What is the workup for a patient with multiple enlarged lymph nodes?

Workup for Multiple Enlarged Lymph Nodes

Begin with excisional or incisional lymph node biopsy as the gold standard for tissue diagnosis, avoiding fine-needle aspiration whenever possible, and simultaneously obtain contrast-enhanced CT imaging of the chest, abdomen, and pelvis along with comprehensive laboratory studies to establish the diagnosis and stage the disease. 1

Initial Clinical Assessment

History and Physical Examination

• Document constitutional B symptoms: fever, night sweats, and unexplained weight loss 2, 1
• Ask about additional symptoms including fatigue and pruritus 1
• Inquire about prior lymphoid neoplasms, particularly Hodgkin lymphoma, nodal anaplastic large cell lymphoma, and mycosis fungoides 2
• Assess for immunosuppression history (HIV, organ transplantation, or immunosuppressive therapy) 2
• Measure all accessible peripheral lymph node groups to identify the most suitable biopsy site 1
• Examine for hepatosplenomegaly 2, 1
• Evaluate performance status 1

Tissue Diagnosis (First Priority)

Biopsy Approach

• Excisional or incisional lymph node biopsy is mandatory and should almost always be performed 1, 3
• Core needle biopsy may be considered only in specific circumstances such as emergency treatment or difficult-to-access nodes 1
• Fine-needle aspiration should be avoided as it is insufficient for appropriate diagnosis 2, 3
• In patients with suspected lymphoma recurrence, needle biopsy has only 67% sensitivity and 79% specificity, making surgical biopsy preferable 3
• Direct referral for surgical biopsy reduces investigative time from 3 months to 1.25 months compared to initial needle biopsy 3

Lymph Node Selection

• Target nodes >1.5 cm in greatest transverse long axis diameter 2, 4
• Prefer excisional biopsy of accessible peripheral nodes when available 2, 1

Laboratory Studies (Concurrent with Biopsy)

Essential Blood Work

• Complete blood count with differential to assess for cytopenias or leukocytosis 2, 1
• Comprehensive metabolic panel including liver enzymes, alkaline phosphatase, and albumin 1
• Lactate dehydrogenase (LDH) as a marker of tumor burden and prognostic indicator 2, 1
• Uric acid level, especially if high tumor burden is present, to assess tumor lysis risk 2, 1

Infectious Disease Screening

• Hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (HBcAb) must be checked before any treatment 1
• Hepatitis C screening 1
• HIV screening 2, 1
• HTLV-1/2 serology only in endemic areas to identify adult T-cell lymphoma/leukemia 2

Imaging Studies

Initial Radiologic Workup

• Contrast-enhanced CT scan of the neck, chest, abdomen, and pelvis is the primary imaging modality 1, 5
• Baseline chest radiograph 2, 1
• PET-CT should be considered after tissue diagnosis is confirmed, particularly for staging lymphoma 2, 1, 5

Imaging Interpretation

• Nodes >1.5 cm in short axis diameter require workup for potential malignancy 4
• Nodes >25 mm are always pathologic, while nodes ≤15 mm are typically reactive 4
• Loss of fatty hilum, round shape, heterogeneous echogenicity, and central necrosis suggest malignancy 4

Bone Marrow Evaluation

When to Perform Bone Marrow Biopsy

• If PET-CT is performed, bone marrow biopsy may not be necessary 1
• If PET-CT is not available, bone marrow aspirate and biopsy are essential 2, 1, 5
• Not performed in patients with typical lymphomatoid papulosis 2
• Optional in patients with solitary primary cutaneous anaplastic large cell lymphoma without extracutaneous involvement 2

Additional Specialized Studies

High-Risk Features Requiring Further Workup

• Lumbar puncture with prophylactic intrathecal chemotherapy in high-risk patients with more than two adverse parameters by International Prognostic Index or bone marrow involvement 1
• Gastrointestinal endoscopy is mandatory in suspected mantle cell lymphoma, as the majority have GI involvement when systematically evaluated 5
• Pelvic CT scan is recommended in the setting of inguinofemoral lymphadenopathy to rule out associated pelvic or retroperitoneal lymphadenopathy 2

Common Pitfalls and Caveats

Critical Errors to Avoid

• Do not assume benignity based solely on imaging 1
• Do not accept inadequate tissue for diagnosis 1
• Do not delay hepatitis B screening, as reactivation can occur with chemotherapy and anti-CD20 therapy 1
• Do not rely on size alone: normal-sized nodes can harbor microscopic metastases, and enlarged nodes may be hyperplastic rather than neoplastic 4
• Avoid fine-needle aspiration as the primary diagnostic modality, as it has poor sensitivity (68%) and specificity (71%) for lymphoma in patients without prior malignancy 3
• Do not perform extensive radiologic staging in patients with typical lymphomatoid papulosis who have papulonodular skin lesions with spontaneous regression and no evidence of extracutaneous disease 2

Differential Diagnosis Considerations

• Tuberculosis is the most common cause of lymphadenopathy in many regions (52.7%), followed by reactive lymphoid hyperplasia (16.1%) and metastatic carcinoma (8.7%) 6
• In thoracic lymphadenopathy, consider infectious causes (tuberculosis, fungal disease), sarcoidosis, silicosis, drug reactions, and heart failure 7
• Persistent cervical lymphadenopathy has a 38% malignancy rate (metastatic disease or lymphoma), warranting prompt biopsy 8