Very large radiolucencies tend to tooth, the cyst being delivered at the same time.
be cysts rather than abscesses, although they too Recurrence is rare.
can become infected. Very common, over 70% of Odontogenic keratocyst: A developmental
jaw cysts with 60% occurring in the maxilla; all cyst characterized by a distinctive lining of kera-
ages but rare in children and with deciduous tinizing stratified squamous epithelium and a
teeth. Arise when the contents of the necrotic marked tendency for recurrence. Common, about
pulp canal leak out of the apical foramina and 10% of jaw cysts; all ages, any site (but espe-
stimulate an inflammatory reaction at the apex. cially near angle of mandible). Well-defined
The persistent inflammatory stimulus induces radiolucency, often multilocular in form with a
granulation tissue formation to help wall off the sclerotic border, which may be in dentigerous
necrotic debris. Epithelial rests around the root relationship. Anteroposterior dimension is
(cell rests of Malassez) proliferate, initially as greater than vertical dimension reflecting the pat-
complex strands and arcades, then as a well- tern of growth through pathways of least resis-
defined lining; when present, the epithelium tance, a combination of epithelial proliferation as
allows the term radicular cyst to be used. Cysts well as luminal keratin/fluid accumulation, may
enlarge by a hydrostatic mechanism—the high resorb roots of adjacent teeth. Histology shows a
protein content of the inflammatory exudate in thin lining of highly organized keratinizing strati-
the lumen draws water into the cyst while the fied squamous epithelium, which has a promi-
lack of lymphatics in the wall prevents it draining nent palisaded basal layer. Daughter cysts within
away—producing a rounded radiolucency usu- the wall are common. Derived from primordial
ally with a sclerotic border. May resorb the apical dental structures, the epithelium has an active
portion of the tooth. Most are located apically but growth potential of its own, unlike that of radicu-
10% are seen in lateral relationship (accessory lar cysts and dentigerous cysts. This infiltrative
apical foramina). Treatment usually involves growth pattern produces a multilocular radiolu-
endodontic therapy (root canal treatment), api- cency, in contrast to the ovoid or circular
cectomy (removing the apical 2 mm of the tooth unilocular lesion of expansile cysts like the radic-
root via a surgical approach and sealing off the ular cyst. Recurrences (20%) are due to small
pieces of lining and/or daughter cysts that remain but can be very subtle in more cystic areas.
following curettage. Large cysts are treated by Peripheral tall columnar ameloblast-like cells
marsupialization and packing; over time, the cyst with polarized hyperchromatic oval nuclei and
shrinks in size and may disappear completely. clear cytoplasm (“piano keyboard”) surrounding
A small proportion of patients with kerato- more centrally placed cells resembling stellate
cysts, particularly those aged under 18 years, reticulum. The tumour grows by epithelial prolif-
have Gorlin’s syndrome (many stigmata, includ- eration and infiltrates along the soft tissues
ing multiple synchronous and metachronous ker- between bone trabeculae, usually extending far
atocysts, skeletal abnormalities especially of beyond the radiographic margins. Recurrence is
skull form, ribs and vertebrae, multiple basal cell inevitable if not resected completely. Multiple
carcinomas). recurrences run the risk of soft tissue involve-
Other cysts: A large variety of cysts can occur ment (especially into the parapharyngeal spaces)
in the jaws. Some will be developmental cysts and dissemination of tumour into lungs and
unrelated to teeth (nasopalatine duct cyst, nasola- lymph nodes.
bial cyst, dermoid cyst), others will be associated There are many different histological sub-
intimately with the odontogenic apparatus and types: follicular, plexiform, acanthomatous, des-
will be developmental (lateral periodontal cyst, moplastic, granular cell, etc., which probably
gingival cyst of adults, glandular odontogenic have no real clinical significance. Two variants
cyst) or inflammatory in nature (paradental cyst). have a better prognosis—the unicystic amelo-
In addition, samples from a periodontal pocket or blastoma and the extraosseous ameloblastoma.
inflamed dental follicle can mimic cystic lesions. Unicystic ameloblastoma: Younger patients
Of these only the glandular odontogenic cyst is (teens/early twenties), predominantly in the
likely to recur because of the presence of daugh- lower third molar region associated with an
ter cysts in its wall. unerupted tooth in dentigerous relationship. A
single large cystic cavity is lined by epithelium
that is not always typical of ameloblastoma;
15.4.2 Neoplastic Conditions sometimes, there is epithelial proliferation into
the wall or as a luminal polyp. On account of the
Odontogenic neoplasms and hamartomas pro- subtle character of the epithelium, diagnosis is
vide a bewildering array of complex histological easily missed. Fortunately, this type of amelo-
patterns although they are relatively uncommon blastoma usually responds to thorough curettage
clinical problems. Classification is based on or marsupialization and does not always require
resemblance to normal tooth formation. Most are resection.
benign or self-limiting and can be managed in a Extraosseous ameloblastoma: Less than 5%
similar semiconservative fashion. Of the many of ameloblastomas and arise in gingival soft tis-
different types, only ameloblastoma and odont- sue alone without bone involvement where they
ome are common. may resemble a fibrous epulis. Histologically
Ameloblastoma: The commonest odontogenic fairly typical of ameloblastoma, less radical sur-
neoplasm, accounting for 1% of all jaw tumour. gery is required than their intraosseous cousins;
Usually found in the mandible, especially near nevertheless, cortical bone may have to be
the angle (60%), although up to 20% arise in the removed from the deep aspect of the tumour to
maxilla. Peak in fourth and fifth decades, but all ensure clearance.
ages can be affected. Radiographically usually Odontome: Hamartomatous malformation
but not exclusively multilocular, often in dentig- forming distinct tooth-like structures ( compound),
erous relationship with erosion of the lingual cor- disorganized masses of dentine, enamel, cemen-
tex or lower border is a characteristic sign; roots tum (complex), or any combination of the two
can also be resorbed. forms. Commonly identified as incidental find-
The tumour may be solid, cystic, or microcys- ings in teenagers or young adults. Most are small,
tic; in solid areas the histology is characteristic are related to the permanent dentition, and are
discovered accidentally when an unerupted tooth 15.5 Surgical Pathology

is being investigated; larger ones may produce Specimens: Clinical Aspects
bony expansion. X-rays show dense radiopaque
masses surrounded by a well-defined radiolucent 15.5.1 Biopsy Specimens
zone; lesions in younger patients may have large
radiolucent portions. Complex odontomes are The vast majority of teeth are removed because
seen most often in the posterior segments; com- of dental caries or periodontal disease and are not
pound odontomes in the anterior segments (espe- submitted for histological examination unless
cially maxilla). Multiple odontomes suggest there are unusual clinical or radiological findings.
Gardner’s syndrome. Histologically they are Teeth adjacent to cystic lesions are removed
composed predominantly of dentine with varying either as part of the treatment for the lesion (e.g.,
amounts of enamel, cementum, and other soft tis- the unerupted tooth associated with a dentigerous
sue components typical of the odontogenic appa- cyst) or because they cannot be restored to useful
ratus. Less well-developed forms have abundant function (e.g., a tooth whose roots have been
pulpal and ameloblastic areas and can resemble extensively resorbed by a keratocyst). Where a
other types of odontogenic tumour (e.g., amelo- primary neoplastic lesion is suspected, teeth may
blastic fibroma, ameloblastic fibro- odontoma), be removed to provide access to underlying
while odontomes may be associated with other lesional tissue via the socket. Teeth may be sub-
odontogenic tumours such as the calcifying mitted whole or as fragments; deeply buried
odontogenic cyst. unerupted teeth are most likely to be divided by
Other rarer benign tumours or hamartomatous the surgeon prior to removal.
lesions include calcifying epithelial odontogenic Apicectomy is the removal of a short portion
tumour (of Pindborg), adenomatoid odontogenic of the tooth root apex to control persistent peri-
tumour, calcifying cystic odontogenic tumour, apical infection not responsive to nonsurgical
ameloblastic fibroma, odontogenic fibromyx- endodontic procedures. A flap of mucosa and
oma, cementoblastoma. Many will display speck- associated periosteum is reflected to expose the
led calcification on X-ray, differentiating them area, the apical portion of the tooth is removed
from cysts. with a drill, and the pulp canal opening sealed
Malignant tumours: Involvement of the jaw- following appropriate preparation. Soft tissues
bones by malignant tumour is usually a conse- associated with periapical infection are removed
quence of direct spread into the bone from en passant; most will represent a radicular cyst,
mucosal or salivary lesions, although a number of apical granuloma, or chronic dental abscess.
primary bone and soft tissue sarcomas can arise Other benign-looking odontogenic lesions, such
in the jaws. Malignant tumours of the odonto- as small cysts or odontomes, will be accessed in
genic apparatus are rare and are usually only a similar fashion, shelled out, and the cavity
diagnosed histologically, although pain, pares- curetted. The resulting specimens are usually
thesia, rapid growth, mucosal fixation, or ulcer- submitted in total. Very large cystic lesions tend
ation may be present. Radiographs may show to be marsupialized rather than removed in total
irregular bone destruction. because of the risk of fracture or iatrogenic injury
They include malignant ameloblastoma/ame- to nerves. A portion of the lining will be sampled,
loblastic carcinoma, clear cell odontogenic carci- primarily to detect ameloblastoma, which
noma, carcinoma arising in an odontogenic cyst requires more radical surgery than a keratocyst.
(any type of odontogenic cyst and usually squa- The close proximity of important anatomical
mous cell carcinoma), primary intra-osseous car- structures in the jaws means that biopsy samples
cinoma, and odontogenic sarcomas, the latter of primary bone lesions tend to be small. Benign-
being very rare. Overall they tend to be low-grade looking lesions will be removed in total, often as
malignancies, although uncontrolled local fragments, while suspected malignancies will be
tumour growth, recurrences, and metastasis com- sampled to avoid compromising later definitive
plicate some cases. surgery. Accurate histological assessment often
requires demonstration of the interface with nor- tomy). Rim resection is performed for tumours of
mal bone so, in the mandible in particular, it is the lower alveolus or floor of mouth mucosa
important to avoid sampling only the cortical where there is minimal invasion of bone. If teeth
bone. Access to lesional tissue is achieved either are present, the line of excision passes below
by reflecting a mucoperiosteal flap or extracting their apices, often including the inferior alveolar
teeth in the region and using the sockets to expose canal. If the ascending ramus is involved, the
the lesion. Biopsies are taken either as curettings excision line may include the coronoid process.
or intact pieces removed with a drill or trephine. Hemimandibulectomy is indicated for exten-
sion of mucosal tumour into the cancellous bone
of the body of the mandible either from the alve-
15.5.2 Resection Specimens olar aspect or from the buccal or lingual cortical
plates such that preservation of sufficient bone at
Resection specimens of maxilla for neoplastic the lower border to prevent stress fracture cannot
processes include maxillary alveolectomy, palatal be achieved. Reconstruction is facilitated by pre-
fenestration (also known as partial maxillectomy), serving as much bone as possible, consistent with
maxillectomy (also known as hemimaxillec- clearance. However, if there is a risk of perineu-
tomy), and radical maxillectomy (also known as ral spread of tumour within the mandible, a block
extended maxillectomy). Maxillary alveolectomy of bone containing the entire inferior alveolar
is indicated when a small tumour of the alveolar canal is excised from lingula to mental foramen.
mucosa encroaches on or invades for a short dis- Ameloblastomas and other locally aggressive
tance into the bone. The resection lies within the odontogenic tumours in the mandible usually
alveolar process and does not involve the maxil- require hemimandibulectomy.
lary sinus. Palatal fenestration is performed for
relatively localized tumours of the upper alveolar
mucosa or floor of the maxillary sinus. The speci- 15.6 Surgical Pathology
men comprises a portion of unilateral maxillary Specimens: Laboratory
alveolar bone and alveolar mucosa, the opposing Aspects
mucosa on the floor of maxillary sinus with a
minimum of the medial and lateral sinus walls. 15.6.1 Biopsy Specimens
Tissue from the upper buccal sulcus and a portion
of the palatal vault may be included. Maxillectomy 15.6.1.1 Teeth
is indicated for larger tumours of the maxillary Should be received in formalin. Identify tooth
sinus and mouth that involve all or part of the (e.g., upper left second premolar or lower right
maxillary sinus. There are a number of modifica- second deciduous molar). Note the presence of
tions, but the specimen includes all of the maxil- caries or restoration, root resorption, or attached
lary alveolar bone from the midline to the soft tissue. Sample the soft tissue and process in
tuberosity; bone from the lateral and medial walls the usual manner.
of the maxillary sinus are included at least to the For an intrinsic developmental disorder of
level of the zygomatic buttress. The orbital floor dental hard tissue (e.g., dentinogenesis imper-
may be included or left intact. Radical maxillec- fecta), submit for preparation an undemineral-
tomy is indicated for tumours extending beyond ized 50-micron slice through the buccolingual
the confines of the maxillary sinus into adjacent plane of the tooth.
sites. The specimen includes the orbital floor, If no such intrinsic abnormality is suspected,
orbital contents, or pterygoid plates and muscles decalcify in 5% formic acid. Endpoint can be
with the maxillectomy. tested radiographically or with ammonia water.
Resection specimens of mandible for neoplas- Stronger acids can be used although close atten-
tic processes include rim resection (also known tion must be paid to detecting the endpoint. When
as marginal mandibulectomy) and hemimandibu- negative, bisect molars in the mesio-distal plane;
lectomy (also known as segmental mandibulec- others in the buccolingual plane. Demineralize
further briefly (2 or 3 days), then process and • Associated soft tissue elements (e.g., oral
embed as normal. Sections should demonstrate mucosa, pterygoid muscles, orbital contents)
pulpal tissue in pulp chamber and root canal as • Tumour maximum dimensions (cm)
well as the interface between pulp and dentine. • Distance to closest mucosal and deep soft tis-
sue limits (cm)
15.6.1.2 Jaw Cysts • Distance to nearest anterior or posterior bone
Usually as fragments free-floating in formalin; limit (cm)
record number of pieces and dimensions of larg-
est. Submit small specimens in total; if large, Sample the mucosal and deep surgical mar-
submit representative slices. gins as “radial” sections before sawing the bone
NB: Small pieces of tooth root and/or bone are and submit separately (reduces contamination of
frequently included. Test carefully; specimens with the margins). Cut with a sharp blade firmly down
hard tissue tend to sink quickly in the fixative. to bone and use a flat blunt instrument to dissect
mucoperiosteum free from the bone in the way
15.6.1.3 Jaw Bone Biopsies one might peel an orange.
Usually as fragments in formalin; record number Sample soft tissue elements of mucosal
of pieces and dimensions of largest. If small, sub- tumour prior to sawing the bone unless the
mit in total for decalcification; otherwise submit tumour is very small (see next section).
representative samples. Saw the bone into 0.5 cm slices in buccolin-
gual plane (vertical plane passing between
crowns of adjacent teeth).
15.6.2.2 Rim Resections of Alveolus
Most maxillary and mandibular resections are for Procedure:
tumour arising in adjacent structures, although some Ink the external periosteal limit along one
will be for bone or odontogenic lesions or reactive aspect to aid orientation of subsequent histologi-
conditions, such as osteoradionecrosis. Rim resec- cal sections.
tions of alveolar bone will usually be accompanied Measurements:
by definitive resection of a mucosal tumour.
• Anteroposterior length (cm) along alveolus
15.6.2.1 Hemimandibulectomy • Maximum bone height (cm)
and Maxillectomy • Associated soft tissue elements (e.g., mucosa)
Specimens in the usual fashion
Procedure:
Radiographs of the specimen can help delin- Saw the bone into 0.5 cm slices in the buccolin-
eate the lesion. gual plane (vertical plane passing between crowns
Ink only the critical external periosteal limit of adjacent teeth). If the attached mucosal tumour is
and associated soft tissue limits around the larger than 1 cm diameter, sample tumour and mar-
tumour, usually posteriorly and superiorly in the gins in the usual fashion prior to sawing the bone.
maxilla. If the attached mucosal tumour is smaller than
Measurements: 1 cm diameter, saw the bone into 0.5 cm slices in
the buccolingual plane (vertical plane passing
• Anteroposterior length (cm) along lower bor- between crowns of adjacent teeth) without dis-
der (hemimandibulectomy) or along alveolar turbing the soft tissue.
process to tuberosity (maxillectomy) Description:
• Maximum bone height (cm) of ramus (hemi-
mandibulectomy) or of nasal aspect Tumour—solid, cystic, or both solid and cystic
(maxillectomy) –– Circumscribed or infiltrative
Arising in bone or extension from adjacent structures changes in adjacent tissues (Figs. 15.1 and
Adjacent bone 15.2).
–– Periosteal reaction? Osteomyelitis?
At least one block of tumour per centimetre
Mucosa
diameter.
–– Origin of tumour or secondarily involved?
Abnormal areas of distant bone or mucosa.
Other
Anterior and posterior surgical bone margins as
–– Associated soft tissue elements (e.g., oral
transverse sections.
mucosa) in the usual fashion
Mucosal and deep soft tissue and neurovascular
surgical margins.
Blocks for Histology:
The histology should represent the tumour, If other specimens are attached as an “in-continuity
its deepest extent, the relationship to the bony, dissection” (e.g., mucosa, skin, lymph nodes), these
mucosal and deep soft tissue margins, and can be cut separately in the usual fashion.
a b
Alveolar process
Teeth
Anterior part of orbital floor
Tumour Cut surface of

zygomatic process
Palatal
vault Upper buccal
sulcus Tumour within
sinus
Infraorbital
margin Tuberosity
Alveolar process
with teeth
Inferior turbinate Lateral wall of maxillary sinus
Upper buccal sulcus

Palatal vault
Tumour
Fig. 15.1 Left maxillectomy specimen for carcinoma. from lateral aspect; (c) view of transverse cut surface
Suggested siting and orientation of tissue blocks for max- (Reproduced, with permission, from Allen and Cameron
illectomy specimens. (a) View of palatal aspect; (b) view (2013))
a b
Sigmoid Coronoid process
notch Lingula and inferior
alveolar nerve foramen
Molar and
premolar teeth
Lingula and
inferior alveolar
nerve foramen
(on lingual side) Mental
foramen
Sigmoid Coronoid
External oblique ridge Radiographic notch process Mental
extent of lesion foramen
Fig. 15.2 Right hemimandibulectomy for ameloblas- intrabony tumour. (a) View from lateral aspect; (b) view
toma. Suggested siting and orientation of tissue blocks for from above (Reproduced, with permission, from Allen
hemimandibulectomy for ameloblastoma or other and Cameron (2013))
Histopathology Report: Barnest L, Eveson J, Reichart P, Sidransky D. WHO

Final jawbone resection reports should include classification of tumours. Pathology and genetics.
Tumours of the head and neck. Lyon: IARC Press;
details on: 2005.
• Specimen type TNM classification of malignant tumours. 8th ed.
• Type of tumour present (and grade, if Oxford: Wiley-Blackwell; 2017.
Helliwell TR, Giles TE. Pathological aspects of the
relevant) assessment of head and neck cancer. UK National
• Extent of spread Multidisciplinary Guidelines. J Laryngol Otol.
• Distance of tumour from the nearest cutane- 2016;130(Suppl. S2):S59–65.
ous/mucosal margin Gnepp DR, editor. Diagnostic surgical pathology of the
head and neck. 2nd ed. Philadelphia: WB Saunders;
• Distance of tumour from the nearest deep soft 2009.
tissue margin Shah JP, Patel SG. Head and neck surgery and oncology.
• Distance of tumour from the nearest bone 3rd ed. Edinburgh: Mosby; 2003.
margin The Royal College of Pathologists. Dataset for histopa-
thology reporting of nodal excisions and neck dis-
section specimens associated with head and neck
carcinomas. November 2013. Available via https://
www.rcpath.org/profession/publications/cancer-
Bibliography datasets.html. Accessed July 2016.
head and neck pathology. January 2016. Available
via https://www.rcpath.org/profession/publications/
cancer-datasets.html.
Pharynx and Larynx
16
by Barry Devlin
16.1 Anatomy the vallecula, the gutter between the posterior

tongue and the epiglottis. The tonsillar fossa lies
The pharynx connects the nasal cavities and mouth in the lateral aspect, between the palatoglossal and
with the larynx and oesophagus. It is divided into palatopharyngeal folds. The hypopharynx extends
three functional parts, namely the nasopharynx, from the upper border of the epiglottis to the lower
the oropharynx, and the hypopharynx (Fig. 16.1). border of the cricoid cartilage. A narrow recess
The nasopharynx lies behind the nasal cavities termed the piriform fossa lies on each side of the
and above the level of the soft palate. The roof and larynx between the aryepiglottic fold and the thy-
posterior wall relate closely to the skull base and roid cartilage. Together with the oropharynx, it is
the first cervical vertebra. The lateral wall is an lined by stratified squamous epithelium and con-
extension of fascia from the skull base called the tains accessory mucous glands (Fig. 16.1).
pharyngobasilar fascia. The Eustachian tube A ring of lymphoid tissue surrounds the open-
opens into the lateral wall of the nasopharynx just ing of the pharynx, comprising the pharyngeal
behind and at approximately the same level as the tonsil (or adenoid), the palatine tonsils, and the
inferior turbinate. It is lined by respiratory mucosa lingual tonsil. The adenoid lies on the posterior
with accessory mucous glands, particularly numer- wall of the nasopharynx in the midline between
ous around the opening of the Eustachian tube. the posterior edge of the nasal septum and the
The slight depression posterior to the opening of openings of right and left Eustachian tubes. The
the Eustachian tube is called the fossa of palatine tonsils each lie in their tonsillar fossa.
Rosenmüller (or pharyngeal recess). The orophar- This group of lymphoid aggregates is collectively
ynx extends from the soft palate into the depth of described as Waldeyer’s ring.
The larynx lies between the posterior one-
third of the tongue superiorly and the trachea
inferiorly. It is composed of three large midline
S.S. Napier (*) cartilages—the epiglottis, the thyroid, and the
Histopathology Laboratory, Institute of Pathology, cricoid—with the smaller paired arytenoid carti-
Royal Victoria Hospital, Belfast Health and Social lages. Other smaller paired cartilages are present,
the corniculate and cuneiform cartilages, that are
of lesser importance in surgical practice.
B. Devlin
ENT Surgery, Royal Victoria Hospital, Belfast Health
The cricoid cartilage is the most inferior of
and Social Care Trust, Belfast, UK the laryngeal cartilages but is the cornerstone of
e-mail: barry.devlin@belfasttrust.hscni.net the larynx. It is shaped like a signet ring, with the

180 S.S. Napier and B. Devlin
Fig. 16.1 Anatomy of Base of skull Fossa of rosenmuller

the pharynx. View of
pharynx opened from
behind to reveal major
subdivisions and
anatomical landmarks of Nasopharynx
the pharynx (Used with Opening of Eustachian tube
the permission of the
Geneva, Switzerland. Oropharynx
The original source for Base of tongue
Hypopharynx
Pyriform fossa
Oesophagus
broadest part, the lamina, located posteriorly and apex (superiorly and posteriorly). Extending
the narrower arch continuous anteriorly encir- anteriorly from the vocal process of each aryte-
cling the opening to the trachea. It is connected to noid to the inner surface of the thyroid cartilage is
the highest tracheal cartilage by the cricotracheal the vocal ligament. Each vocal ligament forms
ligament. The thyroid cartilage overlaps outside the basis of the vocal cord. A complex arrange-
the cricoid cartilage. It is composed of two quad- ment of extrinsic and intrinsic muscles coordi-
rangular laminae that join in the midline anteri- nates the movements of the larynx and its
orly (forming the laryngeal prominence or constituent cartilages.
“Adam’s apple”) and diverge posteriorly, ending The surface anatomy of the endolarynx is
as two slender processes, a larger superior cornu defined by three sets of prominent mucosal
and a smaller inferior cornu. It is attached to the folds—the aryepiglottic folds, the vestibular
cricoid by the cricothyroid membrane and to the folds, and the vocal cords. The aryepiglottic folds
hyoid bone above by the thyrohyoid membrane. sweep upward and laterally from the arytenoid
The epiglottis is a thin leaf-shaped cartilage, cartilages posteriorly to the tip of the epiglottis,
attached at its inferior aspect to the inner surface encircling the inlet to the larynx and representing
of the thyroid cartilage just below where the thy- the border between larynx and hypopharynx. The
roid laminae join anteriorly and extending supe- vestibular folds (or false cords) lie just above the
riorly and posteriorly to overhang the inlet to the vocal cords and run in the horizontal plane paral-
larynx. The whole assembly is suspended from lel to the vocal cords, separated from them by a
the hyoid bone by the thyrohyoid and hyoepiglot- shallow pouch called the vestibule (or ventricle).
tic membranes (Fig. 16.2). The larynx is divided into three regions—supra-
Right and left arytenoid cartilages are smaller glottic, glottic, and subglottic—according to their
than the epiglottis, thyroid, and cricoid cartilages, relationship with the vocal folds. The glottic
and are pyramidal in shape. They sit on top of the region corresponds to the region of the vocal
cricoid lamina, just lateral to the midline and are cords, while supraglottic and subglottic regions
overlapped outside by the thyroid laminae. They lie above and below, respectively (Fig. 16.3). A
each possess a muscular process (posteriorly and number of compartments are present within the
laterally), a vocal process (anteriorly), and an larynx that can influence the spread of tumours.
16 Pharynx and Larynx 181
a b
Epiglottis
Superior cornu
Hyoid bone of thyroid
Superior cornu
cartilage
of thyroid Hyoid bone
Thyrohyiod
cartilage
membrane
Thyrohyoid
Position of Lamina of
membrane
arytenoid thyroid
cartilage cartilage
Left
(on interior) Lamina of
arytenoid
Cricothyroid cricoid
Lamina of cartilage
membrane cartilage
cricoid cartilage
Arch of cricoid
Cricothyroid
cartilage
membrane
Tracheal rings
Tracheal rings
Fig. 16.2 The laryngeal cartilages. (a) View from the right lateral aspect; (b) view from the posterior aspect
(Reproduced, with permission, from Allen and Cameron (2013))
a
Vallecula
Epiglottis
Oropharyngeal limit
Hyoid bone
Aryepiglottic fold
Thyrohyoid membrane
Elevation of mucosa by apex
of left arytenoid cartilage
Superior cornu
of thyroid cartilage
Base of pyriform fossa Supraglottis
Left false cord Pyriform fossa
Ventricle Cut portion of cricoid lamina

Subglottis
Left vocal cord
Inferior cornu of thyroid cartilage
Tracheal rings
b Anterior
Anterior commissure
Lamina of thyroid cartilage

Paraglottic space
Glottis Arytenoid cartilage
Hypopharyngeal mucosa
Pyriform fossa
Posterior
Fig. 16.3 Laryngectomy specimen. (a) Idealized view of laryngectomy specimen opened from posterior; (b) coronal
section through larynx at level of vocal cords (Reproduced, with permission, from Allen and Cameron (2013))
The pre-epiglottic space lies outside the larynx Patients with laryngeal disease may present
between the tongue, the hyoid bone, and the epi- with alterations in the voice, particularly hoarse-
glottis, while the supraglottic space lies just ness or stridor.
below the mucosa of the supraglottic larynx from
epiglottis to the false cords, these spaces commu-
nicating through fenestrations in the epiglottis. 16.3 Clinical Investigations
The paraglottic space lies between the vocal lig-
ament and the lamina of the thyroid cartilage and • The nasopharynx is usually inspected using
communicates superiorly with the pre-epiglottic rigid or flexible endoscopes. The hypophar-
and supraglottic spaces. Reinke’s space is ynx and larynx can be inspected with a
restricted to the submucosa of the vocal cord, fibre-
optic endoscope passed through an
communicating with the paraglottic space and anaesthetized nose or indirectly visualized
the subglottic space, the latter extending submu- using a laryngeal mirror held against the soft
cosally from the vocal cord into the trachea. palate. Biopsies can be readily obtained under
The larynx is covered almost entirely by respi- general anaesthesia using a laryngoscope or
ratory mucosa with many seromucinous acces- operating microscope in malignant disease
sory glands in the submucosal tissues, particularly for staging purposes, or to identify an occult
around the epiglottis and the vestibule. In con- second primary. Endoscopy of the upper
trast, the vocal cords are covered instead by strat- aerodigestive tract is performed for neo-
ified squamous epithelium with only a minimum plasms, and to assess suitability for surgical
of connective tissue around the vocal ligaments resection.
in which few (if any) lymphatic channels are • Serological studies for Epstein–Barr virus
found. (EBV) antigens are useful in nasopharyngeal
Lymphovascular drainage: carcinoma both in assessing the effects of
Lymph vessels from the nasopharynx, oro- therapy and in detecting recurrence. Baseline
pharynx, hypopharynx, and the tonsils drain to function of the thyroid gland should be deter-
Level II nodes in the upper deep cervical chain mined prior to radical surgery or radiotherapy
either directly or via the retropharyngeal groups to the neck.
(see Fig. 20.1). Bilateral drainage is common • Ultrasonography has proved useful in evalua-
with nasopharyngeal, hypopharyngeal, and tion of lymphadenopathy and in guidance of
laryngeal lesions. needles for FNA and core needle biopsy.
• Contrast studies and direct visualization using
an oesophagoscope are performed in cases of
16.2 Clinical Presentation dysphagia to assess swallowing function prior
to treatment for malignant disease. Chest
Disease at any site in the pharynx can present radiographs may identify a concurrent bron-
with dysphagia (difficulty swallowing), dyspho- chial or lung lesion. CT and MRI scanning are
nia (change in voice quality), otalgia (earache), essential in planning surgery by indicating the
cranial nerve palsies, or cervical lymphadenopa- depth of the tumour and detecting other
thy. In the nasopharynx, tumours may evoke changes in the neck. CT has less motion arti-
deafness, middle ear effusion, epistaxis (nose fact and is good for bone detail, while MRI
bleeds), nasal obstruction, or palsy of cranial gives superior soft tissue contrast without den-
nerves (esp. II—VI, IX, X, XII), while those in tal amalgam artifact or exposure to ionizing
the oropharynx usually present with sore throat, radiation. CT is greatly aided by positron
dysphagia or earache. Hypopharyngeal masses emission tomography (PET CT), particularly
may cause dysphagia or signs of laryngeal in cases of metastatic disease in cervical
involvement, such as hoarseness or a whistling lymph nodes whereby a small and undetected
sound during inspiration (stridor). primary tumour might be identified.
• FNA is essential in assessing patients present- Laryngeal cysts may contain mucus or air.
ing with cervical lymphadenopathy, particu- Mucus-filled cysts are the commonest and usu-
larly when there is a high probability of ally represent mucous retention cysts of the
malignant disease. accessory glands in the supraglottic larynx, usu-
ally the ventricle or false cords. They are lined by
ductal epithelium. Laryngoceles and saccular
16.4 Pathological Conditions cysts are both due to obstruction of the saccule in
the laryngeal ventricle, the former containing air
16.4.1 Non-neoplastic Conditions and the latter mucus. Both are lined by respira-
tory epithelium.
Polyps and nodules: Mucosal polyps are uncom- Tonsillar enlargement: Tonsillitis is a com-
monly detected in the nasopharynx and orophar- mon disorder of childhood characterized by fre-
ynx and are likely to represent florid lymphoid quent episodes of sore throat, dysphagia, and
proliferations in association with adenoid or ton- otitis media. Although it tends to resolve with
sillar enlargement. age, persistent exacerbations and/or obstructive
Localized thickenings of the vocal cords usu- sleep apnoea may be treated by tonsillectomy
ally arise at the junction of the anterior and mid- with or without concomitant adenoidectomy.
dle one-thirds and may be unilateral or bilateral. Tonsils may be removed in adults for chronic ton-
They are due to trauma or voice abuse (hence the sillitis or if a neoplasm is suspected, particularly
alternative term singer’s node) but are also asso- if there is asymmetrical or unilateral enlarge-
ciated with smoking. Nodules are broadly based ment. Lymphoid follicles with well-formed ger-
sessile lesions that are usually bilateral and arise minal centres are seen; there may be fibrosis.
in females, while pedunculated polyps are unilat- Actinomyces colonies (sulphur granules) may be
eral and predominate in males. Myxoid degener- present within the crypts. Florid tonsillar follicu-
ation of Reinke’s space (Reinke’s oedema) lar hyperplasia may occur bilaterally in HIV
usually arises in older females, affects both cords infection.
along their length and is associated with smoking
and not voice abuse. All are characterized by
mild hyperplasia of the stratified squamous epi- 16.4.2 Neoplastic Conditions
thelium, accumulation of myxoid matrix in the
lamina propria, increased vascularity, and fibrin Benign tumours: Human Papillomavirus-
deposition. Similar lesions may arise in the associated squamous papillomas arise in the lar-
myxoedema of hypothyroidism. Contact granu- ynx either in children under 5 years of age with
loma or contact ulcer occurs posteriorly between equal gender mix (juvenile-onset laryngeal pap-
the vocal processes of the arytenoid cartilages illomatosis) or in adults over 20 years of age,
and consists of granulation tissue and ulcer mostly in males (adult-onset laryngeal papillo-
slough; voice abuse and recent laryngeal intuba- matosis). The lesions in juvenile-onset laryngeal
tion are common causes. Amyloid may present papillomatosis are multiple and affect the entire
with laryngeal nodules or diffuse submucosal laryngeal mucosa. They may require repeated
thickening but usually affects the ventricle or microdebrider de-bulking or laser microsurgery
false cords; only rarely is there associated sys- for airway obstruction; resolution usually occurs
temic amyloidosis. Post-radiation spindle cell in adolescence, but a small proportion of cases
nodules can mimic spindle cell carcinoma. persists and may even spread into the trachea and
Cysts: Tonsillar cysts arise in the oropharynx bronchi. Adult-onset laryngeal papillomas are
and hypopharynx. They represent accessory ton- fewer in number and relatively easily excised
sillar tissue and are composed of a crypt of strati- although multiple lesions are more likely to recur.
fied squamous epithelium distended by squames Histologically, hyperplastic stratified squamous epi-
and abundant lymphoid tissue in the wall. thelium covers well-formed fibrovascular papillary
cores, sometimes with abundant koilocyte-like laryngeal carcinoma arising against a background
cells. Cytological atypia is absent or minimal of papillomatosis. Epstein-Barr virus is so
although the epithelium often portrays florid strongly associated with nasopharyngeal carci-
basal cell hyperplasia. Development of malig- noma that it is almost a sine qua non, although
nancy is a rare event; these patients usually have the consumption of dietary nitrosamines and
been exposed to other factors known to be associ- smoking play a role.
ated with laryngeal squamous cell carcinoma Squamous epithelial dysplasia: An uncom-
(radiation, tobacco use). mon clinical problem on its own—most often
Nasopharyngeal (juvenile) angiofibroma: An seen adjacent to established tumours—although
uncommon lesion found only in teenage and the more hyperplastic and/or keratotic lesions
young adult males. Arises in the lateral wall of can present because of alterations in voice qual-
the nasal cavity posteriorly and grows into the ity. Strongly associated with tobacco smoking.
nasopharynx; presents with unilateral nasal Characterized histologically by hyperkeratosis,
obstruction and epistaxis. A well-circumscribed epithelial hyperplasia, and/or atrophy with vary-
mass, it has a fibrous cut surface and is character- ing grades of dysplasia. Development of invasive
ized by irregular branching dilated vascular chan- squamous cell carcinoma occurs more frequently
nels with partially muscularized walls. Plump with increasing degrees of cytological distur-
spindle cells and mast cells are present in the bance (less than 5% for non-dysplastic lesions
stroma. and mild/low-grade dysplasia; around 15% for
Other benign tumours that arise uncommonly high-grade dysplasia) but the effects of treatment
in the pharynx and larynx include salivary gland are difficult to evaluate. A number of classifica-
adenomas (e.g., pleomorphic adenoma), neural tion systems have been proposed each with
tumours (e.g., neurilemmoma, neurofibroma, slightly differing terminology but all suffer prob-
granular cell tumour), carcinoid tumours, and lems of reliability. Identifying high-grade dyspla-
paraganglioma (from paraganglia in the supra- sia highlights the considerable risk of synchronous
glottic or less often the subglottic larynx). or metachronous squamous cell carcinoma and
Malignant tumours: Tobacco and alcohol use often triggers further conservative surgery or
are the major risk factors for oropharyngeal, ablative therapy (e.g., by laser) to the lesion.
hypopharyngeal, and laryngeal cancers. Their Squamous cell carcinoma: Accounts for
effects are related to dose and duration of use; approximately 90% of primary malignant
together they have a multiplicative rather than tumours in the larynx, oropharynx, and hypo-
additive effect. Glottic carcinomas are strongly pharynx. Males are affected at least five times
linked to tobacco use and less associated with more often than females and most patients are
alcohol. Post-cricoid carcinoma is associated with aged between 40 and 60 years. In the oropharynx,
Patterson Brown-Kelly syndrome (Plummer– squamous cell carcinoma most commonly arises
Vinson syndrome—Northern European females, in the posterior one-third of the tongue and tonsil.
iron-deficiency anaemia, achlorhydria, and upper Tumours of the posterior tongue tend to be very
oesophageal web) and with alcohol. Approximately large at presentation; tonsillar tumours are often
10% of patients with Patterson Brown-Kelly syn- occult, presenting with nodal metastasis. Most
drome will develop post-cricoid carcinoma. cases of hypopharyngeal squamous cell carci-
Recent interest has focused on the role of viruses noma arise in the pyriform fossa (75%) or the
in pharyngeal and laryngeal malignancy. Human posterior pharyngeal wall (20%).
Papilloma viruses, particularly the so-called high- The commonest site of laryngeal squamous
risk types, HPV 16 and 18, are detected in an cell carcinoma is the glottis (75%), followed by
increasing proportion of tumours in patients who the supraglottic larynx (15–20%), while sub-
are “never- smokers,” especially tonsillar squa- glottic tumours account for less than 5% of
mous cell carcinoma (approximately 70%) and cases. Glottic tumours tend to be small and
localized, while supraglottic and subglottic while still small. In contrast, supraglottic and
tumours tend to be large with nodal metastasis hypopharyngeal tumours are often very large
in over 50% of cases. fungating masses with extensive submucosal
Histological and reportedly prognostic vari- spread at presentation. Lymph node metastasis
ants of squamous cell carcinoma include verru- is rare with glottic cancers but up to two-thirds
cous carcinoma, papillary squamous cell of hypopharyngeal tumours have bilateral nodal
carcinoma (better than usual type), spindle cell disease at presentation. The mucosal/submuco-
squamous cell carcinoma, adenoid squamous cell sal spread of the tumour affects the ability to
carcinoma (same prognosis), basaloid squamous achieve surgical clearance but the depth of inva-
cell carcinoma, and adenosquamous cell carci- sion is probably the most significant factor in
noma (worse prognosis). determining lymph node metastasis. Lymph
Nasopharyngeal carcinoma: Has a striking node metastasis at presentation halves the
geographic distribution, being commonest in chances of survival and doubles the risk of dis-
Southern China. Males are affected more often tant metastasis, although HPV-associated oro-
than females, 3:1. Incidence peaks between 40 pharyngeal squamous cell carcinoma might be
and 60 years, although occasionally adolescents considered the exception to this rule.
and young adults may be affected. The fossa of Extracapsular spread from affected nodes is also
Rosenmüller is the commonest site, although an indicator of limited prognosis, with increased
there may be no obvious mucosal abnormality on risk of recurrence in the neck and of distant
inspection. All are squamous cell carcinomas, spread. The effects of age, tobacco, and alcohol
there are a number of histological subtypes: kera- use influence patient’s general health; comor-
tinizing; non-keratinizing (the latter being subdi- bidity from cardiovascular and respiratory dis-
vided into differentiated and undifferentiated ease is a major adverse factor in survival.
patterns); and basaloid. Two-thirds of cases will Five-year survival with small glottic carcino-
have involved regional lymph nodes at mas is in excess of 80%, falling to less than 20%
presentation. for patients with large tumours.
Other malignant tumours in the pharynx and With nasopharyngeal carcinoma, female
larynx include sinonasal transitional cell carci- patients, those aged less than 40 years at presen-
noma, salivary gland-type adenocarcinoma tation and those with undifferentiated carcinoma
(especially adenoid cystic carcinoma, mucoepi- have improved survival, while patients with cra-
dermoid carcinoma), lymphoma (particularly in nial nerve involvement, keratinizing squamous
the tonsil; diffuse large B-cell type), malignant cell carcinoma, and positive nodes in the lower
melanoma, neuroendocrine carcinomas (larynx; neck do less well. Five-year survival with naso-
moderately and poorly differentiated), chondro- pharyngeal carcinoma is approximately 60%,
sarcoma (larynx), and metastatic tumours. dependent on the response to radiotherapy and
Prognosis: The precise site within the phar- chemotherapy.
ynx and larynx has a major impact on prognosis, Early stage oropharyngeal squamous cell car-
probably because of the mass effect and the den- cinomas respond well to surgical excision or
sity of lymphatic channels in the submucosal radiotherapy (at least 80% 5-year survival) but
tissues. Tumour biology has much influence as larger lesions are best treated with cisplatin-
well as the likely response to therapy eg in the based chemoradiotherapy, surgery being reserved
oropharynx, as evidenced by advanced HPV- for locoregional recurrence (up to 30% of cases).
associated squamous cell carcinomas in the Overall survival is more favourable in cases asso-
younger “never smoker” patients that respond ciated with Human Papilloma virus (80% 3-year
favourably to chemoradiotherapy. Glottic survival in HPV-positive cases compared to 60%
tumours usually affect the anterior portion of in HPV-negative cases). The development of a
the vocal cords, presenting with hoarseness second primary tumour is an ominous event.
16.5 Surgical Pathology becoming more widely used for glottic and
Specimens: Clinical Aspects supraglottic lesions. T3 glottic tumours with stri-
dor are often managed with total laryngectomy
16.5.1 Biopsy Specimens but radiotherapy is an option if disease is limited
and there is no stridor.
Incisional biopsies in the upper aerodigestive tract Total laryngectomy is the operation of choice
are usually directed at a specific lesion located in cases of radiotherapy failure, bulky T3 and T4
either by visualization or by CT or MR imaging. lesions, subglottic tumours, and where cord
“Blind” biopsies may be taken, particularly from immobility and post-radiation perichondritis
the fossa of Rosenmüller, base of the tongue, pyri- result in the so-called “crippled larynx”. The ipsi-
form fossa, and palatine tonsil, in the search for an lateral lobe of thyroid is included when there is a
occult primary carcinoma, although pre-operative likelihood of extralaryngeal spread in the sub-
PET CT is very effective in directing the surgeon. glottic region. The larynx will be included in
Superficial biopsies of tonsil may miss a small major resections of hypopharynx.
submucosal tumour; bilateral tonsillectomy is Partial laryngectomy procedures can be
preferred. Biopsies of pharyngeal and laryngeal divided into supraglottic laryngectomy and verti-
lesions are usually taken at endoscopy with punch cal hemilaryngectomy. Supraglottic laryngec-
or cup forceps. While usually sufficient, it is tomy removes the upper part of the larynx to the
sometimes difficult to make a histological diagno- level of the ventricle, preserving the glottis while
sis of malignancy as the specimens tend to be vertical hemilaryngectomy removes the vocal
superficial and submucosal tumours or the inva- cord and false cord on one side. These operations
sive components of well-differentiated squamous may be indicated for small volume T2 and T3
carcinoma may not be represented. tumours but usually require precise orientation
and stabilization by the clinical team (on slices of
cucumber or potato) prior to submission to the
16.5.2 Resection Specimens laboratory. They can be combined with neck dis-
section procedures. Intraoperative frozen section
In general, tonsillectomy specimens are only sub- analysis is essential to ensure clear margins in
mitted in cases of unilateral enlargement or these conservative procedures.
where malignancy is suspected; specimens from T1–T2 oropharyngeal cancers mucosa are
children for repeated infective episodes or airway resected endoscopically or using transoral robotic
obstruction rarely require histological evaluation. surgery (TORS) and may be relatively straight-
In cases of metastatic squamous cell carcinoma forward (e.g., tonsillectomy) or exhibit complex
to a cervical lymph node, the tonsils are removed anatomy requiring tissue reconstruction (e.g., in
when clinical and radiological evaluation fails to the soft palate). Pharyngectomy with laryngectomy
locate a primary lesion. or pharyngolaryngoesophagectomy are the com-
The type of surgical procedure for tumours of monest operations for T2–T4 hypopharyngeal
oropharynx, hypopharynx, and larynx depends on tumours, the defects being repaired by free jejunal
the precise location of the tumour, its T-stage, the transfer and gastric transposition, respectively. T1
presence of nodal disease, concurrent second pri- hypopharyngeal tumours can be resected endo-
mary lesions, and the health of the patient. The sur- scopically, especially lesions on the posterior wall.
gical clearance possible is limited by the anatomy Lesions of the pyriform fossa may require partial
and is in the region of a few millimeters at best. pharyngectomy with laryngectomy. The provision
In general, T1 and T2 glottic and supraglottic by the surgical team of illustrations of the resected
tumours without neck node metastasis can be tumour and its relationship to anatomical land-
managed either with radiotherapy or conservative marks and margins can greatly aid the pathologist
laser micro-surgery in the first instance. Laser in orientation and sampling—drawings are better
resection using the operating microscope is than photographs in this regard.
Radiotherapy with or without chemotherapy Distances to closest mucosal and deep surgi-
is the mainstay of nasopharyngeal carcinoma, cal margins (cm)
surgery being reserved for recurrent disease. • Mucosal abnormalities
Description:
Specimens: Laboratory • Tumour
Aspects Infiltrative/occult: usual type squamous cell
carcinoma
16.6.1 Biopsy Specimens • Bulky/fleshy: lymphoma
• Mucosa
Usually one fragment is present free-floating in White/thickened: in situ lesions
formalin although several specimens may be • Extent
taken simultaneously. Confined to tonsil or spread into adjacent soft
tissues
Measure:
Blocks for histology:
• Place in cassette; if very small wrap in moist The histology should represent the deepest extent
filter paper. of the tumour, the relationship to the surface,
• Mark for levels. mucosal and deep soft tissue margins, and
• Orientate the specimen at the embedding stage changes in adjacent tonsillar tissue.
to facilitate microscopic assessment. NB: If tumour is not seen macroscopically in
cases of proven nodal metastasis, submit in total.
At least one block of tumour per centimetre of
16.6.2 Resection Specimens maximum dimension
16.6.2.1 Tonsillectomy Specimens • Mucosal and deep surgical margins

Specimen: • Adjacent uninvolved tonsil
Most tonsillectomy specimens are submitted for
exclusion of neoplastic disease in cases of tonsil- Histopathology report:
lar asymmetry or cervical lymphadenopathy. Final reports of tonsillectomy specimens should
Specimens of oropharyngeal mucosa, posterior include details on:
tongue, or neck dissection may be attached.
• Specimen side
Procedure: • Type of tumour present
Squamous cell carcinoma, not otherwise spec-
Orientate the tonsil(s). ified (SCC NOS)
Ink the deep resection margins. SCC variants include basaloid, adenosqua-
Cut the tonsil into 4-mm-thick slices transversely. mous, spindle cell, verrucous
Adenocarcinoma (salivary gland types)
Measurements: Neuroendocrine carcinomas
Lymphoma
• Dimensions of tonsil (cm) and weight (g) • Grade of tumour assessed at the invasive front
• Dimensions of oropharyngeal mucosa, if • Cohesive or non-cohesive patterns (more
present metastasis with non-cohesive)
• Tumour • Extent of local spread
Length × width (cm) • Distance of tumour from the nearest mucosal
Maximum depth (cm) margin
• Distance of the tumour from the nearest deep Cut the larynx into 4-mm-thick slices in the coro-
margin nal plane (i.e., in the plane of the vocal cords)
• Presence of intravascular and perineural spread to provide “rings” of tissue, working from the
• Presence or absence of HPV, e.g., p16 immu- lowermost aspect to the base of the epiglottis.
nohistochemistry or ideally by in situ This is easiest with a band saw or other heavy-
hybridisation duty slicing device but modern rapid decalci-
fying systems permit the use of hand-held
If other specimens are attached as an in- blades in “real time”.
continuity dissection (e.g., oropharyngeal or lin- Slice the remaining supraglottic portion parasagi-
gual mucosa, neck dissection), these can be cut tally with a knife to define precisely the upper
separately in the usual fashion. aspect of supraglottic lesions.
16.6.2.2 Laryngectomy Specimens Measurements:

Specimen:
Most laryngectomy procedures are for neoplastic • Length of the larynx superiorly from to the
disease in the larynx, although some will be required inferior border of the cricoid (cm)
for hypopharyngeal tumours or because of post-radi- • Length of trachea (cm)
ation dysfunction. Specimens of neck dissection, • Dimensions (cm) of mucosal defects and other
hypopharyngeal resection, thyroidectomy, tracheos- specimens
tomy site, or skin from neck may be attached. • Tumour
Partial laryngectomy specimens are handled Length × width (cm)
in a similar fashion but require orientation by the Maximum depth (from reconstructed mucosal
surgeon; the smaller the specimen, the more criti- surface (cm))
cal the orientation. Distances to closest mucosal and deep surgi-
cal margins (cm)
Procedure: • Mucosal abnormalities
Paint a vertical line of ink along one side of the Description:

larynx from epiglottis to tracheal limit to aid
orientation and reconstruction after slicing. • Tumour
Open the larynx vertically from behind with scis- Plaque-like/ulcerated/fungating: usual type SCC
sors and identify site of tumour. Warty: well-differentiated SCC, verrucous
Ink only the critical resection margins. This carcinoma
depends on the location and spread of the Polypoid: spindle cell SCC
tumour, e.g., base of tongue and perihyoid soft • Mucosa
tissues for anterior supraglottic lesions, lateral White/thickened: in situ lesions
pharyngeal wall for lateral supraglottic and • Extent
pyriform fossa tumours, post-cricoid region Confined to larynx or spread through/between
for large glottic or post-cricoid tumours, lat- cartilages
eral perithyroid region for subglottic tumours. • Other
Dissect off the hyoid bone, strap muscles, thyroid, Tracheostomy, neck dissection, thyroid gland
neck dissection, etc. Look out for extralaryn-
geal spread of tumour. Supraglottic tumours Blocks for histology:
often spread out of the larynx via the thyrohy- The histology should represent the deepest
oid membrane and subglottic tumours via the extent of the tumour, the relationship to the
cricothyroid membrane. Tumour will permeate laryngeal cartilages, mucosal and deep soft tis-
directly through ossified cartilages more read- sue margins, and changes in adjacent tissues
ily than through cartilage that is not ossified. (Fig. 16.4).
a
Epiglottis
Hyoid bone
Outline of supraglottic carcinoma
spreading into pre-epiglottlic and subglottic spaces
Pre-epiglottic space
a b
Thyroid cartilage
Cricoid
b Extralaryngeal muscles
Per-commissural
spread to left cord
Extralaryngeal involvement
Left thyroid lamina
Closest laryngeal mucosal limit

in right pyriform fossa
Left arytenoid cartilage
Glottis
Midline
Cricoid cartilage
Paraglottic space
involvement
Section a−b
Fig. 16.4 Laryngectomy for supraglottic carcinoma with men. (a) View from right lateral aspect; (b) slice through
transglottic and extralaryngeal spread. Suggested siting vocal cords viewed from above (Reproduced, with per-
and orientation of tissue blocks for laryngectomy speci- mission, from Allen and Cameron (2013))
• At least one block of tumour per centimetre of Histopathology report:

maximum dimension Final reports of laryngectomy specimens should
• Mucosal and deep surgical margins include details on:
• Both vocal cords (individually identified) even
if normal • Specimen type
• Samples of other lesions, e.g., mucosal white • Type of tumour present
areas Squamous cell carcinoma NOS
• Tracheostomy site (if present) SCC variants include basaloid, adenosqua-
• Perilaryngeal lymph nodes not part of the mous, spindle cell, verrucous
neck dissection Adenocarcinoma (salivary gland types)
Neuroendocrine carcinomas Maximum depth (from reconstructed mucosal

• Grade of tumour assessed at the invasive front surface (cm))
• Cohesive or non-cohesive patterns—(more Distances to closest mucosal and deep surgi-
metastasis with non-cohesive) cal margins (cm)
• Extent of local spread • Mucosal abnormalities
• Distance of tumour from the nearest mucosal
margin Description:
• Distance of the tumour from the nearest deep
margin • Tumour
• Intravascular and/or perineural spread Plaque-like/ulcerated/fungating: usual type
• Involvement of perilaryngeal lymph nodes SCC
• Other pathology such as dysplasia or radiation Warty: well-differentiated SCC, verrucous
injury. carcinoma
Polypoid: spindle cell SCC
If other specimens are attached as an in- • Mucosa
continuity dissection (e.g., neck dissection, thy- White/thickened: in situ lesions
roid gland, oesophagus, skin), these can be cut • Extent
separately in the usual fashion. Confined to pharynx or spread to adjacent
structures
16.6.2.3 Pharyngectomy Specimens • Other
Specimen: Neck dissection, laryngectomy, oesophagec-
Most pharyngectomy procedures are for neo- tomy, thyroid gland
plastic disease in the pharynx, although some
will be required for large laryngeal tumours. Blocks for histology:
Specimens of neck dissection, laryngectomy,
oesophagectomy, thyroidectomy, tracheostomy The histology should represent the deepest extent
site or skin from neck may be attached. Smaller of the tumour, the relationship to the adjacent
tumours removed by laser will already have structures or organs, mucosal and deep soft
been transected by the surgeon—cutting tissue margins, and changes in adjacent
through tumour allows precise assessment of tissues.
the depth—and will arrive in at least two pieces. At least one block of tumour per centimetre of
maximum dimension
Procedure: Mucosal and deep surgical margins
Samples of other lesions, e.g., mucosal white
If required, open the pharynx longitudinally with areas
scissors and identify site of tumour.
Ink the external and mucosal resection margins. Histopathology report:
Slice into 4-mm-thick slices transversely. Final reports of pharyngectomy specimens should
include details on:
Measurements:
• Specimen type
• Length and width of specimen (cm) • Type of tumour present
• Maximum thickness (cm) Squamous cell carcinoma NOS
• Dimensions (cm) of mucosal defects and other SCC variants include basaloid, adenosqua-
specimens mous, spindle cell, verrucous
• Tumour Adenocarcinoma (salivary gland types)
Length × width (cm) • Grade of tumour assessed at the invasive front
• Cohesive or non-cohesive patterns (more Extent of local tumour spread pharynx: TNM 8
metastasis with non-cohesive) for carcinoma
• Extent of local spread Oro-(hypopharynx): oropharyngeal carcino-
• Distance of tumour from the nearest mucosal mas are staged differently under TNM 8
margin according to whether they are HPV-related ie
• Distance of the tumour from the nearest deep negative or positive for p16 immunohisto-
margin chemistry (p16 negative carcinoma staging
• Intravascular and/or perineural spread given below).
• Involvement of peripharyngeal lymph nodes
• Other pathology such as dysplasia or radiation pT1 Tumour ≤2 cm in greatest dimension
(hypopharynx—and limited to one subsite)
injury
pT2 2 cm < tumour ≤4 cm in greatest dimension
(hypopharynx—and more than one subsite)
If other specimens are attached as an in- pT3 Tumour >4 cm in greatest dimension
continuity dissection (e.g., neck dissection, thy- (hypopharynx—or with fixation of hemilarynx)
roid gland, esophagus, skin), these can be cut pT4 Tumour invades adjacent structures, e.g.,
separately in the usual fashion. pterygoid muscles, mandible, hard palate, deep
muscle of tongue, larynx (hypopharynx—
Extent of local tumour spread larynx: TNM 8
thyroid/cricoid cartilage, carotid artery, soft
for carcinoma tissues of neck, pre-vertebral fascia/muscles,
thyroid and/or oesophagus)
pT1a Tumour confined to one subsitea, normal cord Nasopharynx
mobility
pT2a Tumour invades more than one subsitea, pT1 Tumour confined to nasopharynx, oropharynx,
impaired cord mobility and nasal cavity
pT3 Tumour confined to larynx, fixation of one or pT2 Tumour into parapharyngeal space
two cords
pT3 Tumour into bone of skull base and/or nasal
pT4 Tumour through thyroid cartilage and/or sinuses
extends beyond larynx to, e.g., trachea, soft
pT4 Intracranial extension, cranial nerves,
tissues of neck, thyroid, oesophagus,
hypopharynx, orbit, parotid gland, lateral
prevertebral space, mediastinal structures
pterygoid muscle
a
Exact details depend on whether tumour site is supraglot-
tic, glottic, or subglottic
Regional lymph nodes: cervical—lymphade-
Regional lymph nodes: cervical—lymphadenectomy is selective or modified/radical includ-
nectomy is selective or modified/radical including 10 or 15 or more nodes, respectively
ing 10 or 15 or more nodes, respectively Oro- and hypopharynx
pN0 No regional node metastasis pN0 No regional node metastasis

pN1 Metastasis in an ipsilateral single node ≤3 cm pN1 Metastasis in an ipsilateral single node ≤3 cm
without extranodal extension without extranodal extension
pN2 Metastasis in pN2 Metastasis in:
(a) Ipsilateral single node ≤3 cm with (a) Ipsilateral single node ≤3 cm with
extranodal extension, or, >3–6 cm without extranodal extension, or, >3–6 cm without
extranodal extension extranodal extension
(b) Ipsilateral multiple nodes ≤6 cm without (b) Ipsilateral multiple nodes ≤6 cm without
extranodal extension extranodal extension
(c) Bilateral or contralateral node(s) ≤6 cm (c) Bilateral or contralateral node(s) ≤6 cm
without extranodal extension without extranodal extension
pN3 (a) Metastasis in a lymph node >6 cm, or, pN3 (a) Metastasis in a lymph node >6 cm, or,
(b) Extranodal extension with any of; >3 cm, (b) Extranodal extension with any of; >3 cm,
multiple ipsilateral, contralateral, bilateral multiple ipsilateral, contralateral, bilateral
Nasopharynx Multidisciplinary Guidelines. J Laryngol Otol.

2016;130(Suppl. S2):S59–65.
pN1 Unilateral cervical or uni-/bilateral Jones TM, De M, Foran B, Harrington K, Mortimer
retropharyngeal nodal metastasis ≤6 cm, above S. Laryngeal cancer. UK National Multidisciplinary
cricoid cartilage Guidelines. J Laryngol Otol. 2016;130(Suppl. S2):S75–82.
Mehanna H, Evans M, Beasley M, et al. Oropharyngeal
pN2 Bilateral cervical nodal metastasis ≤6 cm,
cancer. UK National Multidisciplinary Guidelines.
above cricoid cartilage
J Laryngol Otol. 2016;130(Suppl. S2):S90–6.
pN3 Metastasis in cervical node(s) >6 cm, or Pracy P, Loughran S, Good J, Parmar S, Goranova R.
extension below cricoid cartilage Hypopharyngeal cancer. UK National Multidisciplinary
Guidelines. J Laryngol Otol. 2016;130(Suppl. S2):
S104–10.
Shah JP, Patel SG. Head and neck surgery and oncology.
Bibliography 3rd ed. Edinburgh: Mosby; 2003.
Simo R, Robinson M, Lei M, Sibtain A, Hickey S.
Allen DC. Histopathology reporting. Guidelines for surgi- Nasopharyngeal cancer. UK National Multidisciplinary
cal cancer. 3rd ed. London: Springer; 2013. Guidelines. J Laryngol Otol. 2016;130(Suppl. S2):
Allen DC, Cameron RI. Histopathology specimens: S97–S103.
clinical, pathological and laboratory aspects. 2nd ed. The Royal College of Pathologists. Dataset for histopa-
Berlin: Springer; 2013. thology reporting of nodal excisions and neck dis-
Barnest L, Eveson J, Reichart P, Sidransky D. WHO classi- section specimens associated with head and neck
fication of tumours. Pathology and genetics. Tumours carcinomas; November 2013. https://www.rcpath.
of the head and neck. Lyon: IARC Press; 2005. org/profession/publications/cancer-datasets.html.
Brierley JD, Gospodarowicz MK, Wittekind C, editors. Accessed July 2016.
TNM classification of malignant tumours. 8th ed. The Royal College of Pathologists. Tissue pathways for
Oxford: Wiley-Blackwell; 2017. head and neck pathology; January 2016. https://www.
Gnepp DR, editor. Diagnostic surgical pathology of the rcpath.org/profession/publications/cancer-datasets.
head and neck. 2nd ed. Philadelphia: WB Saunders; html. Accessed July 2016.
2009. Watkinson JC, Gilbert RW, editors. Stell & Maran’s text-
Helliwell TR, Giles TE. Pathological aspects of the book of head and neck surgery and oncology. 5th ed.
assessment of head and neck cancer. UK National London: Hodder Arnold; 2012.
Salivary Glands
17
by John J. Marley
17.1 Anatomy face at the stylomastoid foramen and running

forward to the anterior surface on the outer
There are three paired major salivary glands—the aspect of the mandible, dividing into five termi-
parotid gland, the submandibular gland, and the nal branches within the gland. The “Stenson’s
sublingual gland—as well as a multitude of duct” runs anteriorly across masseter to pierce
minor salivary glands (see Fig. 20.1). buccinator and open opposite the upper second
The parotid gland is the largest, weighing molar tooth. Accessory parotid gland tissue may
between 15 and 30 g. It is roughly pyramidal in be present on the masseter between the duct and
shape, lying in front of and below the ear in the the zygomatic arch. The gland contains serous
space between anterior aspect of sternocleido- acinar components divided into lobules and
mastoid and the ramus of the mandible, project- varying amounts of fat with a few mucinous or
ing anteriorly onto the external surface of the sebaceous elements.
masseter muscle for a variable distance. The lat- The submandibular gland weighs between 7
eral surface lies just below the skin and is roughly and 15 g and occupies most of the submandibular
triangular in shape with its base superiorly close triangle. It straddles the posterior border of mylo-
to the zygomatic arch and its apex (or tail) in the hyoid; the larger superficial lobe lies just deep to
upper part of the neck. Medially, the gland the skin near the angle of the mandible, while the
extends into the infratemporal fossa, where it is smaller deep lobe lies inside the mouth between
closely related to the pharynx, the carotid sheath, the tongue, mandible, and the sublingual gland.
and the styloid complex. It is traversed by the Posteromedially it is separated from the pharynx
facial nerve, entering on the posteromedial sur- by the styloid complex, glossopharyngeal nerve,
and hypoglossal nerve. The “Wharton’s duct”
begins as tiny branches in the superficial lobe and
runs posteriorly, emerging from the anterior
S.S. Napier (*)
Histopathology Laboratory, Institute of Pathology, aspect of the deep lobe. It runs through the sub-
Royal Hospitals, Belfast Health and Social Care lingual space to open into the anterior floor of
Trust, Belfast, UK mouth at the sublingual papilla. The lobules of
the submandibular gland are populated mostly by
J.J. Marley serous cells with lesser mucinous elements.
Department of Oral Surgery, School of Dentistry,
The sublingual gland is the smallest of the
Royal Hospitals, Belfast Health and Social Care
Trust, Belfast, UK major salivary glands and weighs between 1.5
e-mail: john.marley@belfasttrust.hscni.net and 4 g. It lies in the floor of mouth between the

mucosa, mylohyoid, the mandible, and its fellow Enlargement can affect both major and minor
on the other side. Numerous tiny ducts (“Rivinus’ glands and may be episodic or persistent. In the
ducts”) drain directly into the floor of the mouth major glands, episodic swellings, worse at meal-
but there may also be a larger common sublingual times and accompanied by pain, are due to
duct (“Bartholin’s duct”) that drains into the sub- obstruction of outflow by intraluminal sialoliths
mandibular duct near its opening. It is predomi- or mucous plugs. Symptoms and signs of ascend-
nantly mucinous in type with lesser serous ing infection by pyogenic bacteria may also be
elements. present. Extrinsic pressure on the duct system,
Hundreds of minor salivary glands are dis- e.g., by tumours, can present with obstruction.
persed in the submucosal tissues throughout the The submandibular gland is most often affected
mouth and oropharynx. They are not found in the by obstruction, the parotid gland less so.
anterior hard palate or the attached gingiva except Persistent discrete swellings in the major
in the retromolar regions of the mandible. Each glands are likely to represent a primary salivary
minor gland measures between 1 and 5 mm in gland neoplasm or lymph node disease. Most pri-
diameter and they are usually not palpable clini- mary major gland tumours arise in the parotid
cally except in the lips. Most are innominate but gland and over 80% are benign lesions. From a
for two sets of glands in the tongue, namely the surgical standpoint, the parotid gland is divided
glands of von Ebner around the circumvallate into superficial and deep lobes by the plane of the
papillae and the glands of Blandin and Nunn in facial nerve as it traverses the gland. Most
the ventral surface near the tip. Most minor tumours arise in the superficial lobe and will
glands are mucinous in type, although the glands present as facial swellings, while deep lobe
of von Ebner are serous. lesions may present medially as parapharyngeal
Similar glands are located in the nasal mucosa, swellings or as a diffuse enlargement of the
nasopharynx, larynx, and hypopharynx but are parotid region.
referred to as “accessory glands” rather than sali- Around 10% of salivary gland neoplasms arise
vary glands. in the submandibular gland around half of which
Lymphovascular drainage: will be malignant; sublingual gland tumours are
Lymph nodes are found in intraglandular, very rare and almost always malignant. Motor or
intracapsular, and extraglandular locations in the sensory nerve dysfunction or pain are sinister
parotid region. They drain the tissues of the scalp findings when observed along with a discrete
and lateral face and ultimately empty into the swelling in a major salivary gland and often sig-
lymph nodes of the deep cervical chain. Small nify malignancy. Metastasis to the major salivary
numbers of lymph nodes are located close to the glands, usually the parotid, occurs most often in
submandibular gland but intraglandular and patients with known disease elsewhere within the
intracapsular nodes are rare. Tissues of the lower head and neck region but occasionally may repre-
lip, tongue, and anterior floor of mouth (includ- sent the first presentation of an unidentified dis-
ing the sublingual gland) drain through these tant primary tumour.
nodes, communicating with those elsewhere in Bilateral or multi-gland diffuse swellings
the deep cervical chain (see Fig. 20.1). point to a systemic process such as sarcoidosis,
sialosis, or autoimmune phenomena (myoepithe-
lial sialadenitis or HIV).
17.2 Clinical Presentation Minor salivary gland swellings present as sub-
mucosal masses. Cystic lesions in young patients
Disease affecting the salivary glands will present located toward the front of the mouth, particu-
with enlargement (that may or may not be pain- larly in the lower lip, will be mucous extravasa-
ful) or as a consequence of dysfunction, usually tion cysts; those cystic lesions toward the back of
hypofunction. the mouth in older patients are likely to represent
17 Salivary Glands 195
retention cysts, although some will turn out to be • Open biopsies of major glands carry risks of
cystic tumours. Neoplasms of the minor salivary nerve damage and salivary fistula formation.
glands have an overall benign-to-malignant ratio Core needle biopsies can provide a preopera-
of 1:1 but tumours of the palate and upper lip are tive diagnosis but suffer the same sampling
much more likely to be benign than malignant, problems as FNA. Incisional biopsies of minor
while the converse is true of tumours in the salivary gland lesions are rarely performed
tongue, floor of mouth, and retromolar pad. because most of the lesions are relatively
Hypofunction usually manifests as xerosto- small and are either entirely innocent lesions
mia, although some of those who complain of a or of low-grade malignancy. In either case,
dry mouth will have perceived rather than real optimum results are provided by complete but
salivary dysfunction. Common causes of xero- non-mutilating excision at the first attempt.
stomia include drug effects, post-radiotherapy Diagnostic biopsies of large malignant minor
changes, and autoimmune disease, and, less gland lesions can assist the planning of a more
often, endocrine disturbances. radical excision by providing an estimate of
tumour type and/or grade; they are best taken
from the centre of the lesion rather than at the
17.3 Clinical Investigations periphery where future excision margins
might be sited.
• Ultrasonography can provide useful information
about swellings in the major salivary glands, par-
ticularly with cystic lesions. Plain radiography 17.4 Pathological Conditions
may identify sialoliths while sialography with
injection of contrast media will outline the duct 17.4.1 Non-neoplastic Conditions
system. The relationship of tumour and the adja-
cent tissues can be evaluated with CT scanning Cysts: Common in minor glands, particularly in
(sometimes combined with PET) and MR imag- the lower lip. “Mucocele” is a nonspecific clini-
ing, the differential weighting of MR images cal term used to mean “a localized collection of
often allowing better visualization of the mucin” and may represent a mucous extravasa-
tumour–tissue interface while PET helps to iden- tion cyst, mucous retention cyst, or cystic tumour.
tify tumour elsewhere if a metastasis is sus- Mucous extravasation cyst arises when an excre-
pected. Assessment of the status of the neck tory duct is ruptured; saliva escapes into the tis-
nodes can be performed at the same time. sues, where it evokes a low-grade inflammatory
• Stimulated parotid salivary flow rates are reaction and is walled off by granulation tissue.
assessed in cases of xerostomia and can indi- May arise as a larger lesion from the sublingual
cate the presence of organic disease. gland when the term “ranula” refers to its resem-
Serological investigations or PCR can assist blance to the belly of a frog. Mucous retention
with the diagnosis of viral infections and with cyst occurs when an excretory duct becomes
diseases of autoimmune pathogenesis. obstructed but is not ruptured. The duct becomes
• Fine needle aspiration cytology (FNA) has distended and forms the wall of the cyst so an
greatly facilitated the management of patients epithelial lining is present.
with major salivary gland swellings. Definitive Salivary duct obstruction: Due to calculus for-
diagnosis of primary salivary gland disease mation, duct stricture, mucous plugs, or external
can be difficult, but FNA can be used to iden- pressure on the duct system, and is often accom-
tify cases where open biopsy might not be panied by ascending bacterial sialadenitis.
advantageous, e.g., if a metastatic deposit of Calculi represent foci of dystrophic calcification
squamous cell carcinoma in a juxtasalivary occurring in the duct system. Occurring in the
lymph node were suspected. submandibular gland in 80% of cases, they may
be intraglandular or extraglandular but lie in the phoma from the outset. Overall 10% develop
duct system. The rest are found in the minor lymphoma of major salivary glands; the risk is
glands of the upper lip and in the parotid, usually greater with primary Sjögren’s syndrome.
outside the main body of the gland. Duct stric-
ture, mucous plugs, and external pressure on the
duct can be difficult to locate without sialogra- 17.4.2 Neoplastic Conditions
phy. The changes are often mild; the severity of
the obstructive symptoms is inversely propor- Benign tumours are common.
tional to the degree of tissue destruction. If the Pleomorphic salivary adenoma: Is the com-
gland is smaller than normal, it will be fibrotic monest tumour with peak prevalence in the sec-
and contain a stone. Histologically, there is ductal ond and third decades but occurs in all ages even
dilation, marked periductal and interlobular in the new-born. Common in the parotid, palate,
fibrosis, focal acinar atrophy, and a focal moder- and upper lip. Histologically, “pleomorphic”
ate chronic inflammatory cell infiltrate. describes the architecture, not the nuclear mor-
Respiratory metaplasia is seen in the duct sys- phology. There is an incomplete capsule, a mix-
tem; there may be squamous metaplasia of the ture of ducts, sheets of epithelium, and myxoid
epithelium in contact with the stone. Gross fibro- matrix that may in areas resemble cartilage.
sis and atrophy also raise the possibility of IgG4- Locally, recurrence may follow incomplete exci-
related disease, especially in the absence of a sion, especially if “shelled out” or if the capsule
stone. If the gland is relatively unremarkable ruptures. Malignancy can occur in a pleomorphic
macroscopically, there will be no stone and the adenoma, but usually only after many years. Rare
microscopic changes will be subtle. examples can metastasize to lymph nodes, lung,
Sjögren’s syndrome: A clinical condition liver, or bone. This so-called (benign) metastasiz-
characterized by xerostomia and xerophthalmia. ing pleomorphic adenoma resembles the usual
Secondary Sjögren’s syndrome refers to the variant, although there is usually a history of pre-
changes arising in association with a systemic vious surgery suggesting vascular implantation
connective tissue disease (such as rheumatoid as a major factor.
arthritis), while in primary Sjögren’s syndrome Warthin’s tumour: Occurs at the lower pole of
there is no connective tissue disease. Mostly parotid and may be bilateral. More often seen in
females (9 F:M), peak 30–40 years. Histologically males and usually older patients; never in a minor
there is marked lymphocytic infiltration of the gland and rare in submandibular gland. Probably
major glands (T-cells mostly with occasional represents a form of epithelial proliferation of
B-cells) causing acinar destruction. Proliferation entrapped epithelial elements in a lymph node.
of the ductal cells gives the ducts a solid appear- Histologically, very distinctive with multiple
ance (known as epithelial–myoepithelial papillary projections of altered ductal epithelium
islands). There is little fibrosis. These appear- into cystic spaces containing debris. Many lym-
ances are called “myoepithelial sialadenitis” phocytes in stroma with germinal centres, hence
(MESA) or “benign lymphoepithelial lesion.” the older term “papillary cystadenoma lympho-
Seen best in the parotid, but submandibular matosum.” Benign; behaves like a lymph node in
gland also affected. Minor glands show similar that other tumours may metastasize to a Warthin’s
features, but usually to a lesser degree—myoepi- tumour.
thelial islands are not encountered in minor A number of other benign tumours can arise in
glands. There may be blastic transformation of the salivary glands. The term “monomorphic ade-
the B-cells beginning around the ducts and grad- noma” has been abandoned. All are uncommon
ually extending outward into the parenchyma, and include basal cell adenoma, canalicular ade-
giving rise to a slowly progressive low-grade noma, myoepithelioma (a variant of pleomorphic
non-Hodgkin’s lymphoma (MALToma). Some adenoma), oncocytoma, and a variety of ductal
authorities consider MESA a low-grade lym- papillomas and sebaceous adenomas.
Malignant tumours: Are relatively uncom- 10% metastasize, usually after multiple recur-
mon. There are many different types; most are rences or if cytologically aggressive and usu-
low-grade, although some are aggressive malig- ally to nodes.
nancies that metastasize widely. Males and Acinic cell carcinoma: Uncommon in minor
females are affected equally. There is a wide age glands; 95% occur in the parotid gland.
range, peak prevalence in 40–50 years, but Histologically, lobulated masses of benign-
tumours in elderly patients are often high-grade looking epithelial cells with abundant cytoplasm
cancers. Most patients have no known risk fac- resembling the serous cells of salivary gland.
tors, although increased incidence of salivary Populations of other cells are present in varying
gland malignancy can follow head and neck irra- proportions, e.g., clear cells, cells with vacuo-
diation or a long-standing untreated/recurrent lated cytoplasm, ductal cells, and/or cells of non-
benign tumour (e.g., pleomorphic adenoma). specific glandular type. Low-grade malignancy
Infection by Epstein–Barr virus is linked with with nodal metastasis late (especially after recur-
lymphoepithelial carcinoma in the Inuit. rences rather than at presentation) in 10%.
Adenoid cystic carcinoma: Common in the Polymorphous low-grade adenocarcinoma:
parotid gland and in minor glands, especially in Only found in minor salivary glands.
the palate. Clinically, it is often very subtle. Characterized by variable morphological patterns
Minor gland lesions are soft diffuse and purple, (papillae, cysts, solid areas, cribriform areas,
mimicking a dental abscess, while parotid tubular/ductal areas), cytological uniformity
lesions produce unusual signs like pain, facial (cells often have clear nuclei) and indolent behav-
paralysis, or trismus before there is a palpable ior. Perineural and perivascular whorling is a
mass. Histologically, it has a classical “Swiss characteristic feature. Can recur locally if incom-
cheese” appearance with cribriform clusters of pletely excised; spread to regional nodes in 10%.
small darkly staining epithelial cells without Carcinoma ex-pleomorphic adenoma:
much nuclear pleomorphism, mitotic activity, or Malignant change may occur in pleomorphic
necrosis. Up to half display perineural invasion, adenoma but usually only in long-standing
but this is only significant if it extends beyond lesions in major glands. However, it is increas-
the invasive front. Local spread is often exten- ingly recognized in minor glands, sometimes
sive. Because the tumour evokes no response without the long history. Rapid enlargement of a
from the tissues through which it infiltrates, it long-standing lump, pain, or VII nerve palsy and
extends for considerable distances beyond what fixation to skin or deeper structures are common
is identified clinically as the edge. Survival for findings. Histologically, the commonest finding
10 years is common, but patients are often trou- is a poorly differentiated adenocarcinoma over-
bled by persistent local disease. Metastasis is running an old pleomorphic adenoma. Often,
via haematogenous routes (e.g., to lung) rather there is a mixture of different salivary type carci-
than to nodes. nomas and even squamous cell carcinoma.
Mucoepidermoid carcinoma: Common in Survival is related to the type of the carcinoma-
minor glands, especially in the palate, and the tous component and the extent of invasion beyond
parotid gland. It is the commonest salivary the capsule of the pleomorphic adenoma, so that
tumour in children. Histologically, a mixture of the prognosis for some patients with minimally
goblet cells, squamous cells, and other popula- invasive and/or histologically low-grade lesions
tions such as intermediate cells or clear cells; might not be so bad.
may be solid, cystic, or both. Histology is little Other salivary gland malignancies include
guide to prognosis, although tumours with a epithelial-myoepithelial carcinoma, basal cell
poor prognosis tend to be large, solid rather adenocarcinoma, hyalinizing clear cell carci-
than cystic, predominantly epidermoid in type, noma, mammary secretory analogue carcinoma
are infiltrative and cytologically pleomorphic and MALT lymphoma (low-grade), myoepithe-
with necrosis and many mitotic figures. Only lial carcinoma (intermediate grade), salivary duct
carcinoma, adenocarcinoma NOS, small cell 17.5.2 Resection Specimens

undifferentiated (neuroendocrine) carcinoma,
lymphoepithelial carcinoma, and primary squa- Surgical resections of parotid gland are classi-
mous cell carcinoma (high-grade). Metastatic fied according to their relationship with the
tumours are not rare in the parotid region; nodal facial nerve. Superficial parotidectomy is per-
deposits usually derive from squamous cell carci- formed for tumours lying lateral to the plane of
noma or malignant melanoma in the scalp or the facial nerve as it courses through the gland.
facial skin, while intraparenchymal deposits usu- If the tumour lies in contact with but does not
ally represent haematogenous dissemination of infiltrate branches of the facial nerve, it is dis-
tumour from sites outside the head and neck. sected clear with preservation of the nerve. If
infiltrated by malignant tumour, the nerve may
be sacrificed and repaired with a graft from the
17.5 Surgical Pathology nearby greater auricular nerve if a curative
Specimens: Clinical Aspects (rather than palliative) procedure is anticipated.
Extracapsular resection can be performed when
17.5.1 Biopsy Specimens the tumour is small or lies distant to the nerve.
The surgeon dissects external to the tumour cap-
Salivary cysts are generally dissected intact from sule with preservation of the nerve; although
the surrounding tissues together with adjacent conservative of glandular tissue, there is a risk
minor salivary glands that may have been dam- of capsular rupture. Total parotidectomy proce-
aged by the procedure. Cyst rupture is only prob- dures are divided into nerve-preserving and
lematic if the lesion is a cystic tumour. Ranulas nerve-sacrificing types. Total parotidectomy
are usually marsupialized, although recurrent or with nerve preservation is performed for deep
“plunging” types are treated by excision in- lobe tumours that can be dissected clear of the
continuity with the sublingual gland. nerve. The superficial lobe is removed initially
Open biopsies of minor salivary gland tumours to identify, dissect, and preserve the nerve
are uncommon because precise interpretation of before removing the deep lobe. Total parotidec-
limited samples of large neoplasms is difficult tomy with nerve sacrifice (radical parotidec-
and most tumour types can be managed with tomy) is warranted for curative excision of
clearance by local excision. Core needle biopsies clinically malignant tumours of either lobe that
of parotid gland or, less frequently, submandibu- infiltrate the nerve. Nerve grafting may be per-
lar gland tumours may be necessary for deep lobe formed if the proximal and distal stumps are
tumours where malignancy is suspected but FNA free of tumour. Occasionally access to a deep
inconclusive. lobe tumour is obtained via a median mandibu-
Where Sjögren’s syndrome is suspected, sam- lotomy procedure (splitting the mandible and
pling of minor salivary glands is preferable to reflecting the ipsilateral hemimandible laterally
open biopsy of the parotid or submandibular to expose the parapharyngeal space); the super-
glands, although, given the positive and negative ficial lobe is conserved.
predictive values of serological tests and the The submandibular and sublingual glands are
often nonspecific nature of the changes in the removed in their entirety. If tumour is encoun-
minor salivary glands, the value of this procedure tered in the deep lobe of the submandibular
is generally to exclude other abnormalities, such gland, the dissection can be continued anteriorly
as haemochromatosis, amyloidosis, or a granulo- into the floor of mouth, including the sublingual
matous disorder. When focal lymphocytic sialad- gland and all of Wharton’s duct, if required. En
enititis is identified, categorization of the bloc resection of either gland with adjacent tis-
lymphoid subpopulations is regarded by some to sues as required is performed for widely infiltrat-
assist prediction of increased risk of lymphoma. ing malignant tumours.
17.6 Surgical Pathology dectomy specimens usually resemble an isosce-

Specimens: Laboratory les triangle; the smoothest surface will represent
Aspects the superficial aspect and the shortest side, the
superior aspect of the gland. The markings of
17.6.1 Small Biopsy Specimens the mandibular ramus and/or mastoid process
of Minor Glands may be present. If separate from the superficial
portion, the deep lobe may be impossible to ori-
Excisions of mucoceles: entate. The superficial lobe of the submandibu-
A single tissue nodule, free-floating in fixative, lar gland has a smooth capsular surface, while
non-orientated. Usually less than 20 mm in diam- the irregular edge and the indentation of mylo-
eter and may include overlying mucosa. Adjacent hyoid identify the deep aspect.
minor glands may be present. Measure. Bisect; Ink sparingly and allow to dry fully—gelati-
submit in total. nous pleomorphic adenomas often separate
Specimens from marsupialized ranulas repre- easily from the thin capsule and overrun of ink
sent floor of mouth mucosa. Measure as a muco- will overestimate involvement of the surgical
sal specimen, bisect, and submit in total. limits.
Sampling of Minor Glands for Xerostomia:
Several small tissue nodules free-floating in Measurements:
fixative, non-orientated. Count number of glands
(minimum of six glands recommended for useful • Dimensions of specimen(s) (cm)
assessment of focal lymphocytic sialadenitis). • Weight(s) (g)
Measure largest in three dimensions; submit in • Dimensions of tumour (cm)
total. • Distance (cm) to closest margin
Description:
Tumour
17.6.2.1 Parotidectomy • Location (deep lobe or superficial lobe)
and Submandibulectomy • Consistency of tumour (solid/cystic; gelati-
Specimens nous, fleshy, firm)
Parotidectomy • Interface with adjacent parenchyma
Most superficial and total parotidectomy speci- (encapsulated, circumscribed, or infiltra-
mens are submitted for neoplastic conditions, tive margin)
although less often the gland may be removed • If encapsulated, proportion of capsule
because of persistent infections. In total paroti- exposed on outer surface of specimen
dectomy specimens where the facial nerve has Gland
been preserved, the superficial and deep lobes • Parenchyma—normal, fibrotic, or fatty
will be separate. • Other
Submandibulectomy • Note the presence of stones and lymph
Most submandibulectomy specimens are nodes
removed for calculus/obstructive sialadenitis.
Procedure: Blocks for histology: (Fig. 17.1)
Orientate the specimen. The medial aspect is
usually the most critical margin. The surgeon • One block per centimetre diameter of tumour
should give some indications on the request • Closest margin
form, but it can still be difficult, particularly • Adjacent uninvolved parenchyma
with fragmented specimens. Superficial paroti- • Lymph nodes
Fig. 17.1 Resection of a b

parotid and
submandibular salivary
glands Recommended
siting and orientation of Duct
blocks for resection of
parotid (a) and
submandibular (b) Duct
glands (Reproduced,
Allen and Cameron
(2013))
Sample nodes
Sample nodes
17.6.2.2 M inor Gland Excisions Other

for Tumour • Appearances of adjacent minor glands and
Fifty percent of minor gland lesions will be neurovascular bundles
malignant, although most of these will be of low
as free-floating specimens in formalin. Blocks for histology:
Procedure: The histology should represent the deepest
Orientate the specimen. The deep aspect is extent of the tumour, the relationship to the adjacent
usually the most critical margin. The surgeon structures or organs, mucosal and deep soft tissue
should give some indications on the request form margins, and changes in adjacent tissues.
as to laterality and anterior–posterior orientation • One block per centimetre diameter of
but it can still be difficult particularly with speci- tumour
mens from lip or buccal mucosa. The colour and • Closest mucosal margin (if appropriate)
texture of the mucosa from the hard palate may • Closest deep margin
help orientate palatal resections. • Adjacent uninvolved mucosa and glands
Ink sparingly and allow to dry fully. • Proximal (and distal, if relevant) nerve limits
Measurements:
• Dimensions of mucosa and depth of specimen
Final reports of resection specimens of tumour
(cm)
should include details on:
• Dimensions of tumour (cm)
• Distance to closest mucosal and deep margins
(cm) • Specimen type
• Type of tumour present (and grade if relevant)
Description: • Distance of the tumour from the nearest cuta-
neous/mucosal margin (if appropriate)
Tumour • Distance of the tumour from the nearest deep
• Location margin
• Consistency of tumour (solid/cystic; gelati- • Presence or absence of perineural and vascu-
nous, fleshy, firm) lar invasion
• Interface with adjacent parenchyma (encapsu- • Presence or absence of lymph node metastasis
lated, circumscribed, or infiltrative margin) (if appropriate)
Mucosa • Extent of local tumour spread major salivary
• Intact or ulcerated? glands: TNM 8 for carcinoma
pT1 Tumour <2 cm, without extraparenchymal pN3 ( a) Metastasis in a lymph node >6 cm, or,
extensiona (b) Extranodal extension with any of; >3 cm,
pT2 Tumour >2–4 cm, without extraparenchymal multiple ipsilateral, contralateral, bilateral
extensiona
pT3 Tumour >4 cm, and/or with extraparenchymal
extensiona
pT4 Tumour invades skin, mandible, ear canal,
Bibliography
facial nerve, base of skull, pterygoid Plates or
encases carotid artery Allen DC. Histopathology reporting. Guidelines for surgi-
a
Extraparenchymal extension is clinical or macroscopic evi-
Allen DC, Cameron RI, editors. Histopathology speci-
dence of invasion of soft tissues or nerve, except those listed
mens: clinical, pathological and laboratory aspects.
under pT4. Microscopic evidence alone is not sufficient
2nd ed. Berlin: Springer; 2013.
Regional lymph nodes: cervical—selective Brierley JD, Gospodarowicz MK, Wittekind C, editors.
and modified/radical lymphadenectomy will Oxford: Wiley-Blackwell; 2017.
ordinarily include 10 or 15 or more lymph nodes, Ellis G, Auclair PL. Tumors of the salivary glands,
respectively. Atlas of tumor pathology, vol. 4th series. Fascicle 9.
Washington, DC: AFIP; 2006.
head and neck. 2nd ed. Philadelphia: WB Saunders;
pN0 No regional node metastasis 2009.
pN1 Metastasis in an ipsilateral single node ≤3 cm Shah JP, Patel SG. Head and neck surgery and oncology.
without extranodal extension 3rd ed. Edinburgh: Mosby; 2003.
The Royal College of Pathologists. Dataset for histopa-
pN2 Metastasis in:
(a) Ipsilateral single node ≤3 cm with section specimens associated with head and neck
extranodal extension, or, >3–6 cm without carcinomas. November 2013. https://www.rcpath.
extranodal extension org/profession/publications/cancer-datasets.html.
Accessed July 2016.
(b) Ipsilateral multiple nodes ≤6 cm without
extranodal extension head and neck pathology. January 2016. https://www.
(c) Bilateral or contralateral node(s) ≤6 cm rcpath.org/profession/publications/cancer-datasets.
without extranodal extension html.
Thyroid Gland
18
18.1 Anatomy mus is variable in size, usually measuring about

1 cm in length and width and lies over the trachea
The thyroid gland lies in the lower part of the inferior to the cricoid cartilage. The pyramidal
anterior neck, partly enveloping the larynx and lobe, when present, ascends from the isthmus
upper trachea (Fig. 18.1). It is composed of right along the line of the thyroglossal duct and prob-
and left lobes, interconnected by a narrower isth- ably represents colonization of that embryonic
mus, from which may occasionally arise the structure by thyroid cells during the descent of
pyramidal lobe. The entire gland normally the developing organ in early life from the fora-
weighs 15–30 g, each roughly conical lobe mea- men caecum in the tongue.
suring approximately 4 × 3 × 2 cm. The lower Histologically, the thyroid gland is composed
pole of each lobe is usually located at the level of of follicles of cuboidal epithelial cells surround-
the third or fourth tracheal cartilage with the ing eosinophilic colloid, arranged in small pear-
upper pole ascending and diverging laterally to shaped lobules supported by delicate fibrovascular
lie close to the superior aspect of the lamina of stroma. C-cells that secrete calcitonin are dis-
the thyroid cartilage. Medially, each thyroid lobe persed throughout the gland singly or in small
is related to the thyroid cartilage, the cricoid car- clusters but are most numerous around the junc-
tilage, and the upper tracheal cartilages, anteri- tion of the upper and middle one-thirds of the lat-
orly to the strap muscles of the neck and eral lobes. They are usually inconspicuous on
posterolaterally to the carotid sheath. The isth- routine stains but can be identified with immuno-
histochemical stains lying within the follicles.
Other lesser components of the thyroid gland
include solid cell nests (remnants of the ultimo-
branchial body), thymic tissue, and paraganglia;
occasionally parathyroid glands may become
C.L. Coghlin (*) incorporated within the thyroid.
Histopathology Laboratory, Belfast City Hospital, Lymphovascular drainage:
Belfast Health and Social Care Trust, Belfast, UK The rich lymphatic supply of the thyroid gland
e-mail: caroline.coghlin@belfasttrust.hscni.net drains to lymph nodes in the central and lateral
S.S. Napier compartments of the neck, located in pretracheal,
Histopathology Laboratory, Institute of Pathology, paratracheal, prelaryngeal, retropharyngeal, and
Care Trust, Belfast, UK retro-oesophageal sites and in the deep cervical
e-mail: seamus.napier@belfasttrust.hscni.net chain (see Fig. 20.1).

204 C.L. Coghlin and S.S. Napier
Fig. 18.1 Thyroid a Superior cornu of thyroid cartilage

gland and parathyroid
glands. (a) View of
thyroid gland from
anterior aspect to show Lamina of thyroid cartilage
relation to larynx and
regional lymph nodes; Prelaryngeal nodes
(b) view of thyroid Left lobe of thyroid gland
gland from posterior
aspect to show location
of parathyroid glands Isthmus
(Reproduced, with Perithyroid nodes
and Cameron (2013))
b Epiglottis
Right cornu of hyoid bone
Inferior constrictor opened from behind
Right lobe of thyroid gland
Right superior parathyroid gland
Right inferior parathyroid gland
Disease affecting the thyroid gland can present • Thyroid function is routinely assessed by
as enlargement (called goitre) that may be dif- measuring blood levels of thyroid stimulating
fuse or nodular, or as a consequence of hor- hormone (TSH) and, if appropriate, the levels
monal imbalance; rarely there may be pain. of thyroxine and triiodothyronine in patients
Hypothyroidism is characterized by lethargy, with thyroid gland disease, including those
mental slowness or depression, intolerance of with neoplastic conditions; calcitonin levels
cold, or weight gain, while thyrotoxicosis man- too can be measured. Elevated plasma thyro-
ifests as intolerance of heat, excessive sweat- globulin (with calcitonin and CEA in medul-
ing, weight loss in spite of increased appetite, lary thyroid carcinoma) following ablative
anxiety, tiredness, and, occasionally, cardiac therapy for malignant disease can indicate
arrhythmias. recurrence or metastasis. Autoantibodies to
Tumours of the thyroid gland usually present thyroglobulin, microsomal antigen, and the
with a solitary nodule with normal thyroid func- TSH receptor may also be evaluated.
tion, although some tumours can secrete hor- • Ultrasonography is helpful in distinguishing a
mones. Occasionally metastasis to cervical solitary nodule from a multinodular goitre with
lymph nodes or bone may represent the initial a so-called dominant nodule but cannot differ-
symptom of differentiated thyroid cancer. High- entiate benign from malignant disease. Plain
grade cancers can present with hoarseness, dys- radiographs of the neck and chest may demon-
phagia, or difficulty breathing. strate deviation of the trachea, mediastinal
18 Thyroid Gland 205
expansion, or lymphadenopathy, although they immune disease characterized by elevated levels

are more accurately determined by CT and of circulating anti-peroxidase and anti-
MRI scanning. Scintiscanning, particularly thyroglobulin antibodies; the hypothyroidism is
with Iodine-123 rather than Technetium-99 m, probably due to a combination of inactivation of
can determine the functional status of the tis- the TSH receptor by autoantibodies and destruc-
sue. Functioning or “hot” nodules are very tion of functioning gland. A proportion of patients
unlikely to be malignant. may be euthyroid or hyperthyroid at presentation,
• FNA is the investigation of choice for thyroid but hypothyroidism is inevitable. The gland is
enlargement, particularly for solitary nodules symmetrically and diffusely enlarged, weighing
in euthyroid patients or when there is a his- between 50 and 100 g. Histologically there is dif-
tory of a rapidly growing mass with airway fuse lymphoplasmacytic infiltration with germi-
obstruction. A definitive diagnosis is some- nal centre formation. The follicles are small and
times possible with FNA, although the dis- sparse with reduced or absent colloid. Hürthle
tinction between a cellular colloid nodule, cell change is widespread. A rare variant shows
follicular adenoma, and a follicular carci- much fibrosis, affecting older patients and often
noma is generally impossible. males.
• Assessment of vocal cord function is impor- Multinodular goitre: A common cause of
tant in the clinical assessment of patients with thyroid gland enlargement. Probably the end
goitre; vocal cord paralysis is a sinister result of persistent stimulation of the glandular
finding. epithelium to proliferate and synthesize colloid
through the TSH-negative feedback loop. This
can be due to dietary deficiency of iodine,
18.4 Pathological Conditions ingested goitrogens that interfere with the avail-
ability of iodine or an enzymatic defect, alone or
18.4.1 Non-neoplastic Conditions in combination—essentially, any disruption of
the physiological hypothalamic pituitary axis
Graves’ disease: The commonest cause of hyper- that results in an increased TSH and stimulation
thyroidism, and is characterized by thyrotoxico- of thyroid follicular cell activity. Patients are
sis, a diffuse goitre, ocular signs, and pretibial generally euthyroid but, when severe, hypothy-
myxoedema. It affects females much more often roidism will result; occasionally late-stage dis-
than males and usually presents between the ages ease will be associated with a mild degree of
of 20 and 40 years. It is an autoimmune disease; hyperthyroidism. Congenital enzymatic defi-
the thyrotoxicosis is due to activation of the TSH ciencies (dyshormonogenic goitre) present in
receptor when the autoantibodies bind to it. early childhood, marked dietary iodine defi-
Typically, the gland is symmetrically and dif- ciency or goitrogen ingestion seen in certain
fusely enlarged, weighing between 50 and 150 g. geographical regions (endemic goitre) affects
Histologically the lobular architecture is pre- adolescents, while sporadic (or non-endemic)
served. There is diffuse parenchymal hyperplasia goitre is rarely detected until much later in life.
with scalloped colloid within the small irregular Initially in all forms there is a simple diffuse
follicles, which are lined by tall active-looking goitre, but gradually the gland becomes nodular
columnar cells. Simple non-branching papillary as a consequence of follicle rupture, inflamma-
infoldings are often present. tion and fibrosis. Macroscopically, multinodular
Hashimoto’s thyroiditis: A common cause of goitres are characterized by massive enlarge-
hypothyroidism and characterized by hypothy- ment of the gland with heterogeneous nodular-
roidism and firm diffuse goitre. It affects females ity, histology revealing follicles distended by
much more often than males and usually presents colloid, old and recent haemorrhage, and irregu-
between the ages of 30 and 50 years. It is an auto- lar areas of scarring with calcification.
Others: Ectopic or accessory thyroid gland tis- familial non-medullary thyroid cancer syndrome.
sue, multifocal granulomatous thyroiditis (due to Variable macroscopic appearances from tiny
vigorous palpation of the gland), tuberculosis, grey-white foci to tumours replacing the entire
sarcoidosis, de Quervain’s thyroiditis, radiation gland, but many are 2–3 cm diameter, white,
changes, Reidel’s thyroiditis (a form of IgG4- firm, granular, infiltrative masses. Cystic degen-
related disease). eration is common, especially in nodal metasta-
ses. It has characteristic nuclear features of
enlargement, optical clarity, grooving, and cyto-
18.4.2 Neoplastic Conditions plasmic pseudoinclusions. True papillary pro-
cesses with fibrovascular cores are common but
Follicular adenoma: Expansile round lesion not required for the diagnosis. Psammoma bodies
1–3 cm in diameter with a thin complete capsule. are seen in 50%. Multiple foci of papillary carci-
Soft and fleshy, pale or brown in colour; haemor- noma are found in up to 65% of cases (although
rhage, fibrosis, cyst formation, or calcification this varies widely depending on the study); while
may be present. Uniform pattern of growth; fol- this often represents the emergence of multiple
licles of similar sizes (in contrast to hyperplastic synchronous lesions, it may also represent intrag-
nodules). Embryonal, microfollicular, normofol- landular lymphatic metastases.
licular, or macrofollicular subtypes. No invasion A single papillary microcarcinoma (≤10 mm
of capsule and no evidence of vascular invasion. in diameter) discovered incidentally is not
Variants include Hürthle cell adenoma and hya- thought to have a significant risk of recurrence or
linizing trabecular adenoma. metastasis and is not an indication for further sur-
Thyroid cancer: Risk factors for thyroid carci- gery, although this is controversial.
noma include irradiation (particularly in the first The non-invasive follicular variant of papil-
two decades of life), underlying thyroid disease lary carcinoma, especially if encapsulated, has
(especially Hashimoto’s thyroiditis), family his- a very low metastatic potential. This has
tory of thyroid cancer including rare inherited recently prompted a drive to re-name some
syndromes such as Multiple Endocrine Neoplasia such indolent lesions non-invasive follicular
(MEN) syndromes 2A and 2B, or non-MEN thyroid neoplasm with papillary-like nuclear
familial medullary thyroid carcinoma. features (NIFTP). Numerous morphological
Thyroid carcinomas are classified into three variants of papillary thyroid carcinoma exist.
broad types “differentiated thyroid cancer,” med- Tall cell and columnar variants should be rec-
ullary thyroid carcinoma, and undifferentiated or ognized as these are thought to show more
anaplastic carcinoma. Differentiated thyroid can- aggressive behaviour. Oncocytic and diffuse
cer encompasses papillary carcinoma, follicular sclerosing variants are also recognized but the
carcinoma, and their variants. Poorly differenti- prognostic significance is not clear.
ated thyroid carcinoma lies morphologically and Follicular carcinoma: Second commonest
behaviourally between differentiated and anaplas- thyroid malignancy accounting for 15% of pri-
tic carcinoma. It may show evidence of dediffer- mary tumours, 30–60 years, F:M = 3:1. Similar
entiation from papillary or follicular carcinomas, macroscopic features to follicular adenomas but
but these tumours predominantly exhibit solid, the capsule is thicker. Key diagnostic features are
insular or trabecular growth patterns often pre- full-thickness capsular penetration and vascular
senting as large infiltrative lesions with frequent invasion. Tumours with only focal capsular inva-
vascular invasion. sion have minimal risk of metastasis.
Papillary carcinoma: Commonest thyroid Vascular invasion indicates a higher risk,
malignancy, F:M = 3:1, 20–50 years. A few cases increasing with the frequency of invasion. Those
arise against a background of familial adenoma- with multiple areas of capsular and vascular inva-
tous polyposis syndromes or associated with sion are termed “widely invasive follicular
Table 18.1 GASH risk assessment of patients with dif- differentiated pattern of thyroid cancer (so-called
ferentiated thyroid cancers
“mixed medullary and follicular cell carcinoma”).
Risk category Criteria Anaplastic carcinoma: A rare thyroid malig-
Low-risk Females less than 45 years of age nancy that arises in older patients. Presents as a
patients rapidly enlarging mass (may be a history of goitre
High-risk All patients under 16 years of age
or a preexisting nodule) with hoarseness, dys-
patients All males
pnoea, or dysphagia. Very large pale fleshy tumour
Females over 45 years of age
that infiltrates widely in the neck; may have foci
Low-risk Papillary carcinoma less than 1 cm in
tumours diameter
of haemorrhage and necrosis. Histological pat-
Minimally invasive follicular terns include spindle cell, osteoclastic, carcino-
carcinoma less than 1 cm in diameter sarcoma, lymphoepithelial, and paucicellular
High-risk Papillary or follicular carcinoma types. There is marked nuclear pleomorphism and
tumours greater than 1 cm in diameter a high mitotic count; vascular invasion is usually
Multifocal neoplasms. Metastasis to present. The prognosis is poor, most patients die
regional nodes or beyond from local tumour growth in spite of external
beam radiotherapy. Metastasis occurs frequently
in regional lymph nodes and beyond.
carcinoma,” may metastasise to bone and lung Primary malignant lymphoma: A rare neo-
and have a variable prognosis. Oncocytic (or plasm in the thyroid gland (1–2% of neoplasms),
Hürthle) cell carcinoma, a variant of follicular presenting in elderly patients with a rapidly
carcinoma, tends to have a poorer prognosis (per- enlarging mass, stridor, and dysphagia. There is
haps because these tumours respond less well to a strong association with preexisting Hashimoto’s
therapy). thyroiditis (MALToma). The tumour is large and
Patients with differentiated thyroid cancer are replaces much of the thyroid gland. Diffuse large
stratified according to a number of factors related B-cell lymphoma may arise without a previous
to the risk of recurrence or metastasis, summa- low-grade lesion. The tumour cells infiltrate
rized by the acronym GASH (gender age stage between follicles, produce lymphoepithelial
histology) (see Table 18.1). lesions, and extend into the perithyroid soft tis-
Medullary carcinoma: A neuroendocrine malig- sues. In contrast to anaplastic carcinoma, it
nancy with a pattern of C-cell differentiation responds well to radiotherapy and chemother-
accounting for 5–10% of thyroid neoplasms. About apy, although the long-term prognosis depends
25% of cases of medullary thyroid carcinoma are on the stage.
familial and arise against a background of MEN syn- Others: “Pure” squamous cell carcinoma,
dromes 2A and 2B or as a pure familial form but small cell neuroendocrine carcinoma, sarcoma,
most are sporadic. New cases should undergo testing thymic tumours, carcinomas showing thymus-like
for RET mutations. Macroscopically, it is tan- differentiation (CASTLE), mucoepidermoid car-
coloured or pink, may feel soft, and is usually well cinoma, metastatic carcinoma, paraganglioma.
circumscribed but not encapsulated. There are a
number of histological patterns (solid, nested, tra-
becular) and cell types (spindle, clear, granular); 18.5 Surgical Pathology
amyloid is present in 80%. C cell hyperplasia may Specimens: Clinical Aspects
be present in the background. Metastasis to regional
lymph nodes occurs particularly with larger tumours, 18.5.1 Biopsy Specimens
and spread to lung, liver, or bone may occur. The
prognosis is linked to stage; involvement of soft tis- Open incisional biopsy is rarely performed on the
sues in the neck and regional nodes usually indicate thyroid gland. Core needle biopsy can provide a
reduced survival. Occasionally, it may present with a tissue diagnosis where the differential diagnosis
rests between anaplastic carcinoma and malig- 18.6 Surgical Pathology

nant lymphoma. Very occasionally, incisional Specimens: Laboratory
biopsy and intraoperative frozen section assess- Aspects
ment may be required when an inoperable thy-
roid mass is encountered. 18.6.1 Biopsy Specimens
Usually as small samples from open biopsies or

18.5.2 Resection Specimens core needle specimens, free-floating in formalin.
Measure in three dimensions or length of core
Total thyroidectomy is carried out for treatment and submit in total.
of Graves’ disease when surgery is required. On
the few occasions when operation is required for
aesthetics and/or obstructive symptoms in 18.6.2 Resection Specimens
Hashimoto’s thyroiditis, total thyroidectomy is
the operation of choice. Likewise, total thyroid- Specimen:
ectomy may be required for patients with multi- Most thyroid resections are performed for neo-
nodular goitre because of goitre size and/or plastic disease, to prevent recurrence in Graves’
compressive symptoms; if unilateral, lobectomy disease or to relieve compressive symptoms
may suffice. from multinodular goitre or Hashimoto’s thy-
Lobectomy with resection of the isthmus in roiditis. Some lobectomy specimens will repre-
continuity represents the minimum appropriate sent diagnostic procedures for suspicious lesions
surgical procedure in any patient with a solitary with equivocal FNA findings. Only occasionally
thyroid nodule, particularly when there is suspi- will specimens of neck dissection be included.
cion of a follicular neoplasm on FNA. When a
firm preoperative diagnosis of differentiated thy- Initial procedure:
roid malignancy is made, total thyroidectomy is
performed. Subtotal resection represents ade- • Orientate the specimen, if possible
quate surgery for follicular adenomas but should • Search for parathyroid glands
not be used in the management of thyroid cancer. • Ink the external resection margins
Total thyroidectomy is preferred for high-risk • Slice into 4-mm-thick slices transversely in
tumours in high-risk patients. The intermediate the coronal plane
group of low-risk patients with high-risk tumours • Measurements:
or high-risk patients with low-risk tumours is –– Weight of specimen (g)
managed by either total thyroidectomy or some- –– Dimensions of specimen (cm)
times lobectomy. Extensive differentiated thyroid –– Tumour size (cm)
carcinomas involving adjacent viscera may –– Distance to closest surgical margins (cm)
require laryngectomy, tracheal resection and
pharyngectomy. Medullary thyroid carcinoma is Description:
treated by total thyroidectomy.
Neck dissection is performed in differentiated • Tumour
and medullary tumours if there is clinically pal- Number of tumour deposits
pable nodal metastasis. Nodes from the central Size, shape, and colour
compartment (Level VI) may be removed if there Solid or cystic or both
is no suspicion of metastasis, usually in high-risk Encapsulated or infiltrative
histological types in high-risk patients or where • Capsule
there is proven metastasis elsewhere in the neck. Present or absent
Thick or thin Macroscopically encapsulated neoplastic

Regular or irregular disease:
Intact or breached by tumour
• Adjacent gland • For tumours up to 5 cm in diameter, submit
Outer surface: smooth or roughened/breached total circumference or a minimum of 10
by tumour blocks, the blocks illustrating the interface of
Colour and consistency tumour, capsule, and adjacent gland.
Presence or absence of nodules • For tumours greater than 5 cm in diameter,
• Others submit one additional block of tumour per
Lymph nodes, neck dissection, parathyroid centimetre diameter, again the blocks illustrat-
gland ing the interface of tumour, capsule, and adja-
cent gland.
Blocks for histology: • Closest surgical margin.
In cases of neoplastic disease, the histology • Samples of other lesions, e.g., nodules or
should represent the tumour, its relationship to its fibrous areas.
own capsule (if any), the thin capsule of the thy- • Parathyroid gland(s).
roid gland, and adjacent structures (Fig. 18.2). • Perithyroid lymph node(s).
Focal abnormalities of the thyroid parenchyma
need to be sampled as do adjacent lymph nodes Macroscopically invasive neoplastic disease:
and the parathyroid glands.
In inflammatory or diffuse reactive disease, • Three blocks of tumour to illustrate interface
representative samples of gland and capsule are with adjacent normal tissues
required. • Three blocks of adjacent gland
Pyramidal lobe
a
Tumour in
left lobe
Contralateral lobe
Isthmus
Fig. 18.2 Total
thyroidectomy
specimen. (a)
Recommended block
selection to include
b c
isthmus, pyramidal lobe,
and contralateral lobe if
present. Tissue block
composites depend on
the size of the tumour;
(b) small; (c) large.
Include other nodules
(Reproduced, with
and Cameron (2013))
• Closest surgical margin • Presence or absence of vascular invasion

• Samples of other lesions, e.g., nodules or • Involvement of perithyroid lymph nodes
fibrous areas • Other pathology such as Hashimoto’s thyroid-
• Parathyroid gland(s) itis or radiation injury
• Perithyroid lymph node(s) • If other specimens are attached as an in-
continuity dissection (e.g., neck dissection),
NB: these can be handled separately in the usual
NIFTP requires the entire encapsulated lesion fashion.
to be submitted or this diagnosis cannot be
made as it is dependent on having no cap- Extent of local tumour spread thyroid: TNM 8
sular invasion. for carcinoma including papillary, follicular,
If a single incidental papillary microcarci- poorly differentiated, Hurthle cell and anaplastic
noma is detected, the remaining tissue carcinomas. Separate stage groupings are rec-
should be embedded in entirety to exclude ommended for differentiated (papillary, follicu-
multifocal disease. lar), medullary and undifferentiated (anaplastic)
carcinomas.
Multinodular disease:
pT1a ≤10 mm, limited to thyroid
• One block from each nodule up to a maximum pT1b ≤20 mm but >10 mm, limited to thyroid
pT2 >20 mm, ≤40 mm, limited to thyroid
of five blocks.
pT3 >40 mm, limited to thyroid (pT3a), or gross
• For dominant nodules, submit one additional
extrathyroidal extension invading only strap
block of tumour per centimetre diameter, the muscles (pT3b)
blocks illustrating the interface of nodule and pT4a Tumour invades beyond thyroid capsule and
adjacent gland. invades any of: subcutaneous soft tissues,
larynx, trachea, oesophagus, recurrent
laryngeal nerve
Inflammatory disease:
pT4b Tumour invades prevertebral fascia,
mediastinal vessels, or encases carotid
• Submit three representative blocks from each artery
lobe and one block from the isthmus if pN1a Metastasis in Level VI (pretracheal,
present. paratracheal, and prelaryngeal/Delphian)
lymph nodes or upper/superior mediastinum
Histopathology report: pN1b Metastasis in other unilateral, bilateral or
contralateral cervical (Levels I, II, III, IV, or
Final reports of thyroid specimens should include V) or retropharyngeal lymph nodes
details on:
Regional lymph nodes: cervical and upper/
• Specimen type, side, size (cm), and weight (g) superior mediastinal lymph nodes. A selective
• Type and subtype of tumour present, if any lymphadenectomy will ordinarily include 6 or
–– Follicular adenoma more lymph nodes.
–– Papillary carcinoma and variants
–– Follicular carcinoma and variants
–– Medullary carcinoma Bibliography
–– Anaplastic carcinoma
–– Lymphoma cal cancer. 3rd ed. London: Springer; 2013.
• Macroscopic size of tumour and degree of Allen DC, Cameron RI. Histopathology specimens:
encapsulation clinical, pathological and laboratory aspects. 2nd ed.
• Presence or absence of invasion of the capsule Berlin: Springer; 2013.
and surrounding tissues TNM classification of malignant tumours. 8th ed.
• Distance of tumour from the nearest margin Oxford: Wiley-Blackwell; 2017.
DeLellis RA, Lloyd RV, Heitz PU, Eng C. WHO classi- Sneed DC. Protocol for the examination of specimens
fication of tumours. Pathology and genetics. Tumours from patients with malignant tumours of the thyroid
of endocrine organs. Lyon: IARC Press; 2004. gland, exclusive of lymphomas. Arch Pathol Lab Med.
Gnepp DR, editor. Diagnostic surgical pathology of the 1999;123:45–9.
head and neck. 2nd ed. Philadelphia: WB Saunders; The Royal College of Pathologists. Dataset for thyroid
2009. cancer histopathology reports; February 2014. https://
Mitchell AL, Gandhi A, Scott-Coombes D, Perros www.rcpath.org/profession/publications/cancer-
P. Management of thyroid cancer. UK National datasets.html. Accessed July 2016.
Multidisciplinary Guidelines. J Laryngol Otol. 2016; The Royal College of Pathologists. NIFTP addendum to
130(Suppl. S2):S150–60. the RCPath dataset for thyroid cancer histopathology
Nosé V, Asa SL, Erickson LA, Lopes BS, Tischier reports; June 2016. https://www.rcpath.org/profes-
AS. Diagnostic pathology: endocrine. Salt Lake City: sion/publications/cancer-datasets.html. Accessed July
Amirsys; 2012. 2016.
Rosai J, Kuhn E, Carcanagiu ML. Pitfalls in thyroid
tumour pathology. Histopathology. 2006;49:107–20.
Parathyroid Glands
19
19.1 Anatomy in location, although they tend to be symmetrical

bilaterally. Over half are found around the infe-
There are usually four parathyroid glands, rior pole of the thyroid lobe, although other com-
arranged as superior and inferior pairs on either mon locations include the thymus or high up on
side of the midline closely related to the thyroid the anterior aspects of the thyroid lobe.
gland (see Fig. 18.1). About 5% of people will Occasionally they may be located in the medias-
have more than four glands. These 9 coloured tinum or rarely in association with the roots of
oval structures each normally measure 4–6 mm the great vessels.
in maximum dimension and weigh around Lymphovascular drainage:
30–40 mg, with single glands of >60 mg consid- The rich lymphatic supply of the parathyroid
ered to be enlarged and abnormal. The combined glands drains with that of the thyroid gland to
weight should be between 120 and 140 mg. The lymph nodes in the anterior and lateral neck,
superior parathyroid gland (derived from the located in the deep cervical chain as well as in
fourth pharyngeal pouch) is fairly constant in pretracheal, paratracheal, prelaryngeal, retro-
position and lies on the posteromedial aspect of pharyngeal, and retro-oesophageal sites (see
the superior thyroid pole. A few superior parathy- Fig. 20.1).
roid glands are located medial to the upper pole
or in the retropharyngeal or retro-oesophageal
space. The inferior parathyroid glands, derived 19.2 Clinical Presentation
from the third pharyngeal pouch are less constant
Disease affecting the parathyroid glands may
present as a consequence of altered function but
it can also be an incidental finding.
Hyperparathyroidism describes an altered meta-
bolic state due to increased secretion of parathy-
roid hormone (parathormone) which usually
C.L. Coghlin (*)
Histopathology Laboratory, Belfast City Hospital, manifests as disordered calcium metabolism. The
Belfast Health and Social Care Trust, Belfast, UK clinical presentation of parathyroid disease has
e-mail: caroline.coghlin@belfasttrust.hscni.net shifted in recent years. Rarely seen nowadays is
S.S. Napier the full spectrum of “bones, stones, groans, and
Histopathology Laboratory, Institute of Pathology, moans”, although this remains a common presen-
Royal Victoria Hospital, Belfast Health and Social tation in the developing world. Biochemical
e-mail: seamus.napier@belfasttrust.hscni.net investigation of nonspecific complaints such as

profound tiredness, nausea, or thirst is a relatively of autoantibodies is useful when autoimmune-

frequent method of diagnosis, but the majority of associated hypoparathyroidism is suspected.
patients with primary hyperparathyroidism pre- • Chest radiographs are helpful in excluding a
senting in developed countries are now asymp- paraneoplastic effect of bronchogenic carci-
tomatic at the time of their diagnosis, and are noma as a cause for the hyperparathyroidism.
detected as a result of elevated calcium levels CT and MRI scanning may locate enlarged
identified within routine biochemical blood tests. parathyroid glands in the neck, but currently
Primary hyperparathyroidism is due to an the most reliable method is technetium labeled
increased secretion of parathormone from one or isotope scintigraphy (Technetium 99
more of the parathyroid glands, usually caused sestamibi).
by an adenoma. Secondary hyperparathyroidism
is due to the physiological response of the four
parathyroid glands to persistent hypocalcaemia, 19.4 Pathological Conditions
usually caused by renal failure, malabsorption
syndromes, or Vitamin D deficiency. Tertiary 19.4.1 Non-neoplastic Conditions
hyperparathyroidism is a result of persistent
autonomous hypersecretion of parathormone in Primary chief cell hyperplasia: Usually accounts
long-standing secondary hyperparathyroidism for 15% of cases of primary hyperparathyroid-
following correction of the hypocalcaemia. ism, but is also seen against a background of sec-
Hypoparathyroidism is a result of reduced ondary hyperparathyroidism. About 25% of cases
secretion of parathormone and is characterized of primary chief cell hyperplasia are familial and
by neuromuscular excitability. Rapid onset of arise in multiple endocrine neoplasia (MEN) syn-
hypoparathyroidism, e.g., following surgery to dromes 1 and 2 or as an isolated familial form,
the neck, results in muscular tetany and paraest- but most are sporadic. The four parathyroid
haesia, while an insidious onset, such as with glands are symmetrically enlarged in around
autoimmune disease, may induce mucocutaneous 50% of patients, while the asymmetric enlarge-
candidosis, cataracts, and basal ganglia changes ment of the remainder mimics parathyroid ade-
as well. noma (pseudoadenomatous hyperplasia).
Pseudohypoparathyroidism refers to a rare Microscopically, the glands contain numerous
inherited defect of parathyroid hormone receptor chief cells in diffuse sheets or as nodules with
function in peripheral tissue characterized by oncocytes and transitional forms also present.
insensitivity to circulating parathormone; the Mitotic figures may be present. Intraglandular
glands are hyperplastic. adipocyte numbers are usually much reduced,
although rarely the fat cells may be abundant
(lipohyperplasia). Cystic change may occur in
19.3 Clinical Investigations very large glands. Distinction from adenoma for-
mation can be difficult, but the enlargement of
• Biochemical tests are the mainstay of the multiple glands is usually diagnostic.
diagnosis of parathyroid gland disease. In Primary clear cell hyperplasia: This is seen
conjunction with the clinical history and phys- mostly in men in the fifth decade. The four para-
ical examination, relative plasma concentra- thyroid glands are markedly enlarged, particu-
tions of calcium, inorganic phosphate levels, larly the superior glands. The chief cells are
and parathormone allow classification of arranged in small nests and have profoundly clear
hyperparathyroidism as primary, secondary, cytoplasm (“water-clear” cells). There is usually
or tertiary. Alkaline phosphatase levels are marked hypercalcaemia but water-clear cell
elevated when there is increased osteoblastic hyperplasia is not MEN-associated.
activity as a result of bone resorption and Secondary parathyroid hyperplasia: Very
stimulation of osteoblastic activity. Evaluation similar appearances to primary chief cell
19 Parathyroid Glands 215
h yperplasia, but there tends to be symmetrical Double adenoma: Very rare and requires the
enlargement, particularly in the early stages. presence of two enlarged glands (each weighing
Early changes include loss of the intraglandular more than 70 mg) and two normal sized glands;
adipocytes with conspicuous nests of chief cells MEN 1 syndrome; may be impossible to distin-
but in long-standing cases, the glands usually guish from hyperplasia.
have a marked nodular pattern. Oncocytes may Variants include microadenoma (<6 mm
be prominent in established cases; cystic change diameter), atypical adenoma (may exhibit some
and fibrosis may develop. concerning microscopic features, but not felt to
Cysts: Usually arise due to degenerative be diagnostic for malignancy), oncocytic ade-
changes in an adenoma or hyperplastic parathy- noma, lipoadenoma.
roid gland but some are developmental anomalies Carcinoma: A rare cause of primary hyper-
of the third and fourth branchial arches. Cystic parathyroidism (0.5–5.2%). Patients are usually
degeneration in an adenomatous or hyperplastic older than those with adenomas and often have
gland is usually associated with hyperparathy- very high levels of parathormone secretion with
roidism; typical chief cells line the fibrous wall of symptomatic hypercalcaemia. Usually pale solid
the cyst. Developmental cysts tend not to be func- tumour; may be encapsulated but often infiltrates
tional and are usually associated with the inferior adjacent soft tissues. Microscopically the lesion
parathyroid glands; these cysts are lined by respi- is composed of chief cells arranged in a solid or
ratory or cuboidal epithelium with parathyroid trabecular pattern with thick fibrous bands,
cells in the fibrous wall. numerous mitotic figures, and capsular invasion,
but these changes may also be present in a pro-
portion of adenomas. Invasion of nerves, blood
19.4.2 Neoplastic Conditions vessels, and adjacent soft tissues are more reli-
able features of malignancy. Local recurrence
Adenoma: This accounts for 80% of cases of pri- (38–50%) and hypercalcaemia are the main prob-
mary hyperparathyroidism. It is a benign tumour lems; metastasis to lymph nodes or to lung and
of the parathyroid glands with a F:M ratio of 3:1, liver occur in approximately 25% of cases.
mostly affecting patients aged 40–60 years. Very
rarely may arise in MEN syndromes 1 and 2.
Usually only one gland is affected and it may be 19.5 Surgical Pathology
located either in the neck or at an ectopic site. Specimens: Clinical Aspects
Usually a tan-coloured circumscribed nodule;
large tumours may be cystic. Microscopically, it 19.5.1 Biopsy Specimens
is composed of chief cells in cords and nests with
occasional gland-like structures; neoplastic chief Incisional biopsy is rarely performed for parathy-
cells are larger (a finding not always easy to roid disease, although intraoperative frozen sec-
appreciate) than their normal counterparts. tion analysis may be required to establish that
Variable numbers of oncocytic cells are present parathyroid tissue has been removed rather than a
in clusters. Nuclear pleomorphism is common thyroid nodule or small lymph node.
and is probably a degenerative phenomenon.
Fibrosis is not common but may be present if
there has been previous haemorrhage. Correlation 19.5.2 Resection Specimens
of surgical and pathological findings is required
to distinguish adenoma from hyperplasia; the Surgical exploration of the neck and parathyroid-
presence of one enlarged gland usually signifies ectomy is curative in most cases of primary and
an adenoma. A rim of compressed normal or tertiary hyperparathyroidism. In primary hyper-
atrophic parathyroid tissue may be seen in around parathyroidism, it is usual for both parathyroid
50% but is less commonly seen in larger lesions. glands from the affected side to be removed to
facilitate distinction between hyperplasia and • Adjacent gland

adenoma. Subtotal parathyroidectomy is the Compressed rim of normal or suppressed
treatment of choice for hyperplasia and for ter- parathyroid gland
tiary hyperparathyroidism. Approximately • Other
100 mg of parathyroid tissue is left in the neck or Neck dissection, thyroid gland resection; pres-
transplanted into the patient’s forearm. ence of other parathyroid glands
Parathyroid carcinoma is usually diagnosed
after excision of the affected gland. Recurrent Blocks for histology:
disease is treated by en bloc resection and
removal of the ipsilateral lobe of thyroid gland. • The histology should represent the abnormal
Neck dissection is usually performed only if parathyroid tissue, its relationship to its cap-
there is clinically palpable nodal metastasis. sule (if any), and adjacent parathyroid gland
parenchyma.
• Submit each parathyroid gland in total (maxi-
19.6 Surgical Pathology mum of three blocks for markedly enlarged
Specimens: Laboratory glands).
Aspects
19.6.1 Resection Specimens Final reports of parathyroid specimens should
include details on:
Specimen:
Most parathyroid resection procedures are • Specimen location (right/left, superior/infe-
performed for neoplastic disease or for primary rior), size and weight
or tertiary hyperplasia. Only when recurrent pri- • Type of tumour present, if any
mary carcinomas are being resected will speci- • Macroscopic size of tumour and degree of
mens of neck dissection be included. encapsulation
Procedure: • Presence or absence of invasion of capsule
and surrounding tissues
• In cases of known or suspected parathyroid • Distance of tumour from the nearest margin
carcinoma, ink the external resection margins. • Presence or absence of vascular invasion
• Remove the surrounding fat. If other specimens are attached as an in-
• Slice into 4-mm-thick slices transversely in continuity dissection (e.g., neck dissection),
the coronal plane. If less than 5 mm in maxi- these can be handled separately in the usual
mum dimension, bisect and submit in total. fashion.
• Measurements (after the removal of the peri-
glandular fat):
–– Weight of specimen to three decimal places Bibliography
(g).
–– Dimensions of specimen (mm). Allen DC. Histopathology reporting. Guidelines for surgi-
–– Tumour size (mm). Allen DC, Cameron RI. Histopathology specimens:
Description: Berlin: Springer; 2013.
Carlson D. Parathyroid pathology. Arch Pathol Lab Med.
2010;134:1639–44.
• Tumour DeLellis RA. Tumors of the parathyroid gland, Atlas
Size and colour of tumor pathology, vol. 3rd series. Fascicle 6.
Solid or cystic Washington, DC: AFIP; 1993.
Encapsulated or infiltrative
19 Parathyroid Glands 217
DeLellis RA, Lloyd RV, Heitz PU, Eng C. WHO classi- Marocci C, Cetani F. Primary hyperparathyroidism. N
fication of tumours. Pathology and genetics. Tumours Engl J Med. 2011;365:2389–97.
of endocrine organs. Lyon: IARC Press; 2004. The Royal College of Pathologists. Dataset for parathy-
Gnepp DR, editor. Diagnostic surgical pathology of the roid cancer histopathology reports; February 2016.
head and neck. 2nd ed. Philadelphia: WB Saunders; https://www.rcpath.org/profession/publications/
2009. cancer-datasets.html. Accessed Sept 2016.
Johnson SJ. Changing clinicopathological practice in Thompson LDR. Endocrine pathology. Philadelphia:
parathyroid disease. Histopathology. 2010;56:835–51. Elsevier; 2006.
Johnson SJ, Sheffield EA, McNichol AM. Examination of van der Walt J. Pathology of the parathyroid glands. Diagn
parathyroid gland specimens. ACP Best Practice No. Histopathol. 2012;18:221–33.
183. J Clin Pathol. 2005;58:338–42.
Neck: Cysts, Tumours,
and Dissections 20
Seamus S. Napier and with clinical comments by
Derek J. Gordon
20.1 Anatomy The anterior triangle is divided into:
The neck extends from the lower border of • The submental triangle, which lies between
the mandible and the base of the skull superi- the anterior belly of digastric, the mandible,
orly to the thoracic inlet at the level of the clav- and the body of the hyoid bone
icles inferiorly. Within this area are contained • The digastric triangle, which lies between the
pharynx, larynx and oesophagus, submandibu- anterior and posterior bellies of digastric
lar and the tail of the parotid salivary glands, below and the lower border of the mandible
bones, skeletal muscles, nerves, blood vessels, above
lymph nodes, and the thyroid and parathyroid • The carotid triangle, which lies between the
glands. The side of the neck is divided by the superior belly of the omohyoid, the anterior
sternocleidomastoid muscle, which passes border of sternocleidomastoid, and the stylo-
obliquely across the neck from the sternum and hyoid and posterior belly of digastric muscle
clavicle below to the mastoid process and superiorly
occipital bone above. The area in front of this • The muscular triangle, which extends from
muscle is called the anterior triangle and the hyoid bone to the sternum and is limited
extends to the anterior midline of the neck. The posteriorly by the superior belly of omohyoid
area behind the muscle is called the posterior
triangle and extends to the anterior margin of The posterior triangle of the neck is divided into:
trapezius muscle behind (Fig. 20.1).
• The occipital triangle lying between the ante-
rior border of trapezius, the posterior border
of sternocleidomastoid, and the inferior belly
of omohyoid below
S.S. Napier (*) • The supraclavicular triangle lies between the
Royal Victoria Hospital, Belfast Health and Social inferior belly of omohyoid, the clavicle, and
Care Trust, Belfast, UK the lower part of the posterior border of
e-mail: seamus.napier@belfasttrust.hscni.net sternocleidomastoid
D.J. Gordon
Regional Plastics & Maxillofacial Unit, Ulster Lymphovascular drainage:
Hospital, Southeastern Health and Social Care Trust, The neck contains many lymph nodes subdi-
Dundonald, Belfast, UK
e-mail: derek.gordon@setrust.hscni.net vided into groups and located both superficially

