What are the differentiating features of sarcoidosis and tuberculosis (TB) clinically and radiologically?

Differentiating Sarcoidosis from Tuberculosis

The key to distinguishing sarcoidosis from tuberculosis lies in recognizing that sarcoidosis typically presents with bilateral hilar adenopathy, non-caseating granulomas, elevated CD4:CD8 ratio, and specific extrathoracic manifestations (lupus pernio, uveitis), while tuberculosis shows caseating necrosis, positive acid-fast bacilli staining, and asymmetric or unilateral lymphadenopathy—though this distinction becomes critically challenging in TB-endemic regions where tissue diagnosis with microbiological exclusion of TB is mandatory.

Clinical Features That Favor Sarcoidosis

Highly Specific Clinical Presentations

• Löfgren's syndrome (bilateral hilar adenopathy with erythema nodosum and/or periarticular arthritis) is highly probable for sarcoidosis 1
• Lupus pernio (chronic violaceous skin lesions on nose, cheeks, ears) is highly specific for sarcoidosis 1
• Bilateral uveitis and optic neuritis strongly suggest sarcoidosis 1
• Symmetrical parotid gland enlargement and lacrimal gland swelling favor sarcoidosis 1

Metabolic and Laboratory Features

• Hypercalcemia or hypercalciuria with abnormal vitamin D metabolism (normal-to-low PTH, normal-to-elevated 1,25-dihydroxyvitamin D, normal-to-low 25-hydroxyvitamin D) is highly probable for sarcoidosis 1
• Elevated ACE levels (>50% above upper limit of normal) support sarcoidosis, though this is not specific 1
• BAL lymphocytosis with elevated CD4:CD8 ratio favors sarcoidosis 1, 2
• Alkaline phosphatase >3 times upper limit of normal suggests hepatic sarcoidosis 1

Cardiac Manifestations

• New-onset third-degree AV block in young or middle-aged adults without risk factors 1
• Spontaneous or inducible ventricular tachycardia without traditional risk factors 1
• Reduced left ventricular ejection fraction without other cardiac risk factors 1

Clinical Features That Favor Tuberculosis

Constitutional and Systemic Features

• TB typically presents with more prominent constitutional symptoms including high-grade fever, night sweats, and significant weight loss 3, 4
• TB is more likely to present with a single organ system involvement initially, particularly pulmonary 4

Geographic and Epidemiologic Context

• History of TB exposure or residence in TB-endemic regions strongly raises suspicion 3, 5
• Positive tuberculin skin test (Mantoux) or interferon-gamma release assay supports TB, though these can be negative in active disease 6

Radiological Differentiation

Features Favoring Sarcoidosis

• Bilateral, symmetrical hilar and mediastinal lymphadenopathy is the hallmark of sarcoidosis 1, 2, 5
• Perilymphatic nodular distribution (along bronchovascular bundles, interlobular septa, and pleural surfaces) on chest CT is highly characteristic 1, 2
• Upper lobe predominant or diffuse infiltrates with symmetrical distribution 1
• Peribronchial thickening in a symmetrical pattern 1
• Multiple enlarged extrathoracic lymph nodes (mediastinal, abdominal, peripheral) 1
• Bone involvement showing osteolysis, cysts, or "punched-out" lesions with trabecular pattern 1
• Parotid gland uptake on gallium or PET scanning 1

Features Favoring Tuberculosis

• Asymmetric or unilateral hilar/mediastinal lymphadenopathy 5
• Lymph nodes with central necrosis or cystic changes on CT 5
• Cavitary lesions, particularly in upper lobes 5
• Tree-in-bud pattern suggesting endobronchial spread 5
• Pleural effusion is more common in TB 5
• Miliary pattern (random, diffuse small nodules) suggests miliary TB 5

Histopathological Differentiation

Features Strongly Favoring Sarcoidosis

• Compact, tightly formed, non-caseating granulomas with large epithelioid histiocytes and multinucleated giant cells 1
• Granulomas remain discrete and well-formed 1
• Perilymphatic distribution (around bronchovascular bundles, fibrous septa, visceral pleura) 1
• Sparse surrounding lymphocytic infiltrate 1
• Minimal or absent necrosis (only focal ischemic necrosis if present) 1
• Negative microorganism stains and cultures 1, 2

Features Against Sarcoidosis (Suggesting TB)

• Extensive caseating necrosis 1, 4
• "Dirty necrosis" containing nuclear debris 1
• Loosely organized granulomas 1
• Robust surrounding inflammatory infiltrate (lymphocytes, neutrophils, eosinophils, plasma cells) 1
• Positive acid-fast bacilli staining 4, 6
• Positive mycobacterial cultures 4

Critical Diagnostic Algorithm

Step 1: Clinical Assessment

• Evaluate for highly specific sarcoidosis features (Löfgren's syndrome, lupus pernio, bilateral uveitis) 1
• Assess TB risk factors (endemic area, exposure history, constitutional symptoms) 3, 5

Step 2: Initial Imaging

• Chest radiograph and CT to assess lymphadenopathy pattern (bilateral/symmetrical vs. unilateral/asymmetric) 1, 2, 5
• Look for perilymphatic nodules (sarcoidosis) vs. cavitation/tree-in-bud (TB) 1, 5

Step 3: Laboratory Testing

• Serum calcium, creatinine, alkaline phosphatase, ACE levels 2
• Tuberculin skin test or interferon-gamma release assay 6
• BAL with cell count, differential, CD4:CD8 ratio 1, 2

Step 4: Tissue Diagnosis (Mandatory in TB-Endemic Areas)

• Obtain tissue biopsy showing granulomatous inflammation 2
• Perform acid-fast bacilli staining and mycobacterial cultures on all specimens 1, 2, 4
• Consider PCR for mycobacterial DNA if traditional methods are negative 4
• Assess granuloma morphology and distribution pattern 1

Step 5: Exclusion of TB

• In TB-endemic regions, TB must be definitively excluded before diagnosing sarcoidosis 3, 5, 4
• Negative AFB staining alone is insufficient; cultures and molecular testing are essential 4

Critical Pitfalls to Avoid

Diagnostic Errors

• Never rely solely on elevated ACE levels, as this is neither sensitive nor specific for sarcoidosis 2
• Do not diagnose sarcoidosis without tissue confirmation in TB-endemic areas, even with classic bilateral hilar adenopathy 3, 5
• Recognize that non-caseating granulomas can occur in TB when caseation is not yet developed or is not sampled 4, 6
• Be aware that sarcoidosis and TB can coexist sequentially or simultaneously in the same patient 6, 7

Sampling Issues

• Inadequate tissue sampling may miss caseation in TB 4
• Single negative AFB stain does not exclude TB; multiple samples and cultures are needed 4
• BAL alone cannot establish a specific diagnosis but helps exclude infection 1, 2

Clinical Context Errors

• Failing to consider geographic and epidemiologic risk factors for TB 3, 5
• Overlooking the possibility of sarcoidosis developing during or after TB treatment 7
• Not recognizing that immunosuppression for presumed sarcoidosis can be catastrophic if the patient actually has TB 3

Special Considerations in TB-Endemic Regions

• The diagnostic challenge is greatest in areas with high TB burden where both diseases are granulomatous and can present similarly 3, 5, 4
• Tissue diagnosis with comprehensive microbiological testing (AFB staining, culture, PCR) is mandatory before initiating immunosuppressive therapy 3, 4
• Consider empiric anti-TB therapy if diagnosis remains uncertain and TB cannot be excluded, as the consequences of missing TB are more severe than delaying sarcoidosis treatment 3
• Monitor patients diagnosed with sarcoidosis for development of TB, particularly if immunosuppression is required 6, 7