Diagnostic Approach for Suspected Hodgkin and Non-Hodgkin Lymphoma with Bone Marrow Involvement
Core Diagnostic Principle
For Hodgkin lymphoma with PET-CT available, bone marrow biopsy is no longer indicated; for non-Hodgkin lymphoma, bone marrow aspirate and biopsy remain mandatory unless PET-CT demonstrates bone marrow involvement. 1
Initial Tissue Diagnosis
Biopsy Requirements
- Obtain an excisional lymph node biopsy as the gold standard, providing sufficient tissue for both fresh frozen and formalin-fixed samples 1, 2
- Core needle biopsy should only be performed when excisional biopsy is not feasible due to anatomic constraints 2, 3
- The pathological diagnosis must follow WHO classification with appropriate immunohistochemistry to distinguish classical HL (CD30+, CD15+, CD20 variable, CD45-) from NLPHL (CD20+, CD45+, CD15-, CD30-) and NHL subtypes 1
Clinical Assessment
History and Physical Examination
- Document B symptoms specifically: fever >38°C, drenching night sweats, unexplained weight loss >10% over 6 months 1, 3
- Record additional disease-related symptoms including fatigue, pruritus, and alcohol-induced pain 1
- Perform thorough physical examination of all lymphoid regions with special attention to hepatosplenomegaly and abdominal masses 2, 3
- Document performance status as it impacts treatment decisions and prognosis 2
Laboratory Evaluation
Mandatory Blood Tests
- Complete blood count with differential to assess for cytopenias 2, 3
- Comprehensive metabolic panel including liver and renal function tests 2, 3
- Lactate dehydrogenase (LDH) and uric acid as markers of tumor burden 1, 2, 3
- Hepatitis B, C, and HIV screening is compulsory before initiating therapy, particularly rituximab 1, 2, 3
- Protein electrophoresis for B-cell lymphomas 1, 2
- Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and alkaline phosphatase 1
Imaging Studies
Standard Imaging Protocol
- Baseline whole-body PET-CT is the preferred imaging modality for both HL and NHL staging 1, 2
- If PET-CT is unavailable, obtain contrast-enhanced CT of neck, chest, abdomen, and pelvis 1, 2, 3
- Chest X-ray is mandatory as part of initial evaluation 1
Bone Marrow Assessment: The Critical Decision Point
For Hodgkin Lymphoma
PET-CT has replaced bone marrow biopsy in HL staging. 1
- Bone marrow biopsy is NOT indicated if PET-CT is performed, given the high sensitivity of PET-CT for detecting bone marrow involvement 1
- Bone marrow biopsy must be performed ONLY if PET-CT is unavailable 1
- This represents a paradigm shift from older guidelines, supported by evidence showing PET-CT detects bone/bone marrow involvement with higher sensitivity than blind iliac crest biopsy 4
- PET-CT identified bone marrow lesions in patients with negative BMB, and all BMB-positive cases were also PET-CT positive 4
For Non-Hodgkin Lymphoma
Bone marrow aspirate and biopsy remain mandatory for NHL staging. 1
- Perform bone marrow aspirate and biopsy from the iliac crest in all patients with large B-cell NHL planned for curative therapy 1
- The combination provides both cytologic and histologic assessment 1
- Exception: If PET-CT demonstrates clear bone marrow involvement with multiple FDG-avid foci, some aggressive NHL subtypes (particularly DLBCL) may not require confirmatory biopsy, though this remains controversial 5
High-Risk NHL Requiring Additional CNS Evaluation
- Perform diagnostic lumbar puncture with prophylactic intrathecal chemotherapy (cytarabine and/or methotrexate) in high-risk patients with IPI >2, especially those with bone marrow involvement, testicular involvement, spinal involvement, or skull base involvement 1
Staging Classification
Apply Ann Arbor Staging System
- Stage all patients according to Ann Arbor classification with notation of bulky disease 1, 2
- For HL, allocate patients to limited, intermediate, or advanced stage categories based on EORTC/LYSA or GHSG definitions 1
- For NHL, calculate International Prognostic Index (IPI) for prognostic stratification 1, 2
Pretreatment Assessments
Mandatory Before Therapy Initiation
- Electrocardiography and echocardiography to assess cardiac function before anthracycline-based therapy 1
- Pulmonary function testing before bleomycin-containing regimens 1
- Reproductive counseling with consideration of sperm banking or fertility preservation in patients of reproductive age 1
- Serum pregnancy test in women of reproductive age 1
Follow-Up Bone Marrow Assessment
When to Repeat Bone Marrow Evaluation
- Repeat bone marrow aspirate/biopsy ONLY at end of treatment if initially involved 1
- Do not perform interval bone marrow biopsies during treatment unless clinically indicated by new cytopenias or suspected progression 1
Critical Pitfalls to Avoid
Common Diagnostic Errors
- Do not rely on bone marrow biopsy alone in HL when PET-CT is available, as BMB samples only a limited area and misses involvement in other skeletal sites 4
- Do not omit bone marrow biopsy in NHL based solely on negative PET-CT, as indolent lymphomas may have low FDG avidity 5
- Do not skip lumbar puncture in high-risk NHL with bone marrow involvement, as CNS prophylaxis significantly impacts outcomes 1
- Negative bone marrow biopsy does not exclude tumor involvement; if imaging suggests involvement, consider repeat or guided biopsy 6
- In chronic lymphocytic leukemia, both imaging techniques have frequent false-negative findings 6
Algorithmic Summary
Step 1: Obtain excisional lymph node biopsy for definitive diagnosis 1, 2
Step 2: Complete laboratory evaluation including CBC, CMP, LDH, viral screening 1, 2, 3
Step 3: Perform baseline PET-CT for staging 1, 2
Step 4 - Bone Marrow Decision:
- If Hodgkin lymphoma + PET-CT available: Skip bone marrow biopsy 1
- If Hodgkin lymphoma + NO PET-CT: Perform bone marrow biopsy 1
- If Non-Hodgkin lymphoma: Perform bone marrow aspirate and biopsy 1
- If NHL with IPI >2 + bone marrow involvement: Add diagnostic lumbar puncture with intrathecal prophylaxis 1
Step 5: Complete pretreatment cardiac and pulmonary assessments 1
Step 6: Apply Ann Arbor staging and calculate IPI for prognostication 1, 2