Parotid gland and the

periparotid lymph nodes Suboccipital nodes
Retroauricular nodes
Facial node
Mastoid Process
Mandible
Sublingual gland
Upper and lower
Submental nodes deep cervical chain nodes
Submandibular
gland and nodes Trapezius
Hyoid bone
Posterior triangle nodes
Sternocleidomastoid
Lowermost deep
cervical nodes
Inferior belly of Omohyoid
Fig. 20.1 Lymph node distribution in the lateral neck and the major salivary glands (Reproduced, with permission,
and deep within the neck. While individual Level II

nodes can be described with reference to Level II nodes represent the upper jugular group
adjacent anatomic structures, it is common and consist of the nodes around the upper third of
practice, particularly in oncology, to divide the the internal jugular vein (IJV) and the adjacent spi-
node groupings in the neck into six levels nal accessory (XIth) nerve. They extend from the
(Fig. 20.2). level of the carotid bifurcation (approximating to
Level I the superior border of the thyroid cartilage) to the
This group consists of the nodes within the base of the skull. The posterior boundary of this
submental and digastric triangles and is also group is the posterior border of the sternocleido-
known as the submandibular group. In practice, mastoid muscle and the anterior boundary is the
the submandibular salivary gland is included in lateral border of the sternohyoid muscle. The tail
the specimen when lymph nodes in this level are of the parotid gland is often included when nodes
resected. It can be subdivided into sublevels a from this group are resected. It can be subdivided
and b, Level Ia referring to nodes in the submen- into sublevels a and b, Level IIb referring to nodes
tal triangle. lying above and behind the spinal accessory nerve.
20 Neck: Cysts, Tumours, and Dissections 221
Fig. 20.2 Right radical Submandibular gland

neck dissection. Dashed Tail of parotid
lines indicate the gland
boundaries of the
cervical lymph node Sternocleidomastoid
groups (Reproduced,
Level I
Allen and Cameron
(2013)) Internal jugular vein
Level II (on medial aspect of
specimen)
Level III
Intermediate tendon
of omohyoid
Level IV
Level V
Level III nodes located along the lower half of the spinal
This group of lymph nodes corresponds to the accessory (XIth) nerve and represent the lymph
middle jugular group and consists of lymph nodes in the occipital triangle and includes the
nodes located around the middle third of the so-called subclavian triangle as well which
IJV. They extend from the carotid bifurcation to extends to the clavicle from below omohyoid.
the intermediate tendon of omohyoid, where it The anterior boundary is the posterior border of
crosses the IJV. The posterior boundary is the the sternocleidomastoid muscle; the posterior
posterior border of the sternocleidomastoid mus- boundary is the anterior border of trapezius with
cle and the anterior boundary is the lateral border the clavicle below. It is sometimes subdivided
of the sternohyoid muscle. into sublevels a and b, Level Va referring to nodes
Level IV lying above a horizontal plane defined by the
This group of lymph nodes, also known as the inferior border of the cricoid cartilage.
lower jugular group, consists of nodes located Level VI
around the lower third of the IJV extending from Lymph nodes in this group, also known as the
the intermediate tendon of omohyoid where it anterior compartment group, comprise the nodes
crosses the IJV to the clavicle below. The poste- surrounding the midline structures of the neck
rior boundary is the posterior border of the extending from the level of the hyoid bone above
sternocleidomastoid muscle, while the anterior to the suprasternal notch below. On each side, the
boundary is the lateral border of the sternohyoid lateral boundary is the medial border of the
muscle. Lymph nodes within Levels II, III, and carotid sheath. Individual groups of lymph nodes
IV correspond to the jugular group or deep cervi- within this compartment are the perithyroid
cal chain of lymph nodes. They tend to be nodes, the paratracheal nodes, and the precricoid
regarded as subdivisions of a functional unit nodes.
rather than as distinct groups in their own right. Other groups of lymph nodes within the neck
Level V are also recognized and include the suboccipital,
Lymph nodes in this group, also known as the periparotid, retropharyngeal groups, and the buc-
posterior triangle group, comprise the lymph cal lymph node.
20.2 Clinical Presentation of paralysis or altered sensation, such as Horner’s

syndrome or Trotter’s syndrome. Ultrasound
Lesions in the neck usually present as swellings investigation is helpful in identification of cystic
and may be associated with any of the major ana- lesions or masses associated with blood vessels
tomical structures in the region, in particular and can provide information on the presence of
lymph nodes, thyroid gland, and salivary glands, other lesions in adjacent organs without the risks
or from other tissues such as skin, blood or lym- of ionizing radiation. Plain radiographs of the
phatic vessels, nerves or fat. Disease affecting facial bones or sinuses may reveal clinically unde-
lymph nodes usually presents as enlargement, tected lesions, while barium studies are useful in
affecting either a single lymph node or several visualizing pharyngeal diverticula or in tracking
nodes, unilaterally or bilaterally. The nodes may developmental sinuses or fistulae. CT scanning
be tender or painless and may vary in consistency and MR imaging can determine the consistency of
from soft to firm, rubbery or hard. In young the lesion, identify enlarged lymph nodes, and
patients, cervical lymphadenopathy is usually due detect the presence of occult primary tumours in
to a reactive process but a neoplasm is more likely clinically silent anatomical sites; PET CT scan-
in older patients. Malignant lymphoma commonly ning has greatly facilitated the identification of the
presents as cervical lymphadenopathy; metastatic occult primary tumour as well as aiding the detec-
deposits in cervical lymph nodes may be the pre- tion of distant metastasis. Scintiscans may be
senting feature of tumours in the posterior tongue, required if neoplastic or developmental lesions of
nasopharynx, tonsil, larynx, or thyroid gland. the thyroid or parathyroid glands are suspected.
Metastases in cervical lymph nodes usually derive Angiography will demonstrate the presence of a
from primary lesions above the level of the clavi- significant vascular component within a lesion
cles, although 10% will arise from distant sites and its relationship to adjacent vascular structures.
such as lung, stomach, testis, breast; the neck Fine needle aspiration (FNA) cytology has greatly
mass will usually be present on the left side facilitated the investigation of neck lumps in
(Virchow’s node). Cystic lesions in young patients recent years. Even if characteristic features allow-
are usually due to developmental abnormalities, ing diagnosis are not present, FNA can assist in
such as thyroglossal duct cysts or branchial cysts, the management of cases where open biopsy can-
while those in adults are most likely to represent not be performed effectively; ultrasound guidance
metastasis to a lymph node in which there is cystic allows precise sampling of deeply placed lesions;
degeneration. Sinuses opening onto the skin sur- core needle biopsies likewise. Endoscopic exami-
face may arise from thyroglossal duct cyst or nation of the nasal cavities, pharynx, larynx,
branchial cyst lesions or infective lesions, e.g., oesophagus, and bronchi under general anaesthe-
related to the mandibular teeth. sia with biopsy is commonly performed prior to
definitive surgery for squamous cell carcinoma of
the upper aerodigestive tract; an occult second pri-
20.3 Clinical Investigations mary tumour can occur in up to 10% of cases.
Swellings in the neck require thorough clinical

evaluation to determine the tissue or organ 20.4 Pathological Conditions
affected, whether the enlargement is solid or cys-
tic, and whether or not adjacent tissues are A wide variety of diseases can account for enlarge-
involved. Movement on swallowing tends to point ment of cervical lymph nodes. These may be reac-
to an intimate relationship with the hyoid bone or tive or neoplastic; they may be a consequence of
thyroid gland while pulsation or the detection of a local or systemic conditions and may or may not
bruit indicates association with or origin from have a known cause. Conditions not related pri-
major vascular structures. Tumours may involve marily to reactive disorders of lymph nodes or
adjacent nerves producing characteristic patterns malignant lymphomas are discussed below.
20.4.1 Non-neoplastic Conditions is common, particularly with mucosal squamous

cell carcinoma, cutaneous malignant melanoma,
Thyroglossal duct cyst: Probably the commonest and thyroid gland carcinoma. The frequency of
developmental neck cyst, due to failure of the lymph node involvement and the distribution of
embryonic thyroglossal duct (extending from the metastatic deposits vary with the site and type of
posterior tongue into the neck) to atrophy. the primary tumour. For example, nasopharyngeal
Midline in 90%, below hyoid in 70%; associated carcinoma often involves multiple nodes through-
with a sinus in 40% of cases. Lined by squamous out the neck, while squamous cell carcinoma of
and/or respiratory epithelium; less than half con- the lower lip rarely spreads to nodes and then usu-
tain thyroid follicles and may represent the ally only as a single deposit in Level I. Tumours of
patient’s only functioning thyroid tissue. the anterior two-thirds of the tongue generally
Branchial cleft cyst: Derived from remnants of metastasize to one or two ipsilateral Level II/III
the embryonic branchial apparatus following nodes, while carcinomas from the posterior one-
incomplete obliteration of the branchial pouches; third of the tongue, hypopharynx, or larynx can
the most common form is believed to derive from involve several nodes on both sides of the neck.
the second branchial pouch. Cyst lies in the lat- Cervical lymph node metastasis is not just
eral neck near the angle of the jaw at the anterior reserved for head and neck primaries; tumours of
border of sternocleidomastoid; the sinus may lung or upper gastrointestinal tract can occasion-
open onto the skin at the junction of the middle ally spread to nodes in the supraclavicular region.
one-third and lower one-third, while the tract fol- Lymph node metastasis may be detected either at
lows the carotid sheath and may fistulate into the the time of presentation with the primary lesion or
tonsillar fossa. Lined by squamous epithelium after initial therapy, although in about one-third of
with reactive lymphoid tissue in the wall; 10% patients, the cervical lymph node deposit is the
contain respiratory epithelium. Beware the cystic presenting feature. Usually the primary tumour is
metastasis from an occult head and neck primary located following clinical/endoscopic examina-
squamous cell carcinoma masquerading as a tion or imaging but may not be found in 10% of
branchial cyst in the patient over 40 years of age. cases. Over 80% of occult primary tumours pre-
Miscellaneous lesions: Other developmental senting with cervical metastasis are located in the
cysts in the neck include dermoid cyst (often head and neck, especially nasopharynx, posterior
extending into the neck from the sublingual one-third of tongue, tonsil, hypopharynx, and thy-
region), cervical thymic cyst, and cervical bron- roid gland. Histological clues as to the site of ori-
chial cyst. The “plunging ranula” is a mucous gin for metastatic squamous carcinoma include
extravasation cyst from the sublingual gland that evidence of EBV (nasopharynx) and HPV/p16
extends into the neck through mylohyoid. (oropharynx). Adverse prognostic features can
Cutaneous and subcutaneous haemangiomas are vary with the type of tumour but include the pres-
relatively common but do not differ from their ence of multiple tumour deposits particularly in
counterparts elsewhere. Lymphatic malforma- Levels IV and V, extracapsular spread (i.e., inva-
tions are uncommon in the neck and usually arise sion of tumour through the full thickness of the
low in the posterior triangle. They include com- node capsule) into adjacent tissues, involvement
plex lesions composed of very dilated vessels of extranodal lymphovascular channels, and
and formerly known as cystic hygroma. tumour involvement of surgical margins.
Paraganglioma: An uncommon neuroendo-
crine tumour arising at sites of autonomic para-
20.4.2 Neoplastic Conditions ganglia. In the head and neck, commonest at the
bifurcation of the common carotid artery (carotid
Metastatic malignant tumour in cervical lymph body paraganglioma or chemodactoma); others
nodes: Metastasis to regional lymph nodes from include the superior bulb of the jugular vein
primary tumours elsewhere in the head and neck (glomus jugulare), the promontory of middle ear
(glomus tympanicum), the ganglion nodosum of tract from the base of tongue to the isthmus of the
the vagus nerve, and the larynx. Carotid body thyroid and perhaps beyond (Sistrunk proce-
paraganglioma affects males and females dure); the central portion of the hyoid bone is
equally, although the others are more common in usually included. The risk of recurrence of the
females. Usually adults and presenting as a mass; cyst is much reduced by this procedure.
most are thought to be sporadic but at least 25% Treatment of a branchial cyst requires removal
are hereditary associated with syndromes such as of the entire lesion; fibrosis following infection,
succinate dehydrogenase gene mutations (most and intimate relationships to carotid sheath and a
frequently SDHD) but also neurofibromatosis or number of large nerves in the neck makes the
Multiple Endocrine Neoplasia syndrome; syn- procedure difficult.
dromic cases more likely to be multiple and will Neck dissection is either elective (clinically
present in younger patients. Slowly growing negative neck) or therapeutic (known metasta-
painless mass; may evoke neural symptoms such sis). Justification for an elective neck dissection
as conductive deafness, pulsatile tinnitus, hoarse- rests on three observations: occult disease will
ness or an intracranial mass effect. Characteristic develop into clinically evident disease, some-
histology of discrete cell nests (Zellballen) of times inoperable when eventually detected; there
polygonal endocrine chief cells and spindle- is a risk of distant metastasis with untreated
shaped neural sustentacular cells. Neither occult neck metastasis; and additional histologi-
nuclear pleomorphism nor the presence of cal information of prognostic value may be
mitotic figures signifies malignancy; rather proof gained. Arguments against elective neck dissec-
of metastasis is required. The intimate relation- tion include unnecessary treatment when there is
ship to adjacent vital structures makes complete a low risk of metastasis and significant morbidity
excision challenging; irradiation and embolisa- and a risk of mortality in elective surgery. The
tion are often employed in skull base tumours. decision to perform an elective neck dissection is
based on a risk of metastasis of more than 20%,
whether or not the neck nodes can be easily
20.5 Surgical Pathology assessed clinically, the availability of the patient
Specimens: Clinical Aspects for close follow-up, and the fitness of the patient
for surgery. Elective surgery may also be under-
20.5.1 Biopsy Specimens taken where access to the tumour must pass
through the neck or where access to the neck is
A lymph node in the neck may be excised for his- required to identify vessels for microvascular
topathological assessment when persistently reconstruction. Sentinel node sampling is being
enlarged and when there is no clear reactive used increasingly as a technique to identify
cause; in most cases FNA will have indicated the patients with head and neck cancers in whom an
presence of a lymphoproliferative disorder that elective neck dissection might be avoided; the
might represent lymphoma. Exclusion of meta- vagaries of lymphatic drainage and the require-
static squamous cell carcinoma by FNA is impor- ment for clinical and pathological expertise are
tant; definitive treatment of the neck following not without consequence. Elective irradiation of
such inadvertent open biopsy with possible skin the neck may be an acceptable alternative to a
contamination may be more extensive than might “watch and wait” policy.
otherwise be required. Usually, the less extensive neck dissection
procedures are the operations of choice in the
clinically negative neck. The choice depends on
20.5.2 Resection Specimens the nature and site of the primary tumour and the
expected pattern of nodal spread. Nodes in Levels
Excision of thyroglossal duct remnants and/or I–IV are removed for oral and oropharyngeal
cyst requires clearance of the entire thyroglossal tumours, Levels II and III for laryngeal and hypo-
pharyngeal tumours, but elective dissection is 20.6.2 Resection Specimens

rare for thyroid carcinomas. Bilateral dissection
may be indicated if the primary tumour crosses 20.6.2.1 R esections of Carotid Body
the midline. Paraganglioma
The rationale of therapeutic neck dissection Usually received as non-orientated soft tissue
is the clearance of disease with preservation of mass in formalin. Larger specimens may be
function. Classical radical neck dissection is fragmented.
performed for nodal metastasis >6 cm in diam- Procedure:
eter, multiple large metastatic deposits in sev-
eral levels, recurrent disease following neck • Ink the external limits of the specimen.
irradiation, gross extranodal spread involving • Measurements:
the skull base, involvement of other tissues esp., –– Dimensions of specimen (cm)
IJV, sternocleidomastoid (SCM) and XI nerve, –– Weight (g)
and skin involvement. Other so-called func- –– Tumour maximum dimensions (cm)
tional dissections may be performed to preserve –– Distance (cm) to the closest soft tissue
the spinal accessory nerve, sternocleidomastoid, limits.
and internal jugular vein, consistent with achiev-
ing clearance. Description:
Two or more positive nodes following histo-
logical examination of the specimen and/or the • Tumour
presence of extracapsular spread merit postoper- • Colour; areas of haemorrhage or necrosis
ative radiotherapy. (preoperative embolization?)
• Circumscribed, encapsulated, or infiltrative
margin
20.6 Surgical Pathology • Other
Specimens: Laboratory • Vessels or nerves identifiable.
Aspects
• The histology should represent the tumour
20.6.1.1 Thyroglossal Duct and the relationship to the margins, vessels
Remnants/Cysts and/or nerves.
Usually as a single strip of fibrous tissue with or • Section the specimen into 4 mm thick slices
without a nodule surrounded by fat free-floating and sample the tumour and margins.
in fixative, non-orientated; the body of the hyoid • Select at least one block of tumour per cm
may be present. Measure in three dimensions. If diameter to represent the various morphologi-
10 mm in length or less, submit in total. If larger, cal patterns present.
block serially and submit representative samples.
20.6.1.2 Branchial Cleft Cysts
Usually as a single cystic nodule surrounded by Final paraganglioma reports should include
fat free-floating in fixative, non-orientated. A details on:
sample of adjacent lymph nodes may be present.
Measure in three dimensions. If 10 mm in diam- • The type of tumour present
eter or less, submit in total. If larger, block seri- • The nature of the tumour–tissue interface
ally and submit representative samples. If the • The relationship to major vessels and nerves
patient is aged over 40 years, block serially and • The distance of tumour from the nearest
submit in total. margin.
20.6.2.2 Neck Dissection Specimen Procedure:

The vast majority of neck dissection specimens
are submitted for neoplastic conditions, although • Orientate the specimen. The surgeon should
occasionally nodes from Levels I-III may give some indications on the request form but
be removed to facilitate access to vessels for it can still be difficult particularly with selec-
microvascular anastomosis during reconstructive tive dissections, for example, of Levels II and
jaw surgery. Neck dissection specimens may be III only. Fig. 20.2 and the following anatomi-
classified as “comprehensive” neck dissection cal landmarks may assist:
specimens (radical or modified radical neck dis- –– The superior aspect: Submandibular gland,
sections) or selective neck dissection specimens mandibular periosteum, tail of parotid
(e.g., suprahyoid or supraomohyoid neck dissec- gland, posterior belly of digastric
tion specimens). TNM 8 indicates that these –– The inferior aspect: Intermediate tendon of
would ordinarily include 10 and 15 or more omohyoid where it crosses the IJV; the
lymph nodes, respectively. These are listed in fatty tissues from the posterior triangle
Table 20.1. region (Level V) tend to be bulkier
inferiorly
–– The medial aspect: The IJV running inferi-
Table 20.1 Categories and components of neck dissec- orly and slightly anteriorly
tion specimens –– The lateral aspect: Skin, platysma,
Other sternocleidomastoid
Neck dissection Lymph node structures • Open the IJV longitudinally, if present, to
specimens groups present
view its luminal aspect. Extracapsular spread
Comprehensive
from a tumour deposit is easily identified at
Radical Levels I–V SCM, IJV
and XIth
this time as a white area in the wall of the IJV
nerve and may indicate the location of the closest
Modified radical Levels I–V Variable; one medial deep surgical margin. The involve-
or all will be ment of the lumen of the vein by tumour is not
lacking considered an independent risk factor in
Extended radical Levels I–V Other lymph survival.
node groups
or non- • Dissect off the muscles. Start with platysma,
lymphatic then sternocleidomastoid. The presence and
structures extent of extracapsular spread approaching the
Selective lateral deep surgical margin can be easily
Suprahyoid Levels I–II Variable, one detected at this stage. Then remove mylohy-
or all will be oid, digastric, etc. Leave omohyoid attached
lacking
(if present) to mark the junction of Levels III
Supraomohyoid Levels I–III Variable, one
or all will be and IV. Reducing the bulk of the specimen
lacking improves the detection of smaller nodes.
Anterolateral neck Levels II–IV Variable, one • Divide the specimen into the respective node
or all will be levels (Levels I–V) as detailed above. The pre-
lacking
cise anatomical boundaries of the various
Posterolateral neck Levels II–V Variable, one
and or all will be
node groups are lost during the operation, par-
suboccipital lacking ticularly if the specimen is distorted during
nodes removal, but precise distinction is usually not
Anterior Level VI Variable, one critical.
compartment or all will be • Separate the submandibular gland from Level
lacking
I nodes, by dissecting along the plane of the \r
nodes as usual.
Measurements: • The number of positive lymph nodes in each

level
• Length of IJV, if present (cm). • The location of the largest tumour metastasis
• Dimensions (cm) of tumour deposits (NB: not and its dimensions
the size of the node). • The presence or absence of extracapsular
• If a tumour mass of several matted nodes is spread and the levels involved
present, record its maximum dimensions. • The distance of the tumour from the nearest
• Micrometastasis (<0.2 cm) is recorded as deep margin.
nodal involvement, but its precise significance
is unclear.
• Distance (cm) to the nearest deep surgical
margin (usually medial). Bibliography
Blocks for histology: Allen DC. Histopathology reporting. Guidelines for surgi-

• For large nodes, submit one representative clinical, pathological and laboratory aspects. 2nd ed.
slice; for smaller nodes, submit in total. Berlin: Springer; 2013.
Remember to keep the nodes from each level Barnest L, Eveson J, Reichart P, Sidransky D. WHO
separate. classification of tumours. Pathology and genetics.
Tumours of the head and neck. Lyon: IARC Press;
• One block of each of the following is recom- 2005.
mended unless involved by tumour: Brierley JD, Gospodarowicz MK, Wittekind C, editors.
–– The submandibular and parotid glands. TNM classification of malignant tumours. 8th ed.
–– The closest medial and lateral deep surgi- Oxford: Wiley-Blackwell; 2017.
cal margins. head and neck. 2nd ed. Philadelphia: WB Saunders;
• If other specimens are attached to the neck as 2009.
an “in-continuity dissection” (e.g., skin, man- Paleri V, Urbano TG, Mehanna H, et al. Management of
dible, oral mucosa, thyroid gland, larynx or neck metastasis in head and neck cancer. UK National
Multidisciplinary Guidelines. J Laryngol Otol.
pharynx), these can be cut separately in the 2016;130(Suppl. S2):S161–9.
usual fashion. Shah JP, Patel SG. Head and neck surgery and oncology.
3rd ed. Edinburgh: Mosby; 2003.
Histopathology report: The Royal College of Pathologists. Dataset for histopa-
Final neck dissection reports should include section specimens associated with head and neck
details on: carcinomas; November 2013. https://www.rcpath.
org/profession/publications/cancer-datasets.html.
• The specimen type Accessed July 2016.
• The type and grade of tumour present head and neck pathology; January 2016. https://www.
• The number of lymph nodes recovered from rcpath.org/profession/publications/cancer-datasets.
each level html.
Part IV
Eye
Eye
21
Roy W. Lyness
21.1 Anatomy choroid which also contains the nerve supply to

the ciliary body and pupil. Blood pressure is
The adult eye measures approximately responsible for the tension or firmness of the eye.
23 × 23 × 24 mm (Fig. 21.1). The anterior aspect Take away the blood pressure and the eye will
(cornea) is transparent, allowing light to enter become soft. The choroid is covered on the exter-
and be focused by the crystalline lens before nal surface by the sclera to which the extraocular
being picked up by the photosensitive retina and muscles are attached in order to move the eye.
converted into electrical impulses which are
transmitted to the brain by the optic nerve.
The surface of the cornea is protected by the 21.2 Eyelids
eyelids and lubricated by the lacrimal gland
which produces tears. The tears flow over the eye The ophthalmic surgeon’s most common biopsy
keeping the surface moist and are collected at the is the eyelid. To most intents and purposes the
caruncle where they drain via the naso-lacrimal laboratory management is that of a biopsy of
duct. skin. However, the problem for the ophthalmolo-
The amount of light admitted to the eye is con- gist is gaining adequate clearance for malignant
trolled by the pupil rooted in the ciliary body lesions as a wide excision of a lid lesion may
which controls the focusing of the lens and the deprive the patient of sufficient lid cover for the
production of aqueous humour that fills the ante- eye, resulting in a lack of lubrication and protec-
rior chamber draining to the systemic circulation tion from abrasion and infection. To this end,
(conjunctival veins) via the trabecular meshwork marking the orientation of the specimen and the
in the filtration angle and Schlemm’s canal. limits of excision is of great importance.
The posterior chamber contains gelatinous It is best practice that the surgeon draws a dia-
material known as vitreous humour. gram of the area and marks the lateral or medial,
The eye is “inflated” by systemic blood pres- superior or inferior margins of the biopsy speci-
sure within the capillary meshwork that is the men with sutures and records the marks made on
the diagram. The deep limit can be marked with
dye in the laboratory.
The most common tumours of the eyelid
are basal cell carcinoma and squamous cell
R.W. Lyness carcinoma. Other tumours to be considered
Histopathology Laboratory, Belfast City Hospital, are malignant melanoma, sebaceous gland
e-mail: roylyness@googlemail.com tumour, and Merkel cell carcinoma. In some

232 R.W. Lyness
Orbital bone Zonular

(roof) ligament
Ciliary
body
Lens
Fornix
Posterior chamber
( vitreous)
Upper eyelid
Retina
Choroid
Anterior chamber
Sclera
Cornea
Dura and meninges

Iris
Lower eyelid Optic nerve
Filtration angle
trabecular meshwork
Orbital bone (floor)
Schlemm’s canal
Fornix
Upper eyelid
Cornea
Lacrimal gland
Limbus
Conjunctiva
Caruncle
Nasolacrimal
duct
Pupil
Iris
Fig. 21.1 Anatomy of the eye (Reproduced, with permission, from Allen and Cameron (2013))
oculo-plastic operations, a series of biopsies The gamut of benign tumours includes squa-
from the margins of excision may be sent to the mous papillomas, keratoses, naevi, inclusion
laboratory for frozen section and report, in cysts, chalazion, and molluscum contagiosum.
order to ascertain whether or not excision of a The eyelid biopsy is often a wedge resection of
malignant lesion is complete. This is difficult the lid. A central section through the eyelid to ascer-
work relying on cooperation between surgeon tain the deep limit of excision and a superior or infe-
and the laboratory to identify correctly the ori- rior limit of excision is taken. The lateral blocks are
entation of the specimens. cut through 2–3 mm serial slices from the lateral or
21 Eye 233
Central block
Superior
Tumour or lesion
Edge of eyelid Tumour or lesion
Lateral Medial Lateral Medial
Surgical
limits
Inferior
Tumour or lesion
Epidermis of eyelid Conjunctiva
Side view of eyelid Fornix

(sagittal)
Fig. 21.2 Wedge resection of eyelid (Reproduced, with permission, from Allen and Cameron (2013))
medial aspect toward the centre. This allows all six 2. Pigmented
limits of excision to be judged (Fig. 21.2). Eyelid –– Naevi
resections can be partial (cutaneous aspect only) or –– Malignant melanoma
full thickness (anterior cutaneous, eyelid margin, –– Extrinsic, e.g., injury
and posterior conjunctival aspects). 3. Inflammatory
–– Not usually biopsied but may be scraped
for diagnosis of trachoma or other parasite
21.3 Conjunctiva infection
4. Malignancy
The conjunctiva is covered by specialized squa- –– Basal cell carcinoma
mous epithelium containing mucus-secreting –– Squamous cell carcinoma
cells. The specialized epithelium is on the poste- –– Malignant melanoma
rior aspect of the eyelids and covers the eye to the
limbus, where it becomes entirely squamous epi- The purpose of conjunctival biopsies is usu-
thelium to cover the cornea. ally diagnostic ± cosmesis. As with eyelid biop-
The common lesions of the conjunctiva are sies, an assessment of the limits of excision may
be of importance, but usually the presence of
1. Degenerative infiltrating tumour in a biopsy from the fornix of
–– Pinguecula the conjunctiva is sufficient justification for more
–– Pterygium radical treatment. Incisional biopsies may be
234 R.W. Lyness
used to “map” the full extent of a neoplastic pro- 2. Non-inflamed—Indicating a congenital dys-
cess prior to definitive excision. Classic blister- trophy or abnormality, e.g., keratoconus,
ing disorders affecting the conjunctiva (e.g., Fuch’s dystrophy
pemphigoid, linear IgA disease) require a fresh
specimen and direct immunofluoresence tech- It may be that a congenital abnormality such
niques with specialist interpretation. as keratoconus will result in ulceration and scar-
ring but most dystrophies have little evidence of
inflammation or vascularization.
21.4 Cornea Electron microscopy may have to be used to
differentiate between some of the more obscure
Corneal “scrapes” of ulcerating lesions may be lesions affecting the cornea.
sent to microbiologists in order to identify organ-
isms by direct microscopy and culture. Bacterial
infections, fungi, and Acanthamoeba may be 21.5 Iris
identified this way. Occasionally the edge of a
corneal ulcer may be submitted to the laboratory Small biopsies or localized resections of the iris
for histology as the lesion is resisting antibiotic may be taken to confirm and/or treat a clinical
therapy. These small biopsies are submitted whole diagnosis of malignant melanoma.
and examined through levels. Using special Pigmented lesions of the iris are most often
stains, fungi (usually Aspergillus but occasionally benign naevi. However, serial clinical observa-
Fusarium or Penicillium) or Acanthamoeba may tions may identify lesions that are growing rap-
be identified. It is unusual to find bacteria due to idly, particularly when they involve the filtration
the therapeutic measures taken. angle, have an irregular pattern of growth and
Corneal “buttons,” as they are known in the show changes in pigmentation.
trade, produced at full- or partial-thickness kera- In the laboratory, one uses a dissecting
toplasty, are submitted to the laboratory for eval- microscope to attempt to orientate the small
uation of and corroboration of clinical diagnoses. specimen especially if the operative procedure
They should be measured for maximum diameter has been a sector iridectomy where the root
and described grossly for evidence of ulceration, of the iris (filtration angle, adjacent cornea/
scarring, transparency/opacity, and abnormal sclera, and ciliary body) is included. This is
pigmentation. especially important as the presence of infiltra-
Using a long sharp blade (e.g., disposable tion of the trabecular meshwork and Schlemm’s
microtome blade) the cornea is cut across the canal by tumour is an indicator of a poor
ulcer, the pigmentation, or maximum opacity so prognosis.
as to leave roughly three-fifths of the lesion for
processing and a reserve of two-fifths of the
lesion for other investigations, e.g., electron 21.6 Orbit
microscopy. Care has to be taken to avoid arti-
facted abrasion or removal of the squamous epi- Biopsies of the orbit are of two types:
thelium covering the cornea or the posterior layer
of endothelial cells. 1. Where the clinicians believe they can gain
Histological sections are cut and stained with access to the pathology via Tenon’s capsule
H + E. In essence, there are two main types of and take a pinch from the subjacent tissue.
histology: These are often unsatisfactory.
2. Where after clinical and radiological evalua-
1. Inflamed/scarred—Indicating an ongoing or tion, a formal biopsy for diagnosis and/or
previous infection, ulcer, or failed corneal treatment is made, often involving a lateral
graft orbitotomy (cutting bone at the side of the
21 Eye 235
orbit) to gain access to the lesion deep within glands and is subject to a similar spectrum of
the orbit or in the cone formed by the extra- pathological lesions.
ocular muscles. The two main tumours of the lacrimal gland
are pleomorphic adenoma and adenoid cystic
Lesions of the orbit present clinically as pro- carcinoma. Pleomorphic adenoma is benign
ptosis (eye coming forward) with varying degrees occurring in middle age with a tendency to recur
of squint, double-vision, and discomfort. if inadequately excised. It causes painless propto-
As this is a tricky site for surgery, patients are sis and has bony sclerosis on X-ray. Adenoid cys-
often referred to specialist ophthalmic surgeons and tic carcinoma occurs in a younger age group,
centres with their attendant pathological facilities. infiltrates local structures, causing painful pro-
Patients require a complete clinical examination ptosis as it has an affinity for nerves and erodes
and evaluation as often clues to the cause of the the surrounding orbital bone.
proptosis may be found as a result of detecting the Both require complete excision for adequate
presence of tumour elsewhere, e.g., lobular breast therapy, pleomorphic adenoma being usually
carcinoma, prostate carcinoma, lymphoma, von amenable to lateral orbitotomy in the first
Recklinghausen’s syndrome. Equally, blood bio- instance, but may require more drastic action as
chemistry (thyrotoxicosis, tumour markers), serol- the recurring tumour infiltrates between the two
ogy (systemic lupus erythematosus, Wegener’s bony tables of the skull, causing serious prob-
granulomatosis), and radiology (e.g., bony sclero- lems of tumour control. Adenoid cystic tumour
sis versus bony erosion, presence or absence of cal- may require oculo-plastic surgery to gain ade-
cification, e.g., meningioma, varix within a tumour quate control of the disease.
mass), CT scanning, and MRI are valuable. For the laboratory, besides diagnosing the
The process of clinical evaluation is important lesion, it is important to be able to identify the
as ideally surgeons attempt to remove only small limits of excision and comment on their involve-
resectable primary tumours, e.g., cavernous hae- ment or otherwise by the tumour.
mangioma, pleomorphic adenoma of the lacrimal Tumours of the naso-lacrimal ducts include
gland while avoiding irresectable malignancies, benign polyps and malignancies common to the
and metastatic tumours. nasal sinuses and upper respiratory tract. The
In the laboratory, the investigation of biopsies is clinical presentation is epiphoria as the tears are
the same as from anywhere else in the body with the unable to drain via the duct overflowing the eye-
following caution. Biopsies of inflammatory lesions lid. Laboratory management is as always in ENT
should be investigated thoroughly as missing an cases, which is to diagnose the nature of the
infective lesion (fungus, tuberculosis) may result in lesion, and, if malignant, detail the adequacy of
a patient being treated inappropriately with steroids the excision (see Sect. 21.8.3).
exacerbating the condition. Similarly, confusion
between chronic inflammatory lesions and the usual
low-grade lymphomas seen in the orbit is made 21.8 Eyes: Evisceration,
more likely by the often miserly and inadequate Enucleation
biopsies of the orbital fat taken via Tenon’s capsule. and Exenteration
There are three types of biopsy involving the

21.7 Lacrimal Apparatus eye or “globe” as it is called in ophthalmic
pathology:
This consists of a lacrimal gland situated in the
superolateral aspect of the orbit, making tears 1. Evisceration
which are drained via the punctum to the naso- –– This is where the contents of the eye are
lacrimal duct in the nasopharynx. The gland mea- removed via an incision around the limbus,
sures approximately 1–1.5 cm in diameter, has a taking iris, ciliary body, lens, vitreous, cho-
histological appearance similar to the salivary roid, and retina but leaving the sclera.
236 R.W. Lyness
2. Enucleation phthisical eye) should be identified and processed

–– This is where the eye or globe is removed via acid to avoid damage to microtome blades.
with a short piece of optic nerve. When examining the contents of the eye, it is
3. Exenteration difficult to give a comprehensive account to vali-
–– This is where the eye, surrounding orbital date the clinical history of the eye and one is often
contents, eyelids, naso-lacrimal appara- reduced to noting the degree and type of the inflam-
tus ± orbital bone are removed. matory process and, in the case of acute inflamma-
tion and pus, the presence of and type of organisms.
There are three main reasons for removing an eye Rarely is this procedure used to treat a tumour.
or its contents
1. Life-threatening conditions 21.8.2 Enucleation

–– Either pus or tumour
2. Pain 21.8.2.1 External Anatomy
–– Usually absolute glaucoma with loss of It is necessary to confirm that the specimen
vision is indeed the right or left eye as given on the
3. Cosmesis histopathology request form. This is done by ori-
–– To remove an unsightly eye or to prevent entating the eye using the positions of the rectus
facial asymmetry in young people around a muscle, tendons, and the superior and inferior
collapsed micro-ophthalmic or expanding oblique extraocular muscles. The superior
buphthalmic eye. oblique muscle has a long string-like tendon
inserting into the sclera lateral and slightly poste-
rior to the superior rectus muscle and superior to
21.8.1 Evisceration the optic nerve. The inferior oblique muscle is
fleshy and brown right up to the insertion into the
The dishevelled and disorganized contents of the globe and is situated lateral and inferior to the
eye are submitted in formalin fixative. If possible optic nerve. So the eyes should have the superior
they should be examined grossly and, if recogniz- oblique muscle, optic nerve, and inferior oblique
able, sorted into component parts. Calcified mate- muscles forming a triangle when viewed posteri-
rial (lens or remnants of osseous metaplasia in a orly (Fig. 21.3).
Superior rectus
Superior rectus
Superior Superior
oblique oblique
Medial rectus
Lateral Lateral
rectus rectus
Optic nerve
Inferior oblique
Inferior rectus Inferior rectus

Left eye Right eye
Fig. 21.3 Anatomical orientation of the eye. Landmarks on the eyes as viewed from the posterior aspect (Reproduced,
with permission, from Allen and Cameron (2013))
21 Eye 237
Having orientated the eye a systematic list of in order to have the classical section of central
the external features is made. The normal diameter cornea, centre of pupil, lens, lesion, and optic
is 23–24 mm. Conditions such as glaucoma may nerve.
thin the sclera causing herniations or staphylomata Similarly, X-ray examination for bone or for-
in areas of weakness. Otherwise there may be a eign bodies may be undertaken using needles on
slight increase in diameter as may also be seen in the external surface to help locate the lesion.
myopia. Examination of the cornea includes not- Techniques (Fig. 21.4 ): A thin section of the
ing any surgical or traumatic incisions, sutures, optic nerve is taken first and submitted for
opacities, or pigmentation. Is the iris visible? Is it histology.
symmetrical, abnormally pigmented, or deficient? Vertical cuts to give calottes is the technique
If it is deficient, where on a clock-face (12 used when studying surgical lens extractions and
o’clock = superior) and what size? Is there pus or the surgical site following a failure of or compli-
proteinaceous fluid in the anterior chamber? cations of cataract surgery. An implanted plastic
The conjunctiva and sclera are examined for lens may interfere with the smooth cutting of the
abnormal pigment, incisions, or evidence of blade and therefore should be anticipated.
radiotherapy plaques or bands for the treatment Horizontal cuts give calottes which include
of detached retina. cornea, centre of pupil, lens, lesion, macula, and
The optic nerve and scleral vessels are exam- optic nerve. The inferior oblique helps one iden-
ined for evidence of tumour. After making these tify the posterior temporal sclera.
gross observations, it is advisable to photograph The calottes should be cut first 1 mm from
the external surfaces of the eye. the optic nerve proceeding anteriorly to cut the
cornea about 2 mm medial to the limbus. The
21.8.2.2 Laboratory Details globe is placed on the cutting block and the pro-
Fixation of the eye: Globes are usually fixed in cedure repeated on the other side of the optic
formalin fixative. Prior to cutting, they are trans- nerve. Vertical cutting results in a nasal calotte,
ferred to 95% alcohol as this “hardens” the sclera a central wedge-shaped block, and a temporal
making it slightly easier to cut and improves the calotte. These can be further examined under
colour and presentation of the eye prior to liquid to conserve the anatomy, keeping the ret-
photography. ina in situ.
Tools required: The best instrument to cut a All blocks are examined, carefully noting:
globe is a long, very sharp, thin blade. The idea
is to get one long smooth cut that cuts the whole • The depth and contents of the anterior
of the eye, rather than a series of sawing move- chamber
ments that disrupt the internal anatomy and • The presence or absence of the lens
make processing and sectioning difficult. A dis- • The presence or absence of cataract, the vitre-
posable microtome blade (10–15 cm) may be ous (clear, gelatinous or turbid, the presence
used, but extreme care has to be taken to avoid or absence of membranes)
spilling an innocent person’s blood over the • The retina whether it is in-situ or detached (a
specimen. subretinal exudate indicates a true as opposed
Eyes opened and found to contain bone or cal- to artifactual retinal detachment)
cified debris, are gently decalcified in acid before • The presence or absence of recent/old hemor-
finishing off the cutting. Eyes containing foreign rhage in the vitreous or choroid
bodies should have them removed carefully after • The thickness of the sclera
noting and photographing their location.
Transillumination in eyes containing tumour: 21.8.2.3 Pathological Conditions
It may be possible to transilluminate the eye Tumours: There are two main tumours affecting
using a strong narrow beam of light (usually the eye, malignant melanoma (presents from
fibreoptic) in order to locate the mass. This is second decade to very elderly) and retinoblas-
helpful in deciding how to cut and open the eye toma (which presents in childhood). However,
238 R.W. Lyness
Horizontal cuts for a lateral tumour

producing superior, middle and inferior
calottes
Fig. 21.4 Blocking an eye specimen (Reproduced, with permission, from Allen and Cameron (2013))
many other tumours have been described within Prognosis for these tumours depends on four
the eye, including adenomas and adenocarcino- major factors:
mas of the ciliary body epithelium, schwanno-
mas, lymphomas, haemangiomas, and metastatic 1. Age at presentation: Older is worse than

tumours from lung, breast, and stomach. Prior young.
to treatment, fine needle aspiration cytology 2. Site within the eye: Posterior is better than
is undertaken in some specialist centres to equatorial, which is better than anterior where
distinguish between primary and metastatic it quickly gains access to the venous side of
tumours. the systemic circulation via Schlemm’s canal.
Malignant melanomas may occur anywhere in Iris melanoma has a much lower mortality due
the uveal tract but are most commonly found in to earlier clinical presentation.
the choroid. They arise in the choroid pushing 3. Size of tumour (maximum diameter):
Bruch’s membrane over them until they perforate >15 mm poor prognosis.
it, causing the overlying retina to detach with >10 mm guarded prognosis.
consequent formation of a subretinal exudate. 5 mm interesting, but not immediately lethal.
The tumour gains access to the venous side of the 4. Presence and extent of extraocular invasion.
systemic circulation via the perforations of the
sclera by the artery, vein, and nerve bundles, and The size of tumour covers factors such as cell
may be seen causing black pigmentation in the type, as small tumours tend to be spindle B cell
region of the vortex veins. Alternatively, malig- type and the larger tumours have increasing num-
nant melanomas may infiltrate the filtration angle bers of epithelioid cells. Similarly, larger tumours
of the anterior chamber en route to Schlemm’s tend to exit the eye via the sclera or Schlemm’s
canal and the conjunctival veins. This causes canal. Size is most accurately determined by pre-
abnormal pigmentation of the conjunctiva at the operative ultrasound. Treatment is generally by
limbus. Uveal malignant melanoma classically enucleation, but sight sparing localized resection
metastasizes to the liver. of the iris, ciliary body, or choroid is performed
21 Eye 239
by some specialist centres for tumours of limited intra-ocular pressure causing thinning and anaes-
extent. thesia of the cornea.
TNM 8 classification of tumour spread of cili- Such eyes are cut and processed with attention
ary body and choroid malignant melanoma is to the clinical history in order to corroborate the
based on the tumour maximum thickness, sclera clinical findings and demonstrate the cause of the
basal diameter, and the presence and extent of open- or closed-angle glaucoma.
extraocular invasion. Inflammation: The eye is subject to endo-
Retinoblastoma—two types: phthalmitis secondary to penetrating injuries or
surgical procedures. This may be treated by ste-
1. Congenital: Where both eyes ± the pineal
roids provided it is not infected. Infections, bac-
gland are affected. terial, fungal, helminthic (toxocariasis), and
2. Sporadic: Where one eye is affected and the protozoal (toxoplasmosis), cause a spectrum of
patient carries a genetic risk for the next acute to chronic inflammation. The presence of
generation. pus and the potential of infection to track to the
CNS may necessitate evisceration or enucleation.
The tumour arises in one, two, or all three of Often the inflammation subsides, but the resul-
the layers of the retina, forming retinoblasts tant healing process precipitates detachment of
which may infiltrate the overlying vitreous (endo- the retina and glaucoma requiring enucleation of
phytic) or the underlying subretinal space (exo- a painful blind eye.
phytic). The tumour exits the eye via the optic Granulomatous inflammation affecting the
nerve to the brain. It infiltrates the choroid if choroid or sclera may be the result of sympa-
there has been damage to Bruch’s membrane thetic endophthalmitis, sarcoidosis, rheumatoid
(usually following x-radiation treatment). From arthritis, Wegener’s granulomatosis and the ter-
there it may metastasize systemically. minal stages of miliary tuberculosis.
Treatment of congenital retinoblastoma usu-
ally involves excising the worse eye and treating
the better eye with collumated irradiation, hoping 21.8.3 Exenteration
to conserve some function. For sporadic cases,
the affected eye is removed, hoping to avoid Exenteration is carried out to gain control of a
spread to the brain via the optic nerve. In general, malignant tumour affecting the tissues around the
enucleation for retinoblastoma is carried out in eye, e.g., eyelids, orbital contents, nasal sinuses,
patients with advanced intraocular disease and if palate. Often there is no direct extension of the
there has been failure of conservative tumour into the eye and no evidence of tumour
management. metastasis within the choroid. The object of the
TNM 8 classification and prognosis of retino- laboratory investigation is to determine whether
blastoma are based on whether the tumour is or not the radical surgical excision of tissue from
localized to the eye, and the presence and extent around the eye has removed the tumour with
of involvement of the choroid, the optic nerve clear surgical margins and if the tumour is in the
and its resection limit, and extraocular tissues. microvasculature leading to cervical lymph
These unfavorable high-risk factors warrant con- nodes.
sideration of postoperative adjuvant chemother-
apy and radiotherapy. 21.8.3.1 Procedures
Glaucoma: The main cause for enucleation is Radical dissections may come with many frag-
the painful blind eye. Such eyes usually have a ments including a dissection of the eye, eyelids,
long history of attending an ophthalmologist with and orbital contents. It is necessary to identify
episodes of therapy (medical and surgical) before and orientate the components of the overall dis-
opting for pain relief and preemptively prevent- section in order to determine the surgical limits
ing the eye from rupturing due to the increased of excision.
240 R.W. Lyness
For the central block of eye, eyelids, and orbit, it –– Dataset for the histopathological reporting of
is useful to mark the cut edges of the block of tissue uveal melanoma: 3rd edition January 2015.
with different dyes to ensure that the superior/infe- –– Tissue Pathways for non-neoplastic ophthal-
rior and medial/lateral limits are easily identified. mic pathology specimens: February 2015.
The eye is orientated using the lids and caruncle to
confirm the side from which it was taken according
to the request form and the superior/inferior,
medial/lateral limits. Any gross evidence of tumour Bibliography
should be accurately located and described.
Using the cornea and optic nerve as landmarks, Allen DC. Histopathology reporting. Guidelines for surgi-
cal cancer, 3rd ed. London: Springer; 2013.
as described in the procedures for the enucleated Allen DC, Cameron RI. Histopathology specimens:
globe, antero-posterior incisions are made on clinical, pathological and laboratory aspects. 2nd ed.
either side of the cornea and optic nerve to obtain Berlin/Heidelberg: Springer; 2013.
a central block that should have lids, cornea, lens, Barcroft JD. Histochemical technique. London:
Butterworths; 1967.
vitreous, retina, choroid, sclera, and optic nerve Brierley JD, Gospodarowicz MK, Wittekind C, editors.
within surrounding tissues as a central block leav- TNM classification of malignant tumours. 8th ed.
ing medial and lateral calottes of eye and surround- Oxford: Wiley-Blackwell; 2017.
ing soft tissues. Further blocks may be cut to obtain Font RL, Croxatto JO, Rao NA. Tumors of the eye and
ocular adnexa, Atlas of tumor pathology, vol. 4th
medial and lateral limits of excision as required. series. Fascicle 5. Washington, DC: AFIP; 2007.
These are often in a horizontal plane. Ford AL, Mudhar HS, Farr R, Parsons MA. The oph-
For further details and practical approaches to thalmic pathology cut-up. Part 2. Curr Diagn Pathol.
the handling of ophthalmology specimens the 2005;11:340–8.
Lee WR. Ophthalmic histopathology. London: Springer;
reader is referred to the following Royal College 1993.
of Pathologists publications Lucus DR. Greer’s ocular pathology. Oxford: Blackwell
Scientific; 1989.
–– Dataset for the histopathological reporting of The Royal College of Pathologists. Cancer datasets
(ocular retinoblastoma, conjunctival melanoma and
conjunctival melanoma and melanosis: melanosis, uveal melanoma) and tissue pathways
October 2007. for non-neoplastic ophthalmic pathology specimens.
–– Dataset for ocular retinoblastoma histopathol- Accessed at https://www.rcpath.org/profession/publi-
ogy reports: December 2014. cations/cancer-datasets.html
Part V
Gynaecological Specimens
Ovary
22
22.1 Anatomy tomosing to form capillary channels. Veins

accompany the arteries and in the hilum form a
The ovaries are paired structures lying in the right plexus which drains into the ovarian vein. The
and left iliac fossae, on either side of the uterus ovarian veins course along the surface of the ova-
attached to the posterior aspect of the broad liga- ries, the right draining into the inferior vena cava
ments (Fig. 22.1). In the reproductive age group, and the left into the left renal vein.
each ovary is typically approximately 3 cm in The ovarian lymphatics originate with the
maximum dimension, but the size may vary con- theca layers of the follicles and course through
siderably. In the prepubertal and postmenopausal the ovarian stroma to form a hilar plexus.
periods, the ovaries are usually smaller. Typically Eventually they accompany the ovarian vessels to
the ovary is ovoid in shape. The external surface drain into the upper para-aortic lymph nodes at
may be smooth or convoluted, especially in the the level of the lower pole of the kidney.
late reproductive period. The ovary contains an
outer cortex and an inner medulla. Follicular
structures, including cystic follicles, corpora 22.2 Clinical Presentation
lutea, and corpora albicantia are usually visible
on sectioning. A hilar region is also apparent. Clinical features related to ovarian pathology are
The ovary is covered by a layer of peritoneum, often nonspecific and, in general, with ovarian
the mesovarium. neoplasia symptoms occur late in the course of
Lymphovascular drainage: the disease when the tumour has often spread
The blood supply to the ovary is from the beyond the ovary. Symptoms related to ovarian
ovarian artery, a branch of the aorta. This courses tumours include swelling or a feeling of fullness
along the surface of the ovary and anastomoses in the abdomen or pelvis, the presence of an
with the ovarian branch of the uterine artery. abdominal mass, irregular uterine bleeding,
Subsidiary branches enter the ovarian hilus and abdominal or pelvic pain, and gastrointestinal
then travel through the medulla and cortex, anas- symptoms. There may be associated ascites,
especially with ovarian malignancies, but also
with some benign neoplasms such as fibromas.
O.P. Houghton (*) • W. Glenn McCluggage With ovarian endometriosis, pain and swelling
Histopathology Laboratory, Institute of Pathology, may fluctuate depending on the phase of the men-
Royal Victoria Hospital, Belfast Health and Social strual cycle. In younger patients, ovarian pathol-
Care Trust, Belfast, UK ogy may be discovered during the course of
e-mail: oisin.houghton@belfasttrust.hscni.net; glenn.
mccluggage@belfasttrust.hscni.net investigations for infertility. Ovarian pathology

244 O.P. Houghton and W. Glenn McCluggage
Fallopian tube
Ovary Uterus
Lateral pelvic
wall
Cervix
Vagina
Vulva (labia minora)
Posterior
2
1. Ovarian ligament
2. Round ligament Anterior
Fig. 22.1 Overview of gynaecological anatomy (Used with the permission of the Union for International Cancer
Control (UICC), Geneva, Switzerland. The original source for this material is from Wittekind et al. (2005))
may also be discovered incidentally during even marked elevation of serum CA-125 may
abdominal or pelvic imaging or as a result of an occur in many non-neoplastic diseases or
increased serum CA-125. Serum CA-125 mea- non-ovarian neoplastic diseases, this serum
surements and abdominal ultrasound are cur- marker being relatively nonspecific. CA-125
rently being evaluated in screening programs for is produced by mesothelial cells, and condi-
ovarian cancer. tions which involve the peritoneal cavity with
its lining of mesothelial cells are especially
liable to result in an elevated serum CA-125.
22.3 Clinical Investigations These conditions include ascites, endometri-
osis, peritoneal tuberculosis, and dissemi-
• Serum CA-125 measurements: An increase nated non-ovarian neoplasms.
in serum CA-125 may be an indicator of • Abdominal USS and CT scan: In cases of
ovarian malignancy. However, modest or ovarian neoplasia abdominal USS or CT scan
22 Ovary 245
often shows a complex ovarian mass with Corpus luteum cyst: During the ovulatory
alternating solid and cystic areas. There may cycle, a corpus luteum is formed which, when
be coexistent ascites and an omental cake, fertilization does not occur, involutes. At the time
indicating omental involvement by tumour. of menstruation, the centre of the corpus luteum
Unilocular or multilocular thin-walled cystic is cystic and filled with blood. This is known as a
lesions often indicate benign neoplasms. CT cystic corpus luteum. When this cystic mass
scanning is often performed to stage ovarian becomes greater than 3 cm in diameter, it is des-
neoplasia. ignated a corpus luteum cyst. These lesions are
• Peritoneal aspiration: Aspiration of ascitic often asymptomatic but can be associated with
fluid and cytological examination may be menstrual irregularities. Rupture may result in
performed in the investigation of ovarian pain and intraabdominal haemorrhage.
neoplasia. Grossly a corpus luteum cyst is lobulated or
• Core biopsies: Radiologically guided core well circumscribed. The wall is composed of
biopsies, especially of the omental disease, luteinized granulosa cells and the lumen contains
may be undertaken for definitive diagnosis of fresh or altered blood.
an ovarian malignancy in patients who are not Polycystic ovarian disease: This disease is
likely to be amenable to optimal surgical characterized by anovulation and the develop-
debulking. ment of multiple follicular cysts within both ova-
• Laparoscopy: This may be indicated in certain ries. Often patients are infertile and have
conditions, e.g., suspected endometriosis. menstrual irregularities. Typically the ovaries are
Biopsy can be performed at laparoscopy. enlarged with multiple small cysts located just
below the cortex. The outer cortex of the ovary is
In patients with suspected ovarian neoplasia, a typically thickened. Histologically the cysts are
risk of malignancy index is calculated. This is a usually lined by a thin layer of granulosa cells
means of assessing the likelihood that an ovarian and a more prominent layer of lipid-laden theca
mass is malignant and takes into account the interna cells.
menopausal status (pre- or postmenopausal) of Endometriosis: The ovary is the most com-
the patient, the ultrasound findings, and the serum mon site of endometriosis which is defined as the
CA-125 measurement. presence of endometrial tissue, usually, but not
invariably, both glands and stroma, outside the
uterus. Most common in the reproductive age
22.4 Pathological Conditions group, but occasionally encountered in post-
menopausal women, the symptoms are protean
22.4.1 Non-neoplastic Conditions and varied. Patients may present with a palpable
abdominal mass, abdominal or pelvic pain, dys-
Follicular or functional cysts: These are menorrhea, dysmenorrhoea, irregular uterine
extremely common and are secondary to an bleeding, or infertility.
absence of the normal preovulatory luteinizing Endometriosis within the ovary may take the
hormone surge that triggers ovulation. They are form of an endometriotic cyst. These can be sin-
usually found in the reproductive age group and gle or multiple and are often bilateral. They gen-
are generally asymptomatic, although acute erally have a thick fibrous wall which is yellow to
abdominal pain and bleeding into the peritoneal brown in colour with a ragged internal surface.
cavity may occur secondary to rupture. Follicular The cyst contents are typically dark brown fluid
cysts may be multiple. In children they can be which may be inspissated, giving rise to the term
associated with sexual pseudoprecocity. “chocolate cyst” of the ovary. Rarely tumours can
Grossly follicular cysts are usually thin walled arise within ovarian endometriotic cysts and
and contain watery fluid. Histologically they are these usually take the form of a thickened area
lined by granulosa or theca cells or a combination within the wall. Endometriosis within the ovary
of both. These cell types are often luteinized. may also be non-cystic appearing as small red,
blue, or brown spots. Often endometriotic foci excess. On sectioning the ovary it is typically
are not apparent to the naked eye. oedematous and pale in colour and watery fluid
Histologically endometriosis is typically com- exudes from the cut surface. Histologically there
posed of endometrial glands and stroma. In some is separation of the stromal cells by oedema fluid
cases, one or both of these components may that surrounds residual ovarian structures.
be absent, or obscured by a superimposed haem- Luteinized stromal cells may be present. The
orrhagic, inflammatory, or fibrotic process. outer cortex is typically not oedematous but
Occasionally, all that remains is a fibrotic area rather is composed of dense fibrous tissue.
containing haemosiderin or ceroid-laden macro-
phages. In such cases, a presumptive diagnosis of
endometriosis may be made. 22.4.2 Neoplastic Conditions
Simple cysts: Simple benign cysts are com-
mon within the ovary. They cannot be classified The ovary is unique in that an extremely wide
into any specific type since the lining is attenu- range of neoplasms, both benign and malignant,
ated or lost. Most are probably of epithelial ori- may arise here. Primary tumours may be of sur-
gin being lined by attenuated epithelial cells or of face epithelial, germ cell, or sex cord-stromal
follicular origin lined by atrophic granulosa or derivation.
theca cells. Immunohistochemistry for EMA Benign tumours: May be of surface epithelial
(epithelial cells positive) or α-inhibin (granulosa type (serous, mucinous, or endometrioid cystad-
cells positive) assists in determining the origin of enoma/cystadenofibroma and Brenner tumour),
the cyst. germ cell type (e.g., benign cystic teratoma), or
Stromal hyperplasia: This is relatively com- sex cord-stromal type (e.g., fibroma). They can
mon in the perimenopausal or early postmeno- be solid or cystic or contain a mixture of solid
pausal age group. Both ovaries are enlarged, and cystic components.
often only mildly so, by a nodular stromal Malignant tumours: Primary malignant ovar-
proliferation. Usually the nodules are yellow ian neoplasms are of surface epithelial, germ
to white in colour and they may be confluent. cell, or sex cord-stromal type. Surface epithelial
Histology confirms a nodular proliferation tumours are most common and these comprise
of stromal cells with scant cytoplasm. There high grade and low grade serous, mucinous, sero-
may be androgenic or oestrogenic manifesta- mucinous, endometrioid, clear cell, and undiffer-
tions and, on occasions, associated endometrial entiated carcinomas. Mixed carcinomas can
hyperplasia or adenocarcinoma. occur but are extremely rare. Borderline neo-
Stromal hyperthecosis: This uncommon con- plasms (tumours of low malignant potential) also
dition is often associated with signs of hyperan- occur and these may be one of any of the mor-
drogenism. Oestrogenic manifestations and phological subtypes described, most commonly
coexistent endometrial hyperplasia or adenocar- serous or mucinous. These are neoplasms which
cinoma may also occur. Typically both ovaries exhibit epithelial proliferation but in which there
are enlarged and yellow/white in colour with a is no evidence of stromal invasion. Omental
vague nodular pattern. Histologically there is involvement by serous borderline tumour may be
usually accompanying stromal hyperplasia, but seen in the form of noninvasive or invasive
in addition luteinized stromal cells with clear or implants.
eosinophilic cytoplasm are present singly or in Ovarian surface epithelial carcinomas are
small groups. most common in middle-aged and elderly
Massive oedema: This is a rare cause of uni- women, in nulliparous women, and those with
lateral ovarian enlargement and is probably sec- an early menarche and late menopause. The oral
ondary to partial torsion of the ovary. Presentation contraceptive pill is protective. It has been sug-
is often with abdominal pain and a palpable ovar- gested that women who are exposed to
ian mass. There may be evidence of androgen ovulation-inducing drugs are at increased risk
22 Ovary 247
of the development of ovarian carcinoma. lateral or contralateral ovary or elsewhere in the

Women with BRCA1 or BRCA2 gene muta- pelvis and it is clear that many of these neo-
tions are at increased risk of the development of plasms arise from endometriosis; molecular
both breast cancer and ovarian high grade serous abnormalities are similar to those seen in uter-
carcinoma. Outside BRCA1 and BRCA2 ine endometrioid adenocarcinomas. Since the
groups, there is a familial predisposition to the preferred theory for the development of endo-
development of ovarian cancer. The risk of metriosis is retrograde menstruation, it is inter-
ovarian cancer, specifically ovarian clear cell esting that tubal ligation is protective for the
carcinoma and endometrioid adenocarcinoma, development of ovarian endometrioid and clear
is also increased in patients with Lynch syn- cell carcinomas but not for other morphological
drome (hereditary nonpolyposis colorectal subtypes. Endometrioid neoplasms may coexist
cancer syndrome). The risk of developing ovar- with similar tumours in the endometrium in up
ian adenocarcinoma increases with the number to 25% of cases and most, but not all, of these
of ovulations over a lifetime (incessant ovula- represent synchronous independent neoplasms.
tion theory). Repeated ovulation with disruption In such cases, the finding of endometriosis in
of the ovarian surface mesothelium is thought to close association with the ovarian endometrioid
result in the development of cortical inclusion or clear cell carcinoma or even remote from this
cysts, either through entrapment of ovarian sur- is a helpful clue as to their primary origin. The
face mesothelium or implantation of epithelium ovary is a common site for metastatic carcino-
from the fallopian tube. It is thought that high- mas, and metastatic tumour may closely simu-
grade serous carcinomas may arise from these late an ovarian primary histologically. The most
cortical inclusion cysts or ovarian surface epi- common primary sites include colon, appendix,
thelium. There is now increasing and compel- pancreas, biliary tree, stomach, breast, and
ling evidence that many high-grade serous endometrium. Features favouring metastasis,
carcinomas may arise from the tubal fimbria but by no means specific for this, include bilat-
from a precursor lesion known as serous tubal erality, the presence of nodular tumour deposits
intraepithelial carcinoma (STIC). Two distinct especially on the cortical surface of the ovary,
types of ovarian serous carcinoma occur, low- extensive necrosis and vascular invasion, extra-
grade serous carcinoma and high-grade serous cellular mucin, and signet ring cells.
carcinoma. Low-grade serous carcinoma arises Aetiological factors in the development of
from a preexisting benign and borderline serous malignant ovarian germ cell (e.g., immature tera-
tumour, and has a high frequency of KRAS and toma, yolk sac tumour, dysgerminoma) and sex
BRAF mutations but not TP53 mutation. cord-stromal (e.g., granulosa and Sertoli-Leydig
Virtually all high-grade serous carcinomas dem- tumours) neoplasms are not well known. Adult
onstrate TP53 mutations. There is no relation- granulosa cell tumours have a high incidence of
ship between borderline serous tumour, FOXL2 mutations and Sertoli-Leydig cell
low-grade serous carcinoma and high-grade tumours a high incidence of DICER1 mutations.
serous carcinoma, although low-grade serous Gonadoblastomas often occur in patients with
carcinoma may transform to high-grade serous underlying gonadal dysgenesis, while sex cord-
carcinoma on rare occasions. stromal tumour with annular tubules can be
Mucinous, endometrioid, and clear cell ade- associated with Peutz–Jeghers syndrome. Sex

nocarcinomas have an alternative pathogenesis. cord-stromal neoplasms may cause oestrogenic
For example, K-ras mutations are found in or androgenic excess due to hormone elabora-
mucinous adenocarcinomas and these develop tion. Occasionally this may result in endometrial
from preexisting borderline mucinous neo- hyperplasia or endometrioid adenocarcinoma of
plasms, unlike high-grade serous adenocarcino- the uterine corpus.
mas. Endometrioid and clear cell carcinomas A wide variety of other neoplasms, both
can be associated with endometriosis in the ipsi- benign and malignant, also arise within the ovary.
Treatment: Treatment of malignant ovarian ring in children or young adults, are highly
neoplasms is usually total abdominal hysterec- aggressive but often respond well to modern che-
tomy and bilateral salpingo-oophorectomy. motherapeutic regimens.
Omentectomy and peritoneal washings are usu-
ally performed as part of the staging procedure.
Lymphadenectomy may also be undertaken. 22.5 Surgical Pathology
Unilateral salpingo-oophorectomy and limited Specimens: Clinical Aspects
staging, such as omentectomy and lymphade-
nectomy, may be undertaken for suspected 22.5.1 Biopsy Specimens
malignant neoplasms in young women who
wish to preserve their fertility. Postoperative Fine needle aspiration (FNA) specimens of ovar-
chemotherapy is often necessary, especially for ian cystic lesions may be performed under ultra-
tumours which have spread beyond the ovary or sound guidance (transvaginal or transabdominal)
for tumours which are confined to the ovary but or at laparoscopy or laparotomy. Ovarian wedge
where the neoplasm is high grade, the capsule is biopsies are occasionally performed at diagnostic
deficient and, or, there is ascites or positive peri- laparotomy for lower abdominal pain and core
toneal washings. The FIGO staging system for biopsies may be carried out when it is unclear
ovarian cancer is used. As extrauterine high- whether an ovarian mass is benign or malignant.
grade serous carcinoma (the most common Radiologically guided core biopsies, usually of
ovarian carcinoma subtype) is often advanced at the omental metastasis, may be performed for
diagnosis precluding definitive determination of ovarian neoplasms which are being treated pri-
the site of origin (i.e. ovary, fallopian tube or marily with chemotherapy rather than surgery.
peritoneum), the current FIGO staging system Cystectomy with preservation and reconstruction
incorporates ovarian, tubal and primary of the residual ovary may be performed in young
peritoneal tumours. In the UK, the British patients in whom benign cystic lesions are sus-
Association of Gynaecological Pathologists, pected clinically.
British Gynaecological Cancer Society, and
gynaecological clinical reference group of the
National Cancer Intelligence Network recom- 22.5.2 Resection Specimens
mend that FIGO staging rather than TNM be
used for gynaecological cancers. Borderline In general, with the exception of young women,
tumours should be staged in the same way as when a malignant ovarian tumour is suspected,
invasive carcinomas. total abdominal hysterectomy, bilateral salpingo-
Prognosis: The prognosis of ovarian adeno- oophorectomy, and omentectomy are performed.
carcinoma is generally poor, overall 5-year sur- This is generally via an abdominal approach. Any
vival being in the region of 30–40%. This is ascitic or free peritoneal fluid is sent for cytologi-
largely due to the fact that at presentation many cal examination and if none is present peritoneal
carcinomas have spread beyond the ovary, and washings are performed. The appendix may be
are FIGO stage III or IV. The prognosis for stage removed in cases of a suspected ovarian muci-
I tumours is generally good. Borderline epithelial nous neoplasm. In young women with a c linically
neoplasms have an excellent prognosis, if ade- and/or radiologically malignant ovarian lesion, in
quately staged, and if there are no invasive perito- whom preservation of fertility is desirable, uni-
neal or omental implants. lateral salpingo-oophorectomy (usually with
Some ovarian sex cord-stromal neoplasms, omentectomy) may be performed. This should be
e.g., granulosa cell tumours exhibit a low-grade followed by discussion of the case and assess-
malignant behaviour with late recurrence or ment of the need for further surgery at a multidis-
metastasis being a common feature. Many malig- ciplinary gynaecological oncology meeting. In
nant germ cell tumours, especially those occur- occasional cases, where the presence of wide-
22 Ovary 249
spread disease precludes total tumour debulking, capsular breech is noted. This is important
only small fragments or a proportion of the since if a malignant tumour breeches the cap-
tumour will be removed. Unilateral salpingo- sular surface it is at least stage IC. In many
oophorectomy may be performed when a benign instances, this is the cutoff for adjuvant che-
ovarian neoplasm or a benign cyst is suspected. motherapy. The percentage of the surface
Prophylactic salpingo-oophorectomies may be involved by papillary areas should be
performed in those with a hereditary predisposi- documented.
tion to developing ovarian cancer (e.g., BRCA1 • The ovaries may be sliced to aid fixation prior
or BRCA2 mutation) or where is a strong family to sampling. This should only be done after
history of ovarian cancer. careful examination of the capsular surface
and evaluation for capsular breech. If the
uterus is present, it may also be opened to
22.6 Surgical Pathology ensure fixation of the endometrium.
Specimens: Laboratory • Abnormal ovaries are serially sectioned at
Protocols approximately 1-cm intervals. Note that large
cystic lesions may contain abundant fluid
22.6.1 Biopsy Specimens which can exude under pressure. The character-
istics of the fluid should be noted, e.g., serous,
FNA specimens are centrifuged and the speci- mucinous, or bloody. Scissors can also be of
mens examined cytologically, usually with both use in opening and blocking cystic lesions.
Giemsa and Papanicolaou stains. Ovarian wedge • If the ovary is predominantly solid, the colour
biopsies are weighed and measured, sectioned and consistency of the lesion is noted as is the
thinly, and examined intact. Core biopsies are presence or absence of areas of hemorrhage or
examined intact, usually at multiple levels. necrosis.
• If the lesion is both solid and cystic, record the
proportion of each.
22.6.2 Resection Specimens • If the lesion is cystic, note whether the cyst is
unilocular, multilocular, or whether a main
Initial procedures and description: cyst is present together with multiple smaller
daughter cysts. The presence of residual ovary
• Abrading the cortical surface should be should be documented.
avoided in order to preserve the mesothelial • With a cystic lesion, describe whether the
lining. internal surface of the cysts is smooth or
• Each ovary is weighed and measured in three whether they contain papillary projections or
dimensions (cm) and if necessary photo- nodular thickenings. The percentage of the
graphed. The presence of fallopian tubes is internal surface involved by papillary areas
confirmed and they are measured. should be documented.
• The cortical surfaces of the ovaries may be • The presence of other elements within the
inked. In general, this is not necessary but lesion is recorded, e.g., hair and teeth in der-
some pathologists find this helps identify the moid cysts.
capsular blocks and facilitates assessment of • Ovaries and fallopian tubes removed prophy-
capsule integrity. It may also help determine lactically in those with a hereditary predispo-
whether the block is fully faced when examin- sition to develop ovarian cancer are serially
ing tissue sections histologically. sectioned parallel to the short axis at 2–3 mm
• The cortical surface of each ovary is closely intervals. The presence of any gross abnor-
inspected around the whole circumference. mality is noted. The entire ovaries and fallo-
The presence of obvious tumour deposits on pian tubes should be submitted for histological
the capsular surface or of papillary areas or examination, as mentioned previously, many
high-grade serous carcinomas arise in the fim- coexist with benign and borderline areas. The
bria of the fallopian tube and very small neo- degree of sampling necessary is controversial,
plasms, which are not recognizable grossly, but one block per cm of lesions up to 10 cm in
may be present. maximum dimension and two blocks per cm of
• Grossly normal ovaries removed during a hys- lesions greater than this have been suggested.
terectomy for benign disease or for uterine or • For those lesions with papillary excresences
cervical neoplasms are bisected longitudinally on the internal or external surface, multiple
and inspected. blocks are taken, especially from the papillary
• Any paraovarian cystic or solid lesions should areas. This is important since these areas often
be treated in a similar way. represent borderline foci.
• Omentum is weighed, measured in three • For grossly malignant neoplasms, representa-
dimensions (cm), and sectioned thinly. The tive sections are taken, usually one section per
presence of obvious tumour deposits, gritti- cm of tumour.
ness, or areas of thickening or induration is • Special attention should be given to the sam-
noted. If gross tumour involvement is evident, pling of areas of capsular breech or infiltration
the size of the largest tumour deposit should by tumour and a significant number of blocks
be noted as this has implications for substag- should include the capsule.
ing of stage III ovarian carcinoma. • In neoplasms with a variegated appearance,
• If the uterus is present, it should be measured grossly different areas are blocked.
in three dimensions and weighed. The serosa • Paraovarian lesions should be blocked similarly.
should be examined for tumour involvement. • Representative sections should be taken from
If a synchronous endometrial tumour is identi- the fallopian tubes, including the fimbrial end.
fied, this should be dealt with as per the uter- • Representative sections of omentum are taken.
ine carcinoma protocol (Chap. 24). If the omentum is grossly normal, three or
• If the appendix is submitted, it should be mea- four blocks suffice. Any tumour deposits or
sured and examined for gross tumour involve- areas of thickening, grittiness, or induration
ment, either mucosal or serosal. are preferentially sampled. If histological
examination reveals implants or borderline
Blocks for histology (Fig. 22.2): lesions, then multiple additional sections may
have to be examined.
• Ovaries and fallopian tubes removed prophy- • If the uterus is present, any serosal abnormal-
lactically in those with a hereditary predispo- ity should be sampled. If a synchronous
sition to develop ovarian cancer are examined endometrial carcinoma is present, this should
in their entirety. The fimbria of the fallopian be sampled as per the uterine carcinoma proto-
tube should be transected and sectioned longi- col. If it appears grossly normal, representative
tudinally, while the remainder of the tubes samples from the cervix, endometrium, and
should be sectioned transversely. full thickness of myometrium should be taken.
• A single section through the long axis of the
ovary suffices for grossly normal ovaries Histopathology report:
removed as part of a hysterectomy specimen for
benign disease or uterine or cervical cancer. • Side of tumour—Right/left or bilateral.
• For suspected benign cystic lesions (thin- • Dimensions of tumour—Measure in three
walled unilocular or multiloculated cysts) dimensions (cm).
without thickenings or papillary excresences • Gross appearance—Solid/cystic, colour, and
on the external or internal surfaces, representa- consistency, presence of haemorrhage or
tive sampling suffices. With multiloculated necrosis.
mucinous lesions, extensive blocking is • Tumour type—It is stressed that a wide range
required as malignant areas may be focal and of benign and malignant tumours may arise
22 Ovary 251
Bisect and submit a logitudinal slice

a
Residual ovary
Fallopian tube
Submit
Ovarian
cyst − Tube and residual ovary
− Cyst wall
− Internal/external
projections
b
Internal and external
papillary projections
Submit
− Tube and residual ovary

− Cyst wall
− Internal/external
projections
− Capsular deficiency
Solid
− Solid tumour
tumour
c
Capsular deficiency
Fig. 22.2 Blocking of ovarian tissues: (a) normal; (b) cystic; (c) mixed solid/cystic (Reproduced, with permission,
from Allen and Cameron (2013)
within the ovary. The ovary is also a relatively Dataset in the UK that serous carcinomas be
common site for metastatic carcinomas. graded as either low-grade or high-grade, a
• Tumour grade—There is no universally agreed distinction based primarily on assessment of
grading system for ovarian adenocarcinomas nuclear atypia in the worst area of the tumour.
and different systems exist. It is recommended As discussed previously, low-grade and high-
in the Royal College of Pathologists Cancer grade serous carcinomas are two distinct
tumour types with a different underlying I Tumour confined to ovaries or fallopian

pathogenesis rather than low-grade and high- tube(s)
IA Tumour limited to one ovary (capsule intact)
grade variants of the same neoplasm. Clear
or fallopian tube; no tumour on ovarian or
cell carcinoma is regarded as grade 3. fallopian tube surface; no malignant cells in
Endometrioid carcinoma should be graded the ascites or peritoneal washings
using the FIGO grading system used to grade IB Tumour limited to both ovaries (capsules
endometrial endometrioid carcinomas into intact) or fallopian tubes; no tumour on
ovarian or fallopian tube surface; no
grades I, II, or III, and mucinous adenocarci-
malignant cells in the ascites or peritoneal
nomas are graded in a similar manner. washings
• Capsule—It should be stated whether the cap- IC Tumour limited to one or both ovaries or
sule is intact, deficient, or breeched by tumour. fallopian tubes, with any of the following:
• Lymphovascular invasion—Present/not IC1 Surgical spill intraoperatively
present. IC2 Capsule ruptured before surgery or tumour
• Lymph nodes—Mention sites and presence or on ovarian or fallopian tube surface
absence of tumour involvement. The regional IC3 Malignant cells present in the ascites or
peritoneal washings
lymph nodes are the hypogastric, common
II Tumour involves one or both ovaries or
iliac, external iliac, lateral sacral, para-aortic, fallopian tubes with pelvic extension
retroperitoneal and inguinal nodes—a pelvic (below pelvic brim) or peritoneal cancer
lymphadenectomy will ordinarily include 10 IIA Extension and/or implants on the uterus
or more nodes. and/or fallopian tubes and/or ovaries
• Omentum—Involved/not involved by tumour IIB Extension to other pelvic intraperitoneal
tissues
and maximum size of tumour deposits (cm).
III Tumour involves one or both ovaries, or
• Other organs (fallopian tube, uterus, cervix)—
fallopian tubes, or primary peritoneal
Involved/not involved by tumour. cancer, with cytologically or histologically
• Peritoneal washings/ascitic fluid—Involved/ confirmed spread to the peritoneum
not involved by tumour. outside the pelvis and/or metastasis to the
retroperitoneal lymph nodes
• Other pathology—The presence of coexistent
IIIA Metastasis to the retroperitoneal lymph
pathology should be mentioned. Endometrioid nodes with or without microscopic
and clear cell carcinomas may arise in peritoneal involvement beyond the pelvis
endometriosis. IIIA1 Positive retroperitoneal lymph nodes only
(cytologically or histologically proven)
In the UK, the British Association IIIA1(i) Metastasis ≤10 mm in greatest dimension
of Gynaecological Pathologists, British Gynae IIIA1(ii) Metastasis >10 mm in greatest dimension
cological Cancer Society, and gynaecological IIIA2 Microscopic extrapelvic (above the pelvic
brim) peritoneal involvement with or
clinical reference group of the National Cancer without positive retroperitoneal lymph
Intelligence Network recommend that FIGO nodes
staging rather than TNM be used for gynaeco- IIIB Macroscopic peritoneal metastases
logical cancers. Note that there is close correla- beyond the pelvic brim ≤2 cm in greatest
tion between the two schemes.cathy.maxw. dimension, with or without metastasis to
the retroperitoneal lymph nodes
Extent of local tumour spread: FIGO stage for
IIIC Macroscopic peritoneal metastases
borderline and malignant ovarian epithelial/stro- beyond the pelvic brim >2 cm in greatest
mal, tubal and primary peritoneal Mullerian dimension, with or without metastasis to
neoplasms the retroperitoneal lymph nodes
22 Ovary 253
IV Distant metastasis excluding peritoneal McCluggage WG, Hirschowitz L, Ganesan R, Kehoe S,

metastases Nordin A. Which staging system to use for gynaeco-
logical cancers: a survey with recommendations for
IVA Pleural effusion with positive cytology
practice in the UK. J Clin Pathol. 2010;63:768–70.
IVB Metastasis to extraabdominal organs Robboy SJ, Bentley RC, Russell R, Anderson MC, Mutter
(including inguinal lymph nodes and GL, Prat J. Pathology of the female reproductive tract.
lymph nodes outside of abdominal cavity) 2nd ed. London: Churchill Livingstone/Elsevier; 2009.
Russell P, Farnsworth A. Surgical pathology of the ova-
ries. 2nd ed. New York: Churchill Livingstone; 1997.
Scully RE, Young RH, Clement PB. Tumors of the ovary,
maldeveloped gonads, fallopian tube and broad liga-
Bibliography ment, Atlas of tumor pathology, 3rd series, fascicle 23.
Washington: AFIP; 1998.
Allen DC. Histopathology reporting. Guidelines for surgi- Singh N. Synchronous tumours of the female genital tract.
cal cancer. 3rd ed. London: Springer; 2013. Histopathology. 2010;56:277–85.
Allen DC, Cameron RI. Histopathology specimens: Tavassoli F, Devilee P. WHO classification of tumours.
clinical, pathological and laboratory aspects. 2nd ed. Pathology and genetics. Tumours of the breast and
Berlin/Heidelberg: Springer; 2013. female genital organs. Lyon: IARC Press; 2003.
Brierley JD, Gospodarowicz MK, Wittekind C, editors. The Royal College of Pathologists. Cancer datasets (vul-
TNM classification of malignant tumours. 8th ed. val neoplasms, cervical neoplasia, endometrial cancer,
Oxford: Wiley-Blackwell; 2017. uterine sarcomas, neoplasms of the ovaries and fallo-
Fox H, Wells M, editors. Haines and Taylor obstetrical pian tubes and primary carcinoma of the peritoneum),
and gynaecological pathology. 5th ed. Edinburgh: and tissue pathways for gynaecological pathology.
Churchill Livingstone; 2003. Accessed at https://www.rcpath.org/profession/publi-
Heatley MK. Dissection and reporting of the organs of the cations/cancer-datasets.html. Accessed Dec 2016.
female genital tract. J Clin Pathol. 2008;61:241–57. Wittekind C, Greene L, Hutter RVP, Klimfinger M, Sobin
McCluggage WG. My approach to and thoughts on LH. TNM Atlas: illustrated guide to the TNM/pTNM
the typing of ovarian carcinomas. J Clin Pathol. classification of malignant tumours. 5th ed. Berlin/
2008;61:152–63. Heidelberg: Springer; 2005.
Fallopian Tube
23
23.1 Anatomy 23.2 Clinical Presentation
The fallopian tubes are paired structures that Symptomatology specifically related to pathol-
extend from the uterine cornu to the medial pole ogy in the fallopian tube is relatively rare. Most
of the ovary. They are generally 8–12 cm in fallopian tubes submitted as surgical pathology
length. There are four segments to the fallopian specimens are a component of larger specimens,
tube, which, from medial to lateral, are the intra- and fallopian tubes and ovaries are removed pro-
mural segment, the isthmus, the ampulla, and the phylactically in patients with BRCA mutations.
infundibulum (Fig. 23.1). The lateral aspect of Ectopic pregnancies may occur in the fallopian
the infundibulum is fimbriated and opens into the tube and usually present with abdominal pain. If
pelvic cavity. Microscopically the fallopian tube there is associated haemoperitoneum, the pain is
consists of mucosa, submucosa, muscularis, and severe and associated with signs of peritonism.
serosa, which is covered by a single layer of Other fallopian tube pathologies may result in
mesothelial cells. abdominal pain or patients can present with infer-
Lymphovascular drainage: tility. With neoplasms or other pathological
The fallopian tubes are supplied both by a lesions causing enlargement of the fallopian tube
branch of the ovarian artery and a branch of the there may be a palpable abdominal mass with or
uterine artery. The venous drainage is similar. without associated ascites. Fallopian tube pathol-
The lymphatic channels draining the fallopian ogy is occasionally discovered incidentally dur-
tube descend within the mesosalpinx behind the ing abdominal or pelvic imaging.
ovary where they form part of the subovarian
plexus.
• Serum CA-125 measurements: An increase in

serum CA-125 may be found with primary
fallopian tube carcinoma.
• Abdominal USS scan: Ectopic pregnancies
O.P. Houghton (*) • W. Glenn McCluggage may be seen on ultrasound scan and there is
Histopathology Laboratory, Institute of Pathology, usually a positive pregnancy test. Primary fal-
Royal Victoria Hospital, Belfast Health and Social lopian tube malignancies may also be
Care Trust, Belfast, UK identified on scanning as well as conditions
mccluggage@belfasttrust.hscni.net such as hydrosalpinx or pyosalpinx.

Fig. 23.1 Fallopian Isthmus Ampulla

tube anatomy
(Reproduced, with
and Cameron (2013)) Uterine cornu
Intramural
porion
Infundibulum
Uterus
Fimbriae
Cervix
• Laparoscopy: This is undertaken in order to haematosalpinx. With superimposed infection,

directly visualize the fallopian tube. pus can accumulate within the lumen and wall of
• Fine needle aspiration cytology: This can be the tube, resulting in pyosalpinx. Histology
performed either at laparoscopy or under shows marked dilatation of the lumen of the tube
ultrasound guidance. Paratubal cysts or cystic with oedema within the wall and numerous poly-
lesions of the fallopian tube, such as hydrosal- morphs in the case of pyosalpinx.
pinx, are especially liable to be aspirated. Ectopic pregnancy: With tubal ectopic preg-
nancies, the fallopian tube is generally dilated,
sometimes with an area of rupture. Sectioning the
23.4 Pathological Conditions tube reveals blood clot and sometimes grossly
visible placental tissue within the lumen.
23.4.1 Non-neoplastic Conditions Histology shows blood clot, decidua, chorionic
villi, and a placental site reaction. Fetal parts may
Paratubal or fimbrial cysts: These are extremely be identified.
common, especially paratubal cysts. They are
thin-walled cysts usually containing serous fluid.
They can be multiple and histologically are lined 23.4.2 Neoplastic Conditions
by a single layer of bland, usually ciliated, epi-
thelial cells. The epithelial lining may be attenu- The fallopian tube has traditionally been con-
ated. Cystic Walthard’s rests, lined by transitional sidered a relatively rare primary site of neo-
epithelium, are also extremely common with a plastic lesions, both benign and malignant.
paratubal location. However, there is now growing evidence and
Hydrosalpinx and pyosalpinx: Hydrosalpinx an increasing realization that many high-grade
is dilatation of the fallopian tube. Although rarely serous carcinomas of the ovary and peritoneum
of unknown aetiology, it is usually secondary to actually arise from the fimbria of the fallopian
obstruction of the tube with subsequent dilata- tube, although these rarely result in a dominant
tion. One of the most common causes is pelvic tubal mass.
inflammatory disease. Other causes include Benign tumours: Benign tumours of the fallo-
endometriosis, tumour, or a lesion within the pian tube are rare. They include adenomatoid
uterus. Grossly the fallopian tube is dilated, tumours that are usually firm grey-white or yel-
sometimes massively so. There may be associ- low well-circumscribed nodules that involve part
ated haemorrhage within the lumen, resulting in of the wall of the tube. A variety of other benign
23 Fallopian Tube 257
neoplasms, similar to those found within the 23.5.2 Resection Specimens

ovary, may rarely involve the fallopian tube, the
most common being serous cystadenofibroma. Many fallopian tubes submitted for pathologi-
Malignant tumours: Most primary malignant cal examination are part of a hysterectomy and
neoplasms of the fallopian tube are high-grade bilateral salpingo-oophorectomy performed
serous carcinomas, similar to those that occur in for either benign or malignant disease.
the ovary, although endometrioid carcinomas Sometimes just the fallopian tube and ovary
also occur and a variety of other morphological are removed. The fallopian tube alone may be
subtypes have been described. Primary carcino- resected in tubal ectopic pregnancy or where
mas of the fallopian tubes have traditionally been benign cysts or indeterminate fallopian tube
considered uncommon. However, it is increas- nodules are present. When a malignant neo-
ingly recognized that many ovarian and perito- plasm of the fallopian tube is suspected, hys-
neal high-grade serous carcinomas originate in terectomy and bilateral salpingo-oophorectomy
the fimbrial end of the fallopian tube from a pre- with full staging, including omentectomy, peri-
cursor in situ lesion known as serous tubal toneal washings with or without pelvic and/or
intraepithelial carcinoma (STIC). Fallopian tube para-aortic lymphadenectomy, is usually per-
carcinomas usually occur in the middle-aged or formed. Fallopian tubes may be removed pro-
elderly and are more common in nulliparous phylactically, along with the ovaries, in those
women. There is an increased incidence of fallo- with a hereditary predisposition to developing
pian tube malignancy (specifically high-grade ovarian cancer, e.g., those with BRCA1 or
serous carcinoma) in women with BRCA1 and BRCA2 gene mutations.
BRCA2 mutations.
Treatment: Treatment of malignant tubal neo-
plasms is usually total abdominal hysterectomy, 23.6 Surgical Pathology
bilateral salpingo-oophorectomy, and omentec- Specimens: Laboratory
tomy. Surgical staging is similar to that per- Protocols
formed for ovarian cancer, including peritoneal
washings. Postoperative chemotherapy is often 23.6.1 Biopsy Specimens
necessary since tumours are frequently advanced.
Prognosis: The prognosis of fallopian tube FNA specimens are centrifuged and the speci-
carcinoma is generally poor and is related to the mens examined cytologically, usually with
advanced tumour stage at presentation. Giemsa and Papanicolaou stains. Tubal ligations
are measured, the presence of any gross abnor-
mality noted, and a single transverse section is
23.5 Surgical Pathological examined histologically to document that the fal-
Specimens: Clinical Aspects lopian tube is present. If the tubal fimbria is pres-
ent, this should be submitted for histological
23.5.1 Biopsy Specimens examination.
Segments of fallopian tube are removed during

sterilization procedures (tubal ligation) per- 23.6.2 Resection Specimens
formed either via an open approach, usually dur-
ing Caesarean section, or at laparoscopy. Tubal or Specimen.
paratubal cysts may be aspirated at laparotomy or The specimen may consist of fallopian tube
laparoscopy or under ultrasound guidance and only or, more commonly, both fallopian tubes
the fluid sent for cytological examination. Such are present as part of a hysterectomy and bilat-
cysts may also be removed leaving the fallopian eral salpingo-oophorectomy. In other cases,
tube intact. only one ovary and fallopian tube are removed.
If malignancy is suspected, omentectomy and Blocks for histology:

pelvic and/or para-aortic lymphadenectomy
may be performed. • As stated, fallopian tubes removed prophylac-
Initial procedure and description: tically in those with a hereditary predisposi-
tion to develop ovarian cancer should be
• The length of each fallopian tube is recorded. examined in their entirety.
• The presence or absence of a fimbriated end is • A single transverse section is examined in
noted. cases of tubal ligation.
• If a sterilization clip is present this is • If the fallopian tube is grossly normal, one or
documented. two transverse sections and a section from the
• Note the presence of any gross external abnor- fimbria are examined in a single cassette.
mality, such as rupture, cyst, nodule, or • Any gross lesion, e.g., cyst or nodule, is
tumour. blocked to show its relationship to the tube.
• If the fallopian tube is dilated, the diameter is • In cases of suspected ectopic pregnancy, sev-
measured. eral sections should be taken (Fig. 23.2).
• If necessary any gross lesion may be Blood clot and placental tissue identified
photographed. grossly are sampled as is any site of tubal rup-
• If tumour is present, note the presence or ture. A section should also be taken from an
absence of serosal involvement or breech. area of grossly normal proximal tube. If tro-
• If grossly normal, the fallopian tube is serially phoblastic tissue is not identified in initial sec-
sectioned at 3–5 mm intervals. tions, then extra blocks are taken.
• The presence of any gross abnormality seen • For malignant fallopian tube neoplasms, at
on sectioning, e.g., luminal occlusion, pus, least one block per cm of tumour is submitted
placental tissue, or haemorrhage, is noted. for histology. These are taken preferentially
• If an ectopic pregnancy is suspected, note the from any gross areas of serosal involvement to
presence or absence of tubal rupture. show the most extensive tumour infiltration.
• If a tumour is present, its location, the size in Blocks are also taken to demonstrate origin of
three dimensions (cm), the colour, and consis- the tumour from the fallopian tube epithelium.
tency are noted, as is the presence or absence Blocks of uninvolved fallopian tube should
of haemorrhage and necrosis. also be submitted.
• If a cyst is present, it is measured and docu- • In neoplasms with a variegated appearance,
mented as unilocular or multilocular. The rela- grossly different areas are blocked.
tionship to the fallopian tube should be stated.
The character of the internal and external sur-
faces is noted as is the consistency of the fluid.
• Fallopian tubes removed prophylactically in
those with a predisposition to developing
ovarian cancer (BRCA1 or BRCA2 mutation
or positive family history of ovarian cancer)
are serially sectioned transversely at 2–3 mm
intervals. The entire fallopian tubes and ova-
ries should be examined histologically since
small neoplasms that are not visible grossly 1. Proximal limit
may be present, especially involving the fim- 2. Multiple transverse sections of the dilated tube,
bria. Amputation of the distal 2 cm and longi- its contents and any areas of deficiency
tudinal sectioning of the infundibulum and Fig. 23.2 Blocking the fallopian tube in an ectopic preg-
fimbrial end allow for maximal visualization nancy (Reproduced, with permission, from Allen and
of the tubal fimbrial epithelium. Cameron (2013))
23 Fallopian Tube 259
Histology report: Bibliography
• Side of tumour—right/left or bilateral. Allen DC. Histopathology reporting. Guidelines for surgi-

• Dimensions of tumour—measure in three Allen DC, Cameron RI. Histopathology specimens:
dimensions (cm). clinical, pathological and laboratory aspects. 2nd ed.
• Gross appearance—solid/cystic, colour, and con- Berlin, Heidelberg: Springer; 2013.
sistency, presence of haemorrhage or necrosis. Brierley JD, Gospodarowicz MK, Wittekind C, editors.
• Tumour type—most primary fallopian tube Oxford: Wiley-Blackwell; 2017.
malignancies comprise high-grade serous Fox H, Wells M, editors. Haines and Taylor obstetrical
carcinomas. and gynaecological pathology. 5th ed. Edinburgh:
• Presence of adjacent in situ carcinoma. Churchill Livingstone; 2003.
Heatley MK. Dissection and reporting of the organs of the
• Tumour grade—grading is identical to the female genital tract. J Clin Pathol. 2008;61:241–57.
approach used for ovarian carcinomas. McCluggage WG. My approach to and thoughts on the typing
• Extent of local tumour spread—involvement of of ovarian carcinomas. J Clin Pathol. 2008;61:152–63.
mucosa, submucosa, muscularis, serosa, sur- McCluggage WG, Hirschowitz L, Ganesan R, Kehoe S,
Nordin A. Which staging system to use for gynaeco-
rounding structures. logical cancers: a survey with recommendations for
• Lymphovascular invasion—present/not present. practice in the UK. J Clin Pathol. 2010;63:768–70.
• Lymph nodes—sites, number identified, and Robboy SJ, Bentley RC, Russell R, Anderson MC, Mutter
number involved by tumour. GL, Prat J. Pathology of the female reproductive tract.
2nd ed. London: Churchill Livingstone/Elsevier; 2009.
• Involvement of other organs, e.g., ovary, Scully RE, Young RH, Clement PB. Tumors of the
omentum. ovary, maldeveloped gonads, fallopian tube and broad
• Peritoneal washings/ascitic fluid—involved/ ligament, Atlas of tumor pathology, vol. 3rd series.
not involved by tumour. Fascicle 23. Washington, DC: AFIP; 1998.
Singh N. Synchronous tumours of the female genital tract.
Histopathology. 2010;56:277–85.
The British Association of Gynaecological Tavassoli F, Devilee P. WHO classification of tumours.
Pathologists, British Gynaecological Cancer Pathology and genetics. Tumours of the breast and
Society, and gynaecological clinical reference female genital organs. Lyon: IARC Press; 2003.
group of the National Cancer Intelligence
(vulval neoplasms, cervical neoplasia, endometrial
Network recommend that FIGO staging be used cancer, uterine sarcomas, neoplasms of the ovaries
for gynaecological cancers rather than and fallopian tubes and primary carcinoma of the
TNM. The current FIGO staging system for fal- peritoneum), and tissue pathways for gynaecological
pathology. Accessed at https://www.rcpath.org/pro-
lopian tube carcinoma, which incorporates
fession/publications/cancer-datasets.html. Accessed
ovarian, tubal and primary peritoneal tumours, at Dec 2016.
has been outlined in Chap. 22.
Uterus
24
24.1 Anatomy portion of the uterus which merges with the cer-
vix is known as the isthmus. The anterior surface
The uterus is situated in the pelvic cavity between of the uterus is covered by peritoneum which
the rectum posteriorly and the urinary bladder reflects forward onto the bladder. The peritoneal
anteriorly. The body of the uterus (uterine cor- surface extends lower posteriorly before being
pus) comprises the superior part and this is joined reflected onto the rectosigmoid. The lower peri-
to the cervix, which comprises the inferior por- toneal reflection on the posterior aspect can be
tion of the uterus (Fig. 24.1). The length of the used as a means to distinguish the anterior and
uterus varies widely depending on the parity and posterior surfaces of the uterus. The anterior and
the menopausal status but generally ranges from posterior peritoneal linings merge laterally to
5 to 15 cm in those uteri which are not involved form the broad ligaments which extend to the
by any specific pathologic process. The weight of pelvic side wall.
the uterus also varies widely between 20 and Lymphovascular drainage:
120 g. Multigravid uteri are considerably larger The uterus is supplied by the uterine arteries.
than nulligravid uteri. The uterus is lined by an These are bilateral paired arteries which arise
inner endometrium composed of endometrial from the internal iliac arteries. The veins of the
glands and stroma. Most of the wall is composed uterus drain into the uterovaginal venous plexus
of myometrial smooth muscle. The lumen of the which is located within the broad ligament. These
uterus is connected to the lumen of the fallopian veins ultimately open into the internal iliac veins.
tubes. The part of the uterine body above the ori- Uterine lymphatics drain into the pelvic and peri-
gin of the fallopian tubes is the fundus. The lower aortic lymph nodes (Fig. 24.2).
O.P. Houghton (*) • W. Glenn McCluggage

mccluggage@belfasttrust.hscni.net

Uterine fundus Fallopian tube
Uterine body
Isthmus Ovary
Endocervix
Uterine cervix
Vaginal fornix
Exocervix
Fig. 24.1 Uterine anatomy (Used with the permission of the Union for International Cancer Control (UICC), Geneva,
Switzerland. The original source for this material is from Wittekind et al. (2005))
2 5 Clinical features related to uterine pathology are

most commonly those of abnormal uterine bleed-
4 ing. In premenopausal patients, this may take the
form of menorrhagia (heavy periods), dysmenor-
3 1 rhoea (painful periods), or a variety of other
forms of abnormal uterine bleeding. In post-
menopausal patients, the most common symp-
tomatology is postmenopausal bleeding. This
should always be taken seriously and uterine
malignancy excluded. Other symptomatologies
related to uterine pathology include a palpable
abdominal or pelvic mass, pain within the pelvis
Fig. 24.2 Uterus—regional lymph nodes (1) Hypogastric or abdomen (often deep seated), a feeling of
internal iliac. (2) Common iliac. (3) External iliac (4) fullness within the abdomen, and uterine pro-
Lateral sacral. (5) Para-aortic (Used with the permission
of the Union for International Cancer Control (UICC),
lapse. Uterine pathology may also be associated
Geneva, Switzerland. The original source for this material with symptoms such as constipation, urinary fre-
is from Wittekind et al. (2005)) quency, or infertility.
24 Uterus 263
24.3 Clinical Investigations atrophic endometrium. Endometrial appearances

can also reflect the use of exogenous hormones or
• Ultrasound scan: Transvaginal ultrasound the presence of abnormal levels of endogenous
scan is often performed in patients with abnor- hormones. Noncyclical endometria may be a mani-
mal uterine bleeding and other symptomatol- festation of conditions such as anovulatory cycles
ogy related to the uterus. This may show focal or luteal phase deficiency.
lesions or diffuse thickening of the endome- Endometrial polyps: Endometrial polyps are
trium or myometrium. The endometrial thick- benign endometrial lesions which often result in
ness and endometrial stripe can be measured abnormal uterine bleeding and are most common
and related to the menopausal status of the postmenopausally. They may be single or multi-
patient. ple. They are often removed piecemeal and
• Endometrial sampling: Usually sampling of should be sampled in their entirety when small.
the endometrium to provide material for his- With larger lesions selective pathological sam-
tology is necessary for a definitive pathologi- pling is performed. Occasionally carcinoma
cal diagnosis, especially in cases of abnormal arises in a preexisting polyp. There is an associa-
uterine bleeding such as postmenopausal tion between endometrial polyp formation and
bleeding. In some centres, endometrial brush- the use of tamoxifen.
ings with cytological examination is carried Endometritis: This is an inflammatory condi-
out, but this is rare. Previously the most com- tion of the endometrium which may result in
mon means of sampling the endometrium was abnormal uterine bleeding. Generally the pres-
by dilatation and curettage (D&C). This ence of plasma cells is required for a definitive
requires a general anaesthetic and is per- pathological diagnosis.
formed as an inpatient procedure. However, Products of conception: Products of concep-
pipelle endometrial biopsies can now be per- tion may be submitted for histological examina-
formed as an outpatient procedure without the tion from therapeutic or spontaneous abortions.
need for a general anaesthetic. Histological Adenomyosis: Adenomyosis is a common con-
sampling of the endometrium may also be per- dition characterized by extension of endometrial
formed in women who are being treated with glands and stroma into the underlying myometrium.
tamoxifen or other hormonal agents, or those Usually this results in diffuse uterine enlargement,
who are infertile. although occasionally well-circumscribed nodular
• Hysteroscopy: In many cases, hysteroscopy masses are formed. Typically adenomyosis results
with direct visualization of the endometrium in a trabeculated appearance to the myometrium
is performed and biopsies are taken at this because of the associated smooth muscle hypertro-
procedure. phy around the pale or haemorrhagic adenomyotic
• MRI scanning: In cases where endometrial foci. Adenomyosis is most common in the repro-
sampling confirms a malignancy, radiological ductive age group and is thought to develop under
staging procedures are carried out, and this oestrogenic influence. It is a common cause of
usually comprises MRI scanning. irregular uterine bleeding.
24.4 Pathological Conditions 24.4.2 Neoplastic Conditions
24.4.1 Non-neoplastic Conditions A range of benign and malignant neoplasms can

involve both the endometrium and myometrium.
Cyclical or noncyclical endometrium: Endometrial Endometrial hyperplasias: These are a spec-
sampling may reveal normal proliferative, secre- trum of preneoplastic conditions which confer an
tory, or menstrual endometrium or postmenopausal increased risk of subsequent development of
endometrial adenocarcinoma of endometrioid Endometrial carcinomas may be polypoid in

type. The WHO classification of endometrial appearance and project into the endometrial cav-
hyperplasias is used with hyperplasias catego- ity. Conversely some tumours diffusely infiltrate
rized as hyperplasia without atypia or atypical the underlying myometrium.
hyperplasia (endometrial intraepithelial neopla- Uterine carcinosarcomas (Malignant Mixed
sia) based on the evaluation of architectural fea- Mullerian Tumours) are highly aggressive neo-
tures and cytologic alterations. plasms composed of carcinomatous and sarco-
Endometrial carcinomas: A variety of differ- matous elements. Although historically regarded
ent carcinomas may arise from the endometrium. as a subtype of uterine sarcoma, there is now
There are two main types (Type I and Type II), ample evidence that these are in fact high-grade
although not all neoplasms fall neatly into either metaplastic carcinomas. They are usually bulky
category with mixed tumours being not uncom- neoplasms in elderly patients, often with a polyp-
mon. The prototype type I endometrial carcinoma oid appearance and exhibiting deep myometrial
is endometrioid adenocarcinoma and the proto- infiltration and vascular invasion.
type type II is serous carcinoma. Type I and Type Uterine leiomyomas: Uterine leiomyomas
II neoplasms have different clinicopathologic (fibroids) are benign smooth muscle tumours and
characteristics, although it is emphasized that one of the most common benign neoplasms to
there may be overlap. occur in women, especially within the reproduc-
In general, Type II carcinomas behave in a tive and early postmenopausal age group. They
much more aggressive manner. Endometrial are often multiple but may be solitary. Uterine
carcinomas (especially Type I) are associated leiomyomas can be submucosal, intramural, or
with oestrogen excess and obesity, hyperten- subserosal. Occasionally they may separate from
sion, diabetes, and unopposed oestrogen hor- the uterus and lie within the pelvic cavity—so-
mone therapy. There may also be an association called parasitic leiomyomas. They are usually
with oestrogen-secreting ovarian tumours, well circumscribed, white in colour with a typical
mainly those within the sex cord-stromal firm whorled appearance and bulge above the
group. Type II carcinomas usually arise in an surrounding myometrium. Degeneration may
older age group and are not associated with result in a variety of different gross appearances.
oestrogen excess. Endometrial carcinomas are Malignant uterine mesenchymal lesions:
increasing in incidence and are more common Malignant uterine mesenchymal lesions comprise
in women of low parity, high socioeconomic low-grade endometrial stromal sarcoma, high-
status, and in the postmenopausal age group. grade endometrial stromal sarcoma, leiomyosar-
Occasionally there is a familial predisposition coma, undifferentiated uterine sarcoma, and a
to developing endometrial cancer. Endometrial variety of rare sarcomas, such as rhabdomyosar-
carcinoma is the second most common neo- coma. Low-grade endometrial stromal sarcomas
plasm to arise in patients with hereditary non- usually cause diffuse uterine enlargement due to
polyposis colorectal cancer syndrome (Lynch infiltration of the myometrium by irregular tongues
syndrome); in fact, the incidence of endome- of neoplastic endometrial stromal cells. There is
trial cancer in women with Lynch syndrome often marked vascular permeation and the tumour
approximates or even exceeds that of colonic may extend beyond the uterus. High-grade endo-
cancer. metrial stromal sarcoma is an aggressive tumour
Type I endometrial carcinomas usually arise which often has extra-uterine spread at time of pre-
in a background of endometrial hyperplasia. This sentation. It is characterised by YWHAE-FAM22
association is not apparent with Type II endome- gene fusion. Leiomyosarcomas and undifferenti-
trial cancers which usually arise within an atro- ated sarcomas are generally high-grade malignant
phic endometrium from a precursor known as neoplasms, usually comprising a dominant mass
serous endometrial intraepithelial carcinoma with or without satellite nodules. Grossly areas of
(serous EIC). haemorrhage and necrosis are common.
24 Uterus 265
Other uterine neoplasms: Endometrial stro- often not expected clinically and is only diag-
mal nodules are benign well-circumscribed pro- nosed on a hysterectomy specimen performed for
liferations of endometrial stroma. Histologically menorrhagia.
they are identical to endometrial stromal sarco- Troublesome menorrhagia can in many cases
mas and are differentiated from the latter due to be managed by hormonal agents or endometrial
their circumscription and lack of infiltrative myo- ablation (balloon dilatation, laser ablation, or
metrial permeation or vascular invasion. They hysteroscopic resection) with resort to simple
may involve both the endometrium and myome- hysterectomy in a minority of cases with persis-
trium or may be predominantly located within tence or recurrence of symptoms.
the myometrium. Prognosis: The prognosis of low-grade, early-
Treatment: Treatment of malignant uterine stage (Stage IA) endometrial adenocarcinoma of
lesions (carcinomas, sarcomas, carcinosarcomas) endometrioid type is excellent, but overall sur-
usually comprises total hysterectomy, either vival decreases with increasing tumour stage.
using an abdominal, vaginal, or laparoscopic Prognosis is poor with Type II endometrial adeno-
approach, and bilateral salpingo-oophorectomy. carcinomas, especially uterine serous carcinoma.
Peritoneal washings are usually performed as Leiomyosarcoma, undifferentiated uterine sar-
part of the staging procedure. Pelvic and/or para- coma, and carcinosarcoma usually have a poor
aortic lymph node resection and omentectomy prognosis, especially if large and of advanced
may be performed, especially when preoperative stage. Low-grade endometrial stromal sarcomas
endometrial biopsy shows a high-grade endome- have an overall favourable prognosis, although
trioid carcinoma or a Type II carcinoma or when there is a significant risk of late recurrence after
radiological investigations suggest cervical inva- many years and subsequent metastasis with these
sion or extrauterine spread. Preoperative staging tumours. Adjuvant progesterone therapy may be
comprises MRI scanning to assess the extent of indicated, since these tumours are commonly hor-
tumour spread. Postoperative radiotherapy or mone responsive and oestrogen and progesterone
chemotherapy may be administered depending receptor positive. The prognosis of high- grade
on the histological subtype and the stage. This is endometrial stromal sarcoma is intermediate
especially so with high-grade or Type II endome- between low-grade endometrial stromal sarcoma
trial carcinomas or where there is cervical and undifferentiated uterine sarcoma.
involvement, deep myometrial penetration, or
extrauterine spread. The FIGO staging system for
endometrial carcinoma is used. The British 24.5 Surgical Pathology
Association of Gynaecological Pathologists, Specimens: Clinical Aspects
British Gynaecological Cancer Society, and gyn-
aecological clinical reference group of the 24.5.1 Biopsy Specimens
National Cancer Intelligence Network recom-
mend that FIGO staging be used for gynaecologi- Endometrium pipelle biopsies may be performed
cal cancers rather than TNM. Note that there is blind or under hysteroscopic visualization.
close correlation between the two schemes. Endometrial D&C is performed under general
Occasionally with advanced tumours, surgical anaesthetic. Tissue from therapeutic abortions
resection is not feasible and primary treatment is (performed at D&C) or spontaneous abortions
radiotherapy or chemotherapy. All cases should may also be received.
be discussed at a multidisciplinary gynaecologi-
cal oncology meeting.
Uterine leiomyomas may be treated by hyster- 24.5.2 Resection Specimens
ectomy or, in those who wish to preserve their
fertility, medical treatment or myomectomy The endometrium and superficial myometrium
(simple removal of the fibroids). Adenomyosis is may be removed as multiple chippings at trans-
cervical resection of the endometrium (TCRE). cytometric examination or image cytometry of

Most uterine specimens comprise a hysterec- such specimens may be indicated since partial
tomy, performed either abdominally or vaginally. moles are often triploid, whereas complete moles
Occasionally the cervix is left behind. This is and hydropic abortions are usually diploid. A
known as a subtotal hysterectomy. The ovaries small minority of molar gestations leads to per-
and fallopian tubes may also be removed with the sistent trophoblastic disease and rarely
uterus and cervix. If the uterus is being removed choriocarcinoma.
as part of a tumour operation, then peritoneal
washings are often sent. The omentum may also
be removed as well as pelvic and/or para-aortic 24.6.2 Resections Specimens
lymph nodes. Sometimes for uterine fibroids,
myomectomy is performed, where the fibroid is The uterine corpus is usually removed together
removed, but the uterus is left in situ. A radical with the cervix as part of a hysterectomy.
hysterectomy is often indicated for cervical Occasionally the cervix is left in situ and a subto-
cancer or for endometrial cancer involving the tal hysterectomy is performed. Myomectomies
cervix. This involves removing a segment of the may also be performed, especially for uterine
upper vagina and the parametrium on both lateral fibroids.
aspects of the uterus. Initial procedure and description:
• The specimen is weighed.

