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 A Practical Guide to
Peritoneal Malignancy
The PMI Manual
 A Practical Guide to
Peritoneal Malignancy
The PMI Manual

Edited by
Tom Cecil
Clinical Director, Peritoneal Malignancy Institute Basingstoke
Hampshire Hospitals NHS Foundation Trust
Honorary Transplant Surgeon
Oxford University Hospitals, Oxford, UK

John Bunni
Consultant Colorectal and General Surgeon
Royal United Hospital Bath, Bath, UK
Honorary Lecturer, Cardiff University, Cardiff, Wales
Visiting Lecturer, University of Bath, Bath, UK

Akash Mehta
Consultant Colorectal Surgeon, St Mark’s Hospital and
Academic Institute, London, UK
CRC Press
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Library of Congress Cataloging-in-Publication Data

Names: Cecil, Tom (Colorectal surgeon), editor. | Bunni, John, editor. | Mehta, Akash, editor.
Title: A practical guide to peritoneal malignancy : the PMI manual /
edited by Tom Cecil, John Bunni, Akash Mehta.
Description: Boca Raton, FL : CRC Press, 2019. | Includes bibliographical references and index.
Identifiers: LCCN 2019024858 (print) | ISBN 9781138495111 (paperback ; alk. paper) | ISBN 9781138495050
(hardback ; alk. paper) | ISBN 9781351024860 (ebook) Subjects: MESH: Peritoneal Neoplasms | Peritoneal
Diseases | Cytoreduction Surgical Procedures | Perioperative Care
Classification: LCC RC867 (print) | LCC RC867 (ebook) | NLM WI 575 | DDC 616.3/8--dc23
LC record available at https://lccn.loc.gov/2019024858
LC ebook record available at https://lccn.loc.gov/2019024859

Visit the Taylor & Francis Web site at

http://www.taylorandfrancis.com
and the CRC Press Web site at
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This book is dedicated to all our patients who have trusted us and
given us the privilege of treating and ­caring for them.
Contents

List of Abbreviations ix
Foreword xi
Preface xv
Acknowledgements xix
Contributors xxi

Part I Set: Understanding and assessment of peritoneal disease 1

1 Appendix tumours and pseudomyxoma peritonei: A ‘paradigm’ for peritoneal disease 3

Akash Mehta and Tom Cecil
2 Colorectal peritoneal metastases 17
John Bunni and Brendan Moran
3 Peritoneal mesothelioma 35
Faraz Khan and Faheez Mohamed
4 Miscellaneous peritoneal malignancies 43
Andreas Brandl and Akash Mehta
5 Quantitative assessment of peritoneal disease 51
John Bunni and Sanjeev Dayal
6 Imaging in peritoneal malignancy 59
Anuradha Chandramohan and Andrew Thrower

Part II Dialogue: Intraperitoneal chemotherapy and cytoreductive surgery 75

7 Intraperitoneal chemotherapy 77
Akash Mehta and Faheez Mohamed
8 Perioperative and anaesthetic care 89
Nina Ashraf-Kashani and John Bell
9 Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy 97
John Bunni and Tom Cecil
10 Postoperative care 113
Nina Ashraf-Kashani and James Coakes
11 Postoperative complications 119
Kim Govaerts and Brendan Moran

vii
viii Contents

Part III Closure: Ongoing care and future management options 127

12 Histopathological aspects of peritoneal malignancy 129

Babatunde Rowaiye and Norman Carr
13 Follow-up protocols in peritoneal malignancy 147
Anuradha Chandramohan, Sourav Panda and Nehal Shah
14 Recurrence of pseudomyxoma peritonei 157
Jamish Gandhi and Alexios Tzivanakis
15 Future perspectives in peritoneal malignancy 163
Ioanna Panagiotopoulou, Alexios Tzivanakis and Tom Cecil

Index 183
List of Abbreviations

5FU 5-Fluorouracil ICAM-1 Intercellular adhesion molecule 1

AUC Area under the curve IL-1β Interleukin-1 beta
BSO Bilateral salpingo-oophorectomy IP Intraperitoneal
Cb Concentration in the systemic IPFC Intraperitoneal free cancer cells
circulation IV Intravenous
CMS Consensus molecular subtypes LAMN Low-grade appendiceal mucinous
Cp Concentration in the peritoneal cavity neoplasm
circulation LV Leucovorin
CPM Colorectal peritoneal metastases MMC Mitomycin C
CRLM Colorectal liver metastases MRI Magnetic resonance imaging
CRS Cytoreductive surgery Ox Oxaliplatin
CT Computed tomography PCI Peritoneal Cancer Index
DMPM Diffuse malignant peritoneal PIPAC Pressurized intraperitoneal aerosol
mesothelioma chemotherapy
DW-WB Whole-body diffusion-weighted MRI PMP Pseudomyxoma peritonei
EPIC Early postoperative intraperitoneal PSOGI Peritoneal Surface Oncology Group
chemotherapy International
ESSO European Society of Surgical Oncology Rd Pharmacokinetic advantage
GPM Gastric peritoneal metastases TME Total mesorectal excision
HAMN High-grade appendiceal mucinous TNF-α Tumour necrosis factor-alpha
neoplasm VCAM-1 Vascular cell adhesion molecule 1
HIPEC Hyperthermic intraperitoneal WDPM Well-differentiated papillary
chemotherapy mesothelioma

