Pheochromocytoma is a rare type of tumor that arises from certain cells known as chromaffin cells, which produce hormones necessary for the body to function properly. Most pheochromocytomas originate in one of the two adrenal glands located above the kidneys in the back of the upper abdomen. Most chromaffin cells are found in the adrenal gland's inner layer, which is known as the adrenal medulla. Approximately 90 percent of pheochromocytomas occur in the adrenal medulla. Approximately 10 percent occur outside of this area. These cases are referred to as extra-adrenal pheochromocytomas or paragangliomas. Paragangliomas may be found in the chest, heart, bladder, and/or neck or base of the skull. Symptoms associated with pheochromocytomas include high blood pressure (hypertension), headaches, excessive sweating, and/or heart palpitations. In most cases, pheochromocytomas occur randomly, for unknown reasons (sporadically). In approximately 25 to 35 percent of cases, pheochromocytomas may be inherited as an autosomal dominant trait. Some inherited cases may occur as part of a larger disorder such as multiple endocrine neoplasia types 2a and 2b, von Hippel-Lindau syndrome, neurofibromatosis or familial paraganglioma syndromes types 1, 3 or 4, or as familial isolated pheochromocytoma.
In some cases, individuals with a pheochromocytoma may not develop symptoms (asymptomatic). High blood pressure (hypertension) is the most common finding associated with pheochromocytomas. High blood pressure may be sustained or may come and go. Affected individuals may experience paroxysmal “attacks,” which are chronic episodes of high blood pressure often resulting in headaches, irregular heartbeats (palpitations) and profuse sweating (diaphoresis). The frequency of these episodes varies anywhere from several times a day to a couple of times a month.
Symptoms associated with pheochromocytomas occur because of the release of certain hormones known as catecholamines (e.g., norepinephrine and epinephrine). These hormones are released from chromaffin cells, which are part of the sympathetic nervous system. The sympathetic nervous system controls certain involuntary activities in the body (e.g., regulating the heartbeat or breathing rate, raising blood pressure). The release of excessive catecholamines results in high blood pressure and other characteristic symptoms of pheochromocytoma.
Additional symptoms that occur less frequently may include pain in the chest or abdomen, nausea, vomiting, diarrhea, constipation, pale skin (pallor), weakness, and weight loss. Attacks of anxiety or apprehension may also occur. Some individuals experience an extreme drop in blood pressure upon standing suddenly, sometimes resulting in dizziness (orthostatic hypotension). In some cases, individuals with a pheochromocytoma may have difficulties in the breakdown (metabolism) of carbohydrates and can develop diabetes.
If left untreated, pheochromocytomas may progress to cause serious, life-threatening complications including heart muscle disease (cardiomyopathy), inflammation of the heart muscle (myocarditis), cerebral hemorrhaging, or the accumulation of fluid in the lungs (pulmonary edema). Some individuals with pheochromocytoma may be at risk of developing a stroke or heart attack (myocardial infarction).
Approximately 10 to 15 percent of pheochromocytomas may be malignant. Extra-adrenal pheochromocytomas are more likely to be malignant than adrenal pheochromocytomas. Malignant pheochromocytomas may spread (metastasize) to various areas of the body including the lymph nodes, liver, lungs, and bones.
In most cases, the exact cause of pheochromocytoma is unknown. Most cases occur randomly, for unknown reasons (sporadically).
Approximately 25-35 percent of cases of pheochromocytomas may be familial, resulting from genetic disruptions or changes (mutations) to certain genes. These mutations are inherited as autosomal dominant traits. Genetic diseases are determined by two genes, one received from the father and one from the mother. Autosomal dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy
Cases of familial pheochromocytoma occur as either part of a larger genetic syndrome or as an isolated, nonsyndromic finding. Disorders in which pheochromocytomas may be a secondary finding include multiple endocrine neoplasia types 2a and 2b, von Hippel-Lindau syndrome, neurofibromatosis, familial paraganglioma syndromes types 1, 2, 3 and 4, and isolated familial pheochromocytoma.
