What are pheochromocytomas?
Pheochromocytomas are catecholamine-producing tumors formed by chromaffin cells in the adrenal gland that can occur sporadically or as part of a familial syndrome. Pheochromocytomas can also arise from tissues outside the adrenal glands, in which case they are also referred to as paragangliomas. Fifteen to seventeen percent of patients with these tumors have malignant disease, which has overall 5-year survival rates ranging from 50% to 60%. No curative treatments for malignant pheochromocytoma are available, nor are any reliable pathological methods for distinguishing benign and malignant tumors or assessing the potential for malignancy. The rarity of pheochromocytoma and resulting fragmented nature of studies of this tumor, typically involving small numbers of patients, limit the development of effective treatments and diagnostic or prognostic markers for malignant pheochromocytoma. Such development can be facilitated by the availability of new genomics- and proteomics-based tools, but this ideally requires comprehensive clinical studies involving large numbers of patients, stringently collected clinical data, tumor and blood samples, and interdisciplinary collaborations among multiple specialized centers.
Facts in brief
"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 café 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 the Genetics Working Group report.
- Pathophysiology: The molecular mechanisms linking known gene mutations to development of pheochromocytomas have yet to be precisely elucidated. However, recent evidence suggests that hereditary tumors may develop from neural crest progenitor cells arrested during embryonic development owing to failure to undergo apoptosis. The pathophysiology associated with pheochromocytoma results mainly from the hemodynamic and metabolic actions of catecholamines produced and secreted by the tumor. Variability in the pathophysiology may reflect differences in the types of catecholamines produced, paroxysmal versus sustained patterns of catecholamine secretion, co-secretion of neuropeptides, and underlying gene mutations. Stroke, cardiac hypertrophy, cardiogenic shock, cardiomyopathy, multiple organ failure, pulmonary edema, and intestinal pseudo-obstruction are 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 in a process independent of catecholamine release has led to emphasis on the measurement of plasma free or urinary fractionated metanephrines as the recommended test for diagnosis of pheochromocytoma. With a diagnostic sensitivity approaching 100%, normal results of measurement of plasma free metanephrines allow for 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 are highly sensitive in initially localizing pheochromocytoma. Also, 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. Furthermore, positron emission tomography with fluorodeoxyglucose is very sensitive in localizing succinate dehydrogenase subunit B-mutated tumors.
- Management and Treatment: Surgery is the only effective treatment of pheochromocytoma. Because of the potentially fatal consequences of catecholamines released by tumors during general anesthesia, patients with pheochromocytoma must be appropriately prepared for surgery. Maintenance of adequate blood pressure control using alpha-adrenergic blockers (e.g., phenoxybenzamine, doxazosin, terazosin) or calcium channel blockers for 2-3 weeks before surgery is important. Treatment with beta blockers is required once the patient has orthostatic hypotension or tachycardia. Laparoscopic surgery, a procedure that reduces postoperative morbidity and recovery time, has become the standard of care for surgical resection of intra-adrenal tumors smaller than 5 cm in diameter. Chemotherapy with cyclophosphamide, vincristine, and dacarbazine and radiotherapy using iodine-131–labeled metaiodobenzylguanidine may produce partial remission. For further information on therapies for malignant pheochromocytomas please read the Clinical Trials and Therapeutics Working Group report.