24.6 Surgical Pathology • The specimen is measured in three dimen-
Specimens: Laboratory sions (cm), i.e., superior to inferior, medial to
Protocols lateral, anterior to posterior.
• The specimen is orientated. The peritoneal
24.6.1 Biopsy Specimens reflection extends lower on the posterior
aspect of the uterus than anteriorly.
Endometrial pipelle or curettage biopsies are • Ovaries and tubes, if present, are inspected
weighed and processed intact for histopathogical and dealt with as described in Chap. 22.
examination. Very scanty pipelle samples may • The presence of any external abnormality is
need to be filtered from the fixative. Similarly, noted, e.g., tumour on the serosa, serosal
TCRE chippings are weighed and all examined. adhesions.
If histology of these samples shows the presence • The os of the cervix and the uterine cavity are
of fat, it may be omental in origin and implies entered using a probe.
potential perforation of the uterine wall. The cli- • Cutting along the probe, the uterus is opened
nician should be alerted without delay. For sus- longitudinally either along the lateral axis or
pected products of conception, the specimen is along the anteroposterior axis from the exter-
weighed and the tissue is examined grossly with nal os to the cornu.
particular reference to the presence of blood clot, • The nature of the endometrium is commented
decidua, placental tissue, and fetal parts. Small on. The thickness can be measured and the
specimens can be examined in their entirety, but presence of tumour, polyp, or any focal lesion
with larger specimens representative sections are described and measured (cm).
taken in order to confirm the presence of products • The presence or absence of uterine fibroids is
of conception. When vesicles are identified, note noted. These are counted and the dimensions
their maximum diameter—if 2–3 mm or more, of the largest stated. Usually uterine fibroids
this raises the possibility of a molar pregnancy have a typical white whorled appearance and
and extensive sampling is required in order to bulge above the surrounding myometrium.
confirm the presence of a hydatidiform mole and The presence of any grossly abnormal areas
distinguish a partial from a complete mole. Flow such as haemorrhage, necrosis, abnormal
24 Uterus 267
colouration, calcification, or cystic degenera- transformation zone (one from the anterior
tion is recorded. and one from the posterior lip) are also taken
• Any cervical abnormalities are noted as (Fig. 24.3).
described in Chap. 25. • When grossly visible adenomyosis is present,
• If a tumour is grossly visible, the dimensions this is sampled.
are measured. If this comprises an endome- • If leiomyomas are present and these are grossly
trial carcinoma (usually known from a previ- typical, one or two representative sections suf-
ous biopsy specimen), then the depth of fice. If there are multiple leiomyomas, not all
myometrial invasion is ascertained (inner or need to be examined microscopically.
outer half) as is the presence or absence of • If there are areas of haemorrhage or necrosis
gross cervical involvement. Assessment of within a leiomyoma or if any unusual gross
the depth of myometrial invasion can be dif- findings are present, then extensive sampling
ficult as myometrial invasion may be subtle should be undertaken, especially from the
and these uteri are often atrophic with a thin, periphery of the lesion.
compressed myometrium. Any obvious
• With endometrial carcinomas multiple sec-
spread to the ovaries or fallopian tubes is tions are examined. (Fig. 24.4). They are taken
documented. to show the deepest point of myometrial infil-
• The presence of tumour infiltrating to the tration, and also from uninvolved endome-
serosal surface of the uterus is also noted and trium to assess the presence of coexistent
in those tumours which do not extend to the hyperplasia. If no macroscopic tumour is evi-
serosal surface the minimum thickness of dent in a patient with a biopsy-proven endo-
uninvolved myometrium is measured (mm). metrial carcinoma, the entire endometrial
• The presence of grossly visible foci of adeno- cavity may need to be blocked.
myosis is recorded. • Sections are taken from the cervix from any
• The uterus is then sliced either transversely or gross areas of cervical involvement. When
longitudinally (depending on personal prefer- this is not seen, take three or four representa-
ence) at 3–5 mm intervals. During this proce- tive sections of the lower uterine segment
dure, the presence of previously unidentified and cervix.
leiomyomas and the depth of invasion of • Any grossly visible endometrial polyps are
endometrial carcinomas into the myometrium sampled.
can be better assessed. • When there is a history of endometrial hyper-
• Photography may be undertaken. plasia and no grossly visible lesion is present,
• Myomectomy specimens are enumerated, the endometrium should be extensively sam-
weighed, measured, and described. pled to assess the worst degree of hyperplasia
• The number of lymph nodes (if removed) and to evaluate whether a coexistent adenocar-
from each site should be documented. cinoma is present.
• The omentum (if removed) should be mea- • Ovaries and tubes, when grossly normal, are
sured and weighed. It should be carefully examined as per a benign protocol. Sections of
sliced and the presence of any tumour nodules the fallopian tube should include the fimbrial
or any other gross lesion documented. end. If coexistent ovarian tumour is present,
this should be blocked as outlined in Chap. 22.
Blocks for histology: • All lymph nodes should be submitted for his-
tological examination.
• When the hysterectomy was performed for • Any parametrial tissue should be submitted.
benign disease, two representative sections • If grossly normal, one or two blocks of omen-
showing the endometrial–myometrial junction tum should be submitted. If tumour nodules
and, if possible, the full-wall thickness, are are identified grossly, one or two blocks
examined. Two blocks of cervix showing the should be submitted.
1. Probe
2. Hemisect in a coronal (lateral) plane
3. Amputate
the cervix
Endocervix
Exocervix
4. Take anterior and posterior

cervical blocks to include
the transformation zone
Block of endometruim
plus wall
5. Transverse section the

corpus and sample
endometrium and wall
Fig. 24.3 Blocking a routine hysterectomy specimen (Reproduced, with permission, from Allen and Cameron (2013))
Histopathology report: • Size of tumour—Measure in three dimensions (cm)

• Gross appearance of tumour—Polypoid or
• Site of tumour within the uterus—Fundus, infiltrative. Colour and consistency. Presence
body, lower uterine segment or absence of haemorrhage and necrosis.
24 Uterus 269
Corpus
Endometrium
Tumour
Isthmus Myometrium
Myometrium
Transverse section
of endocervix, tumour
and parametrial/
paracervical tissues
Longitudinal blocks of endocervix,

tumour and transformation zone
1. Process adnexae
2. Probe and hemisect laterally
3. Amputate cervix and block
4. Transverse section corpus and isthmus
D = distance of deepest extent of tumour to nearest part of the serosa (mm)
Fig. 24.4 Blocking a hysterectomy for uterine carcinoma (Reproduced, with permission, from Allen and Cameron
(2013))
• Tumour type—A variety of different adeno- since these are automatically high-grade
carcinomas arise in the endometrium. It is not (Grade III) tumours.
acceptable to simply render a diagnosis of • Myometrial invasion—Presence or absence of
adenocarcinoma. The type of the adenocarci- myometrial invasion. If present—confined to
noma should be stated. inner half or involves outer half.
• Tumour differentiation—Endometrial adeno- • Lymphovascular invasion—Present/not
carcinomas of endometrioid and mucinous present.
types are graded as Grade I–III (FIGO grading • Lymph nodes—Mention sites, number identi-
system). This depends on architectural and fied, and number involved by tumour. The
cytological features. The more uncommon regional nodes are pelvic and para-aortic and a
morphological subtypes such as serous carci- regional lymphadenectomy will ordinarily
noma and clear cell carcinoma are not graded include ten or more lymph nodes.
• Cervical involvement—Presence or absence IVA Tumour invasion of bladder and/or

of involvement of the endocervical glands bowel mucosa
and/or stroma. Cervical stromal involvement IVB Distant metastases, including intra-
abdominal metastases and/or inguinal
is associated with a worse prognosis than
lymph nodes
involvement limited to the endocervical sur-
face or crypt epithelium. 2009 FIGO staging systems for uterine
• Serosal involvement—Present/not present. sarcomas
• Measure minimum distance (mm) from the Uterine leiomyosarcoma and endometrial
deepest point of myometrial infiltration by stromal sarcoma
tumour to the serosa.
• Surrounding endometrium—Presence or I Tumour limited to uterus
absence and type of hyperplasia. IA ≤5 cm
IB >5 cm
• Omental involvement—Present/not present.
II Tumour extends beyond the uterus, within
• Parametrial involvement—Present/not
the pelvis
present.
IIA Adnexal involvement
• Other pathology—The presence of coexistent IIB Involvement of other pelvic tissues
pathology should be mentioned. III Tumour invades abdominal tissues (not just
• Peritoneal washings—Presence or absence of protruding into the abdomen)
tumour cells. IIIA One site
• Ovary and fallopian tube—Presence or IIIB >one site
absence of tumour metastasis. Note that, espe- IIIC Metastasis to pelvic and/or para-aortic
cially with endometrioid tumours, synchro- lymph nodes
nous neoplasms may be present within both IV
the ovary and endometrium. IVA Tumour invades bladder and/or rectum
IVB Distant metastasis
Extent of local tumour spread: FIGO Stage
for carcinoma and carcinosarcoma (malignant Uterine adenosarcoma
mixed Mullerian tumour) of endometrium
I Tumour limited to uterus
IA Tumour limited to endometrium/
I Tumour confined to the corpus uteri
endocervix with no myometrial invasion
IA No or less than half myometrial invasion
IB Less than or equal to half myometrial
IB Invasion equal to or more than half of invasion
the myometrium
IC More than half myometrial invasion
II Tumour invades cervical stroma, but
II Tumour extends beyond the uterus, within
does not extend beyond the uterus
the pelvis
III Local and/or regional spread of the
IIA Adnexal involvement
tumour
IIB Involvement of other pelvic tissues
IIIA Tumour invades the serosa of the corpus
uteri and/or adnexae III Tumour invades abdominal tissues (not just
protruding into the abdomen)
IIIB Vaginal and/or parametrial involvement
IIIA One site
IIIC Metastases to pelvic and/or para-aortic
lymph nodes IIIB >one site
IIIIC1 Positive pelvic nodes IIIC Metastasis to pelvic and/or para-aortic
lymph nodes
IIIIC2 Positive para-aortic lymph nodes with or
without positive pelvic lymph nodes IV
IV Tumour invades bladder and/or bowel IVA Distant metastasis
mucosa, and/or distant metastases IVB Distant metastasis
24 Uterus 271
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Cervix
25
25.1 Anatomy cervix and upper vagina. The veins of the cervix
drain to the uterovaginal plexus in the base of the
The cervix is joined to the body of the uterus and broad ligament. Cervical lymphatics drain into
usually measures 2.5–3 cm in length. The bladder small perforating lymphatic vessels, which even-
is situated anteriorly and is separated from the tually leave the cervix via two main vessels which
cervix by loose connective tissue. On the poste- are closely opposed to the uterine arteries. These
rior aspect the upper cervix is covered by perito- drain into pelvic lymph nodes. The pelvic lymph
neum. Part of the cervix lies within the vagina and nodes which the cervical lymphatics drain into
is surrounded by a reflection of the vaginal wall are the external iliac nodes, the internal iliac
called the fornix. The ectocervix (outer cervix) is nodes, and the common iliac nodes (Fig. 25.1).
covered by non-keratinizing stratified squamous
epithelium and the endocervix (inner cervix) is
lined by a single layer of mucin-secreting epithe-
lial cells. The junction between the two is known
as the transformation zone (see Fig. 24.1).
The blood supply to the cervix is from the 5 6
uterine artery. As the uterine artery approaches

the cervix, it divides into ascending and descend-
ing branches. The descending branch supplies the
7
4
3
Fig. 25.1 Cervix—regional lymph nodes. (1)

Paracervical nodes. (2) Parametrial nodes. (3) Hypogastric
O.P. Houghton (*) • W. Glenn McCluggage (internal iliac) including obdurator nodes. (4) External
Histopathology Laboratory, Institute of Pathology, iliac nodes. (5) Common iliac nodes. (6) Presacral nodes.
Royal Victoria Hospital, Belfast Health and Social (7) Lateral sacral nodes (Used with the permission of the
Care Trust, Belfast, UK Union for International Cancer Control (UICC), Geneva,
e-mail: oisin.houghton@belfasttrust.hscni.net; glenn. Switzerland. The original source for this material is from
mccluggage@belfasttrust.hscni.net Wittekind et al. (2005))

25.2 Clinical Presentation 25.4 Pathological Conditions
A variety of dysplastic preinvasive lesions, of 25.4.1 Non-neoplastic Conditions

both squamous and glandular types, are com-
monly encountered within the cervix. These are A variety of benign non-neoplastic conditions
usually picked up because of an abnormal cervi- occur within the cervix. The chief importance
cal smear, performed in the UK as part of the of these is their potential for misdiagnosis as
NHS Cervical Screening Programme. These cervical intraepithelial neoplasia (CIN) or cer-
abnormalities are often associated with and due vical glandular intraepithelial neoplasia
to infection by human papilloma virus (HPV). (CGIN). These conditions include polyps,
Other symptoms related to cervical pathology reserve cell hyperplasia, immature and mature
include watery vaginal discharge, and postcoital squamous metaplasia, inflammatory induced
and intermenstrual bleeding. With advanced cer- atypia, tubal and tuboendometrial metaplasia,
vical tumours invading the bladder or rectum, endometriosis, and microglandular hyperpla-
there may be urinary or bowel symptoms. Large sia. Mesonephric remnants, when present
tumours can protrude through the external cervi- within the cervix, may also lead to diagnostic
cal os into the vagina. Small cervical tumours problems.
may be asymptomatic. With advanced tumours,
the ureters can become obstructed with resultant
hydronephrosis and renal failure—lymphoe- 25.4.2 Neoplastic Conditions
dema and deep venous thrombosis may also
occur. The two main malignant neoplasms to occur
within the cervix are invasive squamous carci-
noma and adenocarcinoma. Mainly due to the
25.3 Clinical Investigations advent of organized screening programs, precur-
sor lesions (CIN and CGIN) are identified much
Most preinvasive dysplastic lesions are picked up more commonly by cytology and the incidence of
because of an abnormal cervical smear. When a invasive cervical tumours, especially squamous
significant cytological abnormality is identified, carcinoma, is decreasing.
patients are referred to a gynaecologist for col- Cervical intraepithelial neoplasia (CIN): CIN
poscopy. This involves looking at the cervix is the preferred designation in the UK for the
under a special microscope (colposcope) and spectrum of dysplastic preinvasive squamous
often taking a biopsy or performing local exci- lesions which are associated with an increased
sion of an abnormal area of cervix (loop or cone risk of the subsequent development of cervical
biopsy). These areas are identified by their lack squamous carcinoma. These usually arise at the
of uptake of iodine stain (acetowhite epithe- transformation zone of the cervix and are divided
lium—AWE) and abnormal surface appearances into CINI, CINII, and CINIII (previously known
(e.g., vascular punctation or a mosaic pattern). as mild, moderate, and severe dysplasia, respec-
HPV testing (for high risk HPV types) may also tively). Morphological changes associated with
be undertaken and involves molecular testing of HPV infection are termed koilocytosis. In some
material taken at a cervical smear. In patients countries, koilocytosis and CINI are collectively
with cervical discharge, material may be sent for termed low-grade squamous intraepithelial lesion
microbiological investigations. In cases of cervi- (LSIL), while CINII and CINIII are designated
cal tumour, radiological investigation, usually in high-grade squamous intraepithelial lesion
the form of MRI, is carried out for staging (HSIL). The transition from CINI to CINIII may
purposes. take many years and all grades of CIN may revert
25 Cervix 275
to normal, especially CINI. The aim of cervical infection. Smoking is also a risk factor for the
screening is to pick these lesions up in the development of cervical squamous carcinoma.
preinvasive stage. Treatment then reduces the
Treatment: Following referral because of an
risk of development of squamous carcinoma. abnormal cervical smear (or occasionally a clini-
Cervical Glandular Intraepithelial Neoplasia cally suspicious cervix or symptoms such as post-
(CGIN): Similar to the situation with CIN, prein- coital bleeding), colposcopic examination is
vasive glandular lesions may be encountered. performed. In general, low-grade lesions (koilocy-
These are much rarer than the corresponding squa- tosis and CINI) are treated by local ablative proce-
mous lesions and are less likely to be picked up on dures or cytological follow-up, while high-grade
cytological examination. They often coexist with lesions (CIN II and CIN III) are treated by local
squamous lesions. In the UK, the preferred desig- excision, as is CGIN. Usually this is in the form of
nation is cervical glandular intraepithelial neopla- diathermy large loop excision of the transforma-
sia (CGIN). These are divided into low-grade and tion zone (LLETZ) of the cervix. Occasionally
high-grade CGIN. The WHO classification uses cold knife cone biopsies may be performed, espe-
the term adenocarcinoma in situ corresponding to cially if a small invasive carcinoma is suspected or
high-grade CGIN; the WHO feels that low-grade if a cervical glandular lesion is suggested on cytol-
CGIN is poorly reproducible and such cases likely ogy. With more advanced cervical tumours (usu-
represent incompletely sampled or morphologi- ally greater than stage Ia1), radical hysterectomy
cally incomplete examples of high-grade CGIN. A is usually carried out. This involves removing the
variant of CGIN known as “stratified mucin-pro- uterus and cervix with a cuff of vagina. The sur-
ducing intraepithelial lesion (SMILE)” has been rounding parametrium on both sides is also
described. Many of these lesions are associated removed and pelvic lymph node resection is
with HPV infection. undertaken. The FIGO staging system for cervical
Invasive tumours: Approximately 70–80% of cancer is used. With advanced cervical cancers
invasive carcinomas of the cervix are squamous (greater than stage IIa and sometimes with bulky
cell in type. Most of the remainder are adenocar- Ib2 tumours), the initial treatment may be chemo-
cinomas; most of these are of the usual or endo- radiation. This may be followed by salvage hyster-
cervical type, although uncommon variants such ectomy at a later date. Whether chemoradiation is
as adenoma malignum, gastric, mesonephric, given postsurgery for cervical carcinomas depends
clear cell, and serous also occur. Rarer morpho- on a variety of pathological factors.
logical subtypes of cervical carcinoma include LLETZ or cone biopsies with careful assess-
adenosquamous carcinoma and small-cell and ment of margins and cytological follow-up may
large-cell neuroendocrine carcinoma. A variety be performed in patients with early (stage Ia1)
of other malignant tumours occur within the cer- tumours. Occasionally in young patients with
vix, but these are rare. 1a2 or small Ib1 cancers (usually less than 2 cm)
The main risk factor in the development of and who wish to preserve their fertility, a trache-
both squamous carcinoma and adenocarcinoma lectomy may be performed followed by the inser-
of the cervix is infection with HPV, although tion of a suture into the cervix. Trachelectomy
some of the uncommon types of adenocarcinoma, involves a local excision of the cervix with the
for example gastric-type, clear cell and meso- upper vagina and the surrounding parametrium.
nephric, are not usually HPV related. There may Pelvic lymph nodes are usually removed laparo-
be an association with oral contraceptive use and scopically during this procedure. Careful patho-
cervical adenocarcinoma. Other factors impli- logical examination is required to ascertain
cated in the pathogenesis of cervical cancer, whether further, more radical, surgery is needed.
including early age at first intercourse, multiple All cases should be discussed at a multidisci-
sexual partners, etc., are not independent of HPV plinary gynaecological oncology meeting.
Prognosis: Following ablation or local exci- 25.6 Surgical Pathology

sion of premalignant cervical lesions, close Specimens: Laboratory
cytological follow-up is carried out for a period Protocols
of 5–10 years, depending on the diagnosis.
The prognosis of invasive cervical cancers is 25.6.1 Biopsy Specimens
largely dependent on the tumour stage. Stage 1a1
carcinomas have an excellent prognosis and these Small cervical colposcopic punch biopsies are
may be treated by conservative local excision examined intact at multiple histological levels.
therapies, usually in the form of loop or cone Loop and cone biopsies are measured (each indi-
biopsies. The prognosis of more advanced cervi- vidual fragment is measured in three dimensions),
cal cancers, as already stated, largely depends on carefully sectioned into multiple serial blocks
the stage of the tumour and the lymph node sta- (Fig. 25.2), and the entire tissue is examined his-
tus, especially the presence of extracervical tologically. No more than two slices of tissue
spread, with an overall 5-year survival of about should be put into a single cassette. Levels are not
55%. routinely needed for loop or cone biopsies but
may be necessary for a variety of reasons such as
if histology shows the presence of an area suspi-
25.5 Surgical Pathology cious of invasion, incomplete correlation with the
Specimens: Clinical Aspects preceding cytology, or if the full face of the tissue
is not represented in the initial sections. Wedge
25.5.1 Biopsy Specimens biopsies are measured in three dimensions, sec-
tioned thinly, and examined in their entirety.
Many biopsy specimens of cervix submitted to
the pathology laboratory comprise small punch
biopsies performed at colposcopic examination. 25.6.2 Resection Specimens
Cervical polyps are removed following direct
visualization of the cervix. Loop and cone biop- In cases of cervical cancer (usually greater than
sies are local excisions of the cervix, usually stage Ia1), the operation of choice is radical hys-
performed at colposcopic examination. Wedge terectomy together with pelvic lymph node
biopsies are taken with grossly visible neo- removal. Radical (Wertheim’s) hysterectomy
plasms, in order to confirm the presence of involves removal of the uterus and cervix together
tumour. with a cuff of vagina and the surrounding para-
metrium. Both ovaries and fallopian tubes are
also usually removed, although in young women
25.5.2 Resection Specimens they may be left behind in order that ova may be
available for those who wish to have children and
In general, with the exception of Ia1 carcinomas hormonal function may be preserved.
and young women who wish to preserve their fer- A trachelectomy may be performed in young
tility, surgical treatment of cervical carcinoma women with cervical cancer who wish to pre-
comprises radical hysterectomy with removal of serve their fertility. This operation is usually
pelvic lymph nodes. Occasionally simple hyster- undertaken for early stage Ib carcinomas, the car-
ectomy is performed in women with CIN or cinoma measuring less than 2 cm in maximum
CGIN who have other benign uterine pathologies diameter. During the process of trachelectomy,
or symptoms related to the uterus or who do not local excision of the cervix is undertaken together
wish to be subjected to regular cytological with the upper vagina and the surrounding para-
follow-up. metrium and pelvic lymph nodes are removed.
25 Cervix 277

cervical cone or loop
biopsy (Reproduced, Intact
Allen and Cameron
(2013)) Open anteriorly
Multiple longitudinal at 12 o’clock
serial slices of
3mm thickness
or
Label as to
point of clock
face origin
Opened 1 o’clock
12 o’clock
6 o’clock
3 o’clock
Sometimes simple hysterectomy is carried out At this stage, the serosal surface of the uterus
for extensive or recurrent CIN or CGIN, or in and the external surface of the cervix together
patients with CIN or CGIN who are symptomatic with the vaginal resection margin can be inked.
for other reasons, e.g., dysfunctional uterine Different colours of ink may be used to designate
bleeding. No uterus should be dissected or right and left lateral, anterior and posterior. Care
reported without full knowledge of any prior should be taken so that the ink does not contami-
endometrial sampling or cervical cytology nate other surfaces, especially on sectioning.
results.
• The vaginal limit is sectioned in its entirety
25.6.2.1 Radical Hysterectomy and processed for histological examination.
Procedure, description, and blocks for histology Scissors are useful for obtaining these
in a radical hysterectomy (Fig. 25.3): blocks.
The specimen is weighed and the combined • The cervix is detached from the uterus by a
length of the uterus and cervix measured. complete transverse cut. A parallel slice from
The external surfaces of the uterus and cervix the proximal limit of the amputated cervix
are carefully evaluated to ascertain whether there provides blocks of right and left parametrium
is any tumour infiltration. which should be inspected for the presence or
Tumour and
isthmus block
Corpus
Vagina Endometrium
Parametrial/paracervical Myometrium
tissues Transverse
section
vaginal limit
Transverse section of
endocervix, tumour and
parametrial/paracervical
tissues
Longitudinal blocks of tumour and
transformation zone ensuring at
least quadrant representation
1. Process adnexae and paint paracervical/parametrial tissues

2. Transverse section the vaginal limit
3. Amputate cervix and block
4. Probe and hemisect the corpus laterally
5. Transverse section corpus
Fig. 25.3 Blocking a radical hysterectomy for cervical carcinoma (Reproduced, with permission, from Allen and
Cameron (2013))
absence of tumour and lymph nodes. 1–12 o’clock, with 12 being from the anterior
• The cervix is opened longitudinally and the lip of the cervix.
presence of any gross tumour noted. • Two sections are taken from the lower uterine
• If a tumour is apparent, it is measured in three segment to assess the presence or absence of
dimensions (cm) and its site stated (anterior, spread of tumour into the lower uterus.
posterior, left lateral, right lateral, etc.). • The uterus is carefully examined and, if unre-
• If a gross tumour is identified, representa- markable, sampled as per a benign protocol.
tive longitudinal sections are examined, a • The ovaries and tubes are carefully sectioned
minimum of one from each quadrant and, if unremarkable, sampled as per a benign
depending on the tumour location and dis- protocol. It is usually convenient to dissect
tortion of the cervical anatomy. These are and block the adnexae prior to the handling of
taken to show the deepest point of infiltra- the main specimen.
tion into the underlying cervical stroma and • Photography can be undertaken at any stage in
the relationship of the tumour to the closest the cutting process.
margins. Blocks are labeled as to their site • Lymph nodes are carefully sectioned and
of origin. labeled as to their site of origin. The number
• If no tumour is seen grossly, then the entire of lymph nodes from each site is recorded.
cervix should be sectioned and examined his- These are usually dissected and submitted to
tologically. Sections are labeled as to what the laboratory by the surgeon in separately
part of the cervix they are taken from, e.g., labeled pots.
25 Cervix 279
25.6.2.2 Trachelectomy Specimens • Tumour type—Most tumours within the cer-

Procedure for dealing with trachelectomy specimens: vix are either squamous carcinomas or
• The specimen is orientated, weighed, and adenocarcinomas.
measured in three dimensions (cm). • Tumour differentiation—Both squamous car-
• The parametrial surface is inked. cinomas and adenocarcinomas are classified
• The entire vaginal limit is submitted for histo- as being well, moderately, or poorly differen-
logical examination. tiated. For squamous carcinomas, the prog-
• If no tumour is identified grossly, the upper nostic significance of grading is controversial.
limit is submitted as a transverse section. Squamous carcinomas can also be classified
• If a tumour is seen grossly, this is measured in as large-cell keratinizing, large-cell non-
three dimensions. keratinizing, and small-cell non-keratinizing.
• If a tumour is seen grossly, a section is taken • The presence or absence of the following is
to show the relationship between the tumour noted:
and the proximal margin. • Adjacent CIN, CGIN, or signs of HPV
• The tissue is serially sliced longitudinally at infection.
3–4 mm intervals and examined in its entirety. • Vaginal, paracervical, or parametrial soft tis-
• Lymph nodes are dealt with as above. sue tumour involvement.
• Tumour at the circumferential limit (state
25.6.2.3 Hysterectomy for CIN/CGIN anterior, posterior, right or left lateral), or if
Procedure for hysterectomy with CIN and CGIN: clear, the minimum distance (mm) from it
(Fig. 25.4).
• The cervix is amputated and longitudinally • Vaginal limit involvement.
sectioned to give good junctional zone repre- • Lymphovascular permeation.
sentation. The number of blocks obtained • Lymph node involvement (site, number of
depends on the local cervical anatomy and nodes identified and number involved, intra-
distortion/stenosis as a result of previous pro- parenchymal or extracapsular spread)
cedures, e.g., LLETZ. Block numbers may • Response to preoperative chemoradiation
therefore range from 3–4 (quadrants) right up • Uterine involvement, although this does not
to 12. They are labeled as to their site of ori- affect the staging of cervical cancer
gin. It is better to take fewer blocks with good • Coexisting pathology in other organs, e.g.,
junctional zone representation rather than vaginal HPV or VAIN (vaginal intraepithelial
many blocks with poor representation. neoplasia).
• These specimens often contain a vaginal cuff
and the limit of this is submitted in its entirety For tumours confined to the cervix note the
for histological examination. minimum distance (mm) from the tumour to the
external cervical surface (Fig. 25.4) and state
• Histopathology report: which aspect of the cervix.
• The number of blocks of tumour examined When local excision is performed for a small
and the site of the tumour are stated. invasive cancer, record the tumour distance (mm)
• The tumour is measured in three dimensions and the distance of CIN or CGIN to the ectocer-
(cm). If this is not possible grossly, then it is vical, endocervical, and deep limits.
done histologically. The maximum depth and The British Association of Gynaecological
maximum horizontal dimension are measured Pathologists, British Gynaecological Cancer
on the slide. It should be remembered that Society, and gynaecological clinical reference
there is a third dimension and this is calculated group of the National Cancer Intelligence
by taking into account the presence of tumour Network recommend that FIGO staging be used
in adjacent tissue blocks. If a block is taken as for gynaecological cancers rather than TNM with
measuring 3 mm in thickness, then the total recording of the lymph node status for cervical
third dimension can be calculated on this basis. cancer. This may be done by providing a TNM
Fig. 25.4 Cervical Distance to deep aspect

carcinoma—tumour of cervical stroma
dimensions and margins
(Reproduced, with
(2013))
Length
(mm) Parametrium
Length (mm)
of vaginal cuff Depth
(mm)
Width (mm) = sum of involved serial blocks of standard thickness

Tumour volume (mm3) can be estimated by length x depth x width
D
Parametrium
D = tumour distance (mm) to the Circumferential

Radial Margin (CRM) of excision of
the parametrium
stage for this cancer type only or by recording the T1a1/IA1 Measured stromal invasion ≤3.0 mm
lymph node status at the multidisciplinary team and largest extension of ≤7.0 mm
meeting. Note that there is close correlation T1a2/IA2 Measured stromal invasion of
between the two schemes >3.0 mm and not >5.0 mm with an
extension of not >7.0 mm
TNM 8 and FIGO pathological staging of cervical
carcinoma T1b/IB Clinically visible lesion limited to the
cervix uteri or preclinical cancers
T1/I Cervical carcinoma confined to the greater than stage IAa
uterus (extension to the corpus should
be disregarded) T1b1/IB1 Clinically visible lesion ≤4.0 cm in
T1a/IA Invasive carcinoma, diagnosed only greatest dimension
by microscopy, with deepest invasion T1b2/IB2 Clinically visible lesion >4.0 cm in
≤5.0 mm and ≤7.0 mm greatest dimension
25 Cervix 281
T2/II Cervical carcinoma invades beyond M1 Distant metastasis (includes inguinal lymph
the uterus but not to the pelvic wall or nodes and intraperitoneal disease except
to lower third of the vagina metastasis to pelvic serosa). It excludes
T2a/IIA Without parametrial invasion metastasis to vagina, pelvic serosa, and adnexa
T2a1/IIA1 Clinically visible lesion ≤4.0 cm in
greatest dimension
T2a2/IIA2 Clinically visible lesion >4.0 cm in Bibliography
greatest dimension
T2b/IIB With obvious parametrial invasion Allen DC. Histopathology reporting. Guidelines for surgi-
T3/III The tumour extends to the pelvic wall cal cancer. 3rd ed. London: Springer; 2013.
and/or involves lower third of the Allen DC, Cameron RI. Histopathology specimens:
vagina, and/or causes hydronephrosis clinical, pathological and laboratory aspects. 2nd ed.
or nonfunctioning kidneyb Berlin: Springer; 2013.
T3a/IIIA Tumour involves lower third of vagina, Brierley JD, Gospodarowicz MK, Wittekind C, editors.
with no extension to the pelvic wall TNM classification of malignant tumours. 8th ed.
T3b/IIIB Extension to the pelvic wall and/or Oxford: Wiley-Blackwell; 2017.
hydronephrosis or nonfunctioning kidney Fox H, Wells M, editors. Haines and Taylor: obstetrical
and gynaecological pathology. 5th ed. Edinburgh:
T4/IV The carcinoma has extended beyond
Churchill Livingstone; 2003.
the true pelvis or has involved (biopsy
proven) the mucosa of the bladder or
female genital tract. J Clin Pathol. 2008;61:241–57.
rectum. A bullous oedema, as such,
Histopathology Reporting in Cervical Screening.
does not permit a case to be allocated
NHSCSP Publication, 10; 2011.
to stage IV
Kurman RJ, Amin MB. Protocol for the examination of
T4a/IVA Spread of growth to adjacent organs specimens from patients with carcinoma of the cervix.
M1/IVB Spread to distant organs Arch Pathol Lab Med. 1999;123:55–66.
a
All macroscopically visible lesions—even with Kurman RJ, Norris HJ, Wilkinson E. Tumors of the cer-
superficial invasion—are allotted to stage IB carcinomas. vix, vagina and vulva. In: Atlas of tumor pathology:
Invasion is limited to a measured stromal invasion with a third series Fascicle 4. AFIP: Washington; 1992.
maximal depth of 5.00 mm and a horizontal extension of McCluggage WG, Hirschowitz L, Ganesan R, Kehoe S,
not >7.00 mm. Depth of invasion should not be Nordin A. Which staging system to use for gynaeco-
>5.00 mm taken from the base of the epithelium of the logical cancers: a survey with recommendations for
original tissue—superficial or glandular. The depth of practice in the UK. J Clin Pathol. 2010;63:768–70.
invasion should always be reported in mm, even in those Pecorelli S. FIGO Committee on Gynecologic Oncology.
cases with “early (minimal) stromal invasion” (~1 mm) Revised FIGO staging for carcinoma of the vulva,
The involvement of vascular/lymphatic spaces should not cervix and endometrium. Int J Gynecol Obstet.
change the stage allotment 2009;105:103–4.
b
On rectal examination, there is no cancer-free space Robboy SJ, Bentley RC, Russell R, Anderson MC, Mutter
between the tumour and the pelvic wall. All cases with GL, Prat J. Pathology of the female reproductive tract.
hydronephrosis or nonfunctioning kidney are included, 2nd ed. London: Churchill Livingstone/Elsevier; 2009.
unless they are known to be due to another cause Scurry J, Patel K, Wells M. Gross examination of uterine
specimens. J Clin Pathol. 1993;46:388–93.
Regional lymph nodes (N)a (TNM staging system): a pel-
Pathology and genetics. Tumours of the breast and
vic lymphadenectomy will ordinarily include 10 or more
lymph nodes
The Royal College of Pathologists. Cancer data-
NX Regional lymph nodes cannot be assessed sets (vulval neoplasms, cervical neoplasia,
N0 No regional lymph node metastasis endometrial cancer, uterine sarcomas, neoplasms
of the ovaries and fallopian tubes and primary car-
N1 Regional lymph node metastasis
cinoma of the peritoneum), and tissue pathways
a
Regional lymph nodes include paracervical, parametrial, for gynaecological pathology. https://www.rcpath.
hypogastric (internal iliac, obturator); common and exter- org/profession/publications/cancer-d atasets.html.
nal iliac; presacral and lateral sacral nodes. Para-aortic Accessed Dec 2016.
nodes are not regional. Wittekind C, Greene L, Hutter RVP, Klimfinger M, Sobin
LH. TNM atlas: illustrated guide to the TNM/pTNM
Distant metastasis (M) (TNM staging system) classification of malignant tumours. 5th ed. Berlin/
Heidelberg: Springer; 2005.
M0 No distant metastasis
Vagina
26
26.1 Anatomy aspect of the vagina terminates in the inguinal

lymph nodes.
The vagina lies anterior to the rectum and poste-
rior to the bladder. It measures 6–12 cm in length
normally. The upper aspect terminates in a circu- 26.2 Clinical Presentation
lar fold around the cervix to form the vaginal
fornices. The vaginal surface is lined by non- Primary pathology of the vagina is relatively
keratinizing stratified squamous epithelium and rare. Symptomatology related to primary vagi-
the wall comprises fibromuscular connective tis- nal disease may include a mass or feeling of
sues (see Fig. 22.1). discomfort, vaginal bleeding or discharge, dys-
Lymphovascular drainage: pareunia (painful coitus), or postcoital bleed-
The descending branch of the uterine artery ing. Occasionally primary vaginal disease is
supplies the upper vagina. The lower vagina is discovered at colposcopic examination. Many
supplied by branches of the internal pudendal of the signs and symptoms experienced
artery. The veins of the vagina drain to the utero- by women with malignant vaginal lesions are
vaginal plexus, which eventually drains to the similar to those encountered with cervical
internal iliac veins. cancer.
The lymphovascular supply of the vagina is
closely related to that of the cervix and vulva.
Superiorly lymphatics drain along the uterine 26.3 Clinical Investigations
artery into the external iliac lymph nodes. In the
mid-vagina, the lymphatic drainage terminates Usually vaginal tumours can be directly visual-
in the hypogastric nodes, while the inferior ized. Dysplastic squamous lesions (known as
vaginal intraepithelial neoplasia – VAIN) may be
seen at colposcopic examination. With suspected
primary vaginal malignancies, pelvic MRI is
used to assess the stage of the tumour and the
presence or absence of pelvic or inguinal lymph-
O.P. Houghton (*) • W. Glenn McCluggage adenopathy. Exfoliative cytology with micro-
Histopathology Laboratory, Institute of Pathology, scopic examination of cells obtained by aspiration
Royal Victoria Hospital Belfast Health and Social of the vaginal pool is occasionally used in the
Care Trust, Belfast, UK diagnosis of vaginal lesions, but this practice is
mccluggage@belfasttrust.hscni.net not widespread.

26.4 Pathological Conditions cervical smear. Adenocarcinomas rarely arise as

a primary lesion within the vagina; as is the case
26.4.1 Non-neoplastic Conditions with squamous carcinoma, when a vaginal ade-
nocarcinoma is encountered, it is important to
Non-neoplastic vaginal lesions are uncommon. A exclude spread from elsewhere e.g. the uterus,
variety of benign cysts may be encountered, usu- cervix, rectum, ovary, urethra or urinary bladder.
ally involving the subepithelial tissues. These A type of vaginal adenocarcinoma (clear cell car-
include epithelial inclusion cysts, Mullerian cinoma) may be associated with in utero expo-
derived cysts, and mesonephric cysts. sure to diethylstilboestrol. Other malignant
Fibroepithelial stromal polyps are relatively com- tumours of the vagina include adenosquamous
mon. Grossly these are polypoid lesions covered carcinoma, malignant melanoma, and a variety of
by unremarkable or hyperkeratotic surface squa- malignant mesenchymal lesions. The aetiological
mous epithelium. Occasionally following vaginal factors in the pathogenesis of vaginal squamous
hysterectomy, the fallopian tube may prolapse carcinoma are broadly similar to those implicated
and present as a nodule within the vagina. Vaginal in the pathogenesis of the corresponding cervical
granulation tissue may also occur post vaginal lesions. Previous pelvic irradiation and a history
hysterectomy. Endometriosis occasionally pres- of preinvasive or invasive cervical squamous
ents within the vagina and macroscopically is lesions are predisposing factors to squamous car-
seen as small haemorrhagic areas. cinomas of the vagina.
Treatment: Benign vaginal lesions such as
cysts and fibroepithelial polyps are usually
26.4.2 Neoplastic Conditions removed by biopsy. Benign mesenchymal
tumours should be excised preferably with a rim
Primary neoplastic conditions of the vagina are of uninvolved tissue in order to avoid local recur-
relatively rare. rence. Surgical treatment of early-stage malig-
Benign tumours: Benign vaginal tumours nant vaginal tumours is radical hysterectomy.
include squamous papilloma and a variety of Further treatment, usually in the form of radio-
benign mesenchymal tumours, the commonest of therapy or chemoradiation, is then dependent on
which is leiomyoma. staging and these cases should be discussed at a
Malignant tumours: The most common pri- multidisciplinary gynaecological oncology meet-
mary malignant tumour by far to arise within the ing. With advanced vaginal tumours, radiother-
vagina is squamous carcinoma. However, pri- apy or chemoradiation may be the initial
mary squamous carcinomas of the vagina are rare treatment. Occasionally recurrent endometrial
and much less common than spread from a pri- tumours within the vagina may be managed by
mary tumour arising elsewhere, e.g., cervix or vaginectomy (colpectomy).
vulva. If the tumour also involves the cervix or Prognosis: The prognosis of malignant vagi-
vulva, then it is most likely to be of cervical or nal tumours largely depends on the FIGO stag-
vulval origin. Preinvasive vaginal squamous ing. Tumours are staged by a combination of
lesions also occur. They often coexist with CIN clinical and pathological parameters. Clinical
lesions within the cervix and with dysplastic assessment includes speculum examination,
lesions elsewhere in the lower female genital bimanual pelvic and rectal examinations, cystos-
tract, e.g., vulva. They are categorized as vaginal copy, and proctosigmoidoscopy. Overall 5-year
intraepithelial neoplasia (VAIN) and graded I to survival is in the region of 40%. Other prognostic
III, similar to the grading system used for factors such as tumour grade, patient age, and
CIN. These may be identified at colposcopic tumour localization are of less prognostic
examination during investigation of an abnormal significance.
26 Vagina 285
26.5 Surgical Pathology Procedure and description for radical hyster-

Specimens: Clinical Aspects ectomy (Fig. 26.1):
26.5.1 Biopsy Specimens • The specimen is weighed and the length of the
uterus, cervix, and vagina measured (cm). The
Small benign polypoid lesions are often removed serosal surface of the uterus and the external
by biopsy following direct visualization. In cases surface of the cervix and vagina are inked.
of suspected malignancy, punch or wedge biop- Care should be taken so that the ink does not
sies are performed to confirm the diagnosis. contaminate other surfaces.
Cystic lesions and submucosal benign mesenchy- • The distal vaginal limit is transversely sec-
mal lesions are usually removed with a small rim tioned in its entirety and processed for histo-
of surrounding uninvolved tissue. logical examination. Scissors are useful for
obtaining these blocks.
• On opening the vagina the size (cm) and site
26.5.2 Resection Specimens of the tumour and its relationship to the cervix
is assessed and described.
As already stated, with malignant vaginal dis- • The distance of tumour to the distal vaginal
ease, the preferred surgical treatment is radical limit of excision is measured (cm).
hysterectomy. This is similar to that performed • The tumour is carefully transversely sectioned
for cervical cancer. and the minimum distance from tumour to the
circumferential limit measured (mm). The
nearest circumferential limit should be stated.
26.6 Surgical Pathology • The deep soft tissue paravaginal margin is
Specimens: Laboratory sampled for histological examination.
Protocols • The presence or absence of cervical involve-
ment is noted grossly.
26.6.1 Biopsy Specimens • Sections are taken from the cervix to show its
relationship with the vaginal tumour if possible.
Small biopsies are examined in their entirety. The • The uterus is sampled as per a benign protocol.
number of biopsy fragments is counted and the • The ovaries and tubes, if present, are sampled as
entire specimen is submitted and examined at per a benign protocol. It is often convenient to
multiple levels. do this prior to handling of the main specimen.
• Photography may be undertaken at any stage.
• Colpectomy specimens: weigh, measure,
26.6.2 Resection Specimens paint externally, open longitudinally, describe
the tumour (its dimensions and distance to the
Radical or Wertheim’s hysterectomy involves specimen limits), and transverse section into
removal of the uterus and cervix together with the multiple serial slices.
upper vagina. This operation, which generally Blocks for histology (Fig. 26.1):
also involves pelvic lymphadenectomy, is usually • Multiple representative blocks of tumour are
performed for stage I disease located in the upper submitted for histopathological examination.
part of the vagina. Otherwise many vaginal can- These may be taken either transversely or lon-
cers are primarily treated by chemoradiation. gitudinally but should show the relationship
Occasional vaginectomy (colpectomy) speci- with both the cervix and the nearest circum-
mens are encountered. ferential margin.
Longitudinal block
of cervix in relation
to vaginal tumour
Multiple serial transverse

Parametrial/ slices to include tumour,
paracervical vaginal wall and paravaginal
tissues tissues
Transverse section
vaginal limit
1. Transverse section vaginal limit

2. Paint external aspect of paracervical and paravaginal
tissues
3. Amputate the cervix
4. Transverse section the vaginal tumour
5. Block tumour longitudinally in relation to the cervix
6. Sample paracervical/parametrial tissues, endometrium
and myometrium
Fig. 26.1 Blocking a radical hysterectomy specimen for vaginal carcinoma (Reproduced, with permission, from Allen
and Cameron (2013))
• The vaginal distal limit is blocked in its • The site of the tumour (upper, mid, or lower;
entirety for histological examination. anterior or posterior; left side or right side)
• Any lymph nodes submitted are enumerated, within the vagina is stated.
sampled for histology, and their site of origin • The tumour measurement is given in three
noted. dimensions (cm) if possible.
• As already stated, the uterus, ovaries, and • Tumour type—most tumours arising primary
tubes are examined as per a benign protocol. within the vagina are squamous carcinomas.
• Histopathology report: Adenocarcinomas are rarer although they do
26 Vagina 287
occur. With an adenocarcinoma, secondary Regional nodes: upper two-thirds—pelvic

spread from elsewhere should always be nodes; lower third—inguinal and femoral nodes.
excluded, e.g., bladder, uterus, rectum. Inguinal and pelvic lymphadenectomy will
• Tumour differentiation—squamous carcino- ordinarily include 6 and 10 or more lymph nodes,
mas and adenocarcinomas are classified as respectively.
well, moderately, or poorly differentiated.
• The presence or absence of the following are pN0 No regional lymph node metastasis
noted: pN1 Metastasis in regional lymph node(s)
–– Adjacent VAIN or signs of HPV infection
–– Lymphovascular permeation
–– Lymph node involvement (number from
each site and number involved, intraparen- Bibliography
chymal or extracapsular spread)
–– VAIN or tumour at the distal vaginal limit, Allen DC. Histopathology reporting. Guidelines for surgi-
or if clear, the minimum distance (mm) cal cancer. 3rd ed. London: Springer; 2013.
from it Allen DC, Cameron RI. Histopathology specimens:
–– Paravaginal soft tissue (paracolpium) Berlin/Heidelberg: Springer; 2013.
extension Brierley JD, Gospodarowicz MK, Wittekind C. TNM
–– Tumour at the circumferential limit (state classification of malignant tumours. 8th ed. Oxford:
which one), or if clear, the minimum dis- Wiley-Blackwell; 2017.
Fox H, Wells M, editors. Haines and Taylor obstetrical
tance (mm) from it and gynaecological pathology. 5th ed. Edinburgh:
–– Response to preoperative chemoradiation Churchill Livingstone; 2003.
–– Coexistent pathology in other organs, e.g., Heatley MK. Dissection and reporting of the organs of the
CIN female genital tract. J Clin Pathol. 2008;61:241–57.
Kurman RJ, Norris HJ, Wilkinson E. Tumors of the cer-
vix, vagina and vulva, Atlas of tumor pathology, vol.
Extent of local tumour spread: FIGO/TNM 8 3rd series. Fascicle 4. Washington, DC: AFIP; 1992.
stage for primary vagina carcinoma (secondary Robboy SJ, Bentley RC, Russell R, Anderson MC, Mutter
growths from genital/extra-genital sites are GL, Prat J. Pathology of the female reproductive tract.
2nd ed. London: Churchill Livingstone/Elsevier; 2009.
excluded; vagina carcinoma involving the Scully RE. Protocol for the examination of specimens
uterine external os is designated as a cervical from patients with carcinoma of the vagina. Arch
carcinoma). Pathol Lab Med. 1999;123:62–7.
I/pT1 Tumour confined to the vagina Pathology and genetics. Tumours of the breast and
II/pT2 Tumour invades paravaginal tissues
The Royal College of Pathologists. Cancer datasets (vul-
(paracolpium) but does not extend to
val neoplasms, cervical neoplasia, endometrial cancer,
pelvic wall
uterine sarcomas, neoplasms of the ovaries and fallo-
III/pT3 Tumour extends to pelvic wall pian tubes and primary carcinoma of the peritoneum),
IV/pT4 Tumour invades mucosa of bladder or and tissue pathways for gynaecological pathology.
rectum, and/or extends beyond the true Accessed at https://www.rcpath.org/profession/publi-
pelvis cations/cancer-datasets.html. Accessed Dec 2016.
Vulva
27
27.1 Anatomy 27.2 Clinical Presentation
The vulva is lined by skin. Posteriorly it is lim- The vulva may be involved by a variety of derma-
ited by the anus, laterally by the inguinal folds, tological disorders. Often, the main presenting
and anteriorly by the mons pubis. The hymen is symptom with these is itch (pruritis) or redness.
the medial aspect of the vulva. The vulva com- Preinvasive vulval squamous lesions (known as
prises the outer hair-bearing labia majora and vulval intraepithelial neoplasia—VIN), vulval
inner labia minora, the clitoris, and the urethral dystrophies, especially lichen sclerosus, and
meatus (Fig. 27.1). Mucous glands, including Paget’s disease commonly present in this way.
Bartholin’s glands, open into the vulva. Malignant lesions often present with a mass, itch-
Lymphovascular drainage: ing, bleeding, or an area of ulceration. There may
The internal pudendal artery gives off a branch also be discharge, dysuria (painful micturition),
that provides part of the blood supply to the and a foul smell. The most common sites of
vulva, which is also contributed to by branches tumours are the labia majora, the labia minora
from the femoral artery. The venous drainage fol- and clitoris, in order of frequency. When tumour
lows the arterial blood supply. has spread to the inguinal lymph nodes, a palpa-
The lymphatic drainage of each side of the ble mass may be present and this can ulcerate
vulva is largely to the ipsilateral inguinal and through the skin and discharge. Lymphoedema
femoral lymph nodes although some contralat- and deep venous thrombosis may occur with
eral drainage occurs. Most of the lymphatic advanced tumours.
drainage is to the superficial inguinal lymph
nodes and therefore these are usually the first
lymph nodes involved by metastatic tumour in 27.3 Clinical Investigations
vulval carcinoma. The lymphatic drainage from
the clitoris and the midline perineal area is Most benign dermatological disorders and VIN
bilateral. are diagnosed by a punch biopsy. Colposcopic
examination may be used to directly visualize
lesions. Radiological investigations, usually
O.P. Houghton (*) • W. Glenn McCluggage MRI, are indicated in staging of vulval cancers,
Histopathology Laboratory, Institute of Pathology, in order to ascertain whether regional lymph
Royal Victoria Hospital, Belfast Health and Social nodes are enlarged. In some places, exfoliative
Care Trust, Belfast, UK cytology has been applied to the evaluation of
mccluggage@belfasttrust.hscni.net vulval lesions but this is not in widespread use.

Fig. 27.1 Vulval
anatomy (Used with the
Control (UICC),
Geneva, Switzerland. Clitoris
this material is, from
Wittekind et al. (2005)) Urethra
Labium minora vulva
vagina
Labium majora
Fine needle aspiration biopsy is of value in the vulva are squamous carcinomas. Rarer pri-
assessing enlarged inguinal lymph nodes and mary tumours include basal cell carcinoma, ade-
confirming a diagnosis of metastatic cancer. nocarcinoma, Paget’s disease, adenoid cystic
carcinoma, small cell carcinoma, malignant mel-
anoma, and aggressive angiomyxoma. A variety
27.4 Pathological Conditions of benign epithelial neoplasms, similar to those
occurring elsewhere on the skin, can occur on the
27.4.1 Non-neoplastic Conditions vulva. A variety of mesenchymal lesions also
occur at this site.
A variety of benign dermatoses may affect the Vulval intraepithelial neoplasia (VIN): As
vulval region as with other areas of skin. Non- stated, there are two clinicopathological types of
neoplastic vulval dystrophies (although non- VIN, although there is some overlap. Classic
neoplastic, they may be associated with vulval (undifferentiated) VIN occurs in a younger age
squamous carcinoma) comprise lichen sclerosus group and is often associated with similar lesions
and squamous hyperplasia. in the cervix and elsewhere in the lower female
genital tract and with high risk HPV infection.
Differentiated (simplex) VIN may be associated
27.4.2 Neoplastic Conditions with lichen sclerosus or squamous cell hyperpla-
sia. It occurs in an older age group and is usually
Similar to the cervix, preinvasive dysplastic squa- not associated with HPV infection or lesions
mous lesions occur on the vulva. These are elsewhere in the lower female genital tract.
known as vulval intraepithelial neoplasia (VIN). Classic VIN exhibits diffuse block-type immuno-
This can be categorized into a more common reactivity with p16 while differentiated VIN is
HPV-related type known as classic (undifferenti- negative.
ated, Bowenoid) VIN and a more uncommon Vulval squamous carcinoma: Similar to the
non-HPV-related type referred to as differenti- situation with VIN there are two well-defined
ated (simplex) VIN. Classic VIN is further cate- clinicopathological types of vulval squamous
gorized as VIN I, II, or III; differentiated VIN is carcinoma, although there is some overlap. One
not graded. Most malignant tumours arising on type, which usually has a basaloid or warty
27 Vulva 291
orphology, occurs in a younger age group and

m follow up is therefore necessary. With very super-
is often associated with adjacent classic type of ficially invasive squamous carcinomas (less than
VIN III. It usually exhibits diffuse block-type 1 mm—stage Ia), the prognosis is extremely
immunoreactivity with p16. There may be con- good and the risk of lymph node metastases is
current lesions elsewhere in the female genital close to zero.
tract and there is an association with high risk With invasive carcinomas of the vulva, sur-
HPV infection. The other more common type of vival is primarily related to the stage of the dis-
invasive squamous carcinoma is usually not asso- ease. The most important prognostic factor is the
ciated with VIN, although sometimes there may presence or absence of lymph node involvement.
be adjacent differentiated VIN. It occurs in an Patients with stage I carcinoma have a mean
older age group and there is usually no associa- 5-year survival of 85%. For stage IV tumours,
tion with HPV infection or with lesions elsewhere this drops to approximately 10%.
in the female genital tract. Some cases arise in
lichen sclerosus. It is usually p16 negative.
Treatment: Treatment of VIN is usually wide 27.5 Surgical Pathology
local excision with careful follow up. There is a Specimens: Clinical Aspects
risk of multicentricity and the development of
further lesions, especially with the classic type of 27.5.1 Biopsy Specimens
VIN. Colposcopic examination may be useful in
follow up, and patients with classic VIN should Small vulval punch biopsies are usually taken for
be investigated for lesions elsewhere in the confirmation of the presence of specific dermato-
female genital tract, e.g., CIN. Especially when ses, vulval dystrophies, VIN, or invasive
there are multiple lesions and where invasive car- carcinomas.
cinoma has been excluded by multiple biopsies,
laser ablation and other local ablative techniques
may be used for treatment of VIN. This preserves 27.5.2 Resection Specimens
the normal vulval anatomy. With extensive VIN,
total or partial vulvectomy may be necessary. Resection specimens are usually for VIN or
For early low-stage carcinomas of the vulva, tumours and include wide local excisions, hemi-
the usual treatment is wide local excision with vulvectomies, and radical (total) vulvectomies.
ipsilateral lymph node dissection. For very super- With a total vulvectomy, all the perineum sur-
ficially invasive squamous carcinomas (less than rounding the vagina is removed. Inguinal lymph
1 mm invasion—stage Ia), lymph node dissection nodes from one or both sides are usually submit-
may not be necessary. Local excision of a carci- ted with tumour resections. Ipsilateral lymph
noma can comprise simple excision, hemivulvec- node dissection is undertaken for lateral tumours
tomy, or radical vulvectomy. In those undergoing and bilateral lymph node dissection for midline
radical vulvectomy (usually with centrally tumours or tumours close to the midline.
located tumours), bilateral inguinal lymph node
dissection is usually performed. Sentinel node
biopsy is used in some centres. If the sentinel 27.6 Surgical Pathology
node(s) contain metastatic tumour, there may Specimens: Laboratory
also be spread to the other inguinofemoral lymph Protocols
nodes, whereas, a negative sentinel node(s) sug-
gests that the other nodes are extremely unlikely 27.6.1 Biopsies Specimens
to contain metastatic tumour.
Prognosis: The prognosis of VIN is good and Small vulval punch biopsies are counted and
is largely determined by the risk of subsequent examined in their entirety at multiple histological
development of squamous carcinoma. Careful levels.
27.6.2 Resection Specimens Blocks for histology (Fig. 27.2):
27.6.2.1 Wide Local Excisions • Multiple blocks are taken of all lesions seen
These are treated like a skin ellipse. The deep and grossly.
lateral margins are inked and representative • Transverse blocks are taken to show the point
blocks taken to show the lesion in relation to of deepest invasion and the relationship of the
them. Especially with VIN, it may be difficult to lesion to the nearest margins including the lat-
assess the presence of a lesion grossly as this can eral, deep (soft tissue), vaginal, urethral, and
be very subtle. The presence of a previous biopsy anal margins. The margins are labeled on the
site may assist in this regard. Marking of the pre- slide.
vious biopsy site by the surgeon with tattoo ink or • Also submit representative blocks of grossly
a suture may be helpful. Lymph nodes may be normal skin.
submitted separately. These are carefully dis- • Longitudinal sections of clitoris and any rele-
sected from the fat and the number retrieved from vant lesion are taken.
each site documented. • All lymph nodes are serially sectioned
and completely submitted. The right- and
27.6.2.2 Hemivulvectomy left-
sided lymph nodes are separated.
and Radical Vulvectomy Although ultrastaging sentinel lymph nodes
• Hemivulvectomies (or partial vulvectomies) i.e. examining step sections and performing
require orientation by the surgeon. If this is pancytokeratin immunohistochemistry, is
not done, it may be necessary to contact the performed in some centres, the benefit is
surgeon before sectioning is performed. uncertain.
• A total vulvectomy looks like an ellipse of
skin with a central defect corresponding to the Histopathology report:
vaginal opening. The specimen is orientated.
The clitoris is present superiorly and in the • The site (right, left, labia majora/minora, cli-
midline. The hair-bearing labia majora are toris) and gross characteristics of the tumour
present laterally. Inguinal fat, when present, is are stated, e.g., polypoid, ulcerated.
on the superior aspect of the specimen and to • Tumour measurements—the width of tumour
both sides (Fig. 27.2). in two dimensions (cm) is given.
• If a gross lesion is seen this may be • Tumour type—the vast majority of malignant
photographed. tumours are squamous carcinomas, although
• The specimen is inked including the free lat- rarer morphological subtypes may occur.
eral and deep margins. • Tumour differentiation—squamous carcino-
• The length, width, and depth of the specimen mas are classified as well, moderately, or
is measured (cm). Diagrams may be necessary poorly differentiated.
and help in reporting. • Depth of invasion—the depth of invasion
• If inguinal fat is present on one or both sides, is measured from the epithelial–stromal
this is carefully sectioned looking for lymph junction of the adjacent most superficial der-
nodes. These are separated, enumerated, and mal papilla to the deepest aspect of the
labeled as from the right or left side. tumour.
• The presence of any gross lesion is noted and • The nature of the invasive component—
measured in three dimensions (cm). The dis- whether the invasive squamous carcinoma is
tances to the nearest resection margins are confluent or exhibits a “finger-like” growth
measured and detailed. pattern may be of prognostic importance.
• The presence of any other smaller lesions is • The presence or absence of the following are
documented similar to the main lesion. noted:
27 Vulva 293
Right inguinal Mons pubis Left inguinal

soft tissue Clitoris soft tissue
1. Orientate
2. Paint the lateral and
deep external margins
3. Serially slice the inguinal fat
4. Transverse slice the tumor
in relation to vulvovaginal limits
Labia majora
Urethral meatus
Posterior
fourchette Labia minora
Vaginal opening
Perineum and margin
Longitudinal section of tumour,

clitoris and urethral meatus
Serially section the inguinal

fat to look for nodes and
tumour deposits
Transverse sections of tumour

in relation to vulvovaginal
limits (lateral and deep)
Transverse section
of normal looking
contralateral vulva
Fig. 27.2 Orientation and blocking of a radical vulvectomy specimen (Reproduced, with permission, from Allen and
Cameron (2013))
–– Adjacent VIN (its type and grade), signs of –– VIN or tumour at the skin or vaginal mar-
HPV infection, associated vulval dystro- gins, or, if clear, the minimum distance (mm)
phy or Paget’s disease. from them.
–– Lymphovascular permeation. –– Tumour at the deep margin, or, if clear, the
–– Lymph node involvement (site, number minimum distance (mm) from it.
involved, intraparenchymal or extracapsu- –– Involvement of other structures such as the
lar extension). For small tumour deposits, vagina or anus.
the size of the largest (mm) should
be given. The regional lymph nodes are The British Association of Gynaecological
the inguino-femoral (groin) nodes and Pathologists, British Gynaecological Cancer
a regional lymphadenectomy will ordinar- Society, and gynaecological clinical reference
ily include 6 or more lymph nodes. group of the National Cancer Intelligence
Network recommend that FIGO staging be used Vascular space involvement, either venous or
for gynaecological cancers rather than TNM. lymphatic, does not alter the staging.
Extent of local tumour spread: 2009 FIGO
staging of vulval carcinoma.
I Tumour confined to the vulva

Bibliography
IA Tumour confined to the vulva or perineum,
≤2 cm in size with stromal invasion
≤1 mma, negative nodes
IB Tumour confined to the vulva or perineum, clinical, pathological and laboratory aspects. 2nd ed.
>2 cm in size or with stromal invasion Berlin/Heidelberg: Springer; 2013.
>1 mm, negative nodes Brierley JD, Gospodarowicz MK, Wittekind C, editors.
II Tumour of any size with extension to TNM classification of malignant tumours. 8th ed.
adjacent perineal structures (1/3 lower Oxford: Wiley-Blackwell; 2017.
urethra, 1/3 lower vagina, anus), negative Fox H, Wells M, editors. Haines and Taylor obstetrical
nodes and gynaecological pathology. 5th ed. Edinburgh:
III Tumour of any size with or without Churchill Livingstone; 2003.
extension to adjacent perineal structures (1/3 Heatley MK. Dissection and reporting of the organs of the
lower urethra, 1/3 lower vagina, anus) with female genital tract. J Clin Pathol. 2008;61:241–57.
positive inguino-femoral lymph nodes Kurman RJ, Norris HJ, Wilkinson E. Tumors of the cer-
IIIA vix, vagina and vulva, atlas of tumor pathology, vol.
3rd series. Fascicle 4. AFIP: Washington; 1992.
(i) One lymph node metastasis (≥5 mm)
McCluggage WG, Hirschowitz L, Ganesan R, Kehoe S,
(ii) One to two lymph node metastasis(es) Nordin A. Which staging system to use for gynaeco-
(<5 mm) logical cancers: a survey with recommendations for
IIIB practice in the UK. J Clin Pathol. 2010;63:768–70.
(i) Two or more lymph node metastases Pecorelli S. FIGO committee on gynecologic oncology.
(≥5 mm) Revised FIGO staging for carcinoma of the vulva,
(ii) Three or more lymph node metastases cervix and endometrium. Int J Gynecol Obstet.
(<5 mm) 2009;105:103–4.
Robboy SJ, Bentley RC, Russell R, Anderson MC, Mutter
IIIC Positive nodes with extracapsular spread GL, Prat J. Pathology of the female reproductive tract.
IV Tumour invades other regional structures 2nd ed. London: Churchill Livingstone/Elsevier; 2009.
(2/3 upper urethra, 2/3 upper vagina) or Tavassoli F, Devilee P. WHO classification of tumours.
distant structures Pathology and genetics. Tumours of the breast and
IVA Tumour invades any of the following: female genital organs. Lyon: IARC Press; 2003.
(i) Upper urethra and/or vaginal mucosa, The Royal College of Pathologists. Cancer datasets
bladder mucosa, rectal mucosa, or fixed to (vulval neoplasms, cervical neoplasia, endometrial
pelvic bone cancer, uterine sarcomas, neoplasms of the ovaries
and fallopian tubes and primary carcinoma of the
(ii) Fixed or ulcerated inguino-femoral lymph
peritoneum), and tissue pathways for gynaecological
nodes
pathology. Available via https://www.rcpath.org/pro-
IVB Any distant metastasis including pelvic fession/publications/cancer-datasets.html Accessed
lymph nodes Dec 2016
a
The depth of invasion is defined as the measurement of Wittekind C, Greene L, Hutter RVP, Klimfinger M, Sobin
the tumour from the epithelial–stromal junction of the LH. TNM atlas: illustrated guide to the TNM/pTNM
adjacent most superficial epithelial papilla to the deepest classification of malignant tumours. 5th ed. Berlin/
point of invasion. Heidelberg: Springer; 2005.
Placenta
28
Oisin P. Houghton
28.1 Clinical prise two layers, the chorion and the amnion. The
maternal surface of the placenta is divided into
Routine examination of all placentas is unneces- lobules or cotyledons.
sary: there are maternal, fetal, and placental indi-
cations for examination, which include
hypertension, diabetes, infection, placental 28.3 Surgical Pathology
abruption, prematurity, and fetal death. In gen- Specimens: Laboratory
eral, around 10–15% of pregnancies are compli- Protocols
cated by maternal, fetal, or placental disease and
these are the cases that should be examined. The placenta can be examined fresh or formalin-
fixed (microbiology and karyotyping is possible
from fresh placentas).
28.2 Anatomy These measurements should be made
initially:
The average placenta weighs 400–500 g and
measures approximately 20 cm in diameter at • Trimmed weight (following removal of the
term: there are considerable variations in size, membranes) in grams.
shape, and form. The placental tissue itself is • Size of disc in three dimensions in cm.
composed of chorionic villi lined by cytotropho- • Length and diameter of umbilical cord in cm.
blast and syncytiotrophoblastic cells. The fetal • Note the following:
surface of the placenta is the chorionic plate: the • Placental form: normal, succenturiate/acces-
umbilical cord inserts into this. The umbilical sory lobe, circumvallate, circummarginate.
cord consists of two arteries and one vein embed- • Cord: presence of knots (false, true), cord spi-
ded in a gelatinous matrix, and is covered by ralling (increased, decreased, normal), cord
amnion. The placental (peripheral) membranes insertion (central, eccentric, marginal, vela-
are continuous with the chorionic plate and com- mentous), oedema, number of vessels.
• Membranes: completeness, translucency/
opacity, meconium staining.
• Maternal surface: completeness, crater, adher-
O.P. Houghton ent haemorrhage.
Histopathology Laboratory, Institute of Pathology, • Chorionic plate: distribution of vessels, meco-
Royal Victoria Hospital, Belfast Health and Social nium staining, translucency/opacity, dullness,
e-mail: oisin.houghton@belfasttrust.hscni.net amnion nodosum.

296 O.P. Houghton
The disc is then sliced at 0.5–1.0 cm intervals In 2 and 3, there is a single placental disc
and simultaneous palpation carried out to iden- with two umbilical cords. Common outer
tify infarcts and other anomalies. Infarcts should membranes are present. The dividing mem-
be assessed as old or recent, the size of the largest brane between the two placental territories
recorded, and an estimation of the volume of the must be examined to determine chorionicity.
disc affected made. 4 . Monoamniotic, Monochorionic, Twin Placentas.
Usually 4–5 blocks are sufficient, including. There are two umbilical cords but no dividing
membrane. The two cords are usually positioned
• Three representative sections of placental closely together.
parenchyma. Additional examination for twin placentas:
• Three cross sections of the umbilical cord The dividing membrane comprises two amnions
(taken from at least 2 cm above cord insertion, (in monochorionic twins), or two chorions and
at the midpoint, and at the fetal end of the cord). two amnions (in dichorionic twins with fused
• A membrane roll is prepared by cutting a strip discs). Monochorionic membranes divide easily
of membranes from the site of rupture to the and are thin and transparent, whereas dichorionic
margin of the disc, grasping the edge of the membranes are opaque, thicker, and difficult to
disc with forceps, rolling the membranes separate. There is often a distinct ridge between
around, and sliding the roll from the forceps; a the territories of dichorionic twins on the fused
cross section of the roll is taken. common disc; in monochorionic twins there is no
• Any grossly abnormal area is sampled. ridge. The common membrane is studied histo-
logically from both a non-separated area and the
T zone point of attachment to the chorionic plate.
28.3.1 Multiple Gestations Vascular anastomoses between the two territories
can lead to discrepancies in size and viability of
Twins account for a significant proportion of the infants. The type of anastomosis should be
perinatal morbidity and mortality: placentas from described (artery–artery, artery–vein, vein–vein).
twins demonstrate the same pathology as single- In triplets and higher multiples, similar princi-
ton placentas, as well as pathology related to ples apply with the examination of the dividing
twinning (twin–twin transfusion, asymmetry, membranes between placental territories (Fig. 28.1).
vanishing twin).
Determination of Chorionicity. Histopathology report:
This is the most important step in the examina- The macroscopic description should include
tion of twin placentas. A dichorionic placenta
means that two placentas have formed, but these • The trimmed weight and dimensions of the disc
may be separate or fused together. A monochori- • The length, diameter, coiling index, and inser-
onic placenta indicates a shared disc: monochori- tion of the umbilical cord
onic twins are monozygotic (“identical”), but • A description of the maternal surface, chori-
dichorionic twins can be monozygotic or dizygotic, onic plate, and membranes
depending when the fertilized egg divided into two. • The microscopic description should include
Twin placentas are one of four types: • An assessment of villous maturation (acceler-
ated, delayed, dysmature)
1. Diamniotic, dichorionic separated twin placen- • An assessment of villous morphology (dys-
tas. The two discs are completely separate. morphism, hydrops, molar, oedema, villous
2. Diamniotic, dichorionic, fused twin placentas. inflammation, infarction)
3.
Diamniotic, monochorionic, fused twin • An assessment of the intervillous space (inter-
placentas. villositis, intervillous fibrin)
28 Placenta 297
Fig. 28.1 Examination Non-separated membranes

of membrane
distribution in twin
pregnancy (Reproduced, Fetal surface
Allen and Cameron
(2013))
Maternal surface
T zone point of attachment
• A description of any haematoma (extent, the villi penetrate the full thickness of myome-
position-intervillous, maternal, subchorionic) trium with the risk of uterine perforation and
• An assessment of the chorionic plate (presence haemoperitoneum. There may be variations in
of chorioamnionitis, chorionic plate vasculitis) the depth of penetration and the condition may
• An assessment of the cord (presence of inflam- be focal or diffuse.
mation, number of vessels involved). Examination of a hysterectomy specimen in
which placenta accreta is suspected involves
careful sampling of the placental bed. The
28.3.2 Placenta Accreta larger radial and arcuate arteries of the uterus
may show pregnancy-induced changes, a fea-
This is defined as abnormal adherence of the pla- ture usually only seen in the smaller spiral
centa to the uterine wall. There is considerable arteries, and this may be responsible for the
maternal morbidity and mortality associated with severity of haemorrhage usually seen in pla-
the condition, which is the leading cause of peri- centa accreta.
partum hysterectomy.
Predisposing factors include advanced mater-
nal age, previous caesarean section delivery, pla- Bibliography
centa previa, previous placental retention,
multigravidity, and high parity. Allen DC, Cameron RI. Histopathology specimens:
Pathologically, placental villi are present clinical, pathological and laboratory aspects. 2nd ed.
adjacent to myometrium with no intervening Baergen N. Manual of pathology of the human Placenta.
decidual layer. Placenta accreta is classified 2nd ed. New York: Springer; 2011.
according to the depth of infiltration through the Fox H, Sebire N. Pathology of the placenta, Major prob-
uterus. In placenta accreta vera the villi embed lems in pathology series 7. 3rd ed. London: Saunders;
2007.
directly onto superficial myometrium; in pla- Fox H, Wells M. editors. Haines and Taylor. Obstetrical
centa increta, the villi are found deeper in the and gynaecological pathology. 5th ed. Edinburgh:
body of myometrium; and in placenta percreta, Churchill Livingstone; 2003.
298 O.P. Houghton
Kaplan CG. Color atlas of gross placental pathology. 2nd Silverberg SG, Kurman RJ. Tumors of the uterine cor-
ed. New York: Springer; 2006. pus and gestational trophoblastic disease, Atlas of
Lage JM. Protocol for the examination of specimens tumor pathology, vol. 3rd series. Fascicle 3. AFIP:
from patients with gestational trophoblastic malig- Washington; 1992.
nancies. Arch Pathol Lab Med. 1999;123:50–4. The Royal College of Pathologists. Tissue pathway
Robboy SJ, Bentley RC, Russell R, Anderson MC, for histopathological examination of the placenta.
Mutter GL, Prat J. Pathology of the female reproduc- Available via https://www.rcpath.org/profession/pub-
tive tract. 2nd ed. London: Churchill Livingstone/ lications/cancer-datasets.html. Accessed on December
Elsevier; 2009. 2016.
Part VI
Urological Specimens
Kidney, Renal Pelvis, and Ureter
29
29.1 Anatomy The relative position of the main structures in

the hilum is generally as follows: the vein is in
The kidneys are situated in the retroperitoneum front, the artery in the middle, and the ureter
and lie between the upper borders of the twelfth behind and directed downward. The renal capsule
thoracic and third lumbar vertebrae. Each kidney is easily stripped off, revealing a smooth and
has a convex lateral border and a concave medial even surface. The parenchyma consists of cortex
border which merge at the poles (superior and and medulla that are grossly distinct. The cortex
inferior portions). Surrounding each organ is the forms a 1 cm layer beneath the renal capsule and
fibrous renal capsule, which is loosely adherent extends down between the renal pyramids form-
to it. Adipose tissue (perirenal fat) encases the ing the columns of Bertin. The medulla consists
capsule and is in turn surrounded by the Gerota’s of renal pyramids and is divided into an outer
fascia, which secures the kidney to the posterior medulla and inner medulla or papilla. The papilla
abdominal wall. Much of the medial border com- protrudes into the minor calyx. Its tip has between
prises an indentation, the hilum, through which 20 and 70 openings of the papillary collecting
the renal vessels, nerves, lymphatics, and the ducts (Bellini’s ducts).
renal pelvis enter or leave the renal sinus, the The renal pelvis is the sac-like expansion of
space enclosed by the renal parenchyma. The the upper ureter. Two or three major calyces
kidneys are mobile and their position changes extend from the pelvis and divide into minor
during respiration. The right kidney is usually calyces, into which the papillae protrude. The
slightly lower than the left on account of the liver. ureters measure approximately 30 cm in length
Each kidney is about 11–12 cm in length, equally divided between retroperitoneum and
5–7.5 cm in breadth, and 2.5–3.5 cm in thickness pelvis. They are usually placed on a level with the
and weighs between 115 and 175 g (Fig. 29.1). spinous process of the first lumbar vertebra and run
The persistence of distinct fetal lobes is common downward and medially in front of the psoas
and is a normal anatomical variant. major, and enter the pelvis, reaching the lateral
angle of the bladder. Finally, the ureters run
obliquely for about 2 cm through the wall of the
bladder and open by slit-like apertures into the
D.M. O’Rourke (*) • D.C. Allen cavity at the lateral angles of the trigone. Owing
to their oblique course, the upper and lower walls
e-mail: declan.orourke@belfasttrust.hscni.net; derek. of the terminal portions of the ureters become
allen@belfasttrust.hscni.net closely applied to each other when the bladder is

302 D.M. O’Rourke and D.C. Allen
Fig. 29.1 Anatomy of Adrenal gland

the kidney (Used with
Cancer Control (UICC), Renal cortex Renal vein
Geneva, Switzerland. and artery
Wittekind et al. (2005)) Gerota fascia Renal pelvis
Perinephric fat
Ureter
Renal calyces
distended, and, acting as valves, prevent regurgi-

tation of urine from the bladder.
There is a dual lymphatic drainage system. The
major lymphatic drainage follows the blood ves-
sels from the parenchyma to the renal sinus, then
to the hilum, and terminating in the para-aortic
lymph nodes. There is also a capsular lymphatic
drainage from the superficial cortex extending
from the capsule to the hilum and joining the
major lymphatic flow. When tumour spreads from
the kidney, it is initially to the hilar and then to the
para-aortic lymph nodes (Fig. 29.2).
Presentations of medical renal diseases are best

grouped as nephrotic syndrome, nephritic syn-
drome, acute kidney injury (AKI), and chronic
kidney disease (CKD). Nephrotic syndrome (NS)
is defined as the excretion of more than 3.5 g pro-
tein/24 h associated with hypoalbuminaemia,
hypercholesterolaemia, and oedema. Nephritic
syndrome is usually characterized by the rela- Fig. 29.2 Kidney—regional lymph nodes. The regional
tively sudden onset of haematuria with red blood lymph nodes are the hilar, abdominal para-aortic, and
cell casts and proteinuria accompanied by hyper- paracaval nodes. Laterality does not affect the N catego-
ries (Used with the permission of the Union for
tension, and a reduced glomerular filtration rate. International Cancer Control (UICC), Geneva,
AKI is the loss of renal function occurring Switzerland. The original source for this material is from
rapidly, usually over days. AKI is diagnosed if Wittekind et al. (2005))
29 Kidney, Renal Pelvis, and Ureter 303
serum creatinine increases by 0.3 mg/dL Compared to renal cortical tumours, carcino-

(26.5 μmol/L) or more in 48 h or rises to at least mas of renal pelvis and ureter are relatively
1.5-fold from baseline within 7 days. AKI stages uncommon, accounting for 4–5% of all urothelial
are defined by the maximum change of either tumours. Gross haematuria (67%) is the most
serum creatinine or urine output. It is character- common presenting symptom of renal pelvis and
ized by a rapid increase in creatinine and oligu- ureteric tumours. Pain is the next most common
ria. CKD is the progressive loss of renal function, symptom, either in the flank or in conjunction
occurring over a period of several years as a with gross haematuria and, therefore, due to clot
result of glomerular or tubulo-interstitial pathol- colic. Other presentations include pyuria, weight
ogy. CKD is a worldwide public health problem. loss, anaemia, unexplained fever, hypertension,
Diseases of the kidney and upper urinary tract renal failure, and calculus disease.
can present with a variety of symptoms including
gross haematuria, loin pain, fever, or a mass lesion.
Causes are generally divided into congenital (cysts, 29.3 Clinical Investigations
tumours) and acquired. Of the acquired group these
include medical (acute and chronic pyelonephritis) • Biochemical studies in medical renal disease
and surgical (stones, tumours) causes. i.e., urea and electrolytes, creatinine clear-
Renal cell carcinoma (RCC) may remain clin- ance, 24 h urinary protein, protein/creatine
ically occult for most of its course. The classic ratio (PCR), plasma protein electrophoresis,
triad of flank pain, haematuria, and flank mass is and Bence Jones urinary protein.
infrequent (10%) and is indicative of advanced • Intravenous urogram (IVU)—Not frequently
disease. There were around 11,900 new cases of used in the initial evaluation of renal masses
RCC in the UK in 2013 (3% of all new cancers) because of its low sensitivity and specificity.
and RCC is the seventh most common cancer in • Intravenous pyelogram (IVP)—In pelviure-
the UK (2013). Since the late 1970s, RCC rates teric junction (PUJ) obstruction reveals a
have more than doubled in Great Britain. The delayed nephrogram that may persist for 24 h
increasing incidence of kidney cancer is thought or more. Ultrasound has superceded IVP in
to be partly explained by the use of imaging tech- children.
niques resulting in the detection of asymptomatic • Retrograde pyelography—This tends to be
disease. Up to 30% of patients with RCC present used in two circumstances to confirm the pres-
with metastatic disease, and recurrence develops ence of a constant filling defect, either in the
in 40% of patients treated for localized tumour. ureter or renal pelvis, and to investigate
Other signs and symptoms include patients with a nonfunctioning kidney.
• Cystoscopy and ureteropyeloscopy—This
• Weight loss (33%) procedure is used increasingly for the diagno-
• Fever (20%) sis of upper tract urothelial tumours as biopsy
• Hypertension (20%) forceps or cytology brushings can be used to
• Hypercalcaemia (5%) collect tissue.
• Night sweats • Cytopathology—Voided urine samples
• Malaise obtained for cytopathology lack sensitivity,
• Varicocele (2% males) due to obstruction of especially for low-grade tumours, but this
left testicular vein (usually left) increases for high-grade tumours that tend to
• RCC is a unique tumour because of the frequent shed more tumour cells.
occurrence of paraneoplastic syndromes, includ- • Contrast-enhanced CT scanning (CT)—Has
ing hypercalcaemia, erythrocytosis, and nonmeta- become the imaging procedure of choice for
static hepatic dysfunction (i.e. Stauffer syndrome). diagnosis and staging of renal cell cancer. In
Polyneuromyopathy, amyloidosis and dermato- most cases, CT imaging can differentiate cys-
myositis are also associated with RCC. tic from solid masses and supplies information
about lymph nodes, renal vein, and inferior magnesium ammonium phosphate stones (15%),
vena cava involvement. If contrast material and cystine stones (2%). Plain abdominal film
cannot be intravenously administered, CT is a may diagnose and locate the stone. Treatments
poor choice for evaluating renal masses. MRI include extracorporeal lithotripsy, ureteroscopy,
should be performed instead. endoscopic laser lithotripsy, percutaneous neph-
• Ultrasonography (US)—Can be useful in rolithotomy/nephrostomy, open nephrostomy,
evaluating questionable cystic renal lesions if and, less commonly, nephrectomy (chronic pain,
CT imaging is inconclusive. Large papillary large staghorn calculi, poorly functioning).
renal tumours are frequently undetectable by Chronic pyelonephritis: Refers to renal injury
renal ultrasound. induced by recurrent renal infection in patients
• Renal arteriography—Is not used in the evalu- with urinary tract obstruction, renal dysplasia, or,
ation of suspected renal mass as frequently most commonly, vesicoureteral reflux (VUR). It
now as it was in the past. Noninvasive cross- is associated with progressive renal scarring,
sectional imaging (CT, MRI, US) has replaced which can lead to end-stage renal disease
angiography in the workup of patients with (ESRD). Intravenous urogram establishes the
known or suspected RCC. diagnosis of pyelonephritis, and nephrectomy is
• MRI—MRI is an important alternative in required in cases with significant morbidity or
patients requiring further imaging and because loss of function.
of concern over radiation exposure, hence there PUJ obstruction: One of the most common
has been a trend towards more use of MRI. congenital abnormalities of the urinary tract and
• Positron emission tomography (PET)—PET associated with a number of anomalies. The aeti-
imaging remains controversial in kidney can- ologies are numerous and classified on an ana-
cer and has a better sensitivity for detecting tomic basis as either extrinsic (scars, VUR) or
metastatic lesions than for determining the intrinsic (developmental). Treatment is primarily
presence of primary renal cancer. surgical (pyeloplasty), which can now be per-
• Magnetic resonance venography (MRV) is an formed laparoscopically.
often underappreciated technique which can Hydronephrosis and hydroureter: Common
be highly accurate in assessing the renal vein/ clinical conditions and major causes include
IVC, particularly determining involvement by calculi, reflux (children), prostate enlargement,
RCC. pregnancy, and cervical cancer. Although patients
• DMSA/DPTA scans for renal function (more usually present with some signs or symptoms,
use in paediatric nephrology). hydronephrosis can be an incidental finding, e.g.,
• Doppler scans following renal transplantation found on CT scan done for other reasons. Grossly
to look at renal arterial and venous flow. the pelvi-calyceal system is dilated with com-
• A bone scan is recommended for patients with pression of the papillae and parenchymal thin-
bone pain or an elevated alkaline phosphatase ning, progressing to the point at which only a thin
level. rim of parenchyma is present. IVP is probably
the most useful imaging study for identifying
both the presence and cause of hydronephrosis
29.4 Pathological Conditions and hydroureter. Treatments include ureteral
stenting, nephrostomy tube, and, ultimately, may
29.4.1 Non-neoplastic Conditions require nephrectomy for pain or loss of function.
Pyonephrosis: Refers to infected purulent
Renal stones: Nephrolithiasis affects 2–10% of urine in an obstructed collecting system (e.g.,
the population and symptoms (renal colic) arise stones, tumours, PUJ obstruction) and may
as these calculi become impacted within the ure- develop from ascending infection of the urinary
ter as they pass toward the urinary bladder. Types tract or the haematogenous spread of a bacterial
of renal calculi include calcium stones (75%), pathogen. Similar to an abscess, it is typically
associated with fever, chills, and flank pain. The infection, haemorrhage, suspicion of tumour on
diagnosis is usually confirmed with ultrasound. CT or when they reach a huge size.
This disorder is relatively uncommon and treat- Congenital anomalies: Anomalies in form,
ment options include percutaneous nephrostomy position, mass, and number; parenchyma
and antibiotic therapy. In cases with marked maldevelopment.
obstruction (± staghorn calculi) and loss of func- Vascular diseases: Hypertension, thrombotic
tion, nephrectomy may be required. microangiopathy, renal artery stenosis, dissection
Xanthogranulomatous pyelonephritis (XGP): and aneurysm, renal emboli and infarcts, renal
A chronic inflammatory disorder of the kidney atheroemboloism, renal vein thrombosis,
characterized by a mass originating in the renal vasculitis.
parenchyma. It resembles a true neoplasm in Miscellaneous: Other tubulointerstitial dis-
terms of its radiographical appearance and ability eases, malakoplakia, tuberculosis, and metabolic
to involve adjacent structures or organs. and miscellaneous conditions.
Occurring in late middle-aged females the exact
aetiology of XGP is unknown, but it is generally
accepted that the disease process requires long- 29.4.2 Neoplastic Conditions
term renal obstruction (stones, frequently of stag-
horn proportions) and infection (Proteus or 29.4.2.1 Adult Tumours
Escherichia coli). The gross appearance of XGP Benign tumours
is a mass of yellow tissue with regional necrosis Oncocytoma: Represents 4% of renal tumours
and haemorrhage, superficially resembling that and usually occurs in adults over 50 as an inci-
of a renal cell carcinoma. The pathognomonic dental finding. It has a benign behaviour if strict
microscopic feature is the lipid-laden “foamy” diagnostic criteria are followed. Grossly it is cir-
macrophage accompanied by both chronic and cumscribed, brown-yellow, with a stellate central
acute phase inflammatory cells. Nephrectomy is scar in larger lesions. It may be bilateral or multi-
the treatment of choice. focal and can invade the renal capsule.
Renal cysts: Occur in one third of people Histologically renal oncocytoma is most
older than 50 years. While the majority are sim- commonly comprised of small rounded nests of
ple cysts, renal cystic disease has multiple aeti- eosinophilic cells set in an oedematous or hyalin-
ologies. Broad categories of cystic disease ized background. The nuclei are round with small
include the following: congenital, genetic, nucleoli, but scattered foci with “bizarre” degen-
acquired, cysts associated with systemic disease erative atypia are not uncommon. In some cases,
(von Hippel-Lindau), and malignancy (renal cell oncocytoma may have features that suggest
carcinoma). aggressive behaviour such as vascular invasion
The most common larger cysts are acquired and extrarenal extension. These features are well
cysts, simple cysts, and cysts with ADPKD. recognised and should not be used to distinguish
Autosomal dominant polycystic kidney disease oncocytoma from RCC with oncocytic features.
(ADPKD): One of the most common inherited Patterns not allowed include papillary areas and
disorders in humans, and the most frequent clear/spindle cell change. CD117 and Ksp-
genetic cause of renal failure in adults. ADPKD is cadherin immunohistochemistry typically shows
a multisystem and progressive disorder character- diffuse immunoreactivity, while CK7 is negative
ized by formation and enlargement of cysts in the or only focally positive. Electron microscopy
kidney and other organs (e.g., liver, pancreas, shows the cytoplasm packed with mitochondria.
spleen). Clinical features usually begin in the Angiomyolipoma (AML): Represents less than
third to fourth decade of life, with the major cause 1% of renal tumours. It is a mesenchymal tumour
of morbidity being progressive renal dysfunction, believed to originate from the so-called perivas-
resulting in grossly enlarged kidneys. The kidneys cular epithelioid cell (PEComa) and is closely
sometimes require removal when complicated by related to other PEC group tumours (e.g. clear
cell tumours of lung, pancreas, and uterus). tension, unopposed oestrogen therapy,
Multifocality and bilaterality are often associated occupational exposure to petroleum products,
with tuberous sclerosis. Grossly the cut surface is heavy metals, solvents, and asbestos. The risk of
variable, reflecting the amounts of fat, smooth renal cell carcinoma is increased with the abuse
muscle, or vessels in the tumour. It comprises of phenacetin-containing analgesics, acquired
adipose tissue, smooth muscle, and dystrophic cystic kidney disease associated with chronic
vessels in variable proportions. It is positive for renal insufficiency, renal dialysis, tuberous scle-
melanocytic markers (HMB-45, melan-A). The rosis, von Hippel-Lindau disease, and renal
majority are benign, but retroperitoneal haemor- transplantation with its associated immunosup-
rhage is a rare complication that can be fatal pression. Prognostic factors for RCC include
(usually >4 cm). Several morphological variants, tumour size, stage, nodal/distant metastases, his-
including oncocytic AML, AML with epithelial tological subtype, nuclear grade (in clear cell
cysts, and intraglomerular AML are recognized RCC), sarcomatoid features, and tumour necro-
in the 2016 WHO classification and more often sis. Performance status and presence or absence
seen in association with tuberous sclerosis (TS). of systemic symptoms are also relevant. Partial,
Epithelioid AML is a recognized separate subtotal, or radical nephrectomy (laparoscopic and
entity in the 2016 WHO classification. Epithelioid more recently robotic surgery in some centres) is
AML can be divided into low, intermediate, and the mainstay of treatment options for renal corti-
high risk of disease progression based on the cal tumours. Surgical resection of primary tumour
association with TS or multiple AML, presence is often performed to decrease tumour load even
of necrosis, tumour size, extrarenal extension in patients with metastatic disease. In situ tumour
and/or renal vein involvement, and presence of ablation such as radiofrequency ablation (RFA)
carcinoma-like growth pattern. AML is generally and microwave ablation are becoming more com-
asymptomatic with characteristic CT scan mon, particularly for smaller tumours. RFA is a
appearances; surgical removal is performed only less invasive treatment option that may be prefer-
when they exceed 4 cm due to the risk of rupture able in patients at high surgical risk, but it is asso-
and haemorrhage. ciated with a higher risk of local tumour
Other benign tumours: Papillary adenoma recurrence compared with surgical excision.
(WHO 2016 classification—papillary or tubular Confirmatory biopsy is recommended for all
architecture of low ISUP nucleolar grade and patients undergoing RFA. Alternative ablative
largest diameter ≤15 mm), metanephric ade- techniques used less frequently include thermal
noma, adenofibroma, and cystic nephroma ablation and cryotherapy. Active surveillance
(WHO 2016 classification—mixed epithelial may be an acceptable approach to delay or avoid
stromal tumour family) represent other less com- further intervention in the patient at high surgical
mon tumours. risk. Immunotherapy using IL-2 and interferons
Benign mesenchymal tumours: Renomedullary was the treatment of choice with metastatic dis-
interstitial cell tumour, adult mesoblastic ease but now targeted therapies (multikinase
nephroma, leiomyoma, haemangioma, lymphan- inhibitors and mTOR therapy) are preferred with
gioma, and solitary fibrous tumour. promising results. Clinical trials are currently
Malignant tumours exploring future directions, including combina-
Renal cell carcinoma: More than 90% of tions of approved agents. There are now many
tumours in the kidney that come to surgery are active trials examining subtype specific thera-
renal cell carcinomas and these cause approxi- pies, and it is likely that additional treatment
mately 2.4% of cancer deaths. The age is usually algorithms based on RCC subtype will soon be
>50 years old with an M/F ratio of 2:1. A number developed. As well as their use in metastatic
of cellular, environmental, genetic, and hormonal RCC, these therapies are currently also being
factors have been studied as possible causal fac- evaluated in the adjuvant setting in high-risk
tors, including cigarette smoking, obesity, hyper- tumours. Cytoreductive nephrectomy is carried
out in patients who present with metastatic dis- dal vasculature is common. Useful positive mark-
ease where the bulk of disease is primarily within ers are PAX-8 (strong nuclear marker), carbonic
the kidney. These patients are then commenced anhydrase IX (CA IX), epithelial markers such as
on targeted therapies if suitable. The overall EMA, cytokeratins AE1-AE3 and CAM 5.2 and
5-year survival is 45% (all types), 70% if node- vimentin.
negative, and 15% if there is renal vein or peri- Papillary renal cell carcinoma (PRCC):
nephric fat involvement. Excision of solitary PRCC is the second most common type of RCC
metastases has been found to be effective. The and is more often bilateral and multifocal com-
WHO classification (2004) has now been pared to other common renal cell tumours, and
superceded. surrounded by a fibrous pseudocapsule on gross
2016 World Health Organization classification evaluation. Multifocality is present in >45% of
of renal neoplasms cases, but in some, this is reported as only a
microscopic finding (papillary adenomas). The
• Clear cell renal cell carcinoma majority of PRCCs have a broad morphology,
• Multilocular cystic renal neoplasm of low including papillary, tubular, and solid patterns.
malignant potential Areas containing papillary differentiation are
• Papillary renal cell carcinoma seen in most cases. Cores of papillae are mostly
• Chromophobe renal cell carcinoma loose and fibrovascular, often containing variable
• Collecting duct carcinoma numbers of foamy macrophages. Psammoma
• Renal medullary carcinoma bodies, haemosiderin-laden macrophages, and
• Hereditary leiomyomatosis and renal cell car- haemosiderin deposition within tumour cells are
cinoma (HLRCC)-associated renal carcinoma often seen. The 2016 WHO classification recog-
• MiT Family translocation carcinoma nizes the morphological subtypes, type 1 and
• Succinate dehydrogenase (SDH) deficient type 2. Some tumours have mixed morphological
renal carcinoma features of both types and are impossible to clas-
• Mucinous tubular and spindle cell carcinoma sify precisely. Type 2 PRCCs are probably differ-
• Tubulocystic carcinoma ent tumours with distinct genetic features despite
• Acquired cystic disease associated renal cell their papillary morphology. PRCC are usually
carcinoma positive for PAX8, cytokeratins, racemase,
• Clear cell papillary renal cell carcinoma vimentin and CD10. Type 1 PRCC more fre-
• Renal cell carcinoma, unclassified quently expresses CK 7 in contrast to type 2
PRCC. Type 1 and type 2 PRCCs have different
Clear cell renal cell carcinoma (CCRCC): genetic profiles. Type 1 tumours typically show
Derived from the proximal convoluted tubule, it gains of 7p and 17p. Loss of heterozygosity of
accounts for 70% of renal tumours. Cytogenetic many chromosomes has been reported for type 2
abnormality includes 3p deletion in 98% of cases tumours. The prognosis overall is better than
and this is considered the initial mutation. It is clear cell RCC (80% 5-year survival), and possi-
characterized by a multinodular tumour mass bly worse than chromophobe RCC.
often elevating the renal capsule and compress- Chromophobe renal cell carcinoma (ChRCC):
ing the adjacent renal parenchyma. It has a pre- Origin from the intercalated cells of cortical col-
dominantly yellow cut surface and additional lecting ducts and represents 5% of renal tumours.
brown and white foci. Most are solid, but some The cut surface of the fresh specimen appears
are composed of multiple cysts varying in size up homogeneously orange and turns tan or sandy after
to 2–3 cm in diameter. Histologically it has com- formalin fixation. They have a solid pattern of
pact, tubulocystic, alveolar or rarely papillary growth with a mixture of pale and eosinophilic
architecture. The cells have clear cytoplasm cells with “raisinoid” nuclei, perinuclear halos, and
(from glycogen/lipid) and distinct but delicate prominent cell membranes. Immunohistochemistry
cell boundaries. A chicken-wire/delicate sinusoi- shows diffuse membranous positivity for CK7.
PAX8, and CD117. E-cadherin, MOC-31, CAM 5.2, are high nuclear grade, with prominent papillary
and BER-EP4 are also positive. Electron micros- and/or alveolar growth patterns, and composed
copy shows abundant mitochondria with tubulo- of clear cells. Psammomatous calcifications are
cystic cristae. The 2016 WHO classification often present. The carcinomas are negative or only
includes two morphological types, classic and focally positive for epithelial markers and vimen-
eosinophilic ChRCC. Tumours with overlapping tin. TFE3 and TFEB are highly sensitive and spe-
features characteristic for oncocytoma and ChRCC cific positive immunohistochemical markers for
are termed “hybrid” tumours. These “hybrid” translocation carcinomas. Melanocytic markers
tumours are mostly seen in Birt–Hogg–Dubé syn- may be focally positive in some cases. Additional
drome, but also in renal oncocytosis. These tumours confirmatory tests include break-apart FISH probe
are considered as a ChRCC subtype according to for Xp11/TFE3 translocation.
the 2016 WHO classification. ChRCC has a favour- Mucinous tubular and spindle cell carcinoma:
able prognosis with a 5-year survival of 78–100%. Low-grade biphasic carcinoma usually associ-
Tumour stage, sarcomatoid changes, necrosis and ated with favourable prognosis. It has multiple
lymphovascular invasion are adverse prognostic chromosomal losses and the majority of cases are
factors. ChRCCs commonly have large pleomor- in females. It is a well-circumscribed mass and
phic nuclei and should not be graded with the ISUP histology shows tightly packed elongated tubules
nucleolar grading system as this does not correlate with variable low-grade spindle cell areas and
with prognosis. nuclei similar to epithelial areas.
Collecting duct carcinoma (CDC): Rare (<1% Immunohistochemistry shows a significant over-
of malignant renal cell tumours), high-grade renal lap with papillary renal cell carcinoma (CK7,
cell carcinoma, likely arising from cells of the AMACR-positive). High grade, and even sarco-
collecting ducts of the renal medulla. The 2012 matoid components have been reported in an oth-
ISUP Vancouver classification established strin- erwise typical tumour.
gent diagnostic criteria for CDC. The tumour Acquired cystic disease RCC: This recently
should at least partially involve the medullary described RCC subtype occurs exclusively in
region; exhibit infiltrative growth pattern; have a patients with acquired cystic kidney disease, usu-
predominant tubular pattern; display desmoplas- ally secondary to dialysis. They usually present at
tic stromal reaction; have high grade cytological low stage within a cyst or encapsulated and histo-
features and no other subtype of RCC and/or uro- logically have a sieve-like, cribriform appear-
thelial carcinoma component present. Targeted ance. The neoplastic cells usually have abundant
therapies against tyrosine kinase receptors of eosinophilic cytoplasm and nucleoli. Oxalate
VEGF-related molecules have shown some prom- crystals within the tumour are a characteristic
ise. The prognosis is poor and 50% of patients die feature. These tumours show diffuse reactivity
of disease within 2 years. Frequent metastatic for AMACR with negative or focal staining with
sites at presentation include lymph nodes, lung, CK7.
and bone. It is positive for PAX8, 34βE12, EMA, Succinate dehydrogenase (SDH) deficient
CK7, CK19 and CEA immunomarkers. renal carcinoma: It is composed of vacuolated
Renal medullary carcinoma: This occurs in eosinophilic or clear cells. Immunohistochemistry
younger patients with sickle cell trait, is similar and shows loss of SDHB expression. These tumnours
may be a variant of collecting duct carcinoma. are mostly young adults and most have germline
Translocation carcinoma: Renal carcinomas mutations in the SDH gene. Histology shows dis-
defined by translocations involving MiTF/TFE tinctive cytoplasmic vacuoles. The majority of
family genes (TFE3 or TFEB). They are uncom- these tumours have a good prognosis.
mon, but constitute a larger proportion of renal cell Hereditary leiomyomatosis and renal cell
carcinomas in paediatric age groups. In children, carcinoma (HLRCC)-associated RCC: These
they usually present at an advanced stage. They are are tumours occurring in the setting of non-
also more aggressive in adults. These carcinomas renal leiomyomatosis and demonstrate germline
fumarate hydratase mutations. These tumours Urothelial (Transitional cell) carcinoma

have a papillary architecture and histologically (UC): Upper tract urothelial tumours of the renal
have prominent nucleoli and abundant eosino- pelvis and ureters are relatively rare. Tumours of
philic cytoplasm. The prognosis of these tumours the renal pelvis account for approximately 10%
is generally poor. of all renal tumours and 5% of all urothelial
Renal cell carcinoma, unclassified: These tumours. Ureteral tumours are even more uncom-
include renal cell carcinomas that do not readily fit mon. UC accounts for more than 90% of upper
into one of the usual categories including a combi- tract urothelial tumours. The mean age of occur-
nation of features of more than one recognized rence is 65 years with a male-to-female ratio of
subtype, or sarcomatoid morphology without an 3:1. Aetiological factors are similar to those of
identifiable epithelial component. By definition, bladder cancer. A majority are papillary or exo-
this category not only includes high-grade, aggres- phytic distending and blocking the pelvi-ureteric
sive tumours but also low-grade, indolent tumours, system, but if infiltrative, the firm, grey-white
including some oncocytoma- like features. tumour can involve renal parenchyma causing
Prognosis depends on tumour type, pathologic confusion with other renal cancers in particular
stage, and metastatic status. sarcomatoid carcinoma or collecting duct carci-
Sarcomatoid carcinoma: Represent 1% of noma. Squamous carcinoma and adenocarci-
renal tumours, and not a distinct histological noma are rare but may form a component of
entity but due to progressive transformation of high-grade UC. The distribution of upper tract
different subtypes of renal cell carcinoma. UC is: renal pelvis—58%; ureter—35% (73% of
However, most tumours are clear cell carcino- which are located in the distal ureter); both renal
mas since they are more common. It is very pelvis and ureter—7%, and bilateral involve-
aggressive with a median survival of 19 months. ment—2–5%. Approximately 30–75% of patients
Grossly it is fleshy, grey-white with infiltrative also develop bladder tumours at some point in
margins and composed of atypical spindle or their cancer course.
tumour giant cells with marked nuclear pleo- Laparoscopic nephroureterectomy with exci-
morphism. It must have an epithelial component sion of the bladder cuff is indicated in patients
(may need generous sampling) and a minimum with renal pelvis UC, regionally extensive dis-
proportion of sarcomatoid carcinoma is not ease, and high-grade or high-stage lesions.
required to make the diagnosis (ISUP, Segmental ureterectomy coupled with ureteral
Vancouver). It is often positive with cytokera- reimplantation is a procedure indicated for
tins (focal) and vimentin. tumours located in the distal ureter. Renal-sparing
Different grading systems have been proposed surgery, including segmental ureterectomy and
for renal cell neoplasia. The Fuhrman system was endoscopic therapy is used in patients with small,
the most frequently used grading system in RCC lower-grade superficial lesions. This approach is
(but not applicable to chromophobe RCC). The used more frequently in patients with one kidney,
Fuhrman system has also not been validated for bilateral disease, and compromised renal func-
most of the newer RCC subtypes. The four tiered tion. Medical treatment of upper tract urothelial
WHO/ISUP key grading system is therefore rec- tumours involves the instillation of chemothera-
ommended by the WHO. For Grade 1–3 tumours, peutic agents, mitomycin C or Bacille Calmette-
the system defined tumour grade on the basis of Guérin (BCG). It is most appropriate for patients
nucleolar prominence. Grade 4 is defined by with multiple superficial disease or carcinoma in
marked nuclear pleomorphism, tumour giant situ who also have bilateral disease and/or limited
cells and/or rhabdoid and/or sarcomatoid differ- renal function. Although this appears to be safe as
entiation. This grading system has been validated adjuvant therapy, its efficacy is not firmly estab-
only for clear cell RCC and papillary RCC and is lished. Thus, it should be considered second-line
not yet applied to other tumours due to the small therapy. Various chemotherapies, similar to those
number of reported cases. in bladder tumours, are used for metastatic
tumours. Recently, targeted therapies against mol- nephrectomy prior to chemotherapy. Clinical out-
ecules of multiple pathways active in urothelial comes are excellent in both groups, and there is an
cancer are also being implemented. Tumour stage ongoing debate on the merits of each approach.
is the most important prognostic factor. Others With current strategies, survival rates are
include age, tumour site, grade, and non-transi- approaching 90%.
tional cell histology. The 5-year survival ranges Other paediatric renal tumours: Cystic
from 91% for stage pT1 to 23% for pT3. nephroma, mesoblastic nephroma, clear cell sar-
Other cancers: Leiomyosarcoma, liposarcoma of the kidney, rhabdoid tumour, metaneph-
coma, haemangiopericytoma, malignant fibrous ric adenofibroma, ossifying renal tumour of
histiocytoma, and metastatic neoplasms (mela- infancy, lymphangioma, intrarenal teratoma, and
noma, lung, other kidney, gastrointestinal tract, uncommon tumours—renal cell carcinoma, lym-
breast, ovary, and testes). phoreticular and haematopoietic tumours.
29.4.2.2 Paediatric Tumours

Wilms’ tumours: Comprise more than 80% of 29.5 Surgical Pathology
renal tumours of childhood usually in children Specimens: Clinical Aspects
2–4 years old. There is a slight preponderance of
females. Associations with congenital anomalies: 29.5.1 Biopsy Specimens
cryptorchidism, hypospadias, other genital
anomalies, hemihypertrophy, and aniridia are Fine needle aspiration cytology (FNAC): Less
well recognized. Wilms’ tumours are usually often performed now but usually in association
large masses; more than 5 cm and solid. They are with a renal core biopsy in the investigation of a
composed of variable admixtures of blastema, mass lesion.
epithelium, and stroma. The epithelial compo- Percutaneous needle biopsy: This is more
nent usually consists of small tubules or cysts often in the investigation of medical renal disease
lined by primitive columnar or cuboidal cells. but also used for the evaluation of a renal mass.
The stroma may differentiate along the lines of The latter is to obtain a tissue diagnosis of malig-
almost any type of soft tissue. nancy for treatment options other than curative
They are divided into two categories: favour- intent radical surgery, e.g., RFA or oncological
able and unfavourable histology, based on the drug therapy. This technique obtains a core of
absence or presence of cellular anaplasia, which fresh renal tissue using a biopsy gun under radio-
is found in approximately 6% of Wilms’ tumours logical (ultrasound or CT) guidance.
and can be associated with an adverse outcome. Medical renal biopsies require special collec-
Thus, it is important to sample Wilms’ tumour tion procedures and should be done only in cen-
specimens extensively. There are criteria for sub- tres with appropriate facilities and after
typing Wilm’s tumour (blastema, epithelial, stro- consultation with the pathologist. Two to three
mal predominant or mixed) and subsequently cores are taken with fresh tissue for immunofluo-
categorised into low, intermediate or high risk rescence (IF), fixed tissue for light microscopy
(International Society of Paediatric Oncology (some laboratories use special fixatives, e.g.,
(SIOP) working classification of renal tumours of Bouins) and electron microscopy (3% glutaralde-
childhood). In the UK pre-operative chemother- hyde). Surgical renal biopsies are routinely fixed
apy (Vincristine and Dactinomycin in children in 10% buffered formalin.
with localised tumours, and additional Indications for renal biopsy include AKI, glo-
Doxorubicin in those presenting with metastases) merular haematuria, proteinuria/nephrotic syn-
is favoured for all cases except very young infants. drome, suspected renal neoplasm, and, following
In the UK, a histological diagnosis made on per- renal transplantation, to distinguish rejection
cutaneous needle biopsy is required before preop- (acute cellular or antibody mediated) from other
erative chemotherapy. Other centres perform causes of deterioration in renal function.
Interpretation of findings requires expertise in the either a transperitoneal incision (extended or

categorization of glomerulonephritis and other bilateral subcostal and thoracoabdominal) or an
glomerulopathies (e.g., diabetes mellitus, amyloid, extraperitoneal incision, depending on the size
hereditary renal disease), interstitial nephritis and and location of the tumour and the patient’s con-
renal vascular disease, monitoring transplant dition. The surgical approach is guided more by
rejection, diagnosis of drug toxicity, and systemic individual preference than by necessity.
disease affecting the kidneys (e.g., vasculitis). Laparoscopic nephrectomy is the preferred
Open renal biopsy: Performed under general approach. Benefits conferred by laparoscopic
anaesthesia if core biopsy is not possible and nephrectomy include decreased patient analge-
more often in the transplant situation (donor and sic requirements, shorter hospitalization, and
recipient) when there is uncertainty about the improved cosmetic results.
state of the donor kidney. They often consist only Removal of the adrenal gland has been advo-
of superficial cortex. cated because the gland is enclosed within
Pelvi-ureteric junction obstruction specimen: Gerota’s fascia and because ipsilateral adrenal
The specimen may be funnel-shaped if unopened metastasis occurs in 2–10% of most reported
and triangular if opened. The length, diameter at series. The risk of adrenal metastasis is related to
both ends, and thickness of the wall are measured the malignant potential of the primary tumour, its
and the presence and size of any strictures size, and position. Patients with large tumours or
described. The specimen is opened along the tumours high in the upper pole are probably bet-
main axis. The mucosal surface is examined for ter served by a standard radical nephrectomy that
lesions and irregularities in texture. The outer includes adrenalectomy.
surface is examined for mass lesions and fibrosis. The role of regional lymphadenectomy in
Multiple sections taken along the long axis are patients with localized kidney cancer is contro-
submitted. versial. Because no widely effective treatments
are available for metastatic RCC, regional lymph-
adenectomy may benefit a small number of
29.5.2 Resection Specimens patients. Extensive nodal involvement is associ-
ated with a poor prognosis.
Simple nephrectomy, radical nephrectomy, and Partial nephrectomy (nephron-sparing sur-
partial nephrectomy. Laparoscopic nephrectomy/ gery (NSS)): Recent advances in preoperative
partial nephrectomy is now routine in experi- staging, specifically modern imaging techniques,
enced hands. and improvements in surgical techniques have
Simple nephrectomy: Is indicated in patients made NSS an attractive alternative to nephrec-
with an irreversibly damaged kidney because of tomy in select patients. It allows for optimal sur-
symptomatic chronic infection, obstruction, cal- gical treatment and, at the same time, obviates
culus disease, or severe traumatic injury. It is also overtreatment and nephron loss. Whenever pos-
indicated to treat severe unilateral parenchymal sible this is done laparoscopically. With advances
damage from nephrosclerosis, pyelonephritis, in experience and technique, the indications of
reflux or congenital cystic dysplasia of the LPN have expanded beyond small (<4 cm), exo-
kidney. phytic, and peripheral renal masses to include
Radical nephrectomy: Is the treatment of more challenging cases, such as hilar and deep
choice for patients with RCC. Radical nephrec- infiltrating tumours in additional to tumours in
tomy encompasses ligating the renal artery and solitary kidneys and larger or cystic lesions.
vein, removing the kidney outside the Gerota’s Other indications also include cases of hereditary
fascia, and the ipsilateral adrenal gland, and per- RCC, such as von Hippel-Lindau syndrome
forming a complete regional lymphadenectomy (VHL), hereditary papillary RCC, and Birt-
from the crus of the diaphragm to the aortic Hogg-Dube syndrome, where the risk of future
bifurcation. The surgical approach includes renal lesions after surgery is high.
Robotic-assisted partial nephrectomy(RAPN): cedure should be available. Serial 2–3 μm sec-

With the evolution of robotic technology for sur- tions are prepared for use in histological and
gery, RAPN has evolved as a technique that immunohistochemical staining procedures. Stains
offers similar outcomes to laparoscopic or open employed include Haematoxylin and Eosin
techniques but may have the advantage of (H&E), Periodic-Acid-Schiff (PAS), silver-
improved manoeuvrability and decreased isch- methenamine and the Masson trichrome stain.
aemic times with consequent improved postop- Immunohistochemistry/immunofluorescence:
erative renal function. For native kidney biopsies, the following anti-
bodies should always be used: IgG, IgM, IgA,
complement factors (C3, C4 and C1q), and fibrin.
29.6 Surgical Pathology Additional antibodies can be necessary (kappa
Specimens: Laboratory and lambda light chains for light chain deposition
Protocols disease and AA for amyloid) and for allografts,
antibodies against BK viral antigens, and C4d
29.6.1 Biopsy Specimens (humoral rejection). Anti-phospholipase A2
receptor antibody is used in some centres to dis-
Core needle biopsy (renal tumour): This is usu- tinguish primary (positive) from secondary mem-
ally one or two cores, which are counted, mea- branous glomerulopathy. EM is an important
sured (mm), and processed for initial histological diagnostic role in more than 50% of cases and is
examination through three levels. Careful han- essential for a correct diagnosis in up to 25%.
dling is necessary to avoid crush artifact. When
sectioning levels, intervening unstained sections
may be usefully kept for ancillary immunohisto- 29.6.2 Resection Specimens
chemical studies if required.
Closed core needle biopsy (medical renal) and These specimens include radical nephrectomy,
open wedge biopsy (donor renal transplant): nephrouretrectomy, ureterectomy, simple
These small biopsies (10–15 mm long) are all nephrectomy, partial nephrectomy, and transplant
handled in a similar fashion and embedded in nephrectomy. They are handled similarly by the
total. A minimum of two core biopsies, each con- laboratory with some notable exceptions as
taining renal cortical tissue is recommended to detailed below.
provide adequate material for light microscopy Initial procedure:
(LM), immunofluorescence (IF), and electron
microscopy (EM). Using a microscope, renal tis- • Proper orientation is the first step in the han-
sue can easily be discriminated from fat or mus- dling of kidney specimens, which facilitates
cle. The cores are divided and in certain cases it is identification of the key external landmarks,
reasonable to omit IF or EM to save material for such as the adrenal gland, vascular resection
LM. If immediate transfer of biopsies cannot be margins and the ureteral stump, all of which
accomplished, one unfixed portion for IF is sent in are located on the medial aspect.
phosphate-buffered saline or on crushed ice and • Palpate and locate the tumour through the
samples for LM and EM fixed immediately. For perinephric fat.
LM, fixation in buffered formalin is common • If there seems to be a penetrating tumour, ink
practice particularly if immunohistochemistry the surface prior to opening the perirenal fat/
rather than immunofluorescence is required. capsule. This helps to distinguish true tumour
Fixation with Bouin’s fluid is also used for kidney penetration of the perirenal fat and margins
biopsies due to a superior preservation of mor- from the relatively common finding of eleva-
phological details. For allograft biopsies and if tion of the capsule by a protruding lobulated
diagnosis is urgently needed in native kidney tumour margin. Ink also the parenchymal
biopsies, a frozen section or rapid embedding pro- kidney resection margin in partial nephrec-
tomy for renal tumours. Open and examine the • Tumour size should be estimated after sec-
mucosal surface of the ureter for any abnor- tioning of the entire renal tumour. To establish
mality and sample its margin prior to incision the greatest tumour dimension multiple cuts
of the kidney. through the tumour may be required. The cut
• The initial incision should pass through the off points of 4, 7, and 10 cm are important for
midline of the kidney in the coronal plane. accurate staging. Distances (mm) from
This is facilitated by taking a section along the perinephric fat, ureteric and parenchymal sur-
midline from either the lateral or the medial gical margins
aspect of the specimen and using probes • Photograph the bisected kidney.
placed in the collecting system or in the larg- • Next make a series of parallel slabs in the cor-
est hilar veins. This provides the advantage of onal plane at 1–1.5 cm intervals. Alternatively,
a full cross-sectional view of the collecting serial horizontal slices that correlate with CT
system and renal sinus. cross-sectional images.
• Remove the perirenal fat (Gerota’s fascia) • Use the first cut surface to collect tumour and
with blunt dissection from the capsule and kidney tissue for special purposes (EM,
examine the surface for adenomas, adrenal imprints, flow cytometry, cytogenetics, tissue
rests, and other subcapsular lesions. culture, snap freezing etc.).
• In tumours of adults, if parts of the capsule are • Place the entire specimen in a large container
adherent to the tumour, dissect around them of buffered formalin for fixation overnight
leaving them in place so that they can be taken (24–36 h).
for histological examination.
• In paediatric tumours, the renal capsule and Description:
perirenal fat should not be dissected from the
kidney and tumour as the capsule retracts • Tumour
when the first cut is made and this may obscure –– Ball-shaped, uni—or multinodular, uni- or
the relationship of tumour, pseudocapsule, multifocal
renal capsule, and perirenal tissue. –– Border: sharpness of margins,
• Partial nephrectomy specimens are sectioned pseudocapsule
perpendicular to the surgical parenchymal mar- –– Colour: yellow, grey-white, brown, tan-
gin, which allows for optimal margin assess- brown, beige
ment. Inking of parenchymal resection margin –– Features of the tumour: homogeneous,
is a must. Inking the external surface/perineph- solid, cystic, papillary, whorls
ric fat is usually not required but should be per- –– Regression: necrosis, haemorrhage, scars
formed in cases with apparent extrarenal (central), pseudocysts
involvement or bulging on gross evaluation. . • Surrounding kidney—nodules, other tumours,
• The specimen should be bisected in a coronal scars.
plane into anterior and posterior halves. • Extent of spread—consider the staging crite-
Dissection may be done from the lateral border ria—restricted to the kidney, infiltration of the
towards the hilum but should be from medial perirenal adipose tissue or the hilar region
to lateral if large vessels are noted in the hilum. (renal sinus), macroscopic invasion of hilar
• Measurements: veins (important as affects staging) or pelvis.
–– Kidney—length (cm), breadth (cm), depth Invasion through the kidney of the perinephric
(cm), and weight (g) fat by urothelial carcinoma of the renal pelvis
–– Ureter—length (cm) and diameter (cm) is reported as pT4, in contrast to renal paren-
–– Tumour chymal tumours which would be staged as
Length × width × depth (cm) or maximum dimen- pT3. Close margins should be inked on the
sion (cm). surface of the specimen.
• Other—Identification of lymph nodes is usu- • Separately label each block and clearly docu-
ally restricted only to the adipose tissue in the ment the exact site of origin.
renal hilar area unless submitted separately by • Sample margin blocks (perinephric fat, ure-
surgeons. Dissect the adrenal gland. ter, renal vein, and artery). Ureteric, vessel,
and renal sinus blocks should be taken prior
Blocks for histology (Fig. 29.3—radical to dissection of the main specimen in order to
nephrectomy):
Tumour expanding
capsule and abutting
perinephric fat
Encasing
perinephric fat 1. Transverse section
the hilar vessels
2. Section distal
ureteric limit
3. Hemisect coronally
Tumour and
radial margin Kidney, tumour
and adrenal gland
Tumour and renal

pelvis ± renal sinus
Tumour, cortex
and perirenal fat to
include radial margin
or Gerota’s fascia
Fig. 29.3 Blocking of a
nephrectomy specimen for upper
pole renal carcinoma
(Reproduced, with permission,
from Allen and Cameron
(2013)) Normal kidney and pelvis
minimise the risk of carryover from friable • Sample at least one block from macroscopically
papillary tumours. normal renal parenchyma, away from tumour.
• Sample at least one block/cm diameter of • In cases with multiple tumours, sampling
tumour with a minimum of 4 blocks (subject should include a minimum of the 5 largest
to modification as needed in individual cases). tumours. In cases when >5 tumours are pres-
• Sample to show relationships between tumour ent, sample only the 5 largest tumours, partic-
and the radial margin; tumour and adrenal ularly if the remaining, smaller tumours show
gland (upper pole tumours); tumour and renal similar gross appearances.
pelvis and surrounding renal parenchyma. • Count and sample any grossly identifiable
• Sample one block from each tumour area that lymph nodes and when lymph nodes are sub-
differs in colour. mitted separately, identify and examine all
• Sample at least two to three blocks from lymph nodes.
tumour–renal sinus interface and an appropri- • Sample the adrenal gland when present (one block).
ate/variable number of blocks to identify • In transplant nephrectomies, blocks should be
extension into perirenal fat. taken serially (from without in) of the hilar vessels
• Sample one block from renal vein, renal to examine the nature of the renal vein and artery.
artery, and ureter margin. • In nephrectomies for benign disease, samples
• Multiple blocks from identifiable or suspected to be taken include any abnormal area and one
venous or collecting system invasion. random from otherwise normal parenchyma.
• Sample blocks from all other identifiable renal
Blocks for histology (Fig. 29.4—partial
abnormalities.
nephrectomy):
Tumour and renal

capsule/perinephric
fat.
Ink before cutting
Parenchymal
margin(ink)
Overview with cruciate block

sampling of tumour, renal
parenchyma and surgical
margin

partial nephrectomy specimen
Fig. 29.5 Blocking of a Normal kidney

nephroureterectomy for and pelvis
multifocal ureteropelvic
transitional cell
carcinoma (Reproduced,
Tumour and
renal pelvis
Allen and Cameron
(2013)) Tumour and renal pelvic wall with
peripelvic fat
Transverse sections
Tumour, cortex of ureteric tumour
and perirenal fat
Transverse section vesical intramural

portion of ureter
Transverse section
of distal ureteric limit
• Separately label each block and clearly docu- • Sample blocks from all other identifiable renal
ment the exact site of origin. abnormalities.
• Sample margin blocks (perinephric fat, paren- • Sample at least one block from macroscopi-
chymal resection margin). Separate tumour cally normal renal parenchyma, away from
bed tissue should be submitted in total. tumour.
• The urinary collecting system and the renal • Sample the adrenal gland and lymph nodes if
sinus fat are seen occasionally in partial present.
nephrectomies and if identified, samples for
histological assessment should be taken. Blocks for histology (Fig. 29.5—nephroure-
• Sample at least one block/cm diameter of terectomy/ureterectomy):
tumour. A minimum of 4 tumour blocks
should be sampled but if the tumour is less • Separately label each block, and clearly docu-
than 3 cm, all the tumour should be sampled. ment the exact site of origin.
• Sample to show relationships between tumour • Take one block from each tumour area that
and parenchymal resection—cruciate block differs in colour.
sampling or serial transverse slices can be • One block of tumour/cm of tumour diameter
used. is probably sufficient (minimum of 4 blocks).
• Sample one block from each tumour area that • Sample to show the relationships between
differs in colour. tumour and renal pelvis; tumour, renal pelvic
wall, and peripelvic fat; tumour, cortex, and ISUP grade 4 tumours should encompass
perirenal fat. tumours with rhabdoid or sarcomatoid differen-
• In renal pelvic tumours, sample areas of unre- tiation or those containing tumour giant cells or
markable and abnormal renal pelvic and ure- showing extreme nuclear pleomorphism with
teric mucosa away from the tumour. clumping of chromatin.
• With ureteric tumours, serially section the
tumour transversely at 3-mm intervals and • Tumour edge—infiltrative/pushing/lympho-
sample a minimum of 4 blocks to assess the cytic infiltrate
deepest point of invasion. • Extent of local tumour spread: TNM 8 for
• If ureteric tumour is not seen grossly, sample renal cell carcinoma
and correspondingly label unremarkable and
abnormal mucosal areas. pT0 No evidence of primary tumour
• Transverse sections of the distal ureteric/blad- pT1 Tumour ≤7 cm in greatest dimension, limited
to the kidney
der cuff margin.
pT1a Tumour ≤4 cm in greatest dimension, limited
• Count and sample all lymph nodes. to the kidney
• Additional sections should include renal pel- pT1b Tumour >4 cm but ≤7 cm in greatest
vis, renal artery, renal vein, and ureter. dimension, limited to the kidney
• Sample the adrenal gland if present (one block). pT2 Tumour >7 cm in greatest dimension, limited
• Sample the surrounding kidney. to the kidney
pT2a Tumour >7 cm but ≤10 cm in greatest
dimension, limited to the kidney
Histopathology report renal cell carcinoma:
pT2b Tumour >10 cm in greatest dimension,
limited to the kidney
• Tumour type (WHO 2016)—clear cell/papil- pT3 Tumour grossly extends into major veins or
lary/chromophobe/collecting duct/unclassi- perinephric tissues but not into the ipsilateral
fied/other adrenal gland and not beyond Gerota’s fascia
• Tumour differentiation/grade (Fuhrman and pT3a Tumour grossly extends into the renal vein or
ISUP)—sarcomatoid? its segmental (muscle-containing) branches
or tumour invades perirenal and/or renal sinus
fat but not beyond Gerota’s fascia
Fuhrman grade pT3b Tumour grossly extends into the vena cava
Grade 1 Nuclei round, uniform, approxi- below the diaphragm
mately 10 μm in diameter; nucleoli inconspicu- pT3c Tumour grossly extends into vena cava above
ous or absent diaphragm or invades the wall of the vena
cava
Grade 2 Nuclei slightly irregular, approxi-
pT4 Tumour invades beyond Gerota’s fascia
mately 15 μm in diameter; nucleoli evident
(including contiguous extension into the
Grade 3 Nuclei very irregular, approximately ipsilateral adrenal gland)
20 μm in diameter; nucleoli large and prominent
Grade 4 Nuclei bizarre and multilobated, • Lymphovascular invasion—present/not pres-
20 μm or greater in diameter, nucleoli prominent, ent. Note perineural invasion
chromatin clumped • Regional lymph nodes—hilar, abdominal
WHO/ISUP Grade para-aortic and paracaval
ISUP grade 1 tumours defined as having
inconspicuous or absent nucleoli at ×400 pN0 No regional lymph node metastasis
magnification pN1 Metastasis in regional lymph node(s)
ISUP grade 2 tumours, nucleoli should be dis-
tinctly visible at ×400, but inconspicuous or • Excision margins: Perinephric fat, ureter,
invisible at ×100 magnification renal vein, and in partial nephrectomy, the
ISUP grade 3 tumours, nucleoli should be dis- renal parenchymal margin of tumour clear-
tinctly visible at ×100 magnification ance (mm)
• Other pathology: Multifocal papillary, synchro- pN0 No regional lymph node metastasis
nous tumours, amyloid in tumour, adrenal rests, pN1 Metastasis in a single lymph node, ≤2 cm in
adenomas, tumour regression, cystic disease greatest dimension
• Transplant nephrectomy: Comment on hilar pN2 Metastasis in a single lymph node >2 cm, or
multiple lymph nodes
vessels, presence or absence of acute vascular
and/or cellular rejection, chronic allograft
nephropathy (chronic antibody mediated rejec- • Margins: Ureteral, bladder neck, Gerota’s fas-
tion), donor-related changes cia (perinephric fat margin), hilar soft tissue,
renal parenchyma (partial nephrectomy),
Histopathology report renal pelvis and ureter tumour clearance (mm)
carcinoma: • Additional pathologic findings, if present:
Urothelial carcinoma in situ (focal/multifo-
• Tumour type—UC/squamous/adenocarci- cal), dysplasia, inflammation/regenerative
noma/other changes, therapy related (BCG, mitomycin),
• Tumour differentiation—WHO 1973 grades Urothelial proliferation of uncertain malig-
I–III and WHO 2016 Papillary urothelial nant potential (hyperplasia)—WHO 2016
neoplasm of low malignant potential, Papillary • Other pathology: Cystitis cystica/glandularis,
urothelial carcinoma low grade/high grade keratinizing squamous metaplasia, intestinal
• Pattern of growth metaplasia
1. Noninvasive (pure)—papillary/flat CIS/

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Bladder
30
30.1 Anatomy ately adjacent to the urethral orifice is known as

the bladder neck. The seminal vesicles and vasa
The empty bladder is a pyramidal-shaped organ deferentia lie immediately posterior to the blad-
that lies entirely within the pelvic cavity. Upon der base (Fig. 30.1).
filling (capacity approximately 500 mL), the The mucosal surface lining the bladder base is
bladder assumes a more ovoid shape, rises out of known as the trigone. It is distinct in that, because
the pelvis, and separates the peritoneum from the of firm adherence to the underlying muscle coat,
anterior abdominal wall. The bladder has an apex its surface is always smooth, in contrast to the
(anteriorly), a base (posteriorly), a superior sur- remainder of the mucosa which, when the blad-
face (the dome), and two inferolateral surfaces. der is empty, assumes an undulated appearance.
The apex is anchored to the anterior abdominal The bladder is lined by transitional epithelium
wall by the urachus, a fibrous embryological or urothelium, usually six cell layers thick. This
remnant which, during development, connects rests on a thick layer of fibroelastotic connective
the bladder to the allantois. The relationship of tissue, allowing considerable distention. Below
the bladder to the peritoneum is important surgi- this is the ill-defined muscularis mucosae, com-
cally and clinically. The superior surface of the posed of wispy irregular bundles of smooth mus-
bladder (dome) is covered completely by perito- cle. The main muscular coat of the bladder, the
neum; the peritoneum being densely attached to muscularis propria or detrusor muscle, is com-
this surface. Anteriorly the peritoneum leaves the posed of interlacing bundles of larger smooth
superior surface of the bladder extending upwards muscle fibres loosely arranged into inner longitu-
to the posterior surface of the anterior abdominal dinal, middle circular, and outer longitudinal lay-
wall where it blends with the fascia transversalis. ers. At the bladder neck, the circular layer is
Laterally, the peritoneum extends to the obturator thickened, forming a preprostatic sphincter,
fascia on the lateral pelvic wall. The base is trian- which is responsible for maintaining urinary con-
gular in shape, limited superolaterally by the tinence. This muscle is richly ennervated by sym-
entrances of the ureters into the bladder, and infe- pathetic nerve fibres.
riorly by the urethral orifice. The area immedi- Lymphovascular drainage:
The blood supply to the bladder is from the
superior and inferior vesical arteries and venous
D.M. O’Rourke (*) • D.C. Allen drainage is to the internal iliac veins via the vesi-
Histopathology Laboratory, Belfast City Hospital, cal venous plexus. Most of the lymphatic drain-
Belfast Health and Social Care Trust, Belfast, UK age is to the external and internal iliac lymph
e-mail: declan.orourke@belfasttrust.hscni.net; derek.
allen@belfasttrust.hscni.net nodes (Fig. 30.2).

