Approach

Non-Hodgkin's lymphomas (NHLs) are a heterogeneous group of malignancies with >30 entities. Consequently, the clinical presentation can be very diverse, varying from acute presentation in aggressive lymphomas to asymptomatic in more indolent disease.

Diagnosis of NHL is based on history, physical examination, laboratory tests, tissue biopsy, immunophenotyping (immunohistochemistry and/or flow cytometry), and imaging (positron emission tomography/computed tomography [PET/CT]).[48][49]

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

Pathological evaluation is required to confirm a diagnosis but may be difficult in some complex cases.

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

An additional opinion from an expert haematopathologist may be necessary, especially when clinical features do not fit the pathological diagnosis, or in cases of difficult histological diagnoses such as:

  • Cases with features of both diffuse large B-cell lymphoma (DLBCL) and Hodgkin's disease

  • Cases with features of both DLBCL and Burkitt's lymphoma

  • Differentiating chronic lymphocytic leukaemia (CLL) versus mantle cell lymphoma

  • Differentiating high-grade follicular lymphoma versus DLBCL

  • Cases involving T-cell lymphomas

  • Cases of composite lymphomas (concurrent involvement of two types of lymphomas).

History and physical examination

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

History may reveal a prior viral or bacterial infection (e.g., Epstein-Barr virus [EBV], Helicobacter pylori), coexisting immune system disorder, exposure to certain chemicals (e.g., pesticides), or other risk factors associated with NHL (e.g., breast implants, particularly if textured).

Patients with indolent (low-grade) NHL are often asymptomatic or have minimal symptoms (e.g., painless enlarged lymph nodes) at presentation.

Patients with aggressive (high-grade) NHL or advanced-stage disease may present with the following symptoms:

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

  • Fatigue/malaise

  • Chest pain

  • Shortness of breath (due to pleural or pulmonary involvement)

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

  • Abdominal discomfort (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/back pain (due to bone involvement)

  • Breast pain (due to breast implant involvement)

Physical examination may identify lymphadenopathy, pallor (anaemia), purpura (thrombocytopenia), jaundice (liver failure), hepatomegaly, splenomegaly, skin lesions, neurological abnormalities, or swelling (seroma) or mass in the breasts (in patients with breast implants >1 year).

Laboratory tests

Routine laboratory tests include:[48][49][50][51]

  • Full blood count (FBC) with differential

  • Peripheral blood smear

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

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

  • Risk assessment and prognostication

  • 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

Optimal diagnosis requires an excisional or incisional lymph node biopsy of the largest and most accessible lymph node, as this will allow for pathological assessment of lymph node architecture.[48][49]

A core needle biopsy is less optimal for diagnosis.[48][49]​ But it may be considered in certain situations (e.g., if surgery is not possible).

Fine-needle aspiration (FNA) biopsy alone is not optimal for diagnosis.[48][49]

Combined core needle biopsy and FNA biopsy, with appropriate immunophenotyping and genetic studies, may be considered for diagnosis in certain cases (e.g., when a lymph node is not easily accessible).[48][49]

Biopsy of extranodal sites

Biopsy of extranodal sites may be required for diagnosis. For example, brain biopsy is required for diagnosing primary CNS lymphoma.[53]​ ​Skin biopsy may be helpful for diagnosing certain T-cell lymphomas (e.g., cutaneous T-cell lymphoma) or in cases of skin infiltration by other lymphomas.[49][54]

Bone marrow biopsy and aspirate may be helpful for establishing a diagnosis, depending on the type of NHL or the individual case (e.g., when lymph node biopsy is not diagnostic and bone marrow involvement is suspected).

Assessing the extent of bone marrow involvement is important for staging and guiding treatment (e.g., stem cell transplant). Bone involvement by lymphoma usually signifies stage IV disease. See Criteria.

Immunophenotyping

Immunohistochemistry and/or flow cytometry of the biopsy specimen should be carried out to identify tumour markers to confirm the type of NHL.

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

Genetic tests (including karyotype, fluorescence in situ hybridisation [FISH], polymerase chain reaction [PCR], next-generation sequencing [NGS]) can be used to identify genetic abnormalities associated with NHL, for example:[48][49]

  • Immunoglobulin gene rearrangements (in B-cell lymphomas)

  • Chromosome translocations/rearrangements involving oncogenes such as BCL2 (e.g., t(14;18) in follicular lymphoma), CCND1 (e.g., t(11;14) in mantle cell lymphoma), MYC (e.g., t(8;14) in Burkitt's lymphoma), and BCL6 (e.g., t(3;14) in DLBCL)

  • T-cell receptor gene rearrangements (in T-cell lymphomas)

  • Mutations (e.g., TP53 in mantle cell lymphoma)

These genetic abnormalities can help to establish the diagnosis (e.g., by confirming a malignant clone and determining NHL subtype) and guide prognosis and treatment.

