What is the diagnostic workup for generalized lymphadenopathy?

Diagnostic Workup for Generalized Lymphadenopathy

The diagnostic workup for generalized lymphadenopathy should follow a risk-stratified approach starting with thorough history, physical examination, basic laboratory tests, and ultrasound as first-line imaging, proceeding to tissue sampling for persistent or concerning lymphadenopathy. 1

Initial Evaluation

History and Physical Examination

• Key historical elements:

  • Duration of lymphadenopathy (≥2 weeks is significant)
  • Associated symptoms (fever, night sweats, weight loss)
  • Recent infections, dental problems, trauma
  • Medication use
  • Risk factors for HIV, hepatitis
  • Travel history
  • Age (>40 years increases malignancy risk)

• Physical examination focus:

  • Document location, size, consistency, and mobility of nodes
  • Assess for hepatosplenomegaly
  • Note abnormal nodes: supraclavicular, popliteal, iliac nodes, or epitrochlear nodes >5 mm

Essential Laboratory Tests

• Complete blood count with differential
• Erythrocyte sedimentation rate (ESR)
• Serum lactate dehydrogenase (LDH)
• Comprehensive metabolic panel (liver and renal function)
• Hepatitis B testing (HBsAg and HBcAb)
• Hepatitis C testing (in high-risk patients)
• HIV testing 2, 1

Imaging Studies

First-Line Imaging

• Ultrasound of affected nodal regions to assess:
  • Size and morphology
  • Presence/absence of hilum
  • Vascularity patterns
  • Extracapsular spread 1

Advanced Imaging

• CT chest/abdomen/pelvis with oral and intravenous contrast when:
  • Malignancy is suspected
  • Need to evaluate extent of disease
  • Need to assess deep nodes
  • Need to evaluate adjacent structures 2, 1
• PET-CT may be considered when lymphoma is suspected 2

Tissue Sampling

When to Perform Tissue Sampling

• Persistent lymphadenopathy (>3-4 weeks)
• Presence of risk factors for malignancy
• Abnormal laboratory findings
• Concerning imaging features
• Failure to respond to empiric treatment 1

Biopsy Options

• Fine-needle aspiration cytology (FNAC):
  • Sensitivity 92.3%, specificity 90.0% for differentiating neoplastic from non-neoplastic lymphadenopathy
  • Less invasive but limited sample
• Core needle biopsy:
  • Higher diagnostic yield than FNAC
  • Preserves tissue architecture
  • Allows for additional studies (flow cytometry, molecular testing)
• Excisional biopsy:
  • Gold standard for lymphoma diagnosis
  • Required for accurate classification of lymphoma subtypes 2, 1

Special Considerations

For Suspected Hematologic Malignancy

• Bone marrow biopsy with or without aspirate when:
  • Hematologic malignancy is suspected
  • Unexplained cytopenia is present
  • Abnormal cells are seen on peripheral blood smear 2, 1
• Immunophenotyping panel should include Pan-B and Pan-T-cell antigens 2

For HIV-Positive Patients

• More thorough evaluation for opportunistic infections
• Higher prevalence of non-Hodgkin lymphoma
• Mycobacterial infections are more common 1

For Persistent Generalized Lymphadenopathy

• Consider underlying systemic diseases:
  • Autoimmune disorders (e.g., SLE)
  • Castleman disease
  • Immunodeficiency disorders 1

Management Approach

• Avoid empiric antibiotics without clear evidence of bacterial infection
• Reassess within 2-4 weeks of any treatment
• Proceed to biopsy if lymphadenopathy persists beyond 3 weeks despite antibiotics
• For patients with localized lymphadenopathy, evaluate for etiologies typically associated with the region involved
• For generalized lymphadenopathy (≥2 involved regions), focus on systemic disease evaluation 1, 3

Common Pitfalls to Avoid

• Delaying biopsy in patients with risk factors for malignancy
• Using corticosteroids before establishing a diagnosis
• Inadequate follow-up of resolving lymphadenopathy
• Incomplete tissue sampling leading to missed diagnosis
• Failure to consider rare causes of generalized lymphadenopathy such as autoimmune disorders 1, 3