Fig. 30.1 Anatomy of

the bladder (Used with Urachus
Union for International Dome
Posterior wall
Lateral wall
Anterior wall
Ureteric orifice
Trigone
Bladder neck
Prostate
Urethra
Bladder tumours most commonly present with

the painless passage of blood in the urine (hae-
maturia), sometimes with amorphous clots. This
is a serious symptom necessitating immediate
urological investigation, particularly in the adult.
Haematuria occurring at the end of micturition
(terminal haematuria) points specifically to
pathology in the bladder neck region. Non-
Visible Haematuria (NVH) previously referred to
as ‘microscopic haematuria’ or ‘dipstick positive
haematuria’ is further sub-divided into either
symptomatic Non-Visible Haematuria (s-NVH)
or asymptomatic Non-Visible Haematuria
(a-NVH). NICE referral guidelines (2015) rec-
ommend urgent referral for investigation of blad-
Fig. 30.2 Bladder—regional lymph nodes (pelvic nodes der and upper urinary tract cancer in patients
below the bifurcation of the common iliac arteries) (Used
with the permission of the Union for International Cancer
aged ≥60 years with unexplained NVH.
Control (UICC), Geneva, Switzerland. The original There are usually no other symptoms unless
source for this material is from Wittekind et al. (2005)) there is secondary urinary obstruction and/or
30 Bladder 323
infection. Advanced bladder cancer may present • Intravenous urogram (IVU)—Of limited value
with symptoms related to a pelvic mass, lower in the diagnosis of bladder disease. Tumours
limb oedema due to lymphatic obstruction, or may present as filling defects.
metastatic disease. • Cystoscopy and cytology/biopsy. Two newer
Acute urinary retention is more commonly technologies to improve the detection of flat
due to prostatic enlargement than bladder dis- lesions in the bladder include blue-light cys-
ease. Overdistention causes a constant suprapu- toscopy and narrow-band imaging.Narrow-
bic pain relieved instantaneously by the passage band imaging improves the visibility of blood
of urine. Occasionally, with slowly progressive vessels and other structures on the bladder
urinary obstruction and bladder distention, e.g., mucosa. Molecular assays, such as FISH may
neurogenic (flaccid) bladder of diabetics, there is have a role in patients with atypical findings
no associated pain. on urine cytology or cystoscopy, as a predic-
Inflammatory conditions of the bladder tive marker for patients being given intravesi-
including bacterial infection and interstitial cysti- cal immunotherapy.
tis often present with intermittent suprapubic dis- • Cystography—Occasionally indicated to
comfort or irritative symptoms of painful demonstrate vesicocolic or vesicovaginal fis-
urination (dysuria), increased number of episodes tulae, to evaluate bladder diverticula or post-
of micturition daily (frequency), and a sensation bladder surgery to look for an anastomotic
of sudden, strong impulse to void (urgency). leak.
Diffuse carcinoma in situ of the bladder may also • Micturating cystourethrography—assesses
present in this way. the pathophysiology of micturition as well
Bladder calculi may be asymptomatic or pres- as the lower urinary tract anatomy. In blad-
ent with haematuria. There may be pain associ- der disease, useful for evaluating neuro-
ated with intermittent bladder outlet obstruction genic bladder, diverticula, and vesicoureteral
or symptoms related to secondary infection. reflux.
Rarer conditions such as diverticula or urachal • Loopography—Occasionally performed to
remnants are usually asymptomatic, although examine reconstructed urinary reservoirs or
predisposing to stones and infection. Vesicocolic conduits after resection of the native blad-
fistula due to colonic diverticulitis, Crohn’s dis- der, e.g., to look for obstruction in an ileal
ease, or malignancy can present with the unusual conduit.
symptoms of passage of gas (pneumaturia) or • USS—Can be used to detect radiolucent blad-
faecal material (faecaluria) in the urine. der stones or diverticula or to confirm the
Vesicovaginal fistula due to malignancy may presence of bladder tumour in suspicious fill-
result in the passage of faecal material vaginally. ing defects on IVU. Endoluminal ultrasound
(ELUS) is used to stage bladder cancer in
some specialized centres.
30.3 Clinical Investigations • CT scanning of the abdomen and pelvis with
contrast, with pre-infusion and post-infusion
• Urinalysis—A ‘dipstick’ test will detect NVH phases. This evaluation is ideally performed
which can indicate bladder disease, or pick up with CT urography.
other substances such as protein or sugar in • MRI—Used to stage bladder cancer, primarily
the urine which may flag up bladder infection in looking for metastatic disease in regional
or an underlying medical condition such as lymph nodes and other organs.
diabetes mellitus. • PET—Unfortunately, FDG is excreted into
• Midstream sample of urine (MSSU) culture— the urine and thus accumulates in the bladder,
Will confirm the presence of bacterial making it unsuitable for diagnosis of urinary
infection. tract tumours.
30.4 Pathological Conditions Interstitial cystitis/painful bladder syndrome:

Usually in middle-aged women, the aetiology is
30.4.1 Non-neoplastic Conditions obscure and the diagnosis essentially one of
exclusion. It has also been demonstrated that the
Bacterial cystitis: This, the most common cause prevalence of allergies, fibromyalgia, inflamma-
of cystitis, is usually due to coliform organisms tory bowel disease, and certain autoimmune dis-
(e.g., E. coli) ascending the urethra. Underlying eases are higher in these patients. Symptoms may
structural (diverticula, fistulae, malformations, be extremely severe. On cystoscopy, the typical
stones) or medical (diabetes mellitus, chronic appearances of diffuse punctate haemorrhage
renal failure, immunosuppression) conditions with or without ulceration can closely mimic car-
predispose. Recurrent infections, especially in cinoma in situ (CIS). Biopsies are performed pri-
men, should trigger investigation for an underly- marily to help rule out other varieties of cystitis
ing cause. or neoplastic conditions such as CIS or malig-
Malakoplakia: Is caused by a defect in the nancy. The histological appearances are non-
host macrophage response to bacterial infection specific, with lamina propria congestion, oedema,
and can affect practically any organ in the genito- and inflammation featuring lymphocytes, plasma
urinary system or indeed elsewhere. It is seen pri- cells, and variable numbers of detrusor mast cells
marily in middle-aged women and presents as (best seen histologically if sample submitted in
multiple soft, yellow mucosal plaques on cystos- alcohol rather than formalin). Urine cytology to
copy, sometimes mistaken for carcinoma. Biopsy exclude malignancy and culture for infection are
reveals collections of granular histiocytes in the other important investigations. The diagnosis of
lamina propria, some with characteristic intracy- interstitial cystitis requires close clinical (i.e.,
toplasmic concentrically laminated inclusions history, cystoscopy, and voiding studies) and
(Michaelis–Gutmann bodies). pathological correlation. Treatment is initially
Polypoid/papillary cystitis: These closely medical for symptom relief (amitriptyline, anti-
related conditions describe localized nonspecific histamines, analgesics) with intravesical therapy
inflammation and oedema of the bladder mucosa an alternative, and eventually surgical interven-
commonly seen in association with indwelling tion in the form of urinary diversion with or with-
urinary catheters and less often with vesical fistu- out cystourethrectomy, as a last resort.
lae. They may be difficult to differentiate endo- Therapy-induced changes: Antineoplastic
scopically and microscopically from papillary agents used in the bladder or systemically, such
urothelial carcinoma, which tends to have finer as mitomycin C, cyclophosphamide, Bacillus
stromal papillary cores, more urothelial atypia, Calmette-Guerin (BCG), and radiation therapy
and less associated inflammation. produce urothelial changes that can mimic CIS/
Nephrogenic adenoma (nephrogenic metapla- cancer histologically. Ketamine (cystitis) can
sia): Often associated with previous surgery, renal show urothelial ulceration and atypia that can
transplants, stones, or infection, these are small, mimic CIS but the longer term cancer risk
usually polypoid lesions of metaplastic origin remains unknown.
and, although most commonly found in the blad- Bladder stones: Most commonly seen in men
der (75%), can be seen anywhere in the urinary with bladder outlet obstruction, and associated
tract. Histologically it consists of either small with renal or ureteric stones. Rarely result in sur-
tubules lined by cuboidal or hobnail-like cells or gical material.
small papillary projections that can mimic adeno- Diverticula: Most are seen in elderly males
carcinoma (clear cell or prostate) or urothelial and attributed to increased luminal pressure sec-
carcinoma, respectively. Immunohistochemistry ondary to prostatic enlargement causing outlet
shows pancytokeratin, CK7, PAX8, PAX2 posi- obstruction. Few cause symptoms or require sur-
tive staining and also weak PSA/PsAP and vari- gical treatment. Most are located close to the ure-
able positivity with P504S. teric orifices. Possible complications include
30 Bladder 325
ureteric obstruction, infection, stone formation, presents with haematuria and manifests as a pol-
and rarely malignancy (urothelial, adeno- or ypoid mass. IMT is classically associated with
squamous cell carcinoma). myxoid, spindle cell or hypocellular fibrous pat-
Urachal-related lesions: Persistence of the terns and shows positive staining with SMA and
urachus can result in a completely patent tract low molecular-weight cytokeratin and variable
from bladder to umbilicus, a blind-ended sinus positivity with desmin. ALK-1 expression is seen
opening onto the bladder mucosa or umbilical in 50% with ALK gene rearrangement confirmed
skin, or an enclosed sinus blind at both ends. The in most cases. Most IMTs follow an indolent
lining epithelium may be of urothelial or colum- course after surgical resection, with the main
nar type. Presentation is usually in childhood. concern being local recurrence, which occurs in
Stasis of urine and epithelial debris predispose to 10% of cases.
infection, abscesses, and rarely stones. Cysts may Others: Fibroepithelial polyp, Müllerian
occur at any point within the urachal remnant. lesions, prostatic-type polyps, and florid von
Neurogenic bladder: A wide range of neuro- Brunn’s nests.
muscular conditions (e.g., cerebrovascular acci- Miscellaneous: Other causes of cystitis include
dent, multiple sclerosis, spinal cord trauma, pelvic radiotherapy, intravesical BCG immuno-
diabetes mellitus) can cause voiding dysfunction therapy (granulomatous) or chemotherapy, oral
by interfering with bladder wall compliance, drugs (cyclophosphamide), viral infection (CMV,
detrusor muscle activity, or sphincter function, HSV), and parasite infestation (schistosomiasis).
resulting eventually in either a tightly contracted Amyloidosis may present as a localized, nodular
or flaccid bladder. These are usually treated by bladder mass (“amyloid tumour”).
behavioural, pharmacological, or electrophysio-
logical means, but occasionally surgical interven-
tion may be indicated, e.g., augmentation 30.4.2 Neoplastic Conditions
cystoplasty to increase capacity in a contracted
bladder, where a segment of stomach or intestine Benign tumours: Inverted urothelial papilloma,
is isolated and anastomosed to the native bladder. villous adenoma, paraganglioma, leiomyoma,
Rarely, adenocarcinoma may supervene later in haemangioma, and granular cell tumour of the
the augmented bladder. bladder are occasionally encountered. Benign
Tumour-like conditions: urothelial papilloma is a rarely made diagnosis.
Postoperative necrobiotic granulomas: Seen Keratinizing squamous metaplasia: May be
following transurethral surgery with diathermy. associated with chronic irritation (catheters,
Microscopy reveals central necrosis with periph- stones, parasitic infection). Keratinizing squa-
eral palisading of histiocytes and occasional giant mous metaplasia is a putative precursor lesion of
cells. squamous cell carcinoma and may be present in
Inflammatory myofibroblastic tumour (IMT): epithelium adjacent to squamous cell carcinoma.
Different names have been used for identical, Cystoscopic follow up is advised.
cytologically benign myofibroblastic prolifera- Urothelial dysplasia/carcinoma in situ/carci-
tions (pseudosarcomatous myofibroblastic prolif- noma: Many carcinogenic agents are known to
eration, pseudosarcomatous fibromyxoid tumour, predispose to urothelial malignancy. These
inflammatory myofibroblastic tumour [IMT], include cigarette smoke, industrial aniline dyes
postoperative spindle cell nodule, inflammatory (aromatic amines), petrochemicals, cyclophos-
pseudotumour). IMT is an uncommon spindle phamide, and the analgesic phenacetin. Most
cell lesion that can occur in the urinary bladder invasive tumours are associated with urothelial
and possible aetiologies include autoimmune dis- dysplasia or flat carcinoma in situ. Urothelial
ease and infection. Recent molecular discoveries dysplasia is defined as a flat lesion with cytologi-
of clonality suggest that IMT is a neoplastic pro- cal and architectural abnormalities falling short
cess. In the urinary bladder, IMT most commonly of that required for CIS. Urologists rarely change
management on the basis of dysplasia. Urothelial Lymphoepithelioma-like

CIS rarely occurs in the absence of invasive Plasmacytoid/signet ring/diffuse
tumour, can closely mimic interstitial cystitis Sarcomatoid
both clinically and cystoscopically, presenting Giant cell
with irritative bladder symptoms and appearing Poorly differentiated
as multifocal red, velvety patches. It is more Lipid rich
often seen in association with prior or synchro- Clear cell
nous invasive malignancy which can be multifo- Non-invasive urothelial neoplasia
cal and is a flat lesion composed of cells with Urothelial carcinoma in situ
large, irregular, hyperchromatic nuclei, promi- Non-invasive papillary urothelial carcinoma,
nent nuclear pleomorphism, high nuclear to cyto- high grade
plasmic ratio and mitotic figures. Large cell, Non-invasive papillary urothelial carcinoma,
small cell, clinging and Pagetoid patterns are rec- low grade
ognised. An immunohistochemical panel consist- Papillary urothelial neoplasm of low malig-
ing of CK20, CD44s, p53, and Ki67 may be nant potential
helpful in differential diagnosis. CIS is usually Urothelial papilloma
treated with an induction course of BCG, and if Inverted urothelial papilloma
tolerated, followed by maintenance therapy. Urothelial proliferation of uncertain malig-

Patients with widespread field change (which nant potential
may involve the bladder, ureters, urethra, pros- Urothelial dysplasia
tatic ducts, and seminal vesicles) and those in Squamous cell neoplasms
whom initial intravesical therapy fails are at high Pure squamous cell carcinoma
risk of progression to invasive disease, and cys- Verrucous carcinoma
tectomy may be in their best interest. The behav- Squamous cell papilloma
iour of CIS is somewhat unpredictable, with 50% Glandular neoplasms
of patients developing invasive carcinoma within Adenocarcinoma, not otherwise specified

5 years. They should all be referred for specialist (NOS)
multidisciplinary team (MDT) discussion, and Enteric
should receive either maintenance BCG immuno- Mucinous
therapy or consideration for radical cystectomy if Mixed
there is a high risk of progression or lack of Villous adenoma
response to BCG. The optimum BCG maintenance
regimen remains undefined; however, typically Urachal carcinoma
treatment is recommended for 1–3 years, depend- Tumours of Mullerian type
ing on tolerability to allow a sustained host immune Clear cell carcinoma
response. Careful follow-up with urine cytology Endometrioid carcinoma
and biopsy is advocated to monitor recurrence or Neuroendocrine tumours
progression. Approximately 10–20% of complete Small cell neuroendocrine carcinoma
responders eventually progress to muscle-invasive Large cell neuroendocrine carcinoma
disease compared to 66% of non-responders. Well
differentiated neuroendocrine
carcinoma
WHO 2016 classification of tumours of the Paraganglioma
urothelial tract Melanocytic tumours
Urothelial tumours Malignant melanoma
Infiltrating urothelial carcinoma Naevus
Nested, including large nested Melanosis
Microcystic Mesenchymal tumours
Micropapillary Rhabdomyosarcoma
30 Bladder 327
Leiomyosarcoma tumours of the urothelial tract (2016) reviewed

Angiosarcoma the grading of urothelial neoplasms. Grading of
Inflammatory myofibroblastic tumour urothelial tumours is particularly important in
Perivascular epithelioid cell tumour non-invasive papillary neoplasms (over 95% of
Solitary fibrous tumour invasive tumours are high-grade). Non-invasive
Leiomyoma tumours can be divided into two patterns, either
Haemangioma papillary or flat. Multiple studies have been pub-
Granular cell tumour lished comparing the 1973 WHO classification
Neurofibroma (largely restricted to the UK and Europe) with the
2004 and now 2016 classifications in terms of
Urothelial tract haematopoietic and lym- reproducibility and clinical impact. Advantages
phoid tumours of WHO 2016 include more uniform terminology
Miscellaneous tumours and better definitions for preneoplastic conditions
Carcinoma of Skene, Cowper and Littre and tumour grades, and elimination of ambiguous
glands diagnostic categories in the 1973 WHO system
Metastatic tumours and tumours extending (grade 1–2, grade 2–3). The category of papillary
from other organs urothelial neoplasm of low malignant potential
Tumours arising in a diverticulum (PUNLMP) is included in both 2004/2016 but
Urothelial tumours of the urethra although it has a low risk of progression, some
studies have shown a significant risk of recur-
Urothelial carcinoma: There were over 10,000 rence. Treatment and follow-up regimes for
new cases of bladder cancer in the UK in 2014, PUNLMP are similar to low-grade urothelial car-
and bladder cancer represents the tenth most com- cinoma. The term urothelial proliferation of uncer-
mon cancer in the UK accounting for 3% of all tain malignant potential (UPUMP), has also been
new cases. More than half (55%) of bladder cancer introduced instead of the term hyperplasia. This is
cases in the UK each year are diagnosed in people more frequently seen in patients with history of
aged 75 years and over. Most bladder cancer cases prior carcinoma or adjacent to papillary lesions.
are diagnosed at an early stage. Bladder cancer is The evidence for inclusion is supported by
more common in people living in deprived areas. genomic abnormalities (chromosome 9 deletions).
Urothelial (transitional cell) carcinoma (UC/ The concurrent use of both grading systems (WHO
TCC) accounts for over 90% of primary bladder 1973 and 2016) for urothelial neoplasms is recom-
tumours, most commonly presenting in elderly mended with focus in particular on the subcate-
males as a cystoscopic mass showing an exo- gorisation of grade 2, non-invasive urothelial
phytic or endophytic growth. Diagnosis is con- tumours into low-grade and high-grade.
firmed by biopsy which commonly shows a Invasive urothelial carcinoma with divergent
papillary or solid growth pattern. Urine cytology differentiation: This refers to tumours arising
is of limited value in the initial evaluation of low- within the urothelial tract in which a percentage
grade bladder tumours and is more useful in CIS of usual type urothelial carcinoma is present
and high-grade urothelial carcinoma, industrial along with other morphologies. This is seen most
screening, and follow-up after treatment. commonly in association with high-grade and
Fluorescent in situ hybridization (FISH) is con- locally advanced disease. This is often associated
siderably more sensitive and only slightly less with more aggressive behaviour and the amount
specific than cytology and is a useful initial diag- does not have to be extensive but should be
nostic tool in patients suspected of both new and recorded in the pathology report. Common diver-
recurrent bladder cancer. Note that non-invasive gent differentiation includes along squamous,
urothelial carcinoma (TCC, stage pTa) is also glandular, small cell and even trophoblastic lines.
classified as carcinoma to avoid confusion with Squamous differentiation is seen in up to 40% of
flat CIS (stage pTis). The WHO classification of invasive urothelial carcinomas.
Nested urothelial carcinoma: Is characterised p16 positivity and lack of p63 are helpful in
by cytologically bland tumour cells infiltrating as distinguishing from UC. Molecular genetic
confluent small nests and tubules. A large nested studies have also suggested a common clonal
variant of urothelial carcinoma has also recently origin for bladder SmCC and coexisting blad-
been described. der UC. Histologically, pure SmCC tends to
Micropapillary urothelial carcinoma: Consist have a poorer outcome than mixed SmCC.
of small nests and aggregates of tumour cells Pathological staging: Is extremely important
where the nuclei are atypical and orientated at the for prognostic and treatment purposes and is
periphery of the cell clusters. These tumours are determined by the extent of local tumour spread.
commonly associated with lymphovascular inva- Assessment of small bladder biopsies is crucial
sion, present at high pathological stage and and they must be carefully examined. Muscularis
exhibit aggressive clinical behaviour. It remains mucosae (MM—pT1) versus muscularis propria
controversial whether this tumour should be (MP—pT2) invasion may be difficult as in some
treated differently from other high-grade locally bladders, the junction of MP and lamina propria
advanced bladder cancers but most cases are is not well defined. The MP has large confluent
treated with cystectomy as response to neo-adju- aggregates of thick muscle and of note, is promi-
vant chemotherapy is poor. nent at the trigone where there is minimal submu-
Plasmacytoid urothelial carcinoma: Is a rare cosa. Smoothelin immunohistochemistry may be
tumour characterised by sheets of monomorphic helpful in distinguishing MM from MP. There is
tumour cells with plasmacytoid features. weak, patchy staining in MM and strong diffuse
Commonly tumour cells have prominent cyto- reactivity in the MP. This selective staining may
plasmic vacuoles giving it a signet ring-like be dependent on the staining conditions and
appearance (hence nomenclature plasmacytoid/ occasionally false positive staining may be found
signet ring cell/diffuse). It is normally diagnosed in the muscularis mucosae. Cytokeratin stains
in the locally advanced stage and is associated may be useful in identifying subtle foci of inva-
with a poor outcome. sive carcinoma but should not be confused with
Sarcomatoid urothelial carcinoma: Was origi- cytokeratin-positive myofibroblasts. In bladder
nally termed carcinosarcoma because of the com- biopsy material, distinction is not made between
bination of both epithelial and mesenchymal-type invasion of the inner (superficial, pT2a) and outer
components. The preferred term is sarcomatoid (deep, pT2b) MP due to problems of orientation
carcinoma, as the sarcomatoid features appear to (reported as “at least” stage pT2a). Biopsies
be derived from dedifferentiation of the carcino- should also be examined closely for coexistent
matous (urothelial) component. It represents an CIS. Separate biopsies may be submitted to
aggressive form of UC often presenting with assess prostatic involvement. For tumours invad-
high-grade, high-stage disease at diagnosis and ing MP, subdivision in cystectomy specimens
with a broad spectrum of histopathological fea- into pT2a and pT2b according to inner and outer
tures. Use of pancytokeratin and muscle immu- half of the MP or macroscopic (pT3b) versus
nohistochemical markers may be beneficial to microscopic (pT3a) extension into perivesical fat
exclude non-epithelial neoplasms. has prognostic significance in several studies.
Small cell carcinoma (SmCC) of the urinary There is a correlation between tumour stage and
bladder: Is a rare, aggressive tumour often grade, based on the degree of nuclear atypia, in
present with conventional UC in more than that more poorly differentiated tumours (WHO
50% of cases. Its presents similarly to UC but grade III) show a much higher rate of concurrent
metastasis is common and prognosis is poor. or subsequent muscle invasion. High-grade
Small cell carcinoma of the urinary bladder is tumours commonly show focal squamous or
similar morphologically with SmCC lung but glandular differentiation.
immunohistochemistry for conventional neu- Standard treatment: The definitve gold stan-
roendocrine markers can be variable. Recently dard treatment for patients with stage T2–T4 (and
30 Bladder 329
sometimes grade III, pT1) disease is radical cys- UC. Although cystectomy specimens allow a
tectomy (cystoprostatectomy for men and ante- more clear-cut diagnosis, biopsy and transurethral
rior pelvic exenteration for women) and bilateral resection specimens can prove more challenging.
pelvic lymphadenectomy, often preceded by neo- The co-existence of keratinizing squamous meta-
adjuvant cisplatin-based chemotherapy. Partial plasia with or without dysplasia or verrucous
cystectomy is reserved for solitary tumours (par- squamous hyperplasia (VSH), may be helpful
ticularly at the dome—urachal) with no previous in suggesting that a lesion may represent a pure
history of bladder tumours and no CIS, bladder SCC. However, the final distinction may only
neck or trigone involvement. Bilateral pelvic occur at cystectomy. Immunohistochemistry for
lymphadenectomy (PLND) should be performed uroplakin III, GATA3 and S100P (urothelium)
in conjunction with radical cystoprostatectomy and CK14, Desmoglein-3 (squamous epithelium)
and anterior pelvic exenteration. PLND adds is often helpful. Radical surgery remains the
prognostic information by appropriately staging mainstay of treatment with improved survival.
the patient and may confer a therapeutic benefit. Verrucous squamous carcinoma is an uncom-
Patients keen to preserve their bladder may be mon subtype of SCC, well-differentiated and is
candidates for bladder-sparing trimodality treat- often associated with schistosomiasis infection.
ment, which consists of complete transurethral Grossly, these lesions appear exophytic, and on
resection followed by radiotherapy and concur- histiology shows hyperplastic squamous epithe-
rent radiosensitising chemotherapy. Radiotherapy lium with parakeratosis, with a “pushing” form
is used mostly for palliation (unfit for surgery). of invasion. Cytological atypia and mitoses
Prognostic factors: Depth of invasion in blad- are generally absent. It appears to have a more
der wall determines stage and prognosis and favourable prognosis than that of classic SCC.
some histological variants have a worse outlook Disease is often of advanced stage at presenta-
(small cell carcinoma, micropapillary carcinoma, tion and prognosis therefore poor (overall 5-year
sarcomatoid carcinoma, poorly differentiated survival 15%).
carcinoma,plasmacytoid carcinoma). Adenocarcinoma: Gland-forming carcinoma
Lymphovascular invasion is a controversial prog- of urinary bladder not associated with urothelial
nostic factor and is used for management deci- or squamous carcinoma components. It is a rare
sions in some centres. Associated urothelial CIS primary bladder neoplasm (<2% of bladder can-
and/or tumour multifocality carry a higher risk of cers) associated with bladder exstrophy, chronic
separate new occurrences. Lymph node and dis- irritation, diverticula, and nonfunctioning blad-
tant metastasis carry a poor prognosis. Overall der. The more common metastatic adenocarcino-
prognosis depends largely on stage, with a 70% mas, especially of colorectal origin, need to be
5-year survival rate for stages pTa and pT1 and ruled out before making a diagnosis of primary
50% for pT2b. Within the pT1 group, grade III adenocarcinoma. Based on the morphology they
decreases the 5-year survival to 60%. are classified as adenocarcinoma NOS, enteric,
Squamous cell carcinoma (SCC): Accounts mucinous and mixed forms and as either urachal
for less than 5% of bladder tumours in the or non-urachal in type. Urachal carcinoma is usu-
UK. Chronic irritation from stones, long-term ally mucinous. It is important to differentiate ura-
indwelling catheters, diverticula, chronic urinary chal adenocarcinoma from non-urachal
infections, prolonged cyclophosphamide treat- adenocarcinoma of the bladder, as they may
ment, and, in particular schistosomiasis, predis- require different treatments. Urachal carcinoma
pose, hence a much higher incidence of bladder often responds favourably to a partial cystectomy
squamous cell carcinoma in countries where the with en bloc resection of the urachus and umbili-
latter is endemic, e.g., Egypt. The major differ- cus. In contrast, non-urachal primary adenocarci-
ential diagnosis for SCC is UC with extensive noma of the bladder responds poorly to partial
squamous differentiation, which is a relatively cystectomy. Although it is not difficult to distin-
common form of divergent differentiation in guish urachal from non-urachal adenocarcinoma
in cystectomy specimens, it is challenging to dif- tation can exacerbate the condition. CIS may be
ferentiate them on small biopsy specimens. invisible to the endoscopist and necessitate ran-
Immunohistochemistry is of limited value as dom biopsies to make the diagnosis. Distinction
both urachal and non-urachal adenocarcinomas from interstitial cystitis may require multiple
are commonly positive for CK7, CK20, and biopsies as the surface can be extensively
CDX2 and lack nuclear positivity for β-catenin. denuded. In the presence of an overt tumour, it is
It has a poor prognosis (5-year survival rate var- important to sample abnormal mucosa (red, vel-
ies from 18% to 47%) due to advanced stage at vety) distant from the lesion to look for in situ
presentation. malignancy. Sampling normal looking mucosa
Clear cell carcinoma is characterised by tubu- adjacent to tumour is not advised due to the
locystic, papillary or diffuse growth patterns. potential risk of tumour reimplantation. Deep
Hobnail-like cells are common. While some biopsies (including muscularis propria) are
cases may be confused with nephrogenic ade- essential to provide important staging informa-
noma, the degree of nuclear pleomorphism and tion in invasive tumours.
hyperchromasia should allow the diagnosis. It is
characteristically positive for PAX8, HNFB1,
CA-125 and p53. 30.5.2 Resection Specimens
Other cancers: Spindle cell carcinoma, malig-
nant melanoma, leukaemia/malignant lym- Obviously there are important surgical differ-
phoma, leiomyosarcoma, rhabdomyosarcoma, ences between the sexes. Radical surgery for
choriocarcinoma, yolk sac tumour, and metasta- bladder cancer in the male comprises cystoprosta-
ses (direct spread—prostate, cervix, uterus, rec- tectomy, with urethrectomy if there is prostatic
tum; distant spread—breast, malignant urethra involvement, and in the female an anterior
melanoma, lung, stomach). exenteration (bladder, uterus and adnexae—see
Chap. 35). With surgical and anaesthetic advances,
operative mortality from radical cystectomy has
30.5 Surgical Pathology fallen from 20% to <1%.
Specimens: Clinical Aspects In the male, the bladder is approached through
a midline lower abdominal incision. The urachus
30.5.1 Biopsy Specimens and vasa deferentia are identified and ligated. A
pelvic lymphadenectomy is performed and the
Rigid or flexible cystoscopy allows direct visual- ureters identified and divided close to the bladder.
ization of macroscopic bladder pathology for Ureteric margins are ideally submitted separately
evaluation and biopsy of small lesions using from the main resection specimen for pathologi-
either “cold” cup forceps or a small diathermy cal assessment. The bladder, prostate, and seminal
loop. The latter may cause significant heat arte- vesicles are separated from the rectum and the
fact, reducing the value of histological assess- puboprostatic ligaments divided. The urethral
ment. Rigid cystoscopy employs a larger lumen, sphincter is then divided unless a urethrectomy is
allowing superior visualization (better optics and being considered. Robot-assisted radical cystec-
water flow), greater versatility in the passage of tomy (RARC) is used in many centres now. In
accessory instruments, and easier manipulation. appropriately selected patients RARC may be
It also provides suitable access for transurethral associated with significantly fewer total compli-
resection of superficial bladder tumours with dia- cations with less blood loss, shorter length of hos-
thermy (TURBT). Flexible cystoscopy is more pital stay, lower blood transfusion rate, more
comfortable for the patient, may be easier to pass, lymph node yield and fewer positive lymph nodes.
and allows a range of angles of visualization RARC appears to be a safe, feasible and mini-
within the bladder. Cystoscopy should be avoided mally invasive alternative to its open counterpart
during active urinary tract infection as instrumen- when performed by experienced surgeons.
30 Bladder 331
Simple cystectomy is quite a rare operation, resection of bladder tumours is not yet common
typically performed for benign conditions such as place. En-bloc resection is one of the ways to
interstitial cystitis or neurogenic bladder compli- provide better pathological evaluation for Ta and
cated by chronic infection. It involves bladder T1 tumours and thought to reduce recurrence rate
removal with maintenance of the urethra in women in non-muscle invasive bladder cancer.
or the prostate and seminal vesicles in men.
The need for an alternative urinary drainage
system following cystectomy has raised difficul- 30.6 Surgical Pathology
ties of acceptance for many patients. However, Specimens: Laboratory
new developments in surgical techniques includ- Protocols
ing RARC mean several options are now
available: 30.6.1 Biopsy Specimens
1. Urinary diversion and intestinal conduit for- Tiny pieces of tissue (several mm) retrieved using
mation; an isolated segment of small or large either “cold” cup forceps or a small diathermy
intestine (usually ileum) is anastomosed to loop are counted, measured, processed intact, and
both ureters and a stoma formed on the ante- examined histologically through three levels.
rior abdominal wall. Drainage is continuous TURBT specimens contain larger fragments,
into a worn device. possibly recognizable as papillary tumour
2. Continent cutaneous diversion (e.g., Indiana grossly. There is no evidence concerning sam-
pouch, which uses the ileocecal valve as a pling policies of large TURBTs for the detection
continence mechanism); requires intermittent of invasion. Small resections should be embed-
self-catheterization. ded in total. With larger specimens, the first 20 g
3. Continent orthotopic reservoir; a “neoblad-
should be processed plus at least 2 g for every
der” is formed from an ileal or ileocolonic additional 5 g of tumour. Further tissue should
segment and sutured directly onto the urethra; always be submitted if no muscularis propria
usually confined to men but also possible in (detrusor muscle) is identified which may require
women with an intact urethra. processing of the entire specimen. In particular, if
4. Ureterosigmoidostomy (sigma rectum pouch); the initial sections show invasion into the lamina
the ureters are anastomosed directly onto a propria (pT1), complete embedding of the
detubularized segment of sigmoid colon still remaining specimen may reveal muscle invasion,
in continuity, i.e., remains in contact with fae- leading to clinically important upstaging to pT2.
ces. This avoids the need for a stoma or self- Occasionally, levels in selected blocks will clar-
catheterization but results in the frequent ify stage. A separate biopsy may be sent from the
passage of liquid faeces. base of the lesion (including muscle) to assess
5. Rarely, cutaneous ureterostomy. invasion of deep tissues. Random biopsies from
red areas or from cystoscopically normal urothe-
Long-term complications following these pro- lium may be sent to determine whether dysplasia
cedures include stenosis, adenomatous polyps, or CIS are present. Complete submission of all
and tumour formation (usually adenocarcinoma). tissue to rule out pT1/pT2 disease is recom-
These may necessitate subsequent resection. mended if high-grade (WHO III).
Partial cystectomy is infrequently performed,
but may be indicated for a solitary urothelial car-
cinoma at the bladder dome or for tumour arising 30.6.2 Resection Specimens
in a urachal remnant or diverticulum. Excision of
a benign bladder diverticulum (diverticulectomy) Specimen:
may be performed intravesically, extravesically, Most bladder resections are for biopsy-proven
or, if small, transurethrally. Transurethral en bloc malignant tumours: cystourethrectomy, cysto-
be sampled to detect CIS. If no separate ure-

teric resection margins are received, the ure-
teric margins of the cystectomy specimen
should be examined histologically.
3.
• Place a probe in the bladder via the urethra
4. and open the specimen anteriorly (through the
3. prostate if present) with a sagittal cut using a
1. 1. knife or scissors, trying if possible to avoid
cutting into any localized tumour. Keep the
posterior aspect of the specimen intact to
maintain orientation. In exenteration speci-
mens, some prefer to bisect in the coronal
plane into anterior and posterior halves. Some
2.
pathologists prefer to inflate the bladder with
2.
10% buffered formalin and allow fixation
1. prior to opening. Others like to divide the
specimen into anterior and posterior halves.
Blocks • If there is an obvious tumour, paint the nearest
1. Urethral and ureteric limits
2. Prostate
deep perivesical soft tissue margin; if no
3. Bladder away from tumor tumour is grossly obvious (e.g., following pre-
4. Tumour with adjacent mucosa, operative treatment), paint all peripheral soft
underlying wall and perivesical
fat tissue margins, using different coloured inks
for orientation. Paint the prostate, if present.
Fig. 30.3 Blocking a cystoprostatectomy specimen for • Measurements:
bladder cancer (Reproduced, with permission, from Allen
–– Dimensions (cm) of bladder and, if present,
and Cameron (2013))
prostate, seminal vesicles, female pelvic
organs
prostatectomy (including seminal vesicles), cys- –– Lengths (cm) of ureters (limits may be sub-
toprostatourethrectomy, anterior exenteration mitted separately) and urethra, if attached
(including uterus and adnexae), simple cystec- –– Tumour
tomy, partial cystectomy, diverticulectomy and –– Dimensions (cm)
transurethral en bloc resection of bladder –– Distances to urethral and ureteric margins
tumours. (cm)
Initial procedure (Fig. 30.3): • Photograph.
• Fix by immersion in 10% formalin for at least
• Orientate the specimen with the help, if pres- 24–36 h preferably pinned out or using a wick
ent, of attached pelvic organs (uterus and sem- to fully expose the mucosal surface.
inal vesicles are posterior to the bladder) or • Locate the ureteric orifices at the trigone and
the peritoneal reflection, which descends fur- open the ureters along their full length with
ther on the posterior bladder wall than small scissors.
anteriorly. • Make 3–5-mm parallel, transverse sections
• Locate both ureters in the lateral perivesical through the tumour to demonstrate its deepest
fat (may be marked with sutures). The ureteric point of invasion and its relationship to the
margins are usually sent as separate speci- ureters, prostate, or any other adjacent struc-
mens and are usually not orientated. There is tures. In exenterations specimens transverse
no need to sample the ureteric margins of the incisions may be made through the posterior
bladder specimen unless a length of ureter is wall of the bladder in continuity with the ante-
received attached to the bladder, which should rior half of the uterus and cervix to demonstrate
30 Bladder 333
the macroscopic extent of the tumour. This –– Single/multifocal

can also be achieved with sagittal sections, –– Appearance (papillary/sessile/ulcerated/
which may allow for better anatomical dem- mucoid/keratotic)
onstration of any involvement. –– Edge (circumscribed/irregular)
• Look for and measure lymph nodes in peri- • Mucosa
vesical fat (usually none found). –– Red, velvety CIS away from tumour
• If not involved by the bladder tumour, serially • Wall
section the prostate perpendicular to the ure- –– Tumour confined to lamina propria, into
thra looking for occult primary tumour. muscle wall or through wall into perivesi-
• If not involved by the bladder tumour, process cal fat
female pelvic organs. • Other
• Photograph suitable slices. –– Fistula, diverticulum, stones, urachal
• Partial cystectomies are processed in a similar remnant.
manner, although orientation may be more dif-
ficult (or impossible). The mucosal edges Blocks for histology (Fig. 30.3):
should be treated as surgical margins, i.e., inked
and measurements given from tumour (cm). • Transverse sections the urethral and ureteric
• Diverticulectomy specimens are open in con- limits.
tinuity with the bladder lumen and usually do • If bilateral ureteric limits are submitted sepa-
not require incision prior to dissection. rately, measure the two lengths and sample the
• Transurethral en bloc resection of bladder proximal surgical margin of each (if orien-
tumours is not yet common practise, but the tated by the surgeon), then serially section the
specimen should be orientated and the mar- remainder and process separately.
gins inked to assess completeness of • Sample at least four blocks of tumour to demon-
excision. strate depth of invasion, distance to perivesical
• If a tumour is identified as arising from the soft tissue margins, and relationship to adjacent
urachal tract (usually in a partial cystectomy mucosa, ureters, prostate, or other organs.
specimen comprising dome of bladder, ura- • Sample any suspicious background mucosa or
chal tract and umbilicus), the bladder portion take at least two random mucosal sections.
is processed as before, soft tissue margins sur- • If tumour is not seen grossly, sample and care-
rounding the urachal tract are painted and the fully label all bladder mucosal surfaces includ-
tract serially sectioned transversely up to the ing the trigone, dome, lateral, anterior and
umbilicus. posterior walls. Correlate with the clinical and
• Conduits, augmentation cystoplasty, and neo- radiological findings before blocking if
bladder specimens containing tumours are possible.
processed as before, opening along the urethra • Sample any suspicious ureteric mucosa or
and ureters if possible, painting the nearest submit random ureteric transverse sections.
deep soft tissue margin, and noting the rela- • If not suspicious of harbouring malignancy on
tionship of the tumour to the enteric, bladder, serial sectioning, 3–4 blocks from each pros-
or ureteric mucosa. It may be best to serially tatic lobe and urethra in cystoprostatectomy
section the tumour perpendicular to lines of specimens should be sampled to assess for
anastomoses. involvement by urothelial carcinoma or CIS
and incidental prostate adenocarcinoma. If
Description: suspicious, multiple site orientated blocks are
taken to include the prostatic capsule and rel-
• Tumour evant surgical margins.
–– Site (trigone, lateral walls, dome, neck, • Sample the seminal vesicles and vasa
ureteric orifices) deferentia.
• Sample any attached female pelvic organs. pT2b Invasion of deep muscle (outer half)
• Count and sample all lymph nodes identified. pT3 Invasion of perivesical fat
• In a partial cystectomy, it is important to take a. Microscopically
perpendicular blocks of tumour that include b. Macroscopically
the nearest lateral mucosal margins. pT4 Tumour invades any of the following;
• In diverticulectomy specimens, sections of prostatic stroma, seminal vesicles, uterus,
vagina, pelvic wall, abdominal wall
tumour to include the deepest point of inva-
pT4a Tumour invades prostatic stroma, seminal
sion and the excision margins should be taken. vesicles, uterus or vagina
Flat mucosa should also be sampled to look pT4b Tumour invades pelvic wall or abdominal
for CIS. Muscularis propria (detrusor muscle) wall
may be absent in the attenuated wall and this
can affect staging.
• A tumour arising in the urachus should be • Lymphovascular invasion—present/not
sampled as before, but also to include blocks present
of the soft tissue margins surrounding the ura- • Regional lymph nodes—number involved,
chus and the skin margin surrounding the size of largest deposit if involved and the
umbilicus. presence or absence of extranodal extension.
• Conduits, augmentation cystoplasty, and neo- Regional nodes are the pelvic nodes below the
bladder specimens containing tumour should bifurcation of the common iliac arteries.
be sampled as before, also taking tumour
blocks to demonstrate the relationship with pN0 No lymph node metastasis
enteric/urothelial mucosa and anastomotic pN1 Single regional lymph node metastasis in the
true pelvis (hypogastric, obturator, external
lines. iliac, or presacral lymph node)
pN2 Multiple regional lymph node metastasis in the
Histopathology report: true pelvis (hypogastric, obturator, external
iliac, or presacral lymph node metastasis)
• Tumour type—Urothelial/squamous/adeno- pN3 Lymph node metastasis to the common iliac
lymph node(s).
carcinoma/other
• Tumour with divergent differentiation - pres-
ent/absent—micropapillary, plasmacytoid/dif- • Excision margins
fuse, sarcomatoid, nested, lymphoepithelial, • Distances (mm) to the ureteric, urethral, and
small cell carcinoma nearest perivesical soft tissue margins.
• Tumour growth pattern—Papillary/invasive/ • Presence/absence of dysplasia/CIS at ureteric/
flat in situ urethral limits
• Tumour differentiation—Use WHO grades I– • Cystoprostatectomy: Presence or absence of
III (1973), low-grade/high-grade (WHO 2004, prostatic adenocarcinoma, and, if so, extent,
WHO 2016) based on cytological atypia grade, stage, and margin status
• Tumour edge—pushing/infiltrative/lymphoid • Other pathology: Adenocarcinoma of prostate
response. (use protocol for carcinoma of prostate), uro-
• Extent of local tumour spread: TNM 8 for thelial (transitional cell) carcinoma involving
bladder carcinoma. urethra, prostatic ducts and acini ± stromal
invasion (use protocol for carcinoma of ure-
pTis Flat carcinoma in situ: “Flat tumour” thra), urothelial dysplasia/CIS, inflammation/
pTa Papillary non-invasive regenerative changes, therapy-related changes,
pT1 Invasion of subepithelial connective tissue
cystitis cystica glandularis, keratinizing squa-
pT2a Invasion of superficial muscle (inner half)
mous metaplasia, intestinal metaplasia.
30 Bladder 335
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Prostate
31
31.1 Anatomy in resection specimens the interpretation of cap-

sular penetration by carcinoma and capsular inci-
The normal prostate weighs 20 g by early adult- sion during surgery. Adipose tissue is occasionally
hood and is best thought of as having an inverted found just inside the prostatic capsule.
pyramid shape, with anterior, posterior, and lat- The prostate is composed of branching tubu-
eral surfaces, a narrow apex anteroinferiorly, and loalveolar glands lined by cuboidal or columnar
a broad base superiorly which lies against the epithelium and invested and surrounded by fibro-
bladder neck. It is related anteriorly to the sym- muscular stroma which is continuous with the
physis pubis, laterally to the anterior fibres of the prostatic capsule. The urethra transverses the full
levator ani muscle, and posteriorly to the seminal diameter of the prostate in a curved fashion,
vesicles and rectum, separated from the latter by entering at the centre of the prostate base and
Denonvillier’s fascia. The prostate is surrounded exiting just anterior to the apex. Prostatic ducts
by an ill-defined fibrous capsule which blends empty into the prostatic urethra. The ejaculatory
with the pelvic fascia. There is little consensus ducts, formed at the juncture of the vasa deferen-
about the presence of a true capsule and this cap- tia and seminal vesicle, also secrete into the pros-
sule is best appreciated posteriorly and postero- tatic urethra.
laterally as a more fibrous layer between the The glandular prostatic tissue has been divided
prostatic stroma and extraprostatic fat. Two neu- into four distinct zones, characterised by differ-
rovascular bundles are located posterolaterally to ing embryological origin, location, and patholo-
the gland. Numerous neurovascular bundles are gies (Fig. 31.1a). The anterior fibromuscular
found within this connective tissue. At the apex, stroma, composed mainly of fibromuscular tissue
skeletal muscle fibres of the urethral sphincter are with very few glands, merges with the bladder
admixed with occasional benign prostatic glands neck superiorly and the external sphincter at the
and, at the base, fibres from the bladder detrusor apex inferiorly. The preprostatic zone surrounds
muscle blend imperceptibly with the prostate the urethra proximal to the ejaculatory ducts and
capsule. At these points, the boundaries of the comprises the periurethral ducts and the larger
organ are particularly obscure, rendering difficult transition zone. This region commonly gives rise
to benign prostatic hypertrophy and approxi-
mately 25% of adenocarcinomas. The central
D.M. O’Rourke (*) • D.C. Allen zone, surrounding the ejaculatory ducts, is felt to
Histopathology Laboratory, Belfast City Hospital, differ embryologically from the remainder of the
Belfast Health and Social Care Trust, Belfast, UK gland and is least commonly affected by patho-
e-mail: declan.orourke@belfasttrust.hscni.net;
derek.allen@belfasttrust.hscni.net logical abnormality. Glands in the central zone

Fig. 31.1 (a) Prostatic a

zones (lateral view); (b)
prostatic lobes (anterior
view) (Reproduced, with
Bladder Transition Anterior
and Cameron (2013))
Central Urethra
Peripheral
Seminal
vesicle
b Superior
Right lobe Left lobe

Urethra
Inferior
may show complex papillary infoldings and a Lymphovascular drainage:

cribriform architecture on histology. Lack of Lymphatic drainage from the prostate is to the
cytological atypia distinguishes them from pros- obturator, hypogastric, and external iliac nodes,
tatic intraepithelial neoplasia (PIN). The periph- i.e., pelvic nodes below the bifurcation of the
eral zone occupies approximately 70% of the common iliac arteries (see Fig. 30.2 in Chap. 30).
normal prostate in a horseshoe shape around the The seminal vesicles are paired, convoluted
posterior and lateral aspects of the organ. Glands glands measuring approximately 5 cm in length
are normally small and simple, but this zone is and lying on the posterior wall of the prostate.
the main site of origin for prostatic adenocarcino- Their function is to add a significant volume of
mas (70%). alkaline secretion to the ejaculate, which pro-
To simplify the concept of zones, the prostate motes sperm motility and survival. Cowper’s
may be considered to have significantly differing (bulbourethral) glands are paired, pea-sized,
inner (transition zone) and outer (peripheral and tubular glands found periurethrally immediately
central zones) regions. distal to the prostate.
Clinically the prostate gland is often described
as having right and left lateral lobes, a central sul-
cus, and a middle lobe. These do not equate to 31.2 Clinical Presentation
any anatomically defined structures but rather
relate to palpable masses on rectal examination, Benign prostatic enlargement, usually affecting
usually enlargement of the transitional zone lat- the periurethral glands, causes urinary tract
erally and periurethral glands centrally. obstructive symptoms of delayed start to micturi-
For the purposes of TNM staging, the prostate tion (hesitancy), decreased force of urination,
gland is simply divided into right and left lobes intermittency of the urinary stream and post-
(Fig. 31.1b). micturition dribbling. Secondary changes in
31 Prostate 339
bladder compliance later lead to irritative symp- 31.3 Clinical Investigations

toms of frequency (increase in daily episodes of
micturition), urgency (sudden, strong desire to • Serum prostate specific antigen (PSA)—a
micturate), and nocturia (nocturnal frequency), highly organ-specific biochemical marker
the latter being the most common presenting used as a diagnostic tool in those suspected
complaint. Patients may also present in acute uri- as having prostatic cancer clinically and to
nary retention. These symptoms are often referred screen for prostatic cancer in asymptomatic
as LUTS (lower urinary tract symptoms) but do men. The upper limit of normal for PSA is
not point specifically to a definitive diagnosis. 4 ng/mL. With a PSA level of 4–10 ng/mL,
Digital rectal examination (DRE) usually reveals the likelihood of prostate cancer is about
a rubbery, smoothly enlarged prostate, although 25%; with a level above 10 ng/mL, the like-
there is poor correlation between symptoms and lihood is over 50%. Some advocate age-
gland size. Alternatively, an enlarged asymptom- related PSA cut-offs which are more specific.
atic benign prostate gland may be detected inci- To increase the specificity of the PSA assay
dentally on performing DRE to investigate lower for cancer, adjuvant tests (PSA velocity and
gastrointestinal symptoms or on screening for free PSA) have been recommended. The
prostate cancer. This is a very common finding in velocity of PSA level increase and the per-
men over age 50 years and per se is not a reason centage of free PSA can be helpful to differ-
to precipitate further urological investigation. entiate mildly elevated PSA levels due to
In contrast, carcinoma of the prostate, usually cancer from those due to benign prostatic
involving the periphery of the gland, rarely hyperplasia. A rise by more than 0.75 ng/mL
causes urinary symptoms and is often clinically per year shows a 90% specificity of cancer.
silent. Indeed, presentation with obstructive uri- Free PSA is calculated as a percentage of
nary symptoms implies advanced disease. total PSA and the lower the percentage of
Patients present most commonly with advanced free PSA (<15%), the higher the likelihood
metastatic disease in lymph nodes or bone. Early of cancer. Free PSA is most useful in men
cancer may be picked up by DRE, which fre- with persistently elevated PSA levels who
quently reveals a firm, indurated mass. This may previously underwent a biopsy with negative
be performed as part of a routine physical exami- findings. As the percentage of free PSA
nation, to investigate urinary, gastrointestinal, or declines, the probability that a cancer is
generalized symptoms or as part of a screening present increases. Conversely, a higher per-
procedure along with serum prostatic specific centage of free PSA indicates a lower prob-
antigen (PSA) (see Clinical Investigations). DRE ability of cancer. This information is more
alone is of limited accuracy and cannot reliably useful in men with very large glands (PSA
differentiate malignancy from prostatic stones density) or in those who have had a negative
and granulomas. Early-stage, commonly low- biopsy result. Several studies have shown
grade prostatic carcinoma may be detected inci- that with a PSA cut-off of 4.0 ng/mL, clini-
dentally in transurethral resection specimens cally insignificant cancers are detected in
from men with concomitant benign hyperplasia. less than 20% of men, but nearly 50% of all
Acute or chronic inflammation of the prostate the cancers detected because of an elevated
(prostatitis) usually associated with bacterial PSA level are localised, and these patients
infection may cause perineal pain, which can be are candidates for potentially curative ther-
referred to the back, inguinal region, or testes. It apy. Following prostatectomy, PSA should
is frequently associated with irritative urinary fall to undetectable levels. Persistent or sub-
symptoms of frequency and dysuria. DRE may sequent elevation provides a sensitive indi-
reveal a tender, fluctuant, or boggy prostate but is cator of residual or recurrent disease. PSA
often extremely uncomfortable for the patient. doubling time is a better predictor of time to
clinical recurrence than preoperative PSA, 31.4 Pathological Conditions

stage, and pathological Gleason score. A
PSA doubling time of 6 months or less after 31.4.1 Non-neoplastic Conditions
surgery most likely indicates metastatic
disease. Benign nodular hyperplasia (BNH): An
• Transrectal ultrasound (TRUS) and biopsy— extremely common androgen-dependent disor-
US is more sensitive and accurate than DRE der (castration is protective) caused by hor-
and may detect prostate cancer as peripheral monal imbalance affecting the stromal-epithelial
hypoechoic regions. However, many prostate relationship. No other clear risk factors apart
cancers are not detected on US appearances, from aging have been identified. Benign pros-
and most hypoechoic lesions are not cancer tatic hypertrophy (BPH) is variably defined by
(may represent PIN, benign hyperplasia, the presence of urinary obstructive symptoms,
atrophy, infarction, or infection). TRUS is, macroscopic prostate enlargement, or histologi-
therefore, mainly used to guide needle biopsy cal hyperplasia. The average weight of the pros-
sampling for definitive diagnosis after an tate with histologically confirmed BPH is 33 g
abnormal DRE or elevated serum PSA. As but weights of over 800 g have been recorded.
regards staging, locally extensive disease Incidence increases with age (approximately
will be easily detected but not unexpectedly 50% in the fifth decade and 75% in the eighth
US will understage microscopic capsular decade). BPH first develops in the transition and
penetration. TRUS biopsies can be taken to periurethral (preprostatic) zones, giving rise to
monitor progression following non-surgical enlargement of the clinical lateral and middle
treatment. lobes respectively. Grossly the appearances are
• CT Scan—CT scan can be used to evaluate those of multiple, variably-sized, grey to yellow
extension into the bladder and lymph nodes to central nodules, compressing the urethra and the
help stage prostate cancer or to consider peripheral zone. Histology shows hyperplasia of
lymph node sampling prior to treatment. It is both prostatic glandular and stromal elements
more often used when MRI is (benign prostatic hypertrophy is pathologically
contraindicated. incorrect). This can adopt various forms, some
• MRI—to determine pre-treatment tumour reminiscent of benign breast disease such as
stage by assessing capsular penetration and fibroadenoma—like hyperplasia or sclerosing
regional lymph node metastases (by size), adenosis. Pure stromal nodules composed
although both are of limited sensitivity and almost entirely of smooth muscle may also be
specificity. The combination of T2-weighted seen. Treatment may be initially medical in the
images with diffusion-weighted imaging form of alpha1-adrenergic blockers, which ease
improves the detection of large and poorly dif- obstruction by relaxing prostatic smooth muscle
ferentiated tumours and extracapsular exten- or androgen suppression. 5a–reductase inhibi-
sion, with high negative predictive values in tors (5ARIs) block the enzyme 5a–reductase
low-risk men. It is also superior to bone scans that catalyses the conversion of testosterone into
but impractical for routine use and more use- the more potent androgen dihydrotestosterone
ful to determine the aetiology of questionable and are used to reduce prostatic volume in
lesions found on bone scans. Neither CT scan- symptomatic benign prostatic hyperplasia. They
ning nor MRI can be used to determine if may also have a role in terms of chemopreven-
lymph nodes are reactive or contain tumour. tion, as they appear to reduce the risk of prostate
• Radiolabelled isotope bone scan—investiga- cancer development. Patients suffering serious
tion of choice to detect distant skeletal complications of BPH such as recurrent urinary
metastases. retention or infections, renal insufficiency, or
• PET scan—studies so far have been disap- bladder stones are not suitable for medical ther-
pointing for prostate cancer detection. apy and should be offered surgery. Similarly,
31 Prostate 341
patients whose quality of life is significantly Abscess: Most commonly seen with bladder
affected by their urinary symptoms are appro- outlet obstruction as a complication of urinary
priate surgical candidates. Transurethral resec- tract infection or, less often, following biopsy.
tion of prostate (TURP) has been the gold DRE and TRUS are diagnostic. Treatment is
standard for surgical treatment of BPH for many transurethral drainage and antimicrobial therapy.
years against which new treatments are com- Infarction: Often found in prostates with sig-
pared. High-volume disease is best treated by nificant BNH. Histology shows coagulative
enucleation of the entire gland using a retropu- necrosis of glands and stroma often with promi-
bic or suprapubic approach (open prostatec- nent surrounding squamous metaplasia, not to be
tomy). Newer, less invasive and less morbid, confused with squamous cell carcinoma (excep-
alternatives to TURP include the following: tionally rare in prostate).
Granulomatous prostatitis: Seen following
• Transurethral microwave therapy (TUMT)— BCG therapy for bladder cancer (look for subure-
generates heat causing cell death in the pros- thral distribution of granulomas), with prostatic
tate, leading to prostatic volume reduction involvement in systemic mycobacterial or fungal
• Transurethral needle ablation of the prostate infection (in an immunocompromised host), and
(TUNA) in association with eosinophilia and possibly sys-
• High-intensity ultrasonographic energy ther- temic vasculitis (allergic granulomatous prostati-
apy (HIFU)—currently in the clinical trial tis). Non-specific granulomatous prostatitis, due
stage to an immune response to extravasated prostatic
• Prostatic stents—flexible devices that expand secretions, is the most commonly diagnosed non-
when put in place to improve the flow of urine infectious granulomatous prostatitis and clini-
past the prostate cally can closely mimic prostate cancer (abnormal
• Implanted devices to relieve prostatic DRE and elevated PSA).
obstruction Postoperative necrobiotic granuloma: May be
• Prostate artery embolisation—performed by identified years following TURP and has a char-
radiologists but still in the early stages of acteristic histological appearance of central fibri-
development and usage. noid necrosis with palisading histiocytes.
Adenosis (atypical adenomatous hyperpla-
Prostatitis: Acute bacterial prostatitis is sia): Small- to medium-sized acinar prolifera-
associated with urinary tract infection (UTI) tion, which does not fulfil the cytological criteria
and responds to the same antimicrobial therapy of carcinoma. There is little evidence to suggest
so is rarely seen in surgical pathology practice. that adenosis represents a preneoplastic entity. It
Chronic bacterial prostatitis is characterized is seen as a prostate cancer mimic in needle
by recurrent UTIs caused by the same patho- biopsy or TURP. The lesion is comprised of a
gen and is less responsive to medical treat- well-circumscribed proliferation of small- to
ment. Large infected prostatic stones medium-sized glands in the transition zone, usu-
predispose and resection by TURP may be ally mixed with hyperplastic nodules. There is
attempted, providing surgical material. On his- sometimes a dilated centrally located gland.
tological examination, reactive glandular Basal cell markers frequently show a
atypia may mimic carcinoma. The presence of discontinuous basal cell layer and AMACR is
inflammatory cells and glandular atrophy, often focally positive.
obvious on low power, should prevent misdiag- Miscellaneous: Malakoplakia, stones, pseudo-
nosis. Often in prostatic tissue showing chronic sarcomatous fibromyxoid tumour (inflammatory
inflammation, no organisms are cultured (non- myofibroblastic tumours), postoperative spindle
bacterial prostatitis), hence it is better to report cell nodule (following TURP), although all more
the histology as chronic inflammation rather commonly seen in the bladder, may be found in
than chronic prostatitis. the prostate.
31.4.2 Neoplastic Conditions HGPIN does not elevate the serum PSA. A pre-
served or discontinuous basal cell layer may be
Benign tumours: Extremely rare, e.g., leiomy- readily identified on H&E or with basal cell spe-
oma, cystadenoma. cific immunohistochemistry (p63/34βE12/CK5–
Malignant tumours: Prostate cancer is the sec- 6). AMACR stains acinar cells and may be useful
ond most common cancer (13%) in the UK with in the distinction from benign glands. Detection
around 46,700 new cases annually. One in eight in TURP chippings necessitates processing all of
men will be diagnosed with prostate cancer dur- the tissue. Management is dependent on the
ing their lifetime and over half of prostate cancer extent of HGPIN and re-biopsy considered in
cases in the UK each year are diagnosed in males association with serum PSA and other clinical
over 70. Prostate cancer is most common in features. For cases with one or two cores of
Black males, then White males and least com- HGPIN on needle biopsy it is recommended that
mon in Asian males. Prostate cancer is the second men do not have a routine repeat needle biopsy
most common cause of cancer death in males within the first year after diagnosis, in the absence
after lung cancer in the UK. There are many fac- of other clinical indicators of cancer. In cases
tors, including age, genetics, and exposure to risk with HGPIN and adjacent small atypical glands,
factors (ionising radiation) but not clearly linked where the differential diagnosis of the small
to any preventable risk factors. glands is adjacent cancer or outpouchings off the
Prostatic intraepithelial neoplasia (PIN) repre- HGPIN (PINATYP), the risk of cancer is equiva-
sents a precancerous condition confined to pros- lent to that after a diagnosis of ‘atypical glands
tatic ducts and acini. suspicious for carcinoma’; all these men need re-
Prostatic intraepithelial neoplasia (PIN): biopsy within 3–6 months of their PINATYP
Non-invasive neoplastic transformation of the diagnosis.
lining epithelium of existing prostatic ducts and Intraductal carcinoma of the prostate gland
acini characterized by marked nuclear atypia. (IDC-P): Luminal proliferation of atypical pros-
Although low-grade PIN is recognized, the diag- tatic cells within pre-existing ducts. The associa-
nostic reproducibility is very low and signifi- tion of IDC-P with aggressive high-volume,
cance is uncertain. High-grade PIN (HGPIN) is high-grade and high-stage prostate cancer has
present as an isolated diagnosis in 4–16% of been confirmed by several studies. Greater stan-
needle core biopsies and <5% of transurethral dardisation of the diagnosis and reporting of
resection specimens but present in over 80% of IDC-P is required, and necessitates use of basal
prostate glands containing adenocarcinoma. cell layer immunohistochemistry. The published
There are four major architectural patterns; criterion for IDC-P refers to ‘nuclear area >6×
tufted, micropapillary, cribriform, and flat. There normal’ or ‘nuclear diameter >2.5× normal’. It
is scant data on the long-term risk of prostate car- must be clearly indicated when the reported
cinoma (PCa) after a diagnosis of HGPIN but tumour grade or extent has been significantly
some older studies have shown the risk to be influenced by the presence of IDC-P. It is not
around 21% rising to 60% if present in more than given a Gleason score. IDC-P in prostate biopsies
three cores. In recent years, a decline in the pre- has significant clinical implications with radical
dictive value of PCa after an initial diagnosis of therapy for pure IDC-P recommended by most.
HGPIN has been observed. A major factor con- Reporting of IDC-P in patients with low-grade
tributing to this decreased incidence of PCa after invasive cancer is also significant as this would
a diagnosis of HGPIN on needle biopsy is related exclude the option of active surveillance.
to increased needle biopsy core sampling, which Prostatic adenocarcinoma: Of acinar/proxi-
detects many associated cancers on initial biopsy. mal duct origin accounts for over 95% of primary
However, there is epidemiological, morphologi- prostate cancers. 70% arise in the peripheral zone
cal, and molecular evidence that HGPIN is a pre- and most cause few symptoms initially, often pre-
cursor lesion to some carcinomas of the prostate. senting insidiously in elderly men. DRE or serum
31 Prostate 343
PSA may raise suspicion and diagnosis is usually grading system (Grade groups 1–5). It is now
confirmed on TRUS-guided needle biopsy. recommended that tertiary grades are not used in
Alternatively, cancer may be an incidental find- prostate core biopsies and TURPs (most predom-
ing in prostatic chippings following TURP. This inant grade and the highest grade should be
may either have arisen in the transition zone recorded in the Gleason score). Tertiary scores
(20% of cancers—often low volume and grade) should be reported in radical prostatectomies
or represent spread from a larger, often high- with some recommending only when <5%, oth-
grade peripheral tumour. Prostatic carcinoma can erwise should be in combined score (controver-
be difficult to identify grossly, even on radical sial and not agreed by ISUP). Some studies are
resection specimens. It may be visible as solid, also indicating the use of percentage of pattern
firm, pale yellow foci found peripherally in the three and four in selection of Gleason score seven
gland. cases more suitable for active surveillance (<10%
Histology shows small acini arranged in a pattern four).
variety of architectural patterns (acinar, papillary, Following a diagnosis of carcinoma on needle
cribriform, comedo, solid) with cytological biopsy or TURP chippings, the Gleason score, clin-
atypia, at least focal nucleolar prominence and icopathological stage (any evidence of extracapsu-
absence of surrounding basal cell layer on high lar spread) and tumour volume (or length/
power (negative for basal cell specific immuno- proportion of needle core/tissue involved), together
histochemistry (p63/34βE12/CK5–6)). Ancillary with the patient’s age, serum PSA, general health
features which may be seen in carcinoma include and personal preferences, will direct treatment. The
perineural invasion and intraluminal wispy secre- presence of a few prostatic glands in skeletal mus-
tions or crystalloids. These features should help cle does not necessarily imply extraprostatic exten-
distinguish carcinoma from PIN and from the sion (EPE), as toward the apex benign glands are
many benign small acinar proliferations which, intimately associated with skeletal muscle. Growth
especially on needle biopsy, may cause misdiag- within adipose tissue generally indicates EPE as
nosis (e.g. atypical adenomatous hyperplasia, intraprostatic fat is rare. Some studies suggest
basal cell hyperplasia, post-atrophic hyperplasia, strong correlation of perineural invasion (PNI) in a
sclerosing adenosis). Insufficient diagnostic cri- biopsy with EPE on radical prostatectomy (RP).
teria for malignancy present in a limited focus of PNI present in fat is considered as EPE.
acinar proliferation on needle core biopsy may Lymphovascular invasion (LVI) is an independent
lead to a report of “suspicious but not diagnostic predictor of disease progression. Seminal vesicle
of malignancy”, usually prompting re-biopsy. (SV) invasion is defined as carcinoma involving
The Gleason grading system for prostate can- the muscular wall. A portion of SV may be intra-
cer is the predominant grading system used and is prostatic (viewed as ejaculatory duct involvement).
based on glandular architecture. The primary and Only extraprostatic SV involvement should be
secondary patterns, that is, the most prevalent considered. In needle biopsy, do not over interpret
and the second most prevalent patterns are added ejaculatory duct involvement as SV invasion. The
to obtain a Gleason score. Gleason grading has SV has a thick muscular wall, which is not present
undergone considerable revision and the in the ejaculatory duct.
International Society of Urological Pathology At present, the various treatment options for
(ISUP) has produced two guidance documents each stage of prostate cancer are:
(2005 and 2014). The 2005 guidance changed
two main areas, the patterns in Gleason three and Localized prostate cancer
four and tertiary scores in core biopsies. The
more recent ISUP 2014 guidance made recom- • Active surveillance
mendations about grading cribriform glands, glo- • Watchful waiting
meruloid glands, mucinous adenocarcinomas and • Radical prostatectomy
intraductal carcinoma, and the use of a new group • Radical radiotherapy
• Brachytherapy also be appropriate in metastatic disease, to treat

• Novel therapies (HIFU, cryoablation) bone pain. Disease which is locally advanced or
metastatic at diagnosis is best treated with
Locally advanced (non-metastatic) prostate androgen-deprivation therapy, which blocks the
cancer (including high-risk localised) hormonal drive that sustains the tumour cells.
This was achieved previously with surgical cas-
• Radical radiotherapy tration (bilateral orchidectomy) but now much
• Radical prostatectomy more commonly with “medical castration” using
• Hormonal therapy luteinizing hormone-releasing hormone (LHRH)
• Watchful waiting agonists with anti-androgen cover. Cytotoxic
chemotherapy is reserved for androgen-resistant
Metastatic prostate cancer prostate cancer, i.e., when symptoms recur fol-
lowing endocrine therapy. Recently, a multicen-
• Hormonal therapy tre study (STAMPEDE) has reported clinically
• Cytotoxic chemotherapy and statistically significant improvement in sur-
• Palliation vival in men with metastatic prostate cancer at
diagnosis when hormone therapy was combined
The most appropriate treatment for prostate with docetaxel compared to hormone therapy
cancer is highly controversial and truly valid ana- alone.
lytical comparisons between options are lacking. Prognosis: Five year survival from prostate
Active surveillance, or watchful waiting, is a cancer in the UK has risen from 30% in the 1970s
programme of regular examinations used to mon- to 80% in the late 2000s. This improvement has
itor symptoms. Watchful waiting is typically rec- been attributed to the increase in serum PSA test-
ommended or considered in patients of advanced ing. There may also have been real improvements
age or those who have significant comorbid con- in survival due to better treatment of prostate can-
ditions with a life expectancy of less than cer after early diagnosis, and also for more
10 years. For patients with a longer life expec- advanced disease. The main factors affecting sur-
tancy, active surveillance is considered in those vival are stage, Gleason score after biopsy and
with T1/2a disease, a Gleason score of <7, and a serum PSA level. Men with localised disease of
serum PSA level below 10 ng/mL (NICE guide- low or intermediate-grade have about 98% 5 year
lines). They have serum PSA measurement every survival after diagnosis. In those with high-grade
3 months and repeat biopsy at two yearly inter- cancers, this drops to 67%. Men with locally
vals or if the serum PSA velocity rises. Biopsy advanced prostate cancer after radiotherapy and
findings are the most important factor in deciding hormone therapy have between 70 and 80% 5 year
whether to pursue treatment. Radical prostatec- survival after diagnosis. About 30% of men with
tomy should be reserved for men with curable advanced prostate cancer will live for at least
disease (i.e., organ-confined), who will live long 5 years after diagnosis. Since many men with
enough to benefit from the cure (at least 10 years). prostate cancer are older and the disease can be
Clinicopathological index of suspicion of EPE is very slow to develop, it may not affect their life
the main determinant in a man of suitable age and span. After treatment for localised prostate cancer
health contraindicating this major operation. The men are then monitored long term. This is to iden-
ablative therapies of HIFU and cryotherapy tify local recurrence of disease at a stage when fur-
remain experimental as first-line modalities. ther treatment might be effective, and also to
Positive surgical margins following radical identify and treat complications of treatment.
prostatectomy, although not shown to decrease Overall 10-year survival is approximately 50%
long-term disease control or survival, are usually with a 90% 10-year survival in organ-confined
treated with pelvic radiotherapy, as is EPE (stage (pT1/pT2) disease, 60% in pT3/pT4 disease, and
pT3) in the resection. Palliative radiotherapy may only 10% in disease with bone metastases.
31 Prostate 345
Variants of prostatic adenocarcinoma are: the transition zone as some of these have central
Mucinous adenocarcinoma (exclude colorectal or gland tumours. If random, the biopsies should be
bladder primary), adenocarcinoma with signet carefully labelled to direct further biopsies in the
ring cell–like features (exclude gastric, bladder, or event of a non-diagnostic histology report.
colorectal primary), prostatic duct (ductal) adeno-
carcinoma (syn. endometrioid carcinoma), basal 31.5.1.2 Transperineal Template
carcinoma, small cell carcinoma and prostate car- Prostate Biopsy
cinomas with neuroendocrine differentiation (car- Transperineal template-guided saturation pros-
cinoid, mixed, large cell neuroendocrine). tate biopsy, typically providing 20–40 cores
Other carcinomas: Rarely, urothelial carci- (more recent studies suggest only 24 cores are
noma arises in periurethral prostatic ducts, squa- required for template biopsies, but others suggest
mous/adenosquamous carcinoma, sarcomatoid a larger number), is being used as a method to
carcinoma. detect prostate cancer in various situations: high-
Other cancers: Prostate is a common site for risk men with multiple negative extended pros-
rhabdomyosarcoma (usually embryonal) in chil- tate biopsies, including men with an elevated
dren; leiomyosarcoma is the commonest pros- serum PSA that is persistently rising, men with
tatic sarcoma in adults; stromal tumours of atypia on previous prostate biopsy, or men with
uncertain malignant potential, stromal sarcomas, findings of HGPIN on previous biopsy.
inflammatory myofibroblastic tumour (rare), Advantages over TRUS are better access to the
other rare mesenchymal tumours (chondrosar- anterior part of the prostate gland, less infectious
coma, angiosarcoma, synovial sarcoma), leukae- complications, and improved sampling by using
mia/malignant lymphoma (especially secondary a biopsy template with coordinates. Disadvantages
involvement by chronic lymphocytic leukaemia); are that it takes longer and need general
metastases (direct spread—bladder, colorectum; anaesthesia.
distant spread—lung, malignant melanoma).
31.5.1.3 M RI/TRUS Image Fusion
Targeted Biopsy
31.5 Surgical Pathology This is now being used in some centres to enhance
Specimens: Clinical Aspects the precision of targeting suspicious lesions, but
it is not universally available as it requires devel-
31.5.1 Biopsy Specimens opment in a collaborative environment with urol-
ogists, radiologists, pathologists and considerable
31.5.1.1 Transrectal Ultrasound technical support.
(TRUS) Biopsy
Prostate biopsy is indicated for histological diag- 31.5.1.4 Transurethral Resection
nosis of prostate cancer and evaluation of a mass of the Prostate (TURP)
lesion or hypoechoic area. It is performed for ele- Transurethral Resection of Prostate (TURP) is the
vated serum PSA level with or without an abnor- surgical treatment of choice for benign prostatic
mal DRE and via TRUS guidance using an hyperplasia (BPH). Monopolar TURP is the ‘gold
18-gauge needle as an outpatient procedure. standard’ for the surgical management of bladder
However, it may also be performed perineally or outlet obstruction (BOO). Bipolar TURP is also
transurethrally. There are differing biopsy schemes used. Indications include moderate to severe
from sextant biopsy (six cores each lobe from LUTS (not controlled with medical therapy or
base, mid-gland, and apex), extended biopsy because of patient choice), acute urinary retention,
which increases the cancer detection rate and satu- recurrent UTI, recurrent haematuria and obstruc-
ration biopsy (≥20 cores), which is considered in tive uropathy. This procedure is performed via a
men with persistently elevated serum PSA and cystoscope using a diathermy loop for resection
prior negative biopsies. This includes biopsies of (resectoscope) and bladder irrigation to wash out
the resected chippings. Haemostasis is controlled is suited to patients with bladder pathology
using electrocoagulation. The bladder neck may (diverticulum, stone) or a large “middle” lobe of
be incised following resection. Rarely dilutional prostate protruding into the bladder.
hyponatraemia due to absorption of bladder irriga-
tion fluid causes confusion, nausea, and vomiting 31.5.2.2 Radical Prostatectomy
post-operatively (transurethral resection syn- The three aims of this operation are cancer con-
drome). The TURP specimen consists of pale rub- trol, preservation of urinary continence and of
bery fragments called prostate chippings and sexual function. Robotic-assisted radical prosta-
includes the transition zone and areas around the tectomy (RRP) is now widely established,
proximal prostatic urethra. Laser prostate surgery although laparoscopic and open approaches are
is used in some centres and has the significant still in use. The operation may be combined with
advantage of enabling any size of prostate to be a bilateral pelvic lymph node dissection depend-
operated upon. ing on the disease risk stratification. It is a suit-
able treatment option for low-risk localised
prostate cancer (particularly if active surveillance
31.5.2 Resection Specimens is declined), intermediate and high-risk disease if
there is a realistic chance of cure.
31.5.2.1 Open (Simple) Surgery should be deferred for at least 6 weeks
Prostatectomy following needle biopsy and 12 weeks following
This operation is reserved for BPH where the TURP to allow any inflammatory adhesions or
prostate weighs over 50–75 g. It is also appropri- haematoma to resolve. As opposed to laparos-
ate where there is concomitant benign bladder copy the movements of the robotic system are
disease requiring treatment such as a symptom- intuitive, have increased precision by filtering
atic diverticulum or a large stone. Potential risks hand tremors and mimic human wrist movement.
are urinary incontinence, erectile dysfunction, Advantages of RRP include shorter stays, less
retrograde ejaculation, and urinary tract infec- blood loss and postoperative pain, and earlier
tion. The advantages over TURP are complete recovery. Current disadvantages of RRP include
removal of the gland (therefore no recurrence) a lack of availability at all centres, bulkiness of
and no risk of dilutional hyponatraemia. However, equipment, limited availability of instrumenta-
there is an increased risk of intraoperative haem- tion and excess cost which is likely to diminish
orrhage and a longer hospital stay. Previous pros- over time.
tatectomy, prior pelvic surgery, and prostate This major operation has surprisingly low
cancer are contraindications to the operation. post-operative mortality (0.2%) or serious mor-
There are two possible approaches to enucle- bidity. Urinary incontinence, possibly due to dis-
ation of the prostate gland via open prostatectomy: tal urethral sphincter dysfunction or bladder neck
contracture, is often the most troublesome side
• Retropubic—through a direct incision of the effect. Loss of erectile function is now less of a
anterior prostatic capsule. problem, thanks to modern surgical alternatives.
• Suprapubic—through an extraperitoneal inci-
sion of the lower anterior bladder wall.
The retropubic approach allows excellent Specimens: Laboratory
exposure and visualisation of the prostate and Protocols
prostatic fossa during enucleation ensuring com-
plete removal and control of bleeding sites. There 31.6.1 Biopsy Specimens
is minimal trauma to the bladder and precise tran-
section of the urethra distally to preserve urinary TRUS needle biopsy/transperineal template pros-
continence. The suprapubic approach allows tate biopsy: The wide-bore needle cores (18
direct access to the bladder and bladder neck and gauge) are counted and measured (in mm), sub-
31 Prostate 347
mitted separately if labelled accordingly and pro- 31.6.2 Resection Specimens

cessed for initial histological examination
through three levels. Careful handling is neces- Specimen:
sary to avoid crush artefact. Separation and flat-
tening to optimise embedding of the cores is • Most prostate resections are retropubic radical
important and can be achieved by sandwiching prostatectomy specimens (including seminal
the cores between foam pads or nylon meshes. vesicles) for biopsy-proven adenocarcinoma.
Cores may be painted with alcian blue so that • Occasionally simple (retropubic/suprapubic)
they are easily visible on facing the paraffin prostatectomy is performed for BPH.
block. Most of the tissue in the block from super-
ficial to deep should be included in sections with This is an enucleation procedure and usually
at least three levels taken. When sectioning, inter- produces an intact nodule with a wedge-shaped
vening ribbons of unstained sections are usefully cut in one side. Orientation is not usually possi-
kept for ancillary immunohistochemical studies ble, although two distinct lobes should be identi-
if required. fiable. The specimen is weighed and measured
TURP chippings: Weighed and sampled (three dimensions, mm), then serially sectioned
according to laboratory protocol. 14% of speci- at 3–4 mm intervals. These sections are carefully
mens will reveal an unexpected carcinoma (stage examined for areas suspicious of carcinoma (yel-
T1—insufficient tissue to assess the highest pT low, firm) and six to eight cassettes of tissue pro-
category), and the more tissue processed, the cessed, labelling the two lobes separately.
higher the detection rate. The availability of
serum PSA now means that the chances of miss- 31.6.2.1 Radical Prostatectomy
ing a clinically significant carcinoma are reduced. Initial procedure:
The potential management of such a detected
cancer should ideally be known to avoid a sub- • Orientate the specimen using the seminal ves-
stantial waste of resource. If aggressive treatment icles (situated on the posterior aspect) and by
(radical prostatectomy) might be considered, for placing a probe (sometimes a catheter is in
example in a younger patient, all tissue is embed- situ) into the prostatic urethra. This will allow
ded and examined histologically, as is also the identification of the flat base superiorly (prox-
case if there is any clinical suspicion of imal, bladder, base margin) and the more coni-
malignancy. cal apex anteroinferiorly (distal, urethral,
Otherwise, initial sampling of TURP speci- apical margin).
mens is recommended along the following Royal • Weigh the entire specimen (recommended
College of Pathologists guidelines: weighing the prostate after the seminal vesi-
For 12 g or less of tissue, all is processed; for cles have been removed—ISUP guidelines),
over 12 g, 12 g plus an extra 2 g for every 5 g of measure the prostate in three dimensions
tissue in excess of 12 g should be processed. This (mm) and give the lengths (cm) of the attached
will normally equate to approximately six to seminal vesicles and vasa deferentia. Dissect
eight cassettes for the average case. The sugges- off the seminal vesicles and vasa deferentia
tion of scrutinising chippings for suspicious (yel- and serially section these.
low or indurated) areas is felt to be impractical. • Paint the right, left, anterior, posterior, supe-
One level is examined from each block. If carci- rior, and inferior surfaces of the prostate using
noma (or HGPIN) is found, all tissue should be six different-coloured inks, including the soft
processed to give an accurate stage (T1a tumour tissue around the base of the seminal vesicles
in ≤5% of tissue resected; T1b tumour in >5% of but not the seminal vesicles themselves. Make
tissue resected). a note of any areas where the prostatic tissue
If there is a previous diagnosis of carcinoma has been disrupted by the surgical knife, as
of the prostate, only a small amount of tissue, say this may lead to a false positive surgical
6 g or four cassettes, need be embedded. margin.
• Fix the specimen by immersion in 10% forma- –– Multifocality

lin for at least 24–36 h. The prostate under- –– Appearance (soft/firm, pale/yellow/
goes rapid autolysis because of the presence granular)
of proteolytic enzymes. Therefore, radical –– Edge (circumscribed/irregular)
prostatectomy specimens should be immedi- –– Extension beyond capsule/into seminal
ately fixed in abundant 10% formalin (for at vesicles
least 24–36 h). Microwave-assisted technique • Non-neoplastic tissue
and formalin injection to facilitate fixing may –– Appearance (colour, consistency,
be used to shorten fixation time. nodularity)
• The proximal and distal margins are then
removed. The preferred method (the cone Blocks for histology (Fig. 31.2):
method with sagittal slicing) involves ampu-
tating the proximal and distal 5 mm of the • Sample proximal (base) and distal (apical)
prostate (corresponding to the bladder and margins as described.
urethral margins respectively) and serially • Sample the seminal vesicles at their bases
sectioning these at 3 mm intervals perpendicu- (junction with the prostate) and the vasa defer-
lar to the amputating cut (i.e. parallel to the entia at their limits. It is not necessary to sub-
urethra—Fig. 31.2). This technique allows a mit the entire seminal vesicle.
more accurate assessment of how close the • Each serial section is bisected into right and
tumour extends to these margins but, as only left halves (and if necessary into superior and
one section is examined for each 3 mm slice, inferior quadrants) to fit into routine cassettes
the entire margin will not have been sampled. and the entire gland processed for histological
• After removal of the margins, the prostate is examination, labelling each block carefully to
serially sectioned at 3–4 mm intervals in a aid microscopic interpretation.
coronal plane from anterior to posterior. Some • Alternatively, some pathologists prefer to par-
pathologists prefer to section the prostate in a tially sample the prostate initially,
horizontal plane. The slices are laid out concentrating on suspicious areas and random
sequentially and carefully examined, main- sections from the circumferential margin. If
taining orientation with the help of the partial sampling is used, this should be sys-
coloured inks. Malignancy is often not obvi- tematic to allow for assessment of orientation,
ous macroscopically but may appear as multi- volume, and multifocality and the specific
focal, peripheral, usually posterior, solid, grey sampling method should be documented.
to yellow nodules, contrasting with the cen- Complete embedding of the specimen is pre-
tral, spongy, non-neoplastic tissue. Asymmetry ferred as a high proportion of prostate cancers
between lobes may be another clue. are not visible grossly, partial sampling may
• Lymphadenectomy—Lymph nodes are identi- not be representative and surgical margin sta-
fied, counted and described as either normal tus is one of the tools used to audit the quality
or involved by tumour. However there is poor of surgery.
correlation between nodal size and metastatic • Whole mount sectioning may be available in
involvement by tumour. some centres, greatly facilitating histological
interpretation, but is usually reserved for
Description: teaching and research purposes. It is cumber-
some and requires more space filing and stor-
• Tumour age. Whole mounts blocks is up to the
–– Site (right/left, peripheral/central, anterior/ discretion of the individual pathologist.
posterior) • All pelvic lymph nodes (usually submitted
–– Size (mm) separately) should be sampled.
31 Prostate 349
Fig. 31.2 Blocking a 1

radical prostatectomy
specimen (Reproduced,
with permission, from 3
Allen and Cameron
(2013))
1
2
Blocks
1. Proximal (base) and distal (apex) margins
2. Base of seminal vesicles and vas limits
3. Prostate serial sections
4. Slices are bisected/quadranted to fit cassettes
(or whole mounted)
Histopathology report: 2005 guidance changed the scoring of Gleason

3 and 4 and the tertiary scores in core biopsies.
• Tumour type—acinar (proximal duct) adeno- The subsequent ISUP 2014 guidance made
carcinoma/other. recommendations about grading cribriform
• Tumour differentiation—use the Gleason glands, glomeruloid glands, mucinous adeno-
grading system. Each tumour is assigned two carcinomas and intraductal carcinoma. In rad-
grades, based on the most predominant of five ical prostatectomy, provide the Gleason score
different architectural patterns present, rang- (primary and secondary pattern) and sepa-
ing from grade 1 (well-differentiated) to grade rately mention the tertiary pattern. Also assign
5 (undifferentiated). The two grades are separate Gleason scores to dominant tumours
summed to give the Gleason score (maximum in radical prostatectomy. The 2014 ISUP
10). If only one grade is present, the grade is guidance advised using a new group grading
doubled to give the score e.g. 3 + 3 = 6. ISUP system (Grade groups 1–5).
• In radical prostatectomies there is a high pro- Note a positive surgical resection margin at a
portion of multifocal prostatic adenocarcino- point lacking extraprostatic tissue can be reported
mas and there are two methods of grading. as pT2+, i.e., extracapsular extension cannot be
One is to look at the totality of the different accurately assessed. The amount of EPE (focal
foci and assign a composite score by preva- versus extensive) has prognostic importance and
lence, and mentioning the tertiary score if that patients with focal EPE have a more favour-
present. The alternative method is to grade the able outcome. However definitions of focal EPE
dominant nodule, which is generally regarded vary between a few glands immediately exterior
as the tumour of highest stage. Although there to the prostate in 1–2 sections, depth of less than
is no clear evidence to suggest which is supe- one high-power field in 1–2 sections or EPE
rior, ISUP and RCPath recommend giving the reaching less than 0.75 mm outside the prostate.
Gleason score of the dominant nodule
• Tumour volume—the tumour is outlined • Lymphovascular invasion
microscopically on each glass slide and the –– Perineural and lymphovascular space
area involved measured (mm2). The areas for –– Present/not present
all sections are summated, and the overall –– Inside/outside capsule
tumour volume (mm3) is derived from multi- • Regional lymph nodes
plying by the average slice thickness (3–4 mm).
This may be expressed as a proportion of the Pelvic nodes below the bifurcation of the
total volume of the prostate, to give the percent- common iliac arteries. The diameter of the larg-
age gland involvement. However, although the est metastatic deposit appears to be more predic-
ISUP consensus meeting recommended that a tive of survival than the number of nodes
volume of tumour was given, there was no involved.
agreement on the methods used and the use of
maximum tumour diameter may be as good. pN0 No regional lymph node metastasis
• Tumour edge—pushing/infiltrative/lymphoid pN1 Metastasis in regional lymph node(s)
response.
• Extent of local tumour spread: TNM 8 for • Excision margins
prostate adenocarcinoma
Proximal (base), distal (apical), circumferen-
pT1 Clinically inapparent tumour not palpable tial margins involved/uninvolved.
or visible by imaging
Distances (in mm) to nearest margins. The
T1a Incidental finding in ≤5% of tissue resected
margin is positive if tumour cells touch the ink.
T1b Incidental finding in >5% of tissue resected
Report the extent of positive margin in mm and
T1c Identified by needle biopsy
the location. Some also report the Gleason score
pT2 Tumour palpable and confined within the
prostate at the involved margin. Extensive or multifocal
T2a Involves ≤ one half of one lobe positive margins demonstrate a higher risk of
T2b Involves > one half of one lobe but not both relapse and the recurrence risk appears to be sig-
lobes nificantly greater when the length of the involved
T2c Involves both lobes margin is ≥3 mm. The presence of prostate cap-
pT3 Tumour extends through the prostatic sule incisions noted macroscopically may be
capsule helpful for feedback to the surgeon in addition to
T3a Extracapsular extension (unilateral or margin status.
bilateral) including microscopic bladder
neck involvement
T3b Invades seminal vesicle(s) • Other pathology
pT4 Tumour is fixed or invades neighbouring
structures other than seminal vesicles: HGPIN (more for research reasons), inflamma-
external sphincter, rectum, levator muscles, tion (specify type), atypical adenomatous hyper-
and/or pelvic wall.
plasia (adenosis), nodular prostatic hyperplasia,
31 Prostate 351
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decade after the 2005 modified gleason grading sys-
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Male Genital Organs. Lyon: International Agency for
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Griffiths D, Humphrey PA, et al. International
Urethra
32
32.1 Anatomy The penile urethra measures 10–15 cm and is

surrounded by the corpus spongiosum through-
The urethra extends from the internal urethral out most of its length. It includes the bulbous ure-
orifice at the bladder neck to the external thra proximally and the pendulous urethra
meatus. In the male, it is approximately distally. Scattered mucus-secreting (Littre’s)
15–20 cm long and is divided into three sec- glands are present periurethrally. The distal por-
tions (Fig. 32.1). tion within the glans penis is dilated to form the
The prostatic urethra is 3–4 cm long, travers- fossa terminalis before narrowing at the external
ing the prostate in a curved manner. Throughout meatus.
its length, a midline ridge on the posterior wall The female urethra is approximately 4 cm
known as the urethral crest projects into the long and extends from the bladder neck to the
lumen causing it to appear crescentic on trans- external urethral meatus, embedded through-
verse section. The most prominent part of this out its length in the adventitial coat of the ante-
ridge, close to the mid-point, is called the veru- rior vaginal wall. Like the male counterpart it
montanum. Here lies the orifice of the prostatic has a posterior midline ridge, the urethral crest,
utricle, a short, blind-ended vestigial sac. The which gives a crescentic shape on sectioning,
openings of the ejaculatory ducts lie on either and periurethral mucus-secreting (Skene’s)
side of the verumontanum. Prostatic ducts empty glands.
into the urethral sinuses, gutters flanking the ure- The urethra is lined proximally by urothelium
thral crest. and distally by non-keratinizing stratified squa-
The membranous urethra extends from the mous epithelium, and, in males, the intervening
prostatic apex to the bulb of the penis and mea- membranous urethra (and part of the penile ure-
sures 1 cm approximately. Small bulbourethral or thra) by pseudostratified columnar epithelium.
Cowper’s glands lie on either side and secrete However, it should be noted that most urethral
into it. tissue submitted for pathological examination is
diseased or altered by instrumentation and hence
highly susceptible to metaplastic change.
The lymphatics of the proximal urethra drain
D.M. O’Rourke (*) • D.C. Allen to the external iliac, obturator, and hypogastric
Histopathology Laboratory, Belfast City Hospital, nodes (see Fig. 30.2 in Chap. 30), while the distal
Belfast Health and Social Care Trust, Belfast, UK urethra drains to the superficial and then deep
allen@belfasttrust.hscni.net inguinal nodes.


the urethra (Reproduced,
Allen and Cameron
(2013))
Bladder
Prostate
Prostatic
urethra
Penile urethra
Membranous
urethra
Glans penis
Urethral lesions may be asymptomatic or, if caus- • Urethroscopy and biopsy.

ing obstruction, can present with haematuria, uri- • Urethrography (micturating and retrograde)—
nary retention, or symptoms of infection. Urethral the best method for evaluation of urethral
stricture can mimic benign prostatic enlargement, strictures, diverticula and, less often,
presenting with obstructive symptoms in the neoplasms.
absence of haematuria. Urethral cancer tends to • CT/MRI—to determine tumour stage. There
invade locally and metastasize to adjacent soft is increasing evidence that MRI is superior to
tissues and, therefore, most of these tumours are CT in terms of staging accuracy. Imaging for
locally advanced at the time of diagnosis. Primary regional lymph node metastases should con-
urethral malignancy usually presents at a late centrate on inguinal and pelvic lymph nodes,
stage when arising in the proximal urethra. using either MRI or CT. CT should also
Urethral diverticula may cause irritative symp- include CT urography with an excretory
toms or dribbling. phase.
32 Urethra 355
• Positron emission tomography (PET) is gen- and, rarely, malignancy (most commonly adeno-
erally not indicated in patients with primary carcinoma). Diverticulectomy is the recom-
urethral cancer, but it may be useful for the mended treatment.
evaluation of suspected metastases to distant Urethral valves: Folds of mucosa that project
sites after local treatment, and, in assessing into the urethral lumen. They are rarely seen in
treatment for systemic disease after surgical pathology material unless they cause
chemotherapy. obstruction, when they may be associated with
bladder neck hypertrophy.
Urethral polyps: Prostatic urethral polyps
32.4 Pathological Conditions are small, papillary growths seen in the pros-
tatic urethra of adult males. They are usually
32.4.1 Non-neoplastic Conditions asymptomatic but may cause haematuria.
Histology shows a lining of benign prostatic
Urethritis: Usually a sexually transmitted infec- acinar epithelium. These polyps are often seen
tion due to Chlamydia trachomatis, Neisseria incidentally at cystourethroscopy and some-
gonorrhoea, or Gardnerella vaginalis. Usually times biopsied. Congenital urethral polyps,
symptomatic in females, but not in males, with seen in young males most commonly in the
urethral smear diagnostic. Occasionally seen in prostatic urethra, are rare growths lined by uro-
young males as part of Reiter’s syndrome (ure- thelium which can occasionally cause obstruc-
thritis, arthritis, and conjunctivitis). Rarely pro- tive symptoms.
vides surgical biopsy material. Miscellaneous: Inverted urothelial papilloma,
Polypoid urethritis: The urethral equivalent of villous adenoma, nephrogenic adenoma, malako-
polypoid cystitis. This is an oedematous, inflam- plakia, amyloidosis, and condylomata accumi-
matory growth which may be confused with a nata are infrequently encountered within the
papillary neoplasm. It is most commonly seen in urethra.
the prostatic urethra near the verumontanum. An
association with indwelling catheters has not
been shown. 32.4.2 Neoplastic Conditions
Caruncle: A polypoid, fleshy, and friable
lesion seen near the meatus exclusively in Classification of Neoplasms of the Urethra
women. Irritative urinary symptoms are com- Squamous cell carcinoma
mon. Histology reveals a hyperplastic urothelial Typical
lining with prominent stromal inflammation and Variant
vascularity. Scattered bizarre stromal cells may Verrucous carcinoma
cause diagnostic confusion with sarcoma. Basaloid squamous cell carcinoma
Benign stricture: May result from previous Sarcomatoid carcinoma
inflammation or trauma, e.g., catheterization, and Urothelial (transitional cell) neoplasia
can closely mimic malignancy, resulting in Benign
biopsy. Urothelial (transitional cell) papilloma
Diverticula: Usually seen in women and may Inverted urothelial (transitional cell) papilloma
be palpated through the vagina. Most are Papillary urothelial neoplasm of low malignant
acquired, following infection, obstruction, and potential
dilatation of a periurethral gland. Histology often Malignant
fails to reveal an epithelial lining. An infected Urothelial (transitional cell) carcinoma
diverticulum may be the source of recurrent uri- Adenocarcinoma
nary tract infections. Other possible complica- Non–clear cell
tions include stones, bladder outlet obstruction Mucinous
Signet-ring cell tures, chronic irritation, radiation therapy or

Adenocarcinoma not otherwise specified (NOS) radioactive seeds, and chronic urethritis. In
Clear cell female UC, urethral diverticula and recurrent
Tumours of mixed cell types urinary tract infections have been associated
Undifferentiated carcinoma with primary carcinoma. Human papilloma
Non-urethral carcinoma from adjacent anatomi- virus (HPV) has also been associated with some
cal site (direct extension) cases of urethral cancer. Clear cell adenocarci-
noma may also have a congenital origin. In
Benign tumours: The benign urothelial neo- women, squamous cell carcinoma is the most
plasms of papilloma and inverted papilloma share common subtype (75%) and usually in the ante-
the same morphological features as their bladder rior urethra (distal third). Urothelial (transi-
counterparts and rarely arise primarily in the ure- tional cell) carcinoma is next in frequency,
thra. Haematuria is the commonest symptom. followed by adenocarcinoma (10%–15% each).
Both should be managed by transurethral resec- Clear cell adenocarcinomas comprise a signifi-
tion alone. Leiomyomas and haemangiomas cant proportion of adenocarcinomas in women
occur rarely. but are quite rare in men. In males, most tumours
Malignant tumours: The urethra is much more involve the bulbomembranous urethra, followed
commonly involved secondarily by urothelial by penile urethra and prostatic urethra. Most
carcinoma of the bladder than by primary carci- (80%) carcinomas of the male urethra are squa-
noma. As with bladder cancer, secondary urethral mous cell carcinoma, followed by UC and the
involvement is more common in males with a latter are typically more proximally sited.
reported incidence of approximately 10–20%. The WHO classification of tumours of the
This may take the form of papillary urothelial urothelial tract (2016) reviewed the grading of
carcinoma, flat carcinoma in situ (which may urothelial neoplasms (see Chap. 30 for further
extend into periurethral ducts) or prostatic stro- detail). Grading of urothelial tumours is particu-
mal invasion. Distinction is important as the lat- larly important in non-invasive papillary neo-
ter has a worse prognosis. The same diagnostic plasms (over 95% of invasive tumours are
histological criteria apply as in the bladder. In high-grade). Non-invasive tumours can be
females, total urethrectomy is usually performed divided into two patterns, either papillary or flat.
as part of the cystectomy procedure but, in males, Multiple studies have been published comparing
urethrectomy is only performed when separate the 1973 WHO classification (largely restricted
biopsies show prostatic urethra involvement. to the UK and Europe) with the 2004 and now
Recurrence of urothelial carcinoma in the ure- 2016 classifications in terms of reproducibility
thral stump following a urethra-sparing cystec- and clinical impact. Advantages of WHO 2016
tomy may be treated by instillation of BCG include more uniform terminology and better
immunotherapy or, if there is stromal invasion, definitions for pre-neoplastic conditions and
transurethral resection or urethrectomy. tumour grades, and, elimination of ambiguous
Primary urethral carcinoma is more common diagnostic categories in the 1973 WHO system
in females than males and affects mainly those (grade 1–2, grade 2–3).
over 50 years of age. Although smoking and Adenocarcinoma is seen in association with
exposure to aromatic amines are associated with diverticula, prostatic adenocarcinoma, or in
urothelial carcinoma (UC) of the bladder, no women, arising in periurethral glands. The clear
such correlation has been established with ure- cell variant should be distinguished from nephro-
thral carcinoma. However, patients with a his- genic adenoma and spread of malignancy from
tory of bladder cancer are at an increased risk of the female genital tract or kidney.
urethral cancer. Various predisposing factors In males, primary urethral carcinoma is usu-
have been reported, including urethral stric- ally treated by surgical excision, the extent of
32 Urethra 357
which depends on the location and stage of the 32.5 Surgical Pathology
tumour. Endoscopic treatment is performed with Specimens: Clinical Aspects
either transurethral resection or transurethral
laser therapy for diagnostic and therapeutic pur- 32.5.1 Biopsy Specimens
poses. This technique tends to work for patients
with localized low-grade disease (superficial Urethroscopy may be undertaken in isolation or,
tumours), in whom the location allows adequate more commonly, in tandem with cystoscopy.
visualization and reduces the risk of iatrogenic Small urethral lesions are snared using “cold”
incontinence. Prior to any major surgery, the cup forceps or resected with a small diathermy
extent of local invasion must be accurately loop. Staging biopsies of the prostatic urethra are
assessed to ensure en bloc resection of all frequently undertaken at the time of cystoure-
involved structures. Therapeutic lymphadenec- throscopy for evaluation of bladder cancer.
tomy has been reported with success in anterior Follow-up after cystectomy may require biopsy
urethral lesions. Lymphadenopathy secondary to from the urethral stump in the event of positive
primary posterior urethral carcinomas is associ- urethral washings. A relevant history is important
ated with a poor prognosis. Radiotherapy has the for interpretation of urethral biopsies. A history
advantage of preserving the penis but has a higher of stones, recent procedures, infections or prior
rate of tumour recurrence and may result in ure- therapy (chemotherapy or radiation) can lead to
thral stricture. Primary urethral carcinoma in the reactive epithelial changes, potentially mimick-
female usually involves the proximal urethra and ing malignancy.
is locally advanced at presentation. Radiotherapy
has generally been reserved as an adjunct to
definitive surgery in more advanced disease. 32.5.2 Resection Specimens
There is limited information regarding the role of
chemotherapy in urethral cancer treatment but Urethrectomy is performed in one of three
combination chemotherapy with radiotherapy, or, situations:
neoadjuvant chemotherapy with radiotherapy
prior to surgery are other treatment options. • For bladder cancer in continuity with
Local excision is often adequate for distal ure- cystoprostatectomy.
thral carcinoma in the female. • For recurrence of bladder cancer in the ure-
Prognosis: Prognosis relates to anatomical thral stump (secondary urethrectomy).
location and pathological stage. Predictors of • For primary urethral carcinoma.
decreased survival in patients with primary ure-
thral carcinoma are: advanced age (>65 years), In women, up until recently, the urethra was
ethnicity, tumour stage, grade, nodal involvement routinely resected as part of a radical cystectomy
and metastasis, tumour size and proximal loca- procedure for bladder cancer. However, with
tion, extent of surgical treatment and treatment careful pre-operative evaluation, it is now some-
modality, and underlying histology. In men, over- times possible to preserve the urethra for ortho-
all 5-year survival rates are 60–70% for penile topic functional reconstruction of the urinary
urethral carcinomas and only 20% for membra- tract using a neobladder.
nous/prostatic urethral lesions. In men with bladder cancer, the standard sur-
Other cancers: Rare but include adenosqua- gical procedure is a radical cystoprostatectomy.
mous carcinoma, small cell carcinoma, malig- Carcinomatous involvement of the urethra (usu-
nant melanoma, lymphoma/leukaemia, ally prostatic) assessed on pre-operative biopsies
embryonal rhabdomyosarcoma (in children), is an indication for concomitant urethrectomy.
aggressive angiomyxoma (in women), and meta- This is performed in two stages. Prior to the
static carcinoma. cystoprostatectomy, the membranous urethra is
dissected from the urogenital diaphragm and lectively, the number of fragments counted, and
transected. This facilitates the subsequent peri- all tissue embedded if possible (up to ten cas-
neal dissection and preservation of the neurovas- settes). If the tumour is non-invasive by the initial
cular bundle. Cystoprostatectomy is completed sampling, additional submission of tissue (includ-
and then the remainder of the urethra is resected ing submitting all tissue) is necessary to diagnose
from a perineal approach, dividing it distally and or rule out the presence of invasion.
dissecting the bulbar urethra up to the urogenital
diaphragm.
Secondary urethrectomy is indicated if ure- 32.6.2 Resection Specimens
thral washings or biopsy following previous cys-
toprostatectomy for bladder cancer reveal Specimen:
recurrent tumour. This involves perineal dissec-
tion as described for primary urethrectomy but, • Most urethrectomy resection specimens are
because of scarring and proximity of small bowel for neoplasia as part of a cysto(prostato)ure-
to the urogenital diaphragm, it is a much more threctomy. Occasionally isolated urethrec-
difficult operation. Complete excision of the tomy is performed.
membranous urethra proximally is less certain,
but frozen section may offer reassurance that a Initial procedure:
negative margin has been attained.
The best treatment of primary urethral car- • The specimen may be in several tubular frag-
cinoma in the male is surgical excision. Distal ments labelled separately or with attached
tumours may be treated by transurethral resec- sutures to aid orientation. In the absence of
tion, local excision, partial or radical penec- such markers, definitive orientation may not
tomy depending on the extent of tumour be possible, although the distally resected ure-
infiltration. Carcinoma of the bulbomembra- thra may be identifiable, having a smaller
nous urethra usually requires radical cysto- diameter.
prostatectomy, pelvic lymphadenectomy, and • Weigh (g) and measure (cm) each fragment;
total penectomy. This procedure may be record the number of fragments.
extended to include in-continuity resection of • Paint the external circumferential radial mar-
the pubic rami and adjacent urogenital dia- gin comprising adventitial connective tissue.
phragm to improve the margin of resection. • Fix the specimen by immersion in 10% forma-
Primary prostatic urethral carcinoma may be lin for at least 24–36 h.
treated by transurethral resection if superficial • Remove the proximal and distal surgical
but otherwise requires cystoprostatectomy and resection limits (Fig. 32.2) by taking circum-
total urethrectomy. ferential transverse sections (rings) from the
ends of the appropriate fragments. If separate
fragments are not labelled, take sections from
32.6 Surgical Pathology both ends of all fragments for later possible
Specimens: Laboratory correlation with clinical information.
Protocols • After removal of the limits, the remaining ure-
thra is serially sectioned transversely through-
32.6.1 Biopsy Specimens out its length at 3 mm intervals, and the
sections laid out sequentially for examination
Tiny pieces of tissue (several mm) retrieved using and photography, if desired. Alternatively, if a
either “cold” cup forceps or a small diathermy grossly obvious tumour is identifiable on one
loop are counted, measured, processed intact, and luminal surface of the urethra, the specimen is
examined histologically through three levels. opened longitudinally with small scissors
Transurethral specimens should be weighed col- along the opposite surface taking care not to
32 Urethra 359

urethrectomy specimen.
Transverse section the
limits and the tumour at
3 mm intervals
(Reproduced, with
and Cameron (2013))
disturb the tumour. A combination of both margin to the tumour. Sample at least three
approaches often provides the best histological blocks of tumour (one section per cm), in the
material. Documentation of tumour in relation form of transverse or longitudinal sections or
to surrounding anatomical structures (such as both, to show the deepest point of circumfer-
corpus spongiosum, corpus cavernosum, pros- ential invasion and the relationship to the
tate, periurethral muscle, vagina, and bladder) painted circumferential margin and the adja-
is critical to proper staging. cent mucosa.
• Sample at least one random block of back-
Description: ground mucosa to look for carcinoma in situ.
• Count (usually submitted separately) and sub-
• Tumour mit one section from each grossly positive
–– Site (prostatic/membranous/bulbar/pendu- lymph node. All other lymph nodes should be
lous urethra, meatus, anterior/posterior) entirely submitted, as presence of nodal dis-
–– Length × width × depth (mm) ease may be used as an indication for adjuvant
–– Multifocality therapy.
–– Appearance (papillary/polypoid/verru-
cous/sessile/ulcerated/colour) Histopathology report:
–– Edge (circumscribed/irregular)
• Mucosa • Tumour type—squamous/urothelial/adeno-
–– Carcinoma in situ away from tumour may carcinoma (clear cell)/small cell/other
appear red and velvety • Tumour growth pattern—papillary/invasive/
• Wall flat in situ
–– Tumour confined to mucosa or infiltrative • Tumour differentiation—use WHO grades I–
–– Margins: longitudinal/radial—involved/ III (WHO 1973), low−/high-grade (WHO
not involved (mm) 2004/2016)
• Other • Tumour edge—pushing/infiltrative/lymphoid
–– Stricture, dilatation, diverticulum response
• Extent of local tumour spread: TNM 8 for ure-
Blocks for histology (Fig. 32.2): thral carcinoma and urothelial carcinoma of
the prostatic urethra
• Sample the proximal and distal limits of surgi-
cal resection as complete circumferential Urethra (male and female).
rings; more than one fragment may need to be
sampled. However, if the tumour is grossly in pTa Non-invasive papillary, polypoid, or verrucous
close proximity to the margin, a perpendicular carcinoma
section showing relationship to the ink may be pTis Carcinoma in situ
more appropriate. pT1 Invasion of subepithelial connective tissue
• The surrounding radial soft tissue margins pT2 Invasion of any of: corpus spongiosum,
should also be submitted, taking the closest prostate, periurethral muscle
pT3 Invasion of any of: corpus cavernosum, beyond Allen DC, Cameron RI. Histopathology specimens:
prostatic capsule, anterior vagina, bladder neck clinical, pathological and laboratory aspects. 2nd ed.
(extraprostatic extension) London: Springer; 2013.
Amin MB, Smith SC, Reuter VE, et al. Update for the
pT4 Invasion into other adjacent organs (invasion
practicing pathologist: the International Consultation
of the bladder)
on Urologic Disease-European Association of
Urology consultation on bladder cancer. Mod Pathol.
Urothelial carcinoma of prostatic urethra.
2015;28:612–30.
Amin MB, Trpkov K, Lopez-Beltran A, Grignon D. Best
pTis Carcinoma in situ, involvement of prostatic practices recommendations in the application of
pu urethra immunohistochemistry in bladder lesions: report
pTis Carcinoma in situ, involvement of prostatic from the International Society of Urologic Pathology
pd ducts consensus conference. Am J Surg Pathol. 2014;38:
pT1 Invasion of subepithelial connective tissue e20–34.
pT2 Invasion of any of: prostatic stroma, corpus Amin MB, Young RH. Primary carcinomas of the urethra.
spongiosum, periurethral muscle Semin Diag Pathol. 1997;14:147–60.
Bircan S, Candir O, Serel TA. Comparison of WHO 1973,
pT3 Invasion of any of: corpus cavernosum,
WHO/ISUP 1998, WHO 1999 grade and combined
beyond prostatic capsule, bladder neck
scoring systems in evaluation of bladder carcinoma.
(extraprostatic extension)
Urol Int. 2004;73:201–8.
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• Lymphovascular invasion—present/not molecular characterization of urothelial bladder carci-
present noma. Nature. 2014;507:315–22.
Cancer research UK. http://www.cancerresearchuk.org/
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health-professional/cancer-statistics/statistics-by-can-
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pN0 No regional lymph node metastasis Pathol. 2012;43:2097–108.
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Lebret T, Ribal MJ, Sherif AM, European Association
pN2 Metastasis in multiple regional nodes
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• Excision margins—distances (mm) to the
urothelial carcinoma. In: Eble JN, Sauter G, Epstein
nearest longitudinal and circumferential peri- JI, Sesterhenn IA, editors. Pathology and genetics of
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• Presence/absence of dysplasia/carcinoma in Lyon: IARC Press; 2004. World Health Organization
Classification of Tumours.
situ at longitudinal limits
McKenney JK, Amin MB, Epstein JI, Grignon DJ, Oliva
• Other pathology: keratinizing squamous E, Reuter VE, et al. Protocol for the examination
metaplasia, condyloma, squamous dysplasia, of specimens from patients with carcinoma of the
urothelial dysplasia/CIS, inflammation/regen- urethra. Arch Pathol Lab Med. 2010b;134:345–50.
McKenney JK, Amin MB, Epstein JI, Grignon DJ, Oliva
erative changes, therapy-related changes, ure-
E, Reuter VE, Srigley JR, Humphrey PA. Protocol
thritis cystic/glandularis, intestinal metaplasia, for the examination of specimens from patients with
diverticulum. carcinoma of the urethra. Arch Pathol Lab Med.
2010a;134:345–50.
Moch H, Humphrey PA, Ulbright TM, Reuter V. WHO
classification of tumours of the urinary system and
male genital organs. Lyon: International Agency for
Bibliography Research on Cancer; 2016.
Moore KL, Dalley AF, Agur AMR. Clinically oriented
Allen DC. Histopathology reporting. Guidelines for surgi- anatomy. 7th ed. Philadelphia: Wolters Kluwer/
cal cancer. 3rd ed. London: Springer; 2013. Lippincott Williams & Wilkins; 2014.
32 Urethra 361
Oliva E, Young RH. Clear cell adenocarcinoma of the Contribution%20Folders/WebContent/pdf/urethra-

urethra: a clinicopathologic analysis of 19 cases. Mod 13protocol-3210.pdf
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cap.org/ShowProperty?nodePath=/UCMCon/ html.
Testis, Epididymis, and Vas
33
33.1 Anatomy carries the seminal fluid from the testis to the
epididymis.
The testes are suspended in the scrotum by the The epididymis lies on the posterior surface of
spermatic cords, the left testis hangs somewhat the testis. It consists of a central portion or body,
lower (Fig. 33.1). The average size is from 4 to an upper enlarged extremity (the head), and a
5 cm in length, 2.5 cm in breadth, and 3 cm in the lower pointed end (the tail), which is continuous
antero-posterior diameter. Weight varies from with the ductus (vas) deferens. The head is inti-
10.5 to 14 g. Within the scrotum the testis is cov- mately connected with the upper end of the testis
ered on its anterior, medial, and lateral surfaces by means of the efferent ductules of the gland;
by tunica vaginalis, the remnant of a develop- the tail is connected with the lower end by cellu-
mental connection with the peritoneal cavity. lar tissue and a reflection of the tunica vaginalis.
Each testis is covered by a tough fibrous coat, the The epididymis is connected to the back of the
tunica albuginea. The substance of the testis is testis by a fold of the serous membrane. On the
subdivided by septa which run inwards from the upper extremity of the testis, just beneath the
tunica albuginea. The glandular structure consists head of the epididymis, is a minute oval, sessile
of numerous lobules (∼400) contained in one of body, the appendix of the testis (hydatid of
the intervals between the fibrous septa. They con- Morgagni). It is the remnant of the upper end of
sist of from one to four seminiferous tubules, the Müllerian duct. On the head of the epididy-
between which lie the interstitial or Leydig cells, mis is a second small stalked appendage (appen-
responsible for the production of testosterone. In dix epididymis) usually regarded as a detached
the apices of the lobules, the tubules become less efferent duct.
convoluted and unite together to form 20–30 The vas deferens consists of a muscular tube,
larger ducts (tubuli recti). The tubuli recti enter formed of three layers, which connects the tail of
the fibrous tissue of the mediastinum forming a the epididymis to the ejaculatory duct at the pros-
close network of anastomosing tubes (rete testis). tate. The vas passes up in the spermatic cord
The rete testis perforates the tunica albuginea and through the superficial inguinal ring, inguinal
canal, and deep ring to reach the posterior surface
of the bladder. At the ejaculatory duct it is joined
by the duct from the seminal vesicles. The vas is
D.M. O’Rourke (*) • D.C. Allen lined by a tall columnar epithelium.
Histopathology Laboratory, Belfast City Hospital, Lymphovascular drainage:
e-mail: declan.orourke@belfasttrust.hscni.net; derek. The lymphatic vessels of the testes form from
allen@belfasttrust.hscni.net four to eight collecting trunks which ascend with


the testis, epididymis, Spermatic cord
and spermatic cord
(Used with the
Control (UICC),
The original source for head
Appendix testis
Epididymis
body
Testis
tail
the spermatic veins in the spermatic cord. The

testicular lymphatics drain to the periaortic and
pericaval abdominal nodes. Intrapelvic (common
and external iliacs) and inguinal nodes are con-
sidered regional after scrotal or inguinal surgery
(Fig. 33.2).
A painless testicular mass is pathognomonic of a

primary testicular tumour, occurring in only a
minority of patients. The majority present with dif-
fuse testicular pain, swelling, hardness, or some
combination of these findings. Since infectious
epididymitis or orchitis is more common than
tumour, a trial of antibiotic therapy is often under-
Inguinal/intrapelvic taken. If testicular discomfort does not abate or
only after scrotal
or inguinal findings do not revert to normal within 2–4 weeks,
surgery
a testicular ultrasound examination is indicated.
Delays in patients seeking definitive treatment
after recognition of the initial lesion are frequent
(3–6 months) and correlate with development of
Fig. 33.2 Testis—regional lymph nodes. The regional metastasis. Trauma to the testis can sometimes
lymph nodes are the abdominal para-aortic (periaortic), lead to confusion in diagnosis. Endocrine manifes-
preaortic, interaortocaval, precaval, paracaval, retrocaval, tations such as gynaecomastia (2–4% of patients)
and retroaortic nodes. Nodes along the spermatic vein should
be considered regional. Laterality does not affect the N clas-
are sometimes seen in association with sex cord-
sification. The intrapelvic nodes and the inguinal nodes are stromal tumours and choriocarcinoma.
considered regional after scrotal or inguinal surgery (Used Exophthalmos has also been reported with chorio-
with the permission of the Union for International Cancer carcinoma (due to high HCG levels). Men with
Control (UICC), Geneva, Switzerland. The original source
for this material is from Wittekind et al. (2005))
disseminated disease occasionally present with
33 Testis, Epididymis, and Vas 365
back or flank pain, cough, haemoptysis, or dys- ing concentrations of alpha-fetoprotein (AFP),
pnoea (5–10%), but most are asymptomatic. human chorionic gonadotrophin (HCG), or both,
Undescended testicular tumours present with without radiographic or clinical findings, imply
a suprapubic lump, urinary or bowel complaints. active disease and are sufficient reason to initiate
Development of torsion in an undescended testi- treatment if likely causes of false positive results
cle can sometimes be the warning sign of testicu- have been ruled out.
lar tumour. Rarely testicular tumours may present Alpha-fetoprotein: Production is restricted to
with metastasis and symptoms of an abdominal non-seminomatous germ cell tumours, specifi-
lump, chronic cough, or as a “neck node with cally embryonal carcinoma and yolk sac tumours
unknown primary.” (serum half-life is 4–5 days).
HCG: May be observed in both seminomas
and non-seminomatous tumours (serum half-life
33.3 Clinical Investigations is 18–36 h).
Lactate dehydrogenase (LDH): Less specific
33.3.1 Radiological Evaluation but has independent prognostic value in patients
with advanced germ cell tumours. It is not a sen-
• Scrotal ultrasound—an important non-sitive or specific indicator of disease recurrence
invasive diagnostic tool. Seminomas appear as and therefore not a useful marker for post-
well-defined hypoechoic lesions without cys- treatment surveillance.
tic areas, while non-seminomatous germ cell
tumours (NSGCTs) are typically hyperechoic
lesions. 33.4 Pathological Conditions
• Chest X ray—preliminary evaluation of pul-
monary involvement. 33.4.1 Testis
• CT scan—imaging of the abdomen and pelvis
is required. CT or MRI of the brain is per- 33.4.1.1 Non-neoplastic Conditions
formed in patients with neurologic signs or Pyogenic epididymo-orchitis: Usually due to
symptoms, and MRI is also useful in the eval- E. coli and presents as a painful mass, often clini-
uation of bone metastasis. cally confused with testicular cancer. Generally
• Both PET (Positron Emission Tomography) differentiated by ultrasound scanning. Histology
and PET-CT provide superior staging accuracy resembles a granulomatous orchitis. This can be
to conventional imaging. GCTs generally are complicated by venous thrombosis and septic
characterised by high FDG uptake. Pure semi- testicular infarct.
nomas accumulate even more FDG than non- Granulomatous orchitis: Aetiology and
seminomatous lesions. PET, however, is not as pathogenesis unknown, but there is speculation
reliable in mature teratoma differentiated. that the disease may have an autoimmune
• FNAC of testicular tumours is generally not basis. It presents in middle-aged males with
recommended as it is useful only if it is posi- painful unilateral testicular mass and associ-
tive, and there is a theoretical risk of needle ated fever. Some cases are associated with
tract recurrence. FNAC is valuable in the urinary tract infections, history of prostatec-
investigation of possible metastatic lesions tomy, inguinal hernia repair, and trauma.
(seminoma versus non-seminoma). Grossly the testis is enlarged and the cut sur-
face is vaguely nodular, yellowish, and hard.
Testicular involvement may be total or partial.
33.3.2 Serum Tumour Markers Histologically there is a mixed chronic inflam-
matory infiltrate, fibroblasts, and scattered
Serum tumour marker concentrations are deter- multinucleated giant cells.
mined before, during, and after treatment and Other infections: Syphilis, tuberculosis,
throughout long-term follow-up. Increased or ris- mumps.
Cysts: Epidermoid cysts (see below under ter- cerebral metastases) and levels of serum tumour
atoma), cysts of tunica albuginea, rete testis, markers.
efferent ducts, or testicular parenchyma have Germ cell neoplasia in situ (GCNIS): GCNIS
been described. Cystic dysplasia is a rare con- (WHO 2016) is proposed as an alternative, his-
genital disorder with numerous irregular cystic torically referred to by a number of names, and
spaces in the mediastinum testis. officially regarded as intratubular germ cell neo-
Hydrocele: Accumulation of clear serous fluid plasia, unclassified type (IGCNU) in the 2004
between the visceral and parietal layers of the WHO system. GCNIS is seen in 90–100% of tes-
tunica vaginalis, associated with trauma and epi- tes adjacent to germ cell tumours. There is an
didymitis. Histology shows loose to fibrotic con- association with infertility (0.4–1.0%), cryptor-
nective tissue with a mesothelial lining. chidism (2–8% of patients), and in the contralat-
Rare lesions: Include malakoplakia, inflam-
matory pseudotumour, splenogonadal fusion,
Table 33.1 World Health Organization (WHO 2016)
juvenile xanthogranuloma (a histiocytic disorder histological classification of testicular germ cell tumours
of infants and young children).
Germ cell tumours derived from germ cell
neoplasia in situ
33.4.1.2 Neoplastic Conditions Non-invasive germ cell neoplasia
Annually there are around 2400 new cases of tes- Germ cell neoplasia in situ
ticular cancer in the UK (2014) with testicular Specific forms of intratubular germ cell neoplasia in
cancer accounting for less than 1% of all new situ
cases in the UK. Approximately half (47%) of Tumours of a single histological type
testicular cancer cases in the UK each year are Seminoma
diagnosed in males aged under 35. Since the late Seminoma with syncytiotrophoblastic giant cells
1970s, testicular cancer incidence rates in males Non-seminomatous Germ cell tumours
have increased by 90% in Great Britain and by Embryonal carcinoma
10% in the last decade. Huge advances have been Yolk sac tumour, post-pubertal
made in treatment since the 1970s, and the prog- Trophoblastic tumours
nosis of testicular cancer is very favourable. They Choriocarcinoma
are highly curable even if advanced; 95% are Non-choriocarcinomatous Trophoblastic tumours
germ cell tumours and 5% sex cord-stromal Placental site trophoblastic tumour
tumours. The rest are rare but include mixed Epithelioid trophoblastic tumour
tumours not specific to the testis and metastases. Cystic trophoblastic tumour
Predisposing factors include cryptorchidism, Teratoma, post-pubertal
genetic factors, testicular dysgenesis, Teratoma with somatic malignancy
Li-Fraumeni syndrome, prior testicular germ cell Non-seminomatous Germ cell tumours of more than
one histological type
tumour or intratubular germ cell neoplasia.
Mixed germ cell tumour
Germ cell tumours: There has been variability
Germ cell tumours of unknown type
in use of classifications in the past between the Regressed germ cell tumour
British Testicular Tumour Panel (BTTP) in the Germ cell tumours unrelated to germ cell neoplasia
UK versus WHO 2004 in Europe/US. However in situ
the WHO 2016 classification system for testicu- Spermatocytic tumour
lar tumours should be mandatory (Table 33.1) as Teratoma, prepubertal-type
it has much greater correlation and the BTTP Dermoid cyst
classification discouraged. Pathological staging Epidermoid cyst
has minor clinical significance as therapy is Well differentiated neuroendocrine tumour
largely dependent on clinical staging (TNM and (monodermal teratoma)
the modified Royal Marsden systems) based on Mixed teratoma and yolk sac tumour, prepubertal-type
imaging techniques (for abdominal/pulmonary/ Yolk sac tumour, prepubertal-type
eral testis in patients with prior testicular tumour noma or non-seminomatous. Stage I seminoma
(5%). 50% progress to germ cell tumour in is managed by radical inguinal orchidectomy
5 years. Histology shows large seminoma-like followed by surveillance protocol (serum
cells present along a thickened/hyalinised tubular markers and CT scan), single-dose carboplatin
basement membrane. Spermatogenesis is usually adjuvant therapy, or radiation therapy.
absent. The cells are PAS positive but sensitive to Observation of patients with clinical stage I
diastase. Immunohistochemistry shows positive seminoma has shown that about 16% are at risk
staining for CD117, podoplanin, OCT3/4, and for recurrent disease (retroperitoneum or ingui-
PLAP. Cytokeratins, α-fetoprotein, and CD30 are nal region). Risk factors related to increased
negative. Treatment comprises radiotherapy and rates of disease recurrence include tumour size
it can be delayed for fertility issues. If this treat- >4 cm and the presence of direct (not Pagetoid)
ment is to be used the patient needs to be informed rete testis invasion. Surveillance is a safe
that it will lead to irreversible infertility. It is also option for patients who will cooperate with
important to be aware that following low dose long-term follow-up and who are regarded as
radiotherapy to the testis about 30% of patients low risk for relapse. Stage II seminoma is
will develop Leydig cell insufficiency requiring treated by radical inguinal orchidectomy fol-
testosterone replacement therapy. Watchful wait- lowed by radiation or cisplatin-based adjuvant
ing (clinical, ultrasound examination, and serum therapy. As a result chemotherapy is preferred
markers) is advocated by some. for patients with bulky stage II seminoma or if
Seminoma: Represents 30–50% of testicular patients relapse following radiotherapy. Stage
germ cell tumours with a mean age at diagnosis III seminoma is managed by radical inguinal
of 40 years. 40% have increased serum PLAP orchidectomy followed by multidrug
and 70% of patients have stage I disease. chemotherapy.
Metastases are to lymph nodes or bone. The The prognosis is excellent with 98% cure rate
presence of elevated serum HCG does not for stage I or II seminoma. Prognostic factors
change the classification and has no clinical include stage, tumour size (>4 cm), rete testis
significance. However, elevated AFP indicates invasion, and intertubular growth. The term
a non-seminomatous germ cell component (or “anaplastic” seminoma (>3 mitoses per high-
liver disease), even if not seen histologically. power field) is not accepted as a separate entity
The gross appearance is that of a well-circum- and is not an adverse prognostic factor.
scribed pale lobulated fleshy mass with a bulg- Spermatocytic tumour: A major change to the
ing cut surface. Histology shows uniform cells 2016 WHO Classification is the reclassification
with abundant clear cytoplasm, well-defined of spermatocytic seminoma as spermatocytic
cell borders, and vesicular nuclei with promi- tumour. This change labels this entity as a tumour
nent nucleoli. A lymphoplasmacytic infiltrate rather an unequivocal malignancy in keeping
is always present. A variety of unusual growth with the non-aggressive behaviour of usual sper-
patterns have been described, including an matocytic tumours. Removing the term semi-
alveolar or pseudoglandular pattern, tubular noma from the name of this tumour also confirms
and an intertubular/interstitial pattern of that there is no relationship to usual seminoma,
growth. Granulomatous inflammation, tropho- no evidence of GCNIS origin, is negative for
blastic giant cells, and Pagetoid spread to the OCT3/4, occurs in an older patient group and
rete (also seen with GCNIS) are seen in a does not possess chromosome 12p abnormality.
minority of cases. The tumour cells are PAS It is an extremely rare germ cell tumour com-
positive with diastase sensitivity, and positive posed of three cell types of variable size. It forms
for OCT3/4 (nuclear), podoplanin (D2–40), a well-circumscribed, soft, friable, pale mass
CD117, SALL4, and PLAP. Cytokeratin may with a mucoid or gelatinous, bulging cut surface.
be focal or weak. Treatment options depend on Histology shows a diffuse sheet pattern of small
TNM stage and whether the tumour is semi- lymphocyte-like cells, intermediate cells, and
giant cells with an oedematous stroma. It is dis- Stage II NSGCT is treated by radical ingui-
tinguished from seminoma by the absence of nal orchidectomy followed by RPLND, RPLND
stroma, lymphocytes, glycogen, granulomas, and and chemotherapy, or chemotherapy and
GCNIS. It is negative for most germ cell- delayed RPLND. Salvage chemotherapy can be
associated markers (OCT3/4, podoplanin (D2– initiated on detection of relapse. If the concen-
40), PLAP, α-fetoprotein, glypican-3, HCG, and trations of tumour markers fall after chemother-
CD30). It may be positive for SALL4 and CD117. apy and residual retroperitoneal masses are seen
Orchidectomy is typically curative and additional on CT, then lymph node dissection is appropri-
therapy apart from surveillance is generally not ate as 20% of such nodes will harbour residual
required. However, occasional examples of sper- tumour. When the tumour markers do not fall to
matocytic tumour with progression or dedifferen- normal concentrations after chemotherapy,
tiation into sarcoma have been described (less opinion on treatment is divided between lymph
than 1%), particularly rhabdomyosarcomatous node dissection and further chemotherapy.
differentiation. When present it is often associ- Although organ-sparing surgery is not indicated
ated with distant metastases. it can be attempted in certain cases with caution.
Non-seminomatous germ cell tumours Indications include synchronous bilateral tes-
(NSGCT): In general, more aggressive and metas- ticular tumours, metachronous contralateral
tasize earlier than seminomas. The metastases tumours, or a tumour in a solitary testis with
may not resemble the primary tumour and are normal preoperative testosterone levels. Organ-
radioresistant. 80% have elevated AFP or HCG at preserving surgery can be performed when the
diagnosis. The prognosis is good with 95% cure tumour measures less than 2 cm. In those cases,
rate if there is no lymph node or metastatic the rate of associated GCNIS is high (up to
involvement but ranges from 40 to 95% with 80%) and can be treated with radiotherapy. This
metastases. There is a poor prognosis if extensive option has to be carefully discussed with the
pulmonary disease is present. Traditionally the patient and surgery performed in a centre with
treatment for stage I non-seminomatous germ cell experience.
tumours has been orchidectomy followed by ret- Teratoma, post pubertal type: One of the key
roperitoneal lymph node dissection (RPLND) to changes in the 2016 WHO Classification system is
eradicate the disease while confined to the local the discrimination of postpubertal-type teratoma
lymph nodes. It is now believed, however, that from prepubertal-type teratoma. Patients with
most patients with such tumours do not benefit apparently pure testicular teratomas often have
from this dissection, a procedure which is not GCNIS in the testis and may develop metastases
without complications. Currently there is risk consisting of teratoma or other germ cell tumour
stratification of stage I NSGCT to separate men elements. Teratoma represents 5% of germ cell
with stage I from those who are at risk of occult tumours and contains cellular c omponents derived
microscopic metastases. This reserves potentially from two or three germ layers. In adults, there is a
toxic treatments for those men who need them. presumption of malignant behaviour regardless of
Defined pathological findings in the primary tumour differentiation. Grossly they are large
known to be associated with a high risk of occult (5–10 cm), multinodular, and heterogeneous
metastatic spread in clinical stage I are vascular (solid, cartilaginous, cystic). Histologically mature
and/or lymphatic invasion, proliferation rate teratomas contain differentiated tissues including
>70%, absence of yolk sac elements and percent- cartilage, nerve, and various epithelia, whereas
age of embryonal carcinoma >50%. Those at low immature teratomas have foci resembling embry-
risk have standard surveillance (regular serum onic or fetal structures including primitive neuro-
tumour markers and CT scanning). Active treat- ectoderm, poorly formed cartilage, neuroblasts,
ment schedules involve the use of low dose adju- loose mesenchyme, and primitive glandular struc-
vant chemotherapy. tures (amount important). There is no established
prognostic value for discriminating mature from tal-type teratoma as a form of monodermal
immature elements in postpubertal testicular tera- teratoma. Some are associated with prepuber-
tomas. The 2004 and 2016 WHO Classification tal-type teratomas, whereas others are pure
systems do not distinguish mature from immature primary testicular carcinoid tumours.
teratoma for this reason. However, overgrowth of Mixed germ cell tumours: Mixed forms are
primitive neuroectodermal elements should be common accounting for one third of germ cell
reported (resembles paediatric-type central ner- tumours and 70% of non-seminomatous tumours
vous system PNET (primitive neuroectodermal of the testes. Common combinations include
tumour)). embryonal and teratoma; embryonal and semi-
Teratoma with somatic-type malignancy: noma; embryonal, yolk sac tumour and teratoma.
Somatic-type tumours arising from germ cell Clinical presentation and management are the
tumours include carcinomas, sarcomas (more same as non-seminomatous germ cell tumour,
commonly embryonal rhabdomyosarcoma), and the prognosis is usually that of the worst
PNET, glial neoplasms, haematological neo- component.
plasms, and nephroblastoma-like (Wilms) Embryonal carcinoma (EC): Pure tumours
tumour. It is thought that many of these second- represent 2% of germ cell tumours, but 85% of
ary somatic-type malignancies arise via over- NSGCTs have an embryonal carcinoma compo-
growth of a particular component. The term nent. Histologically solid, alveolar, tubular, or
malignant transformation is not recommended, papillary patterns of large, epithelioid, anaplastic
as it implies the teratoma is not malignant. cells. Intratubular embryonal carcinoma is pres-
Overgrowth of a particular element (a low-power ent adjacent to the invasive tumour in about 25%
magnification—×4 field or 5 mm diameter) is of cases. The intratubular component is often
considered diagnostic. However, this is relatively necrotic and it may show calcification. EC com-
rare in the testes. monly invades blood or lymphatic vessels.
Teratoma, prepubertal-type (including der- Syncytiotrophoblastic giant cells (STGC) are a
moid and epidermoid cyst): In contrast to common finding and associated with increased
adult teratoma, teratomas occurring in prepu- serum HCG. Immunohistochemistry shows posi-
bertal patients show no association with tive staining for cytokeratin, CD30, OCT3/4,
GCNIS, largely lack 12p amplification and podoplanin (D2–40), SALL4, LIN28, NANOG,
have not been reported to metastasize. SOX2 and PLAP. Treatment is similar to other
Dermoid and epidermoid cysts are now non-seminomatous germ cell tumours depending
grouped in this overall category of mainly on clinical stage. The prognosis is the
prepubertal-type teratomas. Whereas epider- poorest among all germ cell tumours.
moid cysts are relatively simply characterized Yolk sac tumour (YST), postpubertal type:
by their squamous epithelium-lined cystic The pure form is rare in adults where it usually
cavity containing keratin material (no skin presents as a component of mixed germ cell
adnexal elements), the definition of dermoid tumours. More than 95% patients have elevated
cyst is more controversial, with debate as to serum AFP, which is valuable in diagnosis and
whether non-cutaneous elements, such as car- monitoring treatment. YST has multiple usually
tilage or bone are allowable for diagnosis. A mixed growth patterns. Reticular or microcystic
critical feature of epidermoid/dermoid cysts, patterns are the most frequent (80%). Others are:
which distinguishes them from the usual tera- Endodermal sinus (Schiller Duval bodies), solid,
toma, is the absence of GCNIS. Rare exam- papillary, and glandular. The cells can look very
ples of testicular well-differentiated pleomorphic and difficult to separate from
neuroendocrine tumour (carcinoid tumour) EC. They are positive for cytokeratin, AFP,
have been reported, which in the 2016 WHO PLAP (variable), SALL4, glypican-3, LIN28
Classification is considered under prepuber- and negative for CD30, podoplanin (D2–40),
OCT3/4, and HCG. For adult YST (usually Regression of germ cell tumour: This is an
mixed with other germ cell tumour) treatment is addition to the 2016 WHO Classification. In the
as for NSGCTs. past some germ cell tumours have been labelled
Yolk sac tumour (YST), prepubertal-type: as “primary” retroperitoneal tumours, whereas
Prepubertal-type yolk sac tumour is the most com- current thinking is that these likely represent
mon testicular tumour of children, accounting for metastases from an occult or regressed testicu-
50–60% of such tumours. 75% are found in chil- lar primary tumour. Histological findings in the
dren less than 2 years of age. It is biologically dif- testis typically include a scar, reduced sper-
ferent from postpubertal-type YST, despite having matogenesis, and microlithiasis but findings
a generally similar range of histological features. proposed as specific for germ cell tumour
Association with GCNIS is lacking. There is a low regression are limited to GCNIS in the adjacent
incidence of extratesticular involvement com- parenchyma and coarse, large intratubular calci-
pared to postpubertal germ cell tumours, and when fications as a result from intratubular growth,
advanced, chemotherapy is very effective. necrosis, and calcification of embryonal carci-
Choriocarcinoma: 0.3–1% of germ cell noma. However despite the absence of GCNIS
tumours are pure choriocarcinoma, but mixed or coarse calcifications, the possibility of germ
tumours are more common. It may present ini- cell tumour regression remains a consideration
tially with early haematogenous metastasis (liver, for any testicular scar.
lung, mediastinum, retroperitoneum) and a nor- Sex cord-stromal tumours: In the sex cord
mal testis or small tumour but with increased stromal tumours classification (Table 33.2), the
serum HCG. Patients may have gynaecomastia or sclerosing Sertoli cell tumour is no longer sepa-
hyperthyroidism. It is usually fatal if pure. rately classified. These tumours are now consid-
Histologically there is haemorrhage and necrosis ered to be a morphological variant of Sertoli cell
with a biphasic arrangement of cytotrophoblast tumours, not otherwise specified (NOS), based
and syncytiotrophoblast cells. It is positive for on similar gene mutations (CTNNB1). Sex cord
cytokeratins, HCG, HPL, EMA (only syncytio- stromal tumours represent 4% of testicular neo-
trophoblast), and SALL4. Treatment is radical
orchidectomy and systemic chemotherapy. The
Table 33.2 World Health Organization (WHO 2016)
level of HCG correlates with prognosis, reflect- histological classification of testicular Sex Cord-Stromal
ing tumour load. In the new WHO classification Tumours
trophoblastic tumours are divided into choriocar-
Sex cord-stromal tumours
cinoma and non-choriocarcinomatous tropho-
Pure tumours
blastic tumours. Monophasic choriocarcinoma is Leydig cell tumour
considered a morphological variant of choriocar- Malignant Leydig cell tumour
cinoma. The non-choriocarcinomatous group has Sertoli cell tumour
been expanded to recognise placental site tropho- Malignant Sertoli cell tumour
blastic tumour (PSTT), epithelioid trophoblastic Large cell calcifying Sertoli cell tumour
tumour (ETT) and cystic trophoblastic tumour Intratubular large cell hyalinising Sertoli cell neoplasia
(CTT). PSST consists of aggregates of tropho- Granulosa cell tumour
blastic cells that are positive for human placental Adult type granulosa cell tumour
lactogen (HPL) and negative for p63. ETT has a Juvenile granulosa cell tumour
more cohesive arrangement of cells and is HPL Tumours in the fibroma/thecoma group
negative and p63 positive. CTT occurs typically Thecoma/Fibroma
in metastatic sites after chemotherapy for germ Mixed and unclassified sex cord-stromal tumour
cell tumours that may or may not have contained Mixed sex cord-stromal tumour
choriocarcinoma. It consists of cysts lined by one Unclassified sex cord-stromal tumour
or multiple layers of squamoid trophoblastic cells Tumour containing both germ cell and sex cord-
with eosinophilic cytoplasm. Stains for HCG are stromal elements
focally positive. Gonadoblastoma
plasms (increased in the paediatric population), functional and rarely associated with gynaeco-
containing epithelial elements of sex cord origin mastia. It is usually benign but metastasis occur
(Sertoli and granulosa cells) admixed with mes- in 10% (associated with size >7 cm, haemor-
enchymal components (Leydig and theca-lutein rhage, necrosis, lymphovascular invasion). The
cells) in varying combinations and degrees of dif- juvenile form is the most common neonatal tes-
ferentiation. Specific types of sex cord-stromal ticular tumour with an average age of onset less
tumour may be associated with genetic syn- than 1 month or even congenital. There is an
dromes. e.g., large cell calcifying Sertoli cell association with trisomy 12 and sex chromo-
tumour in Peutz-Jeghers syndrome and testicular some mosaicism if abnormal external genitalia.
feminization syndrome for Sertoli cell tumours. There is no association with endocrine manifes-
Almost all are immunoreactive for inhibin. tations. It has a benign behaviour following
Leydig (interstitial) cell tumours: No orchidectomy.
changes were made in the WHO 2016 classifi- Sertoli cell tumours: One-third present with
cation related to Leydig cell tumours. They gynaecomastia without virilism and 10% are
account for 1–3% of testicular tumours (age malignant (to local lymph nodes) indicators
20–60 years) with 3% bilateral. They secrete being nuclear pleomorphism, size >5 cm, mitoses
sex hormones and symptoms include gynaeco- (>5/10 high power fields), necrosis, and lympho-
mastia with virilism, precocious puberty, and a vascular invasion. Grossly firm, small well–cir-
testicular mass. There are no obvious aetiolog- cumscribed yellow-white nodules. Histology
ical factors but a rare association with germ shows trabeculae lined by Sertoli-like cells. They
line fumarate hydratase (FH) mutations in are positive for AE1/AE3, EMA, vimentin,
patients with hereditary leiomyomatosis and α-inhibin, melan-A (MART-1), WT1, CD99, cal-
renal cell carcinoma syndrome is noted. In retinin, S100 (weak), β-catenin, SF-1, FOXL2,
adults, 10% have malignant behaviour with and synaptophysin. They are typically negative
metastasis to lymph nodes, lung, and liver. for PLAP, OCT3/4, SALL4, α-fetoprotein and
They are positive for inhibin-α, calretinin, CD30. Electron microscopy shows Charcot-
melan-A (MART-1), WT1, androgenic hor- Böttcher filaments which are pathognomonic of
mones, SF-1, FOXL2, and vimentin. They are Sertoli cell differentiation. Treatment is orchi-
typically negative for cytokeratins, OCT3/4, dectomy—radiation and chemotherapy have lit-
SALL4, S100, PLAP, and HMB-45. Lack of tle effect.
nuclear β-catenin expression and strong inhibin Mixed germ cell-sex cord stromal tumours:
staining supports the diagnosis of Leydig cell Tumour containing both germ cell and sex cord-
tumour over Sertoli cell tumour. Features sug- stromal elements and gonadoblastoma is the only
gesting malignancy include large size (>5 cm), entity in this category in the new classification.
necrosis, vascular invasion, nuclear atypia, Germ cell-sex cord/gonadal stromal tumour,
infiltrative margins, older patients, aneuploidy, unclassified has been removed from the classifi-
atypical and numerous mitoses (>3/10 high- cation as there is debate on its existence.
power fields) and high MIB-1 (Ki67) activity. Other tumours not specific to testis:
Mean survival when malignant is 4 years. Leukaemia: Testis may be the first site of
Grossly they are solid brown tumours and 10% relapse, e.g., ALL in children.
have extratesticular extension. Histology Lymphoma: 50% of testicular neoplasms in
reveals sheets of large, round/polygonal cells men aged 60+ years, 20% bilateral.
with eosinophilic cytoplasm and round central Granulocytic sarcoma: 20–35% patients
nuclei. Reinke crystals are present in 25% of involved.
cases. Treatment includes orchidectomy and/or Metastasis to testes: Rarely the first clinical
lymph node dissection if malignant. sign of disease. Lung, prostate, and skin (Merkel
Granulosa cell tumour: Resembles the anal- cell carcinoma, melanoma) are the usual primary
ogous ovarian tumour. The adult form is rare sites. Immunohistochemistry may help in distin-
with an age range 20–53 years, usually non- guishing the primary site.
33.4.2 Epididymis 33.4.2.2 Neoplastic Conditions