Individuals with isolated, nonsyndromic pheochromocytoma may have a genetic predisposition to developing the disorder. A person who is genetically predisposed to a disorder carries a mutated gene for the disease, but it may not be expressed unless it is triggered or “activated” under certain circumstances. Some of these cases may occur randomly as the result of a spontaneous genetic change (i.e., new mutation).
Investigators have determined that pheochromocytomas may be caused by mutations of one of at least ten different genes: the RET gene located on chromosome 10q11.2, which is also associated with multiple endocrine neoplasia type 2; the VHL gene located on chromosome 3pp25.3, which is also associated with von Hippel-Lindau syndrome; the neurofibromatosis (NF1) gene, located in chromosome 17q11.2; the succinate dehydrogenase subunit A (SDHA) gene located on chromosome 5p15, the succinate dehydrogenase subunit B (SDHB) gene located on chromosome 1p36.1-p35; the succinate dehydrogenase subunit C (SDHC) gene located on chromosome 1q21, the succinate dehydrogenase subunit D (SDHD) gene located on chromosome 11q23, the succinate dehydrogenase complex assembly factor 2 (SDHAF2) , located on chromosome 11q12, the TMEM127 gene located on chromosome 2q11, and the MAX gene located on chromosome 14q23.
Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Pairs of human chromosomes are numbered from 1 through 22, and an additional 23rd pair of sex chromosomes which include one X and one Y chromosome in males and two X chromosomes in females. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 11p13″ refers to band 13 on the short arm of chromosome 11. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
Pheochromocytomas affect males and females in equal numbers and may affect individuals of any age. These tumors occur most often in individuals between 30 and 50 years of age. At the present time, it is thought that approximately 10 percent of cases occur in children.
Pheochromocytomas are rare tumors, occurring in less than 1 percent of all individuals with high blood pressure. The true incidence of pheochromocytomas is unknown. Many individuals with pheochromocytomas go undiagnosed during their lifetime. Approximately 90 percent of pheochromocytomas are benign.
A diagnosis of pheochromocytoma may be suspected based upon a detailed patient history (including previous pheochromocytoma cases in the family), a thorough clinical evaluation, and identification of characteristic findings (paroxysmal attacks, hypertension unresponsive to normal treatment, etc.). Blood and urine analysis can confirm a diagnosis of pheochromocytoma by detecting elevated levels of catecholamines or its metabolites in the urine and blood (plasma). Metabolites are the byproducts of catecholamines that are produced when the body breaks down (metabolizes) catecholamines. A specialized test, the clonidine suppression test, may be performed to rule out other causes of elevated catecholamines. Clonidine reduces the production of catecholamines to normal ranges in individuals without a pheochromocytoma but not those with a pheochromocytoma.
Imaging techniques such as computed tomography (CT scan) and magnetic resonance imaging (MRI) are often performed to determine the specific location and size of a pheochromocytoma. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of internal structures. MRI uses a magnetic field and radio waves to create detailed cross-sectional images of certain organs and tissues. MRI is the imaging technique of choice for pregnant women that are suspected of having a pheochromocytoma.
The diagnosis and therapeutic management of pheochromocytoma may require the coordinated efforts of a team of medical professionals, such as specialists who diagnose and treat endocrine disorders (endocrinologists); physicians who specialize in the diagnosis and treatment of cancer (medical oncologists); specialists in the use of radiation to treat cancers (radiation oncologists); oncology nurses; surgeons; dietitians; and/or other healthcare professionals.
Specific therapeutic procedures and interventions may vary, depending upon numerous factors, tumor size; tumor location; whether the tumor is benign or malignant; the presence or absence of certain symptoms; an individual's age and general health; and/or additional elements. Decisions concerning the use of particular drug regimens and/or other treatments should be made by physicians and other members of the health care team in careful consultation with the patient based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors.
