What is the recommended workup for a patient with suspected lymphoma?

Lymphoma Workup

For suspected lymphoma, obtain an excisional lymph node biopsy (or core needle biopsy if excisional is not feasible), perform PET-CT for staging in most cases, obtain bone marrow biopsy when indicated by lymphoma subtype, and complete essential laboratory testing including CBC, comprehensive metabolic panel, LDH, and hepatitis B/C screening. 1

Tissue Diagnosis

Biopsy Approach

• Excisional or surgical lymph node biopsy is the gold standard for initial diagnosis, providing adequate tissue for morphology, immunohistochemistry, flow cytometry, and molecular studies 2, 1, 3
• Core needle biopsy is acceptable when excisional biopsy is impractical or poses excessive risk, but must provide sufficient material for ancillary testing 1
• Fine needle aspiration is inadequate and should not be used for initial lymphoma diagnosis 2, 1, 3
• If core biopsy is nondiagnostic, proceed to excisional biopsy 3

Pathology Requirements

• Diagnosis must be reviewed by an expert hematopathologist 2, 1
• Classification according to WHO criteria is mandatory 2, 1
• Immunophenotyping is essential in all cases 1, 3
• Store additional tissue (fresh-frozen and paraffin-embedded) for future molecular analysis when possible 2, 3
• For DLBCL specifically, assess MYC and BCL2 rearrangement using FISH whenever technically possible 1

Staging Workup

Imaging

PET-CT is the gold standard for staging in most lymphomas, including:

• Hodgkin lymphoma
• Diffuse large B-cell lymphoma (DLBCL)
• Follicular lymphoma
• Other FDG-avid aggressive and many indolent lymphomas 2, 1, 3

PET-CT is mandatory to confirm localized stage I/II disease before involved-field radiotherapy 2, 4

For small lymphocytic lymphoma/chronic lymphocytic leukemia (SLL/CLL), use contrast-enhanced CT instead of PET-CT for baseline staging 5

If PET-CT is unavailable or the lymphoma subtype is not reliably FDG-avid, obtain CT of neck, chest, abdomen, and pelvis with contrast 2, 4

Bone Marrow Evaluation

• Bone marrow aspirate and biopsy are required for follicular lymphoma staging 2, 4
• For DLBCL and other aggressive lymphomas, PET-CT can rule out bone marrow involvement if negative; biopsy may be omitted when PET-CT shows advanced-stage disease 1
• Bone marrow biopsy remains appropriate when negative PET-CT results would change prognosis or treatment, particularly if shortened therapy is considered 1

Laboratory Testing (Essential)

• Complete blood count with differential 1, 4, 6
• Comprehensive metabolic panel 6
• Lactate dehydrogenase (LDH) 1, 4
• Uric acid 2, 4
• Hepatitis B surface antigen and core antibody (mandatory before rituximab or immunochemotherapy) 1, 6
• Hepatitis C screening 1, 4
• HIV testing 1, 4
• Beta-2 microglobulin (for prognostic scoring in follicular lymphoma) 4
• Protein electrophoresis (recommended for B-cell lymphomas) 1

Additional Testing in Selected Cases

• Lumbar puncture with CSF analysis in high-risk patients: those with >2 IPI risk factors, bone marrow involvement, testicular involvement, paraspinal masses, or skull base involvement 7
• Consider prophylactic intrathecal chemotherapy (cytarabine or methotrexate) at time of diagnostic lumbar puncture 7
• MRI for suspected CNS lymphoma 1
• Cardiac function assessment (LVEF) before anthracycline-based therapy 1
• Pregnancy testing in women of childbearing age if chemotherapy is planned 6

Risk Stratification

Staging System

Use Ann Arbor/Lugano classification for all lymphomas 1, 4, 3

Prognostic Indices

• International Prognostic Index (IPI) for DLBCL and age-adjusted IPI (aa-IPI) 1
• Follicular Lymphoma International Prognostic Index (FLIPI) for follicular lymphoma 2, 4
• Document presence of bulky disease (>6 cm) 4

Common Pitfalls

• Avoid fine needle aspiration as the sole diagnostic method—it provides insufficient tissue for subtyping and molecular studies
• Do not skip hepatitis B testing before rituximab therapy; reactivation can be life-threatening
• Do not omit PET-CT in potentially curable early-stage disease—it prevents undertreatment by detecting occult sites
• In follicular lymphoma, core biopsies may miss grading heterogeneity; re-biopsy if material is inadequate 2
• Small peripheral lymph nodes (<2 cm) can be diagnostic when larger nodes are inaccessible, avoiding more invasive procedures 8