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ESSENTIALS OF DIAGNOSIS

  • “Attacks” of headache, perspiration, palpitations, anxiety. Multisystem crisis.

  • Hypertension: sustained but often paroxysmal, especially during surgery or delivery; may be orthostatic.

  • Elevated plasma free metanephrines. Normal serum T4 and TSH.

  • Frequent germline mutations.

GENERAL CONSIDERATIONS

Both pheochromocytomas and non–head-neck paragangliomas are rare tumors of the sympathetic nervous system. Pheochromocytomas arise from the adrenal medulla and usually secrete both epinephrine and norepinephrine. Paragangliomas (“extra-adrenal pheochromocytomas”) arise from sympathetic paraganglia and often metastasize. About 50% of paragangliomas secrete norepinephrine; the rest are nonfunctional or secrete only dopamine, normetanephrine, or serum chromogranin A (CgA). Tumoral secretion of norepinephrine or neuropeptide Y cause hypertension. Excessive epinephrine causes tachyarrhythmias. These tumors may be located in either or both adrenals or anywhere along the sympathetic nervous chain, and sometimes in the mediastinum, heart, or bladder.

These tumors are particularly dangerous and deceptive and cause death in at least one-third of patients prior to diagnosis. They account for less than 0.4% of hypertension cases. The incidence is higher in children and patients with moderate to severe hypertension, particularly in the presence of suspicious symptoms of headache, significant palpitations, or diaphoretic episodes. Over 10% of cases are discovered incidentally on imaging studies. They account for about 4% of adrenal incidentalomas. The yearly incidence is 2 to 4 new cases per million. However, many cases are undiagnosed during life, since the prevalence of pheochromocytomas and paragangliomas in autopsy series is 1 in 2000. Tumors that secrete catecholamines have a histologic affinity for chromium salts and are therefore known as "chromaffin" tumors.

Nonsecretory paragangliomas arise in the head or neck, particularly in the carotid body, jugular-tympanic region, or vagal body; only about 4% secrete catecholamines. They often arise in patients who have SDHD, SDHC, or SDHB germline mutations.

About 35% of patients with pheochromocytomas or paragangliomas harbor a germline mutation in 1 of at least 16 known susceptibility genes that predispose to the tumor, usually in an autosomal dominant manner with incomplete penetrance. Thorough genetic testing is recommended for all patients with these tumors. Genetic testing is particularly warranted for every patient with pheochromocytoma or paraganglioma who have bilateral pheochromocytomas, multiple sites of primary tumor, or a family history of these tumors. Pathologic germline mutations are also more likely to be discovered when there is a personal or family history of tumors or conditions that are associated with different germline mutations, particularly the following: medullary thyroid carcinomas, uterine leiomyomas, renal cell carcinomas, pituitary adenomas, hemangioblastomas, hyperparathyroidism, mucosal neuromas, Marfan-like habitus, pectus excavatum, cutaneous neurofibromas, or erythrocytosis.

Pheochromocytoma eventually develops in about 30% of patients with von Hippel–Lindau (VHL) disease type 2; it can present as early as age 5 years or later in adulthood. Pheochromocytomas in patients with VHL are usually adrenal, less likely to be malignant (3.5%), and more likely to be bilateral. About 25% of patients with VHL-1–related pheochromocytomas are ...

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