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), von Hippel–Lindau (VHL) disease, or several other pheochromocytoma-associated syndromes. The diagnosis of pheochromocytomas identifies 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 hypertensive crisis with associated cerebrovascular or cardiac complications.
Pheochromocytoma was first described in 1800 by Charles Sugrue from Cork, Ireland, and the histological findings were first reported by Felix Fraenkel and Max Schottelius from Freiburg, Germany, in 1886. Pheochromocytoma is estimated to occur in 2–8 of 1 million persons per year, and ~0.1% of hypertensive patients harbor a pheochromocytoma. The mean age at diagnosis is ~40 years, although the tumors can occur from early childhood until late in life. The classic “rule of tens” for pheochromocytomas states that ~10% are bilateral, 10% are extra-adrenal, and 10% are malignant.
ETIOLOGY AND PATHOGENESIS
Pheochromocytomas and paragangliomas are well-vascularized tumors that arise from cells derived from the sympathetic (e.g., adrenal medulla or sympathetic trunk) or parasympathetic (e.g., carotid body, glomus tympanicum, glomus jugulare, glomus vagale) paraganglia (Fig. 380-1). The name pheochromocytoma reflects the formerly used black-colored staining caused by chromaffin oxidation of catecholamines; although a variety of terms have been used to describe these tumors, most clinicians use this designation to describe symptomatic catecholamine-producing tumors, including those in extra-adrenal retroperitoneal, pelvic, and thoracic sites. The term paraganglioma is used to describe catecholamine-producing tumors in the skull base and neck; these tumors may secrete little or no catecholamine. In contrast to common clinical parlance, the World Health Organization (WHO) restricts the term pheochromocytoma to adrenal tumors and applies the term paraganglioma to tumors at all other sites.
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, 25–33% of patients have an inherited condition, including germline mutations in the classically recognized RET (rearranged during transfection), VHL, NF1 (neurofibromatosis type 1), SDHB, SDHC, and SDHD (subunits of SDH) genes or in the more recently recognized SDHA, SDHAF2, TMEM127 (transmembrane protein 127), MAX (myc-associated factor X), FH (fumarate hydratase), PDH1, PDH2 (pyruvate dehydrogenase), HIF1alpha (hypoxia-inducible factor), MDH2 (malate dehydrogenase), and KIF1Bß (kinesin family member) genes. Biallelic gene inactivation, a characteristic of tumor suppressor genes ...