Phaeochromocytoma and paraganglioma (PPGL) are now recognized to be hereditary in approximately 40% of cases. The germline mutation most commonly associated with malignant PPGL (paraganglioma with metastasis), particularly of the head and neck paraganglioma subtype, involves:
- A VHL mutation causing pVHL loss, HIF-1alpha stabilization, and VEGF overproduction driving angiogenesis
- B NF1 (neurofibromin) loss activating RAS-MAPK pathway causing predominantly adrenal phaeochromocytoma
- C SDHB (succinate dehydrogenase subunit B) loss-of-function mutation, causing SDH complex II dysfunction, succinate accumulation, pseudohypoxic HIF activation, and high metastatic potential ✓
- D RET proto-oncogene activating mutation in MEN2A/2B causing exclusively adrenal bilateral phaeochromocytoma
Explanation
SDHB (succinate dehydrogenase iron-sulfur subunit B) mutations are associated with the highest risk of malignant paraganglioma/PPGL among all hereditary PPGL syndromes. Loss of SDHB impairs complex II of the respiratory chain, causing succinate accumulation. Excess succinate competitively inhibits alpha-ketoglutarate-dependent dioxygenases including PHDs (prolyl hydroxylases), preventing HIF-1alpha hydroxylation and proteasomal degradation, resulting in a pseudohypoxic cellular state driving the 'cluster 1' molecular signature. SDHB-mutant PPGLs are more likely to be extra-adrenal, secretory, and metastatic (up to 40% malignancy rate) compared to SDHA (5–30%), SDHC (<5%), or SDHD (~5%) mutations. VHL mutations cause predominantly clear cell RCC with associated hemangioblastomas and adrenal/extra-adrenal pheo. NF1 and RET mutations are associated with adrenal pheo, which rarely metastasize.
Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.
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Written and medically reviewed by the StethoPrep medical team.