Imaging

Fluorodeoxyglucose (FDG)-PET/CT scan or CT scan alone (of chest, abdomen, pelvis, neck [in some cases]) should be carried out as part of the standard work-up (diagnosis, staging) and follow-up of NHL.[48][49]

FDG-PET/CT scan is more accurate than CT scan alone in detecting nodal and extranodal lesions.[55] FDG-PET/CT scan is the preferred imaging modality for staging and end-of-treatment evaluation in patients with FDG-avid lymphomas (e.g., DLBCL, follicular lymphoma).[56]

FDG-PET/CT scan may be useful in identifying biopsy targets with the highest diagnostic yield, identifying disease transformation (i.e., from an indolent lymphoma to aggressive lymphoma), and guiding rebiopsy to confirm histological transformation if clinically suspected (i.e., elevated LDH level; B symptoms).[48][56]​​​​[57][58]​ FDG uptake is higher in aggressive lymphomas than low-grade (indolent) lymphomas.[56][59]

Interim FDG-PET/CT scan may be useful for restaging and adapting treatment for certain NHLs (e.g., DLBCL); its role continues to be investigated.[48][60][61][62]​​​​​​[63]

Other imaging studies

​MRI of the brain and spine should be carried out if there are neurological signs or symptoms suggesting CNS involvement (e.g., primary CNS lymphoma, Burkitt's lymphoma).[48][53]

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).[49]​ If imaging of the breasts shows periprosthetic effusion or an abnormal mass, then a biopsy (e.g., FNA biopsy for effusion; and/or excisional, incisional, or core needle biopsy for an abnormal mass) should be carried out for cytological and immunophenotypic evaluation. FNA biopsy of a large volume of fluid (>50 mL) from around the breast may improve diagnostic yield.[49]

Investigations to consider

Serum protein electrophoresis (with immunofixation) and measurement of quantitative immunoglobulin levels may be useful for diagnosis in suspected cases of splenic marginal zone lymphoma or lymphoplasmacytic lymphoma (Waldenström's macroglobulinaemia), where a monoclonal immunoglobulin may be detected.[48]

Endoscopy and colonoscopy may be useful for the diagnosis of certain lymphomas (e.g., extranodal marginal zone lymphoma, mantle cell lymphoma).[48]

Serum beta-2 microglobulin measurement may be useful for assessing prognosis for certain lymphomas (e.g., follicular lymphoma).[48][64]​ See Criteria.

H pylori testing is indicated if gastric mucosa-associated lymphoid tissue (MALT) lymphoma is suspected.[48] See MALT lymphoma.

Echocardiogram or multigated acquisition scan can be used for detecting and monitoring cardiotoxicity if an anthracycline- or anthracenedione-based treatment is planned.[48][49]​​

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 in Burkitt's lymphoma, primary CNS lymphoma, and other HIV-related B-cell lymphomas, or if there are neurological signs or symptoms suggesting CNS involvement.[48][53]

Lumbar puncture may 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.[48] See Criteria.​

Viral screening

Hepatitis B virus (HBV) and Hepatitis C (HCV) virus status needs to be determined prior to treatment, because of the risk of virus reactivation during chemotherapy and/or immunosuppressive therapy.[48][65]​​​​ All patients receiving anti-CD20 monoclonal antibody therapy (e.g., rituximab, obinutuzumab) should be screened for HBV prior to starting treatment.[48]

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).[48][53]​​​​ NHL (particularly Burkitt's lymphoma) in a person with HIV is an AIDS-defining condition.[66][67]​​ Burkitt's lymphoma may be the presenting sign of HIV/AIDS.

Epstein-Barr virus (EBV) testing (e.g., PCR, in situ hybridisation) can guide diagnosis and treatment, particularly for HIV-related B-cell lymphomas (e.g., DLBCL) and certain T-cell lymphomas (e.g., peripheral T-cell lymphoma, extranodal NK/T-cell lymphomas).[48][49]​​​​​ 

Human T-cell lymphotropic virus (HTLV) testing can guide diagnosis for certain T-cell lymphomas (e.g., adult T-cell leukemia/lymphoma [ATLL]).[49]

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