Definitive Diagnosis of Sarcoidosis
The definitive diagnosis of sarcoidosis requires three essential criteria: compatible clinical presentation, histopathologic evidence of noncaseating granulomas in at least one organ, and exclusion of alternative causes of granulomatous inflammation. 1
Diagnostic Criteria
Clinical Features
Highly probable clinical features:
- Löfgren's syndrome (erythema nodosum, bilateral hilar lymphadenopathy, fever)
- Lupus pernio (violaceous skin lesions)
- Uveitis
- Optic neuritis
- Erythema nodosum
Probable clinical features:
- Seventh cranial nerve paralysis
- Treatment-responsive renal failure or cardiomyopathy
- Atrioventricular node block
- Maculopapular skin lesions
- Symmetrical parotid enlargement
- Hepato-/splenomegaly
Imaging Findings
Highly suggestive radiologic features:
- Bilateral hilar adenopathy on chest X-ray, CT, or PET
- Perilymphatic nodules on chest CT
- Gadolinium enhancement on CNS MRI
- Osteolytic bone lesions
- Parotid uptake on gallium or PET scans
Supportive imaging findings:
- Upper lobe or diffuse pulmonary infiltrates
- Peribronchial thickening
- Two or more enlarged extrathoracic lymph nodes
- Inflammatory cardiac activity on imaging
- Hepatic/splenic nodules
Histopathological Features
- Numerous compact, tightly formed granulomas
- Discrete granulomas that remain separate
- Nonnecrotic or minimal ischemic necrosis
- Fibrosis beginning at granuloma periphery
Diagnostic Approach
Step 1: Initial Assessment
- Evaluate for characteristic clinical features
- Perform chest imaging (X-ray, CT)
- Conduct baseline laboratory tests:
- Serum calcium
- Creatinine
- Alkaline phosphatase
- Consider ACE level (elevated in ~60% of cases)
Step 2: Exclude Alternative Diagnoses
- Microbiological studies to rule out infections
- Testing for beryllium exposure if suspected
- Antineutrophil cytoplasmic antibodies
- IgG4 levels
- Other granulomatous conditions to exclude:
- Infections (tuberculosis, fungal)
- Chronic beryllium disease
- Hypersensitivity pneumonitis
- Medication-induced granulomatous reactions
- Erdheim-Chester disease
- IgG4-related disease
- Granulomatosis with polyangiitis
Step 3: Tissue Biopsy
- Required in most cases except highly characteristic presentations (e.g., Löfgren's syndrome)
- Fine-needle aspiration cytology can show:
- Epithelioid cell granulomas
- Multinucleate giant cells
- Possible crystalline structures inside giant cells
Organ-Specific Evaluation
Cardiac Sarcoidosis
- Consider cardiac MRI, PET, or gallium scanning
- Particularly important in patients with new-onset third-degree AV block
Neurosarcoidosis
- MRI with gadolinium enhancement
- CSF analysis
Hepatic Sarcoidosis
- Baseline alkaline phosphatase testing
- May require liver biopsy if diagnosis is uncertain
Treatment Approach
Indications for Treatment
- Treatment should be offered to:
- Palliate symptoms and improve quality of life
- Prevent end-organ damage
- Address significant functional impairment
First-Line Therapy
- Systemic corticosteroids (prednisone) are the mainstay of treatment 2, 3
- Indicated for:
- Symptomatic pulmonary disease
- Serious extrapulmonary disease
- Progressive disease
Second-Line/Steroid-Sparing Options
- For steroid-intolerant or refractory cases:
- Methotrexate (most widely used)
- Azathioprine
- Leflunomide
- Mycophenolate
Biologic Agents
- Anti-TNF antibodies (e.g., infliximab) for refractory cases
Common Diagnostic Pitfalls
- Misdiagnosis due to failure to exclude other granulomatous diseases
- Incomplete evaluation of organ systems
- Over-reliance on ACE levels (not specific)
- Inadequate follow-up
- Misinterpreting spontaneous remission
Special Considerations
- Prognosis varies based on:
- Epidemiologic factors (worse in African Americans)
- Mode of onset
- Initial clinical course
- Specific organ involvement
- Despite treatment, some patients may develop life-threatening complications requiring organ transplantation 4