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, von Hippel–Lindau 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 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 parasympathetic (e.g., carotid body, glomus vagale) paraganglia (Fig. 53-1). 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 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 germ-line mutations in the classically recognized RET, VHL, NF1, SDHB, SDHC, and SDHD genes or in the more recently recognized SDHA, SDHAF2, TMEM127, and MAX genes. Biallelic gene inactivation has been demonstrated for the VHL, NF1, and SDH genes, whereas RET mutations activate 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.
Its clinical presentation is so variable that ...