Diagnostics

• Suspect NHL in patients with suggestive clinical or laboratory features.

• Confirm the diagnosis and determine the subtype via lymph node and/or tissue biopsies.

• Stage and classify the disease (see “Staging of NHL”), e.g.:

  • Imaging studies: to determine the extent of the disease and detect possible CNS involvement

  • Bone marrow aspiration and biopsy: to detect bone marrow involvement

• Routine laboratory studies

  • CBC: may show anemia, thrombocytopenia; WBC count may be high or low (commonly leukopenia, lymphocytosis)

  • Serum calcium: may show hypercalcemia

• Markers of disease activity [16][20]

  • LDH: usually elevated

  • Serum β2-microglobulin: may be elevated

• Viral serologies

  • HIV screening

  • Additional studies can be suggestive of the underlying etiology (e.g., hepatitis B and C, EBV, HTLV-1).

Selection of biopsy sample

• Nodal disease

  • Select the most appropriate node for biopsy (e.g., a node with significant, progressive, and persistent enlargement).

  • Techniques [17]

    • Preferred: excisional lymph node biopsy or core needle biopsy

    • Alternative: incisional lymph node biopsy

    • Avoid fine-needle aspiration biopsy.

• Extranodal disease

  • Excisional tissue biopsies are recommended.

  • Biopsies frequently require guidance, e.g., with endoscopy or using ultrasound.

These studies help determine the subtype of NHL.

• Histopathology: provides a detailed morphology of individual proliferating cells and a description of the pattern of lymph node (or tissue) infiltration (e.g., nodular, diffuse)

• Immunophenotype (e.g., flow cytometry, immunohistochemistry)

  • Detects surface antigens, determines the specific cell type (B cell/T cell), and identifies specific markers

  • Possible findings include:

    • B-cell lymphomas: CD20 positive

    • T-cell lymphomas: CD3 positive

• Indicated in all patients for staging and to assess response to therapy

• Choice of imaging modality depends on the suspected subtype of NHL (uptake of FDG varies between subtypes)

  • FDG-avid NHLs (most subtypes): PET-CT

  • Non-FDG-avid NHLs : CT whole body with contrast

indicated in most newly diagnosed patients with NHL

• Indications

  • Patients considered high-risk for CNS involvement [21]

  • Primary CNS lymphoma

  • Patients with neurological signs and symptoms

  • Patients with HIV

• Recommended modalities include:

  • Imaging (MRI or CT brain)

  • Lumbar puncture with CSF assessment (cytology; detection of EBV DNA)

• Lugano classification is the preferred classification method for primary nodal NHL.

  • Imaging is used to assess the number and location of affected lymph nodes, tumor bulk, and liver and spleen involvement.

  • Bone marrow biopsy to assess bone marrow involvement

  • The disease is then classified as either:

    • Limited disease (stage I + II): one node or conglomerate (stage I), or ≥ 2 nodes or conglomerates on one side of the diaphragm (stage II)

    • Advanced disease (stage III + IV): nodes on both sides of the diaphragm or supradiaphragmatic nodes with splenic involvement (stage III), or diffuse or disseminated disease (stage IV)

• Previously, a version of the Cotswolds-modified Ann Arbor system was used, excluding the presence of B symptoms.