A pheochromocytoma is an adrenal medullary tumor composed of chromaffin cells and capable of secreting biogenic amines and peptides, including epinephrine, norepinephrine, and dopamine. These tumors arise from neural crest–derived cells, which also give rise to portions of the central nervous system and the sympathetic (paraganglion) system. Because of this common origin, neoplasms of the sympathetic ganglia, such as neuroblastomas, paragangliomas, and ganglioneuromas, may produce similar amines and peptides.

Pheochromocytomas are relatively rare. Data from the Mayo Clinic indicate that pheochromocytomas occur in 2 to 8 per million people per year; autopsy data from the same institution reflect an incidence of 0.3% (3/1000 autopsies), indicating that many pheochromocytomas go undetected during life. The incidence of pheochromocytoma from other countries, such as Japan, is lower, 0.4 cases per million people per year.

Nearly 90% of tumors arise within the adrenal glands, whereas approximately 10% are extra-adrenal and therefore classified as paragangliomas. Sporadic, solitary pheochromocytomas are located more commonly in the right adrenal gland, but familial forms (10% of all pheochromocytomas) are bilateral and multicentric. Bilateral adrenal tumors raise the possibility of multiple endocrine neoplasia 2A or 2B (MEN-2A or MEN-2B) syndromes (see Chapter 51).

Paragangliomas occur most commonly within the abdomen but also have been described along the entire sympathetic paraganglia chain from the base of the brain to the testicles. The common locations for paragangliomas are the organ of Zuckerkandl, the aortic bifurcation, and the bladder wall; the mediastinum, heart, carotid arteries, and glomus jugulare bodies are less frequent.

Yes. Demonstration of a metastatic focus in tissue normally devoid of chromaffin cells is the only accepted indication that a pheochromocytoma is malignant. Metastasis occurs in 3% to 14% of cases. The most common sites of metastases are regional lymph nodes, liver, bone, lung, and muscle.

Approximately 10% are extra-adrenal, 10% bilateral, 10% familial, and 10% malignant.

The signs and symptoms of a pheochromocytoma are variable. The classic triad, consisting of sudden severe headaches, diaphoresis, and palpitations, carries a high degree of specificity (94%) and sensitivity (91%) for pheochromocytoma in a hypertensive population. The absence of all three symptoms reliably excludes the condition. Hypertension occurs in 90% to 95% of cases and is paroxysmal in 25% to 50% of these (Fig. 28-1). Orthostatic hypotension occurs in 40% of cases because of hypovolemia and impaired arterial and venous constriction responses. Tremor, pallor, and anxiety may also be accompanying signs, whereas flushing is uncommon.

Signs and symptoms of other endocrine disorders may dominate the presentation of a pheochromocytoma. Tumors may elaborate corticotropin (ACTH) with resultant manifestations of Cushing’s syndrome and hypokalemic alkalosis. Vasoactive intestinal peptide (VIP) may be produced, resulting in severe diarrhea and hypokalemia. Hyperglycemia, resulting from catecholamine-associated antagonism of insulin release, and hypercalcemia, resulting from adrenergic stimulation of the parathyroid glands or elaboration of parathyroid hormone–related peptide (PTHrP), have also been encountered. Lactic acidosis may occur as a result of catecholamine-associated decrements in tissue oxygen delivery.

Cardiovascular manifestations of pheochromocytomas include arrhythmias and catecholamine-induced congestive cardiomyopathy. Atrial and ventricular fibrillations commonly result from precipitous release of catecholamines during surgery or from therapy with tricyclic antidepressants, phenothiazines, metoclopramide, and naloxone. Although cardiogenic pulmonary edema may result from cardiomyopathy, noncardiogenic pulmonary edema may also occur as a result of transient pulmonary vasoconstriction and increased capillary permeability.

Seizures, altered mental status, and cerebral infarctions may occur as a result of intracerebral hemorrhage or embolization.

Most pheochromocytomas secrete norepinephrine. Tumors that produce epinephrine are more commonly intra-adrenal, because the extra-adrenal sympathetic ganglia do not contain phenylethanolamine-N-methyltransferase (PNMT), which converts norepinephrine to epinephrine. Dopamine is most commonly associated with malignant tumors.

 Pheochromocytomas elaborate different biogenic amines. Epinephrine, a beta-adrenergic stimulatory vasodilator that causes hypotension, is secreted by some intra-adrenal tumors, whereas norepinephrine, an alpha-adrenergic stimulatory vasoconstrictor that causes hypertension, is produced by most intra-adrenal and all extra-adrenal tumors.