ix
Foreword

1987. The presentation concerned 14 patients with

BASINGSTOKE a rare disease referred to as pseudomyxoma peri-
tonei. We combined surgical removal of this large
I have been fascinated by the natural history of volume but minimally aggressive malignancy that
gastrointestinal and gynecologic malignancy arose from an appendiceal adenoma with a chemo-
throughout my surgical career. Why do surgeons therapy washing of the peritoneal space with the
so often fail in their efforts to cure the primary drugs available at that point in time. These drugs
malignancy when all the disease is removed that were mitomycin C and 5-fluorouracil. Amazingly
is visible to the naked eye? Liver metastases take about half of these patients are still alive today, and
the lives of many of our patients. Of course, cancer several of them lived over a decade prior to their
cells that cause liver metastases travel through the death from local progression of disease within the
portal blood where these cells are trapped within peritoneal space. This early report was published in
the sinusoids of the liver, implant and then grow. the Disease of the Colon and Rectum in the October
Although rejected early on, successful treatment of 1987 issue [2].
liver metastases from colon and rectal cancer was A second success story with appendiceal
eventually established [1]. malignancy was published in 1993. This report
Perhaps the dissemination of cancer to the peri- concerned 69 patients we accumulated over a
toneal surfaces is considerably more complex. The 10-year interval appendiceal peritoneal metasta-
spread can occur prior to, but often at the time of a ses. This report showed that a low-grade histol-
cancer resection. Definitely, the surgical procedure ogy, presence of extensive abdominal mucinous
is part of the natural history of gastrointestinal and ascites, complete resection and absence of lymph
gynecologic malignancy. How much does the sur- node metastases were associated with long-term
geon’s dissection contribute to the high incidence survival. There was a 35% serious complication
of peritoneal metastases documented in follow-up rate in this group of patients and a single post-
in patients with gastric cancer, pancreatic cancer, operative death from central venous line catheter
and colorectal cancer? sepsis [3].
The presence of peritoneal metastases, liver It is my assumption that Professor Bill Heald,
metastases or lung metastases in the 1980s was with his great compassion for the optimal man-
considered as a terminal condition with no reason- agement of patients and his innate intellectual
able treatments available. Of course, resection of curiosity, associated this publication in Diseases
liver metastases has become a standard of care. The of the Colon and Rectum with a patient that he
story of peritoneal metastases did not move quite had heard about in Scotland. Brian was a young
so briskly. Perhaps the first report of success in the and otherwise healthy Scotsman in his mid-30s
management of peritoneal metastases was reported who had an expanding abdomen. He had been
at the American Society of Colon and Rectal given the diagnosis of pseudomyxoma peritonei.
Surgery meeting in Washington, DC, in April of Although not the responsible physician, Professor

xi
xii Foreword

Heald wondered if these new, recently described to Waterloo Station in London. There we met with
treatments were applicable to this individual. Mr. an Officer of the National Health Service, Dr.
Heald called my office in Washington, DC, and Peter Doyle. We discussed the problem of pseu-
talked with my wife, Ilse. I then called him back domyxoma peritonei and the mucinous appendi-
from Vienna, Austria where I was participating in ceal malignancies within the UK. It was quite an
a continuing medical education course devoted to extensive discussion and required a pile of scones
peritoneal metastases. I flew to London on Sunday, and several cups of tea. Surprisingly enough, this
March 20, 1994, and visited with the patient. On enthusiastic NHS administrator seemed interested
Tuesday, March 22, 1994, Bill Heald, his Senior in this problem despite the lack of firm evidence
Registrar, Brendan Moran, and I performed a that this was a valid treatment option and that the
13-hour surgical procedure on Brian. experience at Basingstoke was limited. An initial
We had almost all of the equipment necessary application for NHS support for peritoneal malig-
for an optimal cytoreductive surgical event. We nancy was rejected, but a subsequent application
had the Thompson fixed/self-retaining retractor, by Brendan Moran for ‘Pseudomyxoma Peritonei
we had a Birtcher 5000 electrosurgical generator, of Appendiceal Origin’ was approved based on his
and we had lots of enthusiasm towards trying to now underestimated calculation that this rare dis-
help out in what was considered an impossible ease had an incidence of one per million per year.
clinical situation. We lacked a smoke evacuation Basingstoke was approved as a National Treatment
apparatus. There was a slight inconvenience for Centre in April 2000.
the fire brigade in North Hampshire. The exces- Additional cases of pseudomyxoma peritonei
sive electrosurgical smoke set off the fire alarm on were referred to Basingstoke. These all came as a
three different occasions causing the fire brigade to result of word-of-mouth contact among physi-
repeatedly come to the hospital, peer into the oper- cians around the UK and surgeons at the North
ating room and then leave with a smile on their Hampshire Hospital. In order to move this along,
faces but somewhat disgusted in that they came Mr. Heald and Mr. Moran organized the first ever
such a distance with all of their equipment to view peritoneal metastases meeting within the UK.
a surgical procedure performed by ball-tip electro- It was courageous of the group in Basingstoke to
surgical dissection. go ahead with a meeting at the North Hampshire
We placed all the tubes and drains required for Hospital on October 9 and 10, 1998. Although the
early postoperative intraperitoneal chemotherapy. attendance was limited to approximately 30 peo-
I tried to make sure that the early postoperative ple, lots of ideas regarding expansion of this con-
intraperitoneal chemotherapy would happen with- cept of cytoreductive surgery and perioperative
out incident and left to perform a liver resection in chemotherapy to other countries in Europe and
Italy. I remember that at a meeting in Venice, the around the world were formulated. It is amazing
Italian professor rebuked this concept of a surgical to me the foresight that Bill Heald and the group
treatment of peritoneal metastases as an unrealis- at Basingstoke had regarding the management of
tic surgical exercise in futility. peritoneal metastases!
Due to the expert care given Brian at the North In late 1999, a particularly problematic patient
Hampshire Hospital, he recovered from his five who had had extensive prior surgery came up on the
peritonectomy procedures, two colon resections, operative schedule at North Hampshire Hospital.
and early postoperative chemotherapy without Mr. Brendan Moran and I operated together on
incident. He lived after this for nine years, passing September 28, 1999. John was a mid-50-year-old
on August 26, 2003 of recurrent disease intimately Irishman with a recurrent pseudomyxoma perito-
associated with the small bowel and its mesentery. nei post-debulking in Dublin, having had 7 prior
He was not thought to be a candidate for a reopera- operations in Dublin. The surgery and his periop-
tive surgical event. erative chemotherapy went well. John remained
My next trip to Basingstoke was on June 11, 1997. cured from his pseudomyxoma and sadly died
Bill Heald and I took the train from Basingstoke from an unrelated pneumonia two years ago.
 Foreword xiii

