A 58-year-old woman presents with progressive dyspnea and bilateral hilar lymphadenopathy on chest X-ray. Serum calcium is elevated at 11.8 mg/dL. Histopathology of the mediastinal lymph node shows non-caseating granulomas composed of epithelioid histiocytes and multinucleated giant cells without central necrosis. Which is the most common cause of non-caseating chronic granulomatous inflammation in this patient?

## Diagnosis: Sarcoidosis with Non-Caseating Granulomas **Key Point:** Sarcoidosis is the most common cause of non-caseating granulomatous inflammation in developed countries and is a leading differential diagnosis for granulomatous disease in any patient with systemic symptoms and lymphadenopathy. ### Clinical Features Supporting Sarcoidosis - Bilateral hilar lymphadenopathy (classic radiological finding) - Hypercalcemia (due to extrarenal 1α-hydroxylase activity in granulomas) - Non-caseating granulomas on histology - Systemic presentation (dyspnea, constitutional symptoms) ### Pathophysiology of Non-Caseating Granulomas in Sarcoidosis 1. Unknown antigen (possibly organic or inorganic) triggers Th1/Th17-mediated immune response 2. Activated macrophages and epithelioid cells aggregate 3. Multinucleated giant cells form from fusion of epithelioid cells 4. **Absence of central caseous necrosis** — distinguishes from TB 5. Fibroblasts encapsulate the granuloma **High-Yield:** The distinction between caseating (TB, fungal) and non-caseating (sarcoidosis, berylliosis) granulomas is critical for diagnosis. Sarcoidosis accounts for >90% of non-caseating granulomas in Western populations. **Mnemonic: CREST** — Calcium elevation, Respiratory symptoms, Erythema nodosum, Salivary gland enlargement, Thoracic (hilar) lymphadenopathy — classic features of sarcoidosis. **Clinical Pearl:** Hypercalcemia in sarcoidosis occurs because activated macrophages in granulomas produce 1α-hydroxylase, converting 25-hydroxyvitamin D to the active 1,25-dihydroxyvitamin D, leading to increased intestinal calcium absorption. ### Differential: Caseating vs Non-Caseating Granulomas | Feature | Caseating | Non-Caseating | |---------|-----------|---------------| | **Central necrosis** | Present (cheese-like) | Absent | | **Common causes** | TB, fungal infections | Sarcoidosis, berylliosis, Crohn's disease | | **Hypercalcemia** | Rare | Common (sarcoidosis) | | **AFB stain** | Often positive in TB | Negative | | **Geographic variation** | TB universal; fungi regional | Sarcoidosis worldwide | [cite:Robbins 10e Ch 8]