Adenomatoid tumour: Benign paratesticular tumour
33.4.2.1 Non-neoplastic Conditions of mesothelial cell origin (similar to the tumour in
Epididymitis: Primary cause of epididymal spermatic cord, fallopian tube and uterus) found
obstruction and usually related to cystitis, prostati- mostly in the epididymis but also in the tunica vagi-
tis or urethritis that spreads through the vas defer- nalis, albuginea, and rete testis. They are the most
ens or lymphatics. It may cause testicular common mesothelial tumours of the paratesticular
ischaemia and necrosis. Causes include Chlamydia region. Grossly forms a circumscribed white mass
trachomatis, Neisseria gonorrhoea, E. coli, pseu- up to 5 cm. Histology shows a variety of growth
domonas, other urinary tract infection organisms, patterns including glands, cysts, tubules, and cords
and rarely tuberculosis and brucellosis. (32%). Lymphoid aggregates may be prominent
Cysts of epididymal appendix and epididymal within or at the periphery of the tumour. It is immu-
cysts: The former can twist, necrose, and present nopositive for cytokeratin, calretinin, podoplanin,
with pain, while the latter form an epididymal CK5/6, thrombomodulin, and WT1. D2–40 positiv-
mass separate from the testis. Cysts occasionally ity has been noted. Resection is curative.
seen with von Hippel–Lindau disease or polycys- Papillary cystadenoma and cystadenofibroma:
tic kidney disease. Treatment is resection of the Familial, unilateral, or bilateral (40%) with a mean
necrotic appendix and cyst aspiration respec- age of 36 years. Associated with von Hippel-
tively, or if persistent, epididymectomy. Lindau disease, particularly when bilateral.
Spermatic granuloma/epididymitis nodosa: Carcinoma of epididymis: Rare, with a poor
Inflammation or trauma damage to the epithe- prognosis. It usually presents as a scrotal mass. It
lium or basement membrane, causing spillage of is large and often haemorrhagic or necrotic.
spermatozoa into the interstitium (similar to vasi-
tis nodosa). It consists of a nodule up to 3 cm in
the head of the epididymis with histological fea- 33.4.3 Rete Testis
tures of non-caseating granulomas around sper-
matozoa. More than 40% of sperm granulomas 33.4.3.1 Non-neoplastic Conditions
are related to a previous vasectomy and up to Adenomatous hyperplasia: Solid/cystic mass in
10% of men who have vasectomies develop testicular hilum and usually an incidental micro-
sperm granulomas. Trauma, infection, and previ- scopic finding. A second type of rete testis hyper-
ous surgery may also be associated aetiologies. plasia occurs as an incidental finding in patients
Spermatocele: Cystic dilation of efferent ducts with testicular germ cell tumours and is charac-
lined by ciliated columnar cells with thin connec- terized by epithelial proliferation within dilated
tive tissue wall, no smooth muscle. The cysts are rete testis spaces.
usually translucent and contain spermatozoa and Cystic dilation (transformation): Due to
proteinaceous fluid. obstruction of epididymis or intratesticular excre-
Granulomatous inflammation: The most com- tory ducts and also seen after haemodialysis,
mon cause of granulomatous epididymitis is where they may have oxalate crystals in the cyst
tuberculosis and there is an association with BCG lumens. May also follow postvasectomy inflam-
therapy. It is characterised by necrotizing granu- mation or related to epididymitis.
lomatous inflammation with palisading histio- Cystic dysplasia: Presents as testicular mass
cytes and Langhans giant cells. Ischaemia is also in infants and children. Consists of cystic dilation
associated with granulomatous epididymitis. of rete testis with compression/atrophy of semi-
ANCA related vasculitis: Polyarteritis nodosa niferous tubules. It is thought to be a develop-
is the most common vasculitis seen in the para- mental anomaly sometimes associated with
testicular region. ipsilateral renal agenesis.
33.4.3.2 Neoplastic Conditions ligation or occlusion of the left spermatic vein,

Rete testis adenocarcinoma: Very rare and resem- and after treatment, 40–55% are fertile.
bles mesothelioma of the tunica vaginalis. Wide
age range with a poor prognosis. 33.4.4.2 Neoplastic Conditions
Sertoliform cystadenoma of rete testis: Benign tumours are usually lipomas. Fat collec-
Extremely rare benign tumour (ages 34–62) usu- tions around a hernia sac are not true lipomas.
ally presenting as a unilateral painless testicular Non-neoplastic masses include mesothelial and
mass. dermoid cysts.
Aggressive angiomyxoma: More usual in the
vulva with local recurrence common, but no
33.4.4 Spermatic Cord metastasis. Grossly non-encapsulated with bland
and Paratesticular Region spindle cells in myxoid stroma containing promi-
nent thick-walled/hyalinised vessels. It stains
33.4.4.1 Non-neoplastic Conditions positively for smooth muscle actin, desmin,
Torsion: May cause testicular infarct if not treated CD34, and androgen receptor.
quickly. This usually occurs in the first year of Angiomyofibroblastoma: Benign soft tissue
life or also towards puberty due to trauma. It is tumour, which is well circumscribed consisting
associated with incomplete descent, absent scro- of alternating hypocellular and hypercellular
tal ligaments, absent gubernaculum testis, or tes- zones. Angiomyofibroblastomas are benign neo-
ticular atrophy causing the testis to be abnormally plasms and are treated by local resection.
mobile. On average, the time elapsed between Embryonal rhabdomyosarcoma: The most
onset of pain and performance of de-torsion, and common site for rhabdomyosarcomas is the para-
the corresponding salvage rate, is as follows; testicular region and the most common childhood
<6 h—90–100% salvage rate; 12–24 h—20–50% malignant tumour of the spermatic cord. The
salvage rate; >24 h—0–10% salvage rate. peak age is 15 years with an 80% overall sur-
Treatment consists of untwisting (± using warm vival. It is a fleshy white to tan tumour, 4–6 cm,
saline gauze) and fixing the testis to dartos mus- and may be mucoid. Small cells, eosinophilic
cle or orchidectomy. The opposite testis should cells, and spindle cells with variable cross stria-
be fixed to dartos muscle as a preventive tions. Immunopositive for desmin, sm-actin,
measure. myoglobin, myoD-1, myogenin, and vimentin.
Vasitis nodosa: Granulomatous condition of Sarcomas: Adults—most common tumours
the vas deferens, which resembles spermatic are liposarcoma, malignant fibrous histiocytoma,
granuloma of the epididymis. It is usually post leiomyosarcoma, and fibrosarcoma. Treatment is
vasectomy or herniorrhaphy and occasionally orchidectomy with high ligation of the cord and
associated with recanalization. Histology shows radiation therapy.
proliferating ductules and dilated tubules con- Liposarcoma: The most common malignant
taining spermatozoa in the wall of the vas defer- tumour of the paratesticular region and usually
ens with hyperplastic smooth muscle. May see well-differentiated or sclerosing types. There is a
perineural or vascular invasion by the proliferat- 20% recurrence rate following local removal.
ing ductules. Mesothelioma: The most common malignant
Varicocele: Abnormal dilation and tortuosity neoplasm of the paratesticular region that displays
of veins in the pampiniform plexus of the sper- an epithelial growth pattern. Cystic/solid/nodular
matic cord probably due to insufficiency of masses lining a hernial sac and show epithelial
venous valves and occur in about 15% of men. It (60–70%), sarcomatoid (rare) or biphasic (30–
is often associated with infertility. 90% are on the 40%) patterns. They show positive staining for
left and 10% bilateral. Treatment consists of CK5/6, WT-1, and calretinin and are negative for
CEA, Leu-M1, Ber EP4, B72.3, and E-cadherin. 33.5 Surgical Pathology
They have an aggressive behaviour. In contrast to Specimens: Clinical Aspects
the previous classification, there is no recognised
benign mesothelioma. Well-differentiated papil- 33.5.1 Biopsy Specimens
lary mesothelioma is considered as a variant of
mesothelioma. Cystic mesothelioma is regarded 1. Inguinal exposure with testicular isolation and
as non-neoplastic condition. biopsy.
Borderline and Malignant Ovarian-Type Testicular biopsy is standard management in
Epithelial Tumours: Borderline and malignant patients at high risk of GCNIS as it is thought
ovarian-type epithelial tumours are rare in the to progress to invasive tumour in 50–100% of
paratesticular region, and histologically identical cases, and therapy should be considered. It is
to the ovarian counterpart. Most of these tumours also useful in the management of the contra-
in the paratesticular region are serous lateral testis in patients with germ cell
tumours of low malignant potential, but serous tumours, approximately 5% of whom have
carcinomas, Brenner tumours, mucinous GCNIS of the opposite testicle. A high inci-
tumours, endometrioid tumours, and clear cell dence of GCNIS (35%) is found in young
carcinomas have also been reported in this loca- (<30 years) patients where the contralateral
tion. Immunohistochemistry is useful in the diag- testis is small (<16 mL) and of poor quality
nosis as tumours of Müllerian derivation stain (soft). The European Association of Urology
positively with WT1, CK7, BER-EP4, CEA and recommends contralateral biopsy in these
CA-125. Treatment includes radical orchidec- high-risk patients. These contralateral biop-
tomy and Müllerian type chemotherapy. sies are also useful in the assessment of sper-
Tumour of the Adrenogenital Syndrome: matogenesis, which is often overlooked.
Develops in the paratesticular region of men with Biopsy should be 0.3–1.0 cm in maximum
the adrenogenital syndrome who are not ade- dimension and removed atraumatically with-
quately treated with nodules of steroid-type cells out squeezing the tissue or handling it with
within the epididymis, spermatic cord, or the forceps.
tunica albuginea. They show strong melan-A
with absent inhibin staining in contrast to Leydig pen biopsy is considered the normal proce-
O
cells. dure, but needle biopsy may be adequate.
Desmoplastic small round cell tumour: Highly
aggressive small round blue cell primitive neuro- 2. Transscrotal Open or Needle Biopsy
ectodermal tumour that arise in association with Rarely performed for testicular tumours due
mesothelial surfaces and occurs in young men. to the presumed risk of wound seeding and
Grossly it is a 3–4 cm grey-white, firm mass, lymphovascular spread to inguinal lymph
often near the epididymis. Comprises small cells nodes.
in a desmoplastic stroma, and the prognosis is
very poor. Cytokeratin and desmin positivity are
characteristic and they display a unique chromo- 33.5.2 Resection Specimens
somal abnormality, t(11;22) (p13,q12).
Lymphoma: Rare to involve paratesticular Radical inguinal orchidectomy is performed
regions without testicular involvement. when a testis tumour is suspected on examina-
Metastasis to paratesticular region: Tumours tion and/or preoperative imaging studies. This
secondarily involving paratesticular structures by is accomplished via an inguinal incision in
haematogenous metastasis or intraperitoneal order not to alter the lymphatic drainage pattern
spread from distant sites and include prostate, of the testicle (to the retroperitoneal lymph
lung, kidney, and gastrointestinal tract (stomach) nodes) by violating the scrotal wall (drainage to
as the commonest sites of origin. the superficial inguinal lymph nodes). Radical
orchidectomy also allows ligation of the vas testicular volume and normal reproductive hor-
deferens and testicular vessels at the internal mones to differentiate between obstructive and
inguinal ring, so that should subsequent surgi- non-obstructive azoospermia.
cal removal of the spermatic cord and retroperi- Epididymectomy: Weigh (g) and measure
toneal lymph nodes be required (for therapy or (cm), bisect or serially slice noting any focal
staging) the inguinal canal need not be explored lesions (abscess/adenomatoid tumour), and sub-
again. Partial orchiectomy may also be an mit representative blocks. Cysts are submitted in
option for the management of testicular malig- total, or if large, blocks of the wall are sampled.
nancy in a select group of patients in whom Fluid contents can be examined microscopically
radical orchidectomy is not desirable, including for sperm to distinguish from a hernial sac.
those with a solitary testicle, bilateral meta- Appendix epididymis (Hydatid of Morgagni):
chronous testicular malignancies and fertility Measure (mm), process intact.
preservation. Patients must have negative find- Vasectomy: Measure (cm) the segments of
ings on serum marker studies and abdominal right and left vas and submit two complete trans-
CT scanning preoperatively to be suitable. verse sections of each. Lengths vary from 0.5 to
However, 50% of patients undergoing partial 5 cm—small specimens are often distorted by
orchidectomy (incidental testicular mass) surgical clamping and care needs to be taken with
require delayed radical orchidectomy and blocking and embedding to obtain a r epresentative
patients need to be made aware beforehand. In cross section. Levels or re-embedding may be
some cases, frozen-section analysis at the time required.
of surgery yields false-negative results. Final Hydrocele wall: Weigh (g), measure (cm), and
pathology can reveal testicular malignancy and submit representative blocks. Note any contents,
positive margins. e.g., blood/fibrin.
33.6 Surgical Pathology 33.6.2 Resection Specimens

Specimens: Laboratory
Protocols Specimen:
33.6.1 Biopsy Specimens • Most radical orchidectomy specimens are for

malignant tumours, but the diagnosis usually
Testicular biopsy (0.3–1.0 cm): Placed in cannot be definitively made preoperatively.
Bouin’s fixative (or Stieves’s/Zenker’s medium)
as opposed to formalin (for better nuclear pres- Initial procedure:
ervation and because there is less shrinkage
artifact and luminal sloughing of cells which • Fixative can be slow to penetrate the thick
can obscure cellular detail) for a minimum of tunica and therefore incision into this is
2 h (smaller biopsies) and a maximum of 24 h. extremely helpful for tumour preservation.
Paraffin sections are cut through levels and Urologists should be encouraged to send the
stained routinely with haematoxylin and eosin. intact testis to the laboratory rapidly to allow
Comment should be made on the presence or bisection by the pathologist. In the presence of
absence of GCNIS, the degree of spermatogen- a delay, it is better for the Urologist to bisect
esis, and evidence of atrophy of seminiferous the testis for better preservation of the testis, at
tubules. Immunohistochemical assessment of the expense of distorting the relationship
PLAP, CD117, OCT3/4 (present in GCNIS between the tumour and tunica. The tunica
cells) is helpful in a biopsy showing equivocal vaginalis (TV) should be opened and the testis
morphology. Diagnostic testicular biopsy may sliced through the lateral border of the testis,
be performed in men with azoospermia, normal cutting towards the epididymis.
• Partial orchidectomies do not require incision • Other

before fixation as they are smaller and surgical –– Epididymal cysts, scarring, cord or parates-
margins are of greater importance. The testic- ticular involvement, other lesions.
ular parenchymal excision margin should be
inked. Blocks for histology (Fig. 33.3):
• Some tumours spread to involve the cord, and
this should be looked for and sampled prior to • All areas of different macroscopic appear-
opening the testis to minimize the risk of con- ances are sampled in order to identify all the
tamination by tumour. histological patterns present.
• The testis is incised in a plane that bisects the • One block of tumour per centimetre diameter
epididymis and rete testis such that invasion of is taken.
these structures can be recognized (Fig. 33.3). • Submit tumour entirely if small (<2 cm).
• Fix by immersion in 10% buffered formalin • Sample areas demonstrating the relationship
for 24–36 h. of tumour, rete, cord and epididymis, and of
• Cuts parallel to the incised plane to examine any area where tumour appears to invade these
the entire testis are then performed. structures or the tunica (Fig. 33.3).
• Photograph tumour and individual slices if • Sample, where possible, adjacent non-tumour
appropriate. tissue to look for vascular invasion.
• Measurements: • More samples may be required in pure sem-
–– Dimensions (cm) of testis and length (cm) inoma to rule out other germ cell compo-
of spermatic cord. nents, especially if there are areas of
–– Weight of specimen in total (g). haemorrhage and necrosis or elevated serum
–– Tumour—length × width × breadth or AFP levels.
maximum dimension (cm). • Sample the surrounding normal testis to look
• Identify different tumour appearances looking for GCNIS and status of the normal testis, i.e.,
particularly for areas of haemorrhage and scar, inflammation, regressional changes,
necrosis. other tumours, calcification. The adjacent tes-
• All areas of different macroscopic appear- tis (including the capsule) is a common site
ances should be sampled in order to identify for vascular invasion.
all the histological patterns present (semino- • Sample a transverse section of the cut end of
matous versus NSGCT). the spermatic cord and ideally this should be
• Count and submit any lymph nodes with the done before opening the testis to minimize the
main specimen. risk of contamination by tumour.
• Examine the cord and surrounding tissue for • Sample the base of cord in one or two other
abnormality. areas.
• Samples for special studies (e.g. electron
Description: microscopy, cytogenetics, molecular biologic
studies, flow cytometry, image analysis).
• Tumour
–– Location (testis, rete, epididymis, tunica Histopathology report:
albuginea, spermatic cord)
–– Single/multifocal—mixed germ cell • Tumour location: testis/rete/epididymis/cord
–– Colour (pale/uniform—seminoma or involvement.
lymphoma) • Tumour type—seminomatous/non-seminoma
–– Necrosis (embryonal—MTU) tous/sex cord-stromal tumour. Histopathological
–– Haemorrhage (choriocarcinoma) grading is not applicable to germ cell tumours.
–– Cysts/cartilage (teratoma—MTD). • Tumour classification (WHO 2016).
• Surrounding testis • Estimate percentage of each component for
–– Normal, scar, calcification. mixed tumours.
Transverse section the

proximal spermatic cord
margin
Transverse Tumour and

cord sections spermatic cord
Epididymis Tumour
Tumour and
and layers
epididymis
of tunica
Tumour
Hemisect and adjacent
anteroposteriorly Tumour, testis
rete testis
and epididymis
Testis
Testis and
coverings
Fig. 33.3 Blocking of an orchidectomy specimen for tumour (Reproduced, with permission, from Allen and Cameron
(2013))
• Intratubular, invasive, or both. • Regional lymph nodes—abdominal periaor-

• Extent of local tumour spread: TNM 8 for tic, pericaval, and those along the spermatic
germ cell tumours of the testis veins. Generally, not removed at surgery but
–– Invasion or penetration of tunica albuginea retroperitoneal lymph node dissection occa-
(specify). sionally performed—usually following orchi-
–– Involvement of paratesticular structures dectomy and chemo/radiotherapy.
with direct invasion of the hilar soft tissue
or cord (both considered pT3) pN0 No regional lymph node metastasis.
pN1 Regional lymph node metastasis ≤2 cm but ≤5
pT0 No evidence of primary tumour (i.e. scar in positive nodes.
testis) pN2 Regional lymph node metastasis >2 cm but
pTis Intratubular germ cell neoplasia (carcinoma in ≤5 cm or >5 positive nodes or extranodal
situ) extension.
pT1 Tumour involves testis and epididymis or pN3 Regional lymph node metastasis >5 cm.
tunica albuginea, no lymphovascular invasion
pT2 Tumour involves testis and epididymis with
lymphovascular invasion or tunica vaginalis • Other tissue(s)—involved/uninvolved by
pT3 Tumour invades spermatic cord ± tumour.
lymphovascular invasion • Results of special studies (immunohistochem-
pT4 Tumour invades scrotum ± lymphovascular istry)—AFP, HCG, PLAP, OCT3/4, CD117,
invasion. SALL4, Glypican-3, LIN28, podoplanin,
SOX2, HPL, CD30, CAM 5.2, EMA (germ
• Lymphatic/blood vessel invasion (specify if in cell tumours), inhibin, calretinin, β-catenin
testis or paratestis/spermatic cord). (sex cord stromal tumours).
• Comments Howard GCW, Nairn M, Guideline Development Group.

–– Correlation with other specimens, as Management of adult testicular germ cell tumours: sum-
mary of updated SIGN guidline. BMJ. 2011;342:919–21.
appropriate Idrees MT, Ulbright TM, Oliva E, Young RH, Montironi
–– Correlation with clinical information, as R, Egevad L, Berney D, Srigley JR, Epstein JI, Tickoo
appropriate SK. The WHO 2016 classification of testicular non-
–– Presence/absence of embryonal carcinoma, germ cell tumours: a review and update from the
international society of urological pathology testis
yolk sac tumour, and lymphovascular inva- consultation panel. Histopathology. 2016;70:513–21.
sion are prognostically significant Moch H, Cubilla AL, Humphrey PA, Reuter VE, Ulbright
• Resection margin(s) of spermatic cord and TM. The 2016 WHO classification of tumours of
parenchymal margin of partial orchidectomy the urinary system and male genital organs-part
a: renal, penile, and testicular tumours. Eur Urol.
if applicable. 2016;70(1):93–105.
• Additional pathological findings, Leydig cell Rajpert-De Meyts E, McGlynn KA, Okamoto K, Jewett
hyperplasia (correlated with HCG), scarring, MAS, Bokemeyer C. Testicular germ cell tumours.
the presence of haemosiderin-laden macro- Lancet. 2016;387:1762–74.
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term disease control: a longitudinal analysis of 50
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Penis
34
34.1 Anatomy from the corpora cavernosa and constitutes an

important barrier to the spread of cancer to the
The penis (Fig. 34.1) comprises the body or shaft latter. The coronal sulcus is a narrow and circum-
and the two ends, anterior and posterior (root). ferential “cul de sac” located just below the glans
The anterior portion is composed of the glans, corona. It is a common site for recurrence of car-
coronal sulcus, and foreskin (prepuce). There is a cinoma or of a positive margin in cases of fore-
vertical cleft, the meatus, in the apex 5 mm in skin carcinoma. The foreskin is a double
length, and this is attached to the foreskin by a membrane which encases the glans and from
triangular piece of mucosa, known as the frenu- which it is separated by a potential space.
lum. The base of the cone is represented by the The shaft comprises three cylindrical masses
corona, an elevated ridge surrounding the glans. of cavernous erectile tissue bound together by the
The coronal sulcus below the corona separates fibrous tunica albuginea and encased in Buck’s
the glans from the foreskin. fascia. These cylinders are the ventral corpus
The glans is composed of the following lay- spongiosum with a centrally located urethra and
ers: epithelium, lamina propria, corpus spongio- two corpora cavernosa separated by a median
sum, tunica albuginea, and corpus cavernosum. raphe.
The stratified epithelium is thin and nonkera- The posterior part (root) of the penis is deeply
tinized in uncircumcised males but keratinized in embedded in the perineum. It is fixed to the ante-
circumcised males. The lamina propria is loose, rior wall of the pelvis by a ligamentous insertion
1–4 mm thick, and separates the epithelium from of the corpora cavernosa to the ischium and pel-
the corpus spongiosum. The corpus spongiosum vic bones.
is the main component of the glans and consists Lymphovascular drainage:
of specialized erectile tissues with numerous A rich network of lymphatics in the glans and
anastomosing venous sinuses. It is 8–10 mm in corpora cavernosa courses along the dorsal vein
thickness. The tunica albuginea is a very dense and drains into superficial and deep inguinal
white fibrous membrane which terminates in or lymph nodes. The foreskin and shaft skin lym-
near the glans separating the corpus spongiosum phatics drain also to the superficial inguinal
lymph nodes. The sentinel group of the superfi-
cial inguinal lymph nodes is the most common
D.M. O’Rourke (*) • D.C. Allen site for lymph node metastasis. Within the deep
Histopathology Laboratory, Belfast City Hospital, inguinal nodes, the node of Cloquet (highest) is
Belfast Health and Social Care Trust, Belfast, UK significant as the next level of drainage is the iliac
allen@belfasttrust.hscni.net nodes.

Fig. 34.1 Anatomy of Prepuce

the penis (Used with the (foreskin) Corpus spongiosum
permission of the Union Sulcus
for International Cancer Glans
Control (UICC), Corpus cavernosum
The original source for Urethral meatus Urethra
this material is from Corpus spongiosum
Coronal Shaft
sulcus
nodes. MRI is particularly helpful for detect-

34.2 Clinical Presentation ing tumour invasion into the corpora.
• Ultrasound is useful for assessing the inguinal
Infectious lesions present with an area of indura- lymph nodes.
tion or erythema on the glans which is often pain- • PET/CT imaging may be helpful in assessing
ful and itchy. Biopsy or microbiological culture metastatic disease, but some studies have sug-
is usually confirmatory, and treatment is decided gested limitations when disease is
depending on the nature of the lesion. micrometastatic.
Early symptoms of penile cancer include the • Bone scan if indicated.
appearance of a painless nodule, warty growth,
or ulcer, especially on the glans or foreskin, or
swelling at the end of the penis. Any abnormal- 34.4 Pathological Conditions
ity including warts, blisters, sores, ulcers, white
patches, rash, or bumps should be evaluated 34.4.1 Non-neoplastic Conditions
including lesions that have failed to heal. Most
penile cancers do not cause pain, but can result Paraphimosis: Forceful retraction of phimotic
in ulceration and bleeding in later stages. Adult foreskin over the glans may cause marked swell-
circumcision offers little or no protection but ing which blocks replacement of the foreskin.
penile cancer is almost never observed in indi- This is often painful and associated with con-
viduals who are circumcised in the neonatal striction and urinary retention. Treatment con-
period. A number of benign conditions, such as sists of circumcision.
genital warts or infections, can have similar Phimosis: The foreskin orifice is too small to
symptoms. permit its retraction, usually due to scarring from
repeated infection. Smegma (desquamated epithe-
lial cells, sweat, debris) accumulates and causes
34.3 Clinical Investigations secondary infections and possibly carcinoma.
Tumour-like/Inflammatory lesions.
• Full blood picture (low Hb). Balanitis circumscripta plasmacellularis
• Biochemistry—raised calcium in bone metas- (Zoon’s balanitis/Plasma cell balanitis): Occurs
tasis in 20%. Hypercalcaemia has also been in uncircumcised men with an unknown aetiol-
found in some patients in the absence of ogy (possibly autoimmune). It consists grossly of
metastases. well-defined brown/red plaques, solitary or mul-
• Swab if suspected local infection—candida tiple, and clinically resembles erythroplasia of
etc. Queyrat. Histologically there is epidermal atro-
• Chest X-ray. phy, a band-like infiltrate of plasma cells in the
• MRI and CT are useful for local cancer stag- dermis, haemosiderin pigment laden m acrophages
ing and for assessing the inguinal lymph and oedema. There is no association with HPV.
34 Penis 381
Lichen sclerosus (LS)/Balanitis xerotica oblit- andil as a cause of penile ulceration. This is
erans (BXO): This is the male equivalent of essentially a diagnosis of exclusion, and biopsy is
lichen sclerosus et atrophicus of the vulva. It is necessary to rule out malignancy. The ulcers are
more frequent in the inner foreskin, but coronal located on the foreskin or shaft and characteristi-
sulcus, glans and even urethra may be affected cally form a deep, punched out, and well-
with narrowing of the urethral meatus or phimo- circumscribed lesion. Histology shows
sis. LS may have an autoimmune aetiology but granulation tissue and acute inflammatory
there is no strong association with HPV. There is changes with occasional granulomas.
a weak association with low-grade keratinizing Sexually transmitted disease: These include
squamous cell carcinoma (non-HPV variants— granuloma inguinale (Calymmatobacterium
SCC NOS, pseudohyperplastic, verrucous and granulomatis), herpes simplex virus, lympho-
papillary carcinoma of the foreskin). The gross granuloma venereum (Chlamydia trachomatis),
appearances are that of grey-white foci of atro- candida, molluscum contagiosum, scabies, and
phy in the foreskin or perimeatal glans. syphilis.
Histologically, the affected areas show epidermal Others: Inflammatory pseudotumour, lentigi-
atrophy with an underlying “band like” chronic nous melanosis, papillomatosis of glans corona,
inflammatory infiltrate, and hyalinisation in more penile cyst, pseudoepitheliomatous keratotic and
advanced cases. micaceous balanitis, and verruciform xanthoma.
Squamous hyperplasia: This is commonly
identified in association with LS, differentiated
PeIN (penile intraepithelial neoplasia—see 34.4.2 Neoplastic Conditions
below) and low-grade keratinising penile
SCC. Squamous hyperplasia may be difficult to Condyloma accuminatum: Benign tumour caused
separate from differentiated PeIN and may mimic by HPV 6 or 11 and related to verruca vulgaris
a neoplasm as whilst typically flat, it may also (common wart). It is usually sexually transmitted
have a verrucous/papillary appearance. and seen near the coronal sulcus and inner sur-
Balanoposthitis: Infection of the glans and face of the foreskin but can affect the penis, ure-
foreskin, usually due to candida, anaerobes, gard- thra, scrotum and perineum and often multiple.
nerella, or pyogenic bacteria. It is common in The gross features are of papillary, wart-like,
uncircumcised newborns or uncircumcised men often multiple lesions, 1 mm or larger.
with poor hygiene and accumulation of smegma, Microscopically there is parakeratosis, surface
and is due to the propensity of pathogenic bacte- papillomatosis, acanthosis and koilocytosis. It
ria to adhere to the mucosal surface of the fore- has a propensity for recurrence but does not
skin. It causes phimosis. evolve into invasive cancer. Treatment involves
Peyronie’s disease: Fibrous dermal and fascial local preparations (podophyllin).
thickening causing curvature toward the side of Giant condyloma accuminatum: Very rare,
the lesion and restricting movement during erec- benign, exophytic papillary growth of penis
tion. There is an association with Dupuytren’s (Buschke-Löwenstein tumour). Grossly usually
contracture, drugs and carcinoid syndrome and it involves the foreskin and coronal sulcus, 5–10-
is considered a form of fibromatosis. It may cm cauliflower-like verruciform tumour.
regress spontaneously but responds to small Histology resembles that of a condyloma.
amounts of irradiation, steroids, and excision. Penile Intraepithelial Neoplasia (PeIN): The
Fournier’s gangrene: Necrotizing fasciitis of terms such as eythroplasia of Queyrat and
the genitalia due to bacterial infection. Risk fac- Bowen’s disease have been abandoned with
tors include trauma, burns, anorectal disease, dia- adoption of the encompassing term PeIN. Two
betes, leukaemia, and alcoholic cirrhosis. forms are noted, undifferentiated PeIN
Nicorandil-induced penile ulceration: Several (previously designated severe dysplasia/carci-

reports in the literature have implicated nicor- noma in situ and associated with HPV) and dif-
ferentiated PeIN (involving only the basal layers, cases, tumour can invade the dermis and subcuta-
associated with architectural atypia and unrelated neous tissue and may have the potential for
to HPV). PeIN does not need to be graded and is metastasis.
regarded as high grade by definition. Treatment Squamous cell carcinoma of penis: This is
of PeIN includes local excision/Mohs excision relatively rare in the UK (<1% of carcinomas in
with reconstructive surgery, laser therapy, elec- men versus 10–20% in Asia, Africa, South
trodessication and curettage, cryosurgery, and America), affecting ages 40–70 years. The inci-
topical 5-fluorouracil. dence of penile cancer is related to the prevalence
Bowen’s disease: Clinical designation of car- of HPV in the population. Although the incidence
cinoma in situ located on the shaft skin but largely in Europe has been static, a more recent UK lon-
abandoned in penile terminology. gitudinal study confirmed a 21% increase in inci-
Erythroplasia of Queyrat: Clinical designa- dence from 1979 to 2009. It is particularly rare
tion of carcinoma in situ located on the glans, with early circumcision (at birth). There is an
usually erythematous but also largely abandoned association with paraphimosis, phimosis, HPV
in penile terminology. 16, smoking, psoriasis, poor hygiene and patients
Bowenoid papulosis: Multifocal HPV-related treated with UVB radiation. One third of non-
papular condition affecting the anogenital region HPV cases are associated with BXO.
in young adults with benign looking papules of Most tumours arise from the glans or inner
the penile shaft skin. It may also affect the glans foreskin near the coronal sulcus as a slowly grow-
and coronal sulcus. It is often related to HPV 16, ing, irregular mass. Patients occasionally present
and histology shows atypical basaloid and koilo- with inguinal nodal metastases and occult penile
cytic cells either singly or involving the full cancer due to severe phimosis or a very small pri-
thickness of the epithelium. A minority of lesions mary tumour. Metastases to inguinal lymph
evolve to invasive squamous cell carcinoma. It is nodes, lung, liver, or bone occur and are present
best to describe them as Undifferentiated PeIN in 15% of cases at diagnosis. Lymph nodes may
(warty/basaloid) and correlate with the clinicians. be enlarged at clinical presentation due to infec-
Lesions such as Bowen’s disease, Bowenoid pap- tion alone.
ulosis and Erythroplasia of Queyrat are clinically, The gross appearance is papillary or flat
not pathologically, defined lesions and conse- (ulcerated papule). The cut surface shows a white
quently should not be used as diagnostic terms. solid irregular tumour with superficial or deep
Extramammary Paget’s disease (EMPD): penetration. The microscopy is classified accord-
Presents as erythematous patches on the glans. ing to growth patterns as superficial spreading,
Typically occurs in older men and the presence of vertical growth, verruciform, multicentric, or
an underlying urothelial, prostate or rectal carci- mixed. There is little consensus about the criteria
noma should be considered. It consists of large for grading and the proportion of anaplastic cells
round pale cells in all levels of the epidermis required to classify a tumour as high-grade. They
which in primary EMPD are positive for CK7 are generally graded on differentiation as well,
and negative for CK20. Immunohistochemistry moderate or poor (G1, G2, G3) depending on the
can help to differentiate between primary inva- extent of keratinization. The incidence and man-
sive and secondary EMPD. Recently described agement of heterogeneous tumours (tumours har-
Pagetoid PeIN is histologically similar. In sec- bouring more than 1 histological grade) are not
ondary EMPD, there is a more variable immuno- well established. Tumour grading should be per-
histochemical profile and more often an formed considering the highest grade component
association with urothelial carcinoma (CK7, regardless of its proportion. Undifferentiated car-
CK20 and GATA3 positive). Most patients with cinomas are rare. Most cases have associated
EMPD have a good prognosis as it progresses PeIN and/or squamous hyperplasia.
slowly and is usually limited to the epidermis and Prognosis: Dependent on histological grade,
cutaneous adnexal structures. However, in some nodal status, and depth of penetration into the vari-
34 Penis 383
ous anatomical compartments. A Prognostic Index at diagnosis. This usually arises in the glans
(ranging from 2 to 7) is used by some based on penis and is composed of small basaloid cells,
histological grade (1 to 3), anatomical level typically in nests with peripheral palisading,
involved by cancer (1 to 3), and presence of peri- often central comedo–type necrosis, and associ-
neural invasion (PNI) (0 or 1). This has been found ated with basaloid PeIN (undifferentiated). It is
to be a better predictor of inguinal node metastasis usually HPV-related and represents 5–10% of
and patient survival. Inguinal node dissections penile cancers.
might not be necessary for patients with low scores Sarcomatoid carcinoma: Is a rare, aggressive,
(2 and 3) but indicated for higher scores (5 to 7). large tumour with a predominance of anaplastic
Poor prognostic factors are lymphovascular inva- spindle cells. It usually involves the glans and
sion, vertical growth pattern, basaloid, sarcoma- may occur de novo or after radiation therapy and
toid, solid, anaplastic, and pseudoglandular there are frequent recurrences due to inadequate
subtypes. The average 5-year survival is 70–80%. surgery. Exhibits a biphasic epithelial-spindle
morphology and heterologous differentiation
WHO classification of tumours of the penis (2016) (muscle, cartilage, bone) can occur.
Malignant epithelial tumours Immunohistochemistry may be required for diag-
Squamous cell carcinoma nosis particularly when conventional, epithelial
Non-HPV related Squamous cell carcinoma differentiation cannot be identified. The progno-
Squamous cell carcinoma, usual type sis is poor.
Pseudohyperplastic carcinoma Verrucous carcinoma: This is a slow-growing,
Pseudoglandular carcinoma extremely well-differentiated variant of squamous
Verrucous carcinoma cell carcinoma (5–10%) with low malignant
Carcinoma cuniculatum potential. It is locally invasive, one third recur
Papillary Squamous cell carcinoma, NOS (inadequate surgery or multifocal tumour) but
Adenosquamous carcinoma rarely/never metastasizes. It is usually not associ-
Sarcomatoid (spindle) carcinoma ated with HPV. The tumour involves all penile
Mixed Squamous cell carcinoma compartments (glans most common) and pene-
trates through lamina propria with a broad base
HPV-related Squamous cell carcinoma and pushing borders. It shows exophytic type
Basaloid Squamous cell carcinoma invasion (broad based tumour islands without
Warty carcinoma fibrovascular cores). There is an association with
Papillary-Basaloid carcinoma lichen sclerosus in 60% of cases. It is important to
Warty-Basaloid carcinoma distinguish from exophytic HPV- associated
Clear cell Squamous cell carcinoma tumours such as giant condyloma and warty carci-
Lymphoepithelial—like carcinoma noma, and from papillary carcinoma NOS. It is
Other rare carcinomas prone to local recurrence if incompletely excised
and may dedifferentiate with radiotherapy.
Precursor lesions Carcinoma cuniculatum: Rarely reported in
Penile intraepithelial neoplasia—Warty- the penis and usually in elderly men, this tumour
Basaloid (undifferentiated) is large and represented by deep and narrow com-
Differentiated Penile intraepithelial neoplasia plex invaginations connecting to the surface
Paget’s disease through sinus tracts (hence the term cunicula-
tum—mimicking rabbit burrows). Microscopically
Melanocytic lesions this resembles verrucous carcinoma with anasto-
mosing channels and pseudocystic structures that
Basaloid carcinoma: An aggressive high- are lined by well differentiated squamous epithe-
grade and deeply invasive tumour in which 50% lium and filled with keratin material. Carcinoma
have enlarged inguinal nodes (due to metastasis) cuniculatum appears to have a good prognosis.
Papillary squamous cell carcinoma: Low- Lymphoepithelioma-like carcinoma: Extremely

grade malignant tumour representing 5–15% of rare tumour strongly linked to underlying HPV
all penile squamous cell carcinomas with a typi- infection. The tumour forms a syncytial pattern
cal exophytic pattern of growth. It is frequently with a marked lymphoplasmacytic infiltrate.
associated with lichen sclerosus and usually not Immunohistochemistry is often required for defin-
HPV-related. It is less aggressive than usual itive diagnosis.
squamous cell carcinoma and well differentiated Metastatic tumours: Bladder urothelial carci-
with architecturally complex papillae and an noma and prostatic adenocarcinoma account for
irregular jagged base. most cases, with the corpora cavernosa the most
Adenosquamous carcinoma: This is a rare frequently affected site.
tumour with predominantly squamous differenti- Malignant melanoma: Is the most common
ation intermixed with glandular areas. These tumour after squamous cell carcinoma, but is still
tumours tend to originate in the glans and may rare (<1%). It is similar to melanoma at other
arise from metaplastic or heterotopic mucinous sites but shows propensity for lymph node spread
glands which stain with carcinoembryonic anti- (50%).
gen (CEA). There is usually no association with Sarcomas: Extremely rare but include
HPV. It is typically more aggressive. Kaposi’s sarcoma, leiomyosarcoma, epithelioid
Warty carcinoma: Large, slow-growing sarcoma, and rhabdomyosarcoma.
cauliflower-like tumour with cobblestone appear- Others: Naevi and melanocytic proliferations,
ance usually affecting the glans. It is HPV-related haemangioma, glomus tumour, angiokeratoma,
in the majority of cases (HPV 16) and represents fibrous histiocytoma, neurofibroma, granular cell
5–10% of penile squamous cell carcinomas. The tumour, myointimoma, and leiomyoma.
prognosis is intermediate between that of low-
grade verruciform tumours and squamous cell
carcinoma of usual type. It may be associated 34.5 Surgical Pathology
with inguinal nodal metastasis. Warty PeIN may Specimens: Clinical Aspects
be identified in conjunction with this subtype.
Clear cell squamous cell carcinoma: Unusual 34.5.1 Biopsy Specimens
variant of penile SCC and HPV-related.
Histologically it has comedo-like areas with focal Macules, papules, nodules, and ulcers from the
papillary features. It behaves aggressively and is glans are biopsied to exclude neoplasia or confirm
now considered a distinct entity (WHO 2016). the diagnosis particularly if these lesions have
Pseudohyperplastic carcinoma: Rare tumour been long-standing. Specimens are either punch
involving foreskin and strong association with biopsies (3–5 mm) or excision skin ellipses.
lichen sclerosus suggesting that this inflamma- Circumcision specimens consisting of the
tory condition may play a precancerous role. It foreskin are removed more often in the context of
can be multifocal but has an excellent benign penile conditions (BXO, Zoon’s, phimo-
prognosis. sis, and paraphimosis). Occasionally a small can-
Pseudoglandular (acantholytic) squamous cer is removed in this fashion, and margins in this
cell carcinoma: This unusual variant of SCC is case will be important. These are dealt with below.
characterized by the presence of pseudoglandu- For PeIN of the glans with or without adjacent
lar spaces secondary to acantholysis. These skin involvement, therapeutic options include
tumours are typically large and invade deeply local applications of fluorouracil cream, micro-
into the corpora. The pseudoglandular spaces scopically controlled surgery, cryosurgery,
contain acantholytic neoplastic keratinocytes. electrofulguration, and laser ablation for smaller
There is a high incidence of regional metastasis lesions. Mohs microsurgery is used in some cen-
and mortality. tres but is technically demanding and has higher
34 Penis 385
recurrence rates. Wide local excision with cir- rates of local recurrence are low with few
cumcision may be adequate therapy for control of complications.
lesions limited to the foreskin.
34.5.2.3 Glansectomy
This procedure involves removing the foreskin
34.5.2 Resection Specimens and glans and although not commonly per-
formed, is indicated for localized tumours and
The goal of treatment in invasive penile carcinoma PeIN of the glans. Glansectomy is the best sur-
is complete excision with adequate margins. For gical option for T2 lesions confined to the glans
lesions involving the prepuce, this may be accom- with reconstruction. Frozen sections from the
plished with simple circumcision. For infiltrating corporal tips and distal urethra can be taken to
tumours of the glans, with or without involvement ensure negative surgical margins. This allows
of the adjacent skin, the choice of therapy is dic- for maximal function and cosmesis. There is a
tated by tumour size, extent of infiltration, and higher risk of incomplete removal and therefore
degree of tumour destruction of normal tissue. The tumour recurrence.
options include penile amputation (partial or total
penectomy) and irradiation. T3 penile cancer is 34.5.2.4 Partial Penectomy
most frequently managed by penile amputation for Partial penectomy with a tumour-free margin is
local control. Whether the amputation is partial, the standard operation for T2/3 lesions invading
total, or radical will depend on the extent and loca- the corpus spongiosum or corpora cavernosa. The
tion of the neoplasm. Radiation therapy with sur- extent of surgical resection relates to the size of
gical salvage is an alternative approach. T4 lesions the tumour although now a resection margin of
of the penis often require multimodal therapy for 2 cm is not mandatory. During the operation, the
adequate local control. Down-staging with neo- skin is incised circumferentially and the cavern-
adjuvant chemotherapy should be considered. The ous bodies are divided sharply to the urethra. The
standard chemotherapy is usually a platinum- dorsal vessels are then ligated and the urethra is
based regimen with 5-fluoro-uracil (5-FU). The dissected proximally and distally to attain a 1-cm
surgery is a penectomy with perineal urethros- redundancy. After a dorsal urethrotomy, a skin to
tomy. Alternatively, radiotherapy can be consid- urethra anastomosis is performed and the redun-
ered for local control/palliation in selected cases. dant skin approximated dorsally to complete the
Glansectomy, penectomy or distal urethrectomy closure.
may also be used as treatments for other primary
tumours of these sites including malignant 34.5.2.5 Modified Partial Penectomy
melanoma. When the penile stump after partial penectomy is
too short for directing the urinary stream, releas-
34.5.2.1 Mohs Micrographic Surgery ing the corpora from the suspensory ligament,
This is a technique by which histological margins dividing the ischiocavernosus muscle, and par-
are taken in a geometrical fashion around a conus tially separating the crura from the pubic rami
of excision. It is not a highly used approach as can obtain further length. The scrotum is incised
very few centres have expertise and experience. and skin flaps fashioned for penile coverage.
The local recurrence rate was 32% in one series.
34.5.2.6 Total Penectomy
34.5.2.2 Glans Resurfacing If the size/site precludes partial penectomy, then
This is a complex plastic surgery procedure used as part of penile amputation the proximal urethra
in some centres for indolent benign disease such is dissected and transposed to the perineum with
as lichen sclerosus, as well as preinvasive disease an indwelling catheter placed for an adequate uri-
(PeIN) and superficial low-grade tumours. The nary stream.
34.5.2.7 Radical Surgery limitations with micrometastatic disease

This is rarely performed but involves penectomy (<10 mm). However, lymphadenectomy can
including removal of the scrotum, testes, sper- carry substantial morbidity, such as infection,
matic cords, and ilioinguinal lymph node skin necrosis, wound breakdown, chronic
dissection. oedema, and even a low, but finite, mortality rate.
If two or more positive lymph nodes, or one node
34.5.2.8 I lioinguinal Lymph Node with extracapsular extension (pN3), are found
Dissection (ILND) unilaterally, an ipsilateral pelvic lymphadenec-
Inguinal lymphadenopathy in patients with penile tomy is indicated. Robot-assisted laparoscopic
cancer is common but may be the result of infec- ILND may be utilized in the future treatment of
tion rather than neoplasm. If palpable enlarged locally advanced penile cancer with the potential
lymph nodes persist 3 or more weeks after for fewer complications. Few histopathologists in
removal of the infected primary lesion and a the UK have had the opportunity to see and deal
course of antibiotic therapy, surgery should be with large numbers of penile tumours. The
considered. The superficial and deep ILNs (sepa- Urology Cancer Improving Outcome Guidance
rated by the fascia lata) are the first nodes affected proposed the setting up of dedicated multidisci-
by lymphatic metastatic spread. Local or regional plinary teams in Supraregional Penile Cancer
nodal recurrences usually occur within 2 years of Centres serving a population base of four million
primary treatment. In patients with negative or more and expecting to manage a minimum of
inguinal nodes after local treatment, follow-up 25 new patients each year. Developments include
depends on the primary treatment modality and is local excision with organ preservation for low-
also highly dependent on the grade, stage and the grade, early-stage tumours. The surgical margins
presence or absence of lymphovascular invasion are often close and checked by intraoperative fro-
in the primary penile tumour. ILNDs are reserved zen section.
for Grade 2–3 tumours which are T2 or greater,
and G3 T1b tumours (European Association of
Urology guidelines). There are two diagnostic 34.6 Surgical Pathology
procedures, modified inguinal lymphadenectomy Specimens: Laboratory
(mILND) and dynamic sentinel-node biopsy Protocols
(DSNB). Both are standard approaches for inva-
sive diagnosis of inguinal lymph nodes in clini- 34.6.1 Biopsy Specimens
cally node-negative patients. Modified ILND is
the standard surgical operation performed in Diagnostic punch and incisional biopsies: Count,
most centres. measure (mm), process intact, and cut through
In cases of proven regional inguinal lymph three levels. PAS stain for fungi if suspected.
node metastasis (fine needle aspiration cytology Elliptical excisions: Measure (mm), ink the
or biopsy) without evidence of distant spread, deep and lateral (circumferential) margins, and
bilateral ilioinguinal dissection is the treatment cut into multiple transverse serial slices.
of choice. Radiation therapy may be an alterna- Foreskin and Glans resurfacing specimens:
tive in patients who are not surgical candidates.
Postoperative irradiation can decrease the inci- • Measure, inspect, and orientate. The foreskin
dence of inguinal recurrences. Because of the is a cylindrical structure that is usually cut
high incidence of microscopic node metastases, open into a rectangle during circumcision,
elective adjunctive inguinal dissection of clini- therefore the cut ends are not resection
cally uninvolved (negative) lymph nodes in con- margins.
junction with amputation is often used for • Ideally pin the four corners of the specimen
patients with poorly differentiated tumours. PET/ with the mucosa oriented on one side and the
CT may be useful in case selection but there are skin on the other.
34 Penis 387
• Identify the coronal sulcus and ink the muco- cus. Proceed with foreskin as above. If the
sal and cutaneous margins (glans/coronal mar- foreskin is affected by tumour, do not remove.
gin and the peripheral skin/shaft margin) of • Ideal sectioning is longitudinal, centred along
resection with different colours. The free mar- the urethra, with additional parallel parasagit-
gin/edge in glans resurfacing specimens is tal sections on both sides. The urethra is
often ragged. opened along the ventral aspect where it is
• Fix the specimen in 10% buffered formalin closest to the surface and the cut is then con-
overnight. tinued to bisect the penis. The use of a probe
• Specimen photography may be necessary. to identify the urethra is discouraged, except
• In cases of known or suspected penile carci- to allow the initial incision, as it may dislodge
noma or precancerous lesions (PeIN) it is superficial tumours or areas of PeIN.
advisable to block the entire specimen rather • Embed complete sections of the glans and
than sample. tumour, which should include the urethral
• Take sections perpendicular to the skin/muco- meatus. As urethral invasion upstages the
sal surface to include margins. tumour to pT2/3, adequate sampling is
• Include any obvious areas of surface scarring important.
or raised lesions. • Involvement of the foreskin, frenulum, glans,
• Submit entirely if <3–4 cm and if greater, meatus, corpus spongiosum, urethra, and cor-
sample at least one block/cm. pora cavernosa is recorded.
• A transverse section of the urethral margin
should include the mucosal surface, surround-
34.6.2 Resection Specimens ing lamina propria, and corpus spongiosum.
This is usually long in partial penectomy spec-
34.6.2.1 Penectomy (Partial/Total) imens because the surgical technique uses a
and Glansectomy long urethra stump for reconstruction.
Initial procedure: • Shaft margin: usually a large specimen. Divide
The various anatomical components of the it in two, from dorsal to ventral along the cen-
penis should be examined as any of these may be tral septum, and submit the cut surface
the site of involvement. entirely. Each half should be labelled left or
right. If the specimen has a long shaft, cut two
• Photograph the specimen, before and after or three additional sections distal to the
longitudinal sectioning, with emphasis on margin.
tumour invasion of the various anatomical • Examination of the cut surface of the glans
levels. represents the best approach for surgical
• Fix in 10% formalin for 24–36 h. pathology evaluation.
• Measurements: • Glans (glansectomy): The specimen includes
–– Dimensions (cm) of the specimen and indi- glans, meatus, distal urethra and coronal sul-
vidual components (foreskin, shaft, and cus with or without foreskin. The tips of the
glans). corporal heads are included in some
–– Tumour specimens.
Length × width × depth (cm) or maximum • Parasagittal longitudinal sections from right
dimension (cm). and left of the centre of the specimen, for the
Distances (cm) to the urethral and surgical assessment of the relationship of the tumour
resection margins. with the urethra and the ventral and dorsal
• Identify the shaft and glans. skin margins.
• Remove the foreskin, leaving a 2–3-mm • The proximal urethral margin does not pro-
redundant edge of skin around the sulcus. This trude from the deep surface so it is not usually
permits better evaluation of the coronal sul- blocked separately.
• Coronal cruciate sections of right and left –– Appearance (verrucous/warty/exophytic/

sides should be taken to include peripheral sessile/ulcerated)
skin margins. –– Edge (circumscribed/irregular)
• Photograph suitable individual slices. • Foreskin
• If accompanying lymphadenectomy speci- –– Ulcerated/thickened/papule/warty
mens, fix in 10% buffered formalin, prefera- • Glans
bly overnight. –– Erythematous/ulcerated/macule/papule/
• Identify the number and size of all lymph nodes warty
and whether sampling, sentinel lymph nodes or • Others
dissections and anatomical origin of lymph –– LS (BXO), scars of previous surgery/
nodes, iliac or pelvic, including laterality. biopsy
• If orientated, record the location of lymph
nodes as upper inner quadrant, superficial, and Blocks for histology (Fig. 34.2):
deep inguinal nodes.
• Submit all lymph nodes for histological • Shave section from the shaft margin (includ-
examination. ing skin, erectile bodies, and urethra).
• Samples of foreskin to include associated
Description: conditions.
• Sample four sections of tumour to demon-
• Tumour strate depth of invasion and relationships
–– Site (urethral meatus/glans/prepuce/coro- to the adjacent surface epithelium, corpus
nal sulcus/shaft—dorsal, ventral, lateral) spongiosum, corpora cavernosa, and
–– Single/multifocal urethra.
Blocks of foreskin, Blocks of shaft skin,

glans, tumour and sulcus, tumour and
urethra corpus cavernosum
Transverse block the

proximal resection
margin of the shaft
1. Paint and transverse block the shaft proximal resection margin

2. Multiple serial longitudinal blocks to represent tumour in relation
to foreskin, sulcus, glans, corpora and urethra
Fig. 34.2 Blocking a penectomy specimen (Reproduced, with permission, from Allen and Cameron (2013))
34 Penis 389
• Sample two to three transverse sections through • Perineural space invasion (present/absent).
the shaft at different levels. • Regional lymph nodes, site, number, involved/
• Sample longitudinal sections through the not involved, size of largest metastatic deposit
glans to include the urethra. in involved nodes, extranodal spread if pres-
• In larger specimens, it is important to submit ent, lymph node margins positive/negative.
two to three additional sections of the more These are the superficial and deep inguinal
distal urethral cylinder to ensure adequacy of nodes and the pelvic nodes.
the resection margin.
• Count and sample all lymph nodes accompa- pN0 No regional lymph node metastasis
nying the specimen. pN1 Metastasis in one or two inguinal lymph nodes
pN2 Metastasis in more than two or bilateral
inguinal lymph nodes
pN3 Extranodal extension of lymph node metastasis
or pelvic lymph node(s) unilateral or bilateral
• Tumour site (urethra, foreskin, glans, shaft)
• Tumour size and depth (mm)
• Patterns of growth and histological type • Excision margins: urethra, corpora, skin—dis-
• Tumour grade (well, moderately, poorly dif- tances of carcinoma and PeIN (mm)
ferentiated (G1–3)) • Ancillary studies: immunohistochemistry
• Tumour type—Squamous cell carcinoma, usual (p16) and molecular studies for HPV typing
type, pseudohyperplastic, pseudoglandular, ver- • Prognostic index: histological grade/anatomi-
rucous, carcinoma cuniculatum, papillary, ade- cal level and perineural invasion
nosquamous, sarcomatoid, mixed, basaloid, • Other pathology: status of non-neoplastic
warty, papillary-basaloid carcinoma, warty- epithelium (PeIN, squamous hyperplasia,
basaloid, clear cell, lymphoepithelial–like. condyloma, BXO, Zoon’s, inflammatory
• Tumour extension: subepithelial connective process).
tissue, tunica albuginea, corpus spongiosum,
corpus cavernosum, urethra
• PeIN component (present/absent/extent/dif-
ferentiated/undifferentiated, multifocal) Bibliography
Extent of local tumour spread: TNM 8 for Allen DC. Histopathology reporting. Guidelines for surgi-
penile carcinoma. Allen DC, Cameron RI. Histopathology specimens:
pT0 No evidence of primary tumour London: Springer; 2013.
PTis Carcinoma in situ Arya M, et al. Long-term trends in incidence, survival and
PTa Noninvasive verrucous carcinoma mortality of primary penile cancer in England. Cancer
pT1a Tumour invades subepithelial connective Causes Control. 2013;24:2169.
tissue without lymphovascular invasion and is Brierley JD, Gospodarowicz MK, Wittekind C, editors.
not poorly differentiated TNM classification of malignant tumours. 8th ed.
pT1b Tumour invades subepithelial connective Chaux A, Cubilla AL. Diagnostic problems in precan-
tissue with lymphovascular invasion or is cerous lesions and invasive carcinomas of the penis.
poorly differentiated Semin Diagn Pathol. 2012a;29:72–82.
pT2 Tumour invades corpus spongiosum ± urethra Chaux A, Cubilla AL. Stratification systems as prognos-
pT3 Tumour invades corpus cavernosum ± urethra tic tools for defining risk of lymph node metastasis
pT4 Tumour invades other adjacent structures in penile squamous cell carcinomas. Semin Diagn
Pathol. 2012b;29:83–9.
Chaux A, Cubilla AL. The role of human papillomavirus
• Lymphovascular space invasion (present/ infection in the pathogenesis of penile squamous cell
absent). carcinoma. Semin Diag Pathol. 2012c;29:67–71.
Chaux A, Torres J, Pfannl R, et al. Histologic grade in Horenblas S. Sentinel lymph node biopsy in penile carci-
penile squamous cell carcinoma: visual estimation noma. Semin Diagn Pathol. 2012;29:90–5.
versus digital measurement of proportions of grades, Moch H, Cubilla AL, Humphrey PA, Reuter VE, Ulbright
adverse prognosis with any proportion of grade 3 and TM. The 2016 WHO classification of tumours of
correlation of a Gleason-like system with nodal metas- the urinary system and male genital organs - part
tasis. Am J Surg Pathol. 2009;33(7):1042–8. A: renal, penile, and testicul ar tumours. Eur Urol.
Corbishley CM, Rajab RM, Watkin NA. Clinicopathological 2016;70(1):93–105.
features of carcinoma of the distal penile urethra. Semin Oxley JD, Corbishley C, Down L, Watkin N, Dickerson D,
in Diagn Pathol. 2015a;32(3):238–44. Wong NA. Clinicopathological and molecular study of
Corbishley CM, Tinwell B, Kaul A, Ayres B, Watkin penile melanoma. J Clin Pathol. 2012;65:228–31.
NA. Glans resurfacing for precancerous and super- Tang V, Clarke L, Gall Z, Shanks JH, Nonaka D, Parr
ficially invasive carcinomas of the glans penis. NJ, et al. Should centralized histopathological review
Pathological specimen handling and reporting. Semin in penile cancer be the global standard? BJU Int.
Diagn Pathol. 2015b;32(3):232–7. 2014;114:340–3.
Epstein JI, Cubilla AL, Humphrey PA. Tumours of the The Royal College of Pathologists. Datasets and tissue
prostate gland, seminal vesicles, penis and scrotum. pathways: urinary tract and testis. https://www.rcpath.
Washington, DC: Armed Forces Institute of Pathology; org/profession/publications/cancer-datasets.html
2011. p. 405–611. Wittekind C, Greene L, Hutter RVP, Klimfinger M, Sobin
Hakenberg OW, Comperat EM, Minhas S, Necchi A, LH. TNM atlas: illustrated guide to the TNM/pTNM
Protzel C, Watkin N. Guidelines on Penile Cancer, classification of malignant tumours. 5th ed. Berlin/
2014 update. Eur Urol. 2015;67:142–50. Heidelberg: Springer; 2005.
Part VII
Pelvic and Retroperitoneal Specimens
Pelvic Exenteration Specimens
35
Damian T. McManus and Derek C. Allen
35.1 Anatomy increasing frequency for pelvic recurrence of rec-

tal adenocarcinoma or anal carcinoma. Patients
The relevant anatomy is discussed in other sec- undergoing this procedure for these cancers will
tions pertaining to the various organs in which often have been treated by radiotherapy
cancers originate. Specimens may be classified pre-operatively.
into one of three groups (Fig. 35.1): More detailed discussion of the symptoms and
Anterior pelvic exenteration: Bladder, lower clinical signs of the various malignant tumours
ureters, reproductive organs, draining lymph that might result in a pelvic exenteration are
nodes, and pelvic peritoneum. found in the relevant chapters relating to gastro-
Posterior pelvic exenteration: Rectum, distal intestinal tract and gynaecological specimens.
colon, internal reproductive organs, draining Locally advanced malignancies may produce fis-
lymph nodes, and peritoneum. Such procedures tula between viscera such as the rectum and
are also known as composite resections. vagina. Specific symptoms and signs result, e.g.,
Total pelvic exenteration: Bladder, lower ure- fistula between the rectum and urinary bladder
ters, rectum, distal colon, reproductive organs, may result in pneumaturia (gas bubbles in the
draining lymph nodes, and peritoneum. urine) and contamination of the urine by faeces
(faecaluria).

Pelvic exenteration is performed for locally
advanced or recurrent malignant tumours within Exenterations are performed for advanced or
the pelvis. Whilst locally advanced (stage IV) recurrent pelvic malignancy in the absence of
cervical carcinoma was formerly the commonest extra-pelvic metastatic spread. Patients will usu-
indication, this is now much rarer as a result of ally have been staged by one or more radiological
earlier detection of cervical cancer by screening techniques:
programs. Exenteration is now performed with
• CT scanning: This is particularly useful in the
evaluation of pelvic and retroperitoneal
D.T. McManus (*) • D.C. Allen lymphadenopathy and metastatic disease out-
Histopathology Laboratory, Belfast City Hospital, side the pelvis. Magnetic resonance imaging
Belfast Health and Social Care Trust, Belfast, UK has largely replaced CT scanning in the evalu-
e-mail: damian.mcmanus@belfasttrust.hscni.net;
derek.allen@belfasttrust.hscni.net ation of the T stage of cervical, endometrial,

394 D.T. McManus and D.C. Allen
Ovary
Uterus Sigmoid colon
Bladder
Rectum
Urethra
Vagina Anus
Anterior exenteration
Posterior exenteration Total pelvic exenteration
Fig. 35.1 Pelvic exenterations (Reproduced, with permission, from Allen and Cameron (2013))
and rectal tumours. Pelvic exenteration is a with CT (CT-PET) is particularly useful in

major surgical procedure and carries with it identification and localization of recurrent or
considerable morbidity and mortality. metastatic disease.
Although occasionally it might be performed
as a palliative procedure, it is contraindicated
if there is evidence of widespread distant 35.4 Pathological Conditions
metastases.
• Magnetic resonance imaging (MRI): This is Pelvic exenteration may be performed for:
used to clinically stage cervical, endometrial,
and rectal cancers pre-operatively. • Advanced stage IV cervical carcinoma.
• Positron emission tomography (PET scan- • Locally advanced rectal adenocarcinoma.
ning): PET scanning detects metabolic activ- • Recurrent cervical, rectal, or anal carcinoma
ity in malignant tumours and in combination with no evidence of distant metastasis.
35 Pelvic Exenteration Specimens 395
• Certain sarcomas or locally invasive tumours Contraindications to pelvic exenteration

such as aggressive angiomyxoma. The pelvis include significant comorbidity or distant meta-
is a common site for such tumours, which may static disease (except perhaps for isolated resect-
be associated with advanced pelvic disease able liver metastasis from rectal carcinoma).
without distant metastasis elsewhere. Involvement of major pelvic vessels or nerves
• Pelvic exenteration may be used occasionally by carcinoma is generally felt to represent a con-
for advanced endometrial adenocarcinoma traindication to surgery for carcinomas but not
with involvement of the vagina but is gener- necessarily sarcomas. Involvement of pelvic
ally not recommended in ovarian carcinoma side walls or sacral bone are also relative contra-
as there is usually peritoneal disease outside indications, although en bloc resection of the
the pelvis. Advanced vaginal or vulval squa- sacrum can be used for locally advanced primary
mous carcinoma with involvement of the rec- and recurrent rectal carcinoma.
tum or urinary bladder may rarely be treated
by pelvic exenteration but such locally
advanced disease is frequently accompanied 35.6 Surgical Pathology
by pelvic side wall involvement or nodal Specimens: Laboratory
metastasis. Protocols
• Aggressive muscle invasive transitional carci-
noma can be treated by cystoprostatectomy or A general protocol is described. This can be
variants of pelvic exenteration. Prostatic carci- modified according to the type of specimen
noma may be treated by radical prostatectomy received (anterior, posterior, or total pelvic exen-
in certain circumstances, but pelvic exentera- teration) and the primary site of the tumour.
tion has no role in the management of locally
advanced prostatic carcinoma, as such disease Specimen:
is almost invariably accompanied by distant
metastatic spread. • Anterior exenteration
• Posterior exenteration/composite resection
• Total pelvic exenteration
Specimens: Clinical Aspects Initial procedure:
Advanced (stage IV) cervical carcinoma is usu- • Identify and measure each organ that is pres-
ally treated pre-operatively by radiotherapy or ent in the resection.
neoadjuvant chemotherapy with radiotherapy. • Identify and take a limit block from:
Locally advanced rectal cancer may be treated by –– Ureters
long course or short course chemo-/radiotherapy –– Urethra
to downstage tumours prior to resection. Cervical –– Vagina
carcinoma can show an excellent response to –– Proximal and distal bowel
radical radiotherapy treatment, and it is not –– Painted circumferential soft tissue or radial
uncommon to find no evidence of residual dis- fascial margins, and, serosal surface of rec-
ease. There can be a similar downstaging of rectum above peritoneal reflection if present.
tal carcinoma, in some instances obviating the The plane of the mesorectal excision
need for composite resection, and macroscopi- should also be graded for advanced rectal
cally the tumour may only be represented by a tumours as discussed in Chap. 6.
small area of ulceration. Similarly local lymph • Good fixation is crucial but can be problem-
nodes hyalinize becoming difficult to identify atic in such a large specimen. The bladder can
and harvest. be inflated with formalin from without. The
bowel may be partially opened avoiding dis- –– Pericervical tissues with lateral circumfer-
ruption of the serosa and radial margin in the ential soft tissue margins
vicinity of the tumour. –– Ureters
• After fixation, the specimen can be bisected –– Peritoneum
with a long sharp knife in the sagittal plane to –– If no cervical tumour is apparent post-
give roughly equal left and right halves. This radiotherapy, then the cervix must be
should allow visualization of the anatomical blocked to identify residual disease histo-
relationship between cervical tumours and the logically. It may be “clockfaced” submit-
rectum posteriorly, the vagina inferiorly, and ting the entire cervix for histology, or more
the urinary bladder anteriorly. Rectal tumours pragmatically, four quadrants taken from
may spread anteriorly to involve the vagina and the transformation zone.
also the urinary bladder. Fistulae may be pres- • Representative sections are also submitted
ent and can be demonstrated by exploration from non-neoplastic tissues:
with a probe. –– Bladder wall
–– Urethra
Description: –– Ureters
–– Vagina
• List the organs present and dimensions (cm). –– Endometrium/myometrium
• Presence or absence of tumour. –– Fallopian tubes and ovaries
• Site of tumour. –– Colorectum
• Size (cm) of tumour. • Pelvic lymph node dissections will often be
• Extent of tumour; relationship of tumour to submitted separately and individually labeled
adjacent organs and resection margins. and are described later.
• Fistulous tracts involving tumour or
perforation. Rectal carcinoma
• Describe anatomical location, size, and num-
ber of harvested lymph nodes. • Blocks of tumour and tumour in relation to:
• List of any separately submitted lymph node –– Mucosa
groups. –– Posterior vaginal wall
• Other pathology, e.g., dilatation of ureter. –– Dome of urinary bladder
–– Prostate and seminal vesicles (in males)
Blocks for histology: –– Circumferential margin of mesorectum
–– Peritoneum
• It may be helpful to use a labeled digital pho- • The mesorectal fat must be dissected to iden-
tograph or diagram such as Fig. 35.2 to identify lymph nodes.
tify the origin of blocks for histology. • Representative sections of non-neoplastic tis-
• Longitudinal limit blocks of colon, rectum, sues are also submitted.
ureters, urethra, and distal vagina.
• The remaining blocks taken for histology Histopathology report:
depend on the type and origin of the tumour if
a tumour can be identified: • The specific features that should be included in
pathology reports of cervical, rectal cancers,
Cervical carcinoma and soft tissue tumours are detailed in other rel-
evant chapters. The purpose of pelvic exentera-
• Blocks of tumour and tumour in relation to: tion is one of complete local excision, and in
–– Anterior rectal wall view of this, the status of longitudinal and cir-
–– Posterior bladder wall cumferential resection margins and peritoneum
–– Vagina in relation to the tumour must be documented.
35 Pelvic Exenteration Specimens 397
Tumour block harvest in relation to:

Peritoneum Pericervical tissues
Cervix and including the lateral
vagina circumferential limits
Posterior
bladder
wall Anterior rectal
wall
Endo/myometrium
Proximal bowel
block
margin
Tube and
ovary
Sample normal tissues

• bladder wall
• urethra
• vagina
• ureters
• colorectum
• endo/myometrium
• tubes/ovaries
Distal urethra
limit
Distal vaginal
limit Distal bowel
margin
Fig. 35.2 Blocking of total pelvic exenteration specimen for a pT4 cervical carcinoma (Reproduced, with permission,
• Sarcomas and tumour recurrence in soft tissues Bibliography

• The dissection and precise blocking protocol
must be adapted to suit the individual Allen DC. Histopathology reporting. Guidelines for surgi-
specimen. cal cancer. 3rd ed. London: Springer; 2013.
• In general terms, blocks should be taken from Allen DC, Cameron RI. Histopathology specimens:
clinical, pathological, and laboratory aspects. 2nd ed.
tumour (1/cm diameter), tumour and involved Berlin-Heidelberg: Springer; 2013.
pelvic structures, tumour and resection mar- Brierley JD, Gospodarowicz MK, Wittekind C, editors.
gins, and representative blocks of uninvolved TNM classification of malignant tumours. 8th ed.
structures. Oxford: Wiley-Blackwell; 2017.
Ferenschild FTJ, Vermaas M, Verhoef C, Ansink AC, Dawson’s gastrointestinal pathology. 5th ed. Oxford:
Kirkels WJ, Eggermont AMM, de Wilt JHW. Total Wiley-Blackwell; 2013.
pelvic exenteration for primary and recurrent malig- Temple WJ, Saettler EB. Locally recurrent rectal cancer:
nancies. World J Surg. 2009;33:1502–8. role of composite resection of extensive pelvic tumors
Odze RD, Goldblum JR, editors. Odze and Goldblum with strategies for minimizing risk of recurrence.
Surgical pathology of the GI tract, liver, biliary tract, and J Surg Oncol. 2000;73:47–58.
pancreas. 3rd ed. Amsterdam: Elsevier Saunders; 2015. The Royal College of Pathologists. Cancer datasets and
Rodrigues-Bigas MA, Petrelli NJ. Pelvic exenteration and tissue pathways. https://www.rcpath.org/profession/
its modifications. Am J Surg. 1996;171:293–8. publications/cancer-datasets.html Accessed Oct
Shepherd NA, Warren BF, Williams GT, Greenson JK, 2016.
Retroperitoneum
36
Oisin P. Houghton and Damian T. McManus
36.1 Anatomy 3. Common iliac

4. Internal iliac
The retroperitoneal space may be defined as that 5. External iliac
part of the lumbo-iliac region, which is bounded 6. Superficial and deep inguinal
anteriorly by the parietal peritoneum, posteriorly by 7. Sacral
the posterior abdominal wall, superiorly by the 12th 8. Pararectal
rib and vertebra, and inferiorly by the iliac crest and
the base of the sacrum. The lateral borders are The testes drain to the para-aortic lymph
formed by the quadratus lumborum muscles. nodes and the prostate to the sacral and internal
This space contains the kidneys, adrenal iliac nodes. The uterus drains to the external and
glands, ureters, aorta and inferior vena cava and common iliac nodes.
their tributaries, and many lymph nodes. The genitourinary system is considered in
Numerous nerves, the lumbosacral nerve plexus detail in Chaps. 29–34. This section will consider
and ganglia from both the sympathetic and para-
sympathetic autonomic nervous system, are also
present.
The retroperitoneal and pelvic lymph nodes
2 5
are found around the aorta and its branches and
may be divided into the following groups 4
(Fig. 36.1):
3 1
1. Para-aortic
2. Inferior mesenteric
6
6
O.P. Houghton (*)
Fig. 36.1 Retroperitoneal and pelvic lymph nodes. (1)
Hypogastric (internal iliac); (2) common iliac; (3) exter-
e-mail: oisin.houghton@belfasttrust.hscni.net
nal iliac; (4) lateral sacral; (5) para-aortic; (6) inguinal
D.T. McManus (Used with the permission of the Union for International
Histopathology Laboratory, Belfast City Hospital, Cancer Control (UICC), Geneva, Switzerland. The origi-
Belfast Health and Social Care Trust, Belfast, UK nal source for this material is from Wittekind et al. (2005))

400 O.P. Houghton and D.T. McManus
tumours of the retroperitoneum and retroperito- Liposarcoma:

neal lymph node dissections. Diseases of the Arising within the retroperitoneal adipose tissue,
adrenal gland are discussed in Chap. 37. well-differentiated liposarcoma, is one of the com-
monest histological subtypes. Such lesions can
reach a considerable size and can be difficult to
36.2 Clinical Presentation excise from the retroperitoneum; surgery often
requires removal of the kidney and adjacent intes-
The retroperitoneum is rather inaccessible, and tine. Although well-differentiated liposarcoma
because of its anatomical location, tumours can does not metastasise, it may prove lethal because
grow to a large size before becoming clinically of pressure effects on adjacent organs or local
apparent. Symptoms and signs of a retroperito- recurrence if incompletely excised. Importantly,
neal tumour may be vague and only manifest late well differentiated liposarcoma may also undergo
in the course of the disease because of obstruc- dedifferentiation (to a dedifferentiated liposar-
tion/displacement of adjacent structures such as coma) with a significant potential for distant
the ureter. spread; careful macroscopic examination and ade-
quate sampling are important to detect foci of
dedifferentiation in an otherwise well-
36.3 Clinical Investigations differentiated appearing liposarcoma. Pleomorphic
liposarcoma may also arise in the retroperitoneum;
Plain abdominal X-ray, barium enema, or an this is an aggressive tumour with a high risk of
intravenous pyelogram may suggest the presence local recurrence and distant metastasis. Myxoid
of a retroperitoneal tumour due to distortion of liposarcoma is extremely rare in this location,
normal structures. However, the investigations of although myxoid change is common in both well-
choice are ultrasonography, CT scanning, or mag- differentiated and dedifferentiated liposarcoma.
netic resonance imaging (MRI). Arteriography Lipomas also arise at this site although they are
may also be useful, particularly if resection of a very uncommon; careful evaluation is necessary to
large tumour is contemplated. Historically, lym- distinguish from lipoma-like well-differentiated
phangiography was the preferred investigation in liposarcoma as described above.
the evaluation of lymphadenopathy in the retro- Other sarcomas:
peritoneum. Now CT scanning is more com- These include undifferentiated pleomorphic
monly performed. Whilst CT is very good at sarcoma and leiomyosarcoma. Careful consider-
detecting large nodal masses associated with ation must be given before rendering a diagnosis
malignant lymphoma, it is less effective in the of undifferentiated pleomorphic sarcoma in the
assessment of metastatic disease to the pelvic and retroperitoneum as it is increasingly recognized
retroperitoneal nodes. The status of the pelvic that a significant proportion of apparent undiffer-
and retroperitoneal lymph nodes is particularly entiated pleomorphic sarcomas or tumours with a
important in patients with stage 1 non-semino- myxofibrosarcoma-like pattern represent dedif-
matous malignant germ cell tumours of the testis ferentiated liposarcomas. Furthermore, at this
for reasons discussed later, and positron emission site, lesions such as sarcomatoid renal cell carci-
tomography (PET) scanning can occasionally noma should also be excluded. Both benign and
give supplementary information when the CT malignant smooth muscle tumours may occur.
scan is equivocal. Leiomyoma is reported as very rare and is to be
distinguished from leiomyosarcoma and renal
angiomyolipoma. Leiomyosarcoma may arise
36.4 Pathological Conditions from the wall of the inferior vena cava or its
tributaries.
A variety of tumours, both benign and malignant Peripheral nerve tumours:
may arise within the retroperitoneum. The com- Relatively common at this site, although not
moner lesions are discussed here. as frequent as in the mediastinum. Schwannomas
36 Retroperitoneum 401
may be quite large and show cystic degenera- 36.5 Surgical Pathology
tion; neurofibromas and malignant peripheral Specimens: Clinical Aspects
nerve sheath tumours are also described. Rarer
tumours include lesions such as paraganglioma 36.5.1 Biopsy Specimens
(chemodectoma/aortic body tumour), ganglio-
neuroma, neuroblastoma, and other small round Percutaneous CT-guided needle core biopsy or
blue cell tumours such as Ewing’s sarcoma/ fine needle aspiration may be performed for ret-
PNET and intraabdominal desmoplastic small roperitoneal tumours or if there is evidence of
cell tumour. lymphadenopathy suggestive of lymphoma. It is
Extrapleural solitary fibrous tumour and car- not commonly used in the investigation of sus-
cinoid tumours: pected metastatic disease at this site.
The retroperitoneum remains a recognised site
for true extrapleural solitary fibrous tumour;
however, it is stressed that haemangiopericytoma- 36.5.2 Resection Specimens
like areas may be present in various soft tissue
tumours, and this pattern is commonly seen in Retroperitoneal tumours:
dedifferentiated liposarcoma. These may be very large and structures such as
The histogenesis of retroperitoneal carcinoid the kidney enveloped by the tumour. A smaller
tumours is uncertain. Some may represent a form wedge biopsy obtained at laparotomy may also
of germ cell tumour, which also occur at this site be submitted if it is not possible to excise the
either as primary tumours or more commonly as whole tumour or if a needle core biopsy has
lymph node metastasis from a testicular or ovar- proven inconclusive.
ian primary. Retroperitoneal and pelvic lymph node
Other tumours presenting rarely in the retro- dissections:
peritoneum include pleomorphic rhabdomyosar- Nodal dissections are frequently performed in
coma, epithelioid haemangioendothelioma and association with cervical carcinomas unless these
PEComa (perivascular epithelioid cell tumour). fall into the micro-invasive category and/or are
Adrenal gland lesions (adenoma, carcinoma, being managed by a non-radical surgical
metastases) present a relatively common diag- approach. Nodal dissection is also indicated for
nostic problem—see Chap. 37. late stage and high-grade endometrial cancers,
Malignant lymphoma and metastatic disease: radical prostatectomy and cystectomy, but the
Lymphoma not infrequently involves the retro- situation for testicular germ cell tumours is more
peritoneal lymph nodes and can lead to massive complex.
enlargement. Diffuse large B cell lymphoma and Metastatic seminoma is generally treated
follicle centre cell lymphomas are among the with radio/chemotherapy. Retroperitoneal lymph
commonest. Pelvic and retroperitoneal nodes are node dissection (RPLND) may be performed as
a common site for metastatic disease from malig- prophylaxis against abdominal recurrence in
nant germ cell tumours of the testis, prostatic car- clinical stage 1 non-seminomatous germ cell
cinoma, or gynaecological malignancy. tumours or in the context of a residual mass
Miscellaneous: post-chemotherapy. Prophylactic RPLND is gen-
Abdominal aortic aneurysms are only rarely erally not performed in the United Kingdom for
biopsied. Idiopathic retroperitoneal fibrosis is an clinical stage 1 non-seminomatous germ cell
uncommon reactive, inflammatory condition that tumours, in contrast to Europe or the United
may simulate a tumour at laparotomy—it stric- States, where such operations are more
tures and distorts the ureters resulting in hydrone- common.
phrosis. Most cases are of unknown etiology, Clinical stage 1 non-seminomatous testicular
possibly related to IgG4 systemic sclerosing dis- germ cell tumours may be managed conservatively
ease, a minority being drug-related or associated by surveillance with CT scanning and serial serum
with inflammatory type aortic aneurysms. tumour markers or by chemotherapy. The prog-
nostic factors influencing the administration of PCR and clonality or sequence analysis, touch
chemotherapy are considered in more detail in imprints for FISH, and if available, glutaralde-
Chap. 33. However, about 25% of patients man- hyde-fixed tissue for electron microscopy.
aged by surveillance will relapse with abdominal
nodal disease being the most frequent site. 36.6.1.3 Resection Specimens
Chemotherapy will then be administered and if a
residual mass persists this will be excised. Such Initial procedure:
specimens frequently show widespread necrosis
• The specimen is weighed (g) and measured
and fibrosis, but there may be residual areas of
(cm). The relationship of tumour to any recog-
viable tumour. This can range from differentiated,
nizable organs such as the kidney that are
mature tissues that are insensitive to chemotherapy
present in the resection is noted.
and form cystic masses that press on local struc-
• The surface of the specimen is painted with ink.
tures (growing teratoma syndrome) to mixed solid/
• If the specimen is received unfixed, then con-
cystic lesions containing immature/undifferenti-
sideration should be given to the use of ancil-
ated teratoma (10–25% of cases). The factors
lary techniques as described above.
influencing an increased risk of progression are
• The specimen is fixed in formalin for 24–36 h.
the presence of embryonal carcinoma (teratoma
It may be advantageous to cleanly bisect large
undifferentiated), yolk sac tumour or trophoblastic
specimens after a few hours to allow adequate
tumour, and incomplete resection (as judged by
fixation in the centre.
the surgeon). These criteria will influence the deci-
• The specimen is serially sectioned at intervals
sion to give further chemotherapy, and this should
of 1–2 cm.
be borne in mind when the pathologist is examin-
ing these specimens so that sufficient blocks are Description:
sampled and margins inked.
• Weight (g), dimensions (cm) of specimen and
constituents (fat, connective tissue, kidney,
36.6 Surgical Pathology lymph nodes, etc.).
Specimens: Laboratory • Tumour size (maximum diameter or three
Protocols dimensions—cm).
• Edge of tumour (well circumscribed, encapsu-
36.6.1 Retroperitoneal Tumours lated, or infiltrative) and relationship to sur-
rounding structures.
36.6.1.1 N eedle Core Biopsy • Appearance of cut surface of tumour (haemor-
Specimens rhage, necrosis, cystic degeneration, etc.).
These are counted, their length recorded (in mm) • Blocks for histology:
and embedded for histological examination • Representative samples of tumour (approxi-
through multiple levels. Fine cores may be painted mately one block per centimetre to include
with alcian blue to allow visualization when fac- any macroscopically different looking areas).
ing the paraffin block at section cutting. • Tumour and adjacent structures.
• Tumour and inked circumferential margin of
36.6.1.2 Excision Biopsy specimen.
These are weighed (g) and their dimensions (cm) • Lymph nodes.
recorded. The lesion is serially sectioned, and • Uninvolved organs/tissues.
either representative sections taken for histology or
all the tissue is processed. If the biopsy is received Histopathology report:
unfixed and depending on the clinical differential
diagnosis, material may be triaged for appropriate • Tumour type.
ancillary methods including DNA extraction for • Maximum diameter of tumour.
36 Retroperitoneum 403
• Tumour grade (if applicable). the final histology report the number of nodes
• Tumour stage; use the TNM 8 system for soft identified.
tissue sarcomas where retroperitoneum is a • RPLNDs post-chemotherapy for testicular
specific topographical site: pT1 ≤ 5 cm, germ cell tumours present particular chal-
pT2 > 5 cm and ≤10 cm, pT3 > 10 cm and lenges. There may be a recognizable tumour
≤15 cm, pT4 > 15 cm maximum tumour mass present. The circumferential margin is
dimension. inked to assess the adequacy of excision.
• Completeness of excision. Multiple representative sections are taken to
ensure that any residual viable areas of embry-
onal carcinoma or yolk sac tumour are
36.6.2 Retroperitoneal and Pelvic detected (Fig. 36.2).
Lymph Node Dissections • Pelvic lymph node dissections (PLND) are
usually for the staging and treatment of uro-
• Such specimens will often be submitted in logical and gynaecological malignancies.
multiple parts, each representing a specific
anatomical nodal group, and it is important Histopathology report:
that this information is preserved in the final
histology report. • Anatomical location of lymph node groups.
• Weigh (g) each specimen and dissect out rec- • Weight (g) of tissue. Number of nodes identi-
ognizable lymph nodes. The maximum dimen- fied. Number of lymph nodes involved by
sion (cm) of the largest node should be metastatic disease. Maximum diameter of
recorded. Smaller lymph nodes may be sub- largest involved node. Presence or absence of
mitted intact; larger nodes can be bisected or extra-nodal spread.
serially sectioned and then submitted in a sep- • RPLNDs for non-seminomatous germ cell
arate tissue block. It is important to record on tumours post-chemotherapy.

Weigh, measure, paint externally and bisect
retroperitoneal lymph
node dissection
(RPLND) specimen
(Reproduced, with
and Cameron (2013))
Plane of
bisection
External aspect
Cut surface
Sample multiple blocks of cystic and solid areas

• Presence of fibrosis, tumour necrosis, or other Cullen MH, Stenning SP, Parkinson MC, Fossa SD, Kaye
SB, Horwich AH, et al. Short-course adjuvant chemo-
effects of chemotherapy.
therapy in high-risk stage I non-seminomatous germ
• Presence or absence of residual viable tumour. cell tumors of the testis: a Medical Research Council
Mature cystic teratomatous components, report. J Clin Oncol. 1996;14:1106–13.
immature elements, malignancies of somatic Damjanov I, Hes O. The effects of chemotherapy on
metastatic testicular germ cell tumors. Open Pathol
components, i.e., carcinoma, sarcoma, or neu-
J. 2009;3:45–52.
roectodermal malignancies. Miettinen MM. Modern soft tissue pathology. New York:
• Presence or absence of residual viable embry- Cambridge University Press; 2010.
onal carcinoma, yolk sac tumour, or Parkinson MC, Harland SJ, Harnden P, Sandison A. The
role of the histopathologist in the management of tes-
choriocarcinoma.
ticular germ cell tumour in adults. Histopathology.
• Relationship to the inked circumferential 2001;38:183–94.
margin. Rosai J. Chapter 26. Peritoneum, retroperitoneum and
related structures. In: Rosai J, editor. Rosai and
Ackerman’s surgical pathology. 10th ed. Philadelphia:
Elsevier; 2011.
Sinha S, Peach AHS. Diagnosis and management of soft
Bibliography tissue sarcoma. BMJ. 2010;342:157–62.
Stenning SP, Parkinson MC, Fisher C, Mead GM, Cook
Allen DC. Histopathology reporting. Guidelines for surgi- PA, Fossa SD, et al. Postchemotherapy residual masses
cal cancer. 3rd ed. London: Springer; 2013. in germ cell tumor patients: content, clinical features,
Allen DC, Cameron RI. Histopathology specimens: and prognosis. Medical Research Council Testicular
clinical, pathological and laboratory aspects. 2nd ed. Tumour Working Party. Cancer. 1998;83:1409–19.
Berlin/Heidelberg: Springer; 2013. Wittekind C, Greene L, Hutter RVP, Klimfinger M, Sobin
Brierley JD, Gospodarowicz MK, Wittekind C. TNM LH. TNM atlas: illustrated guide to the TNM/pTNM
classification of malignant tumours. 8th ed. Oxford: classification of malignant tumors. 5th ed. Berlin/
Wiley-Blackwell; 2017. Heidelberg: Springer; 2005.
Adrenal Gland
37
Maurice B. Loughrey and Caroline L. Coghlin
37.1 Anatomy itary secretion of adrenocorticotrophic hormone

(ACTH) via a negative feedback system. The
The adrenal glands are paired, yellowish, retro- adrenal cortex secretes the mineralocorticoid
peritoneal organs that lie close to the upper poles hormone aldosterone which is responsible for
of the kidneys (see Fig. 29.1 in Chap. 29). They maintaining fluid and electrolyte balance (mainly
are surrounded by renal fascia but separated from under influence of the renin-angiotensin axis),
the kidneys by perirenal fat. The left adrenal is the glucocorticoid hormone cortisol (important in
almost crescentric in shape whereas the right is control of metabolism), and small amounts of sex
more pyramidal. In adults they average 5 cm in hormones. The outer cortex is lipid laden and
length and 5 g in weight, being proportionately golden yellow in colour whereas the inner cortex
larger at birth. (zona reticularis) is brown due to high lipofuscin
Each gland is divided into an outer cortex and content. The grey-white medulla secretes the cat-
inner medulla, the former being of mesodermal echolamines noradrenaline and adrenaline.
origin and the latter neuroectodermal. Both lay- Lymphovascular drainage:
ers have important physiological roles in hor- Arterial blood supply is from adrenal branches
mone secretion, which is the basis for the most of the aorta and renal and inferior phrenic arter-
common clinical presentations of adrenal patho- ies. The right adrenal vein drains directly into the
logical conditions. The cortex is divided into inferior vena cava whereas the left drains into the
three zones (the glomerulosa, fasciculata, and left renal vein. Lymphatics pass to the lateral aor-
reticularis) and is under direct control from pitu- tic nodes.
Because of their location, adrenal tumours seldom

present with symptoms due to mass effect. Rarely,
M.B. Loughrey (*)
Histopathology Laboratory, Institute of Pathology, a large adrenal carcinoma may cause abdominal
Royal Victoria Hospital, Belfast Health and Social pain, low-grade fever (due to tumour necrosis),
Care Trust, Belfast, UK and a palpable mass. Instead, presentation is more
e-mail: maurice.loughrey@belfasttrust.hscni.net often as an incidental finding on CT scanning of
C.L. Coghlin the abdomen or as a result of symptoms related to
Histopathology Laboratory, Belfast City Hospital, hormones secreted by the adrenal tumour. These
e-mail: caroline.coghlin@belfasttrust.hscni.net hormones give rise to characteristic constellations

406 M.B. Loughrey and C.L. Coghlin
of symptoms and signs (clinical syndromes), and • Saline suppression tests (saline infusion nor-
the initial diagnosis may be confirmed by appro- mally suppresses aldosterone)
priate biochemical investigation, after excluding • Adrenal vein sampling of aldosterone (for lat-
an exogenous cause of hormone excess. eralization of lesion in primary
Hypercortisolism (Cushing’s syndrome): cen- hyperaldosteronism)
tral weight gain, “moon face,” thin skin, striae,
bruising, hirsutism, hypertension, osteoporosis, Hypoadrenalism:
proximal myopathy.
Hyperaldosteronism (Conn’s syndrome): uri- • ACTH stimulation (Synacthen) test (low cor-
nary frequency, weakness, hypertension, hypoka- tisol response indicates hypoadrenalism)
laemia, hypernatraemia, metabolic alkalosis. • Adrenal autoantibodies (+ve in autoimmune
Hypoadrenalism/adrenal insufficiency hypoadrenalism)
(Addison’s disease): anorexia, weight loss, fatigue,
cutaneous pigmentation, orthostatic hypoten- Virilizing tumour:
sion, hyponatraemia, hyperkalaemia, metabolic
acidosis. • Serum adrenal androgen profile
Virilizing adrenal tumours: hirsutism and pri-
mary amenorrhoea. Phaeochromocytoma:
Phaeochromocytoma: headaches, sweating,
anxiety, chest pain, tachycardia, tremor, (parox- • Plasma metanephrine testing
ysmal) hypertension. • 24-h urinary catecholamines
• Clonidine suppression test if above result
ambiguous (normally suppresses catechol-
37.3 Clinical Investigations amine production)
37.3.1 Biochemical Assessment

37.3.2 Radiological Assessment
Hypercortisolism:
• CXR—to look for lung tumour as a possible
• Morning and evening serum cortisols (diurnal ectopic source of ACTH in hypercortisolism
variation is lost in hypercortisolism) • CT/MRI—to assess size, margins, multifocality,
• 24-h urinary cortisol density, homogeneity, and presence of necrosis
• Dexamethasone suppression test (cortisol nor- or calcification in adrenal lesions. Often poor,
mally suppressed) however, at distinguishing benign from malig-
• Plasma ACTH (differentiates primary hyper- nant apart from on size. In overt adrenal carci-
cortisolism (ACTH low) from pituitary- noma used to assess staging and resectability
dependent hypercortisolism or ectopic ACTH preoperatively: contralateral adrenal and pitu-
production (ACTH high)) itary assessment may be helpful in distinguish-
• Petrosal venous sinus sampling (to localize ing adrenal hyperplasia from adenoma
source of ACTH production) • Radioisotope metaiodobenzylguanidine
(MIBG) scan—images medullary tissue and is
Hyper/hypoaldosteronism: particularly useful for detecting extra-adrenal
phaeochromocytomas
• Serum sodium, potassium, bicarbonate • Flourine 18 fluorodeoxyglucose positron emis-
• Serum aldosterone and plasma renin (primary/ sion tomography/CT (18F–FDG PET/CT)—
secondary hyperaldosteronism) useful in staging advanced disease and may help
• Erect and supine aldosterone:renin ratios (nor- differentiate benign from malignant masses.
mally vary with posture) • Core biopsy and FNA
37 Adrenal Gland 407
37.4 Pathological Conditions onist (may see spironolactone bodies on histol-

ogy), but unilateral adrenalectomy is curative in
37.4.1 Cortex some cases.
Adenoma: These may be incidental findings or
Congenital adrenal hyperplasia: This autosomal present with hormone-related symptoms. They
recessive disorder is caused by an enzyme defi- are usually solitary, sharply circumscribed, and
ciency in the cortisol biosynthetic pathway, most weigh less than 50 g.
commonly 21-hydroxylase. ACTH levels are Sectioning reveals a golden-yellow appear-
elevated by negative feedback, causing adrenal ance, possibly with irregular mottling. Histology
enlargement. Symptoms are caused by diversion usually shows lipid-rich cells resembling those of
of cortisol precursors into androgenic steroid the zona fasciculata, arranged in cords or nests.
pathways, leading to virilization. A spectrum of Focal, mild to moderate nuclear enlargement and
severity exists, and the condition may go unrec- pleomorphism is common and not an indication
ognized in males. Affected females may present of malignancy. The best indication of hormone
at birth with sexual ambiguity and adrenal fail- functionality is to look for cortical atrophy in the
ure, or later with hirsutism or primary amenor- adjacent adrenal tissue (indicates Cushing’s syn-
rhoea. Treatment consists of steroid replacement, drome). Conn’s syndrome caused by an
and surgical pathology specimens are seldom aldosterone-secreting adenoma is significant as it
seen. represents a curable form of systemic hyperten-
Addison’s disease: Chronic adrenal cortical sion. Regardless of functionality, most adrenal
insufficiency is most commonly of autoimmune adenomas are surgically excised, although radio-
aetiology but other causes include tuberculosis, logical monitoring (by CT or MRI) for size
malignant infiltration, fungal infection, and sar- increase may be acceptable for small (<5 cm),
coidosis. Treatment is aimed at the underlying non-functioning masses.
cause, in addition to steroid replacement. Surgical Carcinoma: Adrenal cortical carcinoma is
resection is seldom indicated. rare, affecting both sexes equally at an average
Acquired hyperplasia: Is usually due to over- age of 50. Because the hormone-producing capa-
production of ACTH either by the pituitary gland bility is often depleted in tumour cells, clinical
(usually an adenoma) or an ectopic source, most manifestations of hormone secretion usually only
commonly bronchogenic small cell carcinoma. become apparent when the tumour has reached a
Both cause bilateral (may be asymmetrical) adre- large size. Symptoms are often mixed, e.g.,
nal enlargement, which may be diffuse or nodu- Cushing’s syndrome plus virilization, and,
lar. Histology shows thickening of and lipid together with patient age, give some indication as
depletion within the zona fasciculata of the adre- to the likelihood of underlying malignancy.
nal cortex. Occasionally pigmented cortical nod- Adrenal carcinoma rarely causes pure hyperaldo-
ules are seen, possibly as part of Carney’s steronism. The tumours are usually large (almost
syndrome. Pituitary-dependent adrenal cortical all weigh over 100 g) with a variegated appear-
hyperplasia (Cushing’s disease) accounts for ance showing focal haemorrhagic, necrotic, or
60–70% of adult cases of Cushing’s syndrome. It cystic change. A capsule may be seen, often with
is treated by transsphenoidal pituitary surgery obvious tumour infiltration. Histology most char-
and irradiation if this fails. Bilateral adrenalec- acteristically shows a trabecular architectural
tomy is now rarely performed. Ectopic ACTH arrangement of cells with small nuclei and eosin-
production accounts for 15% of adult cases of ophilic cytoplasm but cytological atypia is highly
Cushing’s syndrome and treatment is aimed at variable. The best histological predictors of
the primary tumour. Conn’s syndrome is due to behaviour are mitotic index, clear cells compris-
bilateral adrenal hyperplasia in approximately ing equal to or less than 25% of the tumour, a
25% of cases. Treatment is primarily medical in diffuse growth pattern, fibrous bands, and vascu-
the form of spironolactone, an aldosterone antag- lar invasion. Distinction from metastatic renal
cell carcinoma is important. Spread is via hae- focal cystic degeneration, and a fibrous pseudo-
matogenous and lymphatic routes to liver, lung, capsule. Histology characteristically shows well-
and lymph nodes. In addition, there is often local defined nests of cells (“Zellballen”) separated by
invasion into kidney and possibly inferior vena a delicate fibrovascular stroma. Nuclear enlarge-
cava. Treatment is aimed at complete surgical ment and pleomorphism are common and are not
removal of the tumour, if possible. Adjuvant an indication of malignancy, which is notoriously
mitotane (o,p’-DDD) therapy in combination difficult to predict histologically. In fact, the pres-
with chemotherapy may control endocrine symp- ence of distant metastases is the only reliable cri-
toms and tumour size. The overall 5-year survival terion. Favoured metastatic sites include ribs and
for these aggressive tumours is stage dependent, spine. Treatment is primarily surgical excision of
but for all patients with adrenal cortical carci- the tumour, sometimes solely as a debulking pro-
noma it is only 30–35%. cedure in the presence of advanced malignant
disease. The overall 5-year survival rate for pha-
eochromocytomas is under 50%. Background
37.4.2 Medulla medullary hyperplasia is an indicator of familial
disease.
Phaeochromocytoma: Induces all its clinical Neuroblastoma: A paediatric tumour (80%
manifestations through the production of cate- occur <4 years of age) of the sympathetic ner-
cholamines, which may be intermittent and life- vous system belonging to the family of “small
threatening. Previously known as the 10% tumour round blue cell” tumours. Most present with
(approximately 10% were thought to be bilateral, an intra-abdominal mass. Forty percent arise
10% extra-adrenal, and up to 10% malignant), in the adrenal glands, most of the remainder
due to recent advances in imaging and diagnosis, being retroperitoneal or intrathoracic.
more tumours are now detected in extra-adrenal Ganglioneuroblastoma and ganglioneuroma rep-
locations and more are now known to behave resent better differentiated counterparts which
aggressively. Extra-adrenal phaeochromocyto- are seen in an older age group and less commonly
mas, or paragangliomas, are morphologically involving the adrenal gland. The clinical and lab-
identical and are most commonly found in the oratory aspects of these highly specialized paedi-
retroperitoneum, mediastinum, carotid body, and atric tumours will not be discussed further.
urinary bladder. These have a higher incidence of Miscellaneous conditions: Chronic adrenalitis
malignant behaviour. In up to a third of cases is usually secondary to inflammation in adjacent
there is a strong familial or genetic basis. There is organs, e.g., chronic pyelonephritis; adrenal
an association with multiple endocrine neoplasia haemorrhage (secondary to sepsis, shock, coagu-
(MEN) type 2A/2B, von Hippel-Lindau disease, lopathy), cysts, myelolipoma (composed of fat
and neurofibromatosis type 1. In addition, the and haematopoietic tissue), lipoma, angioma,
familial phaeochromocytoma-paraganglioma schwannoma, and adenomatoid tumour (of meso-
syndrome is defined by a group of patients with thelial origin) are all occasionally encountered in
phaeochromocytomas and/or extra-adrenal para- surgical pathology practice.
gangliomas who have succinate dehydrogenase Other malignant neoplasms: Sarcomas (most
(SDH) gene mutations. SDH-B associated extra- commonly leiomyosarcoma) are very rare in the
adrenal paragangliomas are more likely to be adrenal gland. Malignant melanoma and malig-
malignant (40–70%). Phaeochromocytomas nant lymphoma/leukaemia usually secondarily
average 3–5 cm in diameter and 75–150 g in involve the adrenals but may rarely be primary.
weight and are therefore usually easily seen on Metastatic carcinoma is the commonest patho-
radiographic imaging with CT or MRI. They are logical lesion and can closely mimic primary
soft, pale to tan-coloured often with mottled adrenal carcinoma (lung, breast, and kidney are
areas of congestion, haemorrhage or necrosis, the most common primary sites).
37.5 Surgical Pathology Careful pre- and perioperative medical control of

Specimens: Clinical Aspects blood pressure with adrenergic blockade is essen-
tial and requires expert anaesthetic technique.
37.5.1 Biopsy Specimens Partial adrenalectomy may be occasionally
performed, usually in cases of bilateral neo-
Biopsies of adrenal masses, in the form of fine plasms to leave some functional cortical tissue, or
needle aspiration or needle core, are taken under in rare patients with a solitary adrenal gland.
CT guidance, most often to distinguish primary
and secondary malignancy. Biochemical investi-
gations often render biopsy of an adrenal mass 37.6 Surgical Pathology
unnecessary. Because of the potentially serious Specimens: Laboratory
risk of hypertensive crisis, suspected phaeochro- Protocols
mocytoma has been regarded as a contraindica-
tion to needle biopsy. 37.6.1 Biopsy Specimens
Wide-bore needle cores are counted, measured

37.5.2 Resection Specimens (in mm), and embedded in entirety for histologi-
cal examination through multiple levels. Careful
There are numerous surgical approaches to the handling is necessary to avoid crush artifact.
adrenal gland, and the choice is determined by
the underlying pathology, the size of the adrenal
lesion, patient habitus, and personal preference 37.6.2 Resection Specimens
of the operating surgeon. Each case should be
assessed individually. Specimen:
Advances in laparoscopic surgery now mean
laparoscopic adrenalectomy is commonly offered • Adrenalectomy specimens are usually com-
as treatment of choice, especially for the excision of plete gland resections to remove an adrenal
small, possibly incidentally found, adrenal tumours. tumour, or part of an en bloc radical nephrec-
A posterior (or modified posterior) approach tomy. Partial and bilateral adrenalectomy
is traditional for small, well-localized lesions. specimens are rare. Laparoscopic resection
This approach was also used for bilateral adrenal may result in a fragmented specimen. Extra-
exploration in primary hyperaldosteronism, but adrenal phaeochromocytomas (paraganglio-
as preoperative radiographic localization is now mas) are handled in a similar manner to their
mandatory, the bilateral posterior approach is intra-adrenal counterparts, obviously with
reserved for bilateral adrenalectomy. some variation depending on their location.
A solitary large phaeochromocytoma or a
large adrenal adenoma or carcinoma may be best Initial procedure:
approached through a thoracoabdominal (ninth
or tenth rib) incision. Multiple phaeochromocy- • Weigh the specimen (g) and measure in three
tomas necessitate an abdominal approach to dimensions (mm). If the gland appears grossly
allow careful exploration for metastases. Children normal, attached soft tissue may be dissected
and those with MEN or a positive family history off and the naked gland reweighed.
of phaeochromocytoma are considered at high • Identify and measure (cm) any adjacent organs
risk for multiple lesions. or structures such as the adrenal vein, if
Surgical manipulation of a phaeochromocy- attached.
toma causes extreme cardiovascular instability • If the specimen is infiltrated by obvious
due to fluctuation in catecholamine release. tumour, paint the entire surrounding connec-
tive tissue; if there is a localized mass, paint its –– Colour (yellow, pale, white, tan, red-brown,
outer surface. mottled)
• Fix the specimen by immersion in 10% forma- –– Site (relationship to cortex/medulla)
lin for at least 24 h. –– Appearance (haemorrhagic/necrotic/cys-
• Serially section the entire specimen at 3-mm tic/calcified areas)
intervals perpendicular to the longest axis of –– Edge (capsule/circumscribed/irregular/
any localized mass (Fig. 37.1) and lay the sec- invasion into soft tissue)
tions out sequentially for examination and • Non-neoplastic tissue
photography. –– Nodularity, colour, atrophy
• Look for lymph nodes in any attached soft • Others
tissue. –– Cysts, haemorrhage
Description: Blocks for histology:
• Tumour Lesions <30 mm in size should be processed in

–– Size in three dimensions (mm) their entirety. For larger lesions, one block for
Section perpendicular
to the long axis of the lesion
Adrenal cortical mass
Adrenal
cortex
Adrenal medulla
Adrenal mass,
cortex and capsule
Adrenal mass
Adrenal mass, medulla

cortex and capsule
Fig. 37.1 Sectioning an
adrenal gland mass
(Reproduced, with
and Cameron (2013))
each 10 mm is recommended. Samples should • Regional lymph nodes are the hilar, abdomi-
be processed from all morphologically dis- nal para-aortic and para-caval nodes.
tinct zones, including areas of necrosis.
Sample tumour according to size (see above) tak- pN0 No regional lymph node metastasis
ing blocks to show all grossly different areas, pN1 Regional lymph node(s) involved
pNX Cannot assess regional nodes.
capsule and the relationship to adjacent adre-
nal tissue, other structures if attached (e.g. the
adrenal vein) and the painted circumferential • Excision margins
soft tissue margin. • Distances (in mm) to the nearest circumferen-
One representative section should be submitted tial soft tissue limit
from grossly normal adrenal tissue. • Other pathology
Count and sample any lymph nodes identified. • Nodularity, atrophy, spironolactone bodies,
medullary hyperplasia
• Tumour type—cortical adenoma/cortical car-

cinoma/phaeochromocytoma/other. Bibliography
• Features of malignancy—extremely difficult
to predict using histological criteria alone, but Allen DC. Histopathology reporting. Guidelines for surgi-
the following may be important and are usu- Allen DC, Cameron RI. Histopathology specimens:
ally reported: clinical, pathological and laboratory aspects. 2nd ed.
• Nuclear pleomorphism, mitotic index, MIB 1/ Berlin-Heidelberg: Springer; 2013.
Ki 67 (proliferation index), atypical mitotic Brierley JD, Gospodarowicz MK, Wittekind C, editors.
figures, architecture, presence of necrosis, Oxford: Wiley-Blackwell; 2017.
capsular penetration (in cortical tumours) and DeLellis RA, Lloyd RV, Heitz PU, Eng C. WHO classifi-
broad fibrous bands. Scoring systems such as cation of tumours. Pathology and genetics. Tumours
the Weiss or modified Weiss system may be of endocrine organs. Lyon: IARC Press; 2004.
Komminoth P, Perren A, van Nederveen FH, de Krijger
useful for assessing malignancy in adrenal RR. Familial endocrine tumours: phaeochromo-
cortical carcinoma and similarly, the PASS cytomas and extra-adrenal paragangliomas. Diagn
score (Phaeochromocytoma of the Adrenal Histopathol. 2009;15:61–8.
gland Scoring Scale) can be used to assess Lester SC. Chapter 11: Adrenal glands. In: Manual of
surgical pathology. 3rd ed. Philadelphia: Elsevier/
phaeochromocytomas. Saunders; 2010. p. 227–36.
• Tumour edge—circumscribed/irregular/cap- Metser U, Miller E, Lerman H, Lievshitz G, Avital S,
sule/pseudocapsule. Even-Sapir E. 18F-FDG PET/CT in the evaluation of
• Extent of local tumour spread—TNM 8 for adrenal masses. J Nucl Med. 2006;47:32–7.
Mihai R. Diagnosis, treatment and outcome in adrenocor-
adrenal cortical carcinoma—adrenal medul- tical carcinoma. Br J Surg. 2015;102:291–306.
lary tumours and sarcomas are excluded Moonim MT. Tumours of chromaffin cell origin: phaeo-
chromocytoma and paraganglioma. Diagn Histopathol.
pT1 ≤5 cm, no extra-adrenal invasion 2012;18:234–44.
pT2 >5 cm, no extra-adrenal invasion McNicol AM. Update on tumours of the adrenal cortex,
pT3 Any size, locally invasive but not invading phaeochromocytoma and extra-adrenal paragangli-
adjacent organsa oma. Histopathology. 2011;58:155–68.
Singh PK, Buch HN. Adrenal incidentaloma: evaluation
pT4 Any size with invasion of adjacent organsa and management. J Clin Pathol. 2008;61:1168–73.
a
Including kidney, diaphragm, great vessels (renal vein or Stephenson TJ. Prognostic and predictive factors in endo-
vena cava), pancreas, and liver crine tumours. Histopathology. 2006;48:629–43.
Tischler AS. Phaeochromocytoma and extra-adrenal
paragangliomas: updates. Arch Pathol Lab Med.
• Lymphovascular invasion—present/not present 2008a;132:1272–84.
Tischler AS. Phaeochromocytoma and extra-adrenal pathology. https://www.rcpath.org/profession/publica-

paragangliomas: updates. Arch Pathol Lab Med. tions/cancer-datasets.html. Accessed Oct 2016.
2008b;132:1272–84. Westra WH, Hruban RH, Phelps TH, Isacson C. Chapter
The Royal College of Pathologists. Cancer datasets (adre- 38: Adrenal glands. In: Surgical pathology dissec-
nal cortical carcinoma and phaeochromocytoma/para- tion: an illustrated guide. 2nd ed. New York: Springer;
ganglioma 2nd ed) and tissue pathways for endocrine 2003.
Part VIII
Skin Specimens
Skin
38
Maureen Y. Walsh
38.1 Anatomy lymphatic vessels, nerves and nerve endings with

skin appendage structures. The dermis is divided
The skin is the largest organ in the body. There into the papillary dermis which is the superficial
are regional variations in the structure and func- structure that folds between the rete pegs of the
tion of skin between different sites in the body, epidermis and the reticular dermis (deeper
and this is reflected in the microscopic appear- dermis).
ance of the skin. The skin at all sites consists of Skin appendages: The skin appendage struc-
three layers: (a) epidermis which provides a pro- ture is derived from the epidermal cells which
tective waterproof covering, (b) dermis which flow down into the dermis. These may form hair
gives structural support and contains skin append- follicles and sebaceous glands which are closely
ages, and (c) subcutaneous fat. associated with each other, forming a piloseba-
Epidermis: The epidermis is a keratinizing ceous unit. There are also eccrine and apocrine
stratified squamous epithelial layer. The cells sweat glands. The skin appendage structures
arise from the basal layer and divide to form the often extend into the subcutaneous fat.
spinous cell layer. At the granular layer, cell Subcutaneous fat: Beneath the dermis is a
death occurs, and the dead cells form the keratin layer of adipose tissue with an associated fibro-
(horny) layer, which is shed from the body. The vascular stroma. Hair follicles and sweat gland
epidermis also contains two other cell types: (a) structures extend into it.
melanocytes, which produce melanin pigment. Hair and nails: The hair and nails are special-
These cells are scattered individually along the ized structures formed from keratin. They are
basal layer of the epidermis and (b) Langerhans located at specific specialized sites in the body.
cells which are located within the epidermis. Lymphovascular drainage: Drains to the
They have a role in the immunoresponse of the locoregional lymph nodes of the body site at
body. which the skin lesion occurs.
Dermis: The dermis is the layer of connective
tissue and elastic tissue containing blood and
Clinical dermatology can be divided into two

M.Y. Walsh broad categories: (a) skin rashes and (b) tumours/
Histopathology Laboratory, Institute of Pathology, tumour-like lesions.
Royal Victoria Hospital, Belfast Health and Social Skin rashes: Skin rashes present with a wide
e-mail: maureen.walsh@belfasttrust.hscni.net range of clinical appearances and include