The Millennial Masterclass on peritoneal Table 1. Time Line for Pseudomyxoma Institute
metastases organized by Professor Heald was held
• Sugarbaker et al., 69 appendiceal cancer
at the Royal College of Surgeons on June 1 and
patients treated by cytoreductive surgery and
2, 2000. The attendance was limited to approxi-
intraperitoneal chemotherapy, April 1993,
mately 50 people, but some very important persons
Diseases of the Colon & Rectum. Read and
were there and took these concepts back to their
appreciated by Bill Heald.
home institutions. I remember well having some
extended discussions with Professor Dominique • Brian operated on at North Hampshire
Elias, the new professor at Villejuif, France. He was Hospital on March 22, 1994, by Sugarbaker,
very interested in an exhibit of the open method for Heald and Moran. 9-year survival.
hyperthermic intraoperative intraperitoneal che- • Heald and Sugarbaker meet at Waterloo
motherapy administration. Apparently, Dr. Elias Station in London on June 11, 1997, with
was impressed because he started his own pro- NHS Administrator, Peter Doyle.
gram in Villejuif, which has been one of the most • First PSM meeting in Basingstoke, October
successful in terms of new information regarding 9–11, 1998.
peritoneal metastases. • John operated on at North Hampshire
A final meeting that helped firmly establish Hospital on September 28, 1999, by
Basingstoke as the centre for peritoneal metastases Sugarbaker and Moran. 13-hour surgery, 20
work in the UK was a meeting at the newly orga- years and no evidence of disease.
nized Pelican Centre. To my knowledge this was the • Millennial Masterclass, June 1–2, 2000, and
first time a live surgery was transmitted to a large Royal College of Surgeons.
audience. We performed a pseudomyxoma peri- • North Hampshire Hospital, Basingstoke
tonei surgery on December 5, 2002, and then had commissioned by NSCAG in 2000 to treat
a series of didactic sessions on December 6, 2002. pseudomyxoma peritonei.
The pictures from this event are still available. • Pelican Centre live surgery and didactic
It is abundantly clear to me that the centraliza- presentations, December 6, 2002.
tion of the complex treatment of a rare disease has • Christie Cancer Centre, Manchester
been of great success both in terms of high quality commissioned by NSCAG in 2002 to treat
patient care and academic productivity. The struc- appendiceal neoplasms.
tured approach with proper funding provided by • Good Hope Hospital, Birmingham
the National Specialist Advisory Commissioning commissioned by NHS England in 2014 to
group with Basingstoke as a National Treatment treat colorectal peritoneal metastases.
Centre has been a great success. This foresight
has allowed the unit to grow into one of the larg- Clinical Director, and the manual that Tom Cecil
est centres for peritoneal malignancy in the world put together with John Bunni and Akash Mehta
and allowed the development of a second National is a contribution to the continued development
Pseudomyxoma Unit at the Christie Cancer Centre of the peritoneal malignancy treatment centre.
in Manchester in 2002. In 2013, NHS England The manual aims to provide a practical informa-
commissioned the treatment of colorectal peri- tion for the understanding, assessment and treat-
toneal metastases making this treatment eas- ment of peritoneal disease for both the generalist
ily accessible for patients with a third centre for and the specialist. It is broken into three sections
Colorectal Peritoneal Metastases at Good Hope based on the UK Lapco National Train the Trainer
Hospital in Birmingham, established by Haney learning structure—the ‘Set’ focusing on under-
Youssef (Table 1). standing and assessment of peritoneal disease,
It has been my great pleasure to be associated the ‘Dialogue’ looking at the technical and prac-
with the Peritoneal Malignancy Institute at North tical aspects of delivering cytoreductive surgery
Hampshire Hospital. They have accomplished and HIPEC with special focus on the management
an incredible amount over these last 35 years. of complications, and finally ‘Closure’ exploring
The program is now headed by Tom Cecil, the ongoing care and future developments. The experts
xiv Foreword

