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Last updated: October 19, 2021
Years published: 1988, 1989, 1996, 1997, 2004, 2011, 2021
NORD gratefully acknowledges Cole Carpenter and Brett Cordell, NORD Editorial Interns from the University of Notre Dame, Kasturi Haldar, PhD, Director, Boler-Parseghian Center for Rare and Neglected Diseases, University of Notre Dame, and Lauren Fishbein, MD, PhD, MTR, Associate Professor, University of Colorado School of Medicine, Department of Medicine, Division of Endocrinology, Metabolism and Diabetes, Division of Biomedical Informatics and Personalized Medicine, for assistance in the preparation of the report.
Pheochromocytoma is a rare type of tumor that arises in adrenal glands, specifically from certain cells known as chromaffin cells in the center of the adrenal gland called the adrenal medulla. These cells secrete hormones epinephrine and norepinephrine, and the pheochromocytoma continuously overproduces them. Pheochromocytomas originate in one of the two adrenal glands located above the kidneys in the back of the upper abdomen. Paragangliomas are similar tumors which form in the paraganglia (nerve bundles) throughout the body. Under the microscope, pheochromocytoma and paraganglioma are the same. They are named differently largely just based on the location. For all pheochromocytoma/paraganglioma, approximately 80-85% occur in the adrenal medulla. Approximately 15-20% occur outside of this area in the chest, heart, abdomen, pelvis, bladder, and/or neck or base of the skull. The paraganglioma from the head and neck, and sometimes other locations, are silent meaning they do not produce high epinephrine or norepinephrine. Symptoms associated with secreting pheochromocytomas/paragangliomas include high blood pressure (hypertension), headaches, excessive sweating and/or heart palpitations. In most patients, pheochromocytomas/paragangliomas occur randomly for unknown reasons (sporadically). In approximately 35% of cases, pheochromocytomas may be inherited in an autosomal dominant pattern. Some inherited cases may occur as part of another disorder such as multiple endocrine neoplasia types 2a and 2b, von Hippel-Lindau syndrome, neurofibromatosis type 1 or hereditary paraganglioma-pheochromocytoma syndromes or as familial isolated pheochromocytoma. Most pheochromocytomas/paragangliomas can be treated via targeted surgery.
Some people with a pheochromocytoma/paraganglioma may not develop symptoms (asymptomatic). High blood pressure (hypertension) is the most common finding associated with pheochromocytomas. High blood pressure may be always present or may come and go. Affected individuals may experience 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/paragangliomas occur because of the release of certain hormones known as catecholamines (e.g., norepinephrine and epinephrine). 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). Some individuals with a pheochromocytoma/paraganglioma may have difficulties in the breakdown (metabolism) of carbohydrates and can develop diabetes.
If left untreated, pheochromocytomas/paragangliomas may progress to cause serious, life-threatening complications including heart muscle disease (cardiomyopathy), bleeding in the brain (cerebral hemorrhaging) or the accumulation of fluid in the lungs (pulmonary edema). Some individuals with pheochromocytoma/paraganglioma may be at risk of developing a stroke or heart attack (myocardial infarction).
Approximately 15% of pheochromocytomas/paragangliomas may be cancer-causing (metastatic, meaning spread to other locations in the body). Extra-adrenal paragangliomas are more likely to be metastatic than adrenal pheochromocytomas. Metastatic pheochromocytomas/paragangliomas can spread (metastasize) to various areas of the body including the lymph nodes, liver, lungs and bones.
In most cases, the exact cause of pheochromocytoma/paraganglioma is unknown. Most cases occur randomly, for unknown reasons (sporadically).
Approximately 35% of cases of pheochromocytomas result from genetic disruptions or changes (mutations) to certain genes. These mutations are inherited in an autosomal dominant pattern. Autosomal dominant genetic disorders occur when only a single copy of an altered gene is necessary for the appearance of the disease. The altered 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 altered gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females.
Some cases of pheochromocytoma/paraganglioma occur as part of a genetic syndrome. Disorders in which pheochromocytomas/paragangliomas may be a secondary finding include multiple endocrine neoplasia types 2a and 2b, von Hippel-Lindau syndrome, neurofibromatosis type 1, hereditary paraganglioma-pheochromocytoma syndromes and isolated familial pheochromocytoma.
Individuals with isolated, nonsyndromic pheochromocytoma/paraganglioma still may have a genetic predisposition or cause to developing the tumor. 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 โactivatedโ under certain circumstances. Some people with the genetic predisposition may never have a trigger and may never develop a tumor. Some of these cases may occur randomly as the result of a spontaneous genetic change (i.e., new mutation) which does not come from either parent but now can be passed on to their children.
Pheochromocytomas/paragangliomas may be caused by mutations of one of at least ten different genes: the RET gene, which is also associated with multiple endocrine neoplasia type 2; the VHL gene, which is also associated with von Hippel-Lindau syndrome; the neurofibromatosis (NF1) gene, associated with neurofibromatosis type 1; the succinate dehydrogenase subunit genes (SDHA, SDHB, SDHC, SDHD, SDHAF2), which are associated with the hereditary paraganglioma-pheochromocytoma syndromes; the TMEM127 gene; and the MAX gene.
Pheochromocytomas/paragangliomas 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% of cases occur in children.
Pheochromocytomas/paragangliomas 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 85% of pheochromocytomas/paragangliomas are non-cancerous.
A diagnosis of pheochromocytoma/paraganglioma may be suspected based upon a detailed patient history (including previous pheochromocytoma/paraganglioma cases in the family), a thorough clinical evaluation, and identification of characteristic findings (paroxysmal attacks, hypertension unresponsive to normal treatment, etc.). Blood and/or urine analysis can confirm a diagnosis of secreting pheochromocytoma/paraganglioma by detecting elevated levels of catecholamines or their metabolites in the urine and blood (plasma). Metabolites are the byproducts of catecholamines that are produced when the body breaks down (metabolizes) catecholamines.
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/paraganglioma. 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/paraganglioma.
Lobenguane I 123 injection (AdreView) and gallium 68 dotatate are molecular imaging agents for the detection of rare neuroendocrine tumors in children and adults, and are approved by the U.S. Food and Drug Administration (FDA) for diagnosis. These are often used when metastatic disease (spread through the body) is suspected.
Treatment
The diagnosis and therapeutic management of pheochromocytoma/paraganglioma 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 localized or spread (metastasized); the presence or absence of certain symptoms; an individualโs 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 the 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/paraganglioma. Approximately 80-85% of pheochromocytomas are successfully removed by surgery. Surgical removal of one or both adrenal glands (adrenalectomy) or another location in case of extra-adrenal paragangliomas, may be performed. The most common surgical procedure for treating adrenal 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 (called cortical sparing surgery). 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 possibly beta-adrenergic blockers to minimize the effects of adrenal hormones. Alpha-adrenergic blockers such as doxazosin and prazosin are used to control high blood pressure (hypertension). In some patients, beta-adrenergic blockers such as propranolol or metoprolol can be added to treat arrhythmias fast heart rates (tachycardia).
Surgery may be used to treat cases of metastatic pheochromocytoma/paraganglioma. 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 metastatic or unresectable pheochromocytoma/paraganglioma. 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.
In 2018, the FDA approved Iobenguane I 131 (brand name: Azedra) for the treatment of patients 12 years and older with a pheochromocytoma/paraganglioma that cannot be surgically removed, has spread beyond the original tumor site and requires systemic anticancer therapy.
Genetic counseling is recommended for all individuals who have pheochromocytoma/paraganglioma 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
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website: https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact: www.centerwatch.com
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder.
JOURNAL ARTICLES
Jain A, Baracco R, Kapur G. Pheochromocytoma and paraganglioma-an update on diagnosis, evaluation, and management. Pediatr. Nephrol. 2020: 35: 581-594
Farrugia FA, Charalampopoulos A. Pheochromocytoma. Endocr Regul. 2019; 53 191-212.
Fishbein L. Pheochromocytoma/paraganglioma: is this a genetic disorder? Curr Cardiol Rep. 2019; 21:104.
Jimenez C. Treatment for patients with malignant pheochromocytomas and paragangliomas: a perspective from the hallmarks of cancer front. Endocrinol. 2018; 9: 277.
Pappachan JM, Raskauskiene D, Sriraman R. Diagnosis and management of pheochromocytoma: a practical guide to clinicians Curr. Hypertens Rep. 2014; 16: 442.
Comino-Mรฉndez I, Gracia-Aznรกrez 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.
Kawasaki Y, Ishidoya S, Kaiho Y, et al. Laparoscopic simultaneous bilateral adrenalectomy: Assessment of feasibility and potential indications. Int J Urol. 2011 Nov;18(11):762-7. doi: 10.1111/j.1442-2042.
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.
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.
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.
Qin Y, Yao L, King EE, et al. Germline mutations in TMEM127 confer susceptibility to pheochromocytoma. Nat Genet. 2010;42(3):229-33.
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.
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.
INTERNET
Mayo Clinic for Medical Education and Research Pheochromocytoma. Updated March 2020. Symptoms and causes https://www.mayoclinic.org/diseases-conditions/pheochromocytoma/symptoms-causes/syc-20355367 Accessed August 2021.
Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Pheochromocytoma Entry #171300. Updated August 2021.Available at: https://www.omim.org/entry/171300. Accessed September 8, 2021.
National Cancer Institute. PDQ. Pheochromocytoma and Paraganglioma Treatment. Updated October 2020.https://www.cancer.gov/types/pheochromocytoma/hp/pheochromocytoma-treatment-pdq Accessed September 8, 2021.
Sweeney AT. Pheochromocytoma. Emedicine. Updated August 2021. https://emedicine.medscape.com/article/124059-overview . Accessed September 8, 2021.
National Cancer Institute. PDQ. Pheochromocytoma. Updated October 2020.https://www.cancer.gov/cancertopics/pdq/treatment/pheochromocytoma/HealthProfessional. Accessed September 8, 2021.
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