What is the diagnostic approach and treatment for differentiating between lymphoma, disseminated tuberculosis (TB), sarcoidosis, histoplasmosis, and brucellosis?

Diagnostic Approach to Differentiating Lymphoma, Disseminated TB, Sarcoidosis, Histoplasmosis, and Brucellosis

The diagnostic strategy requires a systematic three-step approach: first, obtain detailed epidemiologic and exposure history to narrow the differential; second, perform targeted imaging and laboratory testing based on clinical suspicion; and third, secure tissue diagnosis with appropriate microbiological and histopathologic analysis, always excluding infectious causes before diagnosing sarcoidosis. 1

History: Critical Epidemiologic and Exposure Details

Geographic and Travel History

• Endemic exposure patterns: Histoplasmosis is endemic to Ohio and Mississippi River valleys; recent travel to TB-endemic regions (Southeast Asia, sub-Saharan Africa, Eastern Europe) significantly increases dissemination risk 1
• Occupational exposures: Livestock contact, unpasteurized dairy products, or work in endemic regions suggests brucellosis 1
• Demographic patterns: Sarcoidosis has higher incidence in northern Europeans and African Americans, with no specific exposure pattern 1

Constitutional Symptom Patterns

• Fever characteristics: Undulating fever pattern with profound sweats and arthralgias strongly suggests brucellosis 1
• Duration and severity: Constitutional symptoms (fever, night sweats, weight loss, extreme fatigue) lasting weeks to months are common in disseminated TB and histoplasmosis 1
• B symptoms: Fever, night sweats, weight loss with painless lymphadenopathy suggest lymphoma 1
• Löfgren's syndrome: Bilateral hilar adenopathy with erythema nodosum and/or periarticular arthritis is highly specific for sarcoidosis 2, 1

Additional Clinical Clues

• Skin manifestations: Lupus pernio is highly specific for sarcoidosis 2
• Ocular involvement: Uveitis and optic neuritis suggest sarcoidosis 1
• Hyperpigmentation: May be observed in visceral leishmaniasis (kala-azar) in persons infected in India and Bangladesh 2

Examination: Specific Physical Findings

Lymphadenopathy Characteristics

• Painless, bulky mediastinal adenopathy: Suggests lymphoma 1
• Bilateral hilar adenopathy: Classic for sarcoidosis, especially with erythema nodosum 2, 1
• Hepatosplenomegaly: Common in disseminated TB, histoplasmosis, and visceral leishmaniasis 2, 1

Organ-Specific Findings

• Splenomegaly with pancytopenia: Characteristic of visceral leishmaniasis 2
• Skin lesions: Erythema nodosum (sarcoidosis), lupus pernio (sarcoidosis), or disseminated skin lesions (histoplasmosis in HIV) 2, 1
• Cardiac findings: Arrhythmias or conduction abnormalities may indicate cardiac sarcoidosis 2

Laboratory Testing: Stepwise Algorithm

Step 1: Exclude Infectious Causes First (Mandatory)

This is the critical first step—never diagnose sarcoidosis without excluding TB and fungal infections 3

Mycobacterial Testing

• Sputum AFB smear and culture (minimum 3 specimens) 2, 1
• Interferon-gamma release assay (IGRA) or tuberculin skin test 1
• Molecular testing: Nucleic acid amplification tests for rapid TB detection 3
• Bronchoscopy with BAL: If sputum negative, proceed to flexible bronchoscopy with BAL for AFB smear, culture, and molecular testing 2

Fungal Testing

• Histoplasma urine and serum antigen (highly sensitive for disseminated disease) 1
• Fungal cultures from blood, sputum, or BAL 1
• Fungal serology 1

Brucellosis Testing

• Blood cultures (prolonged incubation required) 1
• Brucella serology (agglutination tests) 1

Step 2: Sarcoidosis-Specific Testing (Only After Excluding Infections)

Baseline Screening for Confirmed Sarcoidosis

• Serum calcium (strong recommendation for screening abnormal calcium metabolism) 2, 3
• Serum creatinine (screen for renal sarcoidosis) 2, 3
• Alkaline phosphatase (screen for hepatic sarcoidosis) 2, 3
• ECG (screen for cardiac involvement) 2, 3

BAL Analysis

• Lymphocytosis with elevated CD4:CD8 ratio (>3.5) suggests sarcoidosis while helping exclude infections 3
• Total cell count and differential 3

Serum ACE Levels

• Not reliable for diagnosis due to lack of specificity (sensitivity 60%, specificity 70%) 2, 3
• May be elevated but cannot differentiate sarcoidosis from other granulomatous diseases 2

Step 3: Lymphoma Evaluation

Hematologic Testing

• Complete blood count with differential 1
• Serum LDH (elevated in lymphoma and adult T-cell leukemia/lymphoma) 2, 1
• Flow cytometry on peripheral blood or tissue 2, 1
• HTLV-I serology if adult T-cell leukemia/lymphoma suspected 2