from the Peritoneal Malignancy Institute have all the liver for colorectal carcinoma metasta-
contributed to the manual, and I hope that you find ses: A multi institutional study of indications
it interesting and useful in the future safe manage- for resection. Surgery 1987; 103: 278–288.
ment of your patients. 2. Sugarbaker PH, Kern K, Lack E. Malignant
Respectfully submitted, pseudomyxoma of colonic origin. Natural
history and presentation of a curative
Paul H. Sugarbaker, MD approach to treatment. Dis Colon Rectum
MedStar Washington Cancer Institute 1987; 30: 772–779.
Washington, DC, USA 3. Sugarbaker PH, Zhu B, Banez Sese G,
Shmookler B. Peritoneal carcinomatosis from
REFERENCES appendiceal cancer: Results in 69 patients
treated by cytoreductive surgery and intra-
1. Hughes KS, Simon RM, Songhorabodi S, peritoneal chemotherapy. Dis Colon Rectum
Sugarbaker PH, other members of the 1993; 36(4): 323–329.
Hepatic Metastases Registry: Resection of
Preface

It is an honour to be editor of the A Practical Guide the biological host response, and probably less so
to Peritoneal Malignancy: The PMI Manual. It is than previously thought as ‘the highways of metas-
especially humbling to see this book materialise tases’ and certainly clinically less significant than
from what started off as an idea and discussion vascular invasion, which would more often than
in the ‘Ark’ in Basingstoke to the culmination of not result in liver metastases.
a vast array of doyens putting their expertise and But the next part of the story, the deeper under-
wisdom into print. standing of the transcoelomic spread of exfoli-
Despite all of the surgical advances and readily ated tumour cells through the redistribution
accessible information in today’s digital era, peri- phenomenon, was of immense importance to me.
toneal malignancy still seems to be a mystery to It highlighted that cases of peritoneal metastases
many surgeons. The pathophysiology, clinical sub- represented, biologically speaking, regional dis-
types and management are much less familiar to ease and not necessarily systemic disease as most
cancer clinicians than the assessment and manage- oncologists and physicians believe. This was of
ment of liver metastases, for example. immense and fundamental importance to my
I was originally attracted to Basingstoke for its intellectual grasp of cancer surgery.
foundation as the ‘home of total mesorectal exci- Peritoneal metastasis, treated with good sur-
sion (TME)’. A beautiful surgical concept, rooted gery in the right patients, is not a terminal process
in embryology, which highlights the primacy of anymore. Management of this challenging condi-
precise, ontogenetic surgery, whereby the cure of tion highlights more than ever that the foundation
the patient is found in the surgeon’s hands faith- of effective surgery is truly in the decision making,
fully dissecting along ‘Holy Planes’ in correctly reinforcing the mantra that ‘decisions are more
selected patients. This concept alone has changed important than incisions’.
the outcome for rectal cancer patients worldwide The model for understanding peritoneal disease
and is one to which all colorectal surgeons remain all began with appendiceal mucinous tumours,
wedded. I, for one, have spent many, many hours now known as low-grade appendiceal mucinous
mesmerised watching Bill and Brendan’s open neoplasms (LAMN). These tumours, whilst not
TME videos from years ago, which were the mech- spreading via the blood vessels (and lymph nodes)
anism for spreading this vital idea. as traditional malignancy does, spread transcoe-
During my time at PMI Basingstoke, another lomically throughout the abdomen, continuously
chapter of surgical understanding descended onto dividing and eventually resulting in the clinical
me. This was somewhat unexpected as my main syndrome of pseudomyxoma peritonei. Without
passion was rectal cancer. As a result of PMI, I had intervention, this condition will cause nutritional
developed a fuller comprehension of peritoneal dis- failure, obstruction, sepsis and death. Here one
ease: the mechanisms of metastases, their clinical has a tumour traditionally considered ‘benign’
manifestation, management and prognosis. When but with deleterious consequences for the patient
considering systemic disease, I had always believed due to a different but equally dangerous mode of
that lymph node metastases were more a marker of spread, of all albeit, ‘low-grade’ disease.