416 M.Y. Walsh
b listering disorders, skin manifestations of sys- mal inclusion cysts—clinically termed sebaceous
temic disease, congenital, and genetic syndromes. cysts.
The dermatologist usually makes a diagnosis Melanocytic naevi (moles): Most Caucasians
based on the history and clinical appearance have several benign moles or naevi on their body,
including the distribution of the rash. Pathologists the number relating to sun exposure and to the
dealing with specimens from these lesions need age of the patient. Naevi vary both in size and
to have good clinicopathological correlation and colour. They may be the patient’s skin tone,
a knowledge of clinical dermatology to ensure white, or red through to shades of brown to blue/
that the appropriate and best diagnosis is arrived black in colour. Melanocytic naevi are removed
at for the patient. for various reasons. They may have changed in
Tumours/tumour-like lesions: The second cat- appearance or developed symptoms suspicious
egory of dermatology involves removal of a vast clinically of malignant change requiring excision
array of “lumps and bumps” by the clinician. for histological examination. Naevi are also
These can range from benign cysts and tumours removed for cosmetic reasons, because they are
through to malignant skin tumours. Once again, being traumatized, occur at a hidden site on the
the clinical background, appearance, site, and body, or constitute a newly formed naevus in an
distribution of the lesion may aid in the adult. There are a variety of histological types of
diagnosis. benign naevi that are dependent on microscopic
examination for correct diagnosis.
Malignant melanomas: Malignant melano-
38.3 Clinical Investigations mas, like benign naevi, are derived from melano-
cytes. They may arise de novo or from within an
In skin diseases, the clinical history and examina- existing melanocytic naevus. Changes in a pre-
tion of the patient will usually assist the derma- existing mole that cause concern include (a)
tologist or plastic surgeon in making the correct asymmetry; (b) irregular borders; (c) change or
diagnosis. Diagnostic biopsy for histological variation in colour; (d) size >6 mm; (e) elevation
examination is often the next stage in the man- and also itching, bleeding or symptoms associ-
agement process. Particularly in inflammatory ated with naevus. When the clinician is suspi-
disorders, the skin may be involved in systemic cious of a diagnosis of malignant melanoma, the
disease and full clinical examination and investi- lesion is removed in total, usually with an ellipse
gation of the patient are required. Similarly, of normal skin around it. Depending on the
patients with congenital anomalies often have degree of certainty of the clinical diagnosis, a
multiple abnormalities emphasising the need for wide excision may or may not be done at that
full clinical assessment. time. Melanomas are the third most common
malignant skin tumour. Their incidence is rising,
and they are the primary skin tumour most likely
38.4 Pathological Conditions to metastasize and cause death. Malignant mela-
nomas typically occur after puberty, and their
Inflammatory disease biopsies require histology incidence increases with advancing age.
and close correlation with clinical details as do Actinic keratosis, Bowen’s disease, basal cell
tumourous lesions which can arise from all the carcinoma, squamous cell carcinoma: Most skin
structures in the three skin layers resulting in a cancers and pre-cancerous lesions of the skin are
range of benign and malignant conditions. related to chronic sun exposure in white skin, and
Cysts: There are a variety of benign epithelial their incidence is increasing. Other aetiological
cysts that usually occur in the dermis and present factors include a genetic pre-disposition and
as a dermal swelling. The type of cyst is deter- immunosuppression. Patients who have had
mined by microscopic examination of the cell organ transplants are at greater risk of developing
lining. Common examples are pilar and epider- skin neoplasia.
38 Skin 417
Actinic (solar) keratosis: Actinic keratoses The clinician may submit a variety of specimen
present usually as multiple red, scaly lesions on types to the laboratory depending on the surgical
sites of chronic sun exposure, particularly the technique used. These may be curettage, shave,
head and neck, back of hands and forearms. The punch, or excision. Based on clinical need, Mohs
lesions are usually removed and submitted for micrographic surgery is used in the treatment of a
pathology when the clinician is concerned that small number of cases. Occasionally basal cell
there may be malignant change, and particularly carcinomas may be treated by radiotherapy fol-
invasive malignancy. Often patients with actinic lowing a confirmatory diagnostic biopsy.
(solar) keratosis have multiple lesions, which are Squamous cell carcinoma: Squamous cell car-
treated by a variety of topical agents and are not cinoma is the second most common malignant
submitted for histological examination. Various tumour of the skin typically at sun exposed sites
biopsy techniques may be used to remove actinic in patients with fair skin. Increasing numbers of
keratoses including curettage, shave, punch and patients who are immunosupressed including
excision biopsies. renal transplant patients are at increased risk of
Bowen’s disease (carcinoma in situ): Bowen’s developing squamous cell carcinoma. A small
disease is a pre-invasive or in situ malignancy of number of squamous cell carcinomas occur in
the skin usually presenting as a red scaly patch. patients with predisposing genetic disorders or at
Most of these lesions present in a background of sites of chronic scarring. These tumours arise
solar damage although it can occur in areas of from the surface epithelium. They have a variety
non-sun damaged skin, where it may be associ- of clinical appearances including nodules and
ated with a higher incidence of internal malig- ulcers, and they also can vary in colour. These
nancy. Bowen’s disease is often treated by tumours do have the potential to metastasize
dermatologists with topical agents and may be although the vast majority are cured by adequate
biopsied to confirm the diagnosis and to exclude local treatment. The treatment of choice is surgi-
invasive malignancy. Occasionally there will be a cal, and the clinician will submit various speci-
biopsy to remove the lesion. Depending on mens including curettage, shave, punch, and
whether the biopsy is excisional or diagnostic in excision biopsies. Mohs micrographic surgery
intent, the laboratory will receive either a curet- may be used in selected cases. Some cases are
tage, shave, punch, or elliptical specimen. treated with radiotherapy following a pathologi-
Basal cell carcinoma: Basal cell carcinoma is cal diagnosis.
the commonest malignant tumour of the skin,
overall in humans. The vast majority are associ-
ated with chronic sun exposure and occur in the 38.4.1 Other Skin Tumours
head and neck area of fair-skinned people. A few
occur at sites of scarring in the skin and a small Merkel cell carcinomas: Merkel cell carcinomas
number of patients with a genetic predisposition are tumours of neuroendocrine origin that occur
develop multiple basal cell carcinomas. These in elderly patients usually presenting as a rapidly
patients often present at an early age. Basal cell growing nodule often in the head and neck area.
carcinomas have a variety of clinical appearances They may present with skin involvement and
from a nodular lesion to an ulcer or scarred areas, lymph node spread. Prognosis in these tumours is
and they may also be multifocal. The colour of poor. Secondary spread from small cell carci-
the tumours can vary. The cell of origin of basal noma of lung must be excluded.
cell carcinoma is thought to be either the basal Paget’s disease of nipple: Paget’s disease of
cell layer of the epidermis or hair follicle. Basal the nipple presents as an eczematous area on the
cell carcinomas are locally aggressive tumours, nipple or areola. It is associated with underlying
often infiltrating and destroying adjacent tissue. malignancy in the breast.
They do not, however, metastasize to other sites. Extramammary Paget’s disease: Extramammary
The treatment of choice is surgical removal. Paget’s disease occurs at the vulva, perineum,
418 M.Y. Walsh
s crotum, penis, anus, and axilla. It presents as a red small diagnostic biopsy is taken in such cases,
velvety area and on histological examination is an either as a punch or an ellipse.
in situ carcinoma. It may or may not be associated Secondary tumours: Secondary tumours may
with underlying carcinoma in the sweat glands of involve the skin, either as directly from an under-
the skin or visceral malignancy in the gastrointesti- lying tumour or as metastatic spread. A small
nal, urinary, or gynaecological tracts. biopsy is usually used for diagnostic purposes.
Skin appendage tumours (benign and malig- FNA also has a role to play (see below).
nant): The hair follicle and sweat gland structures
are capable of giving rise to a wide variety of skin
appendage tumours. If multiple, they may be 38.5 Surgical Pathology
associated with clinical syndromes. Most of these Specimens: Clinical Aspects
lesions present as nodules in the skin and correct
diagnosis is dependent on histological examina- 38.5.1 Biopsy and Excision
tion. The majority of lesions are benign, although Specimens
a small number are malignant and may metasta-
size and cause death in the patient. A variety of biopsies are submitted depending on
Benign epithelial tumours and tumour-like the clinical diagnosis and the type of information
lesions: Seborrhoeic keratosis is a benign epithe- the clinician wants.
lial tumour arising in the skin of middle-aged and Curettage: A curetted specimen is used to
elderly patients, presenting usually as a stuck-on, remove or sample small warty type lesions,
warty type of lesion. They are often pigmented which are usually benign or small basal or squa-
and may be mistaken by the patient and clinician mous cell carcinomas. This can be associated
for a melanoma. with cautery to the lesion base (C&C).
Viral warts: Most viral warts are treated with Occasionally a basal cell carcinoma, actinic kera-
topical agents and are not submitted for histo- tosis, or squamous cell carcinoma may be
logical diagnosis, unless the diagnosis is unclear. removed by curettage, and then formal surgical
Benign mesenchymal tumours: The mesen- excision is carried out of the curetted area. The
chymal tissue in the dermis and subcutis can give laboratory in this case will receive two specimens
rise to various tumours. Most present as nodules from one patient: a curettage and the excision
in the skin and may be biopsied or excised by the biopsy. This combined technique is used to give a
clinician using curettage, shave, punch, and ellip- good cosmetic result. The curettage removes the
tical excision. bulk of the tumour, and the excision results in a
Malignant mesenchymal tumours (sarcomas): neat scar.
Malignant mesenchymal tumours are rare. These Shave biopsy: Shave biopsies are used to
lesions are often large and may have a history of remove polypoid or raised lesions on the skin.
growth or change. They may be biopsied to estab- Usually the clinician thinks the lesion is benign,
lish the diagnosis or have a wide surgical exci- and a shave will give a good cosmetic result.
sion to remove the lesion. Diagnostic punch biopsy: A diagnostic punch
Leukaemia and lymphoma: Leukaemias and biopsy is usually done to assist in the diagnosis of
lymphomas may affect the skin in two main inflammatory diseases, or to establish the diagno-
ways: (a) as an inflammatory skin rash as a consis of a tumour before formal wider excision is
sequence of the underlying malignancy and (b) as carried out.
a lymphoma/leukaemia involving the skin, either Punch excision: A punch excision biopsy is
as a primary skin lesion or spread to the skin as used to remove completely the lesion on the
part of systemic disease. Lymphoma and leukae- skin such as a small mole or naevus. The lesion
mia involvement of the skin may present as a skin is removed with a rim of normal tissue sur-
rash, plaques, or nodules of tumour. Usually a rounding it.
38 Skin 419
Diagnostic elliptical biopsy: An ellipse of skin excision. Deeper levels are employed as
may be removed to establish the diagnosis in skin appropriate.
rashes. This may involve lesional skin and sur- Shave: Shave biopsies are measured, i.e., the
rounding normal skin, or only lesional skin. length, breadth, and depth, in millimetres. If a
Where the biopsy is taken depends on the clinical lesion is noted grossly, this is also measured in
diagnosis, and where the most likely diagnostic millimetres. Depending on the size of the shave,
pathology is to be found. The dermatologist on it is submitted in total (Fig. 38.1), but if greater
the advice of the dermatopathologist must take than 6 mm, it is first bisected (Fig. 38.2). Shave
the most appropriate site for diagnosis. Diagnostic biopsies are not excisional biopsies, and the
elliptical biopsies are also done for skin tumours lesion often extends to the deep margin. Excision
before, if necessary, formal excisions are carried margins are not commented on in benign lesions
out. They are not recommended for lesions where in a shave biopsy.
malignant melanoma is a suspected diagnosis Diagnostic punch biopsy: Diagnostic punch
clinically. biopsies come in a variety of sizes ranging from
Elliptical excisions: Elliptical excisions are 2 to 8 mm. The smaller-sized punch biopsies are
carried out to remove skin tumours, both benign usually for diagnostic purposes. The size of the
and malignant. The dermatological surgeon will punch is recorded and a description of any lesion
usually remove the lesion with a surrounding rim seen. Small punches less than 4 mm are submit-
of normal skin. ted in total and will require examination of mul-
Pigmented lesions: Where the clinician sus- tiple levels (Fig. 38.1). Punch biopsies 4 mm and
pects that he is dealing with a possible malig- above are bisected and then submitted in total.
nant melanoma, the biopsy should be an Bisecting the specimen through the centre of the
excision biopsy with a rim of normal surround- lesion results in its representation in the initial
ing skin. Only in exceptional circumstances levels.
should a diagnostic biopsy of a suspected mel- Punch biopsy for alopecia: Punch biopsies are
anoma be carried out, e.g., a pigmented lesion taken to establish the cause of alopecia and are
on a digit where full excision would result in embedded in the usual manner. In some centres,
an amputation. depending on the experience of the dermatopa-
Fine needle aspiration biopsies (FNA): FNAs thologist, the punch biopsy may be bisected, with
are used to diagnose subcutaneous lumps in the one half embedded and sectioned in the usual
skin and to establish the diagnosis in secondary vertical fashion and the other half sectioned
carcinoma. The role of FNA in primary tumours transversely. This is thought to give a better view
of the skin is limited because the diagnostic of the hair follicle structures and assist in the
biopsy often comprises surgical removal of the diagnosis of alopecia (Fig. 38.3).
lesion. Punch excision: Punch excisions, like diag-
nostic punch biopsies, come in a variety of sizes,
usually 4 mm and greater. The size of the punch
38.6 Surgical Pathology is measured and the edges inked. Depending on
Specimens: Laboratory the size, the punch may be embedded intact and
Protocols adequate sections cut to see the full face of the
lesion (Fig. 38.1). Larger punch biopsies are
A variety of biopsies are submitted and received. bisected (Fig. 38.2) or sliced through to examine
Curettage: A curetted specimen is usually the lesion (Fig. 38.4). All punch excision biopsies
received in multiple fragments which are all sub- and lesions present are described and measured
mitted for histological diagnosis. The patholo- in millimetres.
gist, based on the curette, makes a diagnosis of Elliptical biopsy: Small ellipses of skin may
the lesion but cannot comment on adequacy of be removed for diagnosis. They are usually
420 M.Y. Walsh
Fig. 38.1 Punch, shave,

or ellipse biopsy
embedded intact
(Reproduced, with
and Cameron (2013))
Embed intact and level
Epidermis
Dermis and
subcutis
Lesion
p rocessed intact or bisected longitudinally and complex to indicate where blocks have been
examined through multiple levels (Figs. 38.1 and taken, but usually a diagram is adequate. The
38.2). Biopsies are measured in millimetres and edges of the ellipse are inked to indicate the
any lesion seen described and measured. They true surgical margins.
may have their edges inked. Elliptical excisions are dealt with in the labo-
Elliptical excision: Skin ellipses are used to ratory in a variety of ways:
remove tumour with a rim of normal tissue
around the lesion. The pathologist needs to see 1. If small (<6 mm), they can be processed intact
the full face of the lesion and examine for ade- and cut along the long axis. Multiple levels
quacy of excision. All skin ellipses are mea- need to be examined to see the full face of the
sured and described. Any sutures and pins etc. lesion (Fig. 38.1).
placed by the clinician for orientation are noted 2. Small ellipses may be bisected across the
and if any specific questions are asked on the short axis and embedded to show the centre
request form regarding the excision, these are of the lesion. This provides information on
considered when sectioning the skin ellipse. the deep limit and nearest peripheral margins
Most elliptical skin excisions are not photo- at the short axis but not the long axis
graphed unless the gross appearance is unusual (Fig. 38.2).
when often it will have been photographed by 3. Quadrant blocks of the lesion. A block is

the clinician before surgical removal. taken through the centre of the lesion across
Photography or a photocopy of the lesion sur- the short axis and two lateral blocks are taken
face may be useful if sampling of the lesion is across the long axis. This gives the full face of
38 Skin 421
Epidermis
Dermis and
subcutis
Lesion
Fig. 38.2 Punch, shave, or ellipse bisected and embedded (Reproduced, with permission, from Allen and Cameron
(2013))
the lesion and margins on four quadrants Wedge excisions: Wedge excisions are used to
(Fig. 38.5). remove skin from the eyelid, lip, ear, and vulval
4. Skin ellipses may be serially sectioned or
areas. These and any gross lesions are described
sliced like a loaf of bread through the lesion at and measured. The surgical limits are the outer
2–3 mm intervals. This ensures that the whole margins of the wedge, and these are sampled for
of the lesion is examined and is useful in histology. A section is then taken through the
melanocytic lesions of the skin (Fig. 38.4). centre of the tumour (Fig. 38.6).
422 M.Y. Walsh
Vertical section Transverse section
Epidermis
Sebaceous Dermis
glands
Sebaceous
glands
Hair shaft
Hair shaft
Dermis and
subcutis
Fig. 38.3 Vertical and horizontal sections of a punch biopsy for the diagnosis of alopecia (Reproduced, with permis-
38 Skin 423
a b c
Multiple sections
Epidermis Epidermis
Dermis and Dermis and

subcutis subcutis
Blocks a and c Block b
Fig. 38.4 Serial section of a skin ellipse (Reproduced, with permission, from Allen and Cameron (2013))
b c
Epidermis Epidermis

subcutis subcutis
Block a Block b and c
Fig. 38.5 Quadrant blocks of a skin ellipse (Reproduced, with permission, from Allen and Cameron (2013))
424 M.Y. Walsh
a b c
a and c b lesion
margins
Epidermis Epidermis

subcutis subcutis
Fig. 38.6 Wedge resection of skin (Reproduced, with permission, from Allen and Cameron (2013))
38.7 Special Techniques should have an intact epidermal/dermal junction.

and Considerations In most of the connective tissue disorders,
lesional skin is submitted for immunofluores-
Immunofluorescence: Immunofluorescence cence except for the lupus band test, where nor-
examinations are required for the diagnosis of mal non-sun exposed skin is used. Most patients
chronic blistering diseases and are useful in con- having skin submitted for immunofluorescence
nective tissue diseases. The site of biopsy is should also have a serum sample sent to the
important for immunofluorescence, particularly laboratory for examination for autoantibodies

in the blistering disorders. In dermatitis herpeti- related to the disease process. Skin biopsy speci-
formis, a biopsy for immunofluorescence should mens for immunofluorescence are either snap
be taken from clinically normal skin away from frozen in liquid nitrogen or sent in Michel’s
the area of blistering. In the other blistering dis- transport medium to the laboratory. Most labora-
orders, perilesional skin is submitted. The skin tories doing immunofluorescence will supply the
38 Skin 425
clinical area with the appropriate transport imen by Mohs micrographic surgery. The speci-
medium. Formalin fixation is inappropriate for men should be laid out flat on a dish or board,
immunofluorescence and will render the speci- and the margins indicated either by sutures or
men unsuitable for examination. Specimens for pins of different colour. It is useful if the sur-
immunofluorescence are either punch or ellipti- geon also draws a diagram of the lesion and its
cal biopsies. location on the patient with appropriate land-
Mohs micrographic surgery: Mohs micro- marks. The pathologist ensures that the com-
graphic surgery is the surgical removal of the plete surgical margins are examined. It is often
tumour under microscopic control. The aim of necessary to divide the specimen into smaller
the technique is to remove all the tumour with blocks to be examined microscopically. They
the minimum of surrounding normal tissue. may need to be marked so that the area involved
This is a time consuming and slow procedure by tumour can be clearly pinpointed. On an
for the patient, dermatological surgeon, and ellipse skin margins can be marked in relation to
laboratory staff, but it is useful in a small num- the clockface or to compass points. The surgical
ber of cases. Mohs micrographic surgery is margins are marked with different coloured inks
used primarily for the treatment of basal cell to aid locating the correct area with tumour
carcinoma but may be used for squamous cell involvement (Fig. 38.7).
carcinoma, some sarcomas of the skin, espe- Surgical margins: On excision biopsies the
cially dermatofibrosarcoma protuberans and, pathologist should comment on the adequacy of
rarely, some types of desmoplastic melanoma excision, and in line with protocols, measure the
and other malignant skin appendage tumours. It tumour distance from the margins. In punch
is especially useful for tumours occurring on biopsies, the specimen is either embedded intact
the face around the eyelids, nose, and mouth or bisected and embedded. The pathologist can
where a good cosmetic result is required. The comment on two lateral and deep margins. The
technique involves examination of frozen sec- edge of the punch biopsy can be inked to indicate
tions of surgical margins with the patient and microscopically the true excision margins which
the surgeon awaiting the results. If limits are are also often associated with red blood cells.
involved, a further excision of this area is car- Similarly, in an elliptical biopsy, the margin
ried out and examined by frozen section. This is status is documented by the pathologist. Quadrant
repeated until the margins are clear. The defect blocks result in four lateral margins and a deep
is then repaired by the surgeon on the same day. margin being examined. Bread-loaf slicing
In some units, the tissue is fixed, processed to through the ellipse results in all the margins being
paraffin, and margin sections examined the next seen microscopically but this is only suitable for
day. If the margins are involved, further tissue relatively small ellipses. The margins can be
is removed, processed to paraffin, and sections inked to assist microscopic identification,
examined. Only when the margins are clear is although usually red blood cells are present. To
repair carried out. This is a slower procedure examine all the surgical margins in a large skin
over a period of days in which the patient has a biopsy, the best approach is a modified Mohs
defect which has to wait for confirmation of technique. The pathologist sections the margins,
clearance before repair can take place. This and these are marked with different coloured inks
technique is useful for rarer types of tumour to aid identification.
where there may be an infiltrate of single spin- Sutures and markers: The surgeon will often
dle cells such as a desmoplastic malignant mel- mark margins with sutures to help orientate the
anoma or where immunocytochemistry is specimen and an accompanying diagram is also
required to identify tumour cells. useful. Techniques of margin sampling in large
Mohs laboratory procedure: It is essential excisions may need to be modified in the light of
that there is clear communication between the attached sutures or clinical request form
surgeon and the pathologist examining the spec- information.
426 M.Y. Walsh
N lnk colour 1
W E lnk colour 2
N N
lnk
colour
1
W E
lnk colour 2 lnk colour 2
W E
lnk
colour
1
S S
N E Epidermis
N
Dermis and
subcutis
Embedded
outer edge
E
lnk lnk
colour colour
1 2
Fig. 38.7 Sections for Mohs micrographic surgery (Reproduced, with permission, from Allen and Cameron (2013))
38 Skin 427
Grafts: Tumours may recur under and around easier to demonstrate if the skin biopsy has
an area of skin grafting. These specimens are been fixed in alcohol. Where a mast cell lesion
dealt with in the usual manner for a skin ellipse. is suspected, the biopsy should be divided and
Re-excisions: The most common cause for halves placed in formalin and alcohol. However,
re-excision is when a malignant tumour is if mast cells are present in large numbers, they
incompletely excised, or in the case of a malig- can still be seen in formalin fixed tissue.
nant melanoma, despite complete primary exci- Similarly, the urate crystals in gout dissolve in
sion, the margins are not wide enough to follow formalin. It is still possible to diagnose gout on
standard guidelines. Re-excision biopsies are formalin fixed tissue, but it is easier to demon-
sampled as for primary excisions. Tumour, if strate the crystals if the tissue has been placed
present, is usually at the edge of the previous in alcohol fixative.
biopsy scar. Again, margins of excision are
commented on.
Diagrams: Diagrams are also useful in orien- 38.8 Special Sites
tating specimens.
Transmission electron microscopy (TEM): As Hair: Hair samples should be plucked, not cut,
in other branches of pathology, the role of diag- from the patient and sent unfixed to the labora-
nostic TEM is declining. Immunocytochemistry tory. The hair is mounted unfixed on glass slides
has reduced the need for it in diagnosing undif- and examined for hair shaft anomalies or to look
ferentiated tumours and viral infections, although at the hair roots and count the telogen:anagen
it is still useful for inborn errors of metabolism. ratio—this requires a minimum of 50 hairs.
All such samples of skin should be placed in glu- Scanning electron microscopy provides more
taraldehyde fixative. Other indications for TEM information in patients with hair shaft anomalies
are in the diagnosis and subclassification of: (1) and picks up more subtle changes than those seen
congenital anomalies, e.g., ichthyosis, (2) blister- at light microscopy.
ing diseases as in the epidermolysis bullosa group Nails: Fragments of nails may be submitted
(it may be necessary to obtain a fresh blister by for examination either to detect fungi or the
rubbing up with an eraser), and (3) acquired blis- cause of nail pigmentation. The fragments are
tering disorders (in conjunction with softened in phenol and then processed in the
immunohistochemistry). usual way for histology. For pigmented lesions
Scanning electron microscopy (SEM): or growths beneath the nail, the nail must be
Scanning electron microscopy is useful in the removed by the surgeon before skin biopsy of
diagnosis of hair shaft anomalies. The hair sam- the nail bed is taken. Nails may be involved in
ple should be sent unfixed to the laboratory. several skin diseases, but usually a biopsy of
Microprobe analysis: A microprobe attached skin involved elsewhere is taken to confirm the
to the scanning electron microscope can be use- diagnosis.
ful to detect small amounts of elements present in Digits: Pigmented lesions beneath nails
the skin that may be causing increased abnormal often cause diagnostic problems in distinguish-
pigmentation. ing between benign lesions, trauma, and malig-
Skin scrapings: Scrapings from the skin sur- nant melanoma. Trauma to the nail which
face can be examined for fungal particles or sca- bleeds grows outwards as the nail grows,
bies mites. This may be a wet preparation by whereas naevi and melanomas do not. If mela-
putting the scrapings in potassium hydroxide or noma is suspected, the clinician must first
fixing the tissue and processing it. This is a useful remove the nail and biopsy the lesion on the
way to make a diagnosis without a full surgical nail bed. Excision biopsy is ideal but if this is
biopsy. not possible then a diagnostic biopsy is permit-
Fixation: The usual fixation for skin biopsies ted. This is allowed in the nail bed as treatment
for histology is 10% formalin. Mast cells are for melanoma is amputation of the digit.
428 M.Y. Walsh
Because of this the pathologist should only should be sampled. Benign lesions will have a
diagnose melanoma when there is a high degree variety of biopsy samples which are dealt with in
of certainty, otherwise another biopsy is the usual way. Tumours are often removed as a
requested. Digits are measured and described in wedge and dealt with accordingly (Fig. 38.6).
the usual manner including which joints have Lip: Lip biopsies from benign lesions are
been disarticulated. The tumour is measured treated as other biopsies, but malignant tumours
and described. The surgical margin of excision are removed as a wedge and dealt with accord-
is blocked and the tumour sampled through its ingly (Fig. 38.6).
deepest area. Pilonidal sinus: Occurs in the natal cleft of
Eyelid: The eyelid margins can be involved in young to middle-aged males due to insinuation of
a variety of benign and malignant tumours. hair shafts into the dermis and subcutis forming a
Benign tumours are dealt with in the usual man- tract variably lined by epidermis and/or granula-
ner. In malignant tumours, especially basal cell tion tissue. It is associated with serous discharge
carcinomas, squamous cell carcinomas, and mel- and potentially infection with pain and abscess
anomas, the surgeon’s aim is to remove all the formation. There may be several tracts present
tumour with as little normal tissue as possible. and communication points with the surface epi-
The surgeon may use a modified Mohs technique dermis. Treatment involves wide elliptical exci-
to do this or orientate the specimen with pins and sion of the skin and subcutis down to the level of
sutures. This will then be treated in the laboratory the sacral fascia. The specimen is measured, and
as a wedge excision and the margins carefully the presence of opening(s)/tract(s) noted. A hori-
marked. zontal transverse block of the deep limit allows
Ear: The ear may be involved in skin rashes, microscopic assessment of tract extension to the
benign and malignant tumours. Skin rashes rarely deep margin. The tract is demonstrated by serial
only involve the ear, and skin from elsewhere vertical slices (Fig. 38.8).

pilonidal sinus specimen
(Reproduced, with Multiple vertical
serial slices
permission, from Allen Skin
and Cameron (2013)) openings
Subcutis
Transverse
Section deep
limit
Tract and
abscess
38 Skin 429
38.9 Histopathology Reports 38.9.2 Squamous Cell Carcinoma
Inflammatory disease: • Specimen site:

• Specimen type:
• Specimen site, type, and size (mm) • Specimen size:
• Description of histological findings Length ________ mm
• Diagnosis or differential diagnosis with most Breadth _______ mm
likely diagnosis Depth _________ mm
• Maximum diameter of lesion:
Benign tumours: _________ mm
• Histology suptype:
• Specimen site, type, and size (mm). Classical/spindle cell/acantholytic/verrucous/
• Tumour type and brief description of lesion desmoplastic/other
• If excision biopsy, is the lesion excised? • Differentiation
Grade I (over 75% differentiated)
Malignant tumours: Grade II (between 25 and 75% differentiated)
Grade III (under 25% differentiated)
Grade IV (no differentiation)
38.9.1 Basal Cell Carcinoma • Tumour thickness:
_________ mm
• Specimen site: • Clark level:
• Specimen type: I/II/III/IV/V
• Specimen size: • Invasion:
Length _________ mm Lymphatic/vascular invasion:
Breadth ________ mm Yes/no/uncertain
Depth __________ mm Perineural invasion:
• Size of lesion: Yes/no/uncertain
Length _________ mm • Excision margins:
Breadth ________ mm • Nearest peripheral:
Depth __________ mm Clear _______ mm/involved (in situ/invasive)
• Growth pattern: • Nearest deep:
Nodular/superficial/infiltrative (morphoeic)/ Clear _______ mm/involved (in situ/invasive)
micronodular/other • Extent of local tumour spread: TNM 8 for car-
• Differentiation: cinoma of skin (excluding eyelid, head and
Severely atypical or malignant squamous neck, perianal, vulva, penis, and Merkel cell
component present—yes/no carcinoma)
• Invasion:
Lymphatic/vascular invasion: pTis Carcinoma in situ
Yes/no/uncertain pT1 Tumour ≤20 mm in greatest dimension
Perineural invasion: pT2 Tumour between 21 and 40 mm
Yes/no/uncertain pT3 Tumour >40 mm in greatest dimension, or
minor bone erosion, or clinical/radiological
• Excision margins: perineural invasion, or deep invasion
Nearest peripheral: (beyond subcutaneous fat or >6 mm from
Not involved ________ mm/involved granular layer of adjacent epidermis)
Nearest deep: pT4 Gross cortical bone/marrow invasion or
Not involved ________ mm/involved invasion axial skeleton
• Extent of local tumour spread (see squamous pN0 No regional lymph node metastasis
cell carcinoma) pN1–3 Metastasis in regional lymph node(s)
430 M.Y. Walsh
38.9.3 Malignant Melanoma pN1* 1 lymph node involved

pN2* 2–3 lymph nodes involved
• Specimen site: pN3* ≥4 lymph nodes involved
• Specimen type: *(a) Micrometastasis
• Specimen size: (b) Macrometastasis
Length _______ mm (c) In-transit metastasis/satellites with
Breadth ______ mm 0(pN0/1), 1(pN2) or ≥2(pN3) lymph nodes
Depth ________ mm pM1a Distant skin or nodal metastasis
• Lesion size: pM1b Lung metastasis
pM1c Other non-central nervous system sites
Length _______ mm
(pM1d: central nervous system sites)
Breadth ______ mm
Depth ________ mm Lymph nodes: Lymph nodes may be removed
• Lesion margins: where there is tumour involvement in patients
Regular/irregular with squamous cell carcinoma or malignant mel-
• Profile: anoma. If the lymph node is subcutaneous, a fine
• Histogenic type: needle aspiration will be carried out to confirm
Lentigo maligna/superficial spreading/nodu- the diagnosis prior to surgical removal. The
lar/acral lentiginous/desmoplastic/neurotropic node(s) should be weighed, measured, counted,
• Clark level: and submitted for histological examination.
I/II/III/IV/V Sentinel node biopsy: Sentinel node biopsy is
• Breslow’s depth: used in some centres in patients with biopsy-
_________ mm proven malignant melanoma of the skin. The sen-
• Mitoses/mm2: tinel node is the first drainage node at the site of
• Growth phase: the excised malignant melanoma. This is removed
Radial/vertical and examined in the laboratory for microscopic
• Ulceration: tumour using multiple step sections through the
Yes—diameter _______ mm/no node and both haematoxylin and eosin and
• Microscopic satellitosis: immunocytochemistry markers including S100,
• Excision margins: Melan-A, and HMB45 to confirm small micro-
Nearest peripheral: scopic deposits of malignant melanoma.
Clear _____ mm/involved (in situ/invasive) Subsequent regional lymph node block dissec-
Nearest deep: tion may then be carried out.
Clear _____ mm/involved (in situ/invasive)
• Extent of local tumour spread: TNM 8 for
malignant melanoma of skin Bibliography
pTis Melanoma in situ Allen DC. Histopathology reporting. Guidelines for surgi-
pT1 Tumour ≤1.0 mm cal cancer. 3rd ed. London: Springer; 2013.
(a) Without ulceration and ≤0.8 mm Allen DC, Cameron RI. Histopathology specimens:
(b) With ulceration and ≤0.8 mm or
Berlin-Heidelberg: Springer; 2013.
0.81 mm—1 mm ± ulceration
Balch CM, Gershenwald JE, Soong SJ, Thompson JF,
pT2* Tumour 1.01–2.0 mm Atkins MB, Byrd DR, Buzaid AC, Cochran AJ, Coit
pT3* Tumour 2.01–4.0 mm DG, Ding S, Eggermont AM, Flaherty KT, Gimotty
pT4* Tumour > 4.0 mm PS, Kirkwood JM, McMasters KM, Mihn MF, Morton
*(a) Without ulceration DL, Ross MI, Sober AJ, Sandak VK. Final version
of 2009 AJCC melanoma staging and classification.
(b) With ulceration J Clin Oncol. 2009;27:6199–202.
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Calonje JE, Brenn T, Lazar AJ, McKee PH. McKee’s Shriner DL, McCoy DK, Goldberg DJ, Wagner F Jr.
pathology of the skin. 4th ed. Philadelphia: Elsevier Mohs’ micrographic surgery. J Am Acad Dermatol.
Saunders; 2011. 1998;39(1):79–97.
Cook MG, Di Palma S. Pathology of sentinel lymph nodes Telfer NR, Colver GB, Morton CA. Guidelines for the
for melanoma. J Clin Pathol. 2008;61:897–902. management of basal cell carcinoma. Br J Dermatol.
Marsden JR, Newton-Bishop JA, Burrows L, Cook M, 2008;159:35–48.
Corrie PG, Cox NH, Gore ME, Lorigan P, MacKie The Royal College of Pathologists. Cancer datasets (basal
R, Nathan P, Peach H, Powell B, Walker C. cell carcinoma, malignant melanoma, invasive squa-
Revised UK guidelines for the management of mous cell carcinoma, adnexal carcinoma and lymph
malignant melanoma. Br J Dermatol. 2010;163: nodes, skin cancer electronic reporting tool) and tis-
238–56. sue pathways for dermatopathology (2nd ed.). https://
Motley R, Kersey P, Lawrence C. Multiprofessional guide- www.rcpath.org/profession/publications/cancer-
lines for the management of the patient with primary datasets.html Accessed Dec 2016.
cutaneous squamous cell carcinoma. Br J Dermatol. Weedon D. Skin pathology. 3rd ed. London: Churchill
2002;146(1):18–25. Livingstone; 2009.
Part IX
Cardiothoracic Specimens and Vessels
Lung
39
39.1 Anatomy shaped with their base at the pleural surface.

Each segment is supplied by a segmental artery
The combined weight of both lungs is approxi- and bronchus. Veins draining segments often
mately 850 g in the male, 750 g in the female. The anastomose with those from adjacent segments.
apex of each lung is situated in the root of the neck, Bronchopulmonary segments can be resected
the base of the lung on the diaphragm. The medias- with little haemorrhage or leakage of air from
tinum is medial to the lungs, and ribs are present adjacent raw surfaces. Further divisions of the
laterally. The hilum of each lung contains a main bronchi produce bronchioles. Glands and carti-
bronchus, pulmonary artery, two pulmonary veins, lage are present in the walls of bronchi but not in
pulmonary nerve plexus, and lymph nodes. bronchioles.
The lungs are separated into lobes by invagi- Bronchioles have a diameter of less than
nations of pleura along fissures (Fig. 39.1). The 1 mm. Terminal bronchioles lead to respiratory
right lung is divided into three lobes by the bronchioles, which branch to produce alveolar
oblique and horizontal fissures, the left into two ducts, alveolar sacs, and then alveoli. The lung
lobes by the oblique fissure. The inferior part of may be divided into lobules, areas that measure
the left upper lobe (the lingula) is the homologue 1–2 cm across and are poorly demarcated by
of the right middle lobe. incomplete fibrous septa. Each lobule is made up
The trachea branches at the level of T4 and T5 of 3–10 acini. An acinus or terminal respiratory
(thoracic vertebrae 4 and 5) into two main bron- unit is that portion of the lung supplied by one
chi. The right bronchus enters the lung behind the terminal bronchiole. Pulmonary arteries are
right pulmonary artery, the left bronchus crosses found at the centres of each acinus alongside
behind the left pulmonary artery and enters the bronchioles, whereas pulmonary veins run in the
lung below it. The main bronchi divide to give interlobular septa. Flattened type 1 pneumocytes
five lobar bronchi. These then divide into seg- and occasional rounded type two pneumocytes
mental bronchi supplying the 19 bronchopulmo- line the alveoli.
nary segments. Segments are roughly wedge Lymphovascular drainage:
Lymphatic drainage is by a superficial sub-
pleural lymph plexus and a deep plexus of vessels
accompanying the bronchi. Both groups drain
K.M. Mulholland through hilar (bronchopulmonary) lymph nodes
Histopathology Laboratory, Altnagelvin Hospital, into tracheobronchial nodes around the
Western Health and Social Care Trust, bifurcation of the trachea and from there into
Londonderry, UK
e-mail: kathleen.mulholland@westerntrust.hscni.net mediastinal lymph trunks.

436 K.M. Mulholland
Trachea (phrenic nerve involvement). Tumours in the api-

cal part of the upper lobe (Pancoast’s tumours)
Oblique and
may result in unilateral Horner’s syndrome due to
horizontal involvement of sympathetic ganglia. Pancoast’s
fissures 2 2 tumours may also produce pain and weakness in
the shoulder and arm due to invasion of the bra-
chial plexus. Mediastinal disease may lead to
superior vena cava syndrome with congestion and
oedema of the face, neck, and chest associated
1 with dyspnoea.
Paraneoplastic syndromes are systemic effects
of tumours not mediated by tumour spread. They
3 include Cushing’s syndrome, inappropriate
4 4 antidiuretic hormone secretion, and acromegaly.
Weight loss may occur in chronic inflammatory
diseases such as TB or secondary to tumours.
Fig. 39.1 Anatomy of the lungs. 1 Main bronchus, 2
upper lobe, 3 middle lobe, 4 lower lobe (Used with the
permission of the Union for International Cancer Control 39.3 Clinical Investigations
(UICC), Geneva, Switzerland. The original source for this
material is from Wittekind et al. (2005)) • Chest x-ray: primary technique for imaging
the thorax.
Blood supply to the lungs is by a dual arterial • CT scan—the only cross sectional imaging
supply—the pulmonary arteries and the bron- technique that adequately evaluates the lung
chial arteries. Blood returns to the heart via the parenchyma and is equivalent to MRI in the
pulmonary veins or travels in the bronchial veins evaluation of mediastinum, pleura, and chest
to the azygos or accessory hemiazygos veins. wall. CT has a sensitivity of 80–94% com-
pared with results obtained by mediastinos-
copy and lymph node sampling. CT scans are
39.2 Clinical Presentation used to stage carcinoma of bronchus and may
be extended to include liver, adrenal glands,
Respiratory symptoms include cough, sputum and brain.
production, dyspnoea (undue respiratory effort), • High Resolution (thin section) CT scan
orthopnoea (breathlessness on lying down), (HRCT)—slices are 1–3 mm thick. HRCT is
wheeze due to airway obstruction, haemoptysis of value for the investigation of sarcoidosis,
(coughing up blood), and chest pain. The com- lymphoma, cryptogenic and extrinsic alveoli-
monest cause of haemoptysis is acute infection. tis, occupational lung disease, bronchiectasis,
Other causes include tuberculosis (TB) and pul- and lymphangitis carcinomatosa. It is also
monary infarction. Tumour, e.g., carcinoid or used to distinguish emphysema from
bronchial carcinoma, may cause haemoptysis due interstitial lung disease or pulmonary vascular
either to ulceration of the expanding tumour or disease.
secondary infection caused by obstruction. Chest • Spiral CT scan and Ventilation/Perfusion
pain can be localized and pleuritic, due to infec- (V/Q) scan—used in detection of pulmonary
tion or infarction or constant, severe, and dull due emboli.
to chest wall invasion by carcinoma. Lung cancer • MRI—less useful than CT because of poorer
can produce secondary pneumonia, bronchiecta- imaging of lung parenchyma. MRI may be
sis, pleural effusions, hoarseness (laryngeal nerve used in assessing disease near the lung apex,
involvement), and paralysis of the diaphragm the spine, the thoracoabdominal regions, and
39 Lung 437
the mediastinum. It can detect invasion into • Bronchial brushings and washings—fibreop-
spinal cord, vertebral bodies, brachial plexus tic bronchoscopy (FOB) can reach and sample
and chest. up to 90% of malignancies.
• PET scan—used to distinguish between • Transbronchial fine needle aspiration—at the
benign and malignant conditions. If the lesion time of FOB makes submucosal and paratra-
does not demonstrate high radiation activity, it cheal lesions accessible.
is interpreted as having a low metabolic rate • Endobronchial and transbronchial biopsy—
and is likely to be benign. Conversely it dem- lead to a histological diagnosis in 95% of cen-
onstrates FDG–avid primary cancers and their tral lung carcinomas, but in only 50–75% of
local and distant metastases. peripheral lesions.
• Respiratory function tests—include peak • Transbronchial biopsy is of particular use in
expiratory flow rate (PEFR), forced expiratory the diagnosis of sarcoidosis and lymphangitis
volume in 1 second (FEV1), vital capacity carcinomatosa.
(VC), forced expiratory ratio (FEV/VC) and • Endobronchial Ultrasound Fine Needle
carbon monoxide transfer (Tco). These tests Aspiration or Biopsy (EBUS FNA or Biopsy)-
are helpful in differentiating between lung dis- the use of ultrasound with bronchoscopy has
ease due to airways obstruction, restrictive increased diagnostic accuracy and yield and
conditions, or respiratory muscle weakness. decreases the need for mediastinoscopy.
• Measurement of blood gases—important in • Bronchoalveolar lavage (BAL)—using a flex-
the diagnosis of respiratory failure. ible fibreoptic bronchoscope small volume
• Full blood picture (FBP)—haemoglobin: lavages (up to 300 ml) are performed. BAL
Anaemia, PCV, secondary polycythaemia. may be used to monitor progression of inter-
• Biochemistry—alpha-1-antitrypsin levels, stitial lung disease. It is useful in eosinophilic
autoantibodies, Aspergillus antibodies, IgE to pneumonia, eosinophilic granuloma, pulmo-
specific allergens. Hypercalcaemia occurs in nary alveolar proteinosis, and in the diagnosis
one in five patients with sarcoidosis, as a para- of opportunistic infections, e.g., in the
neoplastic syndrome notably in association immunosuppressed.
with squamous cell carcinoma and secondary • Mediastinoscopy—allows access to, and
to bony metastases. Hyponatraemia is seen in biopsy of, lymph nodes. Cervical mediasti-
association with small cell carcinoma. noscopy accesses paratracheal and subcari-
• Sputum—cytological examination of sputum nal mediastinal nodes for diagnostic and
can detect between 60% and 90% of malig- staging purposes. Anterior mediastinoscopy
nancies if multiple specimens are examined. is used primarily to sample enlarged nodes or
Gram stain and culture are of value in pneu- tumour in the left aortopulmonary window
monia, TB, and Aspergillus. region.
• Transthoracic needle aspiration and biopsy • Frozen sections—sent intra-operatively to dis-
(TTNA and TTNB)/percutaneous needle aspi- tinguish between inflammatory and neoplastic
ration and biopsy—performed under fluoro- parenchymal lesions, as a prequel to a cancer
scopic or CT guidance. They successfully resection operation or a lung-sparing wedge
diagnose lung cancer with at least 85–90% resection. These specimens should be handled
accuracy. The most common indication for with care in a microbiological safety cabinet.
aspiration is to evaluate a solitary peripheral If there is any suspicion of TB, frozen sections
lung nodule suspicious of carcinoma. Biopsy are inappropriate and should not be per-
is more appropriate when lymphoma or sar- formed. Such tissue needs thorough formalin
coidosis is suspected. Needle core biopsies fixation.
may be obtained from lesions close to the • Open/closed lung biopsy—used to evaluate
chest wall, while more central lesions require pleural/peripheral lesions and interstitial lung
fine needle aspiration. disorders.
438 K.M. Mulholland
39.4 Pathological Conditions types depending on the part of the lung involved
by the process—centrilobular, panlobular (pan-
39.4.1 Non-neoplastic Conditions acinar), and paraseptal. Chronic bronchitis results
from hypersecretion from bronchial mucous
Bacterial pneumonia: Lobar pneumonia can be glands.
of rapid onset in otherwise healthy patients, and Bronchiectasis: Permanent abnormal dilata-
entire lobes are involved by neutrophilic infil- tion of the bronchi with infection of the bronchial
trates. Bronchopneumonia affects older, debili- wall and obliteration of distal airways. Cystic
tated patients and is characterized by more fibrosis is the most common predisposing factor.
circumscribed infiltrates. Endogenous lipoid pneumonia: May occur
Lung abscess: An area of infection with paren- distal to a lung tumour and is secondary to break-
chymal necrosis. Primary lung abscess occurs down of lung parenchyma. The alveoli contain
more often on the right side as the right main bron- lipid-laden macrophages.
chus leads more directly off the trachea and aspira- Pneumoconiosis: Defined as permanent alter-
tion can occur more easily. Secondary abscesses ation of lung structure due to inhalation of min-
occur when there are predisposing factors such as eral dusts and tissue reactions, which follow this.
carcinoma, foreign body, or bronchiectasis. Included in this group are silicosis, asbestosis,
Viral infection: May occur in the lungs due to coal worker’s pneumoconiosis, hard metal dis-
respiratory viruses such as influenza or in an ease, and berylliosis. Asbestosis is a form of
immunocompromised patient (cytomegalovirus, interstitial fibrotic lung disease secondary to
respiratory syncytial virus, varicella zoster, or asbestos exposure. Fibrosis is characteristically
herpes simplex). Histological examination shows found in the lower lobes, especially in the sub-
alveolar cell injury with a mononuclear cell inter- pleural areas. Asbestos bodies are present in the
stitial infiltrate. lung parenchyma. Asbestosis may be graded
Tuberculosis: The characteristic histological depending on the amount of lung substance
lesion is the caseating granuloma. Primary TB involved and the severity of the fibrosis. Other
presents with a solitary parenchymal nodule and asbestos related conditions include benign pleu-
hilar lymph node involvement. Secondary TB ral plaques, diffuse pleural thickening, and malig-
may present as miliary TB, tuberculous pneumo- nant mesothelioma. The incidence of carcinoma
nia, or cavitary TB. of the lung is increased in those with a history of
Mycotic infections: Tangled masses of fungal asbestos exposure.
hyphae and debris may be found in lung cavities Interstitial pneumonia/cryptogenic fibrosing
and are known as fungal balls. These are usually alveolitis/pulmonary fibrosis: Chronic inflamma-
non-invasive unless the patient is immunocompro- tory disease, which shows thickening of the
mised. Aspergillus fumigatus is the most common alveolar walls, initially by lymphocytes and
cause, the fungal balls being called aspergillomas. plasma cells, later by fibroblastic proliferation.
Surgery may be needed for diagnosis and treat- Eventually “honeycomb lung” is produced with
ment of disease resistant to medical treatment. scarring and multiple air-filled spaces. The need
Pneumocystis jiroveci: A fungal organism, to assess both spatial and temporal distribution of
which occurs in immunocompromised patients. the pathology means that open or thoracoscopic
Classically there is an acellular intra-alveolar exu- lung biopsies from different zones are usually
date. However, Pneumocystis jiroveci can produce required. Of clinical value is the sub classifica-
any pattern of lung injury. Silver stains or antibody tion of interstitial pneumonia as prognosis and
techniques demonstrate the organism. response to treatment varies between subgroups.
Chronic bronchitis and emphysema: Often These include usual interstitial pneumonia
occur together. Emphysema is characterized by (UIP), desquamative interstitial pneumonia
an increase in the size of airspaces distal to the (DIP), respiratory bronchiolitis-associated inter-
terminal bronchioles. It is classified into three stitial lung disease (RBILD), and non-specific
39 Lung 439
interstitial pneumonia (NSIP). Prognosis and of minimally invasive surgery such as video-
response to treatment are worse for UIP than assisted thoracic surgery has lowered the thresh-
other subgroups (5-year survival 55%). old for early referral and surgical excision.
Immune-mediated lung diseases: Extrinsic Chondroid hamartoma: The most common
allergic alveolitis is a chronic granulomatous dis- benign lung tumour. It consists of a mass of carti-
ease of the lungs due to inhalation of organic lage with entrapped epithelial structures. Other
dusts, e.g., farmer’s lung, bird—fancier’s lung, connective tissue elements such as bone, adipose
mushroom worker’s lung. Upper lobes are more tissue, and fibrous tissue may be present.
severely affected than basal portions with fibrotic Other benign tumours include lipoma, scle-
changes occurring in advanced disease. rosing pneumocytoma, pleomorphic adenoma
Wegener’s granulomatosis: In the lungs, it is and haemangiopericytoma.
characterized by vasculitis and granulomas. It
may present as isolated pulmonary, upper respi- 39.4.2.2 Malignant Tumours
ratory or renal disease. Serum c-ANCA positivity Lung cancer causes approximately 36,000 deaths
is associated with the condition. annually in the UK and has a strong association
Sarcoidosis: Occurs most often in the lungs with cigarette smoking. Two thirds of lung can-
though lymph nodes, skin, eyes, liver, and spleen cers are inoperable at the time of diagnosis.
may also be affected. Characteristically, sharply Traditionally lung cancer is classified into either
circumscribed non-caseating epithelioid granulo- small cell carcinoma (SCLC) or non-small cell
mas are present, and 25% of cases show marked carcinoma (NSCLC). The behaviour and treat-
interstitial fibrosis. ment of the two groups differs. In general, SCLC
Pulmonary vascular disease: Emboli that is treated by chemotherapy, whereas NSCLC,
lodge in peripheral arteries cause pulmonary after appropriate clinical staging, is either
infarcts in patients, whose pulmonary circulation resected (stage pT2 N1 disease or less) or treated
is already compromised. with radiotherapy or chemotherapy. Few patients
Pulmonary hypertension: Primary or second- with SCLC survive longer than 12–19 months.
ary. Changes in the arteries may be graded Patients with NSCLC have an average 5-year sur-
according to the Heath-Edward’s classification. vival of 10–15%.
Lung transplantation: The most common Increasingly, non-small cell lung carcinomas
indication for lung transplantation is emphysema, are being further sub-classified by specific cell
e.g., secondary to alpha-1-antitrypsin deficiency. type, e.g., squamous cell carcinoma, adenocarci-
Other indications include chronic obstructive noma, using ancillary techniques such as immu-
pulmonary disease, septic disease such as cystic nohistochemistry if morphology is unhelpful. If
fibrosis, fibrotic lung disease, and primary pul- the tumour is an adenocarcinoma, molecular test-
monary hypertension. Surveillance involves ing is done for mutations which respond to
transbronchial biopsy to look for rejection, which targeted therapies eg epidermal growth factor

is graded according to the 2007 working receptor (EGFR), ROS-1, Anaplastic Lymphoma
classification. Kinase (ALK) status.
Rare conditions of variable neoplastic poten- Squamous cell carcinoma: is a malignant epi-
tial include Langerhans cell histiocytosis and thelial neoplasm showing at least one of the fol-
pulmonary lymphangioleiomyomatosis. lowing: keratinization as single-cell keratinization
or keratin pearls, or, intercellular bridges.
Squamous cell carcinomas mainly occur cen-
39.4.2 Neoplastic Conditions trally in a main or lobar bronchus and can reach a
considerable size with central necrosis.
39.4.2.1 Benign Tumours Histological variants include keratinising, non-
Most benign tumours are identified incidentally keratinising and basaloid squamous cell
on chest X-ray as solitary lung nodules. The use carcinoma.
440 K.M. Mulholland
Adenocarcinoma: The commonest sub-type of They have fewer than two mitoses per ten high
lung carcinoma and is a malignant epithelial neo- power fields and show no necrosis. It is recom-
plasm showing glandular differentiation. It is the mended that resection margins should be to
lung malignancy which occurs most frequently in within 5 mm of the tumour.
non-smokers, females, and in the young. It often Atypical carcinoids: Metastasize in 50–70%
involves the upper lobes and may present peripher- of cases with a 5-year survival of 60%. Necrosis,
ally as a subpleural mass or nodule, with retraction which is usually focal, and increased mitotic
of the pleura. Lung adenocarcinoma is classified activity (>2–10/10 high power fields) are the
into the following subtypes: lepidic, papillary, aci- most reliable indicators of malignant behaviour.
nar, micropapillary, solid, invasive mucinous, col- Small cell carcinoma (SCLC): Accounts for
loid, fetal and enteric adenocarcinoma. Minimally 15% of all lung cancers. SCLC is most often
Invasive Adenocarcinoma: a resected lesion located centrally and tends to metastasize early
≤30 mm diameter showing an invasive component and extensively. It is the lung carcinoma most
≤5 mm and is sub classified into mucinous and frequently associated with paraneoplastic syn-
non-mucinous types. Adenocarcinoma in situ: a dromes. It is primarily treated with chemother-
resected lesion ≤30 mm diameter showing a apy, the role of surgery usually being limited to
purely lepidic pattern with no evidence of stromal, obtaining a definitive tissue diagnosis and for
vascular or pleural invasion and can be mucinous staging. Histological examination shows small or
or non-mucinous. Adenosquamous carcinoma: medium-sized cells with scanty cytoplasm,
shows areas of both squamous cell and adenocar- arranged in nests, ribbons, or strands but often
cinomatous differentiation, with the minor compo- showing a lack of an architectural pattern. A vari-
nent accounting for at least 10%. Prognosis is ant of small cell carcinoma is a combined tumour
worse than for pure squamous cell carcinoma or where other tumour elements such as squamous
adenocarcinoma. or adenocarcinoma are present.
Secondary adenocarcinomas: may come from Large Cell Neuroendocrine Carcinoma
pancreas, colon, ovary, or kidney and show vari- (LCNEC): shows a histological pattern of large
ous patterns. If there is involvement of the hilar cells with a high mitotic rate, necrosis and posi-
nodes and significant scarring, then the tumour is tivity for neuroendocrine immunohistochemical
more likely to be a primary; if multiple tumours markers.
are present, it is more likely to be secondary. Salivary gland tumours: Adenoid cystic carci-
Large Cell Carcinoma: is used only in resection noma is most commonly located in the trachea and
specimens for tumours that lack any clear morpho- major bronchi. The tumour shows a cribriform pat-
logic or immunohistochemical differentiation. tern with tubular and solid areas. Perineural infiltra-
Neuroendocrine tumours: these include Small tion is common. It is generally slow growing.
Cell Carcinoma, Typical and Atypical Carcinoids Mucoepidermoid carcinoma arises from minor
and Large Cell Neuroendocrine Carcinoma. salivary gland lining the tracheobronchial tree.
Typical carcinoid tumours: Account for 90% Other cancers include the sarcomatoid carci-
of bronchial carcinoids. The vast majority are nomas—pleomorphic carcinoma, spindle cell
cured by complete excision with more than 90% carcinoma and giant cell carcinoma containing
10-year survival. They are of low malignant spindle cells and/or giant cells. Rare cancers:
potential—only 10–15% spread to local lymph Carcinosarcomas contain both malignant epithe-
nodes and distant metastases are rare. Typical lial and sarcomatous elements. Blastomas have a
carcinoids may occur either centrally or peripher- biphasic pattern consisting of epithelial tubules
ally. Grossly, they are yellowish or pale tan and or cords in an undifferentiated stroma. NUT car-
may be “dumbbell”-like, as they extend into the cinoma is a carcinoma associated with chromo-
lumen of the bronchus and the lung parenchyma. somal rearrangements in the NUT (Nuclear
They are composed of a uniform cell population Protein in Testis) gene.
arranged in ribbons, cords, or islands. In periph- Extranodal marginal zone lymphoma of mucosa-
eral carcinoids, the cells are often spindle shaped. associated lymphoid tissue (Malt lymphoma): is
39 Lung 441
the commonest primary lung lymphoma. It may and may be used for straight ahead viewing or at
be solitary or multifocal. Histological examina- 30° or 90° for visualization of the upper lobe
tion shows a monomorphic population of centro- bronchi. It is essential for complete examination
cyte-like cells. Most malt lymphomas are low of the trachea as a flexible bronchoscopy may
grade but can transform to high grade. Lymphoma miss lesions. It may also be used for brush cytol-
may also present in the lung secondary to nodal ogy, biopsy, and to trap sputum for cytology and
or systemic disease. Other lymphomas include culture.
diffuse large cell lymphoma, lymphomatoid However, it allows visualization of major lobar
granulomatosis and intravascular large B cell orifices only and is usually performed under general
lymphoma. anaesthetic. Flexible bronchoscopes have outer
Tumours of ectopic origin: include germ cell diameters ranging from 3 to 6 mm. Light is trans-
tumours such as mature teratoma and immature mitted through fibreoptic bundles. The broncho-
teratoma, intrapulmonary thymoma, melanoma scope can be attached to a video camera for large
and meningioma. screen display. The working channel allows inser-
Tracheal tumours: Primary tracheal tumours tion of various diagnostic and therapeutic accesso-
are rare, secondary tumours being more common. ries. Biopsy forceps are inserted to obtain bronchial
In adults, most primary tracheal tumours are or transbronchial biopsies. Lesions not accessible to
malignant and include squamous cell carcinoma, direct biopsy can be approached with a brush to
which is usually locally advanced at the time of obtain specimens for cytological or microbiologic
presentation, and adenoid cystic carcinoma. analysis. Needles may also be used for aspiration
Chest wall tumours: Malignant small cell and biopsy. Flexible bronchoscopy is the endo-
tumour of the thoracopulmonary region (Askin scopic procedure of choice as it is simple, quick to
tumour) occurs in the first two decades of life. It use, and is performed under local anaesthetic.
is composed of sheets of undifferentiated, small, Open lung biopsies: Obtained by thoracotomy
hyperchromatic cells, which may form rosettes for the assessment of peripheral lung disease.
around a central tangle of fibrillary cytoplasmic
processes. Other chest wall tumours include
extra-abdominal desmoid tumours, elastofibroma 39.5.2 Resection Specimens
dorsi, and primary tumours of muscle, fat, blood
vessels, nerve sheath, or bone. Video-assisted thoracoscopic surgery (VATS):
Direct thoracoscopy is being replaced by video-
assisted thoracoscopic surgical (VATS) technique.
39.5 Surgical Pathology VATS allows access to peripleural lung nodules,
Specimens: Clinical Aspects biopsy, and sampling of mediastinal nodes, espe-
cially in the aortopulmonary window, examination
39.5.1 Biopsy Specimens of the pleural space for tumour, wedge resection of
lung for diagnosis of diffuse lung infiltrates, or
Percutaneous/transthoracic needle biopsy: peripheral nodules, and resection of apical pleural
Performed under X-ray guidance, an 18-gauge blebs for spontaneous pneumothorax.
needle is inserted with the aid of a spring-loaded Wedge/segmental resections: Obtained via
firing device. The biopsy is rinsed directly into open lung biopsy or video-assisted closed chest
the fixative. Occasional cases require fresh tissue biopsy. They are used to sample focal areas that
to be sent for microbiological culture. Fresh fro- are suspicious, e.g., pleural-based nodules or to
zen or glutaraldehyde fixed tissue may be needed resect tumours if a patient cannot tolerate a more
for special investigations (specialized immuno- extensive procedure. Recurrence rates of tumour
histochemistry, electron microscopy). are higher than with more radical surgery.
Endobronchial/transbronchial biopsies: Taken Bullectomies: Used to excise bulla to improve
by rigid or flexible bronchoscopy. The rigid lung function via a median sternotomy approach,
bronchoscope ranges from 3 to 9 mm in diameter posterolateral thoracotomy, or VATS.
442 K.M. Mulholland
Bronchoplastic or sleeve resections: Used as an Anterolateral thoracotomy and axillary thora-

alternative to pneumonectomy. They are lung cotomy are used with decreasing frequency. Median
sparing and are typically used to resect proximal sternotomy is used in mediastinal tumour resection,
endobronchial lesions at, or adjacent to, the carina bilateral lung volume reduction surgery or bullec-
in order to preserve distal, uninvolved lung. tomy, resection of multiple pulmonary lesions (e.g.,
Sleeve lobectomy: Excision of a lobe with the metastases) and transpericardial access to the tra-
associated lobar bronchus and subsequent anas- chea or bronchus, e.g., carinal tumours.
tomosis of the distal bronchial tree to the proxi- The thoracoabdominal approach is used in
mal airway. procedures where access is needed to both pleu-
Bronchial sleeve resection: Resection of either ral and peritoneal cavities. Bilateral anterior tho-
mainstem bronchus with anastomosis of the dis- racotomies (also known as the clamshell incision)
tal airway to the carina or lower trachea. provide maximum exposure of both hemithora-
Sleeve pneumonectomy: Resection of the ces and mediastinal structures. This approach is
carina with pneumonectomy and anastomosis of used in bilateral lung resections such as lung
the contralateral distal bronchus to the distal transplant and lung reduction surgery.
trachea. Lung volume reduction surgery (LVRS): A pal-
Lobectomy/bilobectomy: Resection of one or liative surgical procedure for patients with end-
two lobes of lung and includes complete resec- stage emphysema in which 20–30% of each
tion of hilar (N1) lymph nodes draining the pri- upper lobe is resected.
mary tumour.
Pneumonectomy: Resection of the whole lung
and accounts for 20% of all lung resections. It is 39.6 Surgical Pathology
indicated when tumour invades hilar structures Specimens: Laboratory
such as the mainstem bronchus or the main pul- Protocols
monary artery. It is also indicated when tumour
crosses the oblique fissure or when there is lymph 39.6.1 Biopsy Specimens
node involvement along the mainstem bronchus
proximal to the upper lobe take-off. In the major- Small biopsies are promptly put into 10% forma-
ity of cases, it is for the purpose of resecting lin fixative.
tumours, an exception being recipient pneumo-
nectomy performed prior to lung transplant. Endobronchial/transbronchial biopsies:
Extended pulmonary resection: Extension of
the limits of conventional pulmonary resection • Count the number of fragments.
with an en bloc excision of contiguous intratho- • Record the greatest dimension of the largest
racic structures involved by tumour. fragment (mm).
Extrapleural pneumonectomy: Indications • Note the colour and consistency of the
include resection of malignant mesothelioma or fragments.
rarely carcinoma of the lung, which is restricted • Place the fragments in cassettes between foam
to the lung, pleura, and local lymph nodes. pads or wrapped in filter paper or in molten
Surgical incisions: The most versatile approach agar for processing.
used by the thoracic surgeon is the posterolateral • Cut through multiple levels, keeping interven-
thoracotomy. The incision is 8 cm lateral to the 6th ing spares for further stains.
thoracic spinous process and curves forward, 2 cm
below the tip of the scapula to the mid-axillary line Open lung biopsy:
in the line of the ribs. It is used in unilateral lung
resection, chest wall tumour resection, unilateral • Re-inflate the lung using a formalin injection.
lung volume reduction surgery, bullectomy, and • Record the size (mm) and weight (g)/number
tumours of the posterior mediastinum. of fragments.
39 Lung 443
• Describe the colour and consistency. • Other pathology—vascular, asbestos bodies,

• Serially transverse section at 3 mm intervals doubly refractile material.
and sample representative blocks. • If transplant, grade rejection according to the
1995 working formulation.
• Nature of biopsy. 39.6.2 Resection Specimens

• Size of biopsy (mm), number of fragments.
• Bronchial wall—epithelium, thickness of Larger specimens are put into dry containers and
wall, goblet cell hyperplasia, malignancy. brought promptly to the laboratory.
• Alveoli—count approximate number, type I or
II pneumocyte proliferation, inflammation, 39.6.2.1 W edge Resections (Or
macrophages in lumen, consolidation. Cornish pastie)
• Nature of inflammatory cells if present. • Consist of a triangular segment of lung and
• Fibrosis if present: type—interstitial, intra- pleura with two staple lines at the margin
alveolar (BOOP), grade of fibrosis—mild, (Fig. 39.2).
moderate, severe. • Palpate the specimen to locate the lesion.
Pleura
1. Locate the lesion and paint

the overlying pleura
Staple
line
2. Cut off the stapled margin
3. Paint the cut parenchymal

margin and serially slice
perpendicular to it
4. Block tumour in relation to

Fig. 39.2 Blocking a lung, pleura and parenchymal
wedge resection of lung margin
(Reproduced, with
and Cameron (2013))
444 K.M. Mulholland
• Record the dimensions (cm). • If the lung disease is diffuse, submit the vast
• Describe the pleura. majority of the specimen for histology.
• Inflate with a syringe of formalin. A disadvan-
tage of inflation fixation is that free cells may 39.6.2.2 Lung Resection for Tumours
be cleared from consolidated alveoli so that Most resections are for tumour: lobectomy,
diagnoses such as desquamative interstitial bilobectomy, and pneumonectomy.
pneumonia (DIP) are obscured. Measure the
length of the margin. Cut off the staple line as Initial procedure:
closely as possible. The cut surface of the lung
can be taken en face or perpendicularly. The • Palpate to locate tumour or areas of abnormality.
open surface is inked. • Specify which lung or lobe.
• Ink the pleural surface over the lesion. • Record the weight (g) and dimensions (cm).
• Serially transverse section at 3 mm intervals. Ink the pleura overlying the tumour.
• Describe the lesion—size, colour, pleural • Remove the bronchial margin by sectioning
involvement, distance (mm) from margin. transversely, before inflation fixation
• Describe the remainder of the lung. (Fig. 39.3). Sample the hilar nodes.
• Take representative sections of any lesion, of • Inflation: If the specimen is intact, instill fixa-
its relationship to the pleura and uninvolved tive from a height of about 25 cm via tubing
lung, and the closest margin. that terminates in a nozzle wedged into the
1. Sample hilar
lymph nodes
and transverse
section proximal
bronchial and
vascular limits
2. Slice open coronally

or parasagitally depending
on tumour location and
using the partially opened
airways as a guide
3. Sample tumour 4. Sample tumour

in relation to airways in relation to
Fig. 39.3 Blocking a and vessels pleura and
pneumonectomy parenchyma
specimen (Reproduced,
Allen and Cameron
(2013))
39 Lung 445
supply bronchus or bronchi. Continue until • Submit all hilar lymph nodes. The surgeon for
the pleural surface is smooth. Immerse in a staging purposes often also submits other sep-
container of fixative overnight with a covering arate named lymph node stations, and these
of lint or filter paper to prevent drying. If the are processed separately. The regional lymph
specimen is not intact, inflate with a syringe. nodes are the intrathoracic (mediastinal, hilar,
Remember to culture, if appropriate, before lobar, interlobar, segmental, subsegmental),
fixation. scalene and supraclavicular nodes. A medias-
• Allow to fix for 24–36 h. tinal/hilar lymphadenectomy will ordinarily
• To access airways open from the hilum, pass include 6 or more lymph nodes.
a probe down to the tumour and then cut • Sample four sections of tumour showing rela-
along it. tionships to uninvolved lung, adjacent bronchi,
• Serially slice the tumour at 3 mm intervals in and vessels and the nearest aspect of the pleura.
the plane that best demonstrates its relation- • Sample uninvolved lung (one or two blocks—
ship to the anatomical structures. In general, more if there is suspected asbestosis).
mid-zone and peripheral lesions are sliced • Sample the margins of any attached parietal
parasagittally, hilar lesions coronally. pleura, chest wall soft tissue, or ribs—repre-
• With vascular lesions such as pulmonary sent the deepest point of rib invasion.
emboli, approach laterally within fissures cut-
ting towards the hilum until the pulmonary Histopathology report:
artery is entered.
• Photograph. • Type of procedure—wedge resection, lobec-
• Ribs—decalcify. tomy, bilobectomy, pneumonectomy.
• Tumour type—squamous carcinoma/adeno-
Description: carcinoma/small cell carcinoma/large cell car-
cinoma/neuroendocrine tumours/salivary
• Lesion site—central/peripheral, main/segmen- gland type adenocarcinoma/others.
tal bronchus. • Tumour differentiation—well/moderate/poor.
–– Endobronchial/bronchial/extrabronchial/ • Tumour edge—pushing/infiltrative/lymphoid
extrinsic compression. response.
–– Distances (mm) to the bronchial or paren- • Elastin stain may be helpful in recognizing
chymal resection margins/pleura. visceral pleural invasion.
• Lesion size—length × width × depth or maxi- • Extent of local tumour spread: TNM 8 for
mum dimension (cm). non-small cell carcinoma, small cell carci-
• Lesion appearance—colour/consistency/ noma and bronchopulmonary carcinoid
necrosis/haemorrhage/cavitation. tumours. Sarcomas are excluded
• Lesion edges—circumscribed/infiltrative.
• Lung—emphysema/fibrosis/bullae/bronchi-
ectasis/mucus plugging/post-obstructive
pT1a Tumour ≤10 mm diameter
pneumonia. pT1b Tumour >10–≤20 mm
• Hilar lymph nodes—number/size/colour/ pT1c Tumour >20–≤30 mm
consistency. pT2 Tumour >30–≤50 mm, or any of:
involves main bronchus but not the
Blocks for histology (Fig. 39.3): carina, invades visceral pleura, partial
atelectasis/obstructive pneumonitis
extending to the hilum
• Transverse section the proximal resection
pT2a >30–≤40 mm
margin and the pulmonary staple margin if the
pT2b >40–≤50 mm
specimen is a lobectomy.
446 K.M. Mulholland
pT3 Tumour >50–≤70 mm; or any of: Association of Directors of Anatomic and Surgical Pathology.
involvement of parietal pleura, chest wall, Recommendations for the reporting of resected primary
phrenic nerve, parietal pericardium or lung carcinoma. Hum Pathol. 1995;26:937–9.
separate tumour nodule(s) in the same Brierley JD, Gospodarowicz MK, Wittekind C, editors.
lobe as the primary TNM classification of malignant tumours. 8th ed.
pT4 Tumour >70 mm, or any of: involvement
Baldwin DR, White B, Schmidt-Hansen M, Champion AR,
of great vessels, mediastinum, heart,
Melder AM, on behalf of the Guideline Development
diaphragm, trachea, recurrent laryngeal
Group. Diagnosis and treatment of lung cancer: summary
nerve, oesophagus, vertebra, or carina.
of updated NICE guidance. BMJ. 2011;343:1019–22.
Separate tumour nodule(s) in different
Baumgartner WA, Reitz B, Kasper E, Theodore J. Heart
ipsilateral lobe to the primary
and lung transplantation. 2nd ed. London: Saunders;
pN0 No regional node involvement 2001.
pN1 Ipsilateral hilar/peribronchial/ Billingham M, Carey N, Stewart S, Goddard M. Atlas of
intrapulmonary nodes (node stations biopsy histopathology for heart and lung transplanta-
10–14) tion. 1st ed. London: Arnold; 2000.
pN2 Ipsilateral mediastinal/subcarinal nodes Casson AG, Johnston MR. Key topics in thoracic surgery.
(node stations 1–9) 1st ed. Washington DC: ßios Scientific Publishers; 1999.
pN3 Contralateral mediastinal, hilar, ipsilateral Corrin B, Nicholson AG. Pathology of the lungs. 3rd ed.
or contralateral scalene, supraclavicular London: Churchill Livingstone; 2011.
nodes Fishman AP, Elias JA, Fishman JA, Grippi MA, Kaiser
LR, Senior RM. Fishman’s manual of pulmonary dis-
pM0 No distant metastasis eases and disorders. 3rd ed. New York: McGraw-Hill;
pM1 Distant metastasis 2002.
pM1a Separate tumour nodule(s) in a Forbes CD, Jackson WF. Atlas and text of clinical medi-
contralateral lobe, pleural or pericardial cine. 3rd ed. London: Mosby-Wolfe; 2002.
nodules or malignant pleural or Stewart S, Fishbein MC, Snell GI, Berry GJ, Boehler A,
pericardial effusion Burke MM. Revision of the 1996 working formula-
pM1b Single extrathoracic metastasis in a single tion for the standardization of nomenclature in the
organ diagnosis of lung rejection. J Heart Lung Transplant.
2007;26(12):1229–42.
pM1c Multiple extrathoracic metastases in a
The Royal College of Pathologists. Dataset for lung can-
single or multiple organs
cer histopathology reports, 4th ed. (2016); Tissue
pathway for non-neoplastic thoracic pathology, 2nd
• Excision margins—distances (mm) to the ed. (2013). https://www.rcpath.org/profession/publi-
proximal bronchial, vascular and mediastinal cations/cancer-datasets.html. Accessed Sep 2016.
Travis WD, Brambilla E, Burke AP, Marx A, Nicholson
limits and pleura.
AG. WHO classification of tumours of the lung,
• Other pathology—atelectasis/bronchiectasis/ pleura, thymus and heart. Lyon: International Agency
lipid or suppurative pneumonia. for Research on Cancer; 2015.
Travis WD, Colby TV, Koss MN, Rosado-de-Christenson
ML, Muller NL, King TE. Non-neoplastic disorders of
the respiratory tract. In: Atlas of nontumor pathology,
Bibliography Fascicle 2. Washington: AFIP; 2002.
West JB. Pulmonary pathophysiology—the essentials. 7th
Allen DC. Histopathology reporting. Guidelines for surgi- ed. Baltimore: Williams & Wilkins; 2007.
cal cancer. 3rd ed. London: Springer; 2013. Wittekind C, Greene L, Hutter RVP, Klimfinger M, Sobin
Allen DC, Cameron RI. Histopathology specimens: LH. TNM atlas: illustrated guide to the TNM/pTNM
clinical, pathological and laboratory aspects. 2nd ed. classification of malignant tumors. 5th ed. Berlin/
Berlin/Heidelberg: Springer; 2013. Heidelberg: Springer; 2005.
Pleura
40
40.1 Anatomy in 25% of cases of malignant mesothelioma.

Paraneoplastic syndromes occasionally arise
The visceral pleura covers the surface of the causing immunosuppression, thrombocytosis,
lungs, and the parietal pleura covers the inner cachexia, amyloidosis, or hypoglycaemia.
surface of the chest wall, mediastinum, and
diaphragm. Under normal circumstances, the
cavity contains 5–20 mL of fluid. The lining of 40.3 Clinical Investigations
the pleura is composed of a continuous layer of
flat or low cuboidal cells, the mesothelium. • Chest X-ray—to detect pleural effusions and
Lymphovascular drainage: calcified pleural plaques.
Branches of systemic arteries supply the pari- • CT scan—may identify an effusion undetect-
etal pleura. The bronchial circulation supplies the able by conventional radiography. It will show
visceral pleura. Venous blood from the visceral pleural thickening and calcification due to
pleura drains into the pulmonary veins, and asbestos exposure. It is important in detecting
lymph from the visceral pleura passes to a super- invasion of chest wall, ribs, and mediastinum
ficial plexus in the lung and then to the hilar by malignant mesothelioma.
nodes. Lymph leaves the pleural cavity mainly • Ultrasound—used to localize pleural effu-
via the parietal lymphatic system. The parietal sions during thoracentesis.
pleura drains to the parasternal, diaphragmatic, • Thoracentesis—aspiration of pleural fluid
and posterior mediastinal nodes. using a sterile technique. 50–100 mL is suffi-
cient for diagnosis, but more may be removed
if the thoracentesis is therapeutic.
40.2 Clinical Presentation • Pleural fluid analysis (cytology, biochemis-
try)—total protein, lactate dehydrogenase,
Pleural disease may present with pain and amylase, glucose, pH, lipids, complement and
breathlessness. Nonspecific symptoms such as antibodies, Gram stain, and culture.
weakness, anorexia, and fever may be present • Pleural needle biopsy—percutaneous closed
needle biopsy with thoracentesis. A diagnosis
of malignancy is achieved in 40–70% of cases.
K.M. Mulholland • Thoracoscopy and pleural biopsy—thoracos-
Histopathology Laboratory, Altnagelvin Hospital, copy, especially if guided by CT findings,
Western Health and Social Care Trust, should improve the diagnostic yield to over
Londonderry, UK
e-mail: kathleen.mulholland@westerntrust.hscni.net 95%. Minimally invasive approaches such as

448 K.M. Mulholland
video-assisted thoracoscopy (VATS) lead to (PJP). Catamenial pneumothorax is associated

earlier diagnosis. with menstruation and may be due to focal endo-
• Open pleural biopsy (with or without decorti- metrial deposits on the pleura. Traumatic pneu-
cation)—occasionally rigid (open tube) pleu- mothorax can be iatrogenic, e.g., secondary to
roscopy or even minithoracotomy is required biopsy, or otherwise, e.g., penetrating chest
to obtain an adequate pleural biopsy. trauma.
Pleural plaques: usually but not always asso-
ciated with asbestos. Histological examination
40.4 Pathological Conditions shows hyalinized fibrous tissue with basket
weave collagen fibres. Plaques are usually pres-
40.4.1 Non-neoplastic Conditions ent on the parietal pleura mainly in the intercostal
spaces on the anterior and posterolateral aspects
Pleural disease is either primary or secondary, of the chest wall and on the dome of the
e.g., to an underlying lung lesion or systemic dis- diaphragm.
order such as systemic lupus erythematosus Diffuse pleural thickening: involves the vis-
(SLE). ceral pleura and is associated with asbestos
Pleural effusions: over 90% of effusions are exposure.
secondary to one of four conditions—congestive Asbestos-induced mesothelial hyperplasia:
heart failure, pneumonia, malignancy, or pulmo- consists of a papillary proliferation of the surface
nary emboli. Transudates are effusions contain- mesothelium with cores of connective tissue and
ing low concentrations of proteins (<3 g/dl), and a surface covering of regular mesothelial cells. It
the majority are due to congestive heart failure. may be difficult to distinguish from malignant
Exudates contain higher concentrations of pro- mesothelioma on pleural biopsy.
tein (>3 g/dl), and over 80% are due to pneumo-
nia, neoplasm, or pulmonary emboli. Depending
on the aetiology, effusions can be serous, fibrin- 40.4.2 Neoplastic Conditions
ous, serofibrinous, purulent, or haemorrhagic.
Empyema is the presence of frank pus in the Metastatic tumours, e.g., from lung and breast
pleural cavity. Noninfective processes such as cancer, are the most common tumours of the
pulmonary infarction, rheumatoid disease, SLE, pleura.
and uraemia may present with a pleural effusion. Malignant mesothelioma: most common pri-
Asbestos-related pleural effusion develops in mary malignant tumour of the pleura. There is a
3% of asbestos workers. In most, it will resolve in proven relationship with asbestos exposure,
1–2 years, but 20% progress to massive pleural although 10–20% appear to be unrelated. Rarely,
fibrosis and 5% develop malignant mesothelioma. they may be associated with therapeutic irradia-
Carcinoma of the lung is the most common malig- tion or intrapleural thorium dioxide (Thorotrast).
nancy to invade the pleura and produce pleural In industrialized countries, malignant mesotheli-
effusions, followed by carcinoma of the breast. oma accounts for about 1% of all cancer deaths.
Pneumothorax: primary spontaneous pneu- There is a latency period of approximately 20 to
mothorax occurs most commonly in 30- to 30 years between exposure to asbestos and devel-
40-year-old tall, thin males. They are most often opment of the tumour.
due to rupture of blebs or bullae on the apical Malignant mesothelioma occurs usually in the
parts of the upper lobes. Rate of recurrence is lower half of the hemithorax on the right side
25%. Secondary pneumothorax occurs in chronic more often than the left. It encases the lung, and
obstructive pulmonary disease, cystic fibrosis, direct extension into the subpleural lung is com-
asthma, tuberculosis, idiopathic pulmonary fibro- mon. If nodular masses are present within the
sis, lymphangioleiomyomatosis, Langerhans his- lung parenchyma, a primary lung carcinoma with
tiocytosis, and Pneumocystis jiroveci pneumonia pleural spread is more likely.
40 Pleura 449
Histological patterns include epithelial, sar- Body cavity-based lymphoma: presents as a

comatoid (or fibrous), and biphasic, a combina- mass lesion. It is associated with EBV, human
tion of both. The epithelial pattern appears to be herpes virus 8, and HIV. It is a high-grade lym-
commonest in most series, with tubules, papil- phoma of null cell phenotype.
lae, and sometimes psammoma bodies being
seen. The pleomorphic subtype has a particularly
poor prognosis. Spindle cells set in varying 40.5 Surgical Pathology
amounts of collagenized stroma are seen in the Specimens: Clinical Aspects
sarcomatoid pattern which also has a poor
prognosis. 40.5.1 Biopsy Specimens
Differential diagnosis includes adenocarci-
noma, reactive mesothelial hyperplasia, and A number of procedures can be undertaken to
fibrosis. Immunohistochemistry, assessment of obtain pleural biopsies.
radiological findings, and disease course are cor- A special needle, usually an Abrams or Cope
related to reach a final diagnosis. needle, may be used during thoracentesis, both to
Distant metastases occur late if, at all, the sar- drain fluid and obtain a pleural biopsy. A pleural
comatoid form showing metastatic spread more needle biopsy often provides insufficient tissue
commonly. Malignant mesotheliomas are rarely for diagnosis. When this is the case, thoracos-
operable. Few patients survive longer than copy and a visually directed pleural biopsy may
2 years, and the outlook is not significantly be required. In some cases, an open pleural
affected by current therapy. biopsy is undertaken with or without decortica-
Occasional patients are suitable for adjuvant tion. Decortication is a procedure to remove con-
chemotherapy with local resection of limited dis- stricting visceral pleural peel in order to expand
ease. Symptomatic relief is gained by multiple the underlying lung. It is of use in very few
paracentesis of malignant effusions supple- patients as the morbidity and mortality usually
mented by intracavitary injection of chemothera- outweigh any benefit.
peutic or sclerosant agents. Approximately 10% of cases of malignant
Solitary fibrous tumour: origin is from the mesothelioma that have a biopsy will have seed-
subpleural mesenchyme, from fibroblasts or ing of the biopsy tract by tumour with subsequent
myofibroblasts, and is unrelated to asbestos chest wall recurrence. To prevent this happening,
exposure. It more often arises from the visceral radiation therapy is used on the biopsy site.
pleura and is often attached by a pedicle.
Histological examination shows a low-grade
spindle cell neoplasm of variable cellularity 40.5.2 Resection Specimens
with tumour cells dispersed in a collagenous
stroma. Surgery may be used to treat pneumothorax. The
The most important prognostic factor is the preferred approach is using minimally invasive
completeness of excision and particularly the techniques (VATS), but thoracotomy can be used
presence or absence of a pedicle. Tumour size with an axillary, muscle sparing approach.
and cellularity correlate with malignancy. Resection of blebs or bullae is achieved using
Prognosis is generally good with a minority mechanical stapling devices.
showing local recurrence. Pleurectomy is a procedure used to debulk a
Calcifying fibrous pseudotumour: occurs in malignant mesothelioma or for diagnosis.
young adults and may be a late stage of inflam- Multiple fragments or strips of pleural membrane
matory myofibroblastic tumour. are obtained.
Pyothorax- associated lymphoma: non- An extrapleural pneumonectomy (EPP) is the
Hodgkin’s lymphoma of B cell phenotype. It is en bloc resection of visceral and parietal pleura,
associated with Epstein-Barr virus (EBV). lung, ipsilateral hemidiaphragm and pericardium.
450 K.M. Mulholland
It has an operative mortality of 5–15%. Combined Extrapleural pneumonectomy:

with postoperative chemotherapy and adjuvant
radiotherapy, it may improve survival. • Tissue may be taken for electron microscopy
before fixation.
• Weigh the specimen (g) and record its dimen-
40.6 Surgical Pathology sions (cm).
Specimens: Laboratory • Inflate and fix the lung.
Protocols • Take the bronchial margin and remove hilar
lymph nodes (number/size).
40.6.1 Biopsy Specimens • Examine the pleura—determine the percent-
age involvement by tumour.
As for lung biopsies, see Chap. 39. • Examine the pericardium for tumour.
• Ink margins close to the tumour.
• Serially section the specimen coronally at
40.6.2 Resection Specimens 1-cm intervals.
• Describe involvement of the diaphragm by
Pleurectomy (Fig. 40.1): tumour—distance from the anterior, posterior,
medial, and lateral margins; depth of invasion
• Record the number of fragments. into diaphragm; and involvement of the peri-
• Measure the dimensions (cm) of the fragments toneal surface of the diaphragm.
unless there are more than three, then note • Describe involvement of visceral pleura—
dimensions of the smallest and largest, and extent of fusion of visceral pleura to parietal
weigh the fragments (g). pleura and size of nodules of tumour.
• Describe any lesions—colour, consistency, • Invasion of lung—usually, tumour invades
and sizes. along interlobar fissures (Fig. 40.2). Describe
• Record the presence of other structures such parenchymal disease such as pneumonia or
as muscle, pericardium, or fat and any involve- fibrosis.
ment of these by tumour. • If rib is attached, describe the dimensions and
• Ink margins and note the distances (cm) of any any tumour involvement seen. If lesions are
lesion from them. seen in the ribs, X-ray.
• Submit one section for each centimetre of
tumour to include the margins. Blocks for histology:
• Take sections perpendicular to the pleura from

the apex of the lung; the anterior, posterior,
Nodules/plaques
medial, and lateral pleura at one level; and the
of mesothelioma anterior, lateral, medial, posterior, and inferior
margins of the diaphragm.
• Take sections of rib if involved.
• If chest wall is attached to the specimen, take
Thickened margins.
fibrotic
pleura Histopathology report:
• Type of specimen—biopsy/pleurectomy/
Fig. 40.1 Blocking a pleurectomy specimen (Reproduced, extrapleural pneumonectomy.
with permission, from Allen and Cameron (2013)) • Size (cm) and weight (g).
40 Pleura 451
Fig. 40.2 Pleural and pT1 Tumour limited to ipsilateral parietal and/or visceral pleura
interlobar spread of
malignant mesothelioma
(Used with the pT1
Control (UICC),
Wittekind et al. (2005)
• Tumour site—visceral/parietal/parenchymal. • Lymphovascular invasion—present/not present.

• Tumour size—length × width × depth or max- • Regional lymph nodes—intrathoracic, inter-
imum dimension (cm). nal mammary, scalene, and supraclavicular.
• Tumour appearance—localized/diffuse/nodu-
lar/plaque/infiltrative/cystic change. pN0 No regional lymph node metastasis
• Tumour histological type—malignant meso- pN1 Metastasis in ipsilateral intrathoracic lymph
thelioma: biphasic, epithelioid, or nodes
sarcomatoid. pN2 Metastasis in contralateral intrathoracic or
• Extent of local tumour spread: TNM 8 for ipsilateral/contralateral supraclavicular lymph
malignant pleural mesothelioma. nodes
pT1 Tumour involves ipsilateral parietal or visceral • Excision margins—distance (mm) to the near-
pleura, ± involvement of visceral, mediastinal est inked margin of local resection of limited
or diaphragmatic pleura disease.
pT2 Tumour involves ipsilateral pleura with one of: • Other pathology—pleural plaques, asbestosis,
invasion of lung parenchyma or diaphragm
muscle
bronchogenic carcinoma, fibrosis, or
pT3 Tumour involves ipsilateral pleura with one of: emphysema.
invasion of endothoracic fascia, mediastinal
fat, solitary focus soft tissues chest wall, or
non-transmural pericardium Bibliography
pT4 Tumour involves ipsilateral pleura with one of:
invasion of contralateral pleura, peritoneum, Allen DC. Histopathology reporting. Guidelines for surgi-
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(oesophagus, trachea, heart, great vessels), Allen DC, Cameron RI. Histopathology specimens:
vertebra, spinal cord, internal surface of clinical, pathological and laboratory aspects. 2nd ed.
pericardium ± pericardial effusion Berlin/Heidelberg: Springer; 2013.
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Brierley JD, Gospodarowicz MK, Wittekind C, editors. Nash G, Otis CN. Protocol for the examination of
TNM classification of malignant tumours. 8th ed. specimens from patients with malignant pleural
Oxford: Wiley-Blackwell; 2017. mesothelioma. Arch Pathol Lab Med. 1999;123:
Casson AG, Johnston MR. Key topics in thoracic sur- 39–44.
gery. 1st ed. Oxford/Washington, DC: Bios Scientific Travis WD, Brambilla E, Burke AP, Marx A,
Publishers; 1999. Nicholson AG. WHO Classification of Tumours
Corrin B, Nicholson AG. Pathology of the lungs. 3rd ed. of the Lung, Pleura, Thymus and Heart. Lyon:
London: Churchill Livingstone; 2011. International Agency for Research on Cancer;
The Royal College of Pathologists. Dataset for the his- 2015.
tological reporting of mesothelioma (2013); Tissue Wittekind C, Greene L, Hutter RVP, Klimfinger M, Sobin
pathway for non-neoplastic thoracic pathology, 2nd LH. TNM atlas: illustrated guide to the TNM/pTNM
ed. (2013). https://www.rcpath.org/profession/pub- classification of malignant tumours. 5th ed. Berlin/
lications/cancer-datasets.html. Accessed Dec 2016. Heidelberg: Springer; 2005.
Mediastinum
41
41.1 Anatomy oesophagus, thoracic duct, descending aorta,

azygos and hemiazygos veins, and lymph nodes.
The mediastinum is that part of the thoracic cav- Lymphovascular drainage:
ity located centrally between the pleural cavi- Lymphatic drainage is to tracheobronchial
ties. It extends anteroposteriorly from the inner lymph nodes situated at the carina.
aspect of the sternum to the spine and superoin-
feriorly from the thoracic inlet to the diaphragm.
It can be subdivided arbitrarily into anterior, 41.2 Clinical Presentation
superior, middle, and posterior compartments
(Fig. 41.1). Almost half of patients with mediastinal cysts or
The anterosuperior compartment contains the tumours are asymptomatic. Lesions are often dis-
thymus gland, lymph nodes, vessels, and fat. The covered incidentally on X-ray or CT scan.
thymus is large at birth but atrophies after puberty Local symptoms may result from compression
and in the adult is variable in size. It can extend or invasion of mediastinal structures and include
down beyond the aortic arch and lie in front of cough, dysphagia, recurrent pulmonary infection,
the brachiocephalic veins and left common dyspnoea, pain, and rarely haemoptysis.
carotid artery. Parathyroid tissue may be embed- Most bronchial, gastric, and gastroenteric
ded in it. The great vessels, the aorta, the superior cysts are asymptomatic, although the latter can
vena cava, and the azygos vein lie in the antero- be life threatening because of gastric secretion
superior compartment. leading to haemorrhage, peptic ulcer, and perfo-
The middle compartment contains the heart, ration. Superior vena cava (SVC) syndrome, due
pericardium, trachea, major bronchi, pulmonary to compression or invasion of the superior vena
vessels, and phrenic and vagus nerves. cava, usually indicates the presence of malig-
The posterior (paravertebral) compartment nancy but can be caused by benign fibrosing
contains the sympathetic chain, vagus nerves, mediastinitis.
The paraneoplastic syndrome myasthenia gra-
vis is present in one third of patients with thymo-
mas. Symptoms include fatigability affecting the
proximal limb muscles, extraocular muscles, and
K.M. Mulholland muscles of mastication, speech, and facial expres-
Histopathology Laboratory, Altnagelvin Hospital, sion. Respiratory difficulties may occur. Other
Western Health and Social Care Trust, paraneoplastic syndromes occurring in 5–10% of
Londonderry, UK
e-mail: kathleen.mulholland@westerntrust.hscni.net cases are red cell aplasia with severe anaemia,

454 K.M. Mulholland
Fig. 41.1 Compartments
of the mediastinum
1
2
Superior
mediastinum 3
5
Anterior
mediastinum
6
Middle
mediastium 7
10
Posterior mediastinum
11
12
hypogammaglobulinaemia resulting in bacterial does not demonstrate high radiation activity, it

infections and diarrhoea, and pemphigus folia- is interpreted as having a low metabolic rate
ceus producing skin blisters. and is likely to be benign.
• MRI scan—particularly useful in determining
tumour invasion of vascular or neural structures,
41.3 Clinical Investigations when coronal or radial body sections are neces-
sary, or when contrast material cannot be given
• Chest X-ray—mediastinal masses commonly intravenously due to renal disease or allergy.
present on chest X-ray obtained for other pur- • Angiography—used in vascular lesions.
poses or in patients with cancer undergoing • Barium swallow—used to investigate poste-
CT scan staging of the chest and abdomen. rior mediastinal lesions.
• CT scan—has limitations when distinguishing • Blood tests:
between cystic and solid structures. –– Mediastinal germ cell tumours: AFP
• PET-CT scan - used to distinguish between (alpha-fetoprotein), β-HCG (beta-human
benign and malignant conditions. If the lesion chorionic gonadotropin)
41 Mediastinum 455
–– Lymphoma/seminoma: LDH (lactate astinum. The lining may be flattened, cuboidal,

dehydrogenase) columnar, or (rarely) squamous epithelium with
–– Parathyroid tumours: serum calcium and thymic tissue in the wall.
alkaline phosphatase Multilocular thymic cysts: acquired and
–– Myasthenia gravis: acetylcholine receptor thought to be secondary to inflammation. Some
antibody. cases are seen in HIV infection. They can mimic
• Blood count—normochromic normocytic an invasive thymic tumour and occur in about
anaemia (red cell aplasia). half of thymuses with nodular sclerosing
• Single fibre EMG (electromyography) and Hodgkin’s disease or seminoma. They also occur
tensilon test—for suspected myasthenia in other tumours such as thymoma and large cell
gravis. lymphoma, though less frequently. Exceptionally,
• Percutaneous or thoracoscopic fine-needle true squamous cell carcinoma arises from these
aspiration—performed under radiological cysts.
guidance. Thymic hyperplasia: strongly associated with
• Percutaneous or thoracoscopic core biopsy— autoimmune disease especially myasthenia gra-
using a larger gauge or cutting needle under vis. There is extreme variability in size and
radiological guidance. weight of the thymus with formation of germinal
• Oesophagoscopy—for dysphagia or for any centres, principally in the medulla, that expand
mass close to the oesophagus. and cause cortical atrophy.
• Bronchoscopy with EBUS (Endobronchial Thymoma: the most common primary neo-
ultrasound guided) biopsy or aspirate—used plasm of the mediastinum. 75% present in the
when there is hilar or peritracheal anterior mediastinum, but they can also occur in
lymphadenopathy. other compartments (neck, thyroid, pulmonary
hilum, lung parenchyma, pleura). A thymoma is a
mixture of neoplastic thymic epithelial cells and
41.4 Pathological Conditions non-neoplastic lymphocytes and is subtyped
based on the morphology of the epithelial cells
41.4.1 Infections and the presence or absence of lymphocytes, par-
ticularly T cells.
Acute mediastinitis: potentially fatal, may affect Thymomas are classified into various sub-
all three compartments and arise from an adja- types: Type A, Atypical Type A variant, Type AB,
cent pneumonia or as a complication of oesopha- Type B1, Type B2, Type B3, Micronodular
geal perforation. Thymoma with lymphoid stroma (MNT) and
Fibrosing mediastinitis: characterized by Metaplastic Thymoma.
fibrosis causing a variety of symptoms depending In general thymomas are indolent. However
on which structures are constricted. Aetiological aggressive behaviour has been shown to occur in
factors include histoplasma capsulatum and all subtypes except the MNT subtype and micro-
tuberculosis. scopic thymomas.
Thymic carcinoma: an epithelial tumour
exhibiting cytological features of malignancy.
41.4.2 Mediastinal Masses Cytoarchitectural features are no longer specific
to the thymus but are analogous to those seen in
See Table 41.1. carcinomas of other organs. No immature lym-
phocytes are present. Microscopic types of thy-
41.4.2.1 Anterior Mediastinal Masses mic carcinoma are squamous cell carcinoma,
Unilocular thymic cysts: of developmental origin basaloid carcinoma, thymic carcinoma with
and occur more often in the neck than the medi- adenoid cystic carcinoma-like features,
456 K.M. Mulholland
Table 41.1 Mediastinal masses

Anterior/superior compartment Middle compartment Posterior compartment
Thymomas Bronchogenic cyst Neurogenic tumours—neurofibroma,
neurilemmoma (schwannoma),
ganglioneuroma, ganglioneuroblastoma,
malignant schwannoma, neuroblastoma,
paraganglioma
Thymolipomas Enteric cyst Malignant lymphoma
Carcinoid tumours Pericardial cyst Gastroenteric cysts
Thymic cyst Malignant lymphoma
Germ cell tumours Primary cardiac tumours
Malignant lymphoma Metastatic carcinoma
Teratomas
Metastatic carcinoma
Thyroid/parathyroid lesions
Mesenchymal lesions–lipoma,
haemangioma, lymphangioma
Aberrant thyroid
Thyroid goitre
ucoepidermoid carcinoma, sarcomatoid car- sclerosis Hodgkin’s lymphoma (composite lym-

m
cinoma, low-grade papillary adenocarcinoma, phoma). Biopsy samples are often small and
NUT (nuclear protein in testis) carcinoma and may be obscured by profuse sclerosis with asso-
undifferentiated carcinoma. ciated cellular crush artifact.
Thymic Neuroendocrine Tumours: include Germ cell tumours: make up 20% of mediasti-
carcinoid tumours-typical and atypical, large cell nal masses.
neuroendocrine carcinoma (LCNEC), combined Mature cystic teratoma: the most common
LCNEC, small cell carcinoma and combined type of mediastinal germ cell neoplasm compris-
small cell carcinoma. ing a disorganized mixture of derivatives of the
Lymphoma: 10–14% of mediastinal masses in three germinal layers—ectoderm, mesoderm,
adults and is the commonest primary neoplasm and endoderm.
of the middle mediastinum. Lymphoma of any Immature teratoma: a germ cell tumour simi-
type may occur, generally as part of widespread lar to mature teratoma but also containing
disease. immature epithelial, mesenchymal, or neural
Mediastinal Hodgkin’s disease: the nodular elements.
sclerosing variety occurs most frequently with Seminoma: the most common malignant germ
mediastinal involvement in 80% of cases. There cell tumour to occur in the mediastinum. These
is a nodular growth pattern, collagen bands, and arise almost always within the thymus.
lacunar cells. Non-seminomatous germ cell tumours:
Non-Hodgkin’s lymphoma: usually high- include malignant teratomas, teratocarcinomas,
grade; T-lymphoblastic (young patients) or large yolk sac tumours, choriocarcinomas and embryo-
B-cell and occasionally low-grade (MALToma). nal carcinomas.
Mediastinal large B-cell lymphoma: thought Malignant germ cell tumours are usually
to be of thymic B-cell origin. Histological treated with chemotherapy and radiotherapy. If a
examination shows a diffuse proliferation of residual mass is left, it is usually a benign tera-
cells, which is compartmentalized into groups toma or necrotic tumour mass that can potentially
by fine bands of sclerosis. There may be thymic degenerate and redevelop malignancy. Excision
remnants. There is an association with nodular may be carried out.
41 Mediastinum 457
41.4.2.2 Middle Mediastinal Masses e.g., malignant lymphoma. The role of needle
Pericardial cysts: benign cysts, the inner surface biopsy for diagnosis of thymoma is controversial.
of which is lined by a single layer of mesothe- Diagnostic accuracy is 59%, but the differentia-
lium and contain clear watery fluid. tion between benign and malignant thymoma is
Bronchial (bronchogenic) cysts: make up 60% difficult. There is also an intraoperative risk of
of all mediastinal cysts and occur along the tra- seeding tumour cells in the mediastinum or pleu-
cheobronchial tree commonly posterior to the ral space.
carina. They are usually lined by ciliated colum- Open biopsy: in some cases, invasive medias-
nar epithelium, but there may be focal or exten- tinal incisional biopsy may be required. Surgical
sive squamous metaplasia. The wall can contain approaches include cervical mediastinoscopy,
hyaline cartilage, smooth muscle, bronchial subxiphoid mediastinoscopy, anterior mediasti-
glands, or nerve trunks. noscopy, and videothoracoscopy.
Oesophageal cysts: usually in the wall of the Cervical mediastinoscopy is performed
lower half of the oesophagus. The lining may be through a small incision in the suprasternal
squamous, ciliated, or columnar epithelium, and notch. It is used to sample masses in the supe-
there is a double layer of smooth muscle in the wall. rior mediastinum or lymph nodes in the
subcarinal and paratracheal area. Anterior medi-
41.4.2.3 Posterior Mediastinal astinotomy (Chamberlain procedure) is per-
Masses formed through a small incision over the second
Gastric and enteric cysts: located in the posterior or third rib on either side. It is used to sample
mediastinum in a paravertebral location and lymph nodes in the para-aortic position or
nearly all are associated with vertebral malfor- anterior mediastinal masses. Biopsy of the thy-
mations. The gastric type has the same coats as mus may cause seeding of tumour into the
the stomach and the enteric type similar to the operative site and violate the tumour capsule.
wall of the small intestine. Combined forms of Diagnostic accuracy for thymoma by open
cysts are termed gastroenteric cysts. biopsy is 81%.
Neurogenic tumours: the most common poste-
rior mediastinal masses. Most are asymptomatic.
MRI scan may be necessary to rule out intraspi- 41.5.2 Resection Specimens
nal extension along the nerve roots (dumbbell
tumours). Nerve sheath tumours account for 65% Thymectomy: performed for benign or malignant
of all mediastinal neurogenic tumours and thymic tumours, treatment of myasthenia gravis,
include neurilemmoma (schwannoma) and neu- or may be incidental during thoracic surgery such
rofibromas. 25–40% of patients with nerve sheath as open-heart surgery. If the thymus is not very
tumours have multiple neurofibromatosis (von large, thymectomy may be carried out through a
Recklinghausen’s disease). Malignant tumours transcervical route. The usual surgical approach
such as neurogenic sarcomas and malignant is through either partial or complete sternotomy.
schwannomas may occur, and other tumours Median sternotomy involves the use of an inci-
include neuroblastomas and paragangliomas. sion in the midline from the suprasternal notch to
just below the xiphoid process with division of
the sternum longitudinally. Ideally there should
41.5 Surgical Pathology be complete removal of the thymus with
Specimens: Clinical Aspects surrounding margins of normal tissue.

Alternatively tumour debulking may be under-
41.5.1 Biopsy Specimens taken. The clinical ease of excision and the
tumour circumscription or degree of spread into
Percutaneous or thoracoscopic fine-needle or adjacent tissues, are strong indicators of potential
core biopsy: used to obtain a tissue diagnosis for future local recurrence and invasion.
458 K.M. Mulholland
41.6 Surgical Pathology • Sample lymph nodes.

Specimens: Laboratory • Block pleura and/or pericardium if present.
Protocols
• Tumour type—metastatic carcinoma, malig-
• Count the number of fragments and measure nant lymphoma, germ cell tumour, neurogenic
their length (mm). tumour, thymoma, sarcoma.
• Describe—colour, consistency. • Tumour differentiation:
• Place in cassettes between foam pads or –– Metastatic carcinoma: well/moderate/poor
wrapped in filter paper. –– Malignant lymphoma: low-grade
• Examine histologically through multiple lev- (MALToma)/high-grade (diffuse large cell
els, and keep intervening sections for stains. lymphoma, lymphoblastic lymphoma)
–– Germ cell tumour (seminoma/nonsemino-
matous): mature, immature, malignant-
41.6.2 Resection Specimens embryonal carcinoma, yolk sac tumour,
choriocarcinoma
Initial procedure and description: –– Neurogenic tumours: small round blue
cell/neuroblastoma component
• Measure and record size— –– Sarcoma—low-grade/high-grade
length × width × depth (cm) and weight (g). –– Thymoma—classify according to mor-
• Appearance—cystic/haemorrhagic/necrosis. phology (see above).
–– Capsule/soft tissue invasion • Tumour edge—pushing/infiltrative/lymphoid
–– Adherence/pleura/pericardium. response.
• Photograph. • Extent of local tumour spread
• Fixation by immersion in 10% formalin for
48 h. All tumours:
• Ink the outer surface.
• Serially section the specimen transversely at • Confined to mediastinal nodes
3–5 mm intervals. • Confined to the thymus
• Describe lesions—size (cm), colour, whether • Into mediastinal connective tissues
lobulated or smooth, relationship to the cap- • Into other organs: pleura, lung, pericardium,
sule and surrounding structures, edges (encap- main vessels.
sulated or infiltrating), the presence of • Thymoma WHO:
calcification, necrosis, or haemorrhage. • Encapsulated: thymoma completely sur-
• Describe uninvolved tissue, e.g., thymus— rounded by a fibrous capsule of varying
colour, consistency, proportions of fat and thickness which is not infiltrated by tumour; it
parenchyma. may infiltrate into but not through.
• Dissect out and submit lymph nodes in any • Minimally invasive: thymoma surrounded by a
attached tissue. capsule which is focally infiltrated by tumour
growth or which invades mediastinal fat.
Blocks for histology: • Widely invasive: thymoma spreading by direct
extension into adjacent structures such as pericar-
• Sample four or five blocks of the lesion and its dium, large vessels, and lung (may appear inva-
relationship to the capsule if present and to the sive to the surgeon—excision may be
rest of the tissue. incomplete).
• Block the margins. • With implants: thymoma in which tumour
• Sample blocks from uninvolved tissue (at least nodules separate from the main mass are
two). found on the pericardial or pleural surface.
41 Mediastinum 459
• With lymph node metastasis: a tumour that • Excision margins—comment on adequacy of

involves one or more lymph nodes anatomi- excision.
cally separate from the main mass (most com-
monly mediastinal and supraclavicular).
• With distant metastases: tumour accompanied Bibliography
by embolic metastases to a distant site (lung,
liver, skeletal system). Allen DC. Histopathology reporting. Guidelines for surgi-
• Encapsulated thymomas with no implants, no Allen DC, Cameron RI. Histopathology specimens:
lymph node metastases, or no distant metasta- clinical, pathological and laboratory aspects. 2nd ed.
ses are benign. All other combinations are Berlin/Heidelberg: Springer; 2013.
malignant. Anastasiadis K, Ratatunga C. The thymus gland: diagno-
sis and surgical management. 1st ed. Berlin: Springer;
• Lymphovascular invasion—present/not pres- 2007.
ent. Note perineural invasion. Casson AG, Johnston MR. Key topics in thoracic surgery.
• Regional lymph nodes—anterior (perithymic), 1st ed. Oxford/Washington: ßios Scientific Publishers;
deep intrathoracic and cervical lymph nodes. 1999.
Thymoma TNM 8: for thymoma, thymic carci- Oxford: Wiley-Blackwell; 2017.
noma and neuroendocrine tumours of the Detterbeck FC, Nicholson AG, Kondo K, et al. The
thymus: Masaoka-Koga stage classification for thymic malig-
nancies: clarification and definition of terms. J Thorac
Oncol. 2011;6:S1710–6.
• pT1: encapsulated or into mediastinal Fletcher CDM, Bridge JA, PCW H, et al. WHO
fat ± mediastinal pleura Classification of tumours of soft tissue and bone.
• pT2: direct involvement of pericardium Lyon: IARC Press; 2014.
Hall-Craggs ECB. Anatomy as a basis for clinical medi-
• pT3: invasion of any of: lung, brachiocephalic cine. 3rd ed. London: Williams and Wilkins; 1995.
vein, superior vena cava, phrenic nerve, chest Muller-Hermelink HK, Marx A, Kircher TH. In: Anthony
wall, or extrapericardial pulmonary artery or PP, MacSween RNM, editors. Recent advances in his-
vein topathology 16. Edinburgh: Churchill Livingstone;
1994. p. 49–72.
• pT4: invasion of any of: aorta, arch vessels, Swerdlow SH, Campo E, Harris NL, et al. WHO
intrapericardial pulmonary artery, myocar- Classification of Tumours of Haematopoietic and
dium, trachea or oesophagus Lymphoid Tissues. Lyon: IARC; 2008.
The Royal College of Pathologists. Dataset for the his-
pN0 No regional lymph nodes involved tological reporting of thymic epithelial tumours, 2nd
pN1 Metastasis to anterior (perithymic) lymph nodes ed. (2016); Tissue pathway for non-neoplastic tho-
racic pathology, 2nd ed. (2013). https://www.rcpath.
pN2 Metastasis to deep intrathoracic or cervical org/profession/publications/cancer-datasets.html.
lymph nodes Accessed Nov 2016.
pM pM1a: separate pleural or pericardial nodules, Travis WD, Brambilla E, Burke AP, et al. WHO classifica-
or, pM1b: metastasis beyond pleura or tion of tumours of the lung, pleura, thymus and heart.
pericardium Lyon: IARC Press; 2015.
Heart
42
42.1 Anatomy The coronary arteries supply blood to the

heart (Fig. 42.1). The right coronary artery arises
The heart is a muscular pump weighing approxi- from the anterior coronary sinus and runs over
mately 300 g. It consists of four chambers, the the anterior surface of the heart before crossing
right and left atria and the right and left ventricles the posterior surface, where it finally anastomo-
(Fig. 42.1). The right side of the heart pumps ses with the left coronary artery. Its major
venous blood through the pulmonary circulation branches are the marginal artery and the posterior
for oxygenation, the left heart oxygenated blood interventricular artery. There are also atrial and
through the systemic circulation for distribution ventricular branches. The left coronary artery
to the tissues. arises from the left posterior aortic sinus.
The superior and inferior vena cavae enter the Major branches include the anterior interven-
right atrium. There is a small projection, the right tricular artery and the circumflex artery. The
auricle, which overlaps the beginning of the anterior interventricular artery descends towards
ascending aorta. The atrioventricular valves, the the apex and anastomoses with the posterior
mitral and tricuspid valves each consist of a valve interventricular artery. A diagonal branch runs to
ring or annulus, leaflets, anchoring chordae ten- the left ventricle. The circumflex artery anasto-
dineae, and papillary muscles. The semilunar moses with the terminal branch of the right coro-
valves, the aortic and pulmonary valves comprise nary artery. It gives off the marginal artery, which
three cusps, each with a sinus. The cusps meet at runs along the left border of the heart.
three commissures. The thickness of the wall of The heart is composed of three layers, the epi-
the right ventricle is normally 0.25–0.3 cm and cardium (serous pericardium), the muscular
the left ventricle 0.9–1.5 cm. myocardium, and the endocardium.
The heart is surrounded by the pericardial sac, Lymphovascular drainage:
which is composed of two layers of connective Lymphatic drainage of the heart is to the tra-
tissue (visceral and parietal pericardia), each cov- cheobronchial lymph nodes.
ered by a layer of mesothelial cells.

K.M. Mulholland
Histopathology Laboratory, Altnagelvin Hospital, Dyspnoea is an awareness of breathlessness and a
Western Health and Social Care Trust, symptom of congestive cardiac failure, the end-
Londonderry, UK
e-mail: kathleen.mulholland@westerntrust.hscni.net stage of many cardiac conditions. Orthopnoea

462 K.M. Mulholland
Fig. 42.1 Anatomy of a Anterior view

the heart (Reproduced
with permission from
AT aortic trunk PA
Allen and Cameron AT
SVC superior vena cava
(2013))
RA right atrium LCA
SVC
LA left atrium
RV right ventricle RCA
LV left ventricle
PA pulmonary artery RA
IVC inferior vena cava LV
LCA left coronary artery
RCA right coronary artery
TV tricuspid valve
MV mitral valve
RV
IVS interventricular septum
IVC
b Coronal section
(rotated on its right axis)
RA LA
Coronary MV
artery TV
IVS
Chordae
Papillary
RV
LV muscles
Posterior
Mital valve leaflets
c Sub-annular transverse
section of the ventricles
Right RV IVS LV Left
Anterior
and paroxysmal nocturnal dyspnoea are shortness arms provoked by exercise and relieved by rest. It
of breath, which arise when the patient has been is due to cardiac hypoxia.
recumbent due to collection of fluid in the pulmo- Myocardial infarction is similar but is not
nary circulation (pulmonary oedema). relieved by rest.
Wheezing (cardiac asthma) is due to swelling Pericarditis presents with severe, sharp, cen-
of the bronchial lining, and ankle swelling is sec- tral chest pain, aggravated by movement, posture,
ondary to congestive cardiac failure with sys- respiration and coughing, and myocarditis with
temic venous congestion. mild pleuritic chest pain and lethargy.
Angina commonly presents as central grip- Sudden unexplained death may be the presen-
ping chest pain radiating to the jaws, neck, or tation of acute cardiac failure due to ischaemic
42 Heart 463
heart disease, and syncope (fainting episodes) sured and allow evaluation of cardiac function
may occur in aortic stenosis, both of which can and assessment of ischaemia and infarction.
also be caused by cardiac dysrhythmia. • Cardiac catheterization and angiography—
Infective endocarditis presents with fever, catheters are advanced into the right and left
weight loss, malaise, splenomegaly, and splinter sides of the heart and pressure and oxygen
haemorrhages of the fingernails due to embolic saturation studies performed. During coronary
infarcts of the skin. Abdominal pain may be sec- angiography, radio-opaque contrast medium
ondary to renal or splenic infarcts. Chest pain due is injected through the catheter into the coro-
to pulmonary infarcts can occur in tricuspid valve nary artery ostia.
endocarditis. • Magnetic Resonance Imaging (MRI)—syn-
In hypertrophic obstructive cardiomyopathy, chronized with the ECG gives systolic and
the patient may present with atrial fibrillation, diastolic images.
ventricular arrhythmias, or sudden death. • Endomyocardial biopsies—taken via cardiac
Cardiac myxoma can present with symptoms catheter.
of mitral stenosis and embolization of fragments
of the tumour or of overlying thrombus. Fever,
cachexia, and malaise also occur. 42.4 Pathological Conditions
Cardiac rhabdomyomas may cause stillbirth
or death within the first few days of life. 42.4.1 Non-neoplastic Conditions
42.4.1.1 Disorders of the Endocardium

42.3 Clinical Investigations Infective endocarditis: A disorder affecting the
endocardial surface of the heart as a result of
• Echocardiography/Doppler flow studies— infection. The characteristic lesion is the vegeta-
used to study valvular heart disease, congeni- tion, which consists of thrombus containing
tal abnormalities, cardiac tumours, and microorganisms. In acute bacterial endocarditis,
pericardial effusions. large friable vegetations are found on the valves,
• Transoesophageal echocardiography (TOE)— which can cause erosion or perforation of the
used to investigate lesions of the left atrium, underlying tissue. Predisposing factors to endo-
the ascending aorta, the aortic valve, and sep- carditis are valvular anatomical abnormalities
tal defects. (congenital or acquired, e.g., rheumatic heart dis-
• Chest X-ray—used to assess heart size and to ease), sepsis, immunosuppression, or IV drug
identify calcification or fluid in the pericardium. abuse.
• Electrocardiogram (ECG)—a resting ECG is Non-bacterial thrombotic endocarditis
useful in the diagnosis of myocardial infarc- (NBTE): Produces small, bland vegetations
tion, cardiac hypertrophy, or abnormalities of attached to the valve surface at the lines of
rhythm. An exercise ECG is useful in patients closure. They are seen in cachetic patients,
with angina, and an ambulatory ECG made e.g., disseminated tumour. Systemic lupus
over 24–48 h may be used when heart rhythm erythematosus can be associated with Libman-
disturbances occur only intermittently. Sacks endocarditis with small bland vegeta-
• Blood tests—in the setting of suspected myo- tions located on both surfaces of the valves or
cardial infarction serum cardiac biomarkers cords.
are measured particularly troponin I and Rheumatic fever: An inflammatory disease,
T. Creatine kinase-MB and myoglobin levels which in the acute phase produces pathognomonic
may also be useful. Aschoff bodies in the heart. Chronic rheumatic
• Nuclear cardiology—assesses the function of heart disease is characterized by organization of
cardiac muscle. Radioactivity from substances the endocardial inflammation with subsequent
injected intravenously into the patient are mea- fibrosis, particularly affecting the valves.
464 K.M. Mulholland
42.4.1.2 Disorders of the Valves Dilated cardiomyopathy (DCM): The clinical

In valvular disease, assessment of the gross presentation of DCM is progressive cardiac fail-
appearance often contributes to the final diagno- ure. There is dilatation particularly of the left
sis more than microscopic examination. ventricle, but often of all chambers with little or
Mitral valve stenosis: Most commonly due to no hypertrophy of the wall. Histological exami-
rheumatic fever with commissural fusion, cusp nation shows non-specific abnormalities with
scarring, and dystrophic calcification. hypertrophy and degenerative changes in the
Mitral valve regurgitation: Due to floppy myocardial fibres. A significant number of cases
mitral valve shows valve cusps, which are are thought to be post-viral or due to excess alco-
increased in area, and dome shaped with myxoid hol intake.
change. Other causes include rheumatic fever, Restrictive cardiomyopathy (RCM): The least
rupture of a papillary muscle or chordae tendin- common of the three types of cardiomyopathy in
eae, ventricular enlargement, or infective developed countries. The ventricles are of
endocarditis. approximately normal size or slightly enlarged,
Aortic valve stenosis: Due to calcification of a and the cavities are not dilated. Histology shows
congenitally bicuspid valve, senile calcific aortic patchy or interstitial fibrosis.
stenosis, or post-inflammatory scarring. Infiltrative cardiomyopathies: May be due to
Aortic regurgitation: Secondary to post- amyloidosis, haemochromatosis, haemosidero-
inflammatory scarring, infective endocarditis, or sis, glycogenosis, or mitochondrial myopathies.
abnormalities of the cusps and commissures. Right ventricular dysplasia: A familial idio-
Pulmonary valve abnormalities: Consist of pathic cardiomyopathy involving mainly the
stenosis, insufficiency, or a combination of the right ventricle. Histological examination shows
two. 95% of cases are due to congenital heart dis- infiltration of the right ventricular myocardium
ease, tetralogy of Fallot being the most common. by adipose and fibrous tissue.
A bicuspid pulmonary valve is the most common Drug-induced cardiomyopathy: Caused by
anomaly. drugs such as adriamycin and cyclophosphamide,
Tricuspid valve abnormalities: Most com- which cause characteristic subcellular changes
monly pure insufficiency and caused by post- seen on electron microscopy.
inflammatory scarring, congenital abnormalities, Heart transplant rejection: Graded using the
infective endocarditis, or dilatation of the valve International Society for Heart and Lung
ring in cardiac failure. Transplantation (ISHLT) grading system.
42.4.1.3 Disorders of the Myocardium 42.4.1.4 Disorders of the Pericardium

Myocarditis: Viral, bacterial or fungal. In devel- Acute pericarditis: Due to infection caused by
oped countries, viral infections predominate. viruses or bacteria. Viruses include coxsackie B,
Parasitic aetiologies include toxoplasmosis and echoviruses, influenza, mumps, and Epstein-Barr
the protozoan Trypanosoma cruzi. Granulomatous virus. Bacterial pericarditis may be due to
myocarditis can occur due to tuberculosis or sar- Staphylococcus aureus, Streptococci, or
coidosis. Myocarditis occurs secondary to colla- Haemophilus influenza. Tuberculous pericarditis
gen vascular disease, especially rheumatic fever, usually becomes chronic.
and may also be drug or radiation induced. Acute pericarditis can also be secondary to
Hypertrophic cardiomyopathy (HCM): Massive acute rheumatic fever, myocardial infarction,
myocardial hypertrophy, and classically, there is connective tissue disorders such as systemic
asymmetric ventricular septal hypertrophy. lupus erythematosus and rheumatoid disease,
Histological examination shows myofibre disarray uraemia, renal transplantation, irradiation, or fol-
with hypertrophy and interstitial fibrosis. A scor- lowing cardiac trauma.
ing system may be used to quantitatively assess Chronic pericarditis: Can lead to constrictive
the degree of myocardial abnormality. pericarditis where the heart is encased in a thick
42 Heart 465
layer of fibrous tissue. Surgical removal of peri- 42.5 Surgical Pathology

cardium is the only effective means of Specimens: Clinical Aspects
treatment.
Endomyocardial biopsies: Right heart biopsies
(and occasionally left) are taken via cardiac cath-
42.4.2 Neoplastic Conditions eter. They are used to evaluate graft status in car-
diac transplant patients and to diagnose
Myxoma: Accounts for 50% of primary tumours cardiomyopathies and intracavitary or myocar-
of the heart. Familial or sporadic, they usually dial tumours.
occur in the left atrium (86%). Familial cases can Cardiac valves: Native aortic valves are gen-
be multicentric and have extra-cardiac abnormal- erally resected because of calcific degeneration
ities (Carney’s syndrome). Histological examina- and are often bicuspid. Mitral valves are usually
tion shows round, polygonal, or stellate cells in replaced because of rheumatic valve disease or
an abundant loose stroma. Mitoses, pleomor- because the valve is myxomatous. Valves are also
phism, and necrosis are minimal to absent. resected due to the sequelae of bacterial endocar-
Myxomas may show ossification (petrified myx- ditis e.g. perforation. Prosthetic valves may be
oma), cartilaginous tissue, extramedullary hae- removed because of infection, thrombosis, anas-
matopoiesis, and thymic or foregut remnants. tomotic or valvular leakage, haemolysis, obstruc-
When myxoma is excised with a partial atrial tive fibrous tissue overgrowth, or mechanical
septectomy, it rarely recurs. failure e.g. fracture.
Rhabdomyoma: The most common primary Open heart surgical procedures: Used in the
tumour of the heart in children. It is often con- repair of ventricular aneurysms, septal resection
genital and has a close association with tuberous in HCM and in the removal of atrial myxomas or
sclerosis. Most rhabdomyomas are multiple, other tumours. In resection of a myxoma, the
occur in the ventricles and regress tumour and site of origin such as the atrial sep-
spontaneously. tum segment or atrial wall segment is removed.
Other benign conditions include mesothelial/ Heart transplant: Performed in patients with
monocytic incidental cardiac excrescences end-stage cardiac failure due to ischaemic heart
(MICE), papillary fibroelastoma, haemangioma, disease or idiopathic cardiomyopathy. The
lipomatous hypertrophy (of the atrial septum), resected specimen usually consists of atria and
mesothelioma of the atrioventricular node, the upper parts of the ventricles.
fibroma, paraganglioma, granular cell tumour,
lymphangioma, and schwannoma.
Primary malignant tumours: Very rare and 42.6 Surgical Pathology
more commonly found in the right side of the Specimens: Laboratory
heart, benign tumours in the left. Angiosarcoma Protocols
is probably the commonest, others being leio-
myosarcoma, rhabdomyosarcoma, and Kaposi’s 42.6.1 Biopsy Specimens
sarcoma. Primary malignant lymphoma of the
heart is very rare, most being diffuse large cell, • Count the number of fragments.
especially those occurring in HIV- • Measure their size (mm).
AIDS. Secondary involvement of the heart by • Describe—colour, consistency.
systemic lymphoma is more usual. • Place in cassettes between foam pads or
The pericardium is involved in approximately wrapped in filter paper.
8.5% of cases of disseminated malignancy, but • Examine histologically through multiple lev-
primary neoplasms are very rare, e.g., mesothe- els and keep intervening sections for stains,
lioma of the pericardial sac, germ cell tumour, e.g., Masson trichrome (fibrous tissue), Congo
and angiosarcoma. Red (amyloid), Perl’s Prussian Blue (iron), or
466 K.M. Mulholland
immunohistochemistry (CMV antibody, B/T • Document the type of valve.

lymphocytes). • Measure the diameter of the external sewing
• Occasional cases may require fresh frozen tis- ring.
sue or glutaraldehyde fixation for specialist • Check function—ability to open and close
techniques (immunohistochemistry, electron fully.
microscopy). • Describe the presence of calcifications,
mechanical degeneration, cracks in any of the
components.
42.6.2 Cardiac Valves • Describe the presence of tissue overgrowth.
• Check for vegetations—colour, site, size, con-
Native valves: Most are received in fragments sistency, presence of underlying destruction.
though some may be submitted intact.
• Identify and document the type of valve—aor-
tic, congenital bicuspid aortic, mitral, • In most cases, it is not possible to submit any
tricuspid. tissue for histology unless vegetations are
• Photograph if intact. present.
• X-ray to document calcification.
• Culture. Bioprosthetic heart valve:
• Measure the dimensions (cm) of the valve and
the valve orifice. • Culture.
• Describe the leaflets or cusps. • Photograph.
–– Number, sizes (mm), consistency. • X-ray—aids type identification, shows calcifi-
–– Abnormalities, e.g., myxoid changes, cation (grade 1 to 4) and ring or stent fracture.
fibrosis, calcifications, thrombi, • Measure the diameter of the external sewing
perforations. ring.
• Describe vegetations if present—distribution, • Inspect leaflets for thrombi, vegetations,
location, consistency, presence of destruction calcifications.
of the valve leaflet or cusp. • Check for fibrous overgrowth.
• Describe the commissures—relationship to • Check the valve leaflets for tears or perfora-
each other, fused or not, completely or tions. Document the location and size of any
partially. lesions and the effect these appear to have on
• Describe the chordae tendineae—length, sta- valve function.
tus—normal/shortened/thickened/stretched/
fused/ruptured. Blocks for histology:
• Describe the papillary muscles—hypertrophy,
elongation, scarring—evidence of recent or • A portion of the valve cusp is submitted for
past myocardial infarction. histological examination. Vegetations are also
• Decalcification may be needed. submitted if present.

• Representative sections are taken from the
free edge of the valve to the annulus. Specimen:
May consist of atrial myxomas and other
Mechanical heart valves: tumours, portions of heart removed during open-
heart surgical procedures such as repair of ven-
• Culture. tricular aneurysms or septal resection in
• Photograph. hypertrophic cardiomyopathy.
42 Heart 467
• Measure the specimen (cm) and weigh (g). may be cut longitudinally or opened
• Document the presence of scarring and if according to the lines of flow. This method
transmural. is useful in ischaemic heart disease.
• Document any inflammation and its pattern. • Describe each ventricle—hypertrophy, dilata-
• Note the presence of necrosis, calcification, tion, fibrosis, infarcts, trabeculation, papillary
mural thrombus, haemorrhage. muscles, mural thrombus.
• Describe the endocardium—colour, thickness • Measure the thickness of the ventricular walls
(mm). (mm).
• Describe the epicardium—colour, thickness • Describe the atria and any endocardial lesions.
(mm). • Describe the valves (as above).
• Section transversely at 3-mm intervals. • Dissect atherosclerotic coronary arteries, fix
• Sample representative blocks for histology. and decalcify them, section transversely at 3-
to 5-mm intervals.
Resection for tumour: • Describe coronary arteries—presence of right
or left dominance, thrombi, atheroma,
• Measure the specimen (cm) and weigh (g). locations.
• Describe the appearance—myxoid, haemor- • Describe bypass grafts if present—type, loca-
rhage, necrosis, site of origin—atrial wall/ tion, presence of thrombus, atheroma.
ventricular wall/atrial septal wall, infiltration
into wall. Blocks for histology:
• Photograph.
• Fix in 10% formalin for 48 h. • Take sections from the left and right ventricu-
• Ink limits—underlying wall. lar walls, the ventricular septum, native coro-
• Section lesion, noting appearance and attach- nary arteries, bypass grafts, other lesions.
ment to the wall.

Bibliography
• Sample representative blocks of tumour,
tumour and adjacent myocardium, and speci- Allen DC, Cameron RI. Histopathology specimens:
men limits. Berlin/Heidelberg: Springer; 2013.
Baumgartner WA, Reitz B, Kasper E, Theodore J. Heart
Heart transplants: and lung transplantation. 2nd ed. London: Saunders;
2001.
Billingham M, Carey N, Stewart S, Goddard M. Atlas of
• Weigh (g). biopsy histopathology for heart and lung transplanta-
• Describe the epicardial surface—fat, pete- tion. 1st ed. London: Arnold; 2000.
chiae, adhesions. Billingham ME, Cary NRB, Hammond ME, et al. A work-
• Fix in 10% formalin for 48 h. ing formulation for the standardisation of nomenclature
in the diagnosis of cardiac and lung rejection: heart rejec-
• Use method of cutting appropriate to the tion study group. J Heart Transplant. 1990;9:587–93.
specimen: Burke A, Jeudy J Jr, Virmani R. Cardiac tumours; an
–– Apical four chamber cut—cut longitudinally update. Heart. 2008;94:117–23.
from apex to base bivalving both ventricles Casson AG, Johnston MR. Key topics in thoracic sur-
gery. 1st ed. Oxford/Washington DC: Bios Scientific
and bisecting the tricuspid and mitral valves. Publishers; 1999.
This method is useful in cutting specimens Cunningham KS, Veinot JP, Butany J. An approach to
showing dilated cardiomyopathy. endomyocardial biopsy interpretation. J Clin Pathol.
–– Serial sectioning—cut heart transversely 2006;59:121–9.
Dare AJ, Harrity PJ, Tazelaar HD, Edwards WD, Mullany
beginning at the apex and extending to the CJ. Evaluation of surgically excised valves; revised
level of the mitral valve at approximately recommendations based on changing operative pro-
1- to 2-cm intervals. The base of the heart cedures in the 1990s. Hum Pathol. 1993;24:1286–93.
468 K.M. Mulholland
Sheppard M, Davies MJ. Cardiac examination and normal The Royal College of Pathologists. Tissue Pathways
cardiac anatomy. In: Practical cardiovascular pathol- for Cardiovascular Pathology. https://www.rcpath.
ogy. London: Arnold; 1998. org/profession/publications/cancer-datasets.html.
Stewart S, Fishbein MC, Snell GI, et al. Revision Accessed Nov 2016.
of the 1996 working formulation for the stan- The Royal College of Pathologists. Guidelines on autopsy
dardization of nomenclature in the diagno- practice. https://www.rcpath.org/profession/publications/
sis of lung rejection. J Heart Lung Transplant. specialty-specific-publications.html.
2007;26(12):1229–42.
Vessels
43
43.1 Anatomy pears on resting for a few minutes. It is caused

by atherosclerosis which is responsible for mul-
Vessels consist of three layers—the lining intima, tiple symptoms depending on the affected arte-
the musculo-elastic media, and the connective rial supply—ischaemic heart disease leading to
tissue adventitia. angina or myocardial infarction, stroke, tran-
Coronary arteries: see Chap. 42. sient ischaemic attacks (TIA) and intestinal
Aorta: The main trunk of the systemic circula- ischaemia.
tion. It arises from the left ventricle and ascends as Internal carotid artery atheroma may lead to a
the ascending aorta, becomes the arch, the descend- transient ischaemic attack or cerebrovascular
ing aorta, and then the abdominal aorta. The arch accident (CVA). A TIA is a transient loss of func-
supplies the main vessels of the head and neck, the tion in one region of the brain lasting less than
abdominal aorta the viscera of the abdomen and 24 h. The patient can present with aphasia, hemi-
pelvis and the legs via the femoral arteries. paresis, hemisensory loss, hemianopic visual
Temporal artery: The external carotid artery loss, and amaurosis fugax (transient loss of vision
ends behind the neck of the mandible by dividing in one eye). A CVA produces similar symptoms
into the maxillary and superficial temporal arteries. lasting longer than 24 h.
The latter ascends over the posterior end of the Aortic abdominal aneurysm presents with epi-
zygomatic arch on the lateral aspect of the scalp, gastric or back pain exacerbated by rupture and
where it divides into anterior and posterior branches. may be associated with a palpable, pulsatile
It supplies the face, the auricle, and the scalp. abdominal mass.
Thoracic aortic aneurysms cause chest pain or
evidence of pressure on other organs such as the
43.2 Clinical Presentation superior vena cava or oesophagus.
Dissecting aortic aneurysm causes severe cen-
Peripheral vascular disease presents with “inter- tral chest pain radiating into the back, arms, and
mittent claudication,” cramp-like pain in the neck. There may be neurological signs due to
calf and thigh muscles on exercise, which disap- involvement of spinal vessels. Rupture of an
aneurysm is a surgical emergency.
Temporal arteritis presents with a headache,
K.M. Mulholland which is often localized to, and tender over, the
Histopathology Laboratory, Altnagelvin Hospital, temporal area. Involvement of the ophthalmic
Western Health and Social Care Trust, artery may lead to blindness, and prompt treat-
Londonderry, UK
e-mail: kathleen.mulholland@westerntrust.hscni.net ment with systemic steroids is necessary.