Surgery is the main form of treatment for pheochromocytoma. Approximately 90 percent of pheochromocytomas are successfully removed by surgery. Surgical removal of one or both of the adrenal glands (adrenalectomy) or another location in case of extra-adrenal pheochromocytomas, may be performed. The most common surgical procedure for treating pheochromocytoma is laparoscopic adrenalectomy. During this procedure, a small incision is made in the abdomen, a small tube is inserted (laparoscope) through the incision, and the tumor is removed. In patients in whom both adrenals are removed, a small amount of the adrenal external layer (or adrenal cortex) can be left behind to preserve normal glucocorticoid production of the adrenal. This may reduce later complications caused by glucocorticoid deficiency in patients that need removal of both adrenals.
Before surgery, affected individuals need to be treated with alpha-adrenergic blockers and beta-adrenergic blockers to minimize the effects of adrenal hormones. Alpha-adrenergic blockers such as phenoxybenzamine (Dibenzyline) is used to control hypertension. In some cases, beta-adrenergic blockers such as propranolol (Inderal) can also be used to treat arrhythmias.
Surgery may be used to treat cases of malignant pheochromocytoma. Radiation therapy, in which radiation is used to target and destroy cancer cells, and certain combinations of anticancer drugs (chemotherapy) may also be used to treat individuals with malignant pheochromocytoma. In cases where surgery cannot remove all affect tissue, periodic reduction of metastasized tissue (debulking) may be beneficial. Individuals in whom surgery does not remove all affect tissue may need to be on medications to control high blood pressure.
Genetic counseling is often of benefit for some affected individuals and their families. Other treatment is symptomatic and supportive.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
For information about clinical trials sponsored by private sources, contact:
An organization known as PRESSOR (Pheochromocytoma Research Support Organization) has been launched to facilitate research on this disorder. Information may be found on the organization’s web site at www.pressor.org.
Contact for additional information about pheochromocytoma:
Patricia Dahia, MD, PhD
Dept. Medicine and Cellular & Structural Biology
Cancer Therapy and Research Center
University of Texas Health Science Center
7703 Floyd Curl Drive, Rm 5053-R3, MC 7880
San Antonio, TX
Tel: (210) 567-4866
Fax: (210) 567-6687
Manger WM. Pheochromocytoma. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:409-10.
Raghavan D., ed. Textbook of Uncommon Cancer, 2nd ed. New York, NY: John Wiley & Sons, Ltd; 1999:251-5.
Fauci AS, et al., eds. Harrison’s Principles of Internal Medicine, 14th Ed. New York, NY: McGraw-Hill, Inc; 1998:2057-60.
DeVita Jr VT, et al., eds. Cancer Principles and Practice of Oncology. 5th Ed. New York, NY: J.B. Lippincott Company; 1997:1669-75.
Bennett JC, Plum F., eds. Cecil Textbook of Medicine. 20th ed. Philadelphia, PA: W.B. Saunders Co; 1996:1254-7.
Wilson JD, et al., Textbook of Endocrinology. 8th ed. Philadelphia, PA: W. B. Saunders Co; 1992:668-83.
Comino-Méndez I, Gracia-Aznárez FJ, Schiavi F, et al. Exome sequencing identifies MAX mutations as a cause of hereditary pheochromocytoma. Nat Genet. 2011;43(7):663-7. doi: 10.1038/ng.861. http://www.ncbi.nlm.nih.gov/pubmed?term=21685915.
Kawasaki Y, Ishidoya S, Kaiho Y, et al. Laparoscopic simultaneous bilateral adrenalectomy: Assessment of feasibility and potential indications [abstract]. [published online ahead of print September 13, 2011].Int J Urol. 2011. doi: 10.1111/j.1442-2042. http://www.ncbi.nlm.nih.gov/pubmed/21914001.
Shen WT, Grogan R, Vriens M, Clark OH, Duh QY. One hundred two patients with pheochromocytoma treated at a single institution since the introduction of laparoscopic adrenalectomy. Arch Surg. 2010;145(9):893-7. http://www.ncbi.nlm.nih.gov/pubmed?term=20855761.
