What are the key clinical differentiators between lymphoma, disseminated tuberculosis (TB), sarcoidosis, histoplasmosis, and brucellosis?

Clinical Pearls for Differentiating Lymphoma, Disseminated TB, Sarcoidosis, Histoplasmosis, and Brucellosis

The key to distinguishing these conditions lies in combining epidemiologic exposure history, specific imaging patterns, histopathologic granuloma characteristics, and targeted microbiologic testing—with the critical principle that infection must always be excluded before diagnosing non-infectious granulomatous disease. 1

Epidemiologic and Exposure History

Geographic and occupational exposures are diagnostic anchors:

• Histoplasmosis: Endemic to Ohio and Mississippi River valleys; exposure within the past month is essential for diagnosis 1
• Tuberculosis: Recent travel to TB-endemic regions (Southeast Asia, sub-Saharan Africa, Eastern Europe) significantly increases dissemination risk 1
• Brucellosis: Occupational exposure to livestock, unpasteurized dairy products, or endemic regions (Mediterranean, Middle East, Latin America)
• Sarcoidosis: Higher incidence in northern Europeans and African Americans; no specific exposure pattern 2

Immunosuppression status dramatically alters disease probability:

• High-dose corticosteroids, TNF inhibitors, organ transplant immunosuppression, or HIV infection dramatically increase dissemination risk for TB and histoplasmosis 1
• Pregnancy (particularly third trimester) increases fungal dissemination risk 1
• Lymphoma itself causes immunosuppression, predisposing to disseminated TB and fungal infections 3

Clinical Presentation Patterns

Constitutional symptoms occur in all five conditions but with distinct patterns:

• Disseminated TB/Histoplasmosis: Fever, drenching night sweats, weight loss, and extreme fatigue lasting weeks to months 1
• Brucellosis: Undulating fever pattern, profound sweats, arthralgias (especially sacroiliitis)
• Lymphoma: B symptoms (fever >38°C, night sweats, >10% weight loss over 6 months), painless lymphadenopathy 4
• Sarcoidosis: Often asymptomatic or Löfgren's syndrome (bilateral hilar adenopathy with erythema nodosum and/or periarticular arthritis) 4

Skin manifestations provide critical diagnostic clues:

• Lupus pernio (violaceous indurated plaques on nose/cheeks) is highly specific for sarcoidosis 1, 4
• Chronic skin ulceration or subcutaneous abscesses indicate cutaneous dissemination of TB or histoplasmosis 1
• Erythema nodosum suggests acute fungal infection or sarcoidosis but does not contain viable organisms 1
• Maculopapular, erythematous, or violaceous skin lesions are probable for sarcoidosis 4

Organ-specific findings:

• Seventh cranial nerve paralysis: Highly probable for sarcoidosis 4, 1
• Uveitis or optic neuritis: Highly probable for sarcoidosis 4, 1
• Focal skeletal pain: Suggests osteomyelitis from disseminated infection (TB, brucellosis, histoplasmosis) 1
• Persistent headache with meningeal signs: Mandates lumbar puncture for fungal or TB meningitis 1

Imaging Characteristics

Chest CT patterns are diagnostically powerful:

• Sarcoidosis: Bilateral hilar adenopathy with perilymphatic nodules (along bronchovascular bundles, interlobular septa, pleura); upper lobe predominance 4, 1
• Disseminated TB/Histoplasmosis: Necrotizing granulomas with cavitation; miliary pattern (random 1-3mm nodules) 1
• Lymphoma: Bulky mediastinal adenopathy, often asymmetric; extranodal masses 4

FDG-PET findings:

• Parotid uptake suggests sarcoidosis 4, 1
• Increased inflammatory activity in heart can occur with sarcoidosis 4

Histopathologic Differentiation

Granuloma characteristics are the gold standard but require special stains: 1

• Tuberculosis: Robust necrotizing granulomas with central acellular necrosis; acid-fast bacilli on Ziehl-Neelsen stain 1, 3
• Histoplasmosis: Large acellular necrotizing granulomas; organisms visible on GMS or PAS stains 1
• Sarcoidosis: Well-formed, concentrically arranged, non-necrotizing granulomas with central macrophage aggregates and multinucleated giant cells, surrounded by loosely organized T lymphocytes; perilymphatic distribution 4, 1
  • Critical caveat: Nodular pulmonary sarcoidosis can present with a mixture of necrotic and non-necrotic granulomas 4
• Brucellosis: Non-caseating granulomas (similar to sarcoidosis) but with positive cultures or serology
• Lymphoma: Monoclonal B-cell population on immunohistochemistry (CD20+, CD79a+); monotypic immunoglobulin expression; absence of granulomas 4

Special stains are mandatory on all biopsy specimens to exclude mycobacteria and fungi before diagnosing non-infectious causes. 1

Laboratory Testing Algorithm

Step 1: Rule out infection first (never diagnose sarcoidosis without excluding infection): 1

• Mycobacterial testing: Sputum AFB smear and culture (3 samples); interferon-gamma release assay (IGRA) or tuberculin skin test 1
• Fungal testing:
  • Histoplasma urine/serum antigen (positive only in extensive infections) 1
  • Fungal cultures from sputum or bronchoscopic specimens 1
  • Serology may be negative despite active infection, especially early or in immunosuppressed patients 1
• Brucellosis: Blood cultures (prolonged incubation required); serology (agglutination titers ≥1:160 or rising titers)

Step 2: Sarcoidosis-specific testing (only after infection excluded):

• Elevated ACE level (non-specific but supportive) 4
• Hypercalcemia or hypercalciuria with abnormal vitamin D metabolism (highly probable for sarcoidosis) 4
• BAL lymphocytosis or elevated CD4:CD8 ratio (probable for sarcoidosis) 4
• Alkaline phosphatase >3× upper limit of normal (probable for sarcoidosis) 4

Step 3: Lymphoma evaluation:

• Complete blood count with differential: Lymphocytosis, anemia, thrombocytopenia 4
• Serum LDH: Elevated in lymphoma 4
• Flow cytometry: CD5+, CD19+, CD20+ (low), CD23+ for CLL 4
• Tissue biopsy with immunohistochemistry: CD20, CD79a, surface/cytoplasmic immunoglobulins, Ki-67 4

Critical Diagnostic Pitfalls to Avoid

Never diagnose sarcoidosis without excluding infection through special stains and cultures. 1

Absence of pulmonary symptoms does not exclude disseminated fungal infection. 1

Negative serology does not exclude histoplasmosis—culture may provide the only diagnosis in severely ill or immunosuppressed patients. 1

Necrotizing granulomas are not exclusively infectious—nodular sarcoidosis can have necrosis. 4, 1

Erythema nodosum and arthralgias in early fungal infections do not represent dissemination. 1

The absence of tissue-destructive focal lesions is strong evidence against disseminated infection. 1

Tuberculosis often complicates lymphoma, and bone marrow necrosis can occur with disseminated TB—consider this triple association in patients with pancytopenia and lymphadenopathy. 3

Sarcoidosis and histoplasmosis can coexist—immune abnormalities in sarcoidosis may predispose to disseminated histoplasmosis. 5