European J of Haematology - 2022 - Paquin - The Diagnosis and Management of Suspected Lymphoma in General Practice
European J of Haematology - 2022 - Paquin - The Diagnosis and Management of Suspected Lymphoma in General Practice
European J of Haematology - 2022 - Paquin - The Diagnosis and Management of Suspected Lymphoma in General Practice
DOI: 10.1111/ejh.13863
REVIEW
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
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
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.
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
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
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
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.
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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.
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