What is the differential diagnosis (Ddx) and management of a granulomatous process in the lungs?

Differential Diagnosis of Granulomatous Lung Disease

The differential diagnosis of pulmonary granulomas must systematically distinguish between infectious and non-infectious etiologies, with infectious causes (particularly mycobacterial and fungal) being the most common worldwide and requiring immediate exclusion before considering non-infectious diagnoses. 1

Primary Diagnostic Categories

Infectious Causes (Must Exclude First)

Mycobacterial Infections:

• Tuberculosis represents a leading cause globally and features robust, frequent necrotizing granulomas 1
• Nontuberculous mycobacteria (NTM) including MAC organisms can cause granulomatous disease, particularly in hot tub lung presentations 2, 3
• Necrotizing granulomas with central acellular necrosis are characteristic 1

Fungal Infections:

• Histoplasma capsulatum produces large acellular necrotizing granulomas 1
• Other endemic fungi (Coccidioides, Blastomyces) and opportunistic fungi (Aspergillus, Cryptococcus) 1
• Rhinosporidiosis in specific geographic regions 1

Non-Infectious Causes

Sarcoidosis:

• Well-formed, non-necrotizing granulomas in a perilymphatic distribution with minimal surrounding lymphocytic inflammation 1, 4
• Bilateral hilar lymphadenopathy and perilymphatic nodules on chest CT are characteristic 1, 4
• Composed of concentrically arranged macrophage aggregates with multinucleated giant cells surrounded by sparse T lymphocytes 1, 4

Hypersensitivity Pneumonitis (HP):

• Poorly formed, non-necrotizing granulomas with extensive surrounding lymphocytic alveolitis in a small airway distribution 1
• Cellular bronchiolitis with uniform lymphocytic interstitial inflammation 1
• Requires identification of inciting antigen exposure (thermophilic actinomycetes in farmer's lung) 5

Granulomatosis with Polyangiitis (GPA/Wegener's):

• Necrotizing granulomatous inflammation with vasculitis affecting small-to-medium vessels 1
• Multiple pulmonary nodules (2-4cm) or large cavitating masses (≥10cm) with fluid levels 1
• Associated with c-ANCA positivity and upper airway involvement 1

Other Non-Infectious Causes:

• Aspiration pneumonia: Bronchiolocentric inflammation with foreign material and giant cell reaction, less uniform than HP 1
• Berylliosis (chronic beryllium disease): Well-formed granulomas indistinguishable from sarcoidosis; diagnosed by blood lymphocyte proliferation test 1
• Drug-induced granulomatous disease: Including immune checkpoint inhibitors and anti-TNF agents 1
• Langerhans cell histiocytosis: Peri-bronchiolar cellular infiltrates with cavitation and/or fibrosis 1
• Connective tissue diseases: Increased plasma cells, lymphoid hyperplasia, pleuritis 1

Diagnostic Approach Algorithm

Step 1: Obtain Tissue Diagnosis

• Perform special stains on all biopsy specimens to exclude mycobacteria (acid-fast bacilli) and fungi (GMS, PAS) 1, 6
• Characterize granuloma morphology: necrotizing vs. non-necrotizing, well-formed vs. poorly formed, distribution pattern 7, 2
• Send tissue for microbiological culture and molecular techniques 8

Step 2: Clinical and Radiographic Correlation

• Chest CT imaging to assess distribution (perilymphatic vs. bronchiolocentric), presence of cavitation, lymphadenopathy pattern 1
• Identify highly probable clinical features: Löfgren's syndrome, lupus pernio, uveitis for sarcoidosis 1, 4
• Assess for systemic involvement (renal, upper airway, skin) suggesting vasculitis 1

Step 3: Laboratory Testing

• Serum calcium, ACE levels (60% sensitivity, 70% specificity for sarcoidosis) 6, 4
• ANCA testing if vasculitis suspected 1
• Beryllium lymphocyte proliferation test if occupational exposure history 1
• Bronchoalveolar lavage (BAL): Lymphocytosis with elevated CD4:CD8 ratio suggests sarcoidosis; helps exclude infection and malignancy 1, 4

Step 4: Exposure History

• Detailed occupational and environmental exposure assessment for HP (organic antigens, birds, mold) 1
• Hot tub or spa exposure for MAC-related HP 5
• Beryllium, silica, or other pneumoconiosis exposures 1
• Medication history for drug-induced disease 1

Critical Diagnostic Pitfalls

Common Errors to Avoid:

• Never diagnose sarcoidosis without excluding infection through special stains and cultures, as misdiagnosis has serious treatment implications 1, 8
• Necrotizing granulomas can occur in sarcoidosis variants (nodular pulmonary sarcoidosis), not exclusively in infections 1
• Absence of organisms on special stains does not exclude infection; culture and molecular testing remain essential 8, 3
• GPA can mimic NK/T cell lymphoma with progressive midfacial destruction 1
• Early GPA may show only non-specific mucosal thickening (87% of cases) without obvious vasculitis features 1

Histopathologic Nuances:

• Occasional eosinophils in GPA can confuse diagnosis with eosinophilic granulomatosis with polyangiitis 1
• Nasal biopsies for GPA have lower sensitivity (47%) than lung/kidney biopsies but maintain 96% specificity when positive 1
• HP granulomas are smaller and more poorly formed than sarcoidosis, with more extensive lymphocytic infiltration 1

When Diagnosis Remains Indeterminate

If histology and initial workup are non-diagnostic:

• Multidisciplinary discussion integrating clinical, radiologic, and pathologic data is essential 1
• Consider FDG-PET for identifying additional biopsy sites or monitoring disease activity in selected cases 6
• Close clinical follow-up with serial imaging if biopsy deferred in asymptomatic bilateral hilar lymphadenopathy 1, 4
• Repeat biopsy from alternative sites may be necessary (lung preferred over nasal mucosa for GPA) 1