A 42-year-old woman is diagnosed with MEN-2A syndrome (RET proto-oncogene mutation). She has medullary thyroid carcinoma and pheochromocytoma. Which is the most common site of pheochromocytoma in MEN-2 syndrome?

Explanation

## Most Common Site of Pheochromocytoma in MEN-2 **Key Point:** Bilateral adrenal medullary pheochromocytoma is the most common site of pheochromocytoma in MEN-2 syndrome, occurring in 50% of MEN-2A and 50% of MEN-2B patients. ### Sites of Pheochromocytoma in MEN-2 | Site | Frequency in MEN-2 (%) | Notes | |---|---|---| | Bilateral adrenal medulla | 50 | Most common; often multifocal | | Organ of Zuckerkandl | 10–15 | Extra-adrenal; sympathetic chain | | Carotid body | Rare | Paraganglioma; <5% | | Urinary bladder wall | Rare | Ectopic chromaffin tissue; <2% | | Unilateral adrenal | 30–40 | Less common than bilateral | ### Characteristics of MEN-2 Pheochromocytoma **High-Yield:** In MEN-2: - Bilateral involvement is present in ~50% of cases (vs. 5–10% in sporadic pheochromocytoma) - Often multifocal within the adrenal medulla - Typically benign (malignancy rate <5%, vs. 10% in sporadic cases) - Presents with classic catecholamine excess: hypertension, palpitations, sweating, headache ### MEN-2 Pathophysiology **Key Point:** MEN-2 is caused by gain-of-function mutations in the *RET* proto-oncogene (chromosome 10q11.2). RET encodes a receptor tyrosine kinase that drives proliferation of neural crest–derived cells (C cells of thyroid, adrenal medulla, parathyroid). ### MEN-2 Subtypes and Pheochromocytoma **Mnemonic:** **MEN-2A = MTC + PHEO + PTH** (Medullary Thyroid Carcinoma + PHEOchromocytoma + ParaTHyroid) - MEN-2A: MTC (100%), pheochromocytoma (50%), primary hyperparathyroidism (20–30%) - MEN-2B: MTC (100%), pheochromocytoma (50%), mucosal neuromas, marfanoid habitus, NO hyperparathyroidism **Clinical Pearl:** Screening for pheochromocytoma in MEN-2 requires plasma free metanephrines or 24-hour urine metanephrines, followed by imaging (CT/MRI) if elevated. Bilateral adrenalectomy may be considered if both glands are involved, with careful perioperative management of catecholamine excess. **Warning:** ~~Organ of Zuckerkandl~~ is the most common extra-adrenal site of pheochromocytoma in the general population, but in MEN-2 specifically, bilateral adrenal involvement is far more frequent. [cite:Harrison 21e Ch 397]