Ku YK, Sangla K, Tan YM, Williams DJ. A case of using cortical sparing adrenalectomy to manage bilateral phaeochromocytoma in neurofibromatosis type 1.Intern Med J. 2010;40(3):239-40. No abstract available. http://www.ncbi.nlm.nih.gov/pubmed?term=20446972.
Yao L, Schiavi F, Cascon A, et al. Spectrum and prevalence of FP/TMEM127 gene mutations in pheochromocytomas and paragangliomas. JAMA. 2010;304(23):2611-9. http://www.ncbi.nlm.nih.gov/pubmed?term=21156949.
Qin Y, Yao L, King EE, et al. Germline mutations in TMEM127 confer susceptibility to pheochromocytoma. Nat Genet. 2010;42(3):229-33. http://www.ncbi.nlm.nih.gov/pubmed?term=20154675.
Hao HX, Khalimonchuk O, Schraders M, et al. SDH5, a gene required for flavination of succinate dehydrogenase, is mutated in paraganglioma. Science. 2009;325(5944):1139-42. http://www.ncbi.nlm.nih.gov/pubmed?term=19628817.
Yip L, et al., Surgical management of hereditary pheochromocytoma. J Am Coll Surg. 2004;198;525-34.
Gimm O, et al., The genetic basis of pheochromocytoma. Front Horm Res. 2004;31:45-60.
Vaughan Ed Jr. Diseases of adrenal gland. Med Clin North Am. 2004;88:443-66.
Jaroszewski DE, et al., Laparoscopic adrenalectomy for pheochromocytoma. Mayo Clin Proc. 2003;78:1501-4.
Mukai M, et al., Malignant pheochromocytoma responsive to multimodal therapy: a case report. Hinyokika Kiyo. 2003;49:583-5.
Arias Martinez N, et al., Treatment of malignant pheochromocytoma with 131I MIBG: a long survival. An Med Interna. 2003;20:575-8.
Pederson LC, Lee JE. Pheochromocytoma. Curr Treat Options Oncol. 2003;4:329-37.
Nicolai N. Laparoscopic adrenalectomy. Tumori. 2003;89:556-9.
Veglio F, et al., Recent advances in diagnosis and treatment of pheochromocytoma. Minerva Med. 2003;94:267-71.
Neumann HP, et al., Germ-line mutations in nonsyndromic pheochromocytoma. N Engl J Med. 2002;346:1459-66.
Aguiar RC, et al., Analysis of the SDHD gene, the susceptibility gene for familial paraganglioma syndrome (PGL1), in pheochromocytomas. J Clin Endocrinol Metab. 2001;86:2890-4.
Dluhy RG, Pheochromocytoma? death of an axiom. N Engl J Med. 2002;346:1486-8.
Astuti D, et al., Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma. Am J Hum Genet. 2001;69:49-54.
Skoldberg F, et al., A family with hereditary extra-adrenal paragangliomas without evidence for mutations in the von Hippel-Landau disease or ret genes. Clin Endocrinol. 1998;48:11-6.
FROM THE INTERNET
Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Pheochromocytoma. Entry No: 171300. Last Edited august 15, 2011. Available at: http://www.ncbi.nlm.nih.gov/omim/. Accessed October 18, 2011.
Online Mendelian Inheritance in Man, OMIM (TM). Johns Hopkins University, Baltimore, MD. MIM Number: 171350:3/23/2004. World Wide Web URL:
Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Paragangliomas 4; PGL4. Entry No: 115310. Last Updated March 21, 2011. Available at: http://www.ncbi.nlm.nih.gov/omim/. Accessed October 18, 2011.
Sweeney AT. Pheochromocytoma. Emedicine. 2003. http://emedicine.medscape.com/article/124059-overview, 2011. Accessed October 18, 2011.
National Cancer Institute. PDQ. Pheochromocytoma. 2003. http://www.cancer.gov/cancertopics/pdq/treatment/pheochromocytoma/HealthProfessional Last Updated October 27, 2010. Accessed October 18, 2011.