What is the recommended workup and treatment for a patient suspected of having sarcoidosis?

Sarcoidosis Workup

The workup for suspected sarcoidosis requires establishing three diagnostic criteria: compatible clinical presentation, histopathologic confirmation of noncaseating granulomas (except in highly specific syndromes), and exclusion of alternative granulomatous diseases, with systematic screening for multiorgan involvement even in asymptomatic patients. 1

Initial Diagnostic Approach

The diagnosis rests on three pillars that must all be satisfied 1:

• Compatible clinical and radiologic presentation with characteristic findings 1
• Pathologic evidence of noncaseating granulomas from tissue sampling (not always required in specific syndromes) 1
• Exclusion of alternative causes including infections (especially tuberculosis), berylliosis, hypersensitivity pneumonitis, vasculitis, lymphoma, and drug-induced sarcoid-like reactions 2

Exceptions to Tissue Diagnosis Requirement

For patients with high clinical suspicion—specifically Löfgren's syndrome, lupus pernio, or Heerfordt's syndrome—lymph node sampling is NOT recommended. 1 These syndromes have sufficiently high diagnostic specificity to establish diagnosis without biopsy 1. However, patients who do not undergo biopsy require close clinical follow-up 1.

Essential Baseline Laboratory Tests

Obtain the following screening tests in all suspected cases 2:

• Serum calcium to detect hypercalcemia from granulomatous production of 1,25-OH vitamin D 2
• Serum creatinine to screen for renal involvement 2
• Serum alkaline phosphatase to screen for hepatic involvement 2
• Both 25-OH and 1,25-OH vitamin D levels if vitamin D assessment is deemed necessary before any replacement 1
• Complete blood count to evaluate for cytopenias from bone marrow or splenic involvement 3

Avoid relying on serum ACE levels for diagnosis, as they lack adequate sensitivity and specificity. 2 While ACE may be elevated and correlate with calcium levels, it should not drive diagnostic decisions 3.

Imaging Studies

Chest Imaging

• High-resolution CT (HRCT) chest without IV contrast is the preferred initial imaging modality 2, 4
• HRCT detects bilateral hilar adenopathy, perilymphatic nodules, and parenchymal infiltrates characteristic of pulmonary sarcoidosis 2
• Chest X-ray should also be obtained as part of initial evaluation 2

Advanced Imaging for Multiorgan Assessment

• FDG-PET/CT is recommended when multiorgan involvement is suspected, for assessing disease extent and severity, and for guiding biopsy sites 2, 4
• PET/CT should be considered case-by-case due to cost and radiation exposure, not for routine follow-up 4

Cardiac Screening Protocol

All patients with extracardiac sarcoidosis require baseline cardiac screening, even without cardiac symptoms, because cardiac involvement can be fatal. 2

Screening Algorithm

• Baseline ECG for all patients with suspected sarcoidosis 1, 2
• Do NOT perform routine transthoracic echocardiography (TTE) or 24-hour Holter monitoring in asymptomatic patients without ECG abnormalities 1

When Cardiac Involvement is Suspected

If ECG shows abnormalities or patient has cardiac symptoms 1:

• Cardiac MRI is the preferred first-line imaging modality 1, 2
• If cardiac MRI is unavailable, use dedicated PET scan rather than TTE for diagnostic and prognostic information 1

Pulmonary Hypertension Screening

When pulmonary hypertension is suspected based on clinical manifestations (exertional chest pain, syncope, prominent P2 or S4, reduced 6-minute walk distance, desaturation with exercise, reduced DLCO, increased pulmonary artery diameter on CT, elevated BNP, or fibrotic lung disease) 1:

• Initial testing with TTE 1
• Right heart catheterization if TTE is suggestive of pulmonary hypertension to definitively confirm or exclude it 1
• If TTE is NOT suggestive of pulmonary hypertension, determine need for right heart catheterization case-by-case 1

Tissue Sampling Strategy

For Asymptomatic Bilateral Hilar Lymphadenopathy

No firm recommendation for or against lymph node sampling in asymptomatic bilateral hilar lymphadenopathy. 1 The committee acknowledges that 85% of such patients will have confirmed sarcoidosis, but 1.9% will have alternative diagnoses (38% tuberculosis, 25% lymphoma among alternatives) 1.