470 K.M. Mulholland
Vasculitides produce a wide spectrum of cification, focal rupture, or gross ulceration.

symptoms depending on the location of the Debris can be discharged into the bloodstream
affected vessels including skin rashes, fever, forming microemboli. Haemorrhage may occur
myalgia, arthralgia, malaise, abdominal pain, and into a plaque or a thrombus may form on the sur-
renal failure. face potentially occluding the vessel. With the
formation of atheromatous plaques the adjacent
media atrophies and aneurysmal dilatation may
43.3 Clinical Investigations occur.
Hyaline arteriolosclerosis: Occurs in the
• Arteriography—used to localize the site and elderly with an increased incidence in hyperten-
extent of vessel blockage and presence of sion and diabetes. There is thickening of the walls
collaterals. with deposition of pink homogenous material
• Doppler studies—used to determine the site of and narrowing of the lumen. Hyperplastic arteri-
blockage and flow rates in vessels. olitis is a characteristic of, but not limited to,
• Duplex ultrasound—used to measure pressure malignant hypertension.
in small arteries. Vasculitis: Inflammation of the walls of blood
• X-ray—plain X-ray of abdomen may show an vessels due to immune-mediated inflammation or
aortic aneurysm if the wall is calcified. to invasion of the wall by pathogenic organisms.
• Ultrasound—used to diagnose abdominal aor- Giant cell arteritis (temporal arteritis): A
tic aneurysm or deep venous thrombosis. granulomatous arteritis affecting the aorta and
• CT scan—a sensitive imaging method that major branches, especially the extracranial
allows precise measurement of size, e.g., branches of the carotid artery (temporal, verte-
abdominal aortic aneurysm. bral, and ophthalmic arteries). Most commonly
• Transoesophageal echocardiography (TOE)— there is a granulomatous inflammation of the
used to diagnose aortic root dissection. inner half of the media centred on the internal
• Ventilation/Perfusion scan (V/Q scan)— elastic lamina. Up to 40% of patients with good
detects pulmonary emboli. clinical evidence of cranial arteritis have a nega-
• Blood tests: tive temporal artery biopsy. The diagnostic
–– Erythrocyte Sedimentation Rate (ESR)— histological findings are often also only found
characteristically over 100 mm in the first focally within an involved segment.
hour in temporal arteritis. Takayasu arteritis (pulseless disease): A rare
–– c-ANCA–associated with Wegener’s gran- granulomatous vasculitis of the aortic arch, its
ulomatosis and some cases of polyarteritis branches, and the pulmonary arteries.
nodosa. Morphological changes may be indistinguishable
–– p-ANCA–associated with polyarteritis from giant cell arteritis, but the clinical profile
nodosa. differs with patients usually being female and
under the age of 40 years but elderly in giant cell
arteritis.
43.4 Pathological Conditions Polyarteritis nodosa: A relatively uncommon
condition causing necrotizing fibrinoid vasculitis
43.4.1 Non-neoplastic Conditions of small- to medium-sized arteries particularly in
the kidneys, heart, liver, and gastrointestinal
Atherosclerosis: Very common and affects the tract. Vessel necrosis, thrombosis, rupture, and
elastic arteries (aorta, carotid, iliac) and large and aneurysms occur with fibrous repair resulting in
medium-sized muscular arteries (coronary and mural nodularity.
popliteal). The vessels show intimal thickening Microscopic polyarteritis (leukocytoclastic
and lipid accumulation producing atheromatous vasculitis): Involves arterioles, capillaries, and
plaques, which may become complicated by cal- venules. It affects skin, mucous membranes,
43 Vessels 471
lungs, brain, heart, gastrointestinal tract, kidneys, Other aneurysms: Berry aneurysms occur in
and muscle in isolation or various combinations. the circle of Willis of the brain, due to congenital
It is much more common than polyarteritis nodosa defects in the vessel wall, and are an important
and may be precipitated by drugs or infections. cause of sudden subarachnoid haemorrhage in
Kawasaki syndrome: A rare arteritis, which young adults.
affects the large, medium, and small arteries Mycotic aneurysm: Occurs in the arterial wall
(often coronary arteries). Eighty percent are less secondary to damage caused by sepsis. They are
than 4 years old and 20% develop cardiovascular rare in developed countries.
sequelae. Polyarteritis nodosa may be associated with
Wegener’s granulomatosis: A focal necrotiz- multiple microaneurysms.
ing or granulomatous vasculitis involving small- Kawasaki disease causes arteritis and aneu-
and medium-sized vessels, most prominent in the rysm of the coronary arteries.
lungs or upper airways and associated with focal Varicose veins: Abnormally dilated, tortuous
or necrotizing (often crescentic) glomerulitis. veins due to prolonged intraluminal pressure or
Aneurysm: An abnormal widening of a blood loss of support of the vessel wall. They affect a
vessel wall. In a true aneurysm, the walls make wide range of patients but particularly obese
up the boundary; in a false aneurysm, the bound- females over 50 years of age. There is also a
ary is made of haematoma or fibrous tissue. familial tendency. Varicosities also occur in the
Abdominal aortic aneurysms: The most oesophagus secondary to portal hypertension in
common site for atherosclerotic aneurysms, association with liver cirrhosis. Haemorrhoids
usually below the renal arteries, above the are varicose dilatations of the haemorrhoidal
bifurcation of the aorta. Repair is either by an plexus of veins at the anorectal junction.
open surgical procedure or endovascular tech-
nique (EVAR—endovascular aneurysm repair).
Aneurysms less than 5 cm diameter rarely rup- 43.4.2 Neoplastic Conditions
ture, while about 50% of those more than 5 cm
suffer fatal rupture within a 10-year period. Benign:
Operative mortality after rupture is approxi-
• Haemangioma—capillary, cavernous, pyo-
mately 50% but 5% prior to it. A small minor-
genic granuloma (lobular capillary
ity are inflammatory in type, with a thick cuff
hemangioma).
of surrounding fibrous tissue, and associated
• Lymphangioma.
with obstruction of the ureters.
• Glomus tumour.
Dissecting aneurysms: Blood enters the wall of
• Vascular ectasia.
the aorta and dissects between layers. It affects
• Bacillary angiomatosis is a reactive vascular
two groups of patients—males predominantly
proliferation.
between the age of 40–60 years with a history of
hypertension and a younger group with an abnor- Intermediate grade neoplasms:
mality of the connective tissue, e.g., Marfan’s syn-
drome. Histological examination shows cystic • Kaposi’s sarcoma
medial degeneration with elastic tissue fragmenta- • Haemangioendothelioma
tion. Surgery involves plication of the aortic wall
(65–75% of patients with dissection survive). Malignant neoplasms:
Syphilitic aneurysms: Obliterative endarteritis
affects the vasa vasorum leading to a thoracic • Angiosarcoma
aortitis and subsequent aneurysmal dilatation of • Haemangiopericytoma
the thoracic aorta and the aortic annulus. While it
had become rare the incidence of syphilis is These specimens are discussed in the skin and
increasing in developed countries. soft tissue chapters.
472 K.M. Mulholland
43.5 Surgical Pathology Blocks for histology:

Specimens: Clinical Aspects
• Sample multiple representative transverse sec-
Dissecting aortic aneurysm: A section of aorta is tions of the vessel.
excised which shows a medial haematoma with an
associated intimal flap entrance site and often either Aortic dissection:
an intimal re-entrant or adventitial rupture site.
Abdominal aortic aneurysm: Surgical repair • Measure (cm) and weigh (g).
involves opening the aneurysm and removing the • Describe the location of the dissection, intimal
clot. The graft is sewn inside the aorta, and the flap entrance, intimal re-entrant site, or adven-
wall of the aorta is closed. The specimen may titial rupture site.
consist of clot only, or clot with media. • Take sections from areas of medial separation
Internal carotid endarterectomy: Considered and from grossly normal tissue. One section
in symptomatic patients who have carotid artery should be stained for elastin.
stenosis that narrows the arterial lumen by more • When embedding, orientate the specimens on
than 70%. The specimen may retain the shape edge to ensure the entire thickness can be
of the bifurcation. It consists of luminal plaque assessed.
with portions of intima and media attached.
Atherectomy: The removal of atherosclerotic Aortic aneurysm:
plaque by cardiac catheterization. Open throm-
bectomy or embolectomy of peripheral vessels, • Measure (cm) and weigh (g).
e.g., femoral artery, is also undertaken for the • Describe—thrombus only or aortic wall also
acutely ischaemic limb. present—colour, consistency, organisation
Vascular grafts: Removed because of throm- (lines of Zahn), and calcification.
bosis, fibrous obstruction, or infection. • Serially section the thrombus to look for
Coronary artery bypass graft (CABG): During tumour or mycotic aneurysm.
the second CABG, the saphenous vein or internal
artery mammary grafts are occasionally removed. Atherectomy specimens:
Temporal artery: A biopsy of approximately
2–10 mm length is taken. • Count and measure the fragments (mm).
Varicose veins: Usually inverted during the • Decalcify plaques.
procedure and not submitted for histology. • Submit all fragments.
Endarterectomy:
Specimens: Laboratory • If intact, open longitudinally.
Protocols • Measure (cm).
• Describe—shape, colour, calcification,
Vessel specimens: stenosis.
• Decalcification may be needed.
• Measure the length, internal and external • Sample representative transverse blocks.
diameter (mm) of the vessel.
• Examine the lumen for thrombi. Embolectomy specimens:
• Estimate the percentage of luminal narrowing
caused by any lesions. • Measure (mm).
• Examine the media—check for aneurysm for- • Examine for tumour fragments.
mation, fibromuscular hyperplasia, calcifica- • Serially slice transversely and submit repre-
tion, and rupture. sentative blocks.
43 Vessels 473
Temporal artery: Varicose veins:
• Measure—length and diameter (mm). • Measure—length and diameter (cm).

• Describe—colour, presence of thrombus, wall • Describe—thrombus, wall thickening,
thickening. nodularities.
• Cut into 2–3 mm cross-sections after process- • Take one transverse section.
ing and before embedding.
• Embed each piece on end.
• Examine histologically through multiple lev-
els and keep intervening sections for stains, Bibliography
e.g., elastin, CD68.
Vascular grafts: clinical, pathological and laboratory aspects. 2nd ed.
Blauwet LA, Edwards WD, Tazelaar HD, McGregor
• Culture. CG. Surgical pathology of pulmonary thromboen-
• Measure—length and diameter (cm). darterectomy: a study of 54 cases from 1990 to 2001.
• Describe—type of graft—saphenous vein, Hum Pathol. 2003;34:1290–8.
Fletcher CDM, Bridge JA, Hogendoorn PCW, Mertens F,
Gore-tex grafts, Dacron grafts; colour, tears or editors. World Health Organisation Classification of
holes, thrombus. tumours: Tumours of Soft Tissue and Bone. 4th ed.
• Sections of graft may be submitted—saphe- Geneva: WHO Press; 2012.
nous vein and Gore-tex are easy to cut; Dacron Gonzalez-Gay MA, Garcia-Porrua C, Miranda-
Filloy JA. Giant cell arteritis: diagnosis and
is difficult. therapeutic management. Curr Rheumatol Rep.
2006;8:299–302.
Coronary artery bypass grafts: Sheppard M, Davies MJ. Diseases of the aorta. In: Practical
cardiovascular pathology. London: Arnold; 1998.
The Royal College of Pathologists. Tissue Pathways for
• Measure—length and diameter (mm). Cardiovascular Pathology. https://www.rcpath.org/
• Describe—atherosclerosis, thrombus. profession/publications/cancer-datasets.html.
• Take multiple cross sections of the graft.
Part X
Osteoarticular and Soft Tissue Specimens
Joint Space, Bone, Soft Tissues,
and Special Techniques 44
Oisin P. Houghton
44.1 Joint Space ground substance composed of collagen fibers and

proteoglycans. The latter are complex biopolymers
44.1.1 Anatomy consisting of a central protein core with attached
chains of carbohydrates. These proteoglycans
Most joints are synovial joints formed by a thin include chondroitin sulfate and keratan sulfate and
lining of synovium which secretes fluid into the can absorb large volumes of water to form gels.
joint (Fig. 44.1). The joint is covered by a cap-
sule. The synovium not only forms the lining of
joints but also covers tendon sheaths and bursae. 44.1.2 Clinical Presentation
The synovial membrane consists of an intimal
layer and the subintimal supportive layer of fibro- Symptoms of joint disease generally tend to be
fatty tissue. The intima is 1–2 cell layers thick nonspecific, and accurate diagnosis depends on
and composed of synoviocytes. About 90% are detailed clinical history noting the number of
fibroblast-like, but the other 10% have ultrastruc- joints involved, sites, and specific patterns of
tural features of macrophages. joint disease. Typical symptoms include pain,
The space between the two articulating bone stiffness, swelling, and reduced range of move-
surfaces is occupied by articular hyaline cartilage ment. Severe acute inflammation such as in septic
(Fig. 44.1). It is firm pliable tissue and resists arthritis results in a red, hot, swollen joint.
compressive forces. In young people, it is bluish- Effusions due to increased fluid, blood, or pus
white and translucent, but in later life, it becomes may also be seen.
opaque and yellow. Cartilage is avascular and
devoid of nerves and lymphatics, obtaining nutri-
ents by diffusion from the surrounding synovial 44.1.3 Clinical Investigation
fluid.
Cartilage is rather poorly cellular tissue com- • Routine blood tests such as white cell count,
posed of chondrocytes laid down within a matrix or ESR, and C-reactive protein to detect active
inflammation. Checking the blood for the
presence of increased quantities of antibodies
(such as rheumatoid factor) is very important
O.P. Houghton in rheumatology. These tests are generally not
Histopathology Laboratory, Institute of Pathology, specific and need to be interpreted carefully in
Royal Victoria Hospital, Belfast Health and Social the light of the patient’s clinical history and
e-mail: oisin.houghton@belfasttrust.hscni.net pattern of joint involvement.

478 O.P. Houghton
Bone
Synovial membrane
Joint capsule
Synovial fluid
Articular cartilage
Fig. 44.1 Synovial joint (Reproduced, with permission, from Allen and Cameron (2013))
• Plain X-ray and tomography are performed in synovium and chronic inflammation. There are
order to detect evidence of arthritis such as really no specific features which can be regarded
loss of joint space (due to destruction of carti- as pathognomonic of any particular type of
lage), osteophytes (bone irregularities), bone synovitis.
sclerosis (thickening), and localized osteopo- Purulent synovitis: the synovium contains
rosis (thinning). large numbers of neutrophil polymorphs and is
• Effusions may be aspirated and investigated consistent with septic arthritis.
for the presence of blood, pus, cell content, Rheumatoid arthritis: a rheumatoid nodule
and crystals. This really constitutes synovial may be seen and is highly suggestive of this con-
fluid analysis. In order to detect the presence dition, but only a small number of biopsies (less
of crystals, the fluid is examined using polar- than 5%) display this feature.
ized light with a red filter. The needle-shaped Granulomatous inflammation: the presence of
crystals associated with gout exhibit a strong granulomata can indicate infection due to tuber-
negative birefringence, whereas the rhomboid- culosis, atypical TB, fungi, sarcoid, or reaction to
shaped crystals associated with pseudogout foreign body material such as prosthetic wear
exhibit weak positive birefringence. products.
• In general, biopsy has very little role to play in Prosthetic reactions: patients who have had
the investigation and diagnosis of joint dis- knee or hip arthroplasty may suffer from joint
ease. Accurate clinical diagnosis seldom loosening years later due to foreign body reaction
depends on histological analysis of the and inflammation caused by breakdown of the
synovium. prosthetic materials. A foreign body reaction
composed of giant cells and macrophages with
doubly refractile material can be seen. Aseptic
44.1.4 Pathological Conditions lymphocytic vasculitis-associated lesion (ALVAL),
a disorder seen in metal-on-metal prostheses, is
44.1.4.1 Non-neoplastic Conditions characterised by necrosis of synovium and under-
Synovitis: the majority of patients have nonspe- lying tissues, a prominent perivascular inflamma-
cific synovitis characterized by hyperplasia of the tory infiltrate (predominantly lymphocytic in
44 Joint Space, Bone, Soft Tissues, and Special Techniques 479
nature) with vessels showing features of high of arthritis from another. For these reasons, syno-
endothelial venules. vial biopsy is not routinely performed.
Crystal arthropathy: this includes gout and
pseudogout. A giant cell reaction to doubly 44.1.5.2 Resection Specimens
refractile material may be seen. Synovial fluid Resection of the synovium is seldom undertaken
analysis can be helpful in this diagnosis. Gout except for a florid synovial chondromatosis or
can also be associated with extra-articular soft pigmented villonodular synovitis. Partial or total
tissue lesions or tophi, e.g., in the skin overlying synovectomy is technically difficult and may
the elbows or ears. often lead to damage to the articular cartilage in
Haemosiderotic synovitis: the presence of later life.
haemosiderin pigment within the synovium may
indicate a reaction to previous haemarthrosis
(haemophilia or trauma). 44.1.6 Surgical Pathology
Specimens: Laboratory
44.1.4.2 Neoplastic Conditions Protocols
Primary synovial tumours are uncommon. Very
rarely a benign giant cell tumour of tendon 44.1.6.1 B iopsy and Resection
sheath (tenosynovial giant cell tumour, local- Specimens
ised type) may occur in a joint space. This is The tissue is submitted in formalin. However, if
seen when the tumour arises within an intra- the clinician strongly suspects the presence of
articular tendon such as the knee. Pigmented gout, the biopsy should be sent in alcohol and not
villonodular synovitis (tenosynovial giant cell formalin so as to better preserve the crystals. The
tumour, diffuse type) is a locally aggressive size of the biopsy should be recorded and is usu-
tumour characterised by a diffuse subsynovial ally submitted in toto. There are usually no dis-
infiltrate of histiocyte-like mononuclear cells tinctive gross features to note except for the tan
with admixed multinucleate giant cells and colouration associated with a haemarthrosis or
prominent haemosiderin pigment. Synovial pigmented villonodular synovitis or the presence
chondromatosis is a benign cartilaginous neo- of cartilage as in synovial chondromatosis.
plasm in which nodules of hyaline cartilage
with varying degrees of calcification or ossifica- Histopathology report:
tion, proliferate in the subsynovial tissues. Other
synovial/joint tumours include synovial hae- • Presence of hyperplasia
mangioma, lipoma and juxta-articular myxoma. • Inflammation—intensity (mild/moderate/severe),
Primary or secondary malignancy is exceed- diffuse/focal, and acute/chronic/granulomatous
ingly rare in the joints. • Presence of haemosiderin/crystals/prosthetic
wear products/cartilage
44.1.5 Surgical Pathology

Specimens: Clinical Aspects 44.2 Bone
44.1.5.1 Biopsy Specimens 44.2.1 Anatomy

In general, biopsy has very little role to play in
the investigation and diagnosis of joint disease. Bones may be classified as long (femur,
Synovium is difficult to biopsy, and sufficient humerus, radius, ulna), tubular (small bones of
material is only reliably obtained at arthroscopy hands and feet), or flat (scapula, pelvis, rib,
or at open joint exploration. Most inflammatory vertebrae). The shell of the bone is called the
arthritides have similar histological features, and cortex, and the interior is known as the medulla
therefore, biopsy will not discriminate one type which consists of interconnecting bars of bone
480 O.P. Houghton
called trabeculae. This trabecular bone is also

referred to as cancellous bone. The thickness
of the cortex varies considerably along the Epiphysis
length of a given bone and especially between
different bones. The proportion of a bone occu-
pied by cortical and cancellous bone also var-
ies between bones and with age. The trabecular
bone is set in a fatty marrow containing hae- Metaphysis
mopoietic tissue. The cortex is covered by a
thin tough mesenchymal layer known as peri-
osteum. The ends of a bone are known as the
epiphysis. The metaphysis is the region imme-
diately adjacent to the epiphysis, and the
diaphysis is the shaft (area between the two
metaphyses) (Fig. 44.2).
Diaphysis
44.2.2 Clinical Presentation
The symptoms of bone disease are few and rather

nonspecific. The most common symptom is pain
which may be of variable intensity. Severe unre-
mitting pain continuing at night in bed is insidi-
ous and suspicious of malignancy. Pain relieved
by non-steroidal anti-inflammatory agents is sug-
gestive of a benign osteoid osteoma. Remember Metaphysis
that sometimes pain felt in one bone may be
referred pain, that is, disease originating else-
Epiphysis
where. A swelling is indicative of a primary bone
tumour. Pathological fracture, a fracture occur-
ring due to low-impact trauma, is indicative of a
diseased bone and suggests a metabolic or neo- Fig. 44.2 A typical long bone (Reproduced, with permis-
plastic disease.
phatase results need to be interpreted in the

44.2.3 Clinical Investigations light of the age of the patient as a child or ado-
lescent during a growth spurt will have very
• Routine blood tests include white cell count, elevated values. Plasma protein electrophore-
ESR, and C-reactive protein for the presence sis will detect a monoclonal gammopathy
of inflammation. A calcium profile consists of indicative of myeloma.
serum calcium, phosphate, and alkaline phos- • Urinary hydroxyproline—a useful measure of
phatase. This test is particularly useful in osteoclast activity and is elevated in Paget’s
endocrine or metabolic bone disease. disease.
Hypercalcaemia is seen in primary hyperpara- • Good quality plain X-ray—using two views is
thyroidism and metastatic disease. A raised still the mainstay of skeletal radiology. X-rays
alkaline phosphatase can be indicative of should be examined carefully for a periosteal
increased osteoblast activity and if very high reaction, indicative of osteomyelitis or a
suggests Paget’s disease. The alkaline phos- tumour.
• Isotope bone scan—measures osteoblast Metabolic bone disease: osteoporosis is very

activity. A positive bone scan confined to one effectively diagnosed using DEXA (dual energy
bone suggests fracture, infection, or tumour. A X-ray absorptiometry) and is almost never rou-
positive result in several long bones indicates tinely biopsied. Osteomalacia is most uncommon
metastatic disease, growth spurt, or general- in the UK but may rarely be seen in renal failure
ized arthritis. or in patients taking long-term phenytoin therapy.
• CT scan—extremely valuable in the diagnosis Paget’s disease is easily diagnosed using plain
of a primary bone tumour and especially use- X-ray, serum alkaline phosphatase, and urinary
ful for characterisation of small lesions such hydroxyproline so it is almost never biopsied.
as an osteoid osteoma. CT guided radiofre- Avascular necrosis: seen in some fractures
quency ablation is the treatment of choice for (neck of femur, scaphoid, talus), chronic steroid
osteoid osteomas. therapy, alcohol abuse, sickle cell anaemia and
• MRI scan - in conjunction with conventional Caisson disease (dysbarism).
X-ray examination, MRI is extremely useful
in diagnosis. It is also used to accurately loco- 44.2.4.2 Neoplastic Conditions
regionally stage bone tumours, assess response Benign tumours: benign tumours are relatively
to neoadjuvant chemotherapy and in postsur- rare, and the most common is the osteochon-
gical follow-up for determination of residual droma, a bony polyp with a cap of hyaline carti-
or recurrent tumour. lage seen usually in long bones. Enchondromas
are cartilaginous tumours occurring in the medul-
lary cavity of long bones. Osteoid osteoma is a
44.2.4 Pathological Conditions painful lesion occurring in the cortex of a long
bone, with a central lytic nidus and a margin of
44.2.4.1 Non-neoplastic Conditions sclerotic bone. A giant cell tumour of bone is
Fracture: a fracture is not routinely biopsied seen in people aged 20–40 years of age and char-
unless there is nonunion, delayed healing or is acteristically represents a lytic lesion occurring
thought to be pathological. In the former, there in the epiphysis of long bones. Other benign
is little or no new bone formation and only loose tumours include osteoblastoma, chondroblas-
fibrous tissue. Sometimes there may be evidence toma, chondromyxoid fibroma, aneurysmal bone
of accompanying infection. Pathological frac- cyst, fibrous dysplasia, non-ossifying fibroma,
ture is most often due to metastatic carcinoma benign fibrous histiocytoma and Langerhans cell
or myeloma although occasionally a primary histiocytosis.
bone tumour such as dedifferentiated chondro- Tumourlike conditions: these include cysts
sarcoma, or a benign bone cyst may be the (such as intraosseous ganglion and unicameral
cause. bone cyst) and giant cell lesion of the small bones
Osteomyelitis: in the acute stages, this disease (giant cell reparative granuloma).
is not routinely biopsied, but when a biopsy is Primary malignant tumour: these are also rare
submitted, material will be routinely sent to and most commonly seen in young people and
microbiology for culture as well. Infection is children. Osteosarcoma is a high-grade sarcoma
most commonly due to Staphylococcus aureus, producing osteoid, typically seen in the metaphy-
but increasingly, low virulence organisms are sis of long bones and people aged 10–25 years
being implicated as in drug addicts or the immu- old. It is very rare in older people but can be asso-
nosuppressed. Chronic osteomyelitis can result ciated with previous radiation exposure and
in marked bone deformity and usually is charac- Paget’s disease. It is treated by a combination of
terized by prominent bone formation with quite chemotherapy and surgery. Ewing’s sarcoma is a
minimal inflammation. The pathologist should poorly differentiated small round blue cell
always be aware of tuberculosis which is increas- tumour seen in the pelvis, ribs and long bones of
ing in incidence. children and young adults. It is treated with a
482 O.P. Houghton
combination of chemotherapy, radiotherapy, and advantage of saving valuable theatre time,

surgery. Chondrosarcomas are usually low-grade requires minimal anaesthesia, and is much less
sarcomas occurring in long bones and flat bones invasive for the patient and for planning future
in middle-aged and older people. Low-grade treatment. It is most important that good radio-
chondrosarcomas have a tendency for recurrence logical imaging is available to ensure that the
rather than metastasis. They do not respond to needle is in the right place. Occasionally needle
chemotherapy, and treatment is surgical removal. biopsy fails to obtain a good sample to allow
Dedifferentiated chondrosarcoma is a high-grade definitive diagnosis to be made and then open
tumour, typically large in size occurring in the biopsy is required.
pelvis, humerus and proximal femur of older
people. These tumours metastasize early and 44.2.5.2 Resection Specimens
have an extremely bad prognosis. Femoral heads removed at hip replacement for
Multiple myeloma: this is a haematological arthritis or repair of hip fracture are not routinely
tumour but sometimes classified as a bone submitted for pathology. They are submitted in
tumour. It is a tumour arising from the plasma cases of pathological fracture, avascular necrosis,
cells and occurs in multiple skeletal sites. It is or in rapidly progressive arthropathy occurring in
treated with chemotherapy. young people.
Metastatic carcinoma: this is by far the most Malignant tumours need to be removed com-
common malignant tumour in bone and presents pletely with a tumour-free margin or else they
as bone pain or pathological fracture. The most will recur. Characteristically malignant bone
common primary sites are lung, kidney, breast, tumours also permeate the soft tissues adjacent to
prostate, and thyroid. Most metastatic tumours the bone. These soft tissues must also be removed.
produce lytic lesions, but prostatic secondaries Detailed preoperative planning and careful exam-
are often sclerotic. The usual skeletal sites are ination of MRI scans is required to determine the
proximal long bones, rib, pelvis, and vertebrae. appropriate dissection. An intralesional excision
Metastatic disease is distinctly uncommon in the occurs when the surgeon cuts through the tumour.
skeleton distal to the elbow or knee. A marginal excision is where the tumour is com-
pletely removed without any significant margin
of normal tissue. A wide excision is where the
44.2.5 Surgical Pathology surgeon removes the tumour completely with a
Specimens: Clinical Aspects cuff of normal tissue. A radical excision is where
the entire muscle compartment of bone is
44.2.5.1 Biopsy Specimens removed, and it usually implies the removal of
Fine needle aspiration (FNA) cytology has only a the joint proximal to the tumour. These are often
very limited role in the diagnosis of primary bone disarticulations.
tumours. Bones are obviously deep-seated and
due to the hard nature of the tissue do not avail
themselves to aspiration cytology. Although this 44.2.6 Surgical Pathology
technique is very well established in breast and Specimens: Laboratory
head and neck pathology, it has almost no role to Protocols
play in the diagnosis of primary bone tumours.
Occasionally radiologically guided fine needle 44.2.6.1 Biopsy Specimens
aspiration can be performed where metastatic If a specimen is submitted unfixed (fresh) to the
disease is suspected. laboratory, tissue can be snap frozen for molecu-
Needle biopsy (Jamshidi needle or Surecut) lar genetic analysis or sampled for microbiologi-
under radiological control is the preferred cal investigations. Otherwise, tissue should be
method used to obtain a biopsy. Often the radi- submitted directly in formalin. If needle biopsy
ologist performs the biopsy. This method has the specimens are gritty or firm, they are put in 4%
acetic acid/formalin for 1–4 h and then in EDTA Initial procedure:

overnight. Decalcification is clearly important so
as to obtain good sections, but gentle decalcifica- • Ideally, amputation specimens should be
tion is necessary in case immunohistochemistry properly fixed before attempting dissection,
is required. Vigorous decalcification using formic but for large specimens especially above-knee
acid can destroy the tumour cells and expressed amputations, it is not practicable, and there-
antigens rendering subsequent immunohisto- fore, extreme care must be taken.
chemistry unhelpful. The number of cores and • The hand (left or right) and limb (upper or
lengths in millimeter should be recorded. lower) are recorded and any orientation mark-
Small bony fragments, curettings, or reamings ers noted.
from a primary bone tumour, infection, or meta- • Palpate for any obvious tumour masses or soft
static disease are placed into cassettes and decal- tissue involvement.
cified in 10% formic acid after adequate fixation. • Look for tumour satellite lesions.
If the curettings are from a suspect bone cyst or • Note any previous scars or biopsy sites includ-
primary tumour, it is advisable to use gentler ing length and location.
methods of decalcification such as 4% acetic • Locate the proximal limit of all major nerves
acid/formalin and overnight treatment with and vessels.
EDTA. • Confirm that the proximal limit is free of
Bone biopsy for osteomalacia requires unde- tumour.
calcified sections cut by a sledge microtome, • Cut through the skin and soft tissues to deter-
plastic embedding, and use of trichrome/tolu- mine if soft tissue spread has occurred; the
idine blue stains. Fluorescent tetracycline label- soft tissue should be incised to the bone.
ing is also used for the assessment of bone • Locate and trace major nerves and vessels to
turnover. ensure they are free and not encased by tumour.
The diagnosis of osseous tumours may also be • The bone itself is bivalved with a bandsaw or
aided by the use of alkaline phosphatase stains. mortuary skull saw. Extreme safety precau-
Briefly, air-dried imprints are made from fresh tions and care must be taken when using the
tissue and stained for alkaline phosphatase dem- bandsaw and only specifically named person-
onstrated by the naphthol ASBI phosphoric acid nel, specially trained in its use, should be
method. The alkaline phosphatase appears as allowed to use this apparatus.
bright red intracytoplasmic granules. • Measurements:
• Amputation specimen
44.2.6.2 Resection Specimens –– Length (cm)
Femoral heads or large chunks of bone require Tumour
adequate fixation and are then cut coronally with –– Length, width, and depth (cm)
a junior hacksaw or vibrating table saw. The –– Distance (cm) to proximal resection
diameter of the specimen should be recorded in margin
centimetres. The thin sawn slices are placed in –– Depth of overlying skin and soft tissues
10% formic acid for decalcification. The decalci- free of tumour
fied slices are then serially blocked, labeled, and –– Extent of extraosseous tumour involvement
submitted in toto. in soft tissues
Amputation specimens are examined to: –– Multifocal tumour
Description:
• Evaluate the resection margins including ves- Tumour
sel involvement –– Location (soft tissue, periosteum, cortex,
• Determine the extent of bone involvement medullary cavity)
• Evaluate the tumour necrosis, a measure of –– Site (epiphysis, apophysis, metaphysis,
response to prior chemotherapy diaphysis)
484 O.P. Houghton
–– Relationship to growth plate, nearby joint

or joint involvement 1 2 Proximal limit
–– Gross features (osseous, cartilaginous,
fibrous, myxoid, cystic change,
3 4
necrosis(assess percentage), haemorrhage,
Distance from
pathological fracture, satellite lesions) tumour to
resection limit 5 6
7 8
• Vessel limits.
• Marrow and proximal margin of resection.
• Any scars related to previous surgery or open 9 10
biopsy.
• Representative blocks of involved soft
tissues. 11 12
• Representative blocks of tumour obviously
around or in major vessels. 13 14
• Blocks to evaluate the tumour characteristics
and extent of necrosis for assessing response
to chemotherapy. 15 16 Sarcoma
• The extent of tumour necrosis is roughly esti-
mated by calculating the tumour necrosis 17 18
present in a whole bone slab 0.4 cm thick.
Having bivalved the affected bone, this 0.4-
cm longitudinal slab is obtained by cutting 19 20
along the plane of maximum tumour diameter.
The slab is drawn out and the whole slab cut 21 22
into blocks for histology. These blocks are
individually labeled and are correspondingly
noted and labeled on the written diagram. 23 24
About 20–40 blocks are required to achieve
this properly (Fig. 44.3). 25 26
• The blocks are properly fixed in formalin
prior to decalcification. It is most important
that blocks, especially these relatively large Fig. 44.3 Taking blocks from a bone slab containing sar-
bone blocks, are well fixed as the acid used coma (Reproduced, with permission, from Allen and
in decalcification can destroy the cell mor- Cameron (2013))
phology. Often about 48 h, fixation is
required. • Extent of local tumour spread—
• Decalcification is obtained using 10% formic medullary cavity/cortex/extraosseous soft
acid. This may take several days. tissues/joint.
• Tumour necrosis—response as a percentage
Histopathology report: for an entire slab (applies only to
osteosarcoma).
• Type of specimen, that is, core, reamings, • Mitotic rate
resection, and amputation. • Tumour grade (WHO classification, 2013)
• Tumour type and subtype –– Grade I—grade 1 chondrosarcoma, clear
• Tumour size (in 3 dimensions). cell chondrosarcoma, parosteal osteosar-
coma, low grade intramedullary M Distant metastasis

osteosarcoma. MX Distant metastasis cannot be assessed
–– Grade II—classic adamantinoma, grade 2 M0 No distant metastasis
chondrosarcoma, periosteal osteosarcoma M1 Distant metastasis (M1a Lung/M1b Other
and chordoma. distant site)
–– Grade III—osteoblastic, telangiectatic, G Histologic grade
small cell and high-grade surface osteosar- GX Grade cannot be assessed
coma, Ewing’s sarcoma, undifferentiated G1 Well differentiated—low grade
high-grade pleomorphic sarcoma, grade 3 G2 Moderately differentiated—high grade
chondrosarcoma, mesenchymal chondro- G3 Poorly differentiated—high grade
sarcoma, dedifferentiated chondrosarcoma, G4 Undifferentiated—high grade
dedifferentiated chordoma and malignant Stage groupings
giant cell tumour of bone.
• Lymphovascular invasion including vessel Stage IA T1 N0 M0 G1 Low
grade
limits
Stage IBa T2 N0 M0 G1 Low
• Status of excision margins (bone and soft tis- grade
sue resection margin), with a comment on the Stage IIA T1 N0 M0 G2,3 High
nature of tissue at the nearest soft tissue resec- grade
tion margin (e.g. fibrous connective tissue/adi- Stage II B T2 N0 M0 G2,3 High
pose tissue). grade
• Immunohistochemical analysis (if relevant). Stage III T3 N0 M0 G2,3 High
grade
• Cytogenetics and molecular pathology (gener-
Stage IVA Any T N0 M1a Any G
ally considered essential for small round cell
Stage IVB Any T N1 Any Any G
sarcomas). M
• Extent of local tumour spread: TNM 8 for pri- Any T N0 M1b Any G
mary malignant bone tumours except malig- a
T3, No, Mo, G1,2 low-grade - should be considered stage
nant lymphoma, multiple myeloma, and IB
surface/juxtacortical osteosarcoma and juxta-
cortical chondrosarcoma. The stage should Residual tumour (R)
ideally be confirmed following sarcoma multi- If there is residual tumour following an attempt
disciplinary team discussion. The scheme to cure (e.g. after surgical resection), an R clas-
below applies to tumours of the appendicular sification can be applied, as outlined below
skeleton, trunk, skull and facial bones—spine RX Presence of residual tumour cannot be
and pelvis are categorized separately assessed
R0 No residual tumour
T Primary tumour R1 Microscopic residual tumour
TX Primary tumour cannot be assessed R2 Macroscopic residual tumour
T0 No evidence of primary tumour
T1 Tumour 8 cm or less in greatest

dimension 44.3 Soft Tissues
T2 Tumour more than 8 cm in greatest

dimension 44.3.1 Anatomy
T3 Discontinuous tumours in the primary

bone site Soft tissue refers to non-epithelial extraskeletal
N Regional lymph nodes tissue of the body, but not including the haemo-
NX Regional lymph nodes cannot be assessed poietic or brain tissue. It really consists of mus-
N0 No regional lymph node metastasis cle, fat, and fibrous tissue along with blood
N1 Regional lymph node metastasis vessels and peripheral nerves.
486 O.P. Houghton
44.3.2 Clinical Presentation They are regarded as herniations of synovium,

usually have no recognizable lining, and a focally
Most soft tissue lesions present as a lump or myxoid fibrotic wall with gelatinous contents.
swelling and are usually painless. The lump may Bursa: this is a swelling which may be pain-
reach quite a size before the patient is aware of its ful, arising from the synovial lining between
existence, particularly if the lump is deep-seated muscles, tendons, and bones. They are espe-
or in the retroperitoneum. From a clinical point, cially common near joints. They include Baker’s
the most important aspect is the possibility that cyst at the back of the knee and housemaid’s
the soft tissue lump could be malignant, that is, a knee.
sarcoma. In general, any lump which is more Rheumatoid nodule: this is an irregular swell-
than 5 cm in size, deep-seated, painful, or growing seen in the soft tissues or in the organs in
ing rapidly should be considered as a possible patients with rheumatoid arthritis. However, not
sarcoma and investigated accordingly. Early every patient has well-established rheumatoid
diagnosis improves patient outcomes. arthritis. It forms part of the necrobiotic collagen
disorders.
44.3.3 Clinical Investigations 44.3.4.2 Neoplastic Conditions

Benign tumour: there are many different benign
• Routine blood tests have no useful role to play soft tissue lesions including lipomas, chondro-
in diagnosing a soft tissue lump. mas, neural tumours, leiomyomas, and a range of
• Plain X-rays also yield very little information fibroblastic tumours including fibromatosis and
unless there is calcification or ossification fasciitis-related conditions. Lipomas are by far
within the lump. This can be present in myosi- the most common and are usually less than
tis ossificans and may sometimes be seen in 2–3 cm in size, mobile, and superficial. Some
synovial sarcomas. lipomas can be quite large and deeply located.
• Ultrasound imaging can rapidly triage benign Fibromatoses, e.g. (Dupuytren’s contracture), are
from more suspicious lesions. irregular, poorly defined lesions which can be
• The most useful investigation in assessing soft difficult to remove surgically and have a high rate
tissue lumps is magnetic resonance imaging of recurrence.
(MRI), but the interpretation of the scans is Nodular fasciitis: a rapidly growing lump
complicated and depends on a highly trained which clinically and microscopically can mimic
and experienced radiologist. MRI can define malignancy.
the composition of a lump, identify the loca- Sarcomas: these are malignant soft tissue
tion and extent of the mass, provide informa- tumours and include such lesions as liposarco-
tion on involvement of nearby structures such mas, fibrosarcomas, synovial sarcoma, malignant
as nerves and vessels, may help differentiate fibrous histiocytoma, and leiomyosarcomas.
between benign and malignant tumours, and They are quite rare, and benign soft tissue lumps
can stage a malignant tumour locally. outnumber sarcomas by a ratio of 50–100:1.
• CT scan is used for detection of bony involve- Surgery remains the mainstay of treatment and
ment and preoperative staging of pulmonary chemotherapy, except in a few specific tumours
metastases. such as extraskeletal Ewing’s sarcoma or child-
hood rhabdomyosarcoma, has little role to play
as the toxicity of the therapy outweighs any ben-
44.3.4 Pathological Conditions efits in increased survival. The most important
features are size, grade, and stage. Grading in
44.3.4.1 Non-neoplastic Conditions turn depends on differentiation, necrosis, and
Ganglion: this is a fibrous-walled cyst typically mitotic rates. The 5-year survival for most sarco-
arising from a tendon in the hands, wrist, or feet. mas is about 40%.
44.3.5 Surgical Pathology 44.3.5.2 Resection Specimens

Specimens: Clinical Aspects Treatment aims to provide complete local exci-
sion with an acceptable resection margin and, if
44.3.5.1 Biopsy Specimens possible, limb salvage surgery with retention of a
Fine needle aspiration cytology has only a lim- functional limb. Large pelvic or retroperitoneal
ited role to play, but in some large national cen- tumours impacting on several organ systems may
tres, with good clinicopathological correlation require a multidisciplinary surgical approach.
and highly experienced operators, it can be used Postoperative radiotherapy improves local con-
to reliably distinguish most benign and malig- trol and is used for intermediate to high-grade
nant soft tissue lumps. If FNA is to be relied on, tumours, deep-seated tumours, and those with a
it is most important that the cytopathologist is close or incomplete resection margin.
well experienced in dealing with soft tissue Intracapsular excision: these are performed
lumps. The technique is quick, relatively pain- inside the tumour and are often piecemeal in
less, and requires no anaesthesia. It is essential nature, and local recurrence is almost 100%.
that any soft tissue swelling is properly assessed Marginal excision: this refers to removal of
clinically and radiologically prior to FNA. Many the lesion but without any significant margin of
lesions may be too deeply located to rely on normal tissue. Sometimes the excision biopsy is
FNA. Sometimes only necrotic tissue is referred to as shelling out. This technique is ade-
obtained. Some benign lesions can contain atyp- quate for superficial tumours or smaller tumours
ical cells such as nodular fasciitis, and some less than 3 cm in diameter. In larger lesions, it can
malignant tumours such as synovial sarcoma or leave satellite nodules in the surrounding zone of
well-differentiated liposarcoma have rather reactive tissue with a high local recurrence rate.
bland cytology. Immunohistochemistry and Wide excision: these are excisions through the
where available cytogenetic analysis may be normal tissue beyond the reactive zone associ-
performed on fine needle aspiration specimens. ated with the tumour but still within the muscle
FNA is also useful for assessing recurrence or compartment of origin. The tumour is never visu-
metastases in patients with previously diag- alized during the procedure. Low recurrence
nosed sarcoma. rates are achieved.
In most UK centres, needle core biopsy Radical excision: this is the en bloc removal of
(Jamshidi or Surecut) performed under radiologi- the tumour and entire muscle compartment of
cal control is the preferred method of obtaining a origin. A radical amputation usually requires dis-
tissue diagnosis. More than 90% of these lesions articulation of the joint proximal to the involved
are diagnosed using this technique. It must be compartment.
emphasized that FNA and needle biopsy are pri-
marily used to determine if a swelling is benign
or malignant, and biopsy may not always provide 44.3.6 Surgical Pathological
a precise diagnosis. As some soft tissue tumours Specimens: Laboratory
have a variety of patterns, needle biopsy may Protocols
result in sampling error.
Open biopsy is used when FNA or closed 44.3.6.1 Biopsy Specimens
needle biopsy have failed. It is performed by a Biopsies are usually in the form of needle-shaped
surgeon, and general anaesthesia is required. pieces of tissue. When unfixed (fresh) tissue is
Only experienced surgeons specifically trained submitted, a portion can be snap frozen for molec-
to deal with soft tissue tumours should perform ular and cytogenic analysis, prior to formalin fixa-
this procedure and not by general surgeons. A tion. If more than one core biopsy is received, they
wedge of tissue is removed, preferably along the should be separated and embedded in separate cas-
long axis of the tumour and directly over the settes if feasible. Open biopsies should similarly
tumour. be sampled in more than one cassette if possible.
488 O.P. Houghton
Biopsies are examined through levels and immu- • Serially cut through the specimen making a
nohistochemistry can be helpful (see later). series of transverse parallel cuts at 0.5-cm
intervals (pan-loafing) (Fig. 44.4).
44.3.6.2 Resection Specimens • If the specimen was received fresh, the tumour
Most resections for soft tissue tumours will consist can be sampled for snap freezing. It should
of the tumour with a margin of uninvolved soft then be fixed in formalin.
tissue. It is very unusual to submit any attached Measurements:
bone, and actual amputations are extremely rare. • Specimen—length × width × depth (cm),
weight (g)
Initial procedure:
Tumour
• Palpate the soft tissue to locate the tumour. –– Length × width × depth (cm) or maximum
• Paint the outer surface in toto or selectively to dimension (cm)
assist the assessment of margins. –– Distance (cm) from overlying skin
• Note the presence of attached skin ellipse and –– Distance (cm) from nearest margins
any scars present.
Paint externally and cut

into multiple transverse slices
Sample non-necrotic tumour

and tumour in relation to the
margins of excision
Fig. 44.4 Blocking a wide excision of a soft tissue mass (Reproduced, with permission, from Allen and Cameron
(2013))
Skin • Tumour edge—circumscribed or infiltrating

–– Length × width (cm) • Extent of local tumour spread: TNM 8 for soft
–– Length (cm) of scar tissue sarcomas of the extremities, superficial
trunk and retroperitoneum. Head and neck
Description: and thoracic and abdominal viscera sarcomas
are categorized separately
Tumour
–– Character of cut surface. pT1 Tumour ≤5 cm in greatest dimension
–– Margins (infiltrating or circumscribed). pT2 Tumour >5–≤10 cm in greatest dimension
–– Presence of necrosis (percent noted), haem- pT3 Tumour >10–≤15 cm in greatest dimension
orrhage, cystic change, and mucinous change. pT4 Tumour >15 cm in greatest dimension
–– Ulceration of overlying skin.
–– Relationship to any major vessels or nerves. • Note ulceration of overlying skin.
Other • Lymphovascular invasion
–– Note tissues included in the specimen • pN1 is regional lymph node metastasis
(muscle, fat, major vessels, bone). • Excision margins—distance (cm) from near-
est excision margin
• Limits of any major nerves or vessels included 44.4 Special Techniques

in the resection
• Representative blocks of margins, including deep 44.4.1 Frozen Section
margin - with the exception of epithelioid sar-
coma and myxofibrosarcoma, there is no need to This is rarely required as patients usually have a
sample margins which are greater than 30 mm. needle core biopsy prior to surgery. It may pro-
• Sufficient blocks to adequately sample the vide information on whether tumour is present,
tumour including different macroscopic however, precise tumour classification is not pos-
appearances such as firm, cystic and necrotic sible in the majority of cases.
areas (about one block per centimetre of great-
est dimension, to a maximum of 12)
• Any bone present 44.4.2 Immunohistochemistry
• Overlying skin and scars
Immunohistochemistry can be useful in diagnos-
Histopathology report: ing bone and soft tissue sarcomas. In bone tumours,
the decalcification process can destroy antigens in
• Tumour type/subtype (often requires immu- the tumour cells, and this can limit the usefulness
nohistochemistry or cytogenetics) of the technique. As with all tumours, the follow-
• Tumour size (in 3 dimensions) ing general points must be emphasized:
• Tumour grade—French Federation of Cancer
Centres Sarcoma Group (FNCLCC)—grades • Antibodies may not be specific to a particular
I, II or III—based on tumour differentiation, type of tumour, and there is often overlap with
percent necrosis (assessed microscopically), several other types.
and mitoses (in 10 high-power fields). • Immunohistochemistry will not directly deter-
Accurate grading is not always possible in mine if the tumour is benign or malignant.
small diagnostic biopsies as low grade sarco- • Beware of interpretation in the presence of
mas may be up-graded on examination of the extensive tumour necrosis.
resection specimen. • Be careful of edge artifact.
490 O.P. Houghton
• Know whether the antibodies you use should sarcoma), MDM2 and CDK4 (atypical lipo-
stain on the membrane, within the cytoplasm, matous tumour/well-differentiated, dediffer-
or nucleus of the cell. entiated liposarcoma, intimal sarcoma, low
• Always use a panel of antibodies. grade central and parosteal osteosarcoma),
• The use of immunohistochemistry in bone and brachyury (chordoma), β-Catenin (deep
soft tissue sarcomas is a huge subject, and fibromatoses).
good standard textbooks of soft tissue tumour
pathology should be consulted. However, the
list below illustrates some diagnostically use- 44.4.3 Cytogenetics and Molecular
ful antibodies: Genetics
• CD45 (leucocyte common antigen), CD20 (B
cell), CD3 (T cell), ALK-1, CD30 Specific chromosomal translocations have been
Chronic inflammation and lymphomas identified in approximately one third of bone and
• Cytokeratins soft tissue sarcomas. As many of these chromo-
Metastatic carcinoma, synovial sarcoma,
somal abnormalities are pathognomonic, their
and epithelioid sarcoma detection is extremely useful in diagnosis and in
• PSAP/PSA/ERG some cases may provide important prognostic
Metastatic prostate carcinoma information; furthermore, oncological protocols
• S100 and clinical trials often require cytogenetic confir-
Peripheral nerve sheath, lipomatous, carti- mation. Translocations can be demonstrated by
laginous, and myoepithelial tumours, clear fluorescence in situ hybridisation (FISH) and the
cell sarcoma and ossifying fibromyxoid specific fusion genes can be determined by reverse
tumour. Also metastatic melanoma (with transcriptase polymerase chain reaction (rtPCR).
melan-A and HMB-45) Many of these molecular tests can be performed
• Smooth muscle actin on paraffin-based tissue, however, fresh tissue can
Muscle tumours and fibroblastic and myo- be useful for cytogenetic analysis.
fibroblastic soft tissue lesions
• Desmin and h-caldesmon
Smooth muscle tumours 44.4.4 Electron Microscopy
• Desmin, myogenin, and myo-D1
Rhabdomyoma and rhabdomyosarcoma Electron microscopy has a very limited role in
• CD99 (MIC-2) and FLI-1 routine diagnostic practice.
Ewing’s sarcoma (note that CD99 can be
positive in many other tumors)
• CD34
Positive in vascular tumours, spindle cell Bibliography
lipoma and some fibrous lesions such as
extrapleural solitary fibrous tumour. Also cal cancer. 3rd ed. London: Springer; 2013.
dermatofibrosarcoma protuberans and epi- Allen DC, Cameron RI. Histopathology specimens:
thelioid sarcoma clinical, pathological and laboratory aspects. 2nd ed.
• CD31 and ERG Berlin-Heidelberg: Springer; 2013.
Athanasou NA. Colour atlas of bone, joint and soft tissue
Positive in vascular tumours. pathology. Oxford: Oxford University Press; 1999.
• Others Brierley JD, Gospodarowicz MK, Wittekind C, editors.
• TLE 1 (synovial sarcoma), DOG 1 and CKIT TNM classification of malignant tumours. 8th ed.
(gastrointestinal stromal tumour), INI 1 Oxford: Wiley-Blackwell; 2017.
Bullough PG. Orthopaedic pathology. 5th ed. St Louis:
(absent in epithelioid sarcoma), MUC4 (low- Mosby Elsevier; 2010.
grade fibro-myxoid sarcoma and sclerosing Dorfman HD, Czerniak B. Bone tumors. Mosby Wolfe:
epithelioid fibrosarcoma), FLI 1 (Ewing’s St Louis; 1998.
Fisher C. Immunohistochemistry in diagnosis of soft tis- Mirra JM, Picci P, Gold RH. Bone tumours: clinical,
sue tumours. Histopathology. 2011;58:1001–12. radiological and pathological correlations. Baltimore:
Fisher C, Montgomery E, Thway K. Biopsy interpreta- Lea and Febiger; 1989.
tion of soft tissue tumours. The Netherlands: Walters Pringle JAS. Osteosarcoma: the experiences of a special-
Kluwer; 2014. ist unit. Curr Diagn Pathol. 1996;3:127–36.
Fletcher CDM, Unni K, Mertens F. WHO classification Sinha H, Peach AHS. Diagnosis and management of soft
of tumours. Pathology and genetics. Tumours of soft tissue sarcoma. BMJ. 2011;342:157–62.
tissue and bone. Lyon: IARC Press; 2002. The Royal College of Pathologists. Cancer datasets (pri-
Goldblum JR, Weiss SW, Folpe AL. Enzinger and Weiss’s mary bone tumours, soft tissue sarcomas) and tissue
soft tissue tumors. 6th ed. Philadelphia: Elsevier pathways (bone and soft tissue pathology). https://
Saunders; 2014. www.rcpath.org/profession/publications/cancer-
Kempson RL, Fletcher CDM, Evans HL, Hendrickson datasets.html. Accessed Oct 2016
MR, Sibley RK. Tumors of the soft tissues, vol. 3rd Unni KK, Inwards CY. Dahlin’s bone tumors. 6th ed.
series: Fascicle 30. AFIP: Washington; 2001. Philadelphia: Lippincott, Williams and Wilkins; 2010.
McCarthy EF, Frassica FJ. Pathology of bone and joint Unni KK, Inwards CY, Bridge JA, Kindblom LG, Wold
disorders. Philadelphia: Saunders; 1998. LE. Tumors of the bones and joints, AFIP atlas of
Miettinen MM. Modern soft tissue pathology. New York: tumor pathology, vol. series 4. Fascicle 8. AFIP:
Cambridge University Press; 2010. Washington; 2004.
Part XI
Haemopoietic Specimens
Lymph Nodes, Spleen, and
Bone Marrow 45
Lakshmi Venkatraman and Damian T. McManus
45.1 Lymph Nodes follicles. The B-cells home to the follicles in

response to cytokine secretion by the follicular
45.1.1 Anatomy dendritic cells. These are separated from each
other and the sinuses by smaller lymphocytes
The lymph node is an ovoid encapsulated structure forming a mantle of darkly staining cells—the
situated at regular intervals along the lymphatic mantle zone and yet another zone of paler cells—
channels. It neutralizes, degrades, or modifies the the marginal zone. Deep to the cortex and between
antigens that are presented to it by the lymphatics follicles is the paracortex or T zone as it is com-
before returning them to the blood. The immune posed mostly of T cells mixed with histiocytes,
response to antigens after birth determines the interdigitating reticulum cells, and Langerhan’s
structure and composition of the node. Each lymph cells. The paracortex also has the characteristic
node has a fibrous capsule from which trabeculae high endothelial venules that are involved in lym-
extend into the parenchyma. The non-stimulated/ phocyte trafficking.
minimally stimulated lymph node is composed of With cognate help from T cells and other anti-
a reticulum meshwork supported by fibroblastic gen presenting cells, antigenic stimulation of the
dendritic cells. The broad functional and anatomi- cells of the primary B follicles and clonal expan-
cal divisions within a lymph node are the outer sion takes place forming the germinal centres of
cortex and the inner medulla, which are sometimes the secondary follicles. These contain immuno-
visible on naked eye examination (Fig. 45.1). The blasts, centroblasts, centrocytes, few T cells, and
cortex or the B zone contains pale staining, densely tingible body macrophages. The paracortical T
packed aggregates of lymphocytes called primary cell response also consists of increased prolifera-
tion and transformation to blast cells. This is nec-
essary for primary immune response by B cells.
The medulla contains large numbers of plasma
cells, which are the terminally mature B cells.
L. Venkatraman (*) The afferent lymphatics enter the lymph node
Histopathology Laboratory, Institute of Pathology, through the convex surface on the cortex and drain
Royal Victoria Hospital, Belfast Health and Social in to the subcapsular venous sinuses. The lymph is
e-mail: lakshmi.venkatraman@belfasttrust.hscni.net
conveyed to the efferent lymphatics in the hilum
by the intermediate and medullary sinuses. The
D.T. McManus
fibroblastic reticular meshwork of cells situated
Belfast Health and Social Care Trust, Belfast, UK predominantly in the paracortex connects the
e-mail: damian.mcmanus@belfasttrust.hscni.net sinuses to the high endothelial venules.

496 L. Venkatraman and D.T. McManus
Afferent
lymphatics
Primary Capsule
follicles
Trabeculae
Subcapsular
sinuses
Medulla
Paracortex Efferent
lymphatics
Cortex
Mantle Blood
vessels
Germinal
centre
Secondary
follicles
Fig. 45.1 Architecture of lymph node (Reproduced, with permission, from Allen and Cameron (2013))
Three lineages of lymphocytes are recognized of immunity are interdependent. Innate immunity
in the lymph node, the B, T, and NK (natural present from birth is a rapid response system
killer) cells. These are derived from the haemato- mediated by macrophages and neutrophils.
poietic stems cells in the bone marrow. Following Adaptive immunity is a slower specific response
immunoglobulin gene rearrangements, the B to antigens. It is initiated by dendritic cells in
lymphocytes express surface and cytoplasmic lymphatic and non-lymphatic tissues interacting
immunoglobulins, which mediate humoral with B and T cells.
immunity. Large quantities of immunoglobulin Immunophenotyping is essential in character-
are produced by the plasma cells. The T cells ization of lymphoid diseases, and it is important
travel from the bone marrow to the thymus where to be familiar with the normal immunoarchitec-
they undergo rearrangement of the T-cell receptor ture of the lymph node (Fig. 45.2).
genes and mature in stages. Antigen dependent In general, the follicles stain strongly with B
interactions result in memory and effector T-cells cell markers (CD19, CD20, CD 79a).
including the helper and suppressor subsets that The interfollicular and paracortical regions
mediate cellular immunity. The two mechanisms express CD3 predominantly. The T-helper cells
45 Lymph Nodes, Spleen, and Bone Marrow 497
Fig. 45.2 Normal
immunoarchitecture of
lymph node
(Reproduced, with
permission, from Allen B cells CD20+
and Cameron (2013))
Tcells CD3+
express CD4 and the T-suppressor cells CD8. In to the cause. Some of the common sites of
the last decade, much has been discovered about lymphadenopathy and causes of enlargement
subsets of T-helper cells i.e. follicular T-helper are listed in Table 45.2.
cells (expressing CD10, CD4 and PD1) localised Small size (<1 cm diameter) usually indicates
in the B-cell follicles and regulatory T-cells a benign lymph node.
(Tregs) that play a major role in autoimmunity. Malignant lymphoma: Large, discrete, sym-
The antigen expression and maturation sequence metric, mobile, rubbery, non-tender lymph nodes.
of B and T cells follows B and T cell receptor Metastatic carcinoma: Hard, non-tender
gene rearrangements. The developmental stages lymph nodes fixed to surrounding tissues.
and immunophenotype of B and T lymphocytes Patients with lymphadenopathy may have
are shown in Fig. 45.3. splenomegaly as seen in chronic lymphocytic
Lymphovascular drainage: leukaemia, lupus erythematosus, toxoplasmosis,
The artery enters the lymph node at the hilum and some haematological disorders.
where it divides into numerous branches. These Non-superficial lymphadenopathy: Thoracic or
follow the trabeculae and reach the cortex to form abdominal. Thoracic lymph nodes may be second-
a capillary network. Some arterioles reach the ary to lung diseases and identified on routine work
medulla through the trabeculae. The post capil- up chest X-ray. Other symptoms are cough and
lary venules draining the cortex and paracortex wheezing from airway compression, hoarseness
coalesce to form collecting veins that leave the from recurrent laryngeal nerve involvement, dys-
hilum of the lymph node. The intra-nodal lym- phagia from oesophageal compression or swelling
phatic flow is detailed above. of the face due to superior vena cava compression.
Abdominal/retroperitoneal lymph nodes if
enlarged are usually malignant. However, tubercu-
45.1.2 Clinical Presentation losis can also cause mesenteric lymphadenopathy.
Lymphadenopathy may be the presenting sign or

symptom of illness or an incidental finding. Up to 45.1.3 Clinical Investigations
two-thirds of patients have non-specific causes or
upper respiratory illness. Patients may present Investigations are done to find the cause sus-
with sore throat, cough, fever, night sweats, and pected from the history and physical findings.
fatigue or weight loss. There are many diseases
associated with lymphadenopathy. The major • ENT examination: Essential in the work-up of
categories are listed in Table 45.1. persistent cervical lymphadenopathy.
Pain is usually secondary to inflammation. • Full blood picture (FBP): Raised WBC count
However, rapid enlargement and pain may be in acute/chronic leukaemias and pyogenic
present in lymphomas and leukaemias. infections.
Lymphadenopathy can be localized or general- • Serology: Raised immunoglobulin titres in
ized. The site of enlargement may provide a clue EBV, CMV, HIV, toxoplasmosis, and
Tdt
C-CD22 HLA-Dr Tdt
Pre Pre B cell Prothymocyte
C-CD79a stem cell CD 7
CD19 HLA-DR
Tdt
C-CD22
Pre B cell C-CD79a
C-M HLA-DR
CD19 CD20
Stage I Tdt
thymocyte CD2 CD5
CD 7
Tdt
Immature S-IgM CD22
B cell CD21CD20 CD19
CD79a HLA-DR
Cyt CD 3
S-IgM+S-IgD Tdt
Mature CD79a CD22 Stage II CD1 CD2
B cell CD21 CD20 thymocyte CD 4 CD8 CD5
CD19 HLA-DR CD7
BCL-6 S-IgM/G/A
CD79a CD22 CD3 CD2 CD3 CD2
Folicle Stage III Stage III
CD10 CD21 CD 5 CD8 CD 4 CD5
centre thymocyte thymocyte
CD20, 19,DR CD7 CD7
B cell
S-IgM/G/A
CD79a CD22 T- suppressor/ CD3 CD2 CD3 CD2
Immunoblast CD 8 CD5 T- helper cell CD 4 CD5
CD138 ± CD20 cytoxic cell
CD19,HLA-DR CD7± CD7±
CD79a
Plasma cell CD138 PCA-1
Fig. 45.3 Development of B and T lymphocytes (Reproduced, with permission, from Allen and Cameron (2013))
Table 45.1 Causes of lymphadenopathy Table 45.2 Sites of lymphadenopathy and the related
causes
Infectious diseases
Viral: Infectious mononucleosis, hepatitis, herpes Occipital: Scalp infection
simplex, HIV, measles, varicella zoster, rubella Pre-auricular: Conjunctival infection
Bacterial: Streptococci, brucellosis, tuberculosis, Neck: Oral, dental and respiratory infections, viral
other mycobacterial infection, plague, primary and diseases, e.g., infectious mononucleosis,
secondary syphilis toxoplasmosis
Fungal: Histoplasmosis, cryptococcosis Malignant neck nodes: Drain thyroid, head and neck,
Chlamydia: Lymphogranuloma venereum breast and lung carcinomas
Parasitic: Toxoplasmosis, leishmaniasis Scalene and supraclavicular (Virchow’s nodes):
Always abnormal if enlarged as these drain lung and
Rickettsial: Rickettsial pox, scrub typhus
retroperitoneum
Immunologic disorders
Causes: Infection, lymphomas, or other malignancies.
Rheumatoid arthritis, lupus erythematosus, Tuberculosis, sarcoidosis, and toxoplasmosis are the
dermatomyositis, Sjogren’s syndrome, primary biliary commonest causes of non-neoplastic enlargement at
cirrhosis this site
Drug hypersensitivity: Diphenylhydantoin, Virchow’s node: Associated with a gastrointestinal
hydralazine, allopurinol, gold, carbamazepine primary. Metastasis from the lung, breast, testes, and
Graft versus host disease ovaries may present as lymphadenopathy at this site
Malignancy Axillary: Non-neoplastic: Trauma, infection of the
Haematological ipsilateral upper extremity
Metastasis: From various sites Neoplastic: Metastasis from malignant melanoma,
Lipid storage disorders breast cancer, or lymphoma
Nieman Pick’s, Gaucher’s Inguinal: Non-neoplastic: Trauma, infection of the
lower extremities, or venereal diseases
Endocrine diseases
Neoplastic: Metastasis from cancers of lower rectum,
Hyperthyroidism
anal canal, genitalia, and melanoma of the lower
Others extremities
Castleman’s disease, sarcoidosis, dermatopathic
lymphadenitis, Kikuchi’s disease, sinus histiocytosis
with massive lymphadenopathy, inflammatory • FDG-PET and PET/CT scans are the most
pseudotumour, autoimmune lymphoproliferative sensitive and specific techniques in pre-
syndrome, amyloidosis
treatment assessment of patients with lym-
phoma (and other cancers) but not routinely
rucellosis. ACPA (anti-citrullinated peptide/
b used for diagnosis.
protein autoantibody), anti-dsDNA: raised in • FNA (fine needle aspiration): >90% sensitiv-
rheumatoid arthritis and lupus erythematosus. ity and specificity in diagnosis of metastatic
• Chest X-ray: If there is an abnormality sug- cancer and even lymphoma in some centres. It
gestive of tuberculosis, sarcoidosis, or cancer, is extremely useful in selecting patients for
further investigations are necessary. lymph node excision biopsy and sometimes
• USS (ultra sound scan): Long axis (L)/short can help focus further evaluation.
axis (S) ratio <2 has 95% specificity and sen- • Indications for lymph node excision biopsy:
sitivity to detect metastatic disease. –– To make a diagnosis in cases of unex-
Endoscopic and endobronchial (EUS, EBUS) plained, persistent lymphadenopathy.
US are widely used for evaluation of medias- –– To confirm an FNA or needle core biopsy
tinal and upper abdominal lymph nodes. of malignant lymphoma or any clinical
• CT (computed tomography) and MRI (mag- diagnosis when adequate information for
netic resonance imaging): 65–90% accurate in therapy is not available from an FNA.
the diagnosis of metastatic malignancy. TNM –– As part of the diagnostic work-up of a sys-
extent of disease for malignant lymphomas is temic disease with lymphadenopathy, e.g.,
staged using a modification of the Ann Arbor rheumatoid arthritis and lupus
classification. erythematosus.
–– Staging protocol for cancers. Necrotizing lymphadenitis (Kikuchi’s dis-

–– To monitor progress in a previously diag- ease): Occurs in young women, is of unknown
nosed malignant lymphoma. aetiology and shows pale patches of large lym-
phoid cells with karyorrhectic debris, crescentic
histiocytes, and plasmacytoid monocytes. It may
45.1.4 Pathological Conditions be confused with a large cell lymphoma.
Paracortical hyperplasia: Commonly a non-
45.1.4.1 Non-neoplastic Conditions specific response but is typical of dermatopathic
These include various patterns of hyperplasia all lymphadenitis, which occurs in generalized exfo-
of which show morphological and immunohisto- liative dermatitis.
chemical preservation of the nodal architecture. Immunoblastic proliferation: Characteristic of
The main patterns are: infectious mononucleosis and prominent in other
Follicular hyperplasia: This is characterized viral infections, hypersensitivity reactions, post
by prominent hyperplastic follicles in the cortex. vaccinial, and Kikuchi’s disease.
It is a common non-specific reaction. It is a strik- Sinus proliferation: Frequently present in
ing feature of lymph nodes in progressive trans- lymph nodes draining carcinomas. Other disor-
formation of germinal centres, HIV-associated ders that show prominent sinus involvement
lymphadenopathy, rheumatoid arthritis, and include Rosai-Dorfman disease (sinus histiocyto-
syphilis. sis with massive lymphadenopathy), Langerhan’s
Mantle zone hyperplasia: The reactive folli- histiocytosis, Whipple’s disease, and virus-
cles have thick mantles. This is best seen in associated haemophagocytic syndrome.
Castleman’s disease and is a common pattern in
reactive mesenteric lymph nodes. 45.1.4.2 Neoplastic Conditions
Marginal zone hyperplasia: Characterized by Malignant lymphomas: The cell of origin and
monocytoid B lymphocyte proliferation within stage of differentiation are the bases of WHO
sinuses. It is seen in toxoplasmosis, HIV- lymphoma classification in 2008 and the 2016
associated lymphadenopathy, B cell-associated update. The neoplasms of the B, T, and NK cells
granulomatous diseases such as cat scratch dis- are well defined disease entities recognized on
ease, lymphogranuloma venereum, and CMV the basis of available information using morphol-
lymphadenitis. ogy, immunophenotyping, genetics, and clinical
Granulomatous inflammation: May be due to features.
infections such as tuberculosis, brucellosis, for- The WHO classification includes both lym-
eign body reaction, sarcoidosis, and in response phomas and leukaemias since both solid and cir-
to malignancy as in lymph nodes draining carci- culatory phases as well as a normal cellular
nomas or in patients with Hodgkin lymphoma. counterpart in lymphoid development are recog-
nized in many haematological neoplasms. The
• Caseating granulomas: Seen in tuberculosis. practical approach to diagnosis is based on mor-
• Suppuration and granulomata: Seen in non- phology and immunophenotype, which correlate
tuberculous mycobacterial infections and fun- with clinical features and response to treatment.
gal infections due to histoplasmosis, Genetic features are diagnostic in several entities
cryptococcosis, aspergillosis, mucormycosis, and are part of the disease definition. Recent
and candidiasis. technological advances in gene expression profil-
• Microgranulomata within germinal centres: ing (GEP) and next generation sequencing (NGS)
Seen in toxoplasmosis. have identified disease specific genetic abnor-
malities (e.g. BRAFV600E in hairy cell leukae-
Suppurative lymphadenitis with/without gran- mia) and mutations of prognostic and/or
ulomata: Seen in cat scratch disease, tularaemia, predictive value in several lymphomas. The clini-
and lymphogranuloma venereum. cal course is variable; both cellular characteris-
tics and phenotype in any given lymphoma may pathological features of the most frequent “indo-
change over time. Hence the WHO classification lent” small B cell lymphomas are listed in the
no longer relies on grade to stratify lymphoid Table 45.3.
neoplasms. Marginal zone lymphoma: Accounts for 7–8%
The prognosis strongly relates to stage of dis- of lymphoid neoplasms. It is rare in the nodes but
ease, treatment protocols, and biological features. nearly always presents at extranodal sites as
Up to 90% of the non-Hodgkin lymphomas MALTomas, e.g., stomach, salivary gland, and
(NHLs) are B cell neoplasms. The clinical and thyroid.
Table 45.3 Indolent small B cell non-Hodgkin lymphomas

SLL/CLL MCL FCL LPL
Clinical ≈6% of NHL ≈6% of NHL ≈22% of NHL Asymptomatic
paraproteinaemia
common, may
present with
lymphadenopathy
Rare under 40 years M:F ratio 5:1 Rare under 20 years M protein,
Disseminated disease at Disseminated at Disseminated at Hyperviscosity,
presentation presentation presentation cryoglobulinaemia
Indolent leukaemic Extranodal variants
non-nodal type skin and duodenum,
recognised paediatric type
Biologically relatively good
aggressive prognosis
Median survival
2–5 years
Architecture Pale staining Diffuse, less Closely packed Diffuse
proliferation centres commonly nodular follicles, absent
Background diffuse proliferation mantles, loss of Interfollicular
small lymphocytes polarity
Cytology Paraimmunoblasts Small- to medium- Centroblasts, Small B
sized lymphocytes centrocytes. May lymphocytes
Prolymphocytes. Small with slight nuclear have signet ring cells Plasmacytoid
lymphoid cells with irregularity. Scattered lymphocytes
clotted chromatin histiocytes and
minimally larger than hyalinized vessels
mature lymphocytes common. Blasts in
blastoid variant
IHC CD5, CD20, CD23, CD5, cyclin D1, CD20, CD10, bcl2, CD20, IgM
LEF-1 positive CD43 positive bcl6 positive positive. CD43±
CD10, cyclin CD10, CD23, bcl6 CD5/43 negative. CD5, CD10, CD23
D1-negative negative CD23± negative
Cytogenetics 13q deletion in 50% t (11:14) t (14:18)
Cyclin D2 1p36 deletion in
translocations with diffuse, inguinal
IgK or IgL in Cyclin variant
D1 negative cases
Molecular P53 mutation implies EZH2, CREBBP MYD88L265P
poor prognosis mutations in >20% mutated in >90%
IgVH mutation is better cases
prognosis
SLL small lymphocytic leukaemia, CLL chronic lymphocytic leukaemia, MCL mantle cell lymphoma, FCL follicle
centre cell lymphoma, LPL lymphoplasmacytic lymphoma, IHC immunohistochemistry
“Aggressive” diffuse large B cell lymphomas: tant insight into disease classification and mecha-
Aggressive and present as nodal, extranodal, nisms with potential for therapeutic target
localized, or disseminated disease. Distinctive identification.
clinical variants are mediastinal large B cell lym- Peripheral T cell lymphoma, NOS: A hetero-
phoma, primary effusion lymphoma, and intra- geneous group of neoplasms with a broad cyto-
vascular lymphoma. Molecular subgroups, i.e., logical spectrum. The tumour cells are of variable
germinal centre and non-germinal centre cell of size with irregular nuclei and may include pleo-
origin predict survival and have largely replaced morphic cells that are Reed-Sternberg like. CD30
the morphologic variants such as centroblastic, and T cell antigens are positive but aberrant anti-
immunoblastic, plasmablastic, T cell rich, and gen loss is common. TCR (T cell receptor) genes
anaplastic. The widespread use of immunoche- are clonally rearranged.
motherapy (R-CHOP) has dramatically improved Angioimmunoblastic lymphoma is a type of
survival. C-MYC translocation occurs in 5–15% peripheral T cell lymphoma characterized by sys-
of the DLBCLs and is often associated with bcl2 temic disease and immunological abnormalities.
or bcl6 gene rearrangements (double/triple hit) In lymph nodes, it is composed of a polymor-
lymphoma. The latter are recognized in the 2016 phous infiltrate of neoplastic T cells (with a fol-
WHO update as High Grade B-cell lymphoma licular helper T-cell phenotype) admixed with B
with MYC rearrangement and have adverse prog- cells that are often EBV driven, a proliferation of
nosis. Concomitant MYC/bcl2 protein expres- high endothelial venules and follicular dendritic
sion (‘double expressor’) in the absence of myc/ meshwork. RHOA, TET2 and IDH2 mutations
bcl2 translocations is more common in DLBCL are common.
(20–35%) and is associated with worse outcome Anaplastic large cell lymphoma (ALCL): Most
than standard risk DLBCL. EBV positive frequently occurs in the first three decades of life.
DLBCL, NOS -not otherwise specified, occur- The tumour cells have pleomorphic horseshoe
ring in immunocompetent patients has been rec- shaped nuclei, abundant cytoplasm, and are
ognized in 2016. referred to as “hallmark cells”. T cell antigens,
Burkitt lymphoma: A tumour of medium size EMA, cytotoxic granule proteins, ALK and
rapidly proliferating B cells that may present as a CD30 are positive. 90% cases have clonal rear-
lymphoma or acute leukaemia. The major clini- rangement of TCR genes. ALK expression is due
cal subtypes include endemic, sporadic, and to t (2:5) (q23; 35). Variant translocations involv-
immunodeficiency related. The c-myc transloca- ing ALK and other partner genes on chromo-
tion is characteristic of this lymphoma but not somes 1, 2, 3, and 17 also occur. Overall 5-year
specific for it hence the diagnosis is based on a survival rate is 80% in ALK1 positive patients.
combination of morphology, immunophenotype, ALK negative ALCL is morphologically similar
and genetic analyses. Burkitt lymphoma without to the ALK positive counterpart. Extranodal
c-myc translocation but with the presence of ALCL such as cutaneous ALCL and breast
chromosome 11q aberrations is a new entity and implant associated ALCL have a better
only a small number of cases are reported. prognosis.
T/NK cell neoplasms: Relatively uncommon Hodgkin lymphoma: A lymphoma of “crip-
and account for approximately 10–15% of the pled” B cells and accounts for 30% of all lym-
lymphoid neoplasms in the West. Clinical fea- phomas. The WHO classification divides
tures are important for subtyping, as the mor- Hodgkin lymphoma into two major subtypes.
phology, immunophenotype, and genetics are not
absolutely specific. The commonest subtypes are • Classic Hodgkin lymphoma (HL)
peripheral T cell lymphoma, not otherwise speci- –– HL, nodular sclerosis
fied, angioimmunoblastic T cell lymphoma, and –– HL, mixed cellularity
anaplastic large cell lymphoma. Gene expression –– HL, lymphocyte-rich
profiling and lately NGS have provided impor- –– HL, lymphocyte depleted
• Nodular lymphocyte predominant HL Plasma cell neoplasms: Include myeloma and

(NLPHL). its variants, plasmacytoma, immunoglobulin
deposition diseases, osteosclerotic myeloma, and
The clinical and pathological features are heavy chain diseases, all of which have a clonal
detailed below (Table 45.4). proliferation of immunoglobulin secreting termi-
Table 45.4 Subtypes of Hodgkin lymphomas

Lymphocyte
Nodular sclerosis Lymphocyte rich Mixed cellularity depleted NLPHL
Clinical Most common Stage I/II in High stage at Rarest subtype. Occurs in
subtype. peripheral nodes. presentation. B Frequently young, often
Peripheral/ Rare B symptomsa associated with single cervical
mediastinal symptomsa. common. Spleen HIV. Involves node involved.
LN. Usually Mediastinal involved in 30%. abdominal organs, Stage I
Stage II disease Usually peripheral retroperitoneal LN, common.
uncommon node involvement and bone marrow. Frequent
Presents as high relapses, usually
stage disease chemosensitive
Architecture Prominent Commonly Obliterated May have diffuse Nodular/
nodularity. nodular, rarely architecture. No fibrosis nodular and
Collagen bands diffuse fibrous bands diffuse
at least around
one nodule
Cytology Lacunar RS Scattered R-S Typical R-S cells Variable numbers Nodules contain
cells. Large cells against a against a of pleomorphic darkly staining
aggregates of nodular polymorphous R-S cells and few small
RS cells- background of background of lymphocytes. Can B-lymphocytes,
‘syncytial small cells including look anaplastic or neoplastic
variant’ lymphocytes eosinophils, fibrohistiocytic “popcorn” L&H
neutrophils, cells and rare
histiocytes and classic R-S cells
plasma cells
IHC CD30/15+, Same as nodular Same as nodular Same as nodular CD20/CD79a/
PAX5 + in 90% sclerosis sclerosis. sclerosis. EMA/bcl6+,
cases EBVLMP1+ in HIV + patients transcription
LCA neg 75% cases express EBVLMP1 factors Oct2/
CD20±. EMA, BoB1 + in L&H
ALK neg. cells. CD15/30
EBVLMP1± usually negative
Prognosis Slightly better As good as Intermediate Aggressive in Excellent
than mixed NLPHL between nodular HIV + patients but prognosis in
cellularity or sclerosis and with modern Stage I. High
lymphocyte lymphocyte chemotherapy stage disease is
depleted. Bulky depleted but prognosis similar rare
mediastinal differences not to other subtypes in
disease and observed with immunocompetent
incomplete modern patients
response to chemotherapy
therapy
identified by
FDG-PET CT
are adverse
EBVLMP Epstein Barr latent membrane protein
B symptoms, e.g., weight loss, night sweats, pain
a
nally differentiated B cells, i.e., plasma cells and phoma grade underestimated. Good transport
plasmacytoid lymphocytes. arrangements and communication are essential to
Metastatic tumours: Lymph nodes are the ensure the samples are submitted for flow cytom-
commonest site of tumour metastasis which may etry and molecular studies.
be the presenting feature. Nodal spread is com-
mon in carcinomas, malignant melanomas, and
germ cell tumours, rare in mesotheliomas and 45.1.6 Surgical Pathology
uncommon in sarcomas and brain tumors. Specimens: Laboratory
Lymphomas mimicking carcinomas: Protocols
Anaplastic large cell lymphoma, diffuse large B
cell lymphoma with sclerosis, large cell lym- 45.1.6.1 Lymph Node Biopsy
phoma with sinusoidal growth pattern, nodular • Usually received intact and fresh/dry or in for-
sclerosing Hodgkin lymphoma, and signet ring malin soon after excision (ideally in 60 min).
lymphoma. • After assigning a laboratory number and
Metastatic carcinoma mimicking lymphoma: assessing infection risk, dissect the lymph
Nasopharyngeal/lymphoepithelial carcinoma, node free from surrounding fat/connective
small cell carcinoma, and lobular carcinoma tissue.
breast. • Count the number of nodes and measure their
Cystic metastases in cervical lymph nodes: size (length × width × depth—mm).
Commonly due to papillary thyroid carcinoma • Make parallel cuts along the transverse axis at
and squamous cell carcinoma. 2–3 mm intervals with a sharp blade.
• A small portion is submitted for microbiologi-
cal investigations if infectious disease is sus-
45.1.5 Surgical Pathology pected clinically. This is usually done in fume
Specimens: Clinical Aspects hoods/biosafety cabinets. If not submitted
immediately, store at 4 °C. Make smears for
45.1.5.1 E xcision Biopsy of Lymph Gram/Ziehl-Nielsen stains.
Node • Make five imprints of the cut surface on coated
The general principle is to remove a representa- or charged, alcohol-cleaned slides.
tive lymph node (usually the largest, deepest and • A small portion is submitted for flow cytome-
most abnormal) and submit it for histology with try and molecular diagnostics if adequate tis-
minimal tissue distortion. It may be possible to sue is available for both.
select the lymph node for excision and appropri- • Submit the slices for histology (entire node if
ate handling by doing a pre-operative FNA. lymph node size is below 3 cm). Fix in 10%
Some lymph node groups are always patho- neutral buffered formalin for 24–48 h prior to
logical, i.e., Virchow’s/supraclavicular. paraffin processing. Prolonged fixation can
Inguinal lymph nodes usually show non-spe- bind antigenic sites and hamper immunohisto-
cific lymphadenitis or scarring and are unlikely chemistry. The size of tissue within each block
to be informative except when markedly need be no more than 15–20 mm. Good qual-
enlarged or the patient has a previous history ity, thin (3–4 μm) sections are required for H
of malignancy. & E for morphology. Correlate imprint find-
Obtaining biopsies from deep lymph nodes is ings with histology of the slice from which it
difficult, and it may not be possible to distinguish was obtained.
lymphadenopathy from visceral or soft tissue
malignancies. In such situations, FNAs and nee- Imprints: Touch the glass slide gently to the
dle core biopsies are taken under radiological cut surface of the node after ensuring the cut sur-
guidance. Note that interpretation may be hin- face is not too wet or bloody. Avoid using force.
dered by handling artifact and cell size/lym- Dry the slides in air. Heating or blow-drying is
unnecessary and creates artifacts. For wet fixa- Cut initial and deeper sections and keep the
tion, the smears are dipped in alcohol-based fixa- intervening ribbons pending morphological
tive immediately after taking imprints. assessment and any need for
Frozen section: Place a 2 × 2 × 1 cm piece or immunohistochemistry.
as large a fragment as feasible on moistened filter
paper in a petri dish. This is useful for intra- Description:
operative staging of cancers and for ensuring that
the material submitted is diagnostic. Adequate • Size (mm) of the node.
unfrozen tissue must be available for routine his- • Capsule present/intact.
tology. Lymphoma may be recognized on frozen • Appearance of the cut surface and colour—
sections, the diagnosis requires ancillary investi- pink or grey in the normal nodes, variegated
gations and the opportunity should be used to with distinct nodules in metastatic carcino-
obtain adequate diagnostic tissue. mas, uniformly whitish with fish-flesh
Cytogenetics/flow cytometry: Place a appearance in lymphomas. Can be black in
0.5–1 cm3 piece of tissue in a bottle containing a metastatic melanomas.
culture medium such as RPMI/DMEM and send • Nodularity—prominent in Hodgkin lym-
to the appropriate laboratory. Snap freeze tissue phoma, sometimes follicles are prominent in
at −70 °C if tissue is not immediately processed. follicular lymphoma.
Immunoglobulin heavy chain and T cell recep- • Haemorrhage.
tor gene rearrangement studies can be carried out • Necrosis—caseous/cheesy in tuberculosis,
using both fresh and paraffin-processed material pale friable areas in high-grade lymphomas,
as determined by local protocols. also seen sometimes in Kikuchi’s disease.
45.1.6.2 Needle Biopsy Blocks for histology:

With good communication and logistics in place,
preparations to collect separate samples for flow • Cross section of the node including capsule.
cytometry, cytogenetics and histopathology can • One to three slices submitted depending on
be made. Transfer medium (RPMI/DMEM) or size and whether the abnormality is focal or
Hank’s buffer solution may be provided to biopsy diffuse on gross examination.
takers for sample collection in preference to for-
malin. The disaggregated cells in the transfer Histopathology report:
medium can be utilized for flow cytometry and An integrated report contextualized with clini-
cytogenetics if dedicated sampling is not possible cal data and incorporating morphological, immu-
or number of cores is limited. nophenotypic and genetic features is to be issued.
• Count number of fragments, search the con- • Indication for investigation—primary diagno-
tainer well for all tissue sis, staging, relapse/progression, re-staging.
• Handle tissue gently, take care not to squeeze • Type of biopsy—excision, needle biopsy,
or transect the biopsy endoscopic biopsy, bone marrow biopsy,
• Record the length and diameter (mm) of all extra-nodal resection, or other biopsy.
cores of tissue • Site and size of—lymph node, skin, bone mar-
• Note the colour and any other distinctive row trephine, and other extra-nodal biopsies.
feature • Tumour type—lymphoma or others. If lym-
• Submit all tissue for histology, in separate phoma, specify type using immunohistochem-
blocks if lymphoma is suspected. Cores may istry and cytogenetics as necessary to
be painted with alcian blue prior to process- characterize entities using terminology of the
ing so that they are readily apparent when current WHO classification.
facing the block and vital tissue is not lost. • Bone marrow—involved or not involved.
45.2 Spleen or infiltration by infectious disease, benign and

malignant haematological disorders, metastatic
45.2.1 Anatomy carcinoma (rare), and storage diseases
(Table 45.5). Rarely the cause is unknown.
The spleen is an encapsulated reticuloendothelial
organ in the left upper quadrant of the abdominal
cavity. Anatomically, it has two compartments— 45.2.3 Clinical Investigations
the red pulp and the white pulp with an intervening
well developed marginal zone. The white pulp • Clinical methods—palpation and percussion
comprises T lymphocytes in the periarteriolar to detect splenomegaly.
lymphoid sheath and B lymphocytes that form pri- • CT scan, MRI, or USS to confirm palpable
mary and secondary follicles eccentrically around swelling of spleen and exclusion of other
this sheath. The follicles are similar to those in causes. These methods also show alteration in
lymph nodes and other lymphoid organs. The red splenic texture.
pulp consists of cords and a complex network of • FDG-PET CT assessment of metabolic activ-
venous sinuses that contain splenic macrophages. ity can show tumour nodules.
Specialized endothelial cells known as littoral • Cytopaenias: May result from hypersplenism
cells line the sinuses. The lining is discontinuous or hyposplenism.
in order to facilitate cell traffic between cords and • Hypersplenism: Splenomegaly, cytopaenia(s),
sinuses. The important physiological roles of the normal/hyperplastic marrow, responds to
spleen are thought to be removal of abnormal and splenectomy.
senescent RBCs, mounting an antibody response
to immunogens, removal of antibody-coated bac-
teria and other antibody-coated particles from the
Table 45.5 Causes of splenomegaly
blood. Haemopoiesis occurs in the fetal spleen,
stops within 2 weeks after birth and may begin Hyperfunction: removal of RBCs, e.g., spherocytosis,
sickle cell disease, haemoglobinopathies, paroxysmal
again when haemopiesis in the bone marrow is
nocturnal haematuria, nutritional anaemias
insufficient to meet the body’s needs. Increased Immune hyperplasia:
normal function of the spleen can cause spleno- Viral—infectious mononucleosis, hepatitis, CMV
megaly. The splenic weight in adults is 150–250 g Bacterial—infective endocarditis, septicaemia,
but depends on age and body weight/habitus. abscess, tuberculosis
Fungal—histoplasmosis
Parasitic—malaria, leishmaniasis
45.2.2 Clinical Presentation Disordered immune regulation: rheumatoid arthritis,
lupus erythematosus, immune haemolytic anemias,
immune thrombocytopenia, drug hypersensitivity,
Patients may be symptomatic either as a result of
sarcoidosis
splenic enlargement or the underlying disease
Extramedullary haemopoiesis: chronic myeloid
causing it. leukaemia, myelofibrosis, marrow failure due to any
cause
• Pain in the left upper quadrant of abdomen. Increased splenic blood flow: portal hypertension of
Rupture of the spleen may be painless and yet any cause—cirrhosis, splenic vein obstruction, portal
vein obstruction including due to schistosomiasis,
cause intraabdominal haemorrhage, shock,
congestive heart failure
and death. Severe pain due to infarction is Infiltration: amyloid, Gaucher’s, Niemann-Pick’s,
common in children with sickle cell disease. hyperlipidaemias
• Early satiety. Benign and malignant infiltrations: leukaemia,
lymphoma, myeloproliferative disorders, metastatic
Palpable spleen is a major physical sign and carcinoma, angiosarcoma, histiocytosis X
may be due to hyperfunction, passive congestion, Unknown
• Hyposplenism: Can be caused by surgical Littoral cell angioma: A multinodular tumour

removal, sickle cell disease, and splenic irra- that resembles splenic venous sinuses
diation for neoplastic/autoimmune disease. histologically.
• Full blood picture: Red blood cell counts and Other benign tumours and tumour-like condi-
indices, i.e., MCV, MCH, MCHC, reticulo- tions include: Hamartoma, epidermoid cysts,
cyte index. pseudocyst, parasitic cyst, inflammatory myco-
• WBC and platelet counts: May be normal, bacterial pseudotumour, lymphangioma and
increased or decreased depending on underly- lipoma.
ing disorders.
Malignant Tumours
Malignant lymphoma: The commonest malig-
45.2.4 Pathological Conditions nant tumour involving the spleen and represents
secondary spread in most cases. The gross pat-
45.2.4.1 Non-neoplastic Conditions tern of involvement often corresponds to the
Traumatic rupture of spleen and iatrogenic microscopic types: Homogeneous in indolent
removal: The most frequent reasons cited for small lymphocytic lymphoma, miliary in follicu-
splenectomy, e.g., road traffic accident, and, lar lymphoma, solitary nodules or multiple
splenic damage or creating access at abdominal masses in large cell lymphoma and Hodgkin
surgery. Spontaneous rupture does occur in dis- lymphoma.
eases such as infectious mononucleosis, infective Primary splenic marginal zone lymphoma:
endocarditis, malaria, lymphoma/leukaemia, and Primarily involves splenic white pulp. It involves
primary non-lymphoid splenic neoplasms. the splenic hilar lymph nodes and bone marrow
Congestive splenomegaly: Due to portal frequently. Lymphoma cells often circulate in
venous hypertension, commonly secondary to peripheral blood as villous lymphocytes. It is
liver cirrhosis but may also result from portal composed of small lymphocytes, which overrun
venous thrombosis, inflammation, sclerosis, or the germinal centres in the white pulp and merge
stenosis. with the transformed larger cells in the peripheral
Amyloidosis: Secondary involvement of the marginal zone. The patients have long-term sur-
spleen results in a characteristic gross appear- vival after splenectomy but respond poorly to
ance, i.e., the sago or lardaceous spleen. chemotherapy.
Hypersplenism: Refers to a condition in which Splenic diffuse red pulp small B-cell lym-
the blood cells are culled excessively within the phoma: with intra-sinusoidal and red pulp
spleen. It usually occurs when the haemopoietic involvement by a monotonous population of
cells are intrinsically abnormal—as in idiopathic small B-cells is an uncommon recently described
thrombocytopenic purpura (ITP), congenital entity.
(congenital spherocytosis), and acquired haemo- Leukaemia: Any leukaemia can involve the
lytic anemias (due to various leukaemias, spleen; however, marked splenomegaly is typical
Hodgkin lymphomas, sarcoidosis, lupus erythe- of chronic myeloid leukaemia, hairy cell leukae-
matosus, etc.). mia, and myelofibrosis. In the latter, extramedul-
lary haemopoiesis occurs in the spleen.
45.2.4.2 Neoplastic Conditions Systemic mastocytosis: Almost always
involves the spleen. The mast cell nodules are
Benign Tumours seen as fibrotic masses on gross examination.
Haemangioma: The commonest primary splenic Other haematolymphoid conditions involving
tumour. It may be an incidental finding and is often the spleen: Hodgkin lymphoma, particularly the
less than 2 cm in size. It is usually of cavernous type nodular sclerosis subtype, Langerhan’s histiocyto-
and associated with haemangiomas elsewhere. sis and follicular dendritic reticulum cell tumour,
Rupture and bleeding are common complications. which is always EBV associated at this site.
Non-haematological malignancies: • Incidental

Angiosarcoma is the commonest non-lymphoid • Traumatically ruptured
primary splenic malignancy. It may present with • Diseased spleen
spontaneous splenic rupture or mimic haemopoi-
etic disease. Malignant fibrous histiocytoma and The specimen is received fresh in the labora-
carcinosarcoma can also present as primary tory and fixed according to established
tumours at this site. protocols.
Metastatic carcinoma: Uncommon. Malignant
melanoma, lung (small cell) and breast cancers • Measurements:
are the commonest primaries to involve the • Length × width × depth (cm).
spleen and can be mistaken for haemopoietic dis- • Number/maximum dimensions (cm) of any
ease. Gastric and pancreatic cancers may also capsular deficits, infarcts, cysts, or tumour
show direct spread to the spleen. nodules.
• Weight (g) must be taken before slicing, as
blood loss from the cut surface reduces the
45.2.5 Surgical Pathology splenic weight considerably.
Specimens: Clinical Aspects • Photograph.
• Look for splenic lymph nodes and dissect
Splenectomy may be a diagnostic procedure. The them off the hilum.
common indications for splenectomy are: • Submit for flow cytometry and cytogenetics/
Traumatic rupture, removal of a primary lym- molecular studies.
phoma, symptom control in massive splenomeg-
aly, e.g., CML and correction of cytopaenia in Fixation: Make parallel thin slices 5 mm thick
hypersplenism. with a sharp knife. Examine each slice for focal
Contraindication: Marrow failure, where hae- lesions. Do not wash in tap water. Submit a
mopoiesis in the spleen is a source of circulating 1 × 1 cm (fresh specimen) section for culture if
blood cells. infectious disease is suspected taking care to do
Immediately after splenectomy there is an this in a biosafety cabinet. Make imprints for
increase in WBC and platelet counts, but this nor- immediate assessment. Fix each slice flat in a
malizes in 2 or 3 weeks. Occasional low WBC container of 10% buffered formalin. For sus-
counts persist. In the long term there are erythro- pected sickle cell disease, fix in formalin imme-
cyte abnormalities including anisocytosis, poi- diately after slicing.
kilocytosis, Howell-Jolly bodies, and Heinz Description:
bodies. A major consequence of splenectomy is
increased susceptibility to bacterial infections • Hilum: Nature of blood vessels, presence of
due to S. pneumoniae, H. Influenzae, and sepsis. lymph nodes, and accessory spleen.
This requires pneumococcal vaccination and life- • Capsule: Colour, thickness—icing in perisple-
long antibiotic prophylaxis. nitis. If defect/laceration is present, record—
location, length, depth. Record any other focal
changes.
45.2.6 Surgical Pathology • Examine the cut surface for:
Specimens: Laboratory –– Colour: Infarcts are pale or haemorrhagic
Protocols –– Consistency: Soft/diffluent in sepsis, firm
in portal hypertension, wax like in
45.2.6.1 Spleen Specimens amyloidosis
Usually of three types: intact whole spleen from –– White pulp: If prominent size of individual
splenectomy, fragments from laparoscopic sple- nodules (cm)
nectomy or needle core biopsies. These may be –– Fibrous bands: Present/absent
–– Nodules/masses: Record number, size, rows of children and neonates as haemopoiesis

colour, presence of haemorrhage or occurs throughout the marrow in all bones. In
necrosis adults, haemopoiesis is limited to certain areas
–– Any diffuse involvement. within bone marrow of skull, vertebrae, sternum,
ribs, pelvic bones, and proximal long bones. The
Blocks for histology: row of fat cells separating haemopoietic cells
from bone trabeculae is called the first fat space.
• A general recommendation is to sample any This is lost in leukaemic proliferations. The
nodule larger than the adjacent white pulp. lamellar bone trabeculae contain osteoblasts and
• No abnormality in an incidental splenectomy: multinuclear osteoclasts on the endosteal surface
four blocks including samples of the superior, and osteocytes within lacunae. In elderly patients
inferior borders, the hilum, and the lateral con- with osteoporosis, the trabeculae are thinned.
vex border. Thin-walled venous sinuses are seen throughout
• Focal gross abnormality: Two or three blocks the marrow and mature haemopoietic cells have a
of the abnormal area depending on size and perisinusoidal location. Small muscular arteries
two blocks from uninvolved parenchyma. and capillaries are also present.
• Diffuse abnormality: Four blocks preferably Haemopoietic elements include the myeloid,
close to the capsule as this is likely to be best erythroid, megakaryocytic, and lymphoid cells;
fixed. all of these have a common precursor stem cell.
• Sample all splenic hilar lymph nodes. The committed stem cells give rise to the distinct
cell lines. The various stages of maturation are
Histopathology report: shown in Fig. 45.4. The morphology of haemo-
Specify: Type of splenectomy, i.e., laparo- poietic cells in general is better appreciated in
scopic, partial, total. Mention reason for splenec- Giemsa stained thin/semi-thin sections. The dif-
tomy, i.e., incidental, traumatic, or therapeutic ferent types of cells and some of their features are
removal of diseased spleen. For incidental and presented in Table 45.6.
traumatic splenectomies mention the presence or Artifacts including non-haemopoietic cells
absence of tears/lacerations and any other pathol- such as epidermis, skin appendages, muscle, and
ogy related to the cause of surgery. For therapeu- bone tissue may be introduced into the trephine
tic splenectomies, confirm the primary diagnosis biopsy inadvertently during the biopsy proce-
and exclude additional pathology. Classify lym- dure. These may be confused with metastatic
phoma/leukaemia in the spleen according to the malignancy.
current WHO classification and integrate cytoge-
netic/molecular features.
45.3.2 Clinical Presentation
45.3 Bone Marrow Anaemia: Most often detected in routine blood

examination. Acute anaemia due to blood loss or
45.3.1 Anatomy haemolysis presents with signs of haemodynamic
instability. Severe back pain, renal failure, and
The bone marrow is a specialized tissue of haema- haemoglobinuria occur in acute haemolysis.
topoietic elements, supporting bony and stromal Chronic anaemia, irrespective of cause, is associ-
tissue with definite spatial organization. The sup- ated with tiredness, shortness of breath, and
porting stromal tissue consists of a fine reticulin tachycardia. Often the symptoms are due to the
meshwork, fat and blood vessels. The amount of underlying cause of anaemia such as rheumatoid
fat varies with age and quantity of haemopoiesis. arthritis causing joint pains.
From 50 to 80% fat is seen in marrows of adults Polycythaemia: Defined as an increase in cir-
and elderly patients. Little or no fat is seen in mar- culating red blood cells. The patients may be
Pluripotent
stem cell
Lymphoid Myeloid
stem cell stem cell
CFUGM BFUE
Pro B cell Cortical
thmocyte
Pro B cell Medullary CFUG CFUM CFUMeg CFU E

thymocyte
Intermediate Myeloblast Monoblast Megakaryoblast Erythroblast

B cell
Promyelocyte Promonocyte Normoblast
Myelocyte Megakaryocyte Reticulocyte
Metamyelocyte
Mature Mature Neutrophil Monocyte Platelet Erthrocyte

B cell T cell
Fig. 45.4 Development and maturation of haemopoietic cells (Reproduced, with permission, from Allen and Cameron
(2013))
asymptomatic, have thrombotic symptoms or following tooth extraction, childbirth, or minor

neurological symptoms such as vertigo, tinnitus, surgery. Bleeding into body cavities, particularly
headache, and visual disturbances. joints, causes deformity and limited mobility.
Bleeding disorders: Usually there is a history Thrombotic disorders: Ischaemia of critical
of prolonged blood loss during menstruation or organs, such as gastrointestinal tract, brain, and
Table 45.6 Haemopoietic cells

Clues to
Usual location pathological
Precursors within marrow Numbers Cytology proliferation
Granulocytes Myeloblasts Immature— 2–4 times the Immature cells— Excess of
including paratrabecular number of high N/C ratio and blasts, present
neutrophils and Mature—central erythroid cells granular cytoplasm in both
eosinophils Mature—lobated paratrabecular
nuclei and and central
specialized granules areas
in cytoplasm
Erythroid Erythroblasts Colonies in 1/3–1/4 of the Immature cells— Paratrabecular
central myeloid cells dark blue proliferation
intertrabecular cytoplasm, round
areas nuclei, coarse
chromatin, and
nucleoli attached to
nuclear membrane.
Mature—dark,
densely staining
perfectly round
nuclei
Megakaryocytes Megakaryoblast Perisinusoidal Variable, Largest cells. Occur Clustering,
usually at least singly. Multilobated paratrabecular
1/field nuclei with location and
abundant cytoplasm nuclear
hypolobation
Lymphoid Lymphoblast Interstitial Up to 50% in Mixed population >3 aggregates/
infiltrates or <3 children, of small mature and diffuse heavy
nodular 5–10% in adult larger lymphoid interstitial
aggregates marrows cells ± germinal proliferation
centres particularly if
monoclonal
Plasma cells Lymphoblast Perivascular Up to 2% in Mature plasma Large clusters
adult marrows cells—eccentric and
nuclei with clock nucleolated
face chromatin, no plasma cells;
nucleoli monoclonality
Immature plasma
cells—nucleolated
Mast cells Myeloblast Perivascular or Few Basophilic coarse Increased
paratrabecular granules in numbers,
cytoplasm, round/ spindle cells,
oval nucleus fibrosis;
aberrant
phenotype
myocardium caused by unregulated clotting 45.3.3 Clinical Investigations

within blood vessels.
Fever, malaise, weight loss, night sweats, • Evaluation of anaemia: Directed toward its
bleeding, fatigue, and increased susceptibility to classification as a hypoproliferative disorder
infections are common features of white blood (e.g., aplasia), maturation disorder (e.g.,
cell disorders. megaloblastic anaemia), blood loss, or due
to haemolysis such as • Other investigations are directed by clinical

haemoglobinopathies. suspicion.
• Full blood picture, red blood cell indices,
reticulocyte count, and red cell morphology
aid classification. Reticulocyte index <2.5 45.3.4 Pathological Conditions
suggests a maturation disorder or a hypopro-
liferative disorder. High reticulocyte index is Many haematological diseases can be diagnosed
usual in haemolytic anemias. on microscopy of the bone marrow aspirate and
• Iron levels and iron storage indices: Low in the currently available ancillary investigations
iron deficiency anaemia. including flow cytometry and molecular biologi-
• Serum erythropoietin levels and red cell mass: cal techniques. The following paragraphs empha-
Increased in polycythaemia. size those conditions in which the trephine biopsy
• Bleeding time: A sensitive measure of platelet has a definite diagnostic role. An integrated
function. multi-technique approach to assessment of
• Platelet count: Normal ranges 150,000– peripheral blood, marrow aspirate and trephine is
450,000/μL. Decreased platelet count mandatory for accuracy. Proactive collection of
increases risk of bleeding from severe trauma clinical information and close liaison with flow
or spontaneously—petechiae in skin or intra- cytometry, molecular and cytogenetic laborato-
cranial haemorrhage. ries ensures quality.
• Prothrombin time, partial thromboplastin
time, thrombin time, clot lysis, clot solubility: 45.3.4.1 Non-neoplastic Conditions
Tests for detecting coagulation defects. Reactive hyperplasia: Occurs commonly in a
• White blood cell count and differential leuko- wide range of infections, autoimmune disorders
cyte counts: Valuable in diagnosing acute and including immune thrombocytopenias, haemo-
chronic leukaemias, infections, and inflamma- lytic anemia, and megaloblastic anaemia, and as
tory disorders such as lupus erythematosus. a non-specific response to systemic malignancy.
• Serology: autoantibodies in haemolytic anae- A variation is the occurrence of reactive/benign
mia, antiviral antibodies (EBV, Hepatitis, lymphoid aggregates. These are non-
CMV, parvovirus B) paratrabecular and polyclonal.
• Marrow aspirate: For definitive diagnosis of Granulomatous inflammation: The causes and
haematological disorders and haematological histological features are similar to granulomas
malignancies. that occur elsewhere in the body, e.g., tuberculo-
• Role of the trephine biopsy: Complementary sis, sarcoidosis, reaction to malignancy.
to the aspirate. Main uses are—evaluation HIV and AIDS: The marrow can show specific
of cellularity, particularly if there has been a features such as neoplasm, opportunistic infec-
dry tap due to a packed or empty marrow, tions, absent iron stores, and Parvovirus-induced
spatial relationships between constituent red cell aplasia.
cell types, enumeration and distribution of Aplastic anaemia: Diagnosed when marrow
cells, staging of lymphomas, assessing lym- cellularity is <25% of normality for the age. It
phoid aggregates, staging other malignant may be congenital or acquired from exposure to
disease, assessing fibrosis and post-chemo- toxins, viral infections, or drugs. There is marked
therapy changes (residual disease/remis- reduction in erythroid, myeloid and megakaryo-
sion/relapse). The sensitivity of FDG-PET cytic series, and increase in fat, perivascular
CT in detecting marrow involvement is high plasma cells and lymphocytes.
in Hodgkin lymphoma and aggressive NHL; The trephine biopsy is useful in diagnosis of
hence bone marrow biopsies are less often megaloblastic anaemia, but the features can be
performed in these diseases than mistaken for acute leukaemia hence correlation
previously. with aspirate findings is mandatory.
45.3.4.2 Neoplastic Conditions dysplasia particularly striking in megakaryocytes

Acute leukaemias: The WHO 2008 classifica- and increased reticulin fibrosis.
tion largely replaced the earlier FAB and EGIL Myeloproliferative neoplasms (MPN): Include
systems. The 2016 updated classification incor- chronic myeloid leukaemia BCR-ABL positive,
porates new knowledge from NGS and other chronic neutrophilic leukaemia, polycythaemia
genomic techniques with better recognition of vera, primary myelofibrosis, essential thrombo-
morphological features. Most acute leukaemias cythaemia, chronic eosinophilic leukaemia, and
can be diagnosed as distinct entities on periph- myeloproliferative neoplasm, unclassifiable.
eral blood and bone marrow aspirate examina- These are characterized by hypercellular and
tion with immunophenotyping and molecular variably fibrotic bone marrows with effective
studies. The trephine is useful when marrow maturation, increased leukocyte, RBC or platelet
aspiration fails due to a dry tap. count, and a disease course that terminates in
Immunohistochemistry and several molecular marrow failure due to fibrosis, ineffective haemo-
investigations are feasible in trephine biopsies poiesis or transformation to acute leukaemia.
and maximize clinically relevant information. Testing for JAK2/MPL/CAL-R mutation is part
The trephine biopsy is helpful in assessment of of the diagnostic algorithm. The WHO also rec-
overall marrow cellularity, topography, and mat- ognizes a category of myeloid neoplasms that
uration of the haemopoietic cells. The presence have features of both MDS and MPN, i.e., the
of blast cells without maturation is diagnostic of myelodysplastic/myeloproliferative neoplasms
leukaemia even in hypocellular marrows where (MDS/MPN). This includes chronic myelomono-
the differential diagnosis includes aplastic anae- cytic leukaemia (CMML), atypical chronic
mia and myelofibrosis. Post-chemotherapy, if myeloid leukaemia, BCR-ABL1 negative, juve-
the disease is sensitive, the tumour cells die, and nile myelomonocytic leukaemia, MPN/MDS
the marrow becomes hypocellular. Regeneration with ring sideroblasts and thrombocytosis, MDS/
of stromal/fat cells occurs followed by restora- MPN unclassifiable.
tion of haemopoiesis. Growth factors and che- Mastocytosis: including cutaneous and sys-
motherapeutic regimens used can cause temic variants as well as those that present with
alarming changes in the quantity and quality of other haematological neoplasms (myeloid or
haemopoiesis. After bone marrow transplanta- lymphoid) are a separate category in the 2016
tion, the changes are similar; disease relapse, WHO updated classification.
graft versus host disease and infections are Myeloid/lymphoid neoplasms associated with
important considerations. eosinophilia and rearrangement of PDGFRA,
Myelodysplastic syndromes (MDS): A group PDGFRB, FGFR and PCM1-JAK2: have several
of clonal haemopoietic stem cell disorders char- overlapping features with other MPN and molec-
acterized by cytopenias, dysplastic features in ular testing is essential for diagnosis.
one or more marrow cell lineages, ineffective The WHO 2008 classification and the 2016
haemopoiesis, and an increased risk of develop- update include disease definitions, description
ing acute myeloid leukaemia. The WHO classifi- and diagnostic inclusion and exclusion criteria
cation recognizes seven types: refractory based on clinical, morphological, phenotypic and
cytopenia with single lineage dysplasia, refrac- genetic features for each of the above categories.
tory anaemia with ring sideroblasts (RARS), In addition to karyotyping, mutation testing
refractory cytopenia with multilineage dysplasia, has a major role in disease definition, diagnosis
refractory anaemia with excess blasts (types 1 and prognosis in myeloid neoplasms. Targeted
and 2) (RAEB-1, RAEB-2), MDS-unclassified NGS including SRSF2, ASXL1, TET2, PTPN1,
(MDS-U), and MDS associated with isolated CSF3R, JAK-STAT and RAS pathway genes are
del(5q). The diagnostically helpful features in the increasingly used to personalize treatment.
trephine biopsy are: ALIPs (abnormally located Lymphoproliferative malignancies: Include
immature precursors), hypercellularity, trilineage acute and chronic lymphoid leukaemias, special
types such as hairy cell leukaemia and lympho- Metastases: Most common from breast, thy-
mas secondarily involving the bone marrow. roid, prostate, lung, stomach, colon, and renal
Lymphomatous involvement of the marrow is cancers in adults. In children, the most common
common in indolent lymphomas, i.e., follicular metastatic tumours in the marrow are neuroblas-
lymphoma, mantle cell lymphoma, well- toma, Ewing’s sarcoma, rhabdomyosarcoma,
differentiated small lymphocytic lymphoma retinoblastoma, and clear cell sarcoma of the
(chronic lymphocytic leukaemia when absolute kidney.
lymphocyte count in the peripheral blood exceeds Miscellaneous: Some bony abnormalities
5000/μl), lymphoplasmacytic lymphoma and such as osteoporosis and Paget’s disease can be
some aggressive lymphomas such as peripheral T diagnosed in a trephine biopsy.
cell lymphoma and Burkitt lymphoma. The pat-
tern of involvement may be obvious or subtle,
diffuse, focal, non-trabecular, focal paratrabecu- 45.3.5 Surgical Pathology
lar, or interstitial. Sometimes appropriate immu- Specimens: Clinical Aspects
nostains are required to demonstrate involvement,
e.g., CD30 in anaplastic large cell lymphoma and 45.3.5.1 Trephine Biopsy
cyclin D1 in mantle cell lymphoma. The cytology There are several reusable and disposable com-
and architecture may be similar to the lymph mercially available instruments for bone marrow
node involved or discordant as in follicular lym- trephine biopsy procedure in adult and paediatric
phoma. Classic Hodgkin lymphoma involves patients. The choice is based on safety, conve-
marrow in approximately 5% of cases; this may nience, and quality of the specimen obtained.
be a presenting feature in the lymphocyte- Smaller gauge needles are used in children
depleted subtype and diagnosis is achieved using and patients with severe osteoporosis.
criteria as in the lymph node. The procedure is usually done in an operating
Hairy cell leukaemia is a chronic B cell lym- theatre under sterile conditions. The patients are
phoproliferative disorder involving the blood, given suitable local anaesthesia/analgesia and
bone marrow, and the spleen simultaneously. It positioned properly for the procedure. The poste-
presents with pancytopaenia and splenomegaly. rior superior iliac spines are the most favorable
The hairy cytoplasmic projections are seen in sites for aspiration. Anterior iliac crest or sternum
peripheral blood, but the cells have characteristic are rarely aspirated.
haloes and cause increased reticulin fibrosis in The technique: The aim is to obtain a biopsy
the trephine biopsy. The BRAF V600E mutation specimen 1.6–2 cm in length avoiding crushing
is present in >90% cases and can be predicted by and excess haemorrhage.
BRAF immunohistochemistry, though there are
problems with specificity.
Myeloma: may be symptomatic or asymptom- 45.3.6 Surgical Pathology
atic and usually comes to attention when patients Specimens: Laboratory
present with paraproteinemia and/or infections, Protocols
renal impairment or pathological fractures. In the
trephine biopsy, it is seen as a clonal proliferation All material should be submitted for histology. If
of plasma cells that may be subtle and interstitial the biopsies are obtained from multiple sites,
or form nodules and sheets. Quantification is these are submitted separately.
facilitated by CD138 and kappa/lambda stains in Make imprints prior to fixation.
the trephine biopsy. The diagnosis is based on a Description:
combination of serum paraprotein level, bone
marrow plasma cell percentage, and end organ • Number and length (mm) of each fragment.
damage. It is usually incurable with a median • Colour, consistency, and whether
survival of 3 years and 10% survival at 10 years. homogeneous.
Procedure: lomata, reticulin, iron stores, sinusoids and immu-

nophenotype results where relevant. The report
• Fixation: Routinely fixed immediately in 10% should take into account the results of other hema-
neutral buffered formalin; 5% formalin or tological investigations, incorporate data from
aceto-zinc formalin (AZF) are also suitable. flow cytometry, cytogenetics, and PCR to present
Fixation time: 20–24 h. Further fixation results a unifying conclusion and/suggest further investi-
in loss of antigenicity and lesser fixation gation for appropriate management of the patient.
yields poor morphology.
• Processing: paraffin embedding assures good
quality morphology, immunohistochemistry Bibliography
and DNA for molecular testing but
decalcification is required. Plastic resin
Adamson JW, Longo DL. Anaemia and polycythemia.
embedding provides excellent morphology Alizadeh AA, Eisen MB, Davis RE. Distinct types of
large B-cell lymphoma identified by gene expression
and does not require decalcification; the DNA profiling. Nature. 2000;403:503–11.
quality is often inadequate for testing. Allen DC. Histopathology reporting. Guidelines for surgi-
• Decalcification: Should be carefully con- cal cancer. 3rd ed. London: Springer; 2013.
trolled and limited to softening the bone Allen DC, Cameron RI. Histopathology specimens:
enough to permit even sectioning. Berlin-Heidelberg: Springer; 2013.
Decalcification in 5–10% formic acid or Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz
Gooding and Stewart’s decalcification fluid is MJ, Le Beau MM, Bloomfield CD, Cazzola M,
more rapid compared to calcium chelation Vardiman JW. The 2016 revision to the World Health
Organization classification of myeloid neoplasms and
(EDTA), which requires 24–48 h for adequate acute leukemia. Blood. 2016;127:2391–405.
bone softening. Brown D, Gatter K, Natkunam Y. Bone marrow diagnosis:
• Sectioning: 2–4 μ m sections are ideal for an illustrated guide. Oxford: Wiley Blackwell; 2006.
good morphological detail. Three (10 μ m) to Brunning RD, Arber DA. Chapter 23: Bone marrow. In:
Rosai J, editor. Rosai and Ackerman’s surgical pathol-
five (5 μ m) sections are sufficient for molecu- ogy. 10th ed. St. Louis: Elsevier; 2011.
lar testing by PCR. Chan JKC. Tumours of the lymphoreticular system,
• Staining: Both reticulin and H&E are essential including spleen and thymus. In: Fletcher CDM, edi-
for routine interpretation. Additional stains— tor. Diagnostic histopathology of tumours, vol. 2. 3rd
ed. London: Harcourt; 2007. p. 1139–310.
Giemsa, Congo Red for amyloid, Giemsa/ Fauci AS, Kasper DL, Hauser SL, Longo DL, Jameson JL,
Toluidine blue for mast cells, Masson editors. Harrison’s principles of internal medicine, vol.
Trichrome for collagen, Perl’s stain for iron, 1. 18th ed. New York: McGraw-Hill; 2011. p. 450–71.
Leder’s stain for granulopoiesis, and Ziehl- Hall JG. The functional anatomy of lymph nodes. In:
Stansfield AG, d’ Ardenne AJ, editors. Lymph node
Nielsen stain for acid fast bacilli are com- biopsy interpretation. 2nd ed. Edinburgh: Churchill
monly used. Livingstone; 1992. p. 3–28.
Henry PH, Longo DL. Enlargement of the lymph nodes
Histopathology report: and spleen.
Holland SM, Gallin JI. Disorders of granulocytes and
Should contain all clinical details including monocytes.
peripheral blood and aspirate findings, comment Konkle BA. Bleeding and thrombosis.
on technical preparation, and whether the sample O’Malley DP, George TI, Orazi A, editors. Benign
is representative. A proforma helps in maintaining and reactive conditions of lymph node and spleen.
Washington, DC: ARP Press; 2009.
uniformity and serves as a checklist for all items Rosai J. Chapter 22: Lymph nodes, spleen. In: Rosai J,
that need to be mentioned in the report. These editor. Rosai and Ackerman’s surgical pathology. 10th
include: Length of the trephine, number of inter- ed. St. Louis: Elsevier; 2011.
trabecular spaces, cellularity, number and distri- Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA,
Stein H, Thiele J, Vardiman JW. WHO classifica-
bution of erythroid, myeloid, and megakaryocytic tion of tumours. Pathology and genetics. Tumours of
series, lymphocytes, plasma cells, other cells haemopoietic and lymphoid tissues. Lyon: IARC
including extra medullary cells if present, granu- Press; 2008.
Swerdlow SH, Campo E, Pileri SA, Harris NL, Stein org/p rofession/publications/cancer-datasets.html
H, Siebert H, Advani R, Ghielmini M, Salles GA, Accessed Mar 2017.
Zelenetz AD, Jaffe ES. The 2016 revision of the World The Royal College of Pathologists. Standards for special-
Health Organization classification of lymphoid neo- ist laboratory integration and dataset for the histopath-
plasms. Blood. 2016;127:2375–90. ological reporting of lymphomas. 2015. https://www.
The Royal College of Pathologists. Tissue pathways rcpath.org/profession/publications/cancer-datasets.
for lymph node, spleen and bone marrow trephine html. Accessed Oct 2016.
biopsy specimens. 3rd ed. 2017. https://www.rcpath.
Part XII
Miscellaneous Specimens and Ancillary
Techniques
Miscellaneous Specimens
and Ancillary Techniques 46
Damian T. McManus
46.1 Needle Core Biopsies biopsy are well established techniques both in the
investigation of tumours and medical conditions.
Minimally invasive techniques for diagnosis and Core biopsy may establish a specific histolog-
treatment are increasingly important in many ical diagnosis of malignancy prior to radical sur-
fields of medicine, and this has implications for gical excision/resection or enable radical or
the types of specimens received by pathologists. palliative radiotherapy and or chemotherapy to
Biopsy needles range in calibre from 22-gauge be administered by oncologists. It may also con-
(skinny core needle) through 18-gauge to the firm metastatic disease, although fine needle
standard 14-gauge Tru-Cut needle. The introduc- aspiration cytology can often represent a less
tion of automated spring-loaded 18-gauge core invasive alternative. The increasing use of sophis-
biopsy guns has been accompanied by a dramatic ticated radiological imaging modalities such as
increase in the use of core needle biopsy of the PET scanning may be associated with increased
breast, prostate, and bone or soft tissue masses. use of needle core biopsy to confirm or refute
Such biopsies are increasingly performed by a metastatic disease. Core biopsy may also be used
radiologist or specialist clinician using ultra- to stage lymphoma or to detect recurrent disease.
sound guidance. Stereotactic core biopsy is fre- Although excision biopsy of an easily accessible
quently used by radiologists in the investigation superficial lymph node is still recommended to
of breast lesions such as microcalcification make a primary diagnosis of lymphoma and for
detected by screening mammography. subtyping, it is increasingly acknowledged that
CT-guided percutaneous biopsy is an invalu- core biopsy may be more appropriate for deeply
able tool in the assessment of deep-seated inac- situated lesions or in the elderly and infirm.
cessible tumours. It may be used to evaluate Transrectal ultrasound directed biopsy is com-
peripherally located lung lesions, anterior medi- monly used in the evaluation of the prostate in
astinal masses, or retroperitoneal/mediastinal patients with a raised serum PSA. Smaller calibre
lymph node masses. Percutaneous liver or kidney 18-G biopsy needles can reduce the complica-
tions associated with this procedure including
infection and clot retention without compromis-
ing sensitivity and specificity. However, it can be
difficult to embed multiple fine tissue cores in a
single wax block, and a variety of techniques
D.T. McManus have been proposed to check that they are fully
Histopathology Laboratory, Belfast City Hospital, faced on sectioning including marking the biop-
e-mail: damian.mcmanus@belfasttrust.hscni.net sies with ink so that they are more easily seen.

