Approach

Non-Hodgkin's lymphomas (NHLs) are a heterogeneous group of malignancies with over 60 subtypes.[1][2] See Classification.

Patients with NHL may present differently depending on the type and location of lymphoma, and disease stage at presentation.

Diagnosis of NHL is based on history, physical examination, laboratory tests, tissue biopsy, immunophenotyping (immunohistochemistry and/or flow cytometry), and imaging (e.g., positron emission tomography/computed tomography [PET/CT]).[70][71]

Genetic studies should be considered to identify genetic abnormalities that can guide diagnosis, prognosis, and treatment.[70][71]

NHL may mimic many other conditions and can be difficult to distinguish from inflammation, benign hyperplasia, carcinomas, germ cell tumours, or melanoma.

Given the complexity and heterogeneity of NHL, an expert haematopathologist should be consulted to establish an accurate diagnosis in patients with clinical features that do not fit the pathological diagnosis, or in the setting of difficult histological diagnoses. Examples may include patients with:

  • Features of both primary mediastinal B-cell lymphoma and classic Hodgkin's lymphoma (i.e., mediastinal grey zone lymphoma)

  • Features of both diffuse large B-cell lymphoma (DLBCL) and Burkitt's lymphoma

  • Suspected primary cutaneous DLBCL, leg type

  • T-cell lymphomas

  • Composite lymphomas (concurrent involvement of two types of lymphomas)

or where there is a need to differentiate:

  • High-grade follicular lymphoma versus DLBCL

  • Mantle cell lymphoma versus chronic lymphocytic leukaemia (CLL)

History and physical examination

History and findings on physical examination will vary depending on the type and location of lymphoma, and disease stage at presentation.

History may reveal risk factors associated with NHL, such as:

  • Prior viral infection (e.g., HIV, Epstein-Barr virus [EBV], hepatitis C virus [HCV], human T-cell lymphotrophic virus type 1 [HTLV-1])

  • Bacterial infection (e.g., Coxiella burnetii)

  • Autoimmune disorder (e.g., Sjogren syndrome, rheumatoid arthritis)

  • Immunodeficiency due to a disorder (e.g., common variable immunodeficiency) or acquired (e.g., post-transplant)

  • Genetic disorder (e.g., Klinefelter syndrome)

  • Exposure to certain chemicals (e.g., pesticides)

  • Use of immunomodulatory drugs, such as tumour necrosis factor (TNF)-alpha antagonists (e.g., infliximab, adalimumab)

  • Breast implant (particularly if textured)

Clinical presentation

Clinical presentation is often vague and can be very diverse, ranging from asymptomatic or minimally symptomatic (e.g., painless enlarged lymph nodes) in those with an indolent NHL (e.g., follicular lymphoma), to acute presentation in those with an aggressive NHL (e.g., DLBCL).

Patients with aggressive (high-grade) NHL or advanced-stage disease may present with the following:[3][4][5][6][7][8][9][10][11][12][13]​​​[14][15]​ 

  • B symptoms (unexplained fever, drenching night sweats, and weight loss >10% of body weight within 6 months)

  • Fatigue/malaise

  • Chest pain

  • Shortness of breath and/or pallor (due to anaemia; pulmonary or pleural involvement; pleural/pericardial effusion)

  • Cough (due to pulmonary, mediastinal, or lymph node involvement)

  • Abdominal discomfort or pain (due to gastrointestinal, liver, spleen, or lymph node involvement)

  • Headache/change in mental status (due to meningeal or parenchymal brain involvement)

  • Focal neurological deficits; for example, ataxia, cognitive changes, and focal weakness (due to central nervous system [CNS] involvement)

  • Bone pain (due to bone involvement)

  • Back pain (due to spinal bone or epidural involvement)

  • Breast pain (due to breast implant involvement)

  • Metabolic abnormalities (acute renal injury, tumour lysis syndrome, hypercalcaemia)

Physical examination may identify the following:[3][10][13][72][73]​​​

  • Lymphadenopathy

  • Purpura

  • Jaundice

  • Hepatomegaly

  • Splenomegaly

  • Skin lesions

  • Neurologic alabnormalities

  • Visual abnormalities

  • Swelling (seroma) or mass in the breasts (in patients with breast implants >1 year

Laboratory tests

Routine laboratory tests include:[70][71][74][75]​​

  • Full blood count (FBC) with differential

  • Comprehensive metabolic panel (including liver function tests [LFTs])

  • Serum lactate dehydrogenase (LDH), an indirect measure of the proliferative rate of the lymphoma

  • Uric acid (particularly for aggressive lymphomas)

The above laboratory tests are required for the purpose of:

  • Assessing blood and organ function (e.g., liver, kidney)

  • Guiding diagnosis and treatment (including tumour lysis syndrome prophylaxis)

  • Risk assessment and prognostication (see Criteria)

  • Monitoring disease course

Venepuncture and phlebotomy animated demonstration
Venepuncture and phlebotomy animated demonstration

How to take a venous blood sample from the antecubital fossa using a vacuum needle.