xv
xvi Preface

These tumours are managed inconsistently and (T4 cancers), but good quality surgery remains
quite often incorrectly in the UK due to a lack of paramount.
familiarity with this confusing pathology. The Despite the clear evidence of surgery for peri-
importance of a clear resection margin and aware- toneal disease, there is still cynicism among col-
ness that the LAMN is not a palpable lesion is leagues. This is quite unusual as everyone happily
important. Pre-operative tumour markers and an recognises the value of liver surgery in select cases,
optical colonoscopy are of importance, as is the despite no randomised controlled trial (RCT) evi-
fact that an R0 (i.e. often a cuff of caecum) and not dence of the benefit of liver surgery in M1 disease.
necessarily right hemicolectomy is key also. Right Some colleagues instead doubt the role for surgery
hemicolectomy is not required as this (usually) in peritoneal disease despite the fact that the first
low-grade condition spreads transcoelomically RCT was performed over 15 years ago. The previ-
and not via the mesentery. Right hemicolectomy ously held belief that this is a terminal illness is not
can also compromise future peritoneal surgery. in line with current evidence and should be chal-
Peritoneal spread is a key behaviour of all appendi- lenged by all clinicians involved in colorectal can-
ceal tumours, and this includes high-grade appen- cer care.
dix tumours and frank adenocarcinoma, and is Peritoneal surface malignancy is a surgical dis-
more important than blood vessel and lymph ease. Despite pleas of caution, the Prodige 7 trial
node spread. We know from the Basingstoke data has shown that high-quality surgery is key, but
that these high-grade tumours, in fact, have 57% needs to be used in appropriate cases. The distinc-
peritoneal involvement, 40% microscopic perito- tion between ‘colorectal peritoneal metastases’ and
neal disease and only 15% have nodal disease. Of ‘peritoneal carcinomatosis’ is crucial and helps
critical importance, 37% have peritoneal disease guide case selection. Case selection and decision
beyond the confines of a standard right hemicolec- making, in general, are based on both tumour
tomy. Having this knowledge has helped our mul- factors and patient factors. This is stressed in this
tidisciplinary team make the right decisions; we manual: Oncologically, tumour biology (assessed
have now set up a local database for these tumours by pathology and imaging) is key and cannot be
in Bath, managed by one surgeon only as a hub- trumped by surgery, no matter how skilled the
and-spoke model with PMI. operator. Well-localised disease after a node-
The understanding of colorectal peritoneal negative, extramural vascular invasion (EMVI)-
metastases (CPM) is an extension of this. A T4 negative T4 cancer with a PCI of 2 in a fit patient
tumour that has shed cells can result in peritoneal will likely fare better with CRS and HIPEC than
disease at predictable intraperitoneal sites away a poorly differentiated with signet ring cell, node-
from the primary. Thus an R0 resection still car- positive, EMVI-positive cancer that has recurred
ries a not insignificant risk of synchronous and within 4 months after adjuvant chemotherapy,
metachronous peritoneal disease in an otherwise with other sites of metastases present.
curable tumour. We have all treated large tumours Understanding that CRS and HIPEC is a major
invading other structures only to find the histol- undertaking and that Quality of Life scores do not
ogy T4N0V0R0 and know that the patient stands return to baseline until after 3 months is another
a good chance of being cured. It is these tumours, cardinal consideration. One does not want to make
however, which may exfoliate cells that dissemi- the treatment of the disease more grievous than
nate intraperitoneally, but can still be treated with endurance of the same if it is of little long-term
regional therapy. This is because the peritoneal benefit.
metastases are a manifestation of transcoelo- Thus this book is designed for the practising
mic regional spread and not systemic disease as colorectal surgeon and team. It includes tips on
if it were, e.g. N2 V1. How this is best addressed what to do if you encounter peritoneal disease; a
is a matter for debate, although the preliminary framework for thinking about it in the MDT and
results of the COLOPEC trial have not demon- in theatre; and it also touches on rarer peritoneal
strated a role specifically for HIPEC in such cases surface malignancy.
 Preface xvii

Preventative strategies are examined and read- the King and Queen, sometimes with
ers are encouraged to engage national programs in temporary apparent victories, but usu-
advanced cancer such as the IMPACT workshops. ally to no long-term avail.
It has been a pleasure to be part of this under-
taking, and I do hope that you all enjoy reading it Dr. Blake Caddy
and that it can help result in better outcomes for
your cancer patients.
I will leave you with this important quote: Mr John Bunni M.B., Ch.B (Hons),
Dip Lap Surg, FRCS [ASGBI Medal]
Biology is King, Selection is Queen, Consultant Colorectal and General Surgeon
Technical Manoeuvres are Prince and Honorary Lecturer, Cardiff University
Princess. Visiting Lecturer, University of Bath
Occasionally the Prince and Princess Royal United Hospitals Bath
try to overthrow the powerful forces of NHS Foundation Trust
Acknowledgements