If lymph node sampling is not obtained, close clinical follow-up is mandatory 1.

Preferred Sampling Methods

• EBUS-guided lymph node sampling has a diagnostic yield of 87%, with 98% confirming sarcoidosis and 2% finding alternative diagnoses (lymphoma, TB, lung cancer), and complication rate <0.1% 1
• Bronchoscopy with BAL and transbronchial biopsy for tissue diagnosis and to exclude other causes 2
• Target the most accessible involved site for tissue sampling 2

Histopathologic Findings

Look for noncaseating (non-necrotizing) epithelioid granulomas comprised of macrophage aggregates with multinucleated giant cells and minimal surrounding lymphocytic inflammation 1. This distinguishes sarcoidosis from hypersensitivity pneumonitis (smaller granulomas with extensive lymphocytic alveolitis) and infectious causes (large acellular necrotizing granulomas) 1.

Screening for Extrapulmonary Involvement

Ophthalmologic Screening

• Referral to ophthalmologist for all patients, even if asymptomatic, as uveitis may be present without symptoms and can cause permanent vision impairment 2, 3
• Screen for uveitis, optic neuritis, scleritis, or retinitis 2

Dermatologic Assessment

• Referral to dermatologist for skin manifestations including lupus pernio, erythema nodosum, or maculopapular lesions 2

Neurologic Evaluation

• Referral to neurologist for neurological symptoms, particularly cranial nerve palsies (especially facial nerve) 2
• Consider screening for small fiber neuropathy, which is common but often overlooked 5

Hepatic Assessment

• Referral to hepatologist if alkaline phosphatase is >3x normal or significant liver abnormalities are present 2

Renal Assessment

• Referral to nephrologist for elevated creatinine, hypercalciuria, or nephrolithiasis 2

Critical Diagnostic Pitfalls to Avoid

Failure to exclude alternative diagnoses is the most serious pitfall. 2 Specifically:

• Infections (especially tuberculosis, histoplasmosis, and other fungal infections) must be ruled out 2
• Berylliosis requires occupational history and beryllium lymphocyte proliferation testing 2
• Hypersensitivity pneumonitis requires exposure history and different histopathologic pattern 2
• Vasculitis and lymphoma must be considered 2
• Drug-induced sarcoid-like reactions from immunotherapeutics and anti-TNF agents require medication review 2

Cardiac involvement can be fatal and requires specific screening beyond routine echocardiography. 2 Cardiac sarcoidosis is present in 25% of all sarcoidosis patients but only causes clinical problems in 5%, yet it may be suddenly fatal 5.

Special Considerations for Hypercalcemia

If hypercalcemia is present, this represents a serious complication requiring urgent treatment 3:

• Measure both 25-OH and 1,25-OH vitamin D levels, as sarcoidosis granulomas produce excess 1α-hydroxylase 3
• Avoid vitamin D supplementation as this will worsen hypercalcemia 3
• Systemic corticosteroids are the mainstay of treatment for sarcoidosis-related hypercalcemia 3
• Monitor serial calcium and creatinine levels to assess treatment response 3

Follow-Up Monitoring Strategy

• Follow-up CT should be clinically driven based on symptoms, pulmonary function changes, or treatment decisions rather than predetermined schedules 4
• HRCT is recommended to assess disease progression, stability, or reversibility in stage II or III disease, and to discriminate active inflammation from irreversible fibrosis 4
• Serial monitoring of calcium, creatinine, and alkaline phosphatase as clinically indicated 3