Pheochromocytoma and paraganglioma

A catecholamine-secreting tumor of the adrenal medulla (pheochromocytoma) or of extra-adrenal sympathetic and parasympathetic ganglia (paraganglioma). Classic clinical picture: episodic headache, palpitations, diaphoresis, hypertension; head-and-neck paragangliomas are often non-secretory and present as a painless mass with pulsatile tinnitus or cranial neuropathy.

Approximately 40% of pheochromocytoma and paraganglioma cases carry a germline predisposition variant, one of the highest heritability fractions in oncology. Every patient gets germline testing regardless of family history. The genes group into signaling clusters that predict tumor location, malignancy risk, and surveillance plan.

Cluster 1: pseudohypoxia (TCA cycle and HIF-stabilization) Predominantly extra-adrenal and head-and-neck disease.

• SDHB: highest malignancy risk; predominantly extra-adrenal abdominal and thoracic paragangliomas. Surveillance must be aggressive (whole-body MRI).
• SDHD: paternal-only expression (maternal imprinting); only paternally-inherited variants express disease. Skull-base and neck paragangliomas.
• SDHC, SDHA, SDHAF2: head-and-neck predominant, lower malignancy than SDHB.
• VHL (von Hippel-Lindau syndrome): pheochromocytoma plus cerebellar and retinal hemangioblastomas, clear cell renal cell carcinoma, pancreatic neuroendocrine tumors, endolymphatic sac tumors.
• FH (hereditary leiomyomatosis and renal cell cancer): rare paraganglioma plus cutaneous leiomyomas plus type 2 papillary RCC.

Cluster 2: kinase signaling Predominantly adrenal, often bilateral.

• RET (multiple endocrine neoplasia type 2): MEN2A (medullary thyroid, pheo, hyperparathyroidism); MEN2B (mucosal neuromas, marfanoid habitus, intestinal ganglioneuromatosis, earlier and more aggressive medullary thyroid).
• NF1 (neurofibromatosis type 1): adrenal pheo, usually unilateral.
• TMEM127, MAX: bilateral adrenal pheo, intermediate malignancy risk.

Wnt cluster

• CSDE1, MAML3 fusions: somatic, not germline, but worth mentioning for path correlation.

• Biochemistry first: plasma free metanephrines or 24-hour urine metanephrines and normetanephrines is the screening test of choice (sensitive). 24-hour urine VMA and HVA are older but still used in neuroblastoma workup.
• Imaging: cross-sectional (CT or MRI) of the abdomen for adrenal/extra-adrenal disease, MRI of the head and neck for skull-base lesions. Functional imaging with 68Ga-DOTATATE PET has largely replaced 123I-MIBG for SDH-associated and metastatic disease.
• Germline testing: comprehensive panel covering SDHA/B/C/D/AF2, VHL, RET, NF1, MAX, TMEM127, FH, MDH2, SLC25A11, others.
• Pre-op alpha-blockade for at least 7-14 days before resection to prevent intraoperative hypertensive crisis.

• SDHB: lifelong whole-body MRI every 1-2 years starting around age 6-10. High malignancy risk drives aggressive monitoring.
• SDHD: head-and-neck MRI plus abdominal imaging; remember paternal imprinting when counseling.
• VHL: ophthalmology annually from infancy, MRI brain and abdomen on schedule.
• RET: prophylactic thyroidectomy timing depends on codon (MEN2B as early as the first year of life; MEN2A varies).