Pheochromocytoma and Paraganglioma

Pheochromocytomas (often abbreviated as pheo) and paragangliomas (often abbreviated as para) are rare types of tumors. Pheochromocytomas form in the adrenal glands, while closely related paragangliomas originate from cells of neuronal origin, which can be located throughout the neck, chest, abdomen, or pelvis. These tumors can produce hormones that control normal body stress reaction and other functions, including heart rate and blood pressure.

The NICHD supports and conducts research on pheochromocytoma and paraganglioma to understand the causes of the disease, improve the detection methods, and develop effective therapies.

On this webpage, the term pheochromocytoma also refers to paraganglioma unless otherwise specified. 

Common Name

  • Pheochromocytoma (pronounced fee-oh-kroh-moh-sigh-TOH-muh)
  • Paraganglioma (pronounced pair-uh-gang-lee-OH-muh)

Pheochromocytoma and Paraganglioma: Condition Information

What is pheochromocytoma?

Pheochromocytoma is a rare tumor that develops in the adrenal glands. There are two adrenal glands in the human body, which are located on top of the kidneys. Each adrenal gland has two parts, the outer cortex and inner medulla. The cortex produces corticosteroid and androgen hormones. The medulla produces catecholamines (epinephrine, norepinephrine, and dopamine).

Pheochromocytomas may be found in one or both glands and may spread, or metastasize (pronounced meh-TAS-tuh-size), beyond the adrenal glands. Pheochromocytomas develop from the center of the adrenal gland, in an area called the adrenal medulla, which secretes catecholamines.1

Hormones that are normally produced by the adrenal medulla, catecholamines (pronounced kat-i-KOL-uh-meens), help to regulate heart rate, blood pressure, and the body's responses to stress. Pheochromocytomas release additional catecholamines, causing higher than normal amounts in the body.2 Changes in hormone levels produce some of the clinical signs and life-threatening symptoms of pheochromocytoma.

Although the majority of pheochromocytomas are benign (non-cancerous or non-metastatic), about one-third are malignant (cancerous or metastatic) and spread to other parts of the body.3 Malignant pheochromocytomas may spread, or metastasize, to the liver, lungs, bone, and lymph nodes.2

On this webpage, the term pheochromocytoma also refers to paraganglioma unless otherwise specified.

What is paraganglioma?

Paragangliomas are tumors originating from neuronal tissue; they were formerly called extra-adrenal pheochromocytomas. There are developmentally two subgroups of these tumors: parasympathetic paragangliomas and sympathetic paragangliomas. These subgroups differ in the type of tissue from which they form (parasympathetic versus sympathetic) and also in their location and hormonal production. Parasympathetic tissue is important for certain body processes, including salivation, urination, and digestion. Sympathetic tissue forms the tissue important for "fight-or-flight" responses.

The group of paragangliomas that develop from parasympathetic-associated tissue in the head and neck are usually referred to as "head and neck paragangliomas." These tumors can be locally invasive but usually do not metastasize or produce catecholamines (stress hormones). Signs and symptoms of head and neck paragangliomas are usually due to the tumor mass itself instead of the secreted catecholamines.

Paragangliomas that develop from sympathetic neuronal tissue are usually localized in the chest, abdomen, or pelvis. These tumors often have excessive hormone secretion, which makes them very similar to pheochromocytomas. As a result of excessive hormone secretion, paragangliomas often cause the signs and symptoms described below (e.g., heart palpitations, irregular heartbeat, hypertension, and sweating). Sympathetic (or extra-adrenal) paragangliomas generally tend to be more malignant than pheochromocytomas (localized to the adrenal gland).4