Imaging: Disease-Specific Patterns

Chest CT Characteristics

Sarcoidosis

• Bilateral hilar adenopathy with perilymphatic nodules (along bronchovascular bundles, interlobular septa, and pleural surfaces) 1, 4
• Symmetrical distribution 4
• Nodularity of mucosal thickening if sinus involvement 2

Disseminated TB or Histoplasmosis

• Necrotizing granulomas with cavitation 1
• Miliary pattern (random small nodules) 2
• Irregular macronodules randomly spread across lungs 5

Lymphoma

• Bulky mediastinal adenopathy 1
• Extranodal masses 1
• Asymmetric distribution 4

Additional Imaging

• FDG-PET: Increased uptake in sarcoid granulomas, lymphoma, and active TB; useful for monitoring severe cases 2
• Gallium scanning: Can demonstrate increased uptake in sarcoid granulomas but has low sensitivity and specificity 2

Pathology: Tissue Acquisition and Interpretation

Sampling Strategy

EBUS-TBNA as Initial Approach

• Pooled diagnostic accuracy of 79% across various conditions 6
• Disease-specific yields: Sarcoidosis 74.5%, TB 79.2-84.8%, lymphoma 68.7% 2, 6
• Minimum 3 needle passes per site for optimal yield (sensitivity increases from 69.8% with one pass to 95.3% with three passes) 6
• ROSE (rapid on-site evaluation): Increases diagnostic yield (78.0% vs 71.4% without ROSE) and reduces needle passes (2.2 vs 3.1) 6

When EBUS-TBNA is Insufficient

• Surgical biopsy via thoracoscopy: Required for multinodular lesions when bronchoscopic aspiration fails, allows multiple large lung biopsies for differential diagnosis 5
• Excisional lymph node biopsy: Necessary for definitive lymphoma diagnosis requiring architecture assessment 2

Special Considerations for Lymphoma

• Cytology alone has limitations: Pooled diagnostic accuracy only 68.7% due to need for cell morphology, immunophenotype, and tissue architecture evaluation 2
• Higher yield for relapsed vs. de novo lymphoma 2, 6
• Hodgkin's lymphoma particularly challenging: Reed-Sternberg cells scarce in aspirates, architecture evaluation impossible 2

Histopathologic Differentiation (Gold Standard)

Granuloma Characteristics

• Tuberculosis: Robust necrotizing (caseating) granulomas with central necrosis 1, 3, 4
• Histoplasmosis: Large acellular necrotizing granulomas; abundant bland necrosis with <2 angular, ragged granulomas per slide 1, 7
• Sarcoidosis: Well-formed, non-necrotizing granulomas with minimal surrounding lymphocytic inflammation; typically >3 granulomas per slide (often >10), rounded with crisp sharp borders 2, 1, 3, 7
• Brucellosis: Non-caseating granulomas similar to sarcoidosis but with positive cultures or serology 1

Critical Staining and Analysis

• Special stains for organisms: Gomori methenamine silver (GMS) and periodic acid-Schiff (PAS) for fungi; Ziehl-Neelsen or auramine-rhodamine for mycobacteria 7
• Yeasts identification: In histoplasmosis, yeasts identified in 97% of specimens with necrosis and 76% overall 7
• Immunohistochemistry for lymphoma: Required to demonstrate monoclonal B-cell population 1

Background Inflammatory Patterns

• Histoplasmosis: Acute (14%) and/or chronic (67%) inflammation; uncommonly giant cells (12%) 7
• Sarcoidosis: Chronic inflammatory background without acute inflammatory cells; 50% contain giant cell infiltrates 7

Microbiological Confirmation

• Cultures: Mycobacterial cultures (6-8 weeks), fungal cultures, Brucella cultures (prolonged incubation) 1
• Molecular testing: PCR for TB, fungal nucleic acid detection 3, 5
• All cultures must be negative for mycobacteria and fungi before confirming sarcoidosis 2, 3

Critical Pitfalls to Avoid

1. Never diagnose sarcoidosis without actively excluding TB through microbiological testing—misdiagnosis is potentially fatal as treatments are opposite 3
2. Histopathologic features alone cannot definitively distinguish sarcoidosis from TB—always require negative cultures 3
3. Do not rely on ACE levels for sarcoidosis diagnosis—lack of specificity makes them unreliable 2, 3
4. In TB-endemic areas, maintain high suspicion for TB even with non-necrotizing granulomas 8, 4
5. For lymphoma diagnosis, cytology alone is often insufficient—may require excisional biopsy for architecture and immunophenotyping 2
6. Consider combined infections (e.g., disseminated histoplasmosis and TB in HIV patients)—persistent symptoms despite treatment should prompt broader workup 9
7. In patients with high clinical suspicion for sarcoidosis (Löfgren's syndrome, lupus pernio, Heerfordt's syndrome), lymph node sampling may not be necessary, but close clinical follow-up is mandatory 2