Akash, John and I would like to thank the fol- We are also grateful to our colleagues in the
lowing people who have helped the Peritoneal wider peritoneal malignancy world who work
Malignancy Institute Basingstoke develop and together through organisations such as PSOGI and
helped to complete this book. Firstly, we are grate- ESSO, who have supported this book to further
ful to the NHS, which has created a system in our knowledge and improve treatment. It is a great
which the unit has been able to grow and flourish. family in which to be part.
Despite the challenges it faces, it remains a won- We also need to acknowledge our loved ones
derful organisation that allows us, at an individ- whose endless patience allows us to find time to
ual level, to treat our patients with no immediate complete ventures such as this book.
financial considerations. Finally, this book is dedicated to our patients
The Peritoneal Malignancy Institute Basingstoke who have trusted us and given us the privilege of
is a fantastic team. We are grateful to all the Fellows treating and caring for them.
and Consultants who have contributed to this book
and to the wider team of managers, administrators, Tom Cecil
nurses, medical and hospital staff who make the Clinical Director, PMI
unit function, provide fantastic care to our patients
and make it a joy to work in.

xix
Contributors

Nina Ashraf-Kashani Tom Cecil

Consultant Anaethetist Clinical Director and Consultant Colorectal
Department of Anaethesia and Peritoneal Malignancy Surgeon
Peritoneal Malignancy Institute Basingstoke Peritoneal Malignancy Institute Basingstoke
North Hampshire Hospital North Hampshire Hospital
Basingstoke, United Kingdom Basingstoke, United Kingdom

John Bell Anuradha Chandramohan

Consultant Anaethetist Professor of Radiology
Critical Care Christian Medical College and Hospital
Department of Anaethesia Vellore, Tamil Nadu
Peritoneal Malignancy Institute Basingstoke
North Hampshire Hospital James Coakes
Basingstoke, United Kingdom Clinical Director Critical Care
Department of Anaethesia
Andreas Brandl Peritoneal Malignancy Institute
Digestive Unit Basingstoke
Fundação Champalimaud North Hampshire Hospital
Champalimaud Centre for the Unknown Basingstoke, United Kingdom
Lisboa, Portugal
Sanjeev Dayal
John Bunni Consultant Colorectal and Peritoneal
Consultant Colorectal and General Surgeon Malignancy Surgeon
Royal United Hospitals Bath NHS Foundation Peritoneal Malignancy Institute
Trust Basingstoke
Bath, United Kingdom North Hampshire Hospital
Basingstoke, United Kingdom
Norman Carr
Director of Research and Consultant Pathologist Jamish Gandhi
Peritoneal Malignancy Institute Basingstoke Consultant Surgeon
North Hampshire Hospital Auckland City Hospital
Basingstoke, United Kingdom Auckland, New Zealand

xxi
xxii Contributors

Kim Govaerts Ioanna Panagiotopoulou

Consultant Colorectal and General Surgeon Consultant Colorectal and General Surgeon
Department of GI-surgery and surgical Oncology Addenbrookes Hospital
Ziekenhuis Oost Limburg Genk Cambridge, United Kingdom
Limburg, Belgium
Sourav Panda
Faraz Khan Radiology Fellow
Peritoneal Malignancy Surgeon Christian Medical College
Department of Peritoneal Malignancy Vellore, India
Institute & Colorectal
National Centre for Peritoneal Malignancy Babatunde Rowaiye
Mater Misericordiae University Hospital Pathology Fellow
Dublin, Ireland Peritoneal Malignancy Unit
Basingstoke Hospital
Akash Mehta Basingstoke, United Kingdom
Consultant Colorectal and Peritoneal
Malignancy Surgeon Nehal Shah
St Marks Hospital and Academic Institute Consultant Radiologist
London, United Kingdom Peritoneal Malignancy Institute Basingstoke
North Hampshire Hospital
Faheez Mohamed Basingstoke, United Kingdom
Consultant Colorectal and Peritoneal
Malignancy Surgeon Andrew Thrower
Peritoneal Malignancy Institute Basingstoke Consultant Radiologist
North Hampshire Hospital Peritoneal Malignancy Institute Basingstoke
Basingstoke, United Kingdom North Hampshire Hospital
Basingstoke, United Kingdom
Brendan Moran
Consultant Colorectal and Peritoneal Alexios Tzivanakis
Malignancy Surgeon Consultant Colorectal and Peritoneal
Peritoneal Malignancy Institute Basingstoke Malignancy Surgeon
North Hampshire Hospital Peritoneal Malignancy Institute Basingstoke
Basingstoke, United Kingdom Hampshire Hospitals NHS Foundation Trust
and Basingstoke, United Kingdom
Honorary Professor of Surgery
Royal Prince Alfred Hospital
University of Sydney
Camperdown, Australia
 Part     I
Set: Understanding and
assessment of peritoneal disease

1 Appendix tumours and pseudomyxoma peritonei: A ‘paradigm’ for peritoneal disease 3

Akash Mehta and Tom Cecil
2 Colorectal peritoneal metastases 17
John Bunni and Brendan Moran
3 Peritoneal mesothelioma 35
Faraz Khan and Faheez Mohamed
4 Miscellaneous peritoneal malignancies 43
Andreas Brandl and Akash Mehta
5 Quantitative assessment of peritoneal disease 51
John Bunni and Sanjeev Dayal
6 Imaging in peritoneal malignancy 59
Anuradha Chandramohan and Andrew Thrower
 1
Appendix tumours and pseudomyxoma
peritonei: A ‘paradigm’ for peritoneal
disease