520 D.T. McManus
The trend towards small-gauge needle core fixatives. This should be done immediately to
biopsies has been accompanied by the increasing avoid drying artifact. Papanicolaou and H&E
use of immunohistochemistry and other ancillary stains are routinely used.
investigations in the diagnosis and classification FNAC is particularly useful in the assessment
of cancer. The conservation of tissue for these of superficial palpable breast lumps and lesions
techniques must be balanced by the need to around the head and neck such as thyroid nod-
examine an adequate number of levels to detect ules, salivary gland lesions, or enlarged lymph
focal areas of involvement by cancer. These two nodes. FNA may also be performed under radio-
somewhat conflicting requirements may be logical guidance and is generally less traumatic
resolved by carefully leveling into the tissue and than core biopsy. However, the technique has its
storing intervening sections as ribbons. These limitations. Diagnostic accuracy depends on ade-
can be used subsequently for immunohistochem- quate sampling of the lesion under investigation,
istry if needed, and it is also possible to select the good preparation, and staining of the slides and
most representative level for the appropriate careful interpretation by an experienced cytopa-
stains. Such an approach is particularly relevant thologist with due consideration given to the
to prostate needle core biopsies and endoscopic clinical and radiological findings. It is not possi-
biopsies from the upper gastrointestinal tract. ble to provide a detailed review here, but in gen-
Individual core biopsies may also be embedded eral, best results are obtained when a large
in separate casettes allowing extended panels of volume of aspirates is examined by a limited
immunohistochemistry; this is particularly number of pathologists. If pathologists are not
appropriate for suspected lymphoma or cancer of actively involved in aspiration, then ideally rapid
unknown primary site. review will provide immediate feedback to the
Concerns have been raised about tumour diag- aspirator on the quantity of aspirated material
nosis using small biopsies. Clearly, tumour het- and on the preparation.
erogeneity is not uncommon, and small biopsies It can be difficult to obtain sufficient material
may not be representative of a large lesion. for extended panels of immunohistochemical
Correlation with radiological and other clinical markers. It is generally not possible to reliably
findings is important. distinguish between in situ and invasive malig-
Conversely, needle core biopsies are now fre- nancies in the breast, and often, material from
quently used for ER, PR, and HER2 testing in areas of microcalcification detected at screening
breast cancer so that these results are available at is scanty. Precise categorization of borderline
multidisciplinary team meetings prior to resec- lesions discovered in breast screening programs
tion. The small size and uniformity of fixation can also be problematic. FNA and core biopsy
can be advantageous for immunohistochemistry. may be performed simultaneously for impalpable
It can be difficult to assess cell size and to accu- screen-detected breast lesions and provide com-
rately subtype malignant lymphomas in needle plementary information.
core biopsies; they are also particularly suscepti- The use of FNAC in the diagnosis of breast
ble to compression artifact. disease has almost stopped in many centres in the
UK with needle core biopsy replacing FNA as
the primary tissue diagnostic modality.
46.2 Fine Needle Aspirates
Fine needle aspiration cytology (FNAC) may 46.3 Cytospins, Liquid-Based

also be used as an alternative to core biopsy. Air- Cytology, and Cell Blocks
dried slides may be stained immediately with a
modified May-Grünwald–Giemsa stain and The interpretation of diagnostic cytology
examined in a small side room in an outpatient specimens (FNA, cell effusions, and respira-
setting. Slides may also be fixed in alcohol-based tory specimens) may be greatly facilitated by
46 Miscellaneous Specimens and Ancillary Techniques 521
the use of immunocytochemical staining tech- tial pictures can be used to record key features of
niques, described in more detail below. the specimen.
A variety of techniques have been used to pre- The principles of specimen photography are
pare such specimens. A cytospin can be used to described in many standard textbooks of surgical
make slides from cell suspensions obtained from pathology and some reviews. It is important that
effusions, needle washings, FNAs, or other speci- there is a clean, textureless background that is
mens. The cells may be partially obscured by suitably illuminated. Reflective glare and wet
blood or proteinaceous debris, and the prepara- highlights should be avoided by switching off the
tion can be improved by lysis of red cells and/or room lights, correct positioning of the illumina-
the addition of agents such as polyethylene gly- tion system, and blotting of the cut surface of the
col to the cell suspension. Alternative methods of specimen. The specimen should be properly cen-
processing are also available such as liquid-based tred and orientated. In general, the cut surface
cytology exemplified by the proprietary ThinPrep usually provides more information than the exter-
system in which vortexing of the cell suspension nal aspect of a specimen. It is important to trim
is followed by transfer to a slide by a membrane away fat and other extraneous tissue and to slice
using gentle vacuum suction. This is claimed to the tissue cleanly. It may be advantageous to
reduce obscuring debris and to produce a repre- open ducts, etc., to highlight these structures, but
sentative cell sample on the slide. Cell blocks the inclusion of probes and forceps or other
may be prepared from effusions or FNAs if a clot objects can be distracting.
forms. This is transferred to formalin for fixation The use of a stand is recommended. A 35-mm
and processed through paraffin wax as a small camera may be used. A smaller lens aperture
biopsy, providing complementary morphological (higher f-stop) will maximize the depth of field
information to that of the direct smear prepara- for specimens of a substantial height, and many
tions and also suitable for conventional photographers will use a number of slightly dif-
immunohistochemistry. ferent exposures. Polaroid cameras offer a con-
venient method to produce specimen pictures
rapidly that can then be marked as to the origin
46.4 Specimen Photography of blocks for histology. However, such pictures
are often of poor quality, and it is not easy to
An accurate macroscopic description of a gross produce 35-mm slides from the prints. Digital
specimen is often vital in making the correct photography is now commonly used to produce
diagnosis (e.g., the pattern of involvement in high-quality images relatively cheaply and hard
inflammatory bowel disease) and in accurately copy rapidly. Digital images may be archived
staging a malignant tumour. With the decline of easily on CD-ROM, and software systems exist
the autopsy and the controversy surrounding that allow the incorporation of digital images
organ retention, macroscopic specimen photo- into biopsy files. While nonspecialized equip-
graphs also play an important role in undergradu- ment can give good results and the use of a sim-
ate teaching and may be correlated with ple scanner has been advocated, there are
radiological images in today’s integrated courses. integrated commercial systems available
Macroscopic specimen photography has also designed to facilitate digital photography at the
been used to audit the plane of mesorectal exci- cut-up bench with archiving of images on labo-
sion in rectal cancers, and it is an important com- ratory computer systems. While conflicting
munication medium in multidisciplinary team advice has been published on the use of photo-
meetings. Another factor that may contribute to micrographs without patient consent, GMC
its increasing use includes participation of bio- guidance on “Making and using visual and audio
medical scientists in specimen dissection and in recordings” explicitly states that specific consent
the selection of tissue for histology; specimen does not need to be separately obtained for the
dissection is inherently destructive, and sequen- use of “images of internal organs and structures”
522 D.T. McManus
or “images of pathology slides” for ethically • Clearance of resection margins, for example,
legitimate purposes as long as patient confidenti- gastrectomy, pulmonary lobectomy, or resec-
ality is not compromised. tions for squamous cell carcinoma of the
upper aerodigestive tract
• Diagnosis of suspicious abdominopelvic
46.5 Specimen Radiography masses at laparotomy, for example, ovarian
tumours.
Specimen radiography may be used in a variety
of different specimens for a range of purposes: Specimens for frozen section are best exam-
ined using a safety cabinet. As the tissue is not
• Breast: to identify and confirm excision of fixed, full precautions must be taken against
small impalpable lesions detected by screen- blood-borne Category Three infections. Thin
ing mammography or to localize areas of fragments of tissue (no more than 2–3 mm thick
microcalcification in excision and core and no wider than the diameter of the chuck)
biopsies should be removed by a scalpel and placed on the
• Bone and joint: to delineate the extent of a surface of a metal chuck in a blob of embedding
tumour involving bone medium such as OCT compound (Tissue Tek) so
• Bioprosthetic heart valves: to document the that the tissue is covered. The chuck is rapidly
degree of calcification cooled by standing it in a small volume of liquid
nitrogen or using a proprietary aerosol spray such
as CryoSpray Freezer Spray (CellPath Plc). The
46.6 Frozen Section sections are then cut using a microtome and cryo-
stat and stained routinely by hematoxylin and
The number of frozen sections appears to be eosin.
declining in the United Kingdom due in part to Touch imprints can be made by gently smear-
improved preoperative diagnosis of breast lumps ing the fresh tissue against a glass slide. This is
and many other tumours by FNA, needle core, or allowed to air-dry and then stained by Giemsa or
endoscopic biopsy. This is in contrast to the situa- proprietary stains such as Diff-Quick. This can be
tion in North America where frozen sections and very useful in the evaluation of lymph nodes and
intraoperative consultations are very common. many tumours providing complementary cyto-
The use of frozen section should be restricted logical detail that cannot be appreciated on fro-
to those cases where the result will change the zen section. Immunocytochemistry and FISH
intraoperative management of the patient. may be performed on touch imprints of tumours
Frozen sections are used in a wide variety of made onto suitable adhesive-coated slides (e.g.,
clinical situations: APES).
Relative contraindications to frozen section
• Confirmation of excised tissue, for example, include certain infections such as suspected
parathyroidectomy versus lymph node or a tuberculosis or where the frozen section is
thyroid nodule unlikely to yield a clinically useful result and
• Evaluation of a suspicious lymph node and may compromise the final diagnosis (e.g., an
liver or lung nodule or suspected peritoneal impalpable breast lesion containing microcalcifi-
metastases as part of an operative staging pro- cation picked up at screening). Some diagnoses
cedure or prequel to consideration of radical cannot be readily made on frozen section;
surgery classical examples being the distinctions between
• Determination of a lung, pancreatic, or ampul- follicular carcinoma and adenoma of the thyroid
lary mass prior to proceeding to lobectomy or and lymph node hyperplasia and follicular
a Whipple’s procedure lymphoma.
46.7 Ancillary Techniques The use of immunohistochemistry continues

to increase rapidly. It plays a crucial role in
46.7.1 Immunohistochemistry tumour diagnosis in particular, and, especially in
and Immunofluorescence the differential diagnosis of tumour types with
similar morphological appearances, for example,
The development of antigen retrieval techniques in the diagnosis of small round blue cell tumours
and the increasing range of monoclonal and poly- and soft tissue lesions and in the differentiation
clonal antibodies have been accompanied by of malignant mesothelioma and metastatic ade-
widespread application of immunohistochemis- nocarcinoma. The accurate classification of lym-
try to routinely fixed, paraffin wax-embedded phoma subtypes is crucially dependent on the use
material. Adequate, controlled fixation is still of appropriate antibody panels and interpretation
crucial in obtaining the best results from immu- of the results; indeed, the latest classifications of
nohistochemistry, but there is little indication for lymphoma fully incorporate both immunopheno-
the use of fixatives other than formalin outside a typing and genotyping results. Panels of immu-
research setting. nohistochemical stains may also be used to help
Heat-mediated antigen retrieval techniques diagnose anaplastic malignant tumours or to
(HMAR) are particularly important for the detec- determine the likely origin of metastatic carci-
tion of nuclear antigens such as ER (oestrogen noma where the primary remains occult
receptor) and Ki67, low density surface antigens, (Table 46.1).
for example, CD5, and other surface antigens The increasing use of diagnostic immunohis-
such as CD20. Both microwaving and pressure tochemistry can cause problems. Anomalous or
cooking have been used for HMAR, with citrate unexpected patterns of staining may be poten-
or EDTA buffer. HMAR avoids the risk of over- tially confusing or indeed misleading and result
digestion and loss of morphology that may in an erroneous diagnosis, unless the pathologist
accompany pretreatments with proteolytic is aware of such a possibility. It is generally bet-
enzymes but can lead to loss of adherence of the ter to use panels of markers rather than to rely on
section to the slide in a significant fraction of one or two isolated stains. The use of extended
cases. This technical problem may be circum- antibody panels with little consideration given to
vented by the use of slides pretreated with an a differential morphological diagnosis is likely to
adhesive material such as APES. confuse and be very expensive. Standardized
Other technical advances in immunohisto- panels are easier to order and to organize on auto-
chemistry include the development of highly sen- mated immunostainers and may assist in the cal-
sitive detection systems and the increasing use of culation of costs. Technical pitfalls may also trap
automated immunostainers. New polymer-based the unwary, and the results of immunohistochem-
detection systems (e.g., Envision, Dako) may istry should always be considered critically.
give superior sensitivity to existing methods, but Judicious use of positive and negative controls
many laboratories will continue to use more and correlation with morphological, clinical, and
established ABC techniques (e.g., Duet, Dako) radiological findings are essential. Reagent costs
which appear adequate for routine use. The use of tend to be particularly high with automated sys-
immunohistochemistry has been reported to have tems, and incorporation of control tissue onto the
risen 600% over the last few years in some labo- test slide has been suggested to contain costs
ratories, and automation is helpful in managing while maintaining quality.
this rising workload. It may also offer more Immunohistochemistry has also been used to
reproducible staining with less batch to batch detect prognostic and predictive biomarkers in
variation, particularly important with stains for malignant tumours and in premalignant condi-
predictive markers such as ER or HER2 which tions. The use of prognostic factors is mainly a
are assessed in a semiquantitative fashion. research activity with the exception of ER/PR
524 D.T. McManus
Table 46.1 Immunoprofile of cancer types

System Tumour/condition Marker panel
Head and neck Salivary gland tumours Calponin, S100, SmActin, AE1/AE3
Thyroid tumours Thyroglobulin, calcitonin, CEA,
TTF1, CK19
Gastrointestinal Oesophageal tumours AE1/AE3, CAM5.2, CK7, CK20,
CK5/6, p63, p40
Barrett’s oesophagus Villin, Ki67, AMACR, p53
Gastric and small bowel CK7, CK20, CEA, MUC-1, MUC-62
and MUC5AC
Colorectal CK7, CK20, CEA, CDX2, β-catenin
Hepatocellular carcinoma α-Fetoprotein, HEPAR1, CEA
polyclonal, CD10, CAM5.2
Pancreaticobiliary carcinoma CK7, CK20, CEA, CA19.9, CA125,
DPC4, MUC-1, MUC-62 and
MUC5AC
Gastrointestinal stromal tumours DOG1,CD117, CD34, SmActin,
desmin, S100, Ki67, vimentin
Neuroendocrine carcinoids Chromogranin, synaptophysin, CD56,
Ki67, gastrin, insulin, glucagon
Respiratory Small cell carcinoma CD45, CAM5.2, synaptophysin,
CD56, TTF1, Ki67
Non-small cell carcinoma CK5/6, p63, p40, CK7, TTF1, napsin
A
Malignant mesothelioma Calretinin, thrombomodulin, HBME1,
CK5/6, WT1, EMA, BerEP4, CEA
Salivary gland type tumours Calponin, S100, SmActin,AE1/AE3
Gynaecological Ovarian carcinoma CK7, CK20, CEA, CA125, WT1, p16,
PAX-8, HNF1Beta
Sex cord stromal Calretinin, vimentin, AE1/AE3,
inhibin, EMA
Uterus, mesenchymal CD10, desmin, h-caldesmon,
SmActin, ER, Ki67
Endometrial carcinoma CK7, CK20, CD10, ER, p53
Cervix-GGIN BCL-2, p16, Ki67
Cervical adenocarcinoma ER, CEA, vimentin
Genitourinary Renal carcinoma CK7, EMA, vimentin, CD10, RCC
Ab, PAX-8
Prostate PSA, PSAP, 34βE12, p63, AMACR,
AR
Transitional carcinoma 34βE12 CK7,CK20, p53, GATA-3
Testicular tumours PLAP, α-fetoprotein, HCG, CAM5.2,
EMA, CD30, CD117, OCT3/4,
SALL4, glycipan-3
Breast Breast carcinoma ER, PR, HER2, p63, SmActin, CK5/6,
CK14, CK8/18, E-cadherin, GATA-3,
GCDFP-15
Soft tissue Spindle cell sarcomas Vimentin, CD34, SmActin, desmin,
h-caldesmon, CD99, TLE1, CAM5.2,
AE1/AE3, S100, Ki67, TLE-1
Small round blue cell tumours CD 45, S100, CD99, FLI1,desmin,
myogenin, WT1, NB84, vimentin,
CD56
Table 46.1 (continued)
System Tumour/condition Marker panel
Epithelioid and vascular INI-1, CD34, CD31, ERG, FLI-1,
HHV-8
Skin Melanoma S100, MelanA, HMB45
Haematopoietic Lymphomas CD45, CD20, CD3, CD5, CD10, CD
15, CD21, CD23, CD30, CD43,
CD56, CD57, ALK, cyclin D1, Ki67,
κ&λ, BCL-2, BCL-6, BCL-10,
LMP-1, EBER, OCT2, BOB1,
granzyme B, TIA1 myeloperoxidase,
CD34, CD117, SOX-11, PD-1,
CXCL-13, CD123, C-MYC
These panels can be adapted and modified to suit individual cases and preferences. It is not really possible to summarize
this rapidly expanding and complex area with a simple table. An “immunohistochemical vade mecum” is also a useful
site accessed at http://e-immunohistochemistry.info/
receptors in breast cancer and proliferation indi- The increasingly important role of immuno-
ces (Ki67) in lesions such as non-Hodgkin lym- histochemistry and the need for standardization
phoma, gastrointestinal stromal tumours and of assays for predictive markers such as ER have
haemangiopericytoma. In multivariate analysis, prompted the development of external quality
many new “prognostic biomarkers” do not show assurance schemes to ensure acceptable technical
effects on prognosis independent of histological standards. Methods have also been developed to
grade or tumour stage. improve the reproducibility of scoring, the best
A tissue microarray consists of an array of examples being the “Histo” and “Quick Score”
small calibre core biopsies of tumours (or other methods used to score ER expression in breast
tissues) prepared either prospectively from cancer.
resected tumour specimens or retrospectively Antibodies to phosphorylated epitopes of
from paraffin-embedded tumour tissue. High- receptors and signaling molecules such as pAKT
density arrays can have hundreds of cores on a have also become available. Research suggests
single glass slide. This innovation represents an applicability to rapidly and uniformly fixed small
“industrial revolution,” and although it has biopsies such as cores or endoscopic biopsies,
greatly facilitated large-scale immunohistochem- but uneven staining is seen in larger resection
ical investigations, it has not seen widespread specimens. They have been used to demonstrate
adoption in diagnostic laboratories. changes in phosphorylation (and by implication,
Predictive biomarkers are used to predict the activation) in cell lines/tumour samples follow-
response of a malignancy to either conventional ing treatments with tyrosine kinase inhibitors.
treatments such as chemotherapy and radiotherapy Immunofluorescence continues to be used in
or novel targeted therapies. Examples include CD many laboratories for the evaluation of renal
20 and rituximab in certain B cell lymphomas, CD biopsies and skin biopsies in conditions charac-
117 (c-kit) and STI 571 in gastrointestinal stromal terized by the deposition of immune complexes
tumours and HER2 and trastuzumab in breast can- or autoantibody binding, fluorescence providing
cer. ER/PR and HER2 are good examples of bio- high resolution and precise localization.
markers that are both prognostic and predictive Immunofluorescence ideally requires frozen sec-
and that have clinical utility in the choice of treat- tions and specialized fluorescence microscopy
ments for patients with breast cancer. The expres- equipment. As fluorescent preparations fade,
sion levels of such markers in tumours vary both photomicroscopy is needed to provide a perma-
within and between tumours, and both technical nent record, and some laboratories have aban-
issues and interobserver variation may affect the doned this technique for conventional
validity and reproducibility of the results. immunoperoxidase.
526 D.T. McManus
46.7.2 Flow Cytometry cancer specimens with equivocal HER2 immu-

nohistochemical staining (2+).
Flow cytometry is a technique that allows the Fluorescence in situ hybridization (FISH)
measurement of fluorescence intensity of large may also be used to detect karyotypic abnor-
numbers of cells in suspension. Cells may be malities in the intact interphase nucleus such as
labeled using antibodies conjugated to fluores- HER2 amplification in breast cancer, and n-myc
cent reporter molecules, and it is possible to amplification in neuroblastoma. It can also be
accurately detect the fraction of cells in a pop- used to detect translocations involving key tar-
ulation expressing an antigen. Two or more get genes using dual colour break-apart probes.
antigens can also be examined simultaneously. The detection of translocations involving c-myc,
This technique has found an important diag- BCL-2 and BCL-6 has rapidly evolved so that
nostic role in leukaemia and lymphoma sub- most cases of diffuse large B-cell lymphoma are
typing. Propidium iodide is a fluorescent dye routinely tested. The development of antibodies
that binds stoichiometrically to DNA. Tumour detecting fusion gene proteins (e.g., NPM–
cell suspensions can be prepared from paraffin ALK) and the availability of PCR and RT-PCR
blocks, and it is possible to produce DNA his- (reverse transcriptase polymerase chain reac-
tograms based on the analysis of thousands of tion) based methods for translocation detection
tumour cells. This can be used to measure S are complementary to such assays (Table 46.2).
phase fraction or to detect aneuploid DNA con- FISH requires access to a good fluorescence
tent, although they generally do not emerge as microscope with appropriate filter sets and a
prognostic markers independent of stage and low-light CCDTV camera to capture and digi-
grade, and therefore, this technique is not rou- tize images. It is a specialized technique only
tinely used. Detection of a triploid DNA con- available in a small number of large centres.
tent is of value in the differentiation between Routinely fixed and processed paraffin sections
complete and partial hydatidiform mole, but may be used, but the technique is equally appli-
this distinction can often be made on histology cable to touch imprints or similar cytological
and is not vital clinically. preparations.
46.7.3 In Situ Hybridization 46.7.4 Electron Microscopy

including FISH
The increasing application of immunohistochem-
This technique has been regarded as a research istry and pressures to contain costs have led to a
tool, but improved technologies (proprietary decline in the use of electron microscopy, which
kits and integrated instruments for automated is usually only available in large institutions.
immunohistochemistry and in situ hybridiza- Nonetheless, EM can still be very useful in the
tion) are leading to clinical applications. In situ evaluation of renal biopsies and in the differential
hybridization may be used to detect viral diagnosis of paediatric small round blue cell
nucleic acid, for example, the detection of EBV tumours and high-grade pleomorphic sarcomas.
in posttransplant lymphoproliferative disorders, It can also help in the differentiation of malignant
certain lymphoma subtypes and some solid mesothelioma from adenocarcinoma and can be
tumours such as gastric carcinoma. In situ used on cytology specimens. Although paraffin-
hybridization for κ and λ light chain mRNA embedded material can be processed for EM, the
may have advantages over conventional immu- best results are obtained when small cubes
nohistochemistry. DDISH (dual colour dual (∼1 mm3) of fresh tissue are fixed without delay
hapten chromogenic ISH) is used in some labo- in a solution such as 3% glutaraldehyde in caco-
ratories to assess HER2 amplification in breast dylate buffer.
Table 46.2 Translocations in cancer types

Translocation Tumour type Testing methods Clinical utility
t(11;22)(q24;q12) EWS– Ewing’s sarcoma/PNET Break-apart FISH assay for Diagnosis
FLI 1 fusion EWS target; RT-PCR for
t(21;22)(q12;q12) specific fusion partners
EWS–ERG fusion also
t(2,7,17;22)
t(11;22)(p13;q12) EWS– Intra-abdominal Break-apart FISH assay for Diagnosis
WT1 fusion desmoplastic small round EWS target; RT-PCR for
cell tumour specific fusion partners
t(12;22)(q13;q12) EWS– Clear cell sarcoma Break-apart FISH assay for Diagnosis
ATF1 fusion EWS target; RT-PCR for
specific fusion partner
t(X;18)(p11;q11) SYT– Synovial sarcoma FISH translocation assay or Diagnosis?
SSX1 or SYT–SSX2 RT-PCR for specific fusion Prognosis
fusion partners
t(2;13)(q35;q14) Alveolar FISH translocation assay or Diagnosis
PAX-3–FKHR fusion rhabdomyosarcoma RT-PCR for specific fusion
t(1;13)(p36;q14) partners
PAX-7–FKHR fusion
t(12;16)(q13;p11) TLS– Myxoid liposarcoma FISH translocation assay or Diagnosis
CHOP fusion RT-PCR for specific fusion
t(12;22)(q13;q12) EWS– partners
CHOP fusion
t(17,22)(q21;q13) Dermatofibrosarcoma FISH translocation assay or Diagnosis/predictive of
COL1A1–PDGFR β protuberans RT-PCR response to imatinib
fusion
t(8,14) (q24;q32) and Burkitt’s lymphoma Break-apart c-myc FISH Diagnosis of Burkitt’s
variants C-myc assay, Southern blot of but also found in
translocated to Ig heavy hmwDNA subset DLBCL where
chain and deregulated it has prognostic
expression implications
t(14,18)(q32;q21) and Follicular lymphoma FISH, PCR Diagnosis of follicular
variants BCL2 BCL2 immunohistochemistry lymphoma but also
translocated to Ig heavy seen in subset DLBCL
chain and deregulated where it has prognostic
expression implications
t(11,14)(q13;q32) and Mantle cell lymphoma FISH, PCR Diagnosis of mantle
variants Cyclin D1 Cyclin D1 cell lymphoma
translocated to Ig heavy immunohistochemistry
chain and deregulated
expression
T(2,5)(p23;q35) NPM– Anaplastic large cell FISH break-apart ALK probe Diagnosis of anaplastic
ALK fusion lymphoma RT-PCR large cell lymphoma/
inflammatory
myofibroblastic tumor
TPM3 clathrin or other Inflammatory Immunohistochemistry ALK Potentially predictive
gene fusion targets myofibroblastic tumor of response to
crizotinib
TMPRSS2–ERG or other Prostatic adenocarcinoma FISH translocation assay or ??Prognostic
ETS family members RT-PCR
(continued)
528 D.T. McManus
Table 46.2 (continued)
Reciprocal translocations are particularly associated with lymphomas and sarcomas but more recently have also been
detected in some carcinomas as well. Translocations may result in altered/overexpression of gene products (most lym-
phomas, e.g., cyclinD1 or BCL2) or result in a novel chimeric fusion gene product (most sarcomas, e.g., EWS–FLI 1).
Translocations can be detected by dual colour interphase FISH assays to a single target gene with break-apart probes
designed to span the breakpoint or by using dual target probes to detect fusion signals. Multiplex RT-PCR may be used
to detect different fusion gene products and in some instances immunohistochemistry can be employed to detect
increased expression (e.g., cyclin D1)/abnormal localization of gene products (e.g., ALK) with appropriate antibodies.
Although such techniques are applicable to conventional formalin-fixed paraffin-embedded tissue sections, submission
of fresh tissue allows preparation of touch imprints for FISH and extraction of higher molecular weight and better pre-
served nucleic acid. Translocations are of particular use in diagnosis as detection of such translocations can help cor-
roborate difficult or rare diagnoses in these tumour types. Some translocations are associated with constitutive activation
of tyrosine kinases (e.g., ALK) and also have a role as predictive biomarkers for novel targeted therapies
46.7.5 Cytogenetics tumour-specific genetic abnormalities, usually

translocations that may be of diagnostic and
Metaphase cytogenetics has become an estab- prognostic relevance (Table 46.2).
lished technique in the evaluation of leukaemias More recently, the use of targeted anticancer
and other haematological conditions. Although it therapies has led to demand for predictive tests
is not used routinely in solid tumours, the detec- based on somatic mutation detection within solid
tion of specific translocations or other cytoge- tumours (Table 46.3). It is also possible to test for
netic abnormalities may be useful in paediatric clonality and cell lineage in lymphomas by
and soft tissue tumours. Metaphase cytogenetics detecting immunoglobulin heavy chain or T cell
requires fresh tissue which should be taken under receptor gene rearrangements. Detection of
sterile conditions. Small cubes of minced tissue somatic hypermutation in the variable region of
are placed in tissue culture medium and sent to the immunoglobulin gene can also be used in the
the cytogenetics laboratory. More detailed karyo- classification of B cell lymphomas.
types can now be gleaned from metaphase Microsatellite instability (MSI) may be
spreads due to improved chromosome banding detected in colorectal and other carcinomas by
techniques and technical innovations such as PCR of standardized panels of microsatellite
chromosome painting and spectral karyotyping. repeats. MSI may be detected in sporadic (often
These techniques have an established role in the right-sided mucinous or poorly differentiated)
classification of leukaemias, lymphomas, and tumours where it is associated with epigenetic
myeloproliferative disorders in large centres and silencing of the mismatch repair gene MLH1
may be used in solid tumours such as kidney promoter by methylation. In the context of a fam-
tumours, small round blue cell tumours of child- ily history (revised Bethesda guidelines), loss of
hood, and soft tissue lesions. expression of mismatch repair genes by immuno-
histochemistry is highly predictive of hereditary
nonpolyposis colorectal carcinoma.
46.7.6 Molecular Genetics Many of these assays now routinely use PCR
and Proteomics or RT-PCR technology and can be adapted so that
the impure, partially degraded DNA and mRNA
Nucleic acid and protein may be extracted from that is extracted from paraffin-embedded mate-
fresh tissue and used as substrate for a wide range rial can serve as a template, although this should
of investigative techniques usually performed as not deter prospective collection of fresh/frozen
part of a research study. However, certain tumour material where the opportunity exists. Even rela-
types such as lymphomas, paediatric small round tively small biopsies can be used for a wide range
cell tumours, and soft tissue sarcomas harbour of investigative techniques, if handled carefully.
Table 46.3 Genetic-based predictive tests in cancer types

Somatic genetic change Cancer type Methodology Clinical relevance
K-ras/N-ras mutations Colon cancer PCR/direct sequencing Predictive: mutation positive less
likely to respond to anti-EGFR
treatment
B-RAF mutations Melanoma PCR/direct sequencing Predictive of response to
or tests for V600E vemurafenib
Thyroid carcinoma mutation Diagnosis?
EGFR mutations Lung PCR/direct sequencing Predictive: mutation positive more
adenocarcinoma likely to respond to gefitinib
treatment
c-kit/PDGFRA Gastrointestinal PCR/direct sequencing Predictive: exon 11 mutations more
mutations stromal tumours likely to respond than exon 9 to
imatinib
HER2 overexpression/ Breast carcinoma, Algorithmic IHC/FISH Predictive: strong (+++) IHC and
amplification gastric carcinoma or CISH moderate IHC(++)/ISH positive
more likely to respond to
trastuzamab
EML4-ALK Lung IHC, ALK break-apart Predictive of response to erlotinib
translocations adenocarcinoma FISH assay
Mismatch repair gene Colorectal IHC In context of family history/
immunohistochemistry carcinoma, fulfillment of revised Bethesda
Endometrial criteria suggests HNPCC
carcinoma
MSI testing PCR, electrophoresis Some evidence as prognostic marker
(good) and effect on response to
conventional fluoropyrimidine-based
adjuvant treatment
XP11 translocations Renal cell carcinoma FISH for translocation/ Diagnosis of subtype of renal
TFE3 carcinoma
immunohistochemistry
Carcinomas are often associated with more genetic complexity and heterogeneity than lymphomas and sarcomas. Fewer
translocations have been detected. However, the introduction of targeted therapies has led to clinical demand for predic-
tive biomarkers of response. While algorithmic testing by IHC and FISH has been successful in predicting response to
trastuzamab, EGFR IHC has been less successful in predicting response to anti-EGFR therapy. Indeed recently, RAS
mutations have emerged as a negative predictive marker for response to cetuximab therapy in colorectal carcinoma as it
lies “downstream” to the EGFR in the phosphorylation cascade signaling mechanism. Activating point mutations in
receptors with tyrosine kinase domains have been associated with response to novel tyrosine kinase inhibitors
The sharp rise in demand for such predictive tests has not always been accompanied by a concomitant increase in capac-
ity in pathology laboratories, and such assays tend to be performed in larger centres with multiprofessional input and
suitable volumes. More targeted therapies (esp. tyrosine kinase inhibitors) are under development/in trials, and this area
is set for significant expansion in coming years, acknowledged by initiatives such as CR UK’s Stratified Medicine
Programme. It is also possible that the falling costs and increased availability of next generation/massively parallel
sequencing platforms will permit the development of predictive assays based on activation or disruption of signaling
networks rather than individual target genes
Small biopsies can be bisected. One half can be techniques variously described as transcriptional
used to make touch imprints for FISH or immu- profiling or molecular fingerprinting. These high-
nocytochemistry and further bisected for EM and throughput techniques generate enormous quanti-
snap freezing. The other half can be processed ties of data and have necessitated new bioinformatics
through to paraffin wax. approaches. The pattern of gene transcription, “the
RNA extracted from tumours and tissues can be transcriptome,” may be used to predict prognostic
hybridized to cDNA or oligonucleotide arrays, or behavioural differences within morphologically
530 D.T. McManus
homogenous or indistinguishable groups. While may be very little evidence of residual tumour.
expression arrays have been used to refine progno- Pathologists have an important role in the triage
sis within DLBCL and breast cancer (e.g., of tissue and in the selection of the most appro-
Oncotype Dx), similar results may be obtained by priate ancillary techniques to assist diagnosis.
the use of immunohistochemical markers for algo- Moreover, pathologists must ensure that the
rithmic testing (e.g., the Hans algorithm or variants removal of tissue for research projects (which
in DLBCL) or the use of conventional histopathol- may be led by basic scientists and usually
ogy in conjunction with established prognostic/ involve exciting cutting-edge technologies as
predictive markers in breast cancer (ER, PR, and described above) does not compromise the diag-
HER2). Expression arrays have also been used to nosis, staging, or assessment of resection mar-
identify a novel signature associated with a defi- gins, which remain fundamental to optimal
ciency in DNA damage response that can be used patient care.
to predict response to neoadjuvant anthracycline The controversy in the United Kingdom
based chemotherapy, but such assays have not been related to the use of retained organs and tissues
widely adopted with the exception of Oncotype removed at autopsy for research and teaching
Dx, used to help in the selection of patients with has led to a reconsideration of the ethical and
early stage node negative ER positive breast cancer legal framework surrounding the use of surplus
for adjuvant chemotherapy. biopsy tissue for research. Detailed guidelines
The burgeoning field of next generation are available from the NCRN and the Royal
sequencing has to date been applied mainly as College of Pathologists. Generally, prospective
a discovery tool, reshaping tumour classifica- investigations involving the procurement of
tions (eg gastric carcinoma) but as costs fall fresh tissue should have been considered and
has the potential to revolutionize molecular approved by an official ethics committee.
pathology, replacing PCR based assays for Informed consent from the patient is usually
individual point mutations and FISH testing needed. It is not always feasible to obtain con-
for translocations/copy number variation with sent retrospectively for archived tissue, and
one test. suitably anonymized studies may be permitted.
Protein may also be extracted from tissues and Some centres have developed biobanks specifi-
analyzed by 2D PAGE, western blotting, and cally to deal with the ethical and practical
variants of mass spectroscopy such as issues outlined above and the future lies with
SELDI. These are specialized research tech- large central well annotated biorepositories
niques and require fresh tissue as formalin fixa- where the tissues have been collected in an
tion irreversibly denatures proteins. ethically approved manner and are stored in
accordance with the provisions of the Human
Tissue Act.
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Clinical Request Form Abbreviations
General H/O History of

Adeno/adCa Adenocarcinoma HPE Histopathological examination
AIDS HIV—acquired immune defi- Hx History of
ciency syndrome Ix Investigation
B9 Benign L (t) Left
Bx Biopsy LFTs Liver function tests
Ca Carcinoma MAI Mycobacterium avium
C. diff Clostridium difficile intracellulare
CIS Carcinoma in-situ MD(T)M Multidisciplinary (team) meeting
CMV Cytomegalovirus mL Millilitre
C/O Complaining of mm Millimetre
Coronal At right angles to the sagittal MRI Magnetic resonance imaging
plane dividing into anterior and MRSA Methicillin resistant staphylococ-
posterior halves cus aureus
CRM Circumferential radial margin Mx Management/treatment
CRP C-reactive protein N Normal
CT scan Computerised tomography scan NAD Nothing abnormal detected
CXR Chest X-ray NCB Needle core biopsy
CXT Chemotherapy NG Neoplasm, new growth or
∆ or DD (differential) diagnosis nasogastric
DPB Diagnostic punch biopsy NGS Next generation sequencing
DXT Radiotherapy O/E On examination
ESR Erythrocyte sedimentation rate P/C Presenting complaint
FDG Fluorodeoxyglucose (a radioac- PCR Polymerase chain reaction
tive labelled sugar metabolised PEG Percutaneous endoscopic
by cancer cells and used in PET gastrostomy
scans) PET Positron emission tomography
FH Family history P(M)H Past (medical) history
FISH Fluorescence in situ PR Per rectum
hybridisation PV Per vagina
FNAB Fine needle aspiration biopsy 1o Primary neoplasm
FNA(C) Fine needle aspiration (cytology) PUO Pyrexia (fever) of unknown
FUP Follow up origin
GEP Gene expression profiling ? Query
HIV Human immunodeficiency virus R (t) Right
HMAR Heat mediated antigen retrieval R/O Rule out
© Springer International Publishing AG 2017

D.C. Allen, R.I. Cameron (eds.), Histopathology Specimens, DOI 10.1007/978-3-319-57360-1 533
534 Clinical Request Form Abbreviations
RT-PCR Reverse transcriptase polymerase CEA Carcinoembryonic antigen—

chain reaction serum/tissue marker of intestinal
Rx Resection or treatment malignancy
sagittal Anteroposterior plane (C)IBD (Chronic) idiopathic inflamma-
SC Subcutaneous tory bowel disease
SCF Supraclavicular fossa CLO Columnar lined (Barrett’s)
2o Secondary neoplasm oesophagus
SLE Systemic lupus erythematosus CMV Cytomegalovirus
Sx Surgery CRC Colorectal cancer
∴ Therefore CRM Circumferential radial margin
Tx Treatment D1-4 Parts of the duodenum
U and E Urea and electrolytes DALM Dysplasia associated lesion or
USS Ultrasound scan mass
x/7 x days DU Duodenal ulcer
x/52 x weeks EATCL Enteropathy associated (or type)
x/12 x months T cell lymphoma
yr Year ECL Enterochromaffin-like cell
EGC Early gastric cancer
Gastrointestinal Specimens ELAPE Extralevator abdominoperineal
AFP Alpha fetoprotein: serum/tissue excision
marker of hepatocellular carci- ELUS Endoluminal ultrasound
noma or germ cell tumour EMA Endomysial antibody
AIH Autoimmune hepatitis EMR Endoscopic mucosal resection
AIN Anal intraepithelial neoplasia ERCP Endoscopic retrograde
AIP Autoimmune pancreatitis cholangiopancreatography
AIS Autoimmune screen ESD Endoscopic submucosal
ALT Alanine aminotransferase dissection
AMA Antimitochondrial antibody FAP Familial adenomatous polyposis
ANA Antinuclear antibody FOB Faecal occult blood
ANCA Antineutrophilic cytoplasmic γGT Gamma glutamyl transferase
antibody GAVE Gastric antral vascular ectasia
AP Alkaline phosphatase GFD Gluten free diet
APC Adenomatous polyposis coli GIST Gastrointestinal stromal tumour
AP(ER) Abdominoperineal (excision of GOR(D) Gastroesophageal reflux
rectum) (disease)
AR Anterior resection GU Gastric ulcer
ASMA Anti-smooth muscle antibody haematemesis Blood in vomitus
AST Aspartate aminotransferase HBV, HCV Hepatitis B, C infection
AXR Abdominal X-ray HCC Hepatocellular carcinoma
Ba enema Barium enema HH Hiatus hernia
Ba meal Barium meal HNPCC Hereditary non-polyposis colon
BCS(P) Bowel cancer screening cancer (Lynch syndrome)
(program) HP Helicobacter pylori
CA19-9 Serum/tissue marker of pancre- HPV Human papilloma virus
atic or upper GI malignancy HSV Herpes simplex virus
CBD Common bile duct IBS Irritable bowel syndrome
CD Crohn’s disease or coeliac IPMN Intraductal papillary mucinous
disease neoplasm
Clinical Request Form Abbreviations 535
IRA Ileo-rectal anastomosis TACE Transarterial

KS Kaposi’s sarcoma chemoembolisation
LAMN Low grade appendiceal muci- TAMIS Transanal microsurgery
nous neoplasm TART Transanal resection of tumour
lap. chole Laparoscopic cholecystectomy TEMS Transanal endoscopic
LFTs Liver function tests microsurgery
MALToma Lymphoma of Mucosa TIBC Total iron binding capacity
Associated Lymphoid Tissue TME Total mesorectal excision
MANEC Mixed adenoneuroendocrine TTG Tissue transglutaminase
carcinoma antibody
MCN Mucinous cystic neoplasm TTO Total thoracic oesophagectomy
melaena Altered blood passed per UC Ulcerative colitis
rectum ZE syndrome Zollinger-Ellison syndrome
MIO Minimally invasive
oesophagectomy Breast Specimens
MMR Mismatch repair pathway/ ANC Axillary node clearance
antibodies ANS Axillary node sampling
MRC(P) Magnetic resonance BBR Bilateral breast reduction
cholangio(pancreato)graphy BCS Breast conserving surgery
MSI Microsatellite instability BRCA1/BRCA2 Genes conferring a strong
NASH Non-alcoholic steatohepatitis family risk of breast cancer
NET Neuroendocrine tumour DCIS Ductal carcinoma in-situ
NSAIDs Non-steroidal anti-inflammatory DDISH Dual colour dual hapten in
drugs situ hybridisation
OGD Oesophago-gastro-duodenoscopy ER Oestrogen receptor
OGJ Oesophago-gastric junction FNAC Fine needle aspiration
PanIN Pancreatic intraepithelial cytology
neoplasia HER 2 Human epidermal growth
PBC Primary biliary cirrhosis factor receptor
PD Pancreaticoduodenectomy LCIS Lobular carcinoma in-situ
PDT Photodynamic therapy LVI Lymphovascular invasion
PP Pseudomyxoma peritonei NAC Nipple areolar complex
PR Per rectum NCB Needle core biopsy
PSC Primary sclerosing cholangitis NPI Nottingham prognostic index
PSIN Perianal squamous intraepithe- PM Partial mastectomy
lial neoplasia PR Progesterone receptor
PTC Percutaneous transhepatic SNB Sentinel node biopsy
cholangiogram TCB Trucut biopsy
PUD Peptic ulcer disease TM Total mastectomy
RFA Radiofrequency ablation WLE Wide local excision
RIF Right iliac fossa
RUQ Right upper quadrant Head and Neck Specimens
SIFT Systemic internal radiation AG Apical granuloma
therapy apic. Apicectomy or apical
∑ or siggy Sigmoidoscopy B (tooth) Buccal surface
SMV/SMA Superior mesenteric vein/artery CASTLE Carcinoma showing thymus
SRUS Solitary rectal ulcer syndrome like differentiation
C/- Upper complete denture RRF Retrograde root filling

-/C Lower complete denture RCT Root canal treatment
C/C Upper and lower complete SCC/SCCa Squamous cell carcinoma
denture SCM Sternocleidomastoid
D (tooth) Distal surface SDHD Succinic dehydrogenase
DIGO Drug-induced gingival deficiency
overgrowth SS Sjögren’s syndrome
DIH Denture-induced hyperplasia TORS Transoral robotic surgery
FE Fibrous epulis TSH Thyroid stimulating hormone
FEP Fibroepithelial polyp TTP Tenderness to percussion
FESS Functional endoscopic sinus UE (tooth) Unerupted
surgery UL (+ numeral) Upper left (tooth designated
EC Ethyl chloride by numeral)
EPT Electric pulp tester UR (+ numeral) Upper right (tooth designated
FOM Floor of mouth by numeral)
GASH Gender/age/stage/histology WSN White sponge naevus
GP Gutta percha
IJV Internal jugular vein Tooth Nomenclature
K-cyst Keratocyst A Deciduous central incisor
L (tooth) Lingual surface B Deciduous lateral incisor
LA Lymphadenopathy C Deciduous canine
LL (+ numeral) Lower left (tooth designated D Deciduous first molar
by numeral) E Deciduous second molar
LN Lymph node(s) 1 Permanent central incisor
LP Lichen planus 2 Permanent lateral incisor
LR Lichenoid reaction 3 Permanent canine
LR (+ numeral) Lower right (tooth designated 4 Permanent first premolar
by numeral) 5 Permanent second premolar
M (tooth) Mesial surface 6 Permanent first molar
MESA Myoepithelial sialadenitis 7 Permanent second molar
MNG Multinodular goitre 8 Permanent third molar
MRND Modified radical neck
dissection Gynaecological Specimens
NG Tumour A = x/52 Amenorrhoea = x weeks
O (tooth) Occlusal surface AIS Adenocarcinoma in-situ
OKC Odontogenic keratocyst AWE Acetowhite epithelium
P/- Upper partial denture (α) AFP Alpha fetoprotein—serum
-/P Lower partial denture marker of yolk sac tumour
P/P Upper and lower partial BRCA1/BRCA2 Genes conferring a strong
dentures familial risk of ovarian cancer
PE (tooth) Partially erupted BTB Breakthrough bleeding
PJC Porcelain jacket crown CA125 Serum/tissue marker of ovar-
P(S)A Pleomorphic (salivary) ian malignancy
adenoma CIN Cervical intraepithelial
Q Quadrant of jaw neoplasia
RAS/RAU Recurrent aphthous CGIN Cervical glandular intraepithe-
ulceration lial neoplasia
RND Radical neck dissection D & C Dilatation and curettage
DUB Dysfunctional uterine TBA Therapeutic balloon ablation

bleeding of the endometrium
EDC Expected date of confinement TCRE Transcervical resection of
EIN Endometrial intraepithelial endometrium
neoplasia TIC Tubal intraepithelial
EIC Endometrial intraepithelial carcinoma
carcinoma TVS Transvaginal ultrasound scan
ET Endometrial thickness UBT Uterine balloon dilatation
EUA Examination under anaesthesia therapy
FIGO International Federation of VAIN Vaginal intraepithelial
Gynecology and Obstetrics neoplasia
HCG Human chorionic gonadotro- VIN Vulval intraepithelial
phin—serum/tissue marker of neoplasia
pregnancy or trophoblastic
tumour Urological Specimens
HPV Human papilloma virus ADPKD Adult polycystic kidney disease
HR HPV High risk human papilloma AFP Alpha fetoprotein—tissue/serum
virus marker of germ cell tumour
HRT Hormone replacement therapy AKI Acute kidney injury
HSV Herpes simplex virus AML Angiomyolipoma (see PEComa)
IMB Intermenstrual bleeding ARF Acute renal failure
LAVH Laparoscopic assisted vaginal AS Active surveillance
hysterectomy BCG Intravesical attenuated tubercle
LLETZ Large loop excision of cervical Bacille-Calmette-Guerin
transformation zone BNH Benign nodular hyperplasia
LMP Last menstrual period BPH Benign prostatic hyperplasia
LMS Leiomyosarcoma BOO Bladder outlet obstruction
MMMT Malignant mixed mesodermal BTTP British testicular tumour panel
tumour (carcinosarcoma) BXO Balanitis xerotica obliterans
NDMCS No dyskaryotic or malignant CAPD Continuous ambulatory peritoneal
cells seen dialysis
OCP Oral contraceptive pill CIS Carcinoma in-situ
PCB Post coital bleeding CRD Chronic renal disease
PLND Pelvic lymph node dissection CRF Chronic renal failure
PMB Post menopausal bleeding DMSA Dimercaptosuccinic acid—radio-
POC Products of conception nucleotide renal function test
PV Per vagina DPTA Diaminopropanoltetraacetic
SIL Squamous intraepithelial acid—radionucleotide renal test
lesion DRE Digital rectal examination
SMILE Stratified mucin producing DSNB Dynamic sentinel node biopsy
intraepithelial lesion EC Embryonal carcinoma
STBM Serous tumour borderline ELUS Endoluminal ultrasound
malignancy EM Electron microscopy
STIC Serous tubal intraepithelial EMPD Extra-mammary Paget’s disease
carcinoma EPE Extraprostatic extension
TAHBSO Total abdominal hysterectomy ESRD End-stage renal disease
with bilateral G1, G2, G3 WHO cytological grade I, II, III
salpingo-oophorectomy (transitional cell carcinoma)
GCNIS Germ cell neoplasia in situ PEComa Perivascular Epithelioid Cell

GCT Germ cell tumour tumour
GG Gleason grade PeIN Penile intraepithelial neoplasia
GS Gleason score PI Prognostic index for penile cancer
Haematuria Blood in the urine PIN Prostatic intraepithelial neoplasia
Hb Haemoglobin PLAP Placental alkaline phosphatase—
HCG Human chorionic gonadotro- tissue marker of seminoma and
phin—serum/tissue marker for carcinoma in-situ: also CD 117,
germ cell tumour OCT3/4
HIFU High intensity focussed PLND Pelvic lymph node dissection
ultrasound pneumaturia Gas in the urine usually from a gut
HPV Human papilloma virus fistula
IF Immunofluorescence post BCG Following therapy with intravesi-
ILND Ilioinguinal lymph node cal attenuated tubercle
dissection (Bacille-Calmette-Guerin)
IMT Inflammatory myofibroblastic PSA Prostate specific antigen—tissue/
tumour serum marker of prostatic tumour
ISUP International Society of Urological PU Pass urine
Pathologists PUJ(O) Pelviureteric junction
ITGCN Intratubular germ cell neoplasia (obstruction)
IVC Inferior vena cava PUNLMP Papillary urothelial neoplasm of
IVP Intravenous pyelogram low malignant potential
IVU Intravenous urogram RBC Red blood cells
LDH Lactate dehydrogenase RCC Renal cell carcinoma—CCRCC
LHRH Luteinising hormone releasing (clear cell), PRCC (papillary),
hormone ChRCC (chromophobe)
LM Light microscopy RFA Radiofrequency ablation
LPN Laparoscopic partial nephrectomy RPF Retroperitoneal fibrosis
LRP Laparoscopic radical RPLND Retroperitoneal lymph node
prostatectomy dissection
LS Lichen sclerosus RAPN Robotic assisted partial
LUTS Lower urinary tract symptoms nephrectomy
mILND Modified inguinal RALN Robotic assisted laparoscopic
lymphadenectomy nephrectomy
MP Muscularis propria RARC Robotic assisted radical
MSSU Mid stream specimen of urine cystectomy
MTD Malignant teratoma differentiated RARP Robotic assisted radical
MTI Malignant teratoma intermediate prostatectomy
MTU Malignant teratoma SV Seminal vesicle
undifferentiated TCC Transitional cell carcinoma
NS Nephrotic syndrome TRUS Transrectal ultrasound of the
NSGCT Non-seminomatous germ cell prostate
tumour TURB(T) Transurethral resection bladder
NSS Nephron sparing surgery (tumour)
NVH Non-visible haematuria—prefix TURP Transurethral resection prostate
a/s = (a)symptomatic UC Urothelial carcinoma
PA(N) Polyarteritis (nodosa) UPUMP Urothelial proliferation of uncer-
PAP Prostatic acid phosphatase tain malignant potential
UTI Urinary tract infection MFH Malignant fibrous histiocytoma

VSH Verrucous squamous hyperplasia MF Mycosis fungoides
VUR Vesicoureteric reflux MM Malignant melanoma
WHO World Health Organisation MPD Mammary Paget’s disease
XGP Xanthogranulomatous MZL Marginal zone B cell lymphoma
pyelonephritis NLD Necrobiosis lipoidica diabeticorum
YST Yolk sac tumour NM Nodular melanoma
PLC Pityriasis lichenoides chronica
Pelvic and Retroperitoneal Specimens PLE Polymorphous light eruption
ACTH Adrenocorticotrophic hormone PLEVA Pityriasis lichenoides et varioliformis
MEN Multiple endocrine neoplasia acuta
syndrome PLC Pityriasis lichenoides chronica
PLND Pelvic lymph node dissection PRP Pityriasis rubra pilaris
RPF Retroperitoneal fibrosis PRPPP Pruritic urticarial papules and plaques of
RPLND Retroperitoneal lymph node pregnancy
dissection SALE Subacute lupus erythematosus
SCC Squamous cell carcinoma
Skin Specimens SEM Scanning electron microscopy
AFX Atypical fibroxanthoma S(eb)K Seborrhoeic keratosis
AK Actinic (solar) keratosis SSM Superficial spreading melanoma
BCC Basal cell carcinoma SLE Systemic lupus erythematosus
BCE Basal cell epithelioma TEM Toxic epidermal necrolysis or transmis-
BCP Basal cell papilloma (seborrhoeic sion electron microscopy
keratosis)
CMN Congenital melanocytic naevus Cardiothoracic Specimens
C&C Curettage and cautery AAH Atypical adenomatous
CBCL Cutaneous B-cell lymphoma hyperplasia
CTCL Cutaneous T cell lymphoma ALK Anaplastic lymphoma kinase
DFSP Dermatofibrosarcoma protuberans ANCA Antineutrophilic cytoplasmic
DH Dermatitis herpetiformis antibody
DLE Discoid lupus erythematosus ARDS Adult respiratory distress
DMN Dysplastic (atypical) melanocytic syndrome
naevus BAC Bronchoalveolar carcinoma
DPB Diagnostic punch biopsy BAL Bronchoalveolar lavage
EED Erythema elevatum diutinum BHLN Bilateral hilar lymphadenopathy
EM Erythema multiforme BOOP Bronchiolitis obliterans
EPD Extramammary Paget’s disease pneumonia
GA Granuloma annulare CABG Coronary artery bypass graft
GVHD Graft-versus-host disease CFA Cryptogenic fibrosing alveolitis
KA Keratoacanthoma COPD Chronic obstructive pulmonary
KP Keratosis pilaris disease
LE Lupus erythematosus CS Churg-Strauss syndrome
LM Lentigo maligna CVA Cerebrovascular accident
LMM Lentigo maligna melanoma DAD Diffuse alveolar damage
LyP Lymphomatoid papulosis DCM Dilated cardiomyopathy
LP Lichen planus DIP Desquamative interstitial
LSC Lichen simplex chronicus pneumonia
LS et A Lichen sclerosus et atrophicus EAA Extrinsic allergic alveolitis
EBUS Endobronchial ultrasound AKA Above knee amputation

EBV Epstein Barr Virus ALVAL Aseptic lymphocytic vasculitis associ-
ECG Electrocardiogram ated lesion
EGFR Epidermal growth factor AS Ankylosing spondylitis
receptor DEXA Dual energy X ray absorptiometry
EPP Extrapleural pneumonectomy FD Fibrous dysplasia
EVAR Endovascular aneurysm repair GCT Giant cell tumour
FEV1 Forced expiratory volume in one LCH Langerhan’s cell histiocytosis
second MFH Malignant fibrous histiocytoma
FOB Faecal occult blood NOF Neck of femur
FVC Forced vital capacity OA Osteoarthritis
Haemoptysis Blood in sputum PSC Primary synovial chondromatosis
HCM Hypertrophic cardiomyopathy PVNS Pigmented villonodular synovitis
HRCT High resolution CT RA Rheumatoid arthritis
IPF Idiopathic pulmonary fibrosis THR Total hip replacement
LCNEC Large cell neuroendocrine TKR Total knee replacement
carcinoma # Fracture
LIP Lymphoid interstitial pneumonia
LVRS Lung volume reduction surgery Haemopoietic Specimens
MI Myocardial infarction AL Acute leukaemia
NBTE Non-bacterial thrombotic ALL Acute lymphoblastic leukaemia
endocarditis AML Acute myeloid leukaemia
NSCLC Non-small cell lung cancer ALCL Anaplastic large cell lymphoma
NSIP Non-specific interstitial BM(T) Bone marrow trephine
pneumonia BMTx Bone marrow transplant
PEFR Peak expiratory flow rate BT Bleeding time
PJP Pneumocystis jirovecii (carinii) CHL Classical Hodgkin lymphoma
pneumonia CLL Chronic lymphocytic leukaemia
PE Pulmonary embolus CML Chronic myeloid leukaemia
RCM Restrictive cardiomyopathy CMML Chronic myelomonocytic
SCLC Small cell lung cancer leukaemia
SVCO Superior vena cava obstruction COO Cell of origin
or syndrome CR Complete remission
TB Tuberculosis CT Clotting time
Tco Carbon monoxide transfer DC Differential count
TIA Transient ischaemic attack DLBCL Diffuse large B cell lymphoma
TOE Transoesophageal (D)WCC (Differential) white cell count
echocardiography EBV-LMP 1 Epstein Barr virus—latent mem-
TTNA Transthoracic needle aspiration brane protein 1
TTNB Transthoracic needle biopsy EBER Epstein Barr virus encoded ribo-
UIP Usual interstitial pneumonia nucleic acid
VATS Video-assisted thoracoscopic ESR Erythrocyte sedimentation rate
surgery ET Essential thrombocythemia
V/Q Scan Ventilation/perfusion scan FBP Full blood picture or count
WG Wegener’s granulomatosis (FBC)
FCM Flow cytometry
Osteoarticular and Soft Tissue Specimens Hb Haemoglobin
ABC Aneurysmal bone cyst HCL Hairy cell leukaemia
HLH Haemophagocytic NSHL Nodular sclerosis Hodgkin

lymphohistiocytosis lymphoma
HD/HL Hodgkin disease/lymphoma PCR Polymerase chain reaction
ITP Idiopathic thrombocytopenic PCM Plasma cell myeloma
purpura PMF Primary myelofibrosis
IVL Intravascular lymphoma PR Partial remission
LDHD/HL Lymphocyte depleted Hodgkin PLT Platelets
lymphoma PP Paraproteinaemia
MCHD/HL Mixed cellularity Hodgkin PT Prothrombin time
lymphoma PUO Pyrexia of unknown origin
MCTD Mixed connective tissue disorder PV Polycythaemia vera
MDS Myelodysplastic syndrome RA Rheumatoid arthritis
MF Mycosis fungoides SLE Systemic lupus erythematosus
MM Multiple myeloma TCRBCL T cell rich B cell lymphoma
MPN Myeloproliferative neoplasms TT Thrombin time
NHL Non-Hodgkin lymphoma WCC White cell count
NLPHL Nodular lymphocyte predomi-
nant Hodgkin lymphoma
Resection Specimen Blocking Summary
Gastrointestinal Resection Specimen Blocking Gynaecological Resection Specimen Blocking

Blocks Blocks
Cancer Vulvectomy for VIN/cancer/
Primary tumour (to serosa/ 4 soft tissue lesion
mesentery) Wide local excision, simple/radical
Longitudinal limit (if <3 cm) 1 vulvectomy
Circumferential limit (if <1 cm) 1 Block to lateral cutaneous/medial
All lymph nodes N mucosal/deep soft tissue margins
Anastomotic ring(s) 1 each Primary lesion 4
Other(s) e.g. polyp(s), appendix N Other(s) e.g. ipsi-/contralateral N
Ischaemia lesion (s)
Longitudinal limits 1 each Vulva e.g. lichen sclerosis
Abnormal/normal bowel 2 Ipsilateral 1
Mesentery 1 Contralateral 2
Lymph node sample 1 cassette All lymph nodes N
Chronic inflammatory Trachelectomy for cervical cancer
bowel disease Vaginal cuff limit 2
Longitudinal limits 1 each Proximal transverse limit 2
Sequential samples every 10–20 cm N Trachelectomy Other(s) e.g. vaginal 4–6 approx. N
lesion
Lymph node sample 2
cassettes All lymph nodes N
Other(s) e.g. DALM/polyp(s)/ulcer/ N Radical hysterectomy for cervical
stricture/fistula/abscess/appendix cancer
Diverticular disease Vaginal cuff limit 2
Transverse sections 2 Cervix 4–6 approx.
Others(s) e.g. polyp(s)/abscess/fistula N Paracervix/parametria 1 each R/L side
Lymph node sample 1 cassette Endometrium and body/lower 2 each
Volvulus uterine segment
Longitudinal limits 1 each Tubes and ovaries 1 each
Bowel 2 Other(s) e.g. vaginal lesion, N
N variable number of blocks/cassettes omentum (2)
All lymph nodes N
543
544 Resection Specimen Blocking Summary
Blocks Urology Resection Specimen Blocking

Hysterectomy for uterine cancer/ Blocks
sarcoma Nephrectomy for cancer
Vaginal cuff limit 2 Primary tumour: to capsule/renal pelvis 4 minimum
Primary tumour (to myometrium/ 4 and sinus/perinephric fat and margin/ or 1/cm dia
serosa) adrenal gland/parenchymal limit
Endometrium and body/isthmus 2 (partial nephrectomy)/Gerota’s fascia
Endocervix (endometrial cancer) 2 Other(s) e.g. white/grey areas, satellite N
nodule(s)
Cervix 2
Renal sinus 2
Tubes and ovaries 1 each
Kidney and adrenal gland 1 each
Other(s) e.g. omentum (2), N
parametrium (2) Renal vein (RCC) 1
All lymph nodes N Ureter (TCC)
Hysterectomy Limit 1
Endometrium and body 2 Pelviureteric lesion(s) N
Cervix (anterior/posterior) 2 All lymph nodes N
Previous CIN 4 minimum Nephrectomy for non-cancer
Fibroids Kidney/renal pelvis 3
Usual/multiple 1–2 Ureter 1
Unusual appearance 3–4 Cystectomy/cystoprostatecomy for
cancer
Adenomyosis 1
Primary tumour (to wall and perivesical 4
Serosal adhesions 1
fat)
Polyp—tip/body, and, base 2
Other(s) e.g. grossly abnormal areas N
Previous hyperplasia endometrium 2–4
Distal urethral limit 1
Ovary
Circumferential limit (if <1 cm) 1
Normal and tube 1 each cross
Ureteric limit(s) or separately 1 each
section tube
and fimbriae labeled specimens
BRCA gene and tube All—N Bladder 2
Inflammatory 3 Prostate 2–4
minimum
Simple cyst 2–3
each
Multiloculated cyst (complex/warty/ 1/cm dia up to
R/L lobe
solid areas) 10 cm, or
1/2cm dia if All lymph nodes N
>10 cm Cystectomy/cystoprostatectomy for
Mixed solid/cystic As above non-cancer
Solid (to capsule) As above Bladder 3
Omentum 3–4 Prostate 2–4
Other(s), tube(s), contralateral 1 each minimum
each
ovary, endometrium and body,
R/L lobes
anterior cervix, posterior cervix
Urethral/ureteric limits 1 each
CIN cervical intraepithelial neoplasia
Radical prostatectomy
Proximal bladder limit 1 cassette
Distal urethral limit 1 cassette
Prostate and seminal vesicles N
All lymph nodes N
Testis for cancer
Primary tumour (to testis/tunica/rete) 1/cm
dia—N
Other(s) e.g. solid/haemorrhagic/ N
Resection Specimen Blocking Summary 545
Blocks Blocks
necrotic areas, satellite lesion(s) Macroscopic lesion (to nearest 3
Testis 1–2 margin(s))
Epididymis (if grossly involved) 1–2 No macroscopic lesion— 6 approx. ± EBs,
representative blocks (sample correlate with
Spermatic cord proximal limit 1
fibrous tissue) specimen/slice
Testis for non-cancer radiography
Testis ± lesion (atrophy/infarct/abscess) 2 Cavity shave(s) (sample fibrous 1–2 each
Hydrocoele 1 tissue)
Spermatic cord 1 EBs extra blocks
Penectomy for cancer
Primary tumour (to corpora/urethra) 4 Lung Resection Specimen Blocking
Other(s) e.g. satellite nodule in N
penile skin Cancer/abscess Blocks
Proximal resection limit 1–2 Proximal bronchial limit 1
All lymph nodes N Mass lesion (to bronchial limit and/or 4
pleura)
TCC transitional cell carcinoma, RCC renal cell
Lung 1
carcinoma
All lymph nodes N
Others(s) e.g. satellite lesion/consolidation N
Breast Resection Specimen Blocking
Blocks
Mastectomy for cancer
Thyroid Resection Specimen Blocking
Primary tumour (to nearest 3 Multinodular colloid goitre 4 maximum
margin(s)) Thyroiditis e.g. Hashimotos 3 each lobe
Breast 1 maximum
Nipple 1 Cyst/solitary nodule/tumour (to All up to 5 cm dia,
Skin (only block if involved) 1 capsule/margins(s)) or, 1/cm dia—N
Others(s) e.g. DCIS, satellite N Other(s) e.g. satellite lesion(s), N
parathyroid(s)
lesion(s)
All lymph nodes N
All lymph nodes N
Cavity shave(s) (sample fibrous 1–2 (more if the
tissue/partial mastectomy) related specimen Salivary Gland Resection Specimen Blocking
margin is
Sialadenitis 3
involved)
Cyst/tumour (to capsule/margin(s)) 1/cm dia—N
Completion mastectomy
Other(s) e.g. satellite lesion(s), N
(previous cancer)
lymph node, facial nerve
Macroscopically identified 2
tumour All lymph nodes N
No tumour—cavity walls 4 minimum
Breast 2 Soft Tissue Resection Specimen Blocking
Nipple 1
Tumour (to capsule/margins(s)) to 1/cm dia up to a
All lymph nodes N cassettes include firm/cystic/necrotic areas maximum of
Fibroadenoma/phyllodes tumour 12—N
1 block/cm dia (to nearest N Vessel/soft tissue proximal limits 2–3
margin(s))
Breast reduction
Representative blocks 4
Other(s) e.g. discrete lesion N
Localization for non-palpable
lesion/calcification
Index
A Adrenal gland
Abdominal aortic aneurysms, 471, 472 anatomy, 405
Abdominal fibromatosis, 126 biopsy specimens, 409
Abdominal oesophagus, 13 clinical investigations
Abdominal wall biochemical assessment, 406
anatomy, 125 radiological assessment, 406
biopsy specimens, 128 clinical presentation, 405
clinical investigations, 126 pathological conditions
clinical presentation, 125 cortex, 407–408
pathological conditions, 126 medulla, 408
resection specimens, 128 resection specimens, 409–411
surgical pathology surgical pathology
clinical aspects, 128 clinical aspects, 409
laboratory protocol, 128–129 laboratory protocols, 409–411
Abdominal X-ray (AXR), 4 Adrenogenital syndrome, 374
Abdominoperineal excision of rectum (APER), 78 Adult tumours, 305–310
Abnormally located immature precursors (ALIPs), 513 Aggressive angiomyxoma, 373
Abscess, 341 AIDS, 512
Accessory glands, 194 Alcohol (C2H5OH), 115
Acinic cell carcinoma, 197 Alpha-fetoprotein, 365
Acquired cystic disease RCC, 308 5a–reductase inhibitors (5ARIs), 340
Acquired hyperplasia, 407 Alveolar process, 169
Actinic (solar) keratosis, 417 Ameloblastoma, 173, 178
Acute appendicitis, 87 Ampulla of Vater, 39, 41
Acute cholecystitis, 105 regional lymph nodes, 40
Acute gastritis, 27 Ampullary adenocarcinoma, 42
Acute kidney injury (AKI), 302 Amyloidosis, 126, 507
Acute mediastinitis, 455 Anaemia, 4, 509
Acute pancreatitis, 39, 41, 47 Anal carcinoma, 98
Acute pericarditis, 464 Anal margin carcinoma, 97
Acute urinary retention, 323 Anaplastic carcinoma, 207
Addison’s disease, 407 Anaplastic large cell lymphoma (ALCL), 502
Adenocarcinoma, 17, 29, 59, 75–76, 90, 329–330, 356 ANCA related vasculitis, 372
ampullary, 42–43 Ancillary techniques
lung, 440 cytogenetics, 528
Adenoid cystic carcinoma, 197, 235, 440 electron microscopy, 526
Adenoma, 59, 74–75, 116, 215, 407 flow cytometry, 526
Adenomatoid tumour, 372 immunofluorescence, 523–525
Adenomatous hyperplasia, 372 immunohistochemistry, 523–525
Adenomatous polyps, 70, 78 in situ hybridization, 526
Adenomyosis, 263 molecular genetics, 528–530
Adenosis, 341 proteomics, 528–530
Adenosquamous carcinoma, 384 surplus biopsy, 530
Adipose tissue, 301 tissue banking, 530

D.C. Allen, R.I. Cameron (eds.), Histopathology Specimens, DOI 10.1007/978-3-319-57360-1
548 Index
Aneurysm, 471 B
Angiodysplasia, 69, 81 Bacille Calmette-Guérin (BCG), 309
Angiography, 113, 222 Bacterial cystitis, 324
Angioimmunoblastic Bacterial pneumonia, 438
lymphoma, 502 Balanitis circumscripta plasmacellularis, 380–381
Angiomyofibroblastoma, 373 Balanitis xerotica obliterans (BXO), 381
Angiomyolipoma (AML), 305–306 Balanoposthitis, 381
Angiosarcoma, 508 Barium enema, 61, 71
Anterior compartment group, 221 Barrett’s dysplasia, 22
Anterior mediastinotomy, 457 Barrett’s metaplasia, 5, 16
Antrochoanal polyp, 151 Barrett’s mucosa, 16
Anus Barrett’s oeosophagus, 16
anatomy, 95–96 Bartholin’s duct, 194
clinical investigation, 97 Basal cell carcinoma, 417, 429
clinical presentation, 95 Basaloid carcinoma, 383
lymphovascular drainage, 95 B-cell lymphomas, 502, 507
pathological conditions Benign epithelial tumours, 418
neoplastic conditions, 97–98 Benign mesenchymal tumours, 306, 418
non-neoplastic conditions, 97 Benign nodular hyperplasia (BNH), 340–341
surgical pathology specimens Benign pancreatic cysts, 42
biopsy specimens, 98–100 Benign prostatic hyperplasia (BPH), 340, 345
neoplastic conditions, 100–101 Benign stricture, 355
resection specimens, 98–99 Benign tumours, 16, 246, 256, 325
Aorta, 469 bone, 481
Aortic regurgitation, 464 breasts, 136
Aortic valve stenosis, 464 larynx and pharynx, 183–184
Apicectomy, 174 lips, 161
Aplastic anaemia, 512 lung, 439
Appendicectomy, 90–91 mouth, 161
Appendicitis, 89 nasal cavity and paranasal sinuses, 152
Appendix salivary glands, 196
anatomy, 87 soft tissues, 486
clinical investigations, 88 spleen, 507
clinical presentation, 87–88 tongue, 161
lymphovascular drainage, 87 Benign vaginal tumours, 284
pathological conditions Berry aneurysms, 471
neoplastic conditions, 89–90 Bile duct
non-neoplastic conditions, 89 bacterial infection in, 39
surgical pathology specimens cancer resection, 52
resection specimens, 90–93 stones, 47
Aryepiglottic folds, 180 Biliary cirrhosis, primary, 115
Arytenoid cartilages, 180 Biomarkers, 525
Asbestos-induced mesothelial Bladder
hyperplasia, 448 anatomy, 321–322
Asbestosis, 438 biopsy specimens, 330, 331
Aseptic lymphocytic vasculitis-associated lesion clinical investigations, 323
(ALVAL), 478 clinical presentation, 322–323
Asymptomatic non-visible haematuria cystoprostatectomy specimen, 332
(a-NVH), 322 neoplastic conditions, 325–330
Atherectomy, 472 non-neoplastic conditions, 324–325
Atherosclerosis, 470 partial cystectomy, 331
Atypical carcinoids, 440 pathological staging, 328
Autoimmune gastritis, 27 regional lymph nodes, 322
Autoimmune hepatitis, 115 resection specimens, 330–334
Autoimmune pancreatitis (AIP), 42 simple cystectomy, 331
Autosomal dominant polycystic kidney disease Bladder calculi, 323
(ADPKD), 305 Bladder outlet obstruction
Avascular necrosis, 481 (BOO), 345
Axillary node clearance (ANC), 140 Bladder stones, 324
Axillary node surgery, 140 Bleeding disorders, 510
Index 549
Body cavity-based lymphoma, 449 Cancer, gallbladder, 107

Bone Candida, 161
anatomy, 479 Carcinoid tumour, 29, 30, 59, 89–90, 401
biopsy specimens, 482 Carcinoma, 106, 215, 407
clinical investigations, 479–480 Carcinoma ex-pleomorphic adenoma, 197
clinical presentation, 480 Carcinoma in situ, 137
pathological conditions Cardiac orifice, 25
neoplastic, 481–482 Cardiac valves, 465
non-neoplastic, 481 Carotid body paraganglioma, resection, 225
resection specimens, 482–485 Cartilage, 477
surgical pathology Caruncle, 355
clinical aspects, 482 Cavity shavings, 140
laboratory protocols, 482–485 Cell blocks, 521
Bone marrow Cervical glandular intraepithelial neoplasia (CGIN), 275
anatomy, 509 Cervical intraepithelial neoplasia (CIN), 274
clinical investigations, 511–512 Cervical mediastinoscopy, 457
clinical presentation, 509–511 Cervical oesophagus, 13
pathological conditions Cervix
neoplastic, 513–514 anatomy, 273
non-neoplastic, 512 biopsy specimens, 276
surgical pathology clinical investigations, 274
clinical aspects, 514 clinical presentation, 274
laboratory protocols, 514–515 pathological conditions
Bone scan, 304 neoplastic, 274–276
Bowen’s disease, 98, 382, 417 non-neoplastic, 274
Bowenoid papulosis, 382 radical hysterectomy, 277–278
Branchial cleft cyst, 223 resection specimens, 276
Breast surgical pathology
anatomy, 133 clinical aspects, 276
biopsy specimens, 139–141 laboratory aspects, 276–281
chemotherapy, 138 CGIN. See cervical glandular intraepithelial neoplasia
clinical investigations, 135 (CGIN)
clinical presentation, 134–135 Chest wall tumours, 441
endocrine treatment, 138 Chest X ray (CXR), 4, 365
pain, 134 Choana, 149
pathological conditions Cholangiocarcinoma, 44, 46, 116, 123
neoplastic, 136–139 Cholangiopancreatoscopy, 41, 45
non-neoplastic, 136 Cholecystectomy, 106
regional lymph nodes, 134 Cholecystitis
resection specimens, 139–146 acute, 105
surgical pathology chronic, 105
clinical aspects, 139–140 Cholecystitis glandularis proliferans, 105
laboratory protocol, 140–146 Cholelithiasis, 105
Breast abscess, 136 Cholesterolosis, 105
Breast implant associated anaplastic large cell Chondroid hamartoma, 439
lymphoma (BIA-ALCL), 138 Chondrosarcomas, 482
Breast-conserving surgery (BCS), 139, 140 Choriocarcinoma, 370
British Testicular Tumour Panel (BTTP), 366 Chromophobe renal cell carcinoma (ChRCC), 307–308
Bronchial (bronchogenic) cysts, 457 Chronic adrenalitis, 408
Bronchiectasis, 438 Chronic bronchitis, 438
Bronchoalveolar lavage (BAL), 437 Chronic cholecystitis, 105
Buccinator, 157 Chronic gastritis, 27, 28
Bullectomies, 441 Chronic inflammatory bowel disease (CIBD), 71–72
Burkitt lymphoma, 502 Chronic ischaemia, 58
Bursa, 486 Chronic kidney disease (CKD), 303
Chronic myelomonocytic leukaemia (CMML), 513
Chronic pancreatitis, 39, 41, 42
C local resection of pancreatic head in, 48
Calcifying fibrous pseudotumour, 449 Chronic pericarditis, 464
Cancellous bone, 480 Chronic proctocolitis, 71
550 Index
Chronic pyelonephritis, 304 Crohn’s disease, 57–58, 61, 64, 71

Chronic ulcerative colitis, 5 Crown, 170
CIN. See Cervical intraepithelial neoplasia (CIN) Crystal arthropathy, 479
Circumferential radial margin (CRM), 9 CT. See Computed tomgraphy (CT)
Clear cell carcinoma, 284, 309, 330 Cyclical endometrium, 263
Clear cell renal cell carcinoma (CCRCC), 307 Cylindrical cell papillomas, 152
Clear cell squamous cell carcinoma, 384 Cystadenofibroma, 372
Cloacogenic polyp, 100 Cystic dilation, 372
Closed core needle biopsy, 312 Cystic dysplasia, 372
Coeliac disease, 56, 57 Cystic lesions, 48
Colitis, 71, 72 Cystic metastases, 504
Collecting duct carcinoma (CDC), 308 Cystic pancreatic exocrine lesions, 43
Colonoscopy, 76 Cysto/prostato urethrectomy, 358
Colorectal carcinoma, 70 Cystogastrostomy, 47
Colorectal inflammatory bowel disease, 80 Cystoscopy, 303, 323, 330
Colorectum Cysts, 136, 183, 195, 215, 416
anatomy, 67–70 Cytokeratin stains, 328
clinical investigations, 70–71 Cytopathology, 303
clinical presentation, 69–70 Cytoplasmic anti-neutrophil cytoplasmic antibodies
lymphovascular drainage, 68–69 (cANCA), 151, 152
pathological conditions Cytoreductive nephrectomy, 306
iatrogenic disorders, 74 Cytospins, 521
inflammatory disorders, 71–72
ischaemic disorders, 73
mechanical disorders, 72–73 D
neoplastic conditions, 74–76 Decalcification, 483, 515
non-neoplastic conditions, 71–74 Decortication, 449
surgical pathology specimens Denonvillier’s fascia, 337
biopsy specimens, 76–77 Dentigerous cyst, 172
resection specimens, 77–85 Dermis, 415
Columnar epithelium lined lower oesophagus Desmoplastic small round cell tumour, 374
(CLO), 16 Diagnostic elliptical biopsy, 419
Computed tomgraphy (CT), 113, 499 Diagnostic punch biopsy, 418, 419
bladder, 323 Diaphragm disease, 58
pelvic exenteration, 393 Dichorionic placenta, 296
pleura, 447 Diffuse malignant mesothelioma, 127
prostate, 340 Diffuse pleural thickening, 448
testes, 365 Digastric triangles, 220
urethra, 354 Digital photography, 521
Computerised coaxial tomography (CT) scan, 4 Digits, 427
Concomitant urethrectomy, 357 Dilated cardiomyopathy (DCM), 464
Condylar process, 170 Dipstick test, 323
Condyloma accuminatum, 381 Direct thoracoscopy, 441
Congenital adrenal hyperplasia, 407 Dissecting aortic aneurysm, 472
Congenital anomalies, 305 Distal extrahepatic bile duct cancer resection, 52
Congestive splenomegaly, 507 Distal oesophagectomy, 19
Conjunctiva, 233 Distal pancreatectomy, 45, 48
Contrast-enhanced CT scanning (CT), 303 Diversion proctocolitis, 72
Core biopsy, 312, 519 Diverticula, 324, 355
Cornea, 231, 234 Diverticulosis, 73
Coronal sulcus, 379 Doppler scans, 304
Coronary artery bypass graft (CABG), 472 Double adenoma, 215
Coronoid process, 170 Drug-induced cardiomyopathy, 464
Corpus luteum cyst, 245 Duct ectasia, 136
Corpus spongiosum, 379 Ductal carcinoma in situ (DCIS), 137, 138
Cortex, 301, 407, 479 Duodenal ulcer (DU), 57
Craniofacial resection, 153, 154 Duodenitis, 57
C-reactive protein (CRP), 4 Duodenum, 41
Cricoid cartilage, 179 anatomy, 37
Crippled larynx, 186 lymphovascular drainage, 37
Index 551
Dysphagia, 15 Ethmoidal sinuses, 150

Dysplasia, 28, 72, 105–106 Eustachian tube, 179
epithelial, 5 Evisceration, 236
polypoid adenomatous, 29 Ewing’s sarcoma, 481
Dysplasia-associated lesions or masses (DALMs), 72 Exenteration, 239–240
Dysplastic Barrett’s mucosa, 16 Exophthalmos, 364
Dysplastic squamous lesions, 283 Extended pulmonary resection, 442
Dyspnoea, 461 Extracapsular resection, 198
Extrahepatic bile duct, 38, 42
cancer resection, 52–53
E carcinoma, 44
Ear, 428 neoplastic lesions of, 46
Early gastric cancer (EGC), 29 Extra-levator abdominoperineal excision (ELAPE), 79
Ectopic pregnancy, 256, 258 Extramammary Paget’s disease (EMPD), 382, 417
Elective neck dissection, 224 Extranodal marginal zone lymphoma, 440
Electron microscopy, 490, 526 Extraosseous ameloblastoma, 173
Elliptical biopsy, 419 Extrapleural pneumonectomy (EPP), 442, 449, 450
Embryonal carcinoma (EC), 369–370 Extrapleural solitary fibrous tumour, 401
Embryonal rhabdomyosarcoma, 373 Extraprostatic extension (EPE), 343
Empyema, 448 Extrinsic allergic alveolitis, 439
En-bloc resection, 331 Eye
Endobronchial ultrasound fine needle aspiration or anatomy, 231, 232
biopsy (EBUS FNA), 437 conjunctiva, 233
Endobronchial/transbronchial biopsy, 441 cornea, 234
Endocardium, disorders of, 463 enucleation
Endogenous lipoid pneumonia, 438 external anatomy, 236
Endolarynx, 180 laboratory details, 237
Endoluminal ultrasound (ELUS) scan, 4 pathological conditions, 237
Endometrial carcinomas, 264 evisceration, 236
Endometrial hyperplasias, 263 exenteration, 239
Endometrial polyps, 263 eyelids, 231, 233
Endometriosis, 245–247 iris, 234
Endometritis, 263 lacrimal apparatus, 235
Endometrium, 263, 265, 270 ophthalmic pathology, 235–240
Endomyocardial biopsies, 465 orbit, 234
Endoscopic mucosal resection (EMR), 78 Eyelids, 231, 233, 428
Endoscopic retrograde cholangiopancreatography
(ERCP), 44, 45
Endoscopic submucosal dissection (ESD), 19 F
Enteropathy-associated T-cell lymphoma Faecal immunochemical testing (FIT), 75
(EATCL), 59 Fallopian tubes
Enucleation anatomy, 255, 256
external anatomy, 236 biopsy specimens, 257
laboratory details, 237 clinical investigations, 255
pathological conditions, 237 clinical presentation, 255
Eosinophilic oesophagitis, 16 pathological conditions
Epidermis, 415, 428 neoplastic, 256
Epididymis, 363 non-neoplastic, 256
adenomatoid tumour, 372 resection specimens, 257–259
carcinoma of, 372 surgical pathological
epididymal appendix, 372 clinical aspects, 257
epididymal cysts, 372 laboratory aspects, 257–259
neoplastic conditions, 372 Familial adenomatous polyposis (FAP), 42, 75
non-neoplastic conditions, 372 Fat necrosis, 136
Epididymitis nodosa, 372 Femoral heads, 483
Epiglottis, 180 Fibroadenoma, 136
Epithelial dysplasia, 5 Fibromatoses, 486
Epstein–Barr virus (EBV), 182 Fibrosing mediastinitis, 455
Erythrocyte sedimentation rate (ESR), 4, 151, 152 Fibrous epulis, 160
Erythroplasia of Queyrat, 382 Fimbrial cysts, 256
552 Index
Fine needle aspiration (FNA), 183, 482, 499 clinical presentation and investigations, 4
neck, 222 flexible endoscopy, 5
ovary, 248, 249 non-neoplastic resections, 10–12
skin, 419 resection specimens
thyroid gland, 205 fixation, 9
Fine-needle aspiration cytology (FNAC), margins, 9–10
6, 135, 160, 195, 310, 365, 520 specimen collection, 5–6
Fistulogram, 126 specimen handling, 6–7
Flourine 18 fluorodeoxyglucose positron emission Gastrointestinal stromal tumours (GISTs), 29, 30, 59–60
tomography/CT (18F–FDG PET/CT), 406 Gastro-oesophageal reflux (GOR), 15
Fluorescence in situ hybridization (FISH), Gene expression profiling (GEP), 500
327, 490, 526, 529 Germ cell neoplasia in situ (GCNIS), 366–367
FNA. See Fine needle aspiration (FNA) Germ cell tumours, 366, 370–371, 456
Focal mass lesions, 115, 120 Gerota’s fascia, 301
Focal nodular hyperplasia (FNHs), 115 Giant cell arteritis, 470
Follicular adenoma, 206 Giant cell epulis, 160
Follicular carcinoma, 206 Giant condyloma accuminatum, 381–382
Follicular cysts, 245 Gingival bleeding, 171
Fossa of Rosenmüller, 179, 185, 186 GISTs. See Gastrointestinal stromal tumours (GISTs)
Fournier’s gangrene, 381 Glandular prostatic tissue, 337
Fracture, 481 Glans, 379
French Federation of Cancer Centres Sarcoma Group Glans resurfacing, 385
(FNCLCC), 489 Glansectomy, 385, 387–389
Frontal process, 169 Glaucoma, 239
Frozen section, 489 Gleason grading system, 343
Fuhrman system, 309 Glossectomy, 163
Full blood picture (FBP), 497 Glottis, 184
Fumarate hydratase (FH) mutations, 371 Goitre, 204
Functional cysts, 245 Gorlin’s syndrome, 173
Functional endoscopic sinus surgery (FESS), 151 Grading systems, 309
Fungiform papillomas, 152 Granulomatosis
with polyangiitis, 152
Granulomatous inflammation, 372, 478, 500, 512
G Granulomatous orchitis, 365
Gallbladder Granulomatous prostatitis, 341
anatomy, 103–104 Granulosa cell tumour, 371
clinical investigation, 104–105 Graves’ disease, 205
clinical presentation, 104 Groin hernias, 128 (see also Hernias)
lymphovascular drainage, 103–104 Gross haematuria, 303
pathological conditions Gynaecomastia, 136
neoplastic conditions, 105–106
non-neoplastic conditions, 105
surgical pathology specimens H
benign conditions, 106 Haemangioma, 507
gallbladder cancer, 107 Haemochromatosis, 120
resection specimens, 107–109 Haemopoiesis, 506, 509
Gallbladder cancer, 107 Haemorrhoids, 97, 99
Gallstones, 105 Haemosiderotic synovitis, 479
Ganglion, 486 Hair, 415, 427
Gastrectomy, 31–33 Hairy cell leukaemia, 514
Gastritis Hamartomas, 173
acute, 27 Hartmann’s procedure, 80
autoimmune, 27 Hashimoto’s thyroiditis, 205
chronic, 27, 28 Heart
Gastroduodenal peptic ulceration, 31 anatomy, 461
Gastrointestinal disorders, 4 biopsy specimens, 465
Gastrointestinal epithelial neoplasia, 28 cardiac valves, 466
Gastrointestinal specimens clinical investigations, 463
anatomy, 3–4 clinical presentation, 461
cancer resection, 10 pathological conditions
Index 553
neoplastic, 465 Hypoadrenalism, 406

non-neoplastic, 463–465 Hypoparathyroidism, 214
resection specimens, 466–467 Hypopharynx, 179, 182
surgical pathology Hysterectomy, for CIN/CGIN, 279–281
clinical aspects, 465 Hysteroscopy, 263
laboratory protocols, 465
Heart transplant, 465
Heat-mediated antigen retrieval techniques (HMAR), I
523 Iatrogenic disorders, 74
Helicobacter pylorii (HP) Ilioinguinal lymph node dissection (ILND), 386
antral gastritis, 28 Immature teratoma, 456
pangastritis, 28 Immune-mediated lung diseases, 439
Hemicolectomy, 91 Immunoblastic proliferation, 500
Hemiglossectomy, 166 Immunofluorescence, 312, 525
Hemimandibulectomy, 175, 176, 178 Immunohistochemistry, 312, 489–490
Hemivulvectomy, 292 In situ hybridization, 526
Hepatectomy, 120–123 Incisive papilla, 158
Hepatic mucinous cystic neoplasms, 116 Infarction, 127, 341
Hepatocellular carcinoma, 114, 116 Infective endocarditis, 463
Hereditary leiomyomatosis and renal cell carcinoma Infective oesophagitis, 16
(HLRCC)-associated RCC, 308–309 Infective proctocolitis, 72
Hernias, 58 Infiltrative cardiomyopathies, 464
clinical investigations, 126 Inflammation, 127, 239
clinical presentation, 125 Inflammatory bowel disease (IBD), 80
pathological conditions, 126 Inflammatory disease, 429
resection specimens, 128 Inflammatory disorders, 71
surgical pathology Inflammatory fibroid polyp, 58
clinical aspects, 128 Inflammatory myofibroblastic tumour (IMT), 325
laboratory protocol, 130 Inflammatory polyps, 151
Herniography, 126 Infratemporal fossa, 169, 171
High resolution CT (HRCT), 436 Inguinal canal, 125
High-grade PIN (HGPIN), 342 Internal carotid endarterectomy, 472
HIV, 512 Internal jugular vein (IJV), 220
Hodgkin lymphoma (HL), 502–503, 507 International Society of Urological Pathology
Horizontal cuts, 237 (ISUP), 343
Human chorionic gonadotrophin (HCG), 365 Interstitial cystitis, 324
Human papilloma virus (HPV), 97, 356 Interstitial pneumonia/cryptogenic fibrosing alveolitis/
Human placental lactogen (HPL), 370 pulmonary fibrosis, 438
Human Tissue Act, 530 Intestinal-type sinonasal adenocarcinoma, 152
Hyaline arteriolosclerosis, 470 Intracapsular excision, 487
Hydatid cysts, 119 Intraductal carcinoma of the prostate gland (IDC-P),
Hydrocele, 366, 375 342–343
Hydronephrosis, 304–305 Intraductal papillary mucinous neoplasms
Hydrosalpinx, 256 (IPMN), 43
Hydroureter, 304 Intramucosal adenocarcinoma, 17
Hyperaldosteronism, 406 Intrathoracic oesophagus, 13
Hypercalcaemia, 480 Intravenous pyelogram (IVP), 303
Hypercortisolism, 406 Intravenous urogram (IVU), 303, 323
Hyperparathyroidism, 213 Invasive carcinoma, 137
Hyperplasia Invasive urothelial carcinoma, 327
follicular, 500 Inverted papillomas, 152
mantle zone, 500 Iris, 234
marginal zone, 500 Ischaemia, 58, 62
paracortical, 500 Ischaemic disorders, 73
reactive, 512 Ivor Lewis technique, 18
Hyperplastic arteriolitis, 470
Hyperplastic polyps, 28
Hypersplenism, 507 J
Hypertrophic cardiomyopathy Jaw cysts, 176
(HCM), 464 Jejunal ring diaphragm disease, 62
554 Index
Joint space Liposarcoma, 373, 400

anatomy, 477 Lips
biopsy specimens, 479 anatomy, 157–158
cinical presentation, 477 biopsy specimens, 162–164
clinical investigation, 477–478 clinical investigations, 159–160
pathological conditions clinical presentation, 159
neoplastic, 479 pathological conditions
non-neoplastic, 478–479 neoplastic, 161–162
resection specimens, 479 non-neoplastic, 160–161
surgical pathology resection specimens, 163–164
clinical aspects, 479 surgical pathology
laboratory protocol, 479 clinical aspects, 162–164
laboratory protocols, 164–168
wedge resection of, 166–168
K Liquid-based cytology, 521
Kaposi’s sarcoma, 384 Littoral cells, 506, 507
Kawasaki disease, 471 Liver
Keratin granulomas, 127 anatomy, 111–112
Keratinizing squamous metaplasia, 325 biopsy specimens, 117, 120
Kidneys clinical investigations, 113–114
biopsy specimens, 310–312 cysts, 119–120
clinical investigations, 303–304 pathological conditions
clinical presentation, 302–303 neoplastic, 116–117
neoplastic conditions, 305–310 non-neoplastic, 114–116
non-neoplastic conditions, 304–305 resection, 117–119
paediatric tumours, 310 resection specimens, 117–124
regional lymph nodes, 302 surgical lobes, 118
resection specimens, 311–318 surgical pathology
Krukenberg tumours, 9 clinical aspects, 117–120
laboratory protocol, 120–124
transplantation, 120
L Liver function tests (LFTs), 113
Lacrimal apparatus, 235 Liver resection, 119, 120
Lactate dehydrogenase (LDH), 365 Lobectomy, 208, 442
Laparoscopic nephrectomy, 311 Lobular carcinoma in situ (LCIS), 137
Laparoscopic nephroureterectomy, 309 Loopography, 323
Large cell carcinoma, 440 Lower jugular group, 221
Large cell neuroendocrine carcinoma (LCNEC), 440 Low-grade appendiceal mucinous neoplasm (LAMN), 90
Large loop excision of the transformation zone (LLETZ), Lumps, 160
275 Lung
Laryngeal cartilages, 181 anatomy, 435
Laryngectomy, 181, 188–190 biopsy specimens, 441, 442
Larynx clinical investigations, 436–437
biopsy specimens, 186, 187 pathological conditions
clinical investigations, 182–183 neoplastic, 439–441
clinical presentation, 182 non-neoplastic, 438–439
pathological conditions resection specimens, 441, 443
neoplastic, 183 surgical pathology
non-neoplastic, 183 clinical aspects, 441–442
resection specimens, 186–192 laboratory protocols, 442–446
surgical pathology Lung abscess, 438
clinical aspects, 186–187 Lung transplantation, 439
laboratory aspects, 187–191 Lung volume reduction surgery (LVRS), 442
Leukaemia, 418, 507, 513 Lymph node excision biopsy, 499–500
Leydig/interstitial cell tumours, 371 Lymph nodes, 123, 159, 430
Lichen sclerosus (LS), 381 anatomy, 495–497
Lining mucosa, 157 biopsy, 504–505
Index 555
clinical investigations, 497–500 prostate, 340

clinical presentation, 497 urethra, 354
lymphovascular drainage, 497 Magnetic resonance venography (MRV), 304
metastasis, 185 Malakoplakia, 324
pathological conditions Malignant lesions, 78–80
neoplastic, 500–504 Malignant lymphoma, 29, 59, 153
non-neoplastic, 500 Malignant melanoma, 238, 416, 430
surgical pathology Malignant mesenchymal tumours, 418
clinical aspects, 504 Malignant mesothelioma, 448
laboratory protocols, 504–505 Malignant tumours, 246–248, 257, 284, 342
Lymphadenectomy, 123, 348 bone, 481–482
Lymphadenopathy, 497 breast, 137–139
Lymphatic drainage larynx and pharynx, 184–185
heart, 461 lips, 161
tongue, 159 lung, 439
Lymphocytes, 495, 496 mouth, 161–162
Lymphoepithelioma-like carcinoma, 384 salivary glands, 197
Lymphoid neoplasm, 513 spleen, 507–508
Lymphomas tongue, 161–162
malignant, 29, 59–60, 497 Malignant uterine mesenchymal lesions, 264
marginal zone, 501 Mammography, 134, 135, 137
mediastinum, 456 Mandible
mimicking carcinomas, 504 anatomy, 169–170
primary splenic marginal zone, 507 biopsy specimens, 174–175
Lymphoproliferative malignancies, 513 clinical investigations, 171
Lymphovascular drainage, 14, 133, 302, 321 clinical presentation, 171
adrenal gland, 405 pathological conditions
cervix, 273 neoplastic, 173–174
fallopian tube, 255 non-neoplastic, 172–173
from prostate, 338 resection specimens, 175–178
larynx, 182 surgical pathology
liver, 112 clinical aspects, 174–175
lung, 435 laboratory aspects, 175–178
mediastinum, 453 Marginal excision, 487
mouth, 159 Massive oedema, 246
nasal cavity, 151 Mastectomy, 140–142
neck, 219 Masticatory mucosa, 157
ovary, 243 Mastocytosis, 513
paranasal sinuses, 151 Mature cystic teratoma, 456
parathyroid gland, 213 Maxilla
pharynx, 182 anatomy, 169
pleura, 447 biopsy specimens, 174–175
salivary glands, 194 clinical investigations, 171–172
skin, 415 clinical presentation, 171
teeth, 171 pathological conditions
thyroid gland, 203 neoplastic, 173–174
uterus, 261 non-neoplastic, 172–173
vagina, 283 resection specimens, 175–178
vulva, 289 surgical pathology
Lymphovascular invasion (LVI), 329, 343 clinical aspects, 174–175
Lynch syndrome, 75 laboratory aspects, 175–178
Maxillary alveolectomy, 175
Maxillary sinuses, 150, 151
M Maxillectomy, 175–177
Magnetic resonance imaging (MRI), Meckel’s diverticulum, 57–58, 61, 62
4, 113, 304, 499 Medial maxillectomy, 153, 154
bladder, 323 Median sternotomy, 442
lung, 436 Mediastinal Hodgkin’s disease, 456
pelvic exenteration, 394 Mediastinal large B-cell lymphoma, 456
556 Index
Mediastinoscopy, 437 Monochorionic placenta, 296

Mediastinum Mouth
anatomy, 453 anatomy, 157–159
biopsy specimens, 457, 458 biopsy specimens, 162–164
clinical investigations, 454 clinical investigations, 159–160
clinical presentation, 453 clinical presentation, 159
compartments, 454 pathological conditions
masses, 456 neoplastic, 161–162
pathological condition non-neoplastic, 160–161
anterior mediastinal masses, 455 resection specimens, 163–164
infection, 455 surgical pathology
middle mediastinal masses, 457 laboratory protocols, 164–168
posterior mediastinal masses, 457 MRI. See Magnetic resonance imaging (MRI)
resection specimens, 457–459 Mucinous cystic neoplasms (MCNs), 43
surgical pathology Mucinous tubular, 308
clinical aspects, 457 Mucocele, 90, 195, 199
laboratory protocols, 458–459 Mucoepidermoid carcinoma, 197
Medical renal diseases, 302 Mucosal biopsy, 6
Medulla, 301, 408 Mucosal blocks, 10
Medullary carcinoma, 207 Mucosal polyps, 6, 8
Melanocytic naevi (moles), 416 Mucosal prolapse, 73
Melanosis coli, 72 Mucous extravasation cyst, 195
Merkel cell tumours, 417 Mucous retention cyst, 195
Mesenchymal tumours, 138 Multilocular thymic cysts, 455
Mesothelial hyperplasia, 127 Multinodular goitre, 205
Mesothelioma, 373–374 Multiple myeloma, 482
Metaiodobenzylguanidine (MIBG), 406 Myasthenia gravis, 453
Metaphase cytogenetics, 528 Mycotic aneurysm, 471
Metastases, 514 Mycotic infections, 438
Metastatic carcinoma, 117, 482, 497, 504, 508 Myelodysplastic syndromes (MDS), 513
Metastatic malignant tumour, in cervical lymph nodes, Myeloid neoplasm, 513
223 Myeloma, 514
Microcalcifications, 134 Myeloproliferative neoplasms (MPN), 513
Microdochectomy, 139 Myocarditis, 464
Micropapillary urothelial carcinoma, 328 Myocardium, disorders of, 464
Microsatellite instability (MSI), 528 Myoepithelial sialadenitis (MESA), 196
Microscopic colitis, 72 Myxoid degeneration of Reinke’s space, 183
Microscopic polyarteritis, 470 Myxoma, 465
Micturating cystourethrography, 323
Middle jugular group, 221
Midstream sample of urine (MSSU) culture, 323 N
Millipore strip, 5, 7 Nails, 415, 427
Minimally invasive oesophagectomy (MIO), 19 Nasal cavity
Mirizzi syndrome, 104 anatomy, 149
Miscellaneous lesions, 137 biopsy specimens, 154
Miscellaneous specimens clinical investigation, 151
cell blocks, 521 clinical presentation, 151
cytospins, 521 pathological conditions
FNAC, 520 neoplastic, 152–153
frozen sections, 522 non-neoplastic, 151–152
liquid-based cytology, 521 resection specimens, 153–156
needle core biopsies, 519–520 right lateral wall, 150
photography, 521–522 surgical pathology
radiography, 522 clinical aspects, 153–154
Mitomycin C, 309 laboratory aspects, 154–156
Mitral valve regurgitation, 464 Nasal endoscopy, 151
Mitral valve stenosis, 464 Nasal vestibule, 149
Mixed germ cell-sex cord stromal tumours, 371 Nasopharyngeal (juvenile) angiofibroma, 184
Modified partial penectomy, 385 Nasopharyngeal carcinoma, 185
Mohs micrographic surgery, 385 Nasopharynx, 179, 182
Index 557
National Health Service Breast Screening Odontome, 173

Programme, 134 Oesophageal carcinoma, 16, 22
Native valves, 466 Oesophageal cysts, 457
Neck Oesophageal neoplasia, 18
anatomy Oesophagectomy
anterior triangle, 219 distal, 19
lymph node, 219–221 thoracoabdominal, 18
biopsy specimens, 224, 225 transhiatal, 18, 19
clinical investigations, 222 Oesophagogastric (OG) junction, 13
clinical presentation, 222 Oesophagogastroduodenoscopy (OGD), 57
dissection specimen, 226–227 Oesophagoscope, 182
pathological conditions Oesophagus
neoplastic, 223–224 anatomy, 13–14
non-neoplastic, 223 biopsy specimens, 18
resection specimens, 224–227 clinical investigations, 15
surgical pathology clinical presentation, 15
clinical aspects, 224–225 EMR specimens, 18, 19
laboratory aspects, 225–227 neoplastic conditions, 16–17
Necrotizing lymphadenitis, 500 non-neoplastic conditions, 15–16
Necrotizing pancreatitis, 47 resection specimens, 18–22
Needle core biopsies (NCB), 7, 135, 139, 505, 519–520 thoracotomy, 18
Neoadjuvant chemotherapy, 144 transhiatal oesophagectomy, 18–19
Neoplasia Oleogranulomas, 105
gastrointestinal epithelial, 28 Omentectomy, 128
oesophageal, 18 Omentum, 128, 130
Neoplastic lesions anatomy, 125
of endocrine pancreas, 46 biopsy specimens, 128
of extrahepatic bile ducts, 46–47 clinical investigations, 126
Nephritic syndrome, 302 clinical presentation, 125
Nephrogenic adenoma, 324 pathological conditions, 127
Nephrogenic metaplasia, 324 resection specimens, 128
Nephron-sparing surgery (NSS), 311 surgical pathology
Nephrotic syndrome (NS), 302 clinical aspects, 128
Nested urothelial carcinoma, 328 laboratory protocol, 130
Neuroblastoma, 408 Oncocytoma, 305
Neuroendocrine tumours (NET), 43–44, 440 Open excision biopsy, 135
Neurogenic bladder, 325 Open heart surgical procedures, 465
Neurogenic tumours, 457 Open pleural biopsy, 448
Next generation sequencing (NGS), 500 Open renal biopsy, 311
Nicorandil-induced penile ulceration, 381 Open wedge biopsy, 312
Nipple biopsy, 139 Open/simple prostatectomy, 346
Nipple discharge, 134, 136, 138 Oral mucosa, 160, 161
Nodular fasciitis, 486 Orbit, 234
Non-bacterial thrombotic endocarditis (NBTE), 463 Oropharynx, 179
Noncyclical endometrium, 263 Osteomyelitis, 481
Non-Hodgkin’s lymphoma, 456 Osteoporosis, 481
Non-keratinizing squamous cell carcinoma. See Osteosarcoma, 481
Squamous cell carcinoma Ovarian-type epithelial tumours, 374
Non-neoplastic polyps, 28, 59 Ovary
Non-seminomatous germ cell tumours (NSGCT), anatomy, 243, 244
368–369, 456 biopsy specimens, 248, 249
Non-superficial lymphadenopathy, 497 clinical investigations, 244
Non-Visible Haematuria (NVH), 322 clinical presentation, 243
pathological conditions
neoplastic, 246–248
O non-neoplastic, 245–246
Obstructive enterocolitis, 73 resection specimens, 248, 249
Obstructive enteropathy, 62–66 surgical pathology
Odontogenic keratocyst, 172 clinical aspects, 248–249
Odontogenic neoplasms, 173 laboratory protocols, 249
558 Index
P Patterson Brown-Kelly syndrome, 184

Paediatric tumours, 310 Pelvic exenteration
Paget’s disease, 137, 417 anatomy, 393
Painful bladder syndrome, 324 anterior pelvic exenteration, 393
Palatal fenestration, 153, 175 clinical investigations, 393–394
Palatine process, 169 clinical presentation, 393
Pancreas, 37–38, 41 pathological conditions, 394–395
endocrine, neoplastic lesions of, 46 posterior pelvic exenteration, 393
lymphovascular drainage, 38 specimen blocking, 397
regional lymph nodes, 40 surgical pathology, 395–398
Pancreatectomy, 45, 49 total pelvic exenteration, 393
Pancreatic carcinoma, 43, 45 Pelvic lymphadenectomy (PLND), 329
Pancreatic neuroendocrine tumours (NET), 43 Pelvi-ureteric junction (PUJ) obstruction, 303, 304
Pancreatic pseudocyst, 47 Penectomy, 387–389
Pancreatitis Penile intraepithelial neoplasia (PeIN), 381–382
acute, 39, 41, 47 Penis
autoimmune, 42 anatomy, 379, 380
chronic, 39, 41, 42 biopsy specimens, 384–387
necrotizing, 47 clinical investigations, 380
Papilla, 44, 301 clinical presentation, 380
Papillary carcinoma, 206 lymphovascular drainage, 379
Papillary cystadenoma, 372 malignant melanoma, 384
Papillary renal cell carcinoma (PRCC), 307 metastatic tumours, 384
Papillary squamous cell carcinoma, 384 neoplastic conditions, 381–383
Papillary urothelial neoplasm of low malignant potential non-neoplastic conditions, 380–381
(PUNLMP), 327 penectomy specimen, 388
Paraganglioma, 223 prognosis, 382
Paranasal sinuses radical surgery, 386
anatomy, 150–151 resection specimens, 385, 387–390
biopsy specimens, 153, 154 squamous cell carcinoma, 382
clinical investigation, 151 WHO classification of tumours, 383
clinical presentation, 151 Peptic ulcer, 28, 30, 31
pathological conditions Percutaneous needle biopsy, 310, 441
neoplastic, 152–153 Percutaneous transhepatic cholangiography (PTC), 41,
non-neoplastic, 151–152 113
resection specimens, 153–156 Perianal margin carcinoma, 97
surgical pathology Pericardial cysts, 457
clinical aspects, 153–154 Pericardium, disorders of, 464
laboratory aspects, 154 Perineural invasion (PNI), 343
Paraneoplastic syndrome, 436, 453 Periosteum, 163, 480
Paraphimosis, 380 Peripheral nerve tumours, 400–401
Parathyroid glands, 204 Peripheral T cell lymphoma, 502
anatomy, 213 Peritoneal inclusion cysts, 127
biopsy specimens, 215 Peritoneal serous epithelial proliferation, 127
clinical investigations, 214 Peritoneum, 130
clinical presentation, 213 pathological conditions, 127
pathological conditions surgical pathology
neoplastic conditions, 215 laboratory protocol, 130
non-neoplastic conditions, 214 PET. See Positron emission tomography (PET)
resection specimens, 215, 216 Peutz–Jegher’s syndrome, 56, 59
surgical pathology Peyronie’s disease, 381
clinical aspects, 215 Phaeochromocytoma, 406, 408
laboratory aspects, 216 Pharyngectomy, 190–191
Paratubal cysts, 256 Pharynx
Parenchyma, 301 anatomy, 179, 180
Parotid gland, 193, 194 biopsy specimens, 186, 187
Parotidectomy, 199 clinical investigations, 182–183
Partial laryngectomy, 186 clinical presentation, 182
Partial nephrectomy, 311 pathological conditions
Partial penectomy, 385 neoplastic, 183–185
Index 559
non-neoplastic, 183 mucosal, 6, 8

resection specimens, 186–188 non-neoplastic, 28, 59
surgical pathology serrated, 74
clinical aspects, 186–187 Porta hepatis, 111
laboratory aspects, 187–191 Positron emission tomography (PET),
Phimosis, 380 4, 182, 304, 340
Phyllodes tumour, 138 bladder, 323
Pigmented villonodular synovitis, 479 lung, 437
Placenta pelvic exenteration, 394
accreta, 297 testes, 365
anatomy, 295 urethra, 355
blocks for histology, 296 Posterior triangle group, 221
clinical, 295 Posterolateral thoracotomy, 442
dichorionic placenta, 296 Postoperative necrobiotic granuloma,
macroscopic description, 296 325, 341
monochorionic placenta, 296 Preinvasive vulval squamous lesions, 289
multiple gestations, 296–297 Primary chief cell hyperplasia, 214
surgical pathology specimens, 295 Primary malignant lymphoma, 207
umbilical cords, 296 Proctocolitis
Placental site trophoblastic tumour (PSTT), 370 diversion, 72
Plasma cell balanitis, 380 infective, 72
Plasma cell neoplasms, 503 Proliferative lesions, 137
Plasmacytoid urothelial carcinoma, 328 Propidium iodide, 526
Pleomorphic adenoma, 235 Prostate
Pleomorphic salivary adenoma, 196 anatomy, 337–338
Pleura biopsy, 340
anatomy, 447 biopsy specimens, 345–346
biopsy specimens, 449 clinical investigations, 339–340
clinical investigations, 447 clinical presentation, 338–339
clinical presentation, 447 CT scan, 340
pathological conditions localized prostate cancer, 343
neoplastic, 448 locally advanced prostate cancer, 344
non-neoplastic, 448 metastatic prostate cancer, 344
resection specimens, 449–451 MRI, 340
surgical pathology neoplastic conditions, 342–345
clinical aspects, 449–450 non-neoplastic conditions, 340–341
laboratory protocols, 450 prognosis, 344–345
Pleural effusions, 448 prostatic lobes, 338
Pleural needle biopsy, 447 prostatic zones, 338
Pleural plaques, 448 resection specimens, 346
Pleurectomy, 449, 450 Prostate specific antigen (PSA), 339–340
Pneumatosis, 81 Prostatic adenocarcinoma, 342–344
Pneumatosis coli, 72 Prostatic intraepithelial neoplasia (PIN),
Pneumoconiosis, 438 338, 342
Pneumocystis jiroveci, 438 Prostatitis, 341
Pneumonectomy, 442 Pseudocyst, pancreatic, 47
Pneumothorax, 448 Pseudoglandular squamous cell carcinoma, 384
Polyarteritis nodosa, 470, 471 Pseudohyperplastic carcinoma, 384
Polycarbonate strip, 5, 7 Pseudohypoparathyroidism, 214
Polycystic ovarian disease, 245 Pseudomyxoma peritonei, 127
Polycythaemia, 509 Pulmonary hypertension, 439
Polymorphous low-grade adenocarcinoma, 197 Pulmonary valve abnormalities, 464
Polypoid adenomatous dysplasia, 29 Pulmonary vascular disease, 439
Polypoid urethritis, 355 Pulp canal, 170
Polypoid/papillary cystitis, 324 Punch excision biopsy, 418
Polyps, 7, 90, 183 Purulent synovitis, 478
adenomatous, 70, 78 Pyogenic abscess/cyst, 119
cloacogenic, 100 Pyogenic epididymo-orchitis, 365
hyperplastic, 6, 28 Pyonephrosis, 304–305
inflammatory fibroid, 58 Pyothorax- associated lymphoma, 449
560 Index
R pathological conditions, 400–401

Radical cystectomy, 357 resection specimens, 401–403
Radical cystoprostatectomy, 357 retroperitoneal tumours, 401
Radical excision, 487 Reverse transcriptase polymerase chain reaction
Radical inguinal orchidectomy, 374 (rtPCR), 490
Radical maxillectomy, 175 Rhabdomyoma, 465
Radical nephrectomy, 311 Rheumatic fever, 463
Radical prostatectomy, 346–352 Rheumatoid arthritis, 478
Radicular cyst, 172 Rheumatoid nodule, 486
Radiofrequency ablation (RFA), 16, 306 Right ventricular dysplasia, 464
Radioisotope scan, 4, 113 Rigid sigmoidoscopy, 76
Radiolabelled isotope bone scan, 340 Rim resections, 175–178
Radiolucency, 172 Rivinus’ ducts, 194
Ramus, 170 Robotic-assisted partial nephrectomy (RAPN), 312
Ranula, 195 Robotic-assisted radical prostatectomy (RRP), 346
Rectal mucosal prolapse, 81 Rokitansky–Aschoff sinuses, 105, 106
Rectal stump, 81
Reduction mammoplasty, 136
Reflux oesophagitis, 15 S
Refractory anaemia with ring sideroblasts (RARS), 513 Salivary duct obstruction, 195
Regional enteritis, 57 Salivary glands, 195–201
Regional lymphadenectomy, 311 anatomy, 193–194
Renal arteriography, 304 biopsy specimens, 198, 199
Renal cell carcinoma (RCC), 303, 306–307 clinical investigations, 195
histopathology report, 317 clinical presentation, 194–195
unclassified, 309 parotid, 193
Renal cysts, 305 pathological conditions
Renal medullary carcinoma, 308 neoplastic, 196–198
Renal neoplasms non-neoplastic, 195–196
2016 World Health Organization classification, 307 resection specimens, 198, 199
Renal pelvis, 301 sublingual, 193
histopathology report, 318 submandibular, 193
Renal stones, 304 surgical pathology
Renal tumour, 312 clinical aspects, 198
Renal-sparing surgery, 309 laboratory aspects, 199–201
Resectable disease, 43 Salivary gland-type adenocarcinoma, 152
Respiratory function tests, 437 Sarcoidosis, 439
Restrictive cardiomyopathy (RCM), 464 Sarcomas, 373, 486
Rete testis Sarcomatoid carcinoma, 309, 383
adenocarcinoma, 373 Sarcomatoid urothelial carcinoma, 328
neoplastic conditions, 373 Scanning electron microscopy (SEM), 427
non-neoplastic conditions, 372 Sclerosing cholangitis, primary, 115
sertoliform cystadenoma, 373 Scrotal ultrasound, 365
Reticulocyte index, 512 Seborrhoeic keratosis, 418
Retinoblastoma, 239 Secondary adenocarcinomas, 127, 440
Retrograde pyelography, 303 Secondary parathyroid hyperplasia, 214
Retromolar trigone, 157, 164, 165 Segmental ureterectomy, 309
Retroperitoneal lymph node dissection (RPLND), 401, Seminal vesicle (SV) invasion, 343
403–404 Seminoma, 367–368, 456
Retroperitoneum Sentinel node biopsy (SNB), 140, 143, 430
anatomy, 399–400 Serological markers, 4
and pelvic lymph node, 399 Serrated polyps, 74
biopsy specimens, 401 Sertoli cell tumours, 371
clinical investigations, 400 Serum prostate specific antigen (PSA), 339
clinical presentation, 400 Serum tumour marker concentrations, 365
excision biopsy, 402 Sessile serrated lesions, 74
liposarcoma, 400 Sex cord-stromal tumours, 370–371
malignant lymphoma, 401 Shave biopsy, 418, 419
metastatic disease, 401 Sigmoid notch, 170
needle core biopsy specimens, 402 Sigmoidoscopy, 76
Index 561
Silicone implants, leakage, 136 pathological conditions

Siliconomas, 136 neoplastic, 486, 487
Simple nephrectomy, 311 non-neoplastic, 486
Sinonasal cancer, 152 resection specimens, 487–489
Sinus proliferation, 500 surgical pathology
Sinusitis, 151 clinical aspects, 487
Sjögren’s syndrome, 196 laboratory protocols, 487–488
Skin Solid pseudopapillary neoplasm, 43
anatomy, 415 Solitary fibrous tumour, 449
appendages, 415 Specialized mucosa, 157
basal cell carcinoma, 429 Spermatic cord
biopsy and excision specimens, 418 neoplastic conditions, 373–374
clinical investigations, 416 non-neoplastic conditions, 373
clinical presentation, 415 Spermatic granuloma, 372
curettage specimens, 418, 419 Spermatocele, 372
diagrams, 427 Spermatocytic tumour, 367–368
digits, 427 Sphenoidal sinuses, 150
ear, 428 Spindle cell carcinoma, 308
eyelid, 428 Spleen
fixation, 427 anatomy, 506
graft, 427 clinical investigations, 506
hair, 427 clinical presentation, 506
histopathology, 429 pathological conditions
immunofluorescence, 424 neoplastic, 507–508
lip, 428 non-neoplastic, 507
malignant melanoma, 430 surgical pathology
Mohs laboratory procedure, 425 clinical aspects, 508
nails, 427 laboratory protocols, 508–509
pathological conditions, 416 Splenectomy, 507, 508
pilonidal sinus, 428 Squamous cell carcinoma, 16, 98, 152, 184, 329–330,
rashes, 415 417, 429
re-excisions, 427 intraoral, 162
scrapings, 427 lung, 439
squamous cell carcinoma, 429 penis, 382
surgical margins, 425 Squamous cell dysplasia/carcinoma, 16
surgical pathology Squamous epithelial dysplasia, 161, 184
clinical aspects, 418–419 Squamous hyperplasia, 381
laboratory protocols, Stenson’s duct, 193
419–424 Stereotactic core biopsy, 519
sutures and markers, 425 Stomach
Sleeve lobectomy, 442 anatomy, 25–26
Sleeve pneumonectomy, 442 clinical investigations, 26–27
Small cell carcinoma (SmCC), clinical presentation, 26
328, 440 lymphovascular drainage, 26
Small intestine pathological conditions
anatomy, 55–56 neoplastic conditions, 28–30
clinical investigations, 56–57 non-neoplastic conditions, 27–28
clinical presentation, 56 regional lymph nodes, 27
lymphovascular drainage, 56 surgical pathology specimens
non-neoplastic conditions, 57–59 biopsy specimens, 30
pathological conditions resection specimens, 31–32
neoplastic conditions, 59–60 Stomas, 126, 129
surgical pathology specimens Stratified epithelium, 379
biopsy specimens, 60, 62 Stromal hyperplasia, 246
resection specimens, 60–62 Stromal hyperthecosis, 246
Soft tissues Subcutaneous fat, 415
anatomy, 485 Sublingual gland, 193
biopsy specimens, 487 Submandibular gland, 193
clinical investigations, 486 Submandibular group. See Digastric triangles
clinical presentation, 486 Submandibulectomy, 199
562 Index
Submental triangles, 220 Thoracoabdominal oesophagectomy, 18

Succinate dehydrogenase (SDH) deficient renal Thoracoscopy, 447
carcinoma, 308–309 Thoracotomy, 18
Superficial parotidectomy, 198, 199 Thrombotic disorders, 510
Surgical lobes, 118 Thymectomy, 457
Sydney system, 27 Thymic carcinoma, 455
Symptomatic non-visible haematuria (s-NVH), 322 Thymic hyperplasia, 455
Syncytiotrophoblastic giant cells (STGC), 369 Thymic neuroendocrine tumours, 456
Synovial chondromatosis, 479 Thymoma, 455
Synovial fluid analysis, 478, 479 Thyroglossal duct cyst, 223
Synovial joints, 477 Thyroid cartilage, 180
Synovitis, 478 Thyroid gland
Synovium, 479 anatomy, 203
Syphilitic aneurysms, 471 biopsy specimens, 207, 208
Systemic diseases, 115 clinical investigations, 204
Systemic internal radiation therapy (SIRT), 117 clinical presentation, 204
Systemic mastocytosis, 507 GASH risk assessment, 207
neoplastic conditions, 206–207
T non-neoplastic conditions, 205
T/NK cell neoplasms, 502 resection specimens, 208–210
Takayasu arteritis, 470 surgical pathology
Teeth clinical aspects, 207
anatomy, 170–171 laboratory aspects, 208–210
biopsy specimens, 174–176 Tongue
clinical investigations, 171–172 anatomy, 159
clinical presentation, 171 biopsy specimens, 164
pathological conditions clinical investigations, 159–160
neoplastic, 173–174 clinical presentation, 159
non-neoplastic, 172–173 resection specimens, 163–166
resection specimens, 175–178 surgical pathology
surgical pathology clinical aspects, 162–164
clinical aspects, 174–175 laboratory aspects, 164–168
laboratory aspects, 175–178 Tonsillectomy, 183, 187–188
Temporal artery, 469, 472 Tonsillitis, 183
Tenderness to percussion (TTP), 171 Torsion, 373
Teratoma Total laryngectomy, 186
post pubertal type, 368–369 Total mesorectal excision (TME), 9
prepubertal-type, 369 Total parotidectomy, 198
with somatic-type malignancy, 369 Total penectomy, 385
Testes Trabeculae, 480, 495, 509
anatomy, 363–364 Tracheal tumours, 441
appendix epididymis, 375 Trachelectomy, 276, 279
biopsy specimens, 374 Transanal microsurgery (TAMIS), 78
clinical investigations, 365 Transanal resection of tumour (TART), 78
clinical presentation, 364–365 Transarterial chemoembolization
epididymectomy, 375 (TACE), 117
histological classification, 366 Transcriptome, 529
lymphovascular drainage, 363 Transhiatal oesophagectomy, 18, 19
neoplastic conditions, 366–371 Transient elastography, 113
non-neoplastic conditions, 365–366 Transient ischaemic attacks (TIA), 469
orchidectomy specimen, 377 Transillumination, 237
radiological evaluation, 365 Transitional cell, 152
regional lymph nodes, 364 Transitional cell carcinoma (TCC), 309, 327
resection specimens, 374–378 Transitional epithelium, 321
testicular biopsy, 375 Translocation carcinoma, 308
Therapeutic neck dissection, 225 Transmission electron microscopy (TEM), 427
Therapy-induced changes, 324 Transoral robotic surgery (TORS), 186
Thermal ablation, 117 Transperineal template-guided saturation prostate
Thoracentesis, 447 biopsy, 345, 347
Index 563
Transrectal ultrasound (TRUS) biopsy, Urethritis, 355

340, 345, 347, 519 Urethroscopy, 357
Transthoracic needle aspiration and biopsy Urinalysis, 323
(TTNA and TTNB), 437 Urinary hydroxyproline, 480
Transurethral resection of prostate (TURP), Urinary tract infection (UTI), 341
341, 345–347 Urothelial carcinoma (UC), 309–310, 327, 356
Trephine biopsy, 512–514 Urothelial dysplasia, 325–326
Tricuspid valve abnormalities, 464 Urothelial proliferation of uncertain malignant
Trigone, 321 potential (UPUMP), 327
Triple assessment approach, 135 Urothelial tract
Tuberculosis, 438 WHO 2016 classification of tumours,
Tumour lymphovascular invasion (LVI), 139 326
Tunica vaginalis (TV), 375 Urothelium, 321
Turbinates, 149 USS. See Ultra sound scan (USS)
Typical carcinoid tumours, 440 Uterine carcinosarcomas, 264
Uterine leiomyomas, 264, 265
Uterus
U anatomy, 261–262
Ulcer, 160 biopsy specimens, 265, 266
duodenal, 57 clinical investigations, 263
peptic, 28, 30, 31 clinical presentation, 262
Ultra sound scan (USS), 4, 126, 135, 182, 195, pathological conditions
204, 222, 263, 304, 323, 447, 499 neoplastic, 263–265
Umbilicus non-neoplastic, 263
anatomy, 125 resection specimens, 265, 270
biopsy specimens, 128 surgical pathology
clinical investigations, 126 clinical aspects, 265
clinical presentation, 125 laboratory aspects, 266–270
pathological conditions, 126
resection specimens, 128
surgical pathology V
clinical aspects, 128 Vacuum assisted biopsy, 135
Unicystic ameloblastoma, 173 Vagina
Unilocular thymic cysts, 455 anatomy, 283
Union for International Cancer Control (UICC), 158 biopsy specimens, 285
Upper jugular group, 220 clinical investigations, 283
Urachal carcinoma, 329 clinical presentation, 283
Urachal-related lesions, 325 pathological conditions
Ureter carcinoma neoplastic, 284
histopathology report, 318 non-neoplastic, 284
Ureteropyeloscopy, 303 resection specimens, 285
Ureterosigmoidostomy, 331 surgical pathology
Urethra clinical aspects, 285
anatomy, 353, 354 laboratory aspects, 285–287
benign tumours, 356 Vaginal intraepithelial neoplasia
biopsy specimens, 357, 358 (VAIN), 283
clinical investigations, 354–355 Valves, disorders of, 464
clinical presentation, 354 Varicocele, 373
female urethra, 353 Varicose veins, 471
lymphovascular drainage, 353 Vascular anomalies, 160
malignant tumours, 356 Vascular grafts, 472
neoplastic conditions, 355–357 Vasculitis, 470
non-neoplastic conditions, 355 Vasectomy, 375
penile urethra, 353 Vasitis nodosa, 373
prostatic urethra, 353 Vermiform appendix, 87
resection specimens, 357–361 Verrucous carcinoma, 383
urethrectomy specimen, 359 Vertical cuts, 237
Urethral polyps, 355 Verumontanum, 353
Urethral valves, 355 Vesiculobullous disorders,
Urethrectomy, 357, 358 160
564 Index
Vessels Vulval intraepithelial neoplasia

anatomy, 469 (VIN), 289, 290
clinical investigations, 470 Vulval squamous carcinoma, 290
clinical presentation, 469 Vulvectomy, 292, 293
neoplastic, 471
non-neoplastic, 470–471 W
surgical pathology Waldeyer’s ring, 179
clinical aspects, 472 Warthin’s tumour, 196
laboratory protocols, Warty carcinoma, 384
472–473 Wedge biopsy, 7
Vestibule, 180 Wedge resection, 441, 443
Video-assisted thoracoscopic surgery Wegener’s granulomatosis, 439, 471
(VATS), 441 Wharton’s duct, 193
VIN. See Vulval intraepithelial neoplasia Wheezing, 462
(VIN) Whipple’s procedure, 43, 46, 48–52
Viral hepatitis, 114 Wide excision, 487
Viral infection, 438 Wilms’ tumours, 310
Viral warts, 418
Virilizing adrenal tumours, 406
Vitreous humour, 231 X
Volvulus, 72, 81 Xanthogranulomatous pyelonephritis (XGP), 305
Vulva Xerostomia, 195, 199
anatomy, 289, 290
biopsy specimens, 291
clinical investigations, 289 Y
clinical presentation, 289 Yolk sac tumour (YST)
pathological conditions postpubertal type, 369–370
neoplastic, 290–291 prepubertal-type, 370
non-neoplastic, 290
resection specimens, 291–294
surgical pathology Z
clinical aspects, 291 Zoon’s balanitis, 380
laboratory aspects, 291–294 Zygomatic process, 169

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Derek C.

ISBN 978-3-319-57359-5 ISBN 978-3-319-57360-1 (eBook)

Library of Congress Control Number: 2017950223

© Springer International Publishing AG 2017

Printed on acid-free paper

This Springer imprint is published by Springer Nature

Since the publication of the second edition of Histopathology Specimens:

Belfast, UK Derek C. Allen

The authors gratefully acknowledge the use of illustrations from Wittekind

Part I Gastrointestinal Specimens

1 Gastrointestinal Specimens: General Comments����������������������� 3

Part II Breast Specimens

Part III Head and Neck Specimens

13 Nasal Cavities and Paranasal Sinuses������������������������������������������ 149

Part IV Eye

Part V Gynaecological Specimens

Part VI Urological Specimens

29 Kidney, Renal Pelvis, and Ureter�������������������������������������������������� 301

Part VII Pelvic and Retroperitoneal Specimens

35 Pelvic Exenteration Specimens ���������������������������������������������������� 393

Part VIII Skin Specimens

Part IX Cardiothoracic Specimens and Vessels

Part X Osteoarticular and Soft Tissue Specimens

44 Joint Space, Bone, Soft Tissues,

Part XI Haemopoietic Specimens

45 Lymph Nodes, Spleen, and Bone Marrow ���������������������������������� 495

Part XII Miscellaneous Specimens and Ancillary Techniques

46 Miscellaneous Specimens and Ancillary Techniques������������������ 519

Derek C. Allen Histopathology Laboratory, Belfast City Hospital, Belfast

Declan M. O’Rourke Histopathology Laboratory, Belfast City Hospital,

The Role of Histopathology Specimens

Histopathology specimens are a vital cornerstone in patient care. They not

The Handling of Histopathology Specimens

Specimen transportation, accession, clinical prioritisation, dissection, audit,

Allocation of a unique laboratory number and accurate computer registration

With ever increasing workload and limited staffing resources, pathologists

Traditionally the role of a medical pathologist specimen dissection is now also

• There is workforce stability and staff are prepared to work together as a

• Dissectors should only work to their individual level of experience and

Specimen Dissection Audit

The quality of specimen dissection must be meaningfully monitored, and the

This combination of approaches forms the basis for an individual dissector’s

Histopathology specimen reports remain the responsibility of an appropri-

The Core Data in Histopathology Specimens

Specimen dissection must be geared to provide information relevant to the

Clear distinction should be made between biopsy and resection specimens as

Histological Tumour Type

Histological Tumour Differentiation or Grade

Tumour differentiation or grade reflects the similarity to the ancestral tissue of

Extent of Local Tumour Spread

Prognosis of a given cancer may be influenced by the character of its invasive

example, evidence of distant metastases, to formulate a clinical stage upon

pT Requires resection of the primary tumour or biopsy adequate for

Other descriptors include unifocality (pT1a) versus multifocality (pT1b), lym-

Usually defined histologically in blocks from the tumour edge or slightly

s­ atellite lesions. This has implications for blocking of resection speci-

The clearance of excision margins has important implications for patient

Predisposing, concurrent, and associated conditions should be noted, blocked,

Ancillary Techniques in Histopathology Specimens

Belfast, UK Derek C. Allen

1 Gastrointestinal Specimens: General Comments�� 3

13 Nasal Cavities and Paranasal Sinuses�� 149

29 Kidney, Renal Pelvis, and Ureter�� 301

35 Pelvic Exenteration Specimens �� 393

44 Joint Space, Bone, Soft Tissues,

45 Lymph Nodes, Spleen, and Bone Marrow �� 495

46 Miscellaneous Specimens and Ancillary Techniques�� 519

The Role of Histopathology Specimens

The Handling of Histopathology Specimens

Specimen Dissection Audit

The Core Data in Histopathology Specimens

Histological Tumour Type

Histological Tumour Differentiation or Grade

Extent of Local Tumour Spread

s atellite lesions. This has implications for blocking of resection speci-

Ancillary Techniques in Histopathology Specimens

1.1 Anatomy Inflammatory disease can be mucosa confined

1.4 Resection Specimens 2–3 cm in an anterior resection for rectal can-

2.1 Anatomy the surface landmark of the suprasternal notch

2.5 Surgical Pathology Table 2.1 Choice of surgical procedure in oesophageal

The surgical techniques for resecting oesophageal 2.5.3.2 Transhiatal Oesophagectomy

3.1 Anatomy The incisura is an important endoscopic

3.4.1 Non-neoplastic Conditions

4.1 Anatomy The mucosa of the duodenum is thick and

4.6.2.1 Local Resection of Cystic 4.6.2.4 Distal Pancreatectomy (Fig. 4.5)