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 fractionated metanephrines.
About 50% discovered as an incidental mass on imaging.
Frequent germline mutations.
Both pheochromocytomas and non–head-neck paragangliomas are rare tumors. The yearly incidence is about 2–6 cases/million; however, many cases are undiagnosed during life since the prevalence of pheochromocytomas and paragangliomas in autopsy series is 1 in 2000. These tumors may be located in either or both adrenals; anywhere along the sympathetic nervous chain; and sometimes in the mediastinum, heart, or bladder. Pheochromocytomas arise from the adrenal medulla and usually secrete both epinephrine and norepinephrine. Paragangliomas (“extra-adrenal pheochromocytomas”) arise from sympathetic paraganglia and frequently metastasize. About 50% of paragangliomas secrete norepinephrine; the rest are nonfunctional or secrete only dopamine, normetanephrine, or chromogranin A (CgA).
These tumors are dangerous and deceptive, causing 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 hypertensive children and patients with moderate to severe hypertension, particularly in the presence of suspicious symptoms of headache, significant palpitations, or diaphoretic episodes. Nearly 50% of cases are discovered incidentally on imaging studies. They account for about 4% of adrenal incidentalomas. 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 40% 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. 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.
von Hippel–Lindau (VHL) disease type 2 is associated with a 30% lifetime incidence of pheochromocytoma that can present as early as age 5 years or later in adulthood. The pheochromocytomas, most commonly associated with mutations in VHL codons 98, 161, and 167, in VHL are less likely to be malignant (3.5%) compared to pheochromocytomas without VHL (about 10%). They are also less likely to metastasize than paragangliomas, where ...