What is the differential diagnosis for this case?

Differential Diagnosis Approach

Critical First Step: Exclude Infection Before Any Non-Infectious Diagnosis

Special stains must be performed on all biopsy specimens to exclude mycobacteria and fungi before diagnosing any non-infectious granulomatous disease, as this distinction has profound treatment implications. 1, 2

Primary Infectious Etiologies

Tuberculosis

• Leading infectious cause of granulomatous disease worldwide, characterized by robust necrotizing granulomas with central acellular necrosis 1, 2
• Geographic exposure to TB-endemic regions significantly increases probability 2
• Calcification develops as the immune system walls off infection, creating the classic "Ghon complex" or calcified hilar nodes 2
• Requires mycobacterial testing including sputum AFB smear/culture and interferon-gamma release assay 2

Histoplasmosis

• Produces large acellular necrotizing granulomas that frequently calcify, appearing as discrete nodules (histoplasmomas) 1, 2
• Endemic to Ohio and Mississippi River valleys 1
• Calcification typically appears in the center or in concentric rings and may require years to develop 2
• Diagnosis requires histoplasma urine/serum antigen and fungal cultures 2

Brucellosis

• Presents with non-caseating granulomas similar to sarcoidosis 1
• Distinguished by positive cultures/serology and exposure to livestock or unpasteurized dairy 1

Other Infectious Considerations

• Epstein-Barr virus, influenza, cytomegalovirus, and hepatitis C have been reported in association with pulmonary fibrosis 3
• Lyme disease can present striking similarities to demyelinating conditions 3

Non-Infectious Granulomatous Diseases

Sarcoidosis

• Characterized by well-formed, non-necrotizing granulomas in a perilymphatic distribution with minimal surrounding lymphocytic inflammation 1, 2
• Bilateral hilar adenopathy with perilymphatic nodules on imaging suggests this diagnosis 2
• Löfgren's syndrome (acute arthritis, erythema nodosum, bilateral hilar adenopathy) is diagnostic of sarcoidosis 2
• Calcification can occur in chronic sarcoidosis, though less commonly than in infectious causes 2
• Critical pitfall: Necrotizing granulomas can occur in sarcoidosis variants, not exclusively in infections 2

Hypersensitivity Pneumonitis

• Features poorly formed, non-necrotizing granulomas with extensive surrounding lymphocytic alveolitis in a small airway distribution 1
• Requires detailed occupational and environmental exposure history 2

Granulomatosis with Polyangiitis (GPA)

• Shows necrotizing granulomatous inflammation with vasculitis affecting small-to-medium vessels 1
• Nasal/sinus involvement with systemic vasculitis; isolated presentations are uncommon 4

Chronic Beryllium Disease

• Presents with well-formed granulomas indistinguishable from sarcoidosis histologically 1, 2
• Mandatory beryllium lymphocyte proliferation test with appropriate exposure history, as this is the only way to distinguish from sarcoidosis 1, 2

Drug-Induced Granulomatous Disease

• Immune checkpoint inhibitors, anti-TNF agents, and other immunotherapeutics can trigger sarcoidosis-like granulomatous reactions 1
• Nitrofurantoin toxicity can cause unclassifiable interstitial fibrosis with patchy fibrosis and prominent lymphoid aggregates 3

Idiopathic Pulmonary Fibrosis and Related Patterns

Usual Interstitial Pneumonia (UIP) Variants

• UIP with additional bronchiolocentric fibrosis: Raises differential of IPF with additional injury (respiratory bronchiolitis from smoking, aspiration, fume/dust inhalation), chronic hypersensitivity pneumonitis, or autoimmune connective tissue disease 3
• UIP with NSIP-like changes: Differential includes IPF and autoimmune connective tissue disease, particularly rheumatoid arthritis 3
• UIP with diffuse alveolar damage: Differential includes acute exacerbation of IPF and autoimmune connective tissue disease 3

Smoking-Related Patterns

• Airspace enlargement with fibrosis (irregular emphysema) may produce subtle subpleural scarring difficult to separate from early UIP 3
• Histological clues include hyalinized alveolar septal fibrosis, stellate centrilobular scars, and accumulation of lightly pigmented smoker's macrophages 3

Familial Interstitial Pulmonary Fibrosis

• Consider in patients with early greying of hair and siblings with pulmonary fibrosis 3
• Probably inherited as autosomal dominant trait with variable penetrance 3

Autoimmune and Connective Tissue Diseases

Rheumatoid Arthritis

• Can present with UIP pattern with NSIP-like changes 3
• Hand involvement typically targets MCPJs and PIPJs, not DIPJs 3

Systemic Lupus Erythematosus

• Multifocal areas of cerebral ischemia or infarction in young adults from phospholipid antibody syndrome 3

Kawasaki Disease (Pediatric)

• Fever ≥5 days with erythema and cracking of lips (not true cyanosis), bilateral conjunctival injection, polymorphous rash, extremity changes, and cervical lymphadenopathy 4

Demyelinating Diseases

Multiple Sclerosis

• Diagnosis based on demonstrating inflammatory-demyelinating injury disseminated in time and space 5, 6
• Best applies to individuals between 10 and 59 years of age with typical clinical presentation 3
• Special care required for younger/older patients, progressive onset, or atypical presentations (dementia, epilepsy, aphasia) 3

MS Mimics

• HTLV1 infection can present striking similarities to MS 3
• CADASIL, Takayasu's disease, meningovascular syphilis, carotid dissection 3
• Acute disseminated encephalomyelitis, Devic's syndrome, acute transverse myelitis 3
• Leukodystrophies should be considered in children and teenagers 3

Inflammatory Bowel Disease

Ulcerative Colitis vs. Crohn's Disease

• Focal basal plasmacytosis has highest predictive value for UC diagnosis, identifiable in 38% within 2 weeks of symptom presentation 3
• Granulomas and focal crypt architectural abnormalities with patchy chronic inflammation suggest Crohn's disease 3
• Critical: Only 20% show crypt distortion within 2 weeks; distinction from infectious colitis is major concern early in disease 3

IBD Differential

• Segmental colitis associated with diverticulitis (SCAD) 3
• Ischemic colitis 3
• Infectious colitis (characterized by preserved crypt architecture and acute inflammation) 3

Hand Osteoarthritis Differential

Erosive vs. Non-Erosive OA

• Erosive OA targets mainly IP joints with severe structural changes (subchondral erosion, ankylosis) and elevated CRP 3
• Subchondral erosion, bony collapse, and ankylosis of IP joints appear specific to erosive OA 3

Other Hand Arthropathies

• Psoriatic arthritis: May target DIPJs or affect just one ray 3
• Rheumatoid arthritis: Mainly targets MCPJs, PIPJs, wrists 3
• Gout: May superimpose on pre-existing HOA 3
• Hemochromatosis: Mainly targets MCPJs, wrists 3

Fetal Alcohol Spectrum Disorders

Diagnostic Requirements

• Documented prenatal alcohol exposure (≥6 drinks/week for ≥2 weeks, or ≥3 drinks per occasion on ≥2 occasions) 3
• For children ≥3 years: cognitive impairment (≥1.5 SD below mean) or behavioral deficit in self-regulation 3
• Differential diagnoses must include genetic disorders or conditions from other teratogens 3

Neuroleptic Malignant Syndrome

Diagnostic Features

• Hallmarks are hyperthermia, altered mental status, muscle rigidity, and autonomic instability 3
• History of antipsychotic use or withdrawal of dopaminergic agent within 3 days 3
• Leukocytosis (15,000-30,000 cells/mm³) and elevated creatine kinase (≥4 times upper limit of normal) 3

NMS Differential

• Serotonin syndrome (distinguished by hyperreflexia, myoclonus, and different medication exposure) 3
• Malignant hyperthermia, central nervous system infections, heat stroke 3

Diagnostic Algorithm Framework

Step 1: Geographic and Exposure Assessment

• TB-endemic regions or histoplasmosis belt 2
• Occupational exposures (beryllium, organic antigens) 2
• Medication history including immunotherapeutics 1, 2

Step 2: Clinical Presentation Analysis

• Constitutional symptoms, age at presentation, symptom progression 3, 2
• Löfgren's syndrome suggests sarcoidosis 2
• Family history of similar conditions 3

Step 3: Imaging Characterization

• Bilateral hilar adenopathy with perilymphatic nodules suggests sarcoidosis 2
• Discrete calcified nodules with concentric ring or central calcification suggest histoplasmoma 2
• Patchy fibrosis with subpleural and bronchiolocentric accentuation raises multiple possibilities 3

Step 4: Laboratory and Histopathology

• Always perform special stains on biopsy specimens to exclude mycobacteria and fungi 1, 2
• Mycobacterial testing (sputum AFB, IGRA) and fungal testing (antigen, cultures) 2
• Beryllium lymphocyte proliferation test with appropriate exposure 1, 2
• Co-oximetry if cyanosis does not improve with oxygen (to exclude methemoglobinemia) 4

Step 5: Multidisciplinary Diagnosis

• Unclassifiable cases on pathology often receive definitive diagnosis through multidisciplinary team discussion incorporating clinical, radiologic, and pathologic data 3

Common Diagnostic Pitfalls

• Never diagnose sarcoidosis without excluding infection through special stains and cultures 1, 2
• Do not assume beryllium disease is sarcoidosis without lymphocyte proliferation testing 1, 2
• A positive test for an MS "mimic" does not exclude MS diagnosis 5
• In early IBD (<2 weeks), crypt architecture may be preserved, mimicking infectious colitis 3
• Necrotizing granulomas can occur in sarcoidosis variants, not exclusively infections 2