Nomenclature: "phaios" - dusky brown - "chromo" - color - "cytoma"- tumor . The nomenclature is historically derived from the color change that tumor tissue undergoes when immersed in chromate salts, "the chromaffin reaction", which results from oxidation of catecholamines produced by the tumor cells.

Definition: The 2004 WHO 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 extra-adrenal paragangliomas. A pheochromocytoma is an intra-adrenal sympathetic paraganglioma. 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. Those include an often adrenergic phenotype, a relatively low rate of malignancy and a predilection to occur in particular hereditary syndromes. However, for purposes of genetic testing and other clinical studies the two types of tumors are often considered together because they often have a common genetic basis and functional similarities. In many publications, especially pre-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 or signs include pallor, dyspnea, nausea, constipation and episodes of anxiety or panic attacks. Signs and symptoms that occur in paroxysms reflect episodic catecholamine hypersecretion. Paroxysmal attacks may last from a few seconds to several hours, with intervals between attacks varying widely and as infrequent as once every few months.

Prevalence: Pheochromocytomas are rare, with an annual detection rate of 2 to 4 per million. Relatively high prevalences of the tumor in autopsy studies (1:2,000) suggest that many are missed during life, resulting in premature death. The actual annual incidence is therefore likely to approach 10 per million.

Genetics: Current estimates indicate that close to 30% of pheochromocytomas occur due to mutations of 5 genes. Family-specific mutations of the von Hippel-Lindau (VHL) tumor suppressor gene determine the varied clinical presentation of tumors in VHL 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 multiple endocrine neoplasia type 2 (MEN 2) result in pheochromocytoma, medullary thyroid cancer and parathyroid disease in MEN 2a and additional cutaneous and mucosal neuromas in MEN 2b. Mutations of the neurofibromatosis type 1 (NF 1) gene carry a relatively small risk of pheochromocytoma, presenting commonly as multiple fibromas on skin and mucosa and "café au lait" spots. More recently discovered mutations of succinate dehydrogenase subunits B and D (SDHB & SDHD) genes lead to familial paragangliomas. Clinical features of pheochromocytomas - such as the frequency of malignancy, adrenal and extra-adrenal locations of tumors, and types of catecholamines produced - vary according to the particular mutation.

Pathophysiology: The molecular mechanisms linking known gene mutations to development of pheochromocytomas have not been precisely elucidated. Recent evidence, however, suggests that hereditary tumors may develop from neural crest progenitor cells arrested during embryonic development due to failure of apoptosis. Pathophysiology associated with pheochromocytoma is mainly the result of the hemodynamic and metabolic actions of catecholamines produced and secreted by the tumor. Variability in pathophysiology may reflect differences in types of catecholamines produced, paroxysmal versus sustained patterns of catecholamine secretion, co-secretion of neuropeptides, and underlying mutations. Strokes, cardiac hypertrophy, cardiogenic shock, cardiomyopathy, multiple organ failure, pulmonary edema, and intestinal pseudo-obstruction represent a few of the many possible sequelae of a pheochromocytoma that can make differential diagnosis troublesome.

Diagnosis: Biochemical evidence of excessive catecholamine production is crucial for diagnosis of pheochromocytoma. Recognition that metabolism of catecholamines to metanephrines occurs continuously within tumor cells by a process independent of catecholamine release has led to emphasis on measurements of plasma free or urinary fractionated metanephrines as the recommended tests for diagnosis of pheochromocytoma. With a diagnostic sensitivity approaching 100%, normal results for plasma free metanephrines allow reliable exclusion of any tumor producing significant amounts of norepinephrine or epinephrine, thereby avoiding the need for multiple tests and unnecessary imaging studies. Computed tomography and magnetic resonance imaging provide high sensitivity for initial localization of pheochromocytoma Metaiodobenzylguanidine scintigraphy is useful for detecting extra-adrenal tumors and metastases. The high specificity of this imaging modality also provides confidence in correctly identifying a pheochromocytoma.

Management and Treatment: Surgery provides the only effective curative treatment for pheochromocytoma. Because of the potentially fatal consequences of catecholamines released by tumors during surgical anesthesia, it is imperative that patients with pheochromocytoma be appropriately prepared for surgery. Maintenance of adequate blood pressure control using alpha-adrenergic blockers (e.g., phenoxybenzamine) or calcium channel blockers for 2 weeks before surgery is important. Laparoscopic surgery, a procedure that reduces post-operative morbidity and recovery time, has fast become the standard of care for surgical resection. There is currently no effective treatment for malignant pheochromocytoma. Chemotherapy with cyclophosphamide, vincristine, and dacarbazine may produce partial remission. Radiotherapy using 131I-labeled MIBG provides benefit in some patients with malignant pheochromocytoma, but again is not curative.