What is the approach to diagnosing and managing lymphadenopathy?

Approach to Lymphadenopathy

Begin with focused history and physical examination to differentiate localized from generalized lymphadenopathy, as this distinction fundamentally determines the diagnostic pathway and urgency of workup.

Initial Clinical Assessment

History - Key Elements to Elicit

• Duration of lymphadenopathy: Nodes persisting >2-4 weeks require investigation 1, 2
• Location: Supraclavicular, epitrochlear (>5 mm), popliteal, and iliac nodes are abnormal and concerning for malignancy 1, 3
• Constitutional symptoms: Fever, night sweats, unintentional weight loss (>10% in 6 months) suggest malignancy or systemic disease 4, 1
• Infectious exposures: Recent infections, animal contacts, travel history, tuberculosis exposure 1, 3
• Medication history: Recent vaccines, new medications that may cause lymphadenopathy 1
• Risk factors for malignancy: Age >40 years, male sex, white race increase malignancy risk 3
• HIV status and immunosuppression: Including transplant history, chronic steroid use 4

Physical Examination - Critical Characteristics

• Size: Nodes >2 cm are more concerning for malignancy, especially in children 1
• Consistency: Hard, matted/fused nodes suggest malignancy or granulomatous disease 1
• Mobility: Fixed nodes to surrounding structures indicate malignancy 1
• Distribution: Localized vs. generalized (≥2 non-contiguous regions) 3
• Associated findings: Hepatosplenomegaly, skin lesions, oropharyngeal examination 4

Diagnostic Algorithm

Step 1: Localized vs. Generalized Lymphadenopathy

Localized lymphadenopathy (single anatomic region):

• Evaluate drainage patterns for infectious source 3
• Head/neck: Consider ENT causes, dental infections, pharyngitis 3
• Axillary: Examine ipsilateral arm, breast, chest wall 3
• Inguinal: Examine lower extremity, genitalia, perineum 3
• Supraclavicular nodes are abnormal and require immediate biopsy - high malignancy risk 1, 3

Generalized lymphadenopathy (≥2 non-contiguous regions):

• Usually indicates systemic disease 3
• Requires comprehensive laboratory evaluation 1

Step 2: Laboratory Evaluation (for persistent nodes >2-4 weeks)

Initial laboratory studies 1, 3:

• Complete blood count with differential
• C-reactive protein and erythrocyte sedimentation rate
• Tuberculosis testing (PPD or IGRA)
• HIV testing (if status unknown) 4
• Hepatitis B and C serologies (if immunosuppressive therapy considered) 4

Additional studies based on clinical suspicion 4:

• Serum immunoglobulins and protein electrophoresis (if monoclonal gammopathy suspected)
• Direct antiglobulin test
• Serum chemistry including LDH, uric acid
• CMV serology (if alemtuzumab or transplant considered) 4

Step 3: Imaging

Ultrasound 2:

• First-line imaging modality
• Assess node architecture, vascularity, size
• Can guide biopsy

CT scan 4:

• Not routinely required for initial evaluation in most cases 4
• Indicated for: staging confirmed malignancy, evaluating deep/mediastinal nodes, assessing surrounding structures 2
• In CLL: staging relies on physical examination and blood counts, not CT 4

PET-CT 4:

• Not useful for routine lymphadenopathy workup 4
• Reserved for: suspected Richter transformation, large-cell lymphoma transformation, staging certain malignancies 4

Step 4: Tissue Diagnosis - When and How

Indications for biopsy 2, 3, 5:

• Lymphadenopathy persisting >4 weeks without clear benign cause
• Supraclavicular, epitrochlear location
• Hard, fixed, or matted nodes
• Size >2 cm (especially in children)
• Constitutional symptoms present
• High-risk features (age >40, male, white race)

Biopsy techniques 4, 2, 3:

• Fine-needle aspiration (FNA): Least invasive, but limited for lymphoma diagnosis 2
• Core needle biopsy: Better tissue architecture than FNA; can include immunocytology and flow cytometry 2
• Excisional biopsy: Gold standard when lymphoma suspected or when FNA/core biopsy inconclusive 4, 2
  • Provides entire node architecture
  • Essential for accurate lymphoma classification 4, 5
  • Required for Richter transformation diagnosis 4

Common Pitfalls to Avoid

Do not use corticosteroids empirically - they mask histologic diagnosis of lymphoma and other malignancies 1, 3

Do not rely on CT for CLL staging - physical examination and blood counts are the standard 4

Do not delay biopsy beyond 4 weeks in unexplained lymphadenopathy, especially with high-risk features 2, 5

Do not assume imaging-only enlarged nodes change clinical stage in CLL - they must be palpable 4

Do not perform PET-CT routinely - it has limited utility except for specific scenarios like Richter transformation 4

Special Populations

HIV-positive patients 4:

• Require infectious disease consultation
• Opportunistic infections commonly mimic malignancy (bacillary angiomatosis, cryptococcosis, blastomycosis)
• Lymphadenopathy more common with higher viral loads and lower CD4 counts
• Coordinate care between HIV specialist and oncology

Patients requiring immunosuppressive therapy 4:

• Screen for hepatitis B/C before treatment
• HBV carriers need prophylactic nucleoside analogs (lamivudine) 4
• CMV monitoring required with alemtuzumab or transplant 4

Management of Benign Lymphadenopathy

Observation alone for nodes <2 cm, soft, mobile, without systemic symptoms, in low-risk patients 1, 3

Antibiotics may be considered for acute unilateral cervical lymphadenitis with systemic symptoms, especially in children 3

Reassess in 2-4 weeks - if persistent or enlarging, proceed to imaging and/or biopsy 1, 2