What is the most appropriate diagnostic test for an HIV-positive male with generalized malaise, fever, sweats, diffusely enlarged lymph nodes, and a new left inguinal mass, who is receiving anti-retroviral therapy (ART)?

Diagnostic Approach for HIV-Positive Patient with Lymphadenopathy and New Inguinal Mass

Perform an excisional biopsy of the new left inguinal mass immediately. This patient's presentation—fever, night sweats, malaise, diffuse lymphadenopathy, and a new discrete mass in an HIV-positive individual on ART—demands tissue diagnosis to differentiate between lymphoma (including AIDS-related Kaposi sarcoma, Hodgkin lymphoma, or non-Hodgkin lymphoma), multicentric Castleman's disease, opportunistic infections, or other malignancies 1.

Rationale for Excisional Biopsy

Excisional biopsy provides the most comprehensive tissue architecture and diagnostic yield for this clinical scenario. In HIV-positive patients with lymphadenopathy and constitutional symptoms, multiple serious conditions can present identically, and adequate tissue is essential for:

• Histopathologic examination to identify lymphoma subtypes, Kaposi sarcoma, or infectious etiologies 1
• Immunophenotyping and flow cytometry to characterize lymphoid malignancies 1
• HHV-8 (KSHV) testing for Kaposi sarcoma and multicentric Castleman's disease 1, 2
• Microbiologic cultures for mycobacteria, fungi (histoplasmosis), and other opportunistic pathogens 3, 4

Why Other Options Are Inadequate

PET Scan (Option A)

PET/CT has significant limitations in HIV-positive patients and should not be the initial diagnostic test 1:

• High false-positive rates due to immune deficiency-related lymphoid hyperplasia and opportunistic infections 1
• Cannot differentiate between lymphoma, Kaposi sarcoma, infections (toxoplasmosis, tuberculosis, histoplasmosis), and reactive lymphadenopathy 1
• PET/CT is useful for staging after tissue diagnosis is established, not for initial diagnosis 1

Core Biopsy (Option B)

Core biopsy provides insufficient tissue for comprehensive evaluation 1:

• Limited architectural assessment compared to excisional biopsy
• May miss heterogeneous pathology in lymph nodes
• Inadequate tissue for multiple diagnostic studies (immunophenotyping, cultures, molecular testing)

Fine Needle Aspiration (Option D)

FNA is explicitly inadequate for this presentation 1:

• Cannot assess lymph node architecture, which is critical for lymphoma diagnosis 1
• In penile cancer guidelines (analogous lymph node evaluation), FNA is only recommended for palpable nodes when DSNB is unavailable, and negative FNA with clinically suspicious nodes requires repeat biopsy or excision 1
• High false-negative rate for lymphomas and may miss infectious etiologies requiring culture 1

Critical Diagnostic Considerations

Differential Diagnosis Priority

This patient's presentation is most concerning for:

1. AIDS-related lymphomas (Hodgkin or non-Hodgkin): More aggressive in HIV-positive patients, often EBV-associated, with extranodal involvement 1, 5
2. Kaposi sarcoma: Can involve lymph nodes and viscera, universally HHV-8-associated 1
3. Multicentric Castleman's disease: HHV-8-associated, presents with fever, lymphadenopathy, and constitutional symptoms 2
4. Opportunistic infections: Mycobacterial (TB, MAC), fungal (histoplasmosis), or CMV 3, 4
5. Hemophagocytic lymphohistiocytosis: Can complicate lymphomas or infections in HIV-positive patients 5, 3

Concurrent Workup During Biopsy Planning

While arranging excisional biopsy, obtain:

• CD4 count and HIV viral load to assess immune status and ART efficacy 1
• Complete blood count for cytopenias suggesting marrow involvement or HLH 5, 3
• LDH, uric acid as markers of tumor burden 1
• HHV-8 serology if available 1, 2
• Chest X-ray to assess for pulmonary involvement 1
• Blood cultures including mycobacterial and fungal 3, 4

Common Pitfalls to Avoid

• Do not delay biopsy for imaging studies 1
• Do not assume reactive lymphadenopathy even with diffuse involvement—malignancy and serious infections commonly present this way in HIV-positive patients 2, 5
• Do not rely on FNA or core biopsy when excisional biopsy is feasible—inadequate tissue leads to diagnostic delays and repeat procedures 1
• Do not attribute symptoms solely to HIV without tissue diagnosis—constitutional symptoms require exclusion of malignancy and opportunistic infections 1, 2

Post-Biopsy Management

Once tissue diagnosis is established:

• Initiate or optimize ART regardless of diagnosis, as it improves outcomes for lymphomas and Kaposi sarcoma 1
• Stage appropriately with PET/CT for lymphomas or Kaposi sarcoma after histologic confirmation 1
• Coordinate care between HIV specialists and oncology for drug-drug interactions and opportunistic infection prophylaxis 1