Biopsy

Excisional or incisional lymph node biopsy should be performed for diagnosis and grading of NHL, as this allows for optimal assessment of morphology (including lymph node architecture) and provides sufficient tissue for immunohistochemistry and molecular studies.[70][71][77]

Core needle biopsy is an appropriate alternative to excisional or incisional biopsy in certain circumstances (e.g., if a lymph node is not easily accessible, or if surgery is not possible or will substantially delay treatment).[70][71]

FNA biopsy alone is insufficient for diagnosis and grading of NHL.[70][71]​​​​ It may be used for the initial diagnostic work-up for certain lymphomas (e.g., breast implant-associated anaplastic large cell lymphoma [BIA-ALCL]).[13][71]​​[78]​​​

Biopsy of extranodal sites

Biopsy of extranodal sites may be required for diagnosising certain types of NHL, for example:[71][79][80]

  • Stereotactic biopsy of brain lesions for diagnosing primary CNS lymphoma

  • FNA biopsy of periprosthetic effusion (>50 mL) and surgical biopsy (excisional, incisional, or core needle) of a breast mass for diagnosing BIA-ALCL

  • Skin biopsy (punch, incisional, or excisional) for diagnosing primary cutaneous lymphomas, or in cases of skin involvement by other lymphomas

  • Vitreous fluid biopsy for primary vitreoretinal lymphoma or primary CNS lymphoma ocular variant

Bone marrow biopsy and aspiration may be helpful for evaluating unexplained cytopenias and establishing a diagnosis (including staging), depending on the type of NHL or the specific setting (e.g., when lymph node biopsy is not diagnostic and bone marrow involvement is suspected).[70][77]

Assessing bone marrow involvement is important for staging and guiding treatment (e.g., stem cell transplant).[81] Bone marrow involvement usually signifies stage IV disease. See Criteria.

Immunophenotyping

Immunohistochemistry and/or flow cytometry of the biopsy specimen should be performed to identify tumour markers to confirm the type of NHL.[70][71]

Flow cytometry is particularly useful when tumour cells are suspended (e.g., in peripheral blood, bone marrow aspirate, lymph node suspensions, effusions, cerebrospinal fluid)​

Genetic studies

The following genetic studies can be used to detect genetic abnormalities associated with NHL, which can help establish a diagnosis (e.g., by confirming a malignant clone and determining the NHL subtype) and guide prognosis and treatment:[70][71]

  • Molecular analysis (e.g., polymerase chain reaction [PCR]) to detect immunoglobulin gene rearrangements (in B-cell lymphomas) or T-cell receptor gene rearrangements (in T-cell lymphomas)

  • Cytogenetic analysis (e.g., karyotype; fluorescence in situ hybridisation [FISH]) to detect chromosome translocations/rearrangements involving oncogenes such as BCL2 (e.g., t(14;18) in follicular lymphoma and DLBCL), CCND1 (e.g., t(11;14) in mantle cell lymphoma), MYC (e.g., t(8;14) in Burkitt's lymphoma and DLBCL), and BCL6 (e.g., t(3;14) in DLBCL)

  • Mutational analysis (e.g., gene sequencing; next-generation sequencing [NGS]) to detect genetic mutations (e.g., TP53 in mantle cell lymphoma)

Imaging

Fluorodeoxyglucose (FDG)-PET/CT scan or CT scan alone (of chest, abdomen, pelvis, head/neck [in some cases]) should be performed as part of the standard work-up (diagnosis, staging) and follow-up of NHL.[70][71][79][80]​​​

FDG-PET/CT scan is the preferred imaging modality for staging and end-of-treatment response assessment in patients with FDG-avid lymphomas (e.g., DLBCL, follicular lymphoma) as it is more accurate than CT scan alone in detecting nodal and extranodal lesions.[70][71]​​​[82][83][84]​​​

