Pheochromocytoma is associated with RET proto-oncogene mutations in MEN2A and MEN2B. The SDH (succinate dehydrogenase) subunit mutation most associated with metastatic (malignant) pheochromocytoma is:
- A SDHA
- B SDHC
- C SDHB ✓
- D SDHD
Explanation
SDHB mutations are the strongest predictor of metastatic pheochromocytoma/paraganglioma — up to 30-40% of SDHB-mutated tumors are metastatic, compared to <10% for other SDH subunits. SDHB loss disrupts Complex II of the electron transport chain; TCA-cycle intermediate succinate accumulates, inhibiting prolyl hydroxylases, stabilizing HIF-1α, and driving a pseudohypoxic pro-metastatic phenotype. SDHD mutations are associated with head-and-neck paragangliomas (parasympathetic, non-secreting) with lower metastatic risk. SDHA and SDHC mutations cause multifocal paraganglioma/pheochromocytoma with lower metastatic risk than SDHB. All SDH-deficient tumors show loss of SDHB immunostaining on IHC.
Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.
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Written and medically reviewed by the StethoPrep medical team.