What are the steps to diagnose lymphoma?

Diagnosing Lymphoma: A Systematic Approach

The definitive diagnosis of lymphoma requires an excisional or incisional lymph node biopsy providing adequate tissue for morphology, immunohistochemistry, flow cytometry, and molecular studies reviewed by an experienced lymphoma pathologist. 1, 2

Step 1: Initial Diagnostic Evaluation

Clinical Assessment

• Evaluate for:
  • B symptoms: fevers >101°F (38.3°C), drenching night sweats, unexplained weight loss >10% over 6 months 1
  • Other symptoms: fatigue, pruritus, alcohol-induced pain (especially in Hodgkin lymphoma) 1
  • Physical examination: measure accessible nodal groups, spleen and liver size 1
  • Concerning features: non-tender firm lymph nodes, lymphadenopathy ≥2 weeks without fluctuation, nodes >1.5cm in cervical region 2

Laboratory Tests

• Complete blood count with differential
• Blood chemistry including:
  • LDH (important prognostic marker)
  • Uric acid
  • Liver function tests
  • Erythrocyte sedimentation rate (ESR)
  • C-reactive protein (CRP)
  • β2-microglobulin (for certain subtypes)
• Screening for HIV, hepatitis B and C 1, 2
• Protein electrophoresis (for B-cell lymphomas) 1, 2

Step 2: Tissue Diagnosis

Biopsy Procedure

• An excisional or incisional lymph node biopsy is mandatory 1, 2
• Core needle biopsy should only be considered when excisional biopsy is not possible 1
• Fine needle aspiration (FNA) alone is inadequate for initial diagnosis 1
• Immediate processing by an experienced pathology institute is essential 1, 2

Pathologic Evaluation

• Morphology assessment
• Immunohistochemistry for lineage markers (e.g., CD20, CD3, CD45, CD30, CD15) 1
• Flow cytometry for immunophenotyping 1
• Molecular/genetic studies when appropriate:
  • Cytogenetics or FISH for chromosomal translocations
  • PCR for immunoglobulin or T-cell receptor gene rearrangements 1
• Classification according to WHO criteria 1, 2

Step 3: Disease Staging

Imaging Studies

• PET-CT scan for FDG-avid lymphomas (most subtypes) 1, 3
• Contrast-enhanced CT of neck, chest, abdomen, and pelvis 1, 2
• Bone marrow assessment:
  • PET-CT is adequate for determining bone marrow involvement in FDG-avid lymphomas 1
  • Bone marrow biopsy if PET-CT is not available or for certain subtypes 1

Special Considerations

• CNS evaluation if high-risk features present:
  • CT or MRI for mass lesions
  • CSF assessment (cytology, flow cytometry) for suspected leptomeningeal disease 1
• Diagnostic lumbar puncture with prophylactic chemotherapy for high-risk patients (>2 adverse IPI parameters) with bone marrow, testicular, spinal, or skull base involvement 1, 2

Step 4: Risk Stratification

Staging Systems

• Ann Arbor classification with Cotswold modifications 1
• Lugano classification for response assessment 1

Prognostic Indices

• International Prognostic Index (IPI) for aggressive lymphomas 1, 2
• Follicular Lymphoma International Prognostic Index (FLIPI) for follicular lymphoma 1, 2

Common Pitfalls and Caveats

1. Inadequate biopsy: Fine needle aspiration or small core biopsies often provide insufficient material for complete diagnosis. Always aim for excisional biopsy when possible 1.

2. Delayed diagnosis: Lymphadenopathy persisting >2 weeks without fluctuation warrants prompt evaluation 2, 4.

3. Incomplete staging: Failure to perform comprehensive imaging can lead to understaging and suboptimal treatment 1.

4. Missing extranodal disease: Careful assessment of extranodal sites (bone marrow, liver, spleen, CNS) is essential for accurate staging 1, 3.

5. Inappropriate antibiotic use: Avoid antibiotics unless clear signs of bacterial infection are present, as this may delay diagnosis 2.

6. Inadequate pathology review: Diagnosis should be confirmed by an experienced hematopathologist familiar with current WHO classification 1.

By following this systematic approach, clinicians can ensure accurate diagnosis, appropriate staging, and optimal treatment planning for patients with suspected lymphoma.