​FDG-PET/CT scan can also be used to:[70][83][85]​​[86][87][88][89]​​​[90][91][92][93]

  • Identify biopsy sites with the highest diagnostic yield

  • Detect histological transformation of an indolent lymphoma to aggressive lymphoma (FDG uptake is higher in aggressive lymphomas)

  • Guide rebiopsy to confirm histological transformation if clinically suspected (e.g., elevated LDH level; B symptoms present)

Interim FDG-PET/CT scan may be useful for restaging and adapting treatment for certain NHLs (e.g., DLBCL, peripheral T-cell lymphomas); its role continues to be investigated.[70][71]

Other imaging studies

​MRI of the brain and spine should be performed if there are neurological signs or symptoms suggesting CNS involvement (e.g., primary CNS lymphoma, Burkitt's lymphoma).[70][79]

Ultrasound of the breast and axilla should be performed if there are signs or symptoms suggesting breast implant involvement (breast implant-associated anaplastic large cell lymphoma).[71]​

Endoscopy may be useful for diagnosis and staging of certain lymphomas (e.g., mantle cell lymphoma).[70]

Echocardiogram or multigated acquisition (MUGA) scan can be used for detecting and monitoring cardiotoxicity if an anthracycline-based treatment is indicated.[70][71]

Lumbar puncture

May be performed to assess CNS involvement and for administration of intrathecal CNS prophylaxis.

Lumbar puncture with cerebrospinal fluid analysis (including flow cytometry) is indicated for patients with Burkitt's lymphoma, primary CNS lymphoma, or patients with neurological signs or symptoms suggesting CNS involvement.[70][79]

Lumbar puncture should be considered for patients with DLBCL who have high-risk disease, including those with: high-risk score on the CNS-International Prognostic Index (i.e., CNS-IPI 4-6); kidney or adrenal gland involvement; testicular lymphoma; primary cutaneous DLBCL, leg type; or stage IE DLBCL of the breast.[70] See Criteria.​

Viral screening

Hepatitis B virus (HBV) status should be determined prior to treatment, because of the risk of HBV reactivation during chemotherapy and/or immunosuppressive therapy.[70][94]​​​​​​ All patients receiving anti-CD20 monoclonal antibody therapy (e.g., rituximab, obinutuzumab) should be screened for HBV prior to starting treatment.[70]

Hepatitis C virus (HCV) testing is required for certain B-cell lymphomas (e.g., marginal zone lymphoma) as it can inform management (e.g., use of direct-acting antiviral [DAA] therapy).[70][95]

HIV testing is required for certain lymphomas (e.g., primary CNS lymphoma, Burkitt's lymphoma) as it can inform management (e.g., use of antiretroviral therapy [ART]).[70][79]​​​​ NHL (particularly Burkitt's lymphoma) in a person living with HIV is an AIDS-defining condition.[96][97]​​ Burkitt's lymphoma may be the presenting sign of HIV/AIDS.

EBV testing (e.g., PCR, in situ hybridisation) can guide diagnosis and treatment, particularly for HIV-related B-cell lymphomas (e.g., DLBCL, primary CNS lymphoma, Burkitt's lymphoma) and certain T-cell lymphomas (e.g., peripheral T-cell lymphoma, extranodal NK/T-cell lymphomas).[70][71]​​​​​​ 

Human T-cell lymphotropic virus (HTLV) testing can guide diagnosis for certain T-cell lymphomas (e.g., adult T-cell leukaemia/lymphoma [ATLL]).[71]

Other investigations to consider

Serum protein electrophoresis and/or measurement of quantitative immunoglobulin levels may be performed as part of the diagnostic work-up for follicular lymphoma and marginal zone lymphoma (particularly splenic).[70] If a monoclonal immunoglobulin is detected or immunoglobulin level is elevated, further testing with immunofixation may be performed.[70]

Serum beta-2 microglobulin measurement may be useful for assessing prognosis for certain lymphomas (e.g., follicular lymphoma, DLBCL, mantle cell lymphoma).[70][98] See Criteria.

Ki-67 measurement may be useful for assessing prognosis for certain lymphomas (e.g., mantle cell lymphoma).​ See Criteria.

Ophthalmological examination (including slit lamp) may be performed to assess ocular involvement (primary vitreoretinal lymphoma) in a patient with primary CNS lymphoma.[79]

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