Citations

  1. National Cancer Institute, PDQ Cancer Information Summaries. (2012). Pheochromocytoma and paraganglioma treatment (PDQ®). Retrieved March 7, 2012, from http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0033247/
  2. Pacak, K. (2011). Phaeochromocytoma: a catecholamine and oxidative stress disorder. Endocrine Regulation 45: 65-90.
  3. Parenti, G., Zampetti, B., Rapizzi, E., Ercolino, T., Giachè, V., & Mannelli, M. (2012). Updated and new perspectives on diagnosis, prognosis, and therapy of malignant pheochromocytoma/paraganglioma. Journal of Oncology, 2012, 872713.
  4. Eisenhofer, G., Lenders J. W., Siegert, G., Bornstein, S. R., Friberg, P., Milosevic, D., et al., (2012). Plasma methoxytyramine: A novel biomarker of metastatic pheochromocytoma and paraganglioma in relation to established risk factors of tumour size, location and SDHB mutation status. European Journal of Cancer, 48: 1739–1749.

What are common symptoms of pheochromocytoma?

Pheochromocytoma causes a variety of signs and symptoms, including (in alphabetical order):

  • Abdominal pain
  • Constipation
  • Chest pain
  • Dizziness
  • Elevated blood sugar
  • Facial flushing (redness)
  • High blood pressure
  • Increased respiratory rate
  • Nausea
  • Nervousness, anxiety, and irritability
  • Pale skin tone
  • Rapid heart rate and heart palpitations
  • Severe headaches
  • Sweating
  • Visual disturbances
  • Weight loss

What is the most common age for diagnosis of pheochromocytoma?

Pheochromocytoma can occur at any age. However, it is diagnosed most frequently between the ages of 30 and 50.1

Up to 20% of pheochromocytomas are diagnosed in children.2

Citations

  1. Eunice Kennedy Shriver National Institute of Child Health and Human Development. The proper diagnosis, treatment, genetics, and research of pheochromocytoma and paraganglioma: Overview. Retrieved March 16, 2012, from https://science.nichd.nih.gov/confluence/display/pheo/Overview
  2. King, K. S., Prodanov, T., Kantorovich, V., Fojo, T., Hewitt, J. K., Zacharin, M., et al., (2011). Metastatic pheochromocytoma/paraganglioma related to primary tumor development in childhood or adolescence: significant link to SDHB mutations. Journal of Clinical Oncology 29: 4137-4142.

What causes pheochromocytoma?

Approximately one-third of pheochromocytoma cases occur when patients inherit a mutated gene from their parents.1 Studies have linked several genes to the disease, but researchers are not sure how these genes contribute to the formation of this tumor.2

The remaining two-thirds of cases are spontaneous and are not associated with a family history. However, genetic inheritance may play a role in the development of the disease through unknown genes. For example, in one study, a significant percentage of patients (7.5% to 27%) with sporadic pheochromocytoma had genetic mutations that have been linked to other family-inherited syndromes.3

Citations

  1. Eunice Kennedy Shriver National Institute of Child Health and Human Development. The proper diagnosis, treatment, genetics, and research of pheochromocytoma and paraganglioma: Genetic screening. Retrieved March 26, 2012, from https://science.nichd.nih.gov/confluence/display/pheo/Genetic+Screening
  2. Karasek, D., Shah, U., Frysak, Z., Stratakis, C., Pacak, K. (In press). , An update on the genetics of pheochromocytoma. Journal of Human Hypertension , doi:10.1038/jhh.2012.20.
  3. Pacak, K., Lenders, J. W. M., & Eisenhofer, G. (2007). Pheochromocytoma: diagnosis, localization, and treatment. Malden, MA: Wiley-Blackwell.

How do health care providers diagnose pheochromocytoma?

A health care provider uses blood and urine tests that measure catecholamines (pronounced kat-i-KOL-uh-meens) and/or their metabolites to diagnose pheochromocytoma. Metabolites are biochemical substances that form when another is broken down in the body. Higher than normal amounts of these biochemical substances in the blood and/or urine can be an indication of the presence of a pheochromocytoma/paraganglioma.

Pheochromocytomas can secrete all, none, or any combination of catecholamines (epinephrine, norepinephrine, dopamine) