Pheochromocytomas and paragangliomas are catecholamine-producing tumors derived from the sympathetic or parasympathetic nervous system. These tumors may arise sporadically or be inherited as features of multiple endocrine neoplasia type 2 (MEN 2) or several other pheochromocytoma-associated syndromes. The diagnosis of pheochromocytomas provides a potentially correctable cause of hypertension, and their removal can prevent hypertensive crises that can be lethal. The clinical presentation is variable, ranging from an adrenal incidentaloma to a patient in hypertensive crisis with associated cerebrovascular or cardiac complications.
Pheochromocytoma is estimated to occur in 2–8 of 1 million persons per year, and about 0.1% of hypertensive patients harbor a pheochromocytoma. Autopsy series reveal prevalence of 0.2%. The mean age at diagnosis is about 40 years, although the tumors can occur from early childhood until late in life. The "rule of 10s" for pheochromocytomas states that about 10% are bilateral, 10% are extraadrenal, and 10% are malignant. However, these percentages are higher in the inherited syndromes.
ETIOLOGY AND PATHOGENESIS
Pheochromocytomas and paragangliomas are well-vascularized tumors that arise from cells derived from the sympathetic (e.g., adrenal medulla) or parasympathetic (e.g., carotid body, glomus vagale) paraganglia (Fig. 51-1). The name pheochromocytoma reflects the black-colored staining caused by chromaffin oxidation of catecholamines. Although a variety of terms have been used to describe these tumors, most clinicians use the term pheochromocytoma to describe symptomatic catecholamine-producing tumors, including those in extraadrenal retroperitoneal, pelvic, and thoracic sites. The term paraganglioma is used to describe catecholamine-producing tumors in the head and neck. These tumors may secrete little or no catecholamines.
The paraganglial system and topographic sites (in red) of pheochromocytomas and paragangliomas. (Parts A, and B from WM Manger, RW Gifford: Clinical and Experimental Pheochromocytoma. Cambridge: Blackwell Science, 1996; part C from GG Glenner, PM Grimley: Tumors of the Extra-adrenal Paraganglion System [Including Chemoreceptors], Atlas of Tumor Pathology, 2nd Series, Fascicle 9. Washington, DC: AFIP, 1974.)
The etiology of sporadic pheochromocytomas and paragangliomas is unknown. However, about 25% of patients have an inherited condition, including germ-line mutations in the RET, VHL, NF1, SDHB, SDHC, SDHD, or SDHAF2 genes. Biallelic gene inactivation has been demonstrated for the VHL, NF1, and SDH genes, whereas RET mutations activate the receptor tyrosine kinase activity. SDH is an enzyme of the Krebs cycle and the mitochondrial respiratory chain. The VHL protein is a component of a ubiquitin E3 ligase. VHL mutations reduce protein degradation, resulting in upregulation of components involved in cell cycle progression, glucose metabolism, and oxygen sensing.
The clinical presentation is so variable that pheochromocytoma has been termed "the great masquerader" (Table 51-1). Among the presenting symptoms, episodes of palpitations, headaches, and profuse sweating are typical and ...