AKASH MEHTA AND TOM CECIL

1.1 Introduction 3 1.3 Pseudomyxoma peritonei 8

1.2 Appendix tumours 4 References 14

LEARNING OBJECTIVES
●● Understand the redistribution phenomenon underlying the fairly predictable patterns of spread of
peritoneal malignancies
●● Understand that appendix tumours and pseudomyxoma peritonei are a model for peritoneal
malignancies
●● Review the rationale behind current classification systems of appendix tumours and pseudomyx-
oma peritonei and the definition of pseudomyxoma peritonei as a malignant disease
●● Review the management algorithms for patients with appendix tumours and pseudomyxoma
peritonei

in intra-abdominal pressure during respiration

1.1 INTRODUCTION and due to intestinal peristaltic motion. Most fluid
ascends via the right paracolic gutter to the right
Peritoneal malignancy refers to a heterogeneous subdiaphragmatic space, as the right paracolic
group of primary and metastatic neoplasms char- gutter is deeper and wider than the left, and direct
acterised by intraperitoneal spread. This spread passage from the right to the left subdiaphrag-
occurs via pre-existing pathways of peritoneal matic space is hindered by the falciform ligament.
fluid circulation. In the normal abdomen (without The circulatory pathway is completed by pas-
peritoneal disease), fluid is circulated upward to sage of fluid into the pelvis via the inframesocolic
the subdiaphragmatic spaces due to fluctuations compartment.

3
4 Appendix tumours and pseudomyxoma peritonei

Fluid stasis creates the following watershed

regions in the peritoneal cavity:

●● Pelvis (pouch of Douglas in women and retro-

vesical space in men)
●● Ileocolic region
●● Superior aspect of sigmoid mesentery
●● Right paracolic gutter

Due to these pre-existing circulatory path-

ways, tumours with transcoelomic spread have a
fairly predictable pattern of dissemination accord-
ing to the redistribution phenomenon (Figure 1.1),
whereby tumour deposits aggregate at the sites of
peritoneal fluid absorption (principally greater and
lesser omentum, diaphragmatic surfaces) and by
gravity in the pelvis, with relative sparing of motile
organs, particularly the small bowel [1]. This pattern
of spread is typically seen in pseudomyxoma perito-
nei arising from a low-grade appendix tumour but
other tumours likely to produce clinically significant
peritoneal dissemination are shown in Table 1.1.

Figure 1.1 Redistribution phenomenon: Pathways

1.2 APPENDIX TUMOURS of flow of intraperitoneal fluid and predominant
sites (*) of stasis in the peritoneal cavity.

Appendiceal neoplasms account for 0.4%–1% of all 25% being malignant [2–4]. At least 50% are esti-
gastrointestinal malignancies; annual incidence mated to present as acute appendicitis (due to
is estimated at 10 per million, with approximately luminal obstruction), with the remainder either

Table 1.1 Principal tumours and tumour-like lesions of the peritoneum

Primary Metastatic
Peritoneal mesothelioma Appendix tumours
• Low-grade mesothelioma • Adenocarcinoma
• Multicystic • Mucinous
• Well-differentiated papillary • Intestinal
• Diffuse malignant peritoneal • Goblet cell
mesothelioma • PMP
• Epithelioid • Acellular mucin
• Sarcomatoid • Low-grade MCP
• Biphasic • High-grade MCP ± signet ring cells
Primary peritoneal carcinoma Colorectal peritoneal metastases (CPM)
Mesothelial cysts/intestinal duplication cysts Gastric cancer
Cystic lymphangioma Ovarian cancer
Fibromatosis Urachal cancer
Desmoplastic small round cell tumour Pancreatic and other
 1.2 Appendix tumours  5

identified on histopathological analysis of an melanoma), most appendiceal neoplasms are pri-

appendicectomy specimen or as an incidental find- mary tumours of the appendix. Various classifica-
ing of a cystically dilated appendix during radio- tion systems exist for these primary appendiceal
logical imaging. In multiple reports on large series neoplasms, the most comprehensive of which is
of appendicectomies, the incidence of appendiceal the 2004 classification by Misdraji and Young [5],
neoplasms ranged from 0.7% to 1.7% [2]. incorporated into the recent consensus classifica-
Though the appendix can harbour meta- tion of appendiceal tumours (Table 1.2) [6].
static tumour deposits from various primary Benign epithelial lesions of the appendix mor-
tumours (including ovarian and colon cancer and phologically can resemble the types of adenomas

Table 1.2 Classification of appendiceal neoplasms

Primary appendiceal neoplasms:

