Nomenclature: "Phaios," dusky brown; "chromo," color; "cytoma," tumor. This nomenclature is historically derived from the color change that tumor tissue undergoes when immersed in chromate salts, known as the chromaffin reaction, which results from oxidation of catecholamines produced by the tumor cells.
Definition: The 2004 World Health Organization classification of endocrine tumors defines pheochromocytoma as a tumor arising from chromaffin cells in the adrenal medulla. Closely related tumors in extra-adrenal sympathetic and parasympathetic paraganglia are classified as paragangliomas. This nomenclature is arbitrary and serves to emphasize important distinctive properties of intra-adrenal tumors that must be taken into account in clinical practice and research. These properties include an often adrenergic phenotype, a lower rate of malignancy than that observed for extra-adrenal tumors, and a predilection to occur in patients with particular hereditary syndromes. However, for the purposes of genetic testing and other clinical studies, both of these types of tumors are often considered because they often have a common genetic basis and functional similarities. In many publications, especially before 2005, extra-adrenal sympathetic paragangliomas were classified as pheochromocytomas.
Clinical Characteristics: Sustained or paroxysmal hypertension is the most common clinical sign of a pheochromocytoma, although some patients present with normotension, or even hypotension. Headaches, excessive truncal sweating, and palpitations are the most common symptoms. Other symptoms and signs include pallor, dyspnea, nausea, constipation, and episodes of anxiety or panic attacks. Signs and symptoms that occur during paroxysms reflect episodic catecholamine hypersecretion. Paroxysmal attacks may last from a few seconds to several hours, with intervals between attacks varying widely, occurring as infrequently as once every few months.
Prevalence: Pheochromocytomas are rare, with an annual detection rate of two to four per million. A relatively high prevalence of the tumor in autopsy studies (1:2000) suggests that many of these tumors are missed, resulting in premature death. The actual annual incidence is therefore likely to be near 10 per million.
Genetics: Approximately one third of pheochromocytomas and paragangliomas occur because of mutations in 1 of 11 genes. Family-specific mutations of the von Hippel-Lindau tumor suppressor gene determine the varied clinical presentation of tumors in patients with von Hippel-Lindau syndrome that, apart from pheochromocytomas, can include retinal and central nervous system hemangioblastomas and tumors and cysts in the kidneys, pancreas, and epididyma. Mutations of the RET proto-oncogene in patients with multiple endocrine neoplasia type 2 result in pheochromocytoma and medullary thyroid cancer. Mutations of the neurofibromatosis type 1 gene carry a relatively small risk of pheochromocytoma, presenting commonly as multiple skin neurofibromas and caf� au lait spots. Mutations of succinate dehydrogenase subunits A, B, C, and D and the co-factor SDHAF2 genes lead to familial pheochromocytomas and paragangliomas and are occasionally associated with gastrointestinal stromal tumors and kidney cancer. Recently, several authors have described mutations of the TMEM127, MAX, RAS, fumarate hydratase, and the hypoxia inducible factor 2 alpha genes as occasional causes of pheochromocytomas. Clinical features of pheochromocytomas and paragangliomas, such as the frequency of malignancy, adrenal and extra-adrenal locations of tumors, and types of catecholamines produced, vary according to mutation. For further details on genetics of pheochromocytomas please read theGenetics Working Groupreport.