Received: 18 May 2022Revised: 26 August 2022Accepted: 29 August 2022

DOI: 10.1111/ejh.13863

REVIEW

The diagnosis and management of suspected lymphoma in general

practice
1 1 1
Ashley R. Paquin | Emmanuella Oyogoa | Hannah Stowe McMurry |
2 2 2,3
Thomas Kartika | Malinda West | Joseph J. Shatzel

1
Division of Internal Medicine, Oregon Health and
Science University, Portland, Oregon, USA
Abstract
2
Division of Hematology and Medical Oncology,
With rapid advancements in diagnosis and treatment of malignancies, the gap between
School of Medicine, Oregon Health and Science
University, Portland, Oregon, USA generalists and subspecialists continues to widen, particularly in cancers like lymphoma where the
3
Department of Biomedical Engineering, spectrum of disease varies from indolent to rapidly progressive. Prior to establishing with a
Oregon Health and Science University,
Portland, Oregon, USA hematologist/oncologist, patients must be accurately and comprehensively diagnosed and managed
for lymphoma in the generalist setting. In the following manuscript, we review the common
Correspondence
Ashley R. Paquin, Oregon Health Sciences clinical presentations in which should raise concern for lymphoma. We summarize the
University, 3181 SW Sam Jackson Park Road, literature regarding the role of laboratory studies including complete blood count and peripheral
Portland, OR 97201-3098, USA.
Email: paquina@ohsu.edu blood flow cyto- metry, the recommendations for lymph node sampling, the role and selection
of imaging modalities, and ideal patient monitoring for high-risk clinical syndromes that may be
encountered in lymphoma.

KE Y W O R DS
lymphoma, primary care, workup

1 | INTRODUCTION nonspecific findings with exceptionally broad differential diagnoses. However,

lymphoma can also have a variety of atypical presentations, for example, extra-
Lymphoma is a heterogenous group of lymphoid neoplasms with marked nodal lymphoma could present with GI symptoms, CNS symptoms, cutaneous
1
differences in clinical course and response to treatment. Lymphomas are symptoms, or other generalized or organ- specific symptoms.
6–8
Despite this,
grouped by their postulated normal cell type of origin (B-cell vs. T-cell), and lymphoma is a rare diagnosis with an incidence of 2.6 and 19.6 cases per 100
morphology (Hodgkin vs. non-Hodgkin) as well as the degree of cellular 000 people per year for Hodgkin and non-Hodgkin lymphoma (NHL),
2
differentiation. With advancements in molecular medicine, more than 100 9,10
respectively. Even for symptoms with more narrow differentials, such as
discrete lymphomas have been identified and grouped by genetic and lymphadenopathy, lymphoma remains an uncommon diagnosis. For example, in
3
morphologic characteristics. Under the most recent classification system, patients presenting to a generalist practice with lymphadenopathy, only
there is increasing emphasis on genetic and pathologic markers in characterizing approximately 4% of patients older than age 40 and less than 0.4% of
2,3
distinct lymphomas and on using these data to drive clinical management. patients under age 40 were ultimately diagnosed with any malignancy.
11

While lymphoma will ultimately be managed by a hematologist/ oncologist To date, there is little guidance for primary care doctors once lym- phoma
in the United States, the initial lymphoma diagnosis and early clinical has emerged as the most likely diagnosis and after other com- peting
management is typically performed in a primary care or general hospital setting. differentials have been effectively ruled out. Furthermore, in our experience,
There is no “classic” presentation, standard workup, nor single test to lymphoma is increasingly being diagnosed during the workup of incidental
4
diagnose or even definitively rule out lymphoma. When symp- tomatic, lymphadenopathy. Most articles that do address the workup of lymphoma focus
lymphoma commonly presents with fatigue, pain, palpable lymphadenopathy, narrowly on a single subset of lym- phoma or stratify by Hodgkin versus
5
and shortness of breath/cough, all of which are non-HL, a distinction that is

Eur J Haematol. 2023;110:3–13. © 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
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4 PAQUIN ET

determined by tissue biopsy which is often unavailable at the time when involved if localized), and character of the nodes as well as the clinical history
12–17
lymphoma is suspected. 21–24
including the time course of lymphadenopathy. History should elicit
This article reviews the current evidence regarding the diagnostic and localizing symptoms, other primary malignancy, specific exposures, such as cat
early clinical management of probable lymphoma including the role of scratches, tick bites, undercooked meat, high- risk sexual activity, injection
laboratory studies, such as complete blood count and periph- eral blood flow drug use, travel to areas with high rates of endemic infection, or recent
cytometry (FC), recommendations for lymph node sampling, the role, and 21
vaccinations. Vaccination against COVID-19 may lead to reactive axillary
selection of imaging modalities, and patient monitoring for high-risk clinical 25
lymphadenopathy up to 10 weeks postvaccination. A history positive for
syndromes that may be encountered in lymphoma.
any of the afore- mentioned items can reveal the etiology and lower the
suspicion of lymphoma. The presence of constitutional symptoms including fever,
drenching night sweats, and weight loss can be suggestive of lym- phoma, but
1.1 | Identification of probable lymphoma 22
can also be seen with most infectious causes of lymphade- nopathy.
Comprehensive lymph exam should include palpation of all accessible lymph nodes
1.1.1 | Palpable lymphadenopathy (cervical, supraclavicular, occipital, preauricu- lar, infraclavicular, axillary,
pectoral, epitrochlear, inguinal, femoral, and popliteal), as well as palpation of
18
Lymphoma can be discovered by palpable lymphadenopathy. Impor- tantly, in 22
the liver and spleen, and visuali- zation of Waldeyer's ring (Figure 1).
patients with lymphadenopathy, the risk of lymphoma is low. In patients
Generalized adenopathy, nodes
presenting to primary care with lymphadenopathy, the overall incidence of any
>1 cm in diameter, firm, rubbery, or hard consistency, fixation to adja- cent
19
malignancy is 1.1%. While most cases have a benign etiology, internet searches
tissue or “matted” fixation to adjacent nodes, splenomegaly, and non-tender
by medically illiterate patients can lead to excessive worry that this symptom
nodes are most concerning for malignancy (not limited to lymphoma), whereas
20
represents lymphoma. <1 cm, freely mobile, tender nodes are far more likely to be of infectious
Briefly, the evaluation of palpable lymphadenopathy should include a 22
etiology.
history and physical exam targeted to the distribution (local- ized vs. generalized),
Expectedly, studies have demonstrated that generalists are highly skilled at
location (which distinct lymph node group is
diagnosing and managing palpable lymphadenopathy and

FIG U R E 1 Lymphoma symptoms

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PAQUIN ET
5
11
appropriately referring for biopsy when indicated. Since lymphade- nopathy
cough could show a large mediastinal mass, or abdominal imaging obtained for
can be a sequalae of multiple infectious, immunologic, endo- crine, drug-
workup of pain or for abnormal liver or kidney function could reveal
induced, and neoplastic processes, much have been written about best
compressive and/or diffuse adenopathy. In these cases, the radiologist may be
21–24
practices for workup of lymphadenopathy without an obvious cause, and able to assist with risk stratification of adeno- pathy and provide impressions
these guidelines will not be discussed in detail in this review. The diagnostic that indicate a high or low concern for lymphoma. Depending on the radiologic
approach for unexplained lymph- adenopathy will vary significantly based on the interpretation and the overall clinical picture after further history, a subset of
physician's overall clin- ical impression of the likelihood of malignancy as the these cases will fall under the diagnostic category of “suspected” and should
cause and the presence of localized versus generalized lymphadenopathy (with follow the steps below for further workup of suspected lymphoma.
a higher likelihood of malignancy and generalized lymphadenopathy being
26
more concerning features that would prompt biopsy rather than watchful waiting).
1.1.4 | Nonlymph node biopsy concerning for
lymphoma
1.1.2 | B-symptoms: Fever, drenching night sweats, and
unexplained weight loss Lymphoma, while typically found in lymph nodes, can develop in other lymphatic
35,36
tissues and spread throughout the body. As such, biop- sies and cytology
Less frequently, lymphoma can be suspected in patients who complain of from sources other than lymph nodes may be the initial indication for
constitutional symptoms including fevers (unexplained tempera- tures >38o C lymphoma. Samples from head and neck masses, gastric mucosa, ascitic fluid,
in the last month), night sweats (recurrent and drenching in the last month), and pleural effusions may provide prelimi- nary evidence of a monoclonal
and weight loss (>10% of body weight within the last 6 months) without lymphoid population suggestive of lymphoma.
37
If the initial sample is
27
known adenopathy. In the context of lym- phoma, these symptoms are insufficient for final diagnosis, fur- ther workup and management is indicated.
known as “B-symptoms” as the presence of one or more of these symptoms
27
corresponds with B staging in the Ann Arbor Staging System. To the best of
our knowledge, there are no studies that characterize the positive predictive 1.2 | Laboratory tests
value of each B-symptom in isolation or in aggregate, in part due to the
vast heterogeneity of distinct lymphomas. Once the diagnosis of lymphoma is suspected, further evaluation includes
In cases where patients present to a generalist with isolated B laboratory testing, imaging, and biopsy. While not always in this order,
symptoms, initial physical exam should include a comprehensive lymph node laboratory testing is often the initial step. These are described in detail below
exam, as lymphoma is on the differential for each inde- pendent symptom. If and summarized in Table 1. Certain patterns of lab abnormalities are consistent
lymphadenopathy is found, the clinician should follow the guidelines for with a diagnosis of lymphoma and can heighten suspicion for complications
workup of lymphadenopathy. B-symptoms without lymphadenopathy or such as bone marrow involvement, compressive adenopathy, or advanced
splenomegaly should not prompt further targeted workup for lymphoma. Instead, disease. Impor- tantly, the absence of abnormalities on any of the following
suggested workups for each symptom have been well established and are blood tests should not be used to definitively rule out a diagnosis of
28–30
expected to uncover fur- ther evidence of lymphoma if present. For lymphoma.
example, lymphoma may be suspected if imaging obtained during workup
of fever of unknown origin (FUO) reveals diffuse lymphadenopathy. Likewise,
if laboratory workup for unexplained weight loss reveals liver or kidney 1.2.1 | Complete blood count
dysfunction this could prompt further workup and possible subse- quent
31
diagnosis of compressive adenopathy. A rare symptom that should trigger Complete blood count (CBC) abnormalities can occur with multiple
32
investigation is new-onset alcohol-related pain or intol- erance. Thought to be complications of lymphoma and should be obtained in the workup of probable
due to vasodilation within the lymph-node capsule, this may be seen in up to lymphoma. However, many patients with lymphoma, even aggressive
5% of cases of HL. lymphoma, will have a normal CBC and this should not be considered evidence
38
against a lymphoma diagnosis.
When present, CBC abnormalities including anemia, thrombocy- topenia,
1.1.3 | Incidental imaging finding of and leukopenia/lymphocytosis can suggest complications, such as bone marrow
lymphadenopathy infiltration, anemia of chronic disease, iron or B12 deficiency, autoimmune
hemolytic anemia, hypersplenism from splenic involvement, or diagnosis of
In primary care and hospital medicine, localized or generalized adeno- pathy can small lymphocytic lymphoma. The presence of anemia in untreated lymphoma is
33,34
be discovered incidentally on imaging ordered for a differ- ent indication. estimated between 32%–45% and up to 57% of patients with anemia
39–42
For example, a chest X-ray ordered for workup of reported symptoms. Early identification of anemia can guide multiple
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6 PAQUIN ET

TA BL E 1 Lab tests for probable lymphoma

Abnormalities suggestive of
Lab test Rationale lymphoma Red flag results
Complete blood Ensure trilineage normality, assess for gross Anemia, thrombocytopenia, Neutropenia, WBC > 100 K, severe
count (CBC) abnormalities suggestive of bone marrow leukopenia/leukocytosis anemia or thrombocytopenia
involvement
Comprehensive Assess for the presence of hepatic or AKI, electrolyte abnormalities, hepatic Significant electrolyte abnormalities or
metabolic panel renal dysfunction suggestive of compressive ororinfiltrative
cholestaticdisease
injury patterns evidence of significant organ injury

Phosphorus Evaluate for evidence of tumor lysis. Tumor lysis Hyperphosphatemia with phosphorus levels
(Although phosphate levels in >4.5 mg/dl in adults or > 25% increase
spontaneous TLS may be normal as from baseline. (In conjunction with
opposed to phosphate levels in post- elevated LDH, uric acid, potassium,
chemotherapy TLS) ±AKI, as this is consistent with TLS)
LDH Evaluate for evidence of rapid cellularElevated LDH In conjunction with elevated
turnover which may be associated with TLS. potassium, uric acid ± AKI, and hyperphosphatemia as th

Uric acid To rule out tumor lysis syndrome No clear association outside of TLS Hyperuricemia with uric acid >8 mg/dl
or 25% increase from baseline In
conjunction with elevated LDH,
potassium, ±AKI, and elevated phosphorus as
this is consistent with TLS

Abbreviations: AKI, acute kidney injury; ED, emergency department; LDH, lactate dehydrogenase; MAHA, microangiopathic hemolytic anemia; TLS, tumor lysis syndrome.

aspects of management including early iron and B12 repletion and heightened and/or cholestatic dysfunction can be seen in cases of compressive adenopathy,
40,43
suspicion for bone marrow involvement. Anemia is also an adverse metastatic hepatic infiltration, paraneoplastic syndromes, and hemophagocytic
56
prognostic factor in some types of lymphoma, with varying degrees of syndrome.
41,44,45
prognostic value by lymphoma subtypes.

1.2.3 | Lactate dehydrogenase, uric acid, and

1.2.2 | Comprehensive metabolic panel phosphate

There are multiple mechanisms by which lymphoma can cause electro- lyte Though not specific, lactate dehydrogenase (LDH) is commonly elevated in
abnormalities. Hypercalcemia, while present in less than 15% of cases of aggressive lymphoma and serves as an important prognos- tic factor for many
46 57
lymphoma, is associated with decreased overall survival. The mechanisms of types of lymphomas. Aside from this, LDH and uric acid levels should be
hypercalcemia in lymphoma may include bone invasion, paraneoplastic syndromes checked to rule out spontaneous TLS (discussed in greater detail below).
involving parathyroid-like-hormones, or prostaglandin release. In addition, Interestingly, unlike post- chemotherapy TLS where high rates of cell death
tumor-associated macrophages or tumor cells themselves can form excess 1,25- cause hyperuricemia and hyperphosphatemia, spontaneous TLS is often seen
dihidroxyvitamin D and clinicians should consider testing for this hormone without hyperphosphatemia, possibly because phosphate released during high cell
47 58,59
specifically. turnover is rapidly used in the synthesis of new cells.
Renal injury may further perturb the metabolic panel. Compressive
adenopathy can directly cause renal dysfunction, although indirect causes are
48
more common. Renal injury more typically occurs from hypercalcemia or from 1.2.4 | Peripheral blood FC
cellular release of monoclonal paraproteinemia, similar to how multiple myeloma
causes renal injury.
49,50
Lymphomas have also been associated with development FC is a method of identifying and quantifying specific cell types by physical
60
of immunologically medi- ated glomerulonephrosis and glomerulonephritis.
51,52
characteristics and surface antigen expression. When malig- nant cells are
Aggressive lym- phomas can present with tumor lysis syndrome (TLS), which identified, the immunophenotype of the atypical cells aids in diagnosis,
53 60
can lead to acute renal failure and electrolyte abnormalities. Of note, there are prognostication, and monitoring. The diagnostic yield of the test, however,
also a handful of cases of non-HL presenting with acute renal failure due to varies greatly by sample source and malig- nancy subtype; atypical
lymphomatous infiltration of the kidneys, although the validity of this finding lymphocytes must be present in the sample tested and must be able to be
remains debated within the literature.
54,55
Hepatic identified by the flow cytometer. This
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PAQUIN ET
7
presents challenges in lymphoma. For example, Reed-Sternberg cells Under ideal conditions, current recommendations from several radiology
(pathognomonic of classical HL) have historically been considered to be too
and nuclear medicine associations recommend low-dose non-contrast CT with
61
big or too sparse to detect using FC, although recent advancements are PET scan, followed by high dose with contrast CT. However, in clinical
61,62
bridging this gap. Apart from leukemic forms of lymphoma, it is rare to see practice, many patients have already had a recent high contrast CT prior to
63
circulating tumor cells. In a real-world study, only 15.4% of clinically PET-CT, and the ICML working group currently recommends against repeat at
suspected lymphoma cases were posi- tive by FC of bone marrow and the time of PET-CT in these cases, unless needed for other reasons such as
peripheral blood combined (peripheral blood samples were not analyzed clinical trial participa- tion or radiation planning.
64
independently). A single-center study reviewed 185 requests for peripheral Molecular and pathologic diagnosis is vital in the interpretation of PET-
blood FC performed over the course of 1 year and found that only 15.1% of CT results; recent research has shown significant variability in predictive value
those tests were positive for a monoclonal lymphoid population (all samples were PET-CT findings in individual lymphoma subcate- gories, and data is overall
B-cell clones). Of those, greater than 50% were chronic lymphocytic leuke- lacking for NK and T-cell lymphomas.
76–78
In some lymphomas, presence of
65
mia; the other 50% were not further characterized. Furthermore, 0 of the 18 bulky disease is a negative prognos- tic factor while in others the association is
tests performed for constitutional symptoms and only 2 of the 12 tests more complex or not yet clear. In Hodgkin lymphoma (HL) and in aggressive
65
performed for lymphadenopathy/ suspicious mass returned positive results. NHL, focal FDG uptake in the bone marrow is highly sensitive for
This study, among others, influenced the statement from the American involvement, and in some cases may spare the patient from bone marrow
Society of Clinical Pathology for the Choosing Wisely initiative that biopsy. How- ever, in more indolent lymphomas, sensitivity for bone
peripheral blood FC is not recom- mended for screening for hematologic marrow involvement is low, and biopsy is required for staging. Since the brain
66
malignancy in most cases. Specifically, it is of low yield in cases of mature has high physiologic FDG uptake, PET-CT may miss less severe cases of
neutrophilia, baso- philia, erythrocytosis, thrombocytosis, isolated anemia, or leptomeningeal disease. In cases where CNS involvement is sus- pected due to
79
isolated thrombocytopenia. Even in cases where morphologically abnormal neurologic symptoms, MRI remains the preferred imag- ing modality.
cells (blasts or lymphoma cells) are seen on peripheral smear, the likeli- hood of
66
obtaining diagnostic results from peripheral blood FC is extremely low.
1.4 | Biopsy

1.3 | Imaging In lymphoma, tissue diagnosis is imperative. Solid tissue samples can be obtained
via needle (fine needle aspiration [FNA] or core needle biopsy) with or without
In the workup of lymphoma, imaging is an important tool for diagnos- tic and imaging guidance, or via surgical biopsy (inci- sional vs. excisional biopsy)
prognostic purposes. Computerized tomography (CT) scan is the imaging (Table 2). The general principles regarding performing and obtaining an ideal (or
modality historically used in the Ann Arbor staging sys- tem, the most common even suitable) biopsy are to per- form the least burdensome procedure (in terms
staging system used in clinical and research settings for prognostic indices, of patient risk and healthcare system resources such as procedural spaces,
therapy selection, and outcomes reporting. Nearly, all lymphomas are personnel, time, and cost) that will provide the diagnostic yield required for
67,68
metabolically active and there- fore fluorodeoxyglucose (FDG) avid. timely and accurate diagnosis and management.
Furthermore, they can be distinguished from other etiologies of FDG uptake, Many benign causes of lymphadenopathy have a morphologic pattern
such as physio- logic or patterns of infection or inflammation, by the overlapping with lymphomas such as reactive follicular or
69,70 80
distribution of avid nodes and/or CT characteristics. Subsequently, PET-CT paracortical/interfollicular hyperplasia or necrosis. Assessment of lymph node
has been widely adopted as the imaging modality of choice to stage and to architecture via histology therefore remains essential for differentiating
80
monitor treatment response in lymphoma. Compared to CT alone, FDG PET- between many subtypes of lymphoma and benign lymphadenopathy. In
CT has superior accuracy for staging and increased specific- ity, particularly for addition, new genetic, pathologic, and immu- nologic markers are increasingly
71
extranodal disease. FDG PET-CT offers further advantage in the diagnosis incorporated into diagnostic criteria, prognostic models, predictive factors, and
and management of indolent lymphomas. Since FDG avidity is higher in more disease-defining lesions, with some lymphomas now being diagnosed
1
aggressive lymphomas, biopsy of sites with higher FDG uptake may increase differently than just a few years ago. For all biopsy types, there is a
72–74
diagnostic yield in cases of suspected transformation. It is important to note concerningly high false negative rate for lymphoma, with a recent study
that not all lym- phomas are FDG avid, and lack of FDG update on PET-CT noting a negative predictive value (NPV) as low as 54.3% for open surgical
81
does not rule out a diagnosis of lymphoma. To this end, multiple international biopsy. Providers should monitor all patients with negative biopsy results for
working groups have crafted consensus statements to standardize PET-CT persistent signs and symptoms of lymphoma and pursue larger- volume
75 4
methods and interpretation. biopsy if clinical suspicion for lymphoma remains high. In addition, FC may
Regarding CT contrast, there is some evidence for benefit of con- trast not accurately pick up T-cell clones and T-cell rear- rangement studies are often
enhancement in the detection of abdominal or pelvic disease. needed for diagnosis of T-cell lymphoma,
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8 PAQUIN ET

TA BL E 2 Tissue studies/ biopsy for probable lymphoma

Diagnostic study Description Limitations Notes

Peripheral blood flow Method of identifying and quantifying Lymphoma cells are rarely detected in Not recommended for screening for
cytometry specific cell types by physical peripheral blood lymphoma under most circumstances, and
characteristics and surface antigen unlikely to be diagnostic even in cases
expression where blasts or lymphoma cells are seen on
peripheral smear
Fine needle aspiration Least invasive sampling technique, can Extremely high false negative rate, Reasonable to consider in combination
be combined with ancillary testing such as IHC,
especially
FC, andfor
cytogenetic
HL. tests to improve diagnostic
with sensitivity
ancillary testing if lymphoma is not the most likely
High rate of incorrect or incomplete subclassification
lymphoma diagnosis and low NPV

Core needle biopsy Less invasive and more readily Not recommended for diagnosis of HL due Reasonable to consider in cases where NHL
available diagnostic technique than to exceptionally high false negative rate. is suspected and robust ancillary testing is
excisional biopsy and non-inferior or Risk of insufficient sample for complete available, though subsequent surgical
superior in some circumstances when subclassification/ actionable diagnosis, or biopsy may be needed.
combined with ancillary testing insufficient sample for follow-up tests for
research/ clinical trial eligibility.
Surgical (excisional) Gold standard sampling technique Most invasive and least available Recommended in all cases where HL is
biopsy technique, NPV < 100 highly suspected or ancillary testing capabilities are limit

Abbreviations: FC, flow cytometry; HL, Hodgkin lymphoma; IHC, immunohistochemistry; NPV, negative predictive value.

though this is typically managed by the pathologist and not the ordering Ultimately, FNA alone is not recommended for diagnosis or rule out of
82
provider. lymphoma due to low sensitivity and low NPV as well as a high rate of
85
incorrect lymphoma subtyping. However, FNA combined with ancillary tests
such as FC and immunohistochemistry (IHC) is rea- sonable to consider if
1.5 | Fine needle aspiration lymphoma is lower on a differential diagnosis than other causes of localized
lymphadenopathy (such as is the case in head and neck lymphadenopathy) or
Overall, FNA is unlikely to yield an actionable, accurate, or complete if the biopsy site cannot be safely accessed for more invasive biopsy techniques.
4

diagnosis of lymphoma, and is not recommended for a targeted workup of

4
suspected lymphoma. Subspecialty guidelines for evalua- tion of head and
neck masses (including lymphadenopathy) do how- ever recommend FNA as 1.5.1 | Core needle biopsy
83
the first line sampling method. This is in part because of the relative ease of
sample access as well as the broad differential diagnosis of head and neck Core needle biopsy (CNB) is subject to many of the same limitations as FNA,
masses, most of which can be diagnosed by FNA alone. The accuracy of 4
although more tissue is obtained. With the rapid advance- ments in molecular
FNA for head and neck masses of all etiologies is high; a single institution diagnosis such as FC, IHC, and FISH/cytogenetics, some studies have reported
review of all (2772) head and neck FNAs performed within a 10-year period reliable diagnosis of certain types of lym- phoma with core biopsy combined
reported an accuracy of 95.1% and a meta-analysis of 3459 FNA samples 81
with appropriate ancillary tests. For example, a recent review article reported
84
demonstrated an accuracy of 96.5%. Sub-group analysis of 542 lymph node diagnostic efficacy of image-guided CNB of 79%–97% with diagnostic
FNA samples from a single institution and 782 FNA samples from a meta- 86
reproducibility among hematopathologists from 87% to 93%. In some
analysis showed diagnostic accuracy of 94.5%, PPV of 98.8%, and NPV of
circum- stances, CNB even may be superior to excisional biopsy, presumably
86.7%. However, the 151 aspi- rates of lymphoma included 39 false negatives
for the ability to sample a more suspicious node that may not be ame- nable to
and 3 nondiagnostic samples for a sensitivity of only 74%, and the authors 81
excision. A recent prospective cohort studies comparing open surgical biopsy
specifically comment on limitations in subclassifying lymphomas and accurate
to doppler-assisted CNB found NPV of 54.3% for surgical biopsy compared
diagnosis of low-grade lymphomas, which they reported requires open
to 84.5% for CNB when samples were compared to the gold standard of a
84
biopsy.
subsequent biopsy demonstrating
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PAQUIN ET
9
81
lymphoma. However, other studies have shown far lower diagnostic yield. A
give a strong recommendation for surgical biopsy when feasible in a clinical
recent metanalysis of CNB for diagnosis of lymphoma in cer- vical 4
setting where HL is suspected. This recommendation is based on studies
lymphadenopathy found a rate of actionable lymphoma diagno- ses as low as
showing high false negative rates for HL and lower diag- nostic sensitivity of
87
30% (range 30%–96.3%) and a recent study of 457 biopsies (339 90
CNB for HL, for example, one study reported sen- sitivity as low as 50%.
excisional and 118 CNB) found that only 56.8% of CNB samples contained
88
adequate tissue compared to 96.8% of exci- sional biopsy samples.
In this rapidly evolving field, the American Society for Clinical
1.6 | Lymphoma emergencies
Pathology and the College of American Pathologists published guide- lines for
the laboratory workup of lymphoma in adults, which was affirmed as having
Lymphoma embodies many heterogenous subtypes, each with varying clinical
4
value for hematologists by the American Society of Hematology. The role of
presentation. Often, lymphoma workup, diagnosis, specialist referral, and
CNB continues to evolve. These guidelines give a strong recommendation
treatment plan can all be done in the outpatient setting. However, some
based on moderate evidence for exci- sional biopsy or CNB in patients with a
lymphoma subtypes are high grade with an aggressive pace of disease. Prompt
high suspicion for lymphoma. This recommendation is written with a caveat recognition of this subset is vital as medical emergencies related to aggressive
that CNB must be used with careful consideration of the patient selection, 91
lymphoma confer a worse progno- sis. Recognition of potential emergencies
technique, and available ancillary diagnostic methods. Specifically, the authors
by the generalist is key as they may be present during initial presentation and
note variable diagnostic accuracy of CNB for lymphoma from 64%–98%
necessitate hospi- talization and stat hematology/oncology consultation for
and for subclassification of lymphoma from 68%–96%, with HL and
intervention and expedited treatment.
follicular lymphoma being the least accurate, with accuracy as low as 8% for
89
High-grade lymphomas include Burkitt lymphoma, subsets of dif- fuse large
Grade 3 follicular lymphoma.
B-cell lymphoma, lymphoblastic lymphoma, some mantle cell lymphomas, and
Other considerations in the selection of CNB versus excisional biopsy 92
peripheral T- and NK-cell lymphomas. They are associated with high tumor
include the possibility of insufficient tissue for complete ancil- lary testing at
proliferation rate and extensive disease burden that can result in medical
the time of diagnosis and/ or for further testing on residual tissue for
4
emergencies. Often, patients with aggressive lymphomas will describe profound B
research and potential clinical trial eligibility. Regarding size of the needle 19
symptoms and rapidly enlarging lymph nodes. Compressive effects from bulky
used for CNB, while intuitively one would expect a larger needle gauge and
adenopathy may result in local damage that can involve any organ system.
higher number of passes/ cores to provide higher diagnostic accuracy, no
Other symptoms due to electrolyte derangements or paraneoplastic pro- cesses
appropriate studies have been performed to address this, and the most recent
4
may be present as well. These emergent lymphoma presenta- tions and the
guidelines refrain from making a recommendation on this.
immediate interventions are described below and summarized in Table 3.

1.5.2 | Incisional/ excisional biopsy 1.6.1 | Compressive or infiltrative tumor effects

Excisional biopsy remains the gold standard sampling method for suspected
Compressive symptoms from lymphadenopathy include: spinal cord
lymphomas, though, as above, some studies are showing equivalent diagnostic
compression, lymphomatous meningitis, CNS mass lesions, airway obstruction,
accuracy of CNB in certain situations. The joint ASCP, ACP guidelines that
pericardial tamponade, SVC syndrome, GI obstruction,
were deemed valuable by ASH specifically

TA BL E 3 Lymphoma emergencies

Hematologic emergency Suggestive signs/symptoms Initial management

Tumor lysis syndrome Elevated lactate dehydrogenase (LDH), uric Acid, Aggressive fluid resuscitation with isotonic fluids, management
Potassium, ±phosphorus. AKI of hyperkalemia if indicated, immediate emergency room
evaluation and hospitalization
Venous thromboembolismUnilateral lower extremity swelling, erythema, pain. If stable for outpatient management, low molecular weight
Sudden onset dyspnea/ hypoxia. heparin (LMWH), apixaban, rivaroxaban have the most evidence for anticoagul

Paraneoplastic processes Neurologic symptoms, dermatologic changes, fever, Commensurate with the severity of presentation. Evidence of MAHA,
hematologic abnormalities, arthralgias, renal severe neurologic involvement, rash and fever, severe AKI should
dysfunction, angioedema be referred to the ED
Compressive or infiltrativeHepatic or renal dysfunction Commensurate with the severity of presentation
tumor effectsEvidence of neurovascular compromise including Severe hepatic or renal dysfunction, evidence of cauda equina syndrome, or rapi
claudication, bowel or bladder dysfunction, saddle anesthesia, motor or sensory dysfunction.
 16000609, 2023, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/ejh.13863 by Egyptian National Sti. Network (Enstinet), Wiley Online Library on [24/05/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons
1 PAQUIN ET

93
liver failure, hydronephrosis, or renal failure. All patients with metastatic 100,101
becoming widely adopted in this space. These treatments can begin in the
spinal compression should undergo urgent evaluation for surgical decompression.
outpatient setting depending on the stability of the patient.
If urgent surgical intervention is not possible, or available or there are delays to
surgical decompression where tis- sue can be obtained, then immediate use of
corticosteroids could be employed. Steroids are lymphodepleting and kill
2 | CONCLUSION
lymphoma tumor cells. Tumor cell death can relieve compressive symptoms but
can also interfere with tissue diagnosis. Therefore, steroid administration
The workup of a patient with potential lymphoma can be challenging given the
should be avoided until biopsy is performed, whenever possible.
many uncertainties that surround the presentation and pos- sible complications.
Likewise, the clinical course of lymphoma ranges from asymptomatic and
indolent to highlight morbid and fatal, thus, complicating the urgency of
1.6.2 | Tumor lysis syndrome
workup. Our aim of this manuscript is to highly the common presentations for
lymphoma and reasonable diag- nostic pathways that consider the operating
TLS is caused by high cell turn over. It most often presents after initia- tion of
characteristics of various diagnostic tools including peripheral blood FC, fine
chemotherapy and is mitigated with preventative medications such as
needle aspiration, core biopsy, and excisional biopsy. Notably, the majority of
allopurinol. However, some tumor lysis may present sponta- neously, prior to
patients with lymphadenopathy presenting to primary care will ultimately be
therapy initiation. Ongoing lysis results in accumula- tion of intracellular contents
found to have an alternative diagnosis. B-symptoms without lymph- adenopathy
in the extracellular serum. Lab findings include elevated potassium,
or splenomegaly should not prompt further targeted workup for lymphoma.
phosphorus, and uric acid and low cal- cium. Symptoms may include nausea,
Peripheral blood FC may be useful in patients with lymphocytosis but can lead
vomiting, diarrhea, arrhythmias, shortness of breath, congestive heart failure,
to false negative findings in patients with predominantly nodal lymphoma. Fine
arthralgias, lethargy, and cloudy urine. If untreated, these symptoms can progress to
needle aspiration is often insufficient for a complete diagnosis; however, core
94,95
acute renal failure, seizures, muscle dystonia, arrhythmias, and death. Ulti- biopsy has a rea- sonable likelihood of leading to an accurate diagnosis.
mately, patient with signs consistent with TLS as described above, should be Excisional biopsy, if feasible, remains the gold standard for diagnosis.
referred for emergent hospitalization.

DATA AVAILABILITY STATEMENT

Data sharing is not applicable to this article as no new data were cre- ated or
1.6.3 | Paraneoplastic processes analyzed in this study.

Paraneoplastic processes can be the presenting symptoms for under- lying

lymphoma. Paraneoplastic symptoms associated with lymphoma include— ORCID
cerebellar degeneration, immune thrombocytopenia, pemphi- gus, autoimmune Ashley R. Paquin https://orcid.org/0000-0003-1237-5742
hemolytic anemia.
96
Other paraneoplastic syn- dromes that occur in Hannah Stowe McMurry https://orcid.org/0000-0002-5596-1285
lymphoma include sweet syndrome and other dermatologic manifestations.
97 Malinda West https://orcid.org/0000-0002-2773-6320
Sweet syndrome presents as sudden erythematous skin lesions, fever, Joseph J. Shatzel https://orcid.org/0000-0001-9396-5976
leukocytosis, and neutrophilia. Sweet syndrome is commonly seen in
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