• Epithelial:
• Benign:
– Tubular/tubulovillous/villous adenoma with low-grade or high-grade dysplasia
– Serrated polyp with or without dysplasia
• Malignant:
– Low-grade appendiceal mucinous neoplasm (LAMN): Mucinous neoplasm with low-grade
cytological atypia (without invasive growth) and any of the following:
– Loss of muscularis mucosae
– Fibrosis of submucosa
– ‘Pushing invasion’: Expansile or diverticulum-like growth
– Dissection of acellular mucin in wall
– Villiform, undulating or flattened epithelial growth
– Rupture of appendix
– Mucin and/or cells outside appendix
– High-grade appendiceal mucinous neoplasm (HAMN): Mucinous neoplasm with architectural
features of LAMN but with high-grade cytological atypia (without invasive growth)
– Mucinous adenocarcinoma (well/moderately/poorly differentiated): Mucinous neoplasm with
infiltrative invasion
– Poorly differentiated mucinous adenocarcinoma with signet ring cells: Neoplasm with signet ring
cell component comprising ≤50% of cells
– Mucinous signet ring cell carcinoma: Neoplasm with signet ring cell component exceeding 50%
of cells
– Adenocarcinoma (well/moderately/poorly differentiated): Non-mucinous intestinal-type
adenocarcinoma
• Non-epithelial:
• Carcinoid tumour:
– Classical neuro-endocrine tumour
– Goblet cell carcinoid tumour:
– Tang A: Goblet cell carcinoid (GCC)
– Tang B: Adenocarcinoma ex GCC with signet ring cells
– Tang C: Poorly differentiated adenocarcinoma ex GCC
• Mesenchymal tumour:
– GIST
– Neuroma
– Sarcoma
– Lymphoma
6 Appendix tumours and pseudomyxoma peritonei

and polyps found throughout the colorectal tract, PMP in patients with an isolated LAMN; moreover,
although the vast majority has a different spectrum the available evidence is either outdated or limited
of genetic abnormalities [7–11]. In general, these by small study populations and/or relatively short
lesions are treated adequately by simple appendi- follow-up. A recently presented combined analysis
cectomy or limited caecectomy if the appendiceal (by the UC San Diego group) of the study popu-
base is involved [2]. lations of various reported cohorts reported a risk
The malignant epithelial appendiceal tumours of developing PMP depending on the presence of
range from low-grade appendiceal mucinous neo- extra-appendiceal mucin and epithelial cells: 1.8%
plasms to frank adenocarcinomas. This classifica- in the absence of extracellular mucin and cells,
tion is based on the degree of atypia in the cellular 6.5% in the presence of extra-appendiceal acellular
component and the presence or absence of infiltra- mucin and 26.5% in the presence of extra-appendi-
tive growth patterns. ceal epithelial cells.
For non-perforated LAMN without any signs
1.2.1 LOW-GRADE APPENDICEAL of extra-appendiceal mucinous disease, appendi-
MUCINOUS NEOPLASM cectomy is sufficient treatment followed by radio-
(LAMN) logical, biochemical and clinical surveillance. In
selected patients with a perforated LAMN with lit-
The term LAMN comprises all mucinous tumours tle or no peritoneal disease, a policy of watch and
with low-grade cellular atypia and has replaced wait may be recommended and definitive surgery
older terms such as mucocele, mucinous cystad- (as detailed in Section 1.3) may be deferred until
enoma, etc. The appendiceal mucocele is a highly (progressive) peritoneal disease becomes appar-
non-specific entity, first described by Rokitansky ent. However, in case of frank PMP or potential
in 1842, describing a thin-walled, mucin-filled PMP due to perforation of a LAMN, more exten-
appendix, irrespective of aetiology; mucoceles may sive surgery may be appropriate, as detailed in
be caused by an epithelial neoplasm, but most are Section 1.3.
essentially of unknown cause (some, but not all, One classification system has described two
are associated with luminal obstruction due to a types of LAMN: LAMN I with mucin con-
faecolith). fined to the appendiceal lumen and LAMN II
LAMNs are capable of transcoelomic dissemi- with mucin and/or neoplastic epithelium in
nation following (often subclinical) rupture of the appendiceal submucosa wall and/or peri-
the appendix, leading to intraperitoneal spread appendiceal tissue, with or without perforation
of mucin (with or without epithelial, mucin-pro- [15]. A so-called risk-reducing laparoscopic
ducing cells) and to the clinical syndrome known CRS and HIPEC procedure has been advocated
as pseudomyxoma peritonei (PMP). The risk of for patients presenting with a LAMN II lesion,
developing PMP from a LAMN remains unclear. although no data comparing the outcomes of
One population-based study showed that approxi- this approach to a more traditional ‘watch and
mately 20% of mucinous appendiceal neoplasms wait’ policy are available [15,16].
will give rise to PMP [3]. However, a recent study
found a 52% risk of developing PMP after resec- 1.2.2 HIGH-GRADE APPENDIX
tion of a mucinous neoplasm, but no distinction TUMOURS
was made between low-grade and high-grade
pathology of the primary appendiceal tumour [12]. High-grade appendiceal mucinous neoplasms
Another recent study of 41 patients demonstrated (HAMN) are a newly defined entity and include
no occurrences of PMP after resection of a LAMN, mucinous neoplasms similar to LAMN but with
after a median follow-up of 5 years [13], whereas features of cellular atypia, including hyperchro-
another study of 22 patients showed a 23% risk of matic cells, increased nuclear/cytoplasmic ratio
developing PMP after a median follow-up of just and loss of cellular polarity (as described in
over 4 years [14]. Therefore, there is considerable Chapter 12) [6]. These high-grade tumours exhibit
variation in the reported rates of development of behaviour comparable to frank adenocarcinomas
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