A 38-year-old woman from rural Maharashtra presents with a 3-month history of progressive dyspnea, dry cough, and low-grade fever. On examination, she has bilateral hilar lymphadenopathy and erythema nodosum on her shins. Chest X-ray shows bilateral hilar and mediastinal lymphadenopathy with right paratracheal involvement. Serum calcium is 11.2 mg/dL (normal 8.5–10.5). A transbronchial lung biopsy shows non-caseating granulomas with multinucleated giant cells. What is the most likely diagnosis?

Question

Accepted Answer

B. Sarcoidosis. ## Clinical Diagnosis: Sarcoidosis

### Key Diagnostic Features

**Key Point:** The combination of non-caseating granulomas on biopsy, bilateral hilar lymphadenopathy, erythema nodosum, and hypercalcemia is pathognomonic for sarcoidosis.

### Pathological Findings

Sarcoidosis is characterized by:
1. **Non-caseating (non-necrotizing) granulomas** — the hallmark histological feature
2. Multinucleated giant cells (both Langhans and foreign-body types)
3. Absence of central necrosis (unlike tuberculosis)
4. Minimal fibrosis in early disease

### Clinical Presentation

| Feature | Sarcoidosis | TB | Histoplasmosis |
|---------|-------------|----|-----------------|
| Granuloma type | Non-caseating | Caseating | Non-caseating |
| Hypercalcemia | Common (10–17%) | Rare | Rare |
| Erythema nodosum | Frequent | Rare | Rare |
| Löfgren syndrome | Yes (acute form) | No | No |
| Geographic predilection | Worldwide | High TB burden areas | Ohio/Mississippi valleys |

**High-Yield:** Hypercalcemia in sarcoidosis results from extrarenal 1α-hydroxylase activity in activated macrophages within granulomas, producing calcitriol (active vitamin D).

### Löfgren Syndrome (Acute Sarcoidosis)

This patient's presentation fits the classic triad:
1. Bilateral hilar lymphadenopathy
2. Erythema nodosum
3. Arthralgia (polyarthritis of ankles/knees)

**Clinical Pearl:** Löfgren syndrome has an excellent prognosis with spontaneous remission in >90% of cases within 2 years.

### Why Non-Caseating Granulomas?

The absence of central necrosis distinguishes sarcoidosis from TB. The mechanism involves:
- Th1/Th17-mediated immune response
- Accumulation of epithelioid histiocytes and lymphocytes
- Formation of tight, compact granulomas without tissue destruction

**Mnemonic for Granulomatous Diseases — CHINA:** Coccidioidomycosis, Histoplasmosis, Inflammatory bowel disease, Noncaseating (Sarcoidosis), Aspergillosis

### Diagnostic Confirmation

- **ACE level:** Often elevated (not specific, but supportive)
- **24-hour urine calcium:** Elevated due to hypercalcemia
- **Chest imaging:** Löfgren pattern (bilateral hilar + right paratracheal lymphadenopathy)
- **Transbronchial biopsy:** Gold standard for lung involvement

**Warning:** Do not confuse non-caseating granulomas of sarcoidosis with the caseating granulomas of TB — this is a common exam trap.

Answer

A. Histoplasmosis

Answer

C. Berylliosis

Answer

D. Tuberculosis

Explanation

Clinical Diagnosis: Sarcoidosis

Key Diagnostic Features

Pathological Findings

Clinical Presentation

Löfgren Syndrome (Acute Sarcoidosis)

Why Non-Caseating Granulomas?

Diagnostic Confirmation

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Feature	Sarcoidosis	TB	Histoplasmosis
Granuloma type	Non-caseating	Caseating	Non-caseating
Hypercalcemia	Common (10–17%)	Rare	Rare
Erythema nodosum	Frequent	Rare	Rare
Löfgren syndrome	Yes (acute form)	No	No
Geographic predilection	Worldwide	High TB burden areas	Ohio/Mississippi valleys