What are the differential diagnoses for a patient presenting with non-caseating granulomas?

Differential Diagnoses of Non-Caseating Granulomas

The differential diagnosis of non-caseating granulomas must systematically distinguish between infectious causes (which must be excluded first despite their typically caseating appearance), sarcoidosis, hypersensitivity pneumonitis, vasculitides, and foreign body reactions. 1

Primary Diagnostic Algorithm

Step 1: Exclude Infectious Causes First

Despite non-caseating appearance, infectious etiologies must be ruled out before considering non-infectious diagnoses:

• Mycobacterial infections (particularly tuberculosis) can occasionally present with non-caseating or poorly-formed granulomas in early disease or immunocompromised states 1
• Fungal infections including Histoplasma capsulatum, Coccidioides, Blastomyces, and Cryptococcus may show variable granuloma formation 1
• Special stains (AFB, GMS, PAS) and cultures are mandatory on all biopsy specimens before diagnosing any non-infectious granulomatous disease 1

Step 2: Non-Infectious Granulomatous Diseases

Sarcoidosis

The most common non-infectious cause:

• Well-formed, non-necrotizing granulomas in perilymphatic distribution with minimal surrounding lymphocytic inflammation 1
• Bilateral hilar lymphadenopathy and perilymphatic nodules on chest CT are characteristic 2, 1
• Elevated serum ACE (60-83% of cases) and hypercalcemia (10-13% of cases) support diagnosis 3, 2
• Diagnosis requires: compatible clinical/radiologic presentation, pathologic evidence of non-caseating granulomas, and exclusion of alternative causes 2, 4
• Can affect virtually any organ: lungs (most common), skin (lupus pernio, maculopapular lesions), eyes (uveitis), heart, nervous system, bones 2, 5

Hypersensitivity Pneumonitis

• Poorly-formed, non-necrotizing granulomas with extensive surrounding lymphocytic alveolitis in small airway distribution 1
• Three-density sign (headcheese sign) on CT with mosaic attenuation is highly specific 3
• Bronchoalveolar lavage shows lymphocytosis 3
• History of antigen exposure is critical (birds, mold, hot tubs) 3

Granulomatosis with Polyangiitis (GPA)

• Necrotizing granulomatous inflammation with vasculitis affecting small-to-medium vessels 1
• c-ANCA/PR3 positive in 95% with systemic disease, 50% with limited disease 3
• Upper and lower respiratory tract involvement with renal disease 3
• Can present with nasal crusting, epistaxis, and sinusitis 3

Eosinophilic Granulomatosis with Polyangiitis (EGPA/Churg-Strauss)

• Blood eosinophilia >10% is characteristic 3
• p-ANCA/MPO positive in 26-48% of cases (75% with renal involvement) 3
• Asthma and allergic rhinitis typically precede vasculitis 3
• Non-specific IgE elevation 3

Step 3: Other Important Differentials

Foreign Body Granulomas

• History of aspiration, injection, or implanted material 3
• Polarizable foreign material visible on histology 3
• Chronic aspiration can show bronchiolocentric fibrosis with granulomas surrounding vegetable particles 3

Crohn's Disease (Metastatic Crohn's)

• Non-caseating granulomas in skin appearing as nodules, plaques, or ulcers 3
• Associated with gastrointestinal symptoms and inflammatory bowel disease 3

Berylliosis (Chronic Beryllium Disease)

• Occupational exposure history (aerospace, electronics, dental prosthetics) is essential
• Histologically indistinguishable from sarcoidosis
• Beryllium lymphocyte proliferation test (BeLPT) is diagnostic

Drug-Induced Granulomatous Disease

• Methotrexate, interferon, anti-TNF agents (paradoxical reaction) can cause granulomatous inflammation 3
• Temporal relationship with medication initiation 3

Critical Diagnostic Pitfalls to Avoid

• Never diagnose sarcoidosis without special stains and cultures to exclude infection - this has serious treatment implications as immunosuppression could be catastrophic in unrecognized infection 1
• Necrotizing granulomas can occur in sarcoidosis variants (not exclusively infectious), so don't automatically exclude sarcoidosis if necrosis is present 1
• Early GPA may show only non-specific inflammation without obvious vasculitis on initial biopsy 1
• Biopsying macroscopically abnormal nasal mucosa in suspected sarcoidosis has 91% yield, while normal-appearing mucosa is 92% negative 3

Recommended Diagnostic Workup

Laboratory Studies:

• Complete blood count with differential (eosinophilia suggests EGPA) 3
• Serum ACE, calcium, alkaline phosphatase (elevated in sarcoidosis) 3, 2
• c-ANCA/PR3 and p-ANCA/MPO (for vasculitis) 3, 1
• ESR and CRP (elevated in active inflammation) 3

Imaging:

• High-resolution chest CT to assess distribution pattern, lymphadenopathy, and parenchymal involvement 2, 1
• FDG-PET can identify active disease sites and guide biopsy 3

Tissue Diagnosis:

• Biopsy from most accessible involved organ (skin, lymph node, lung) 2, 6
• Mandatory special stains: AFB, GMS, PAS on all specimens 1
• Multiple biopsy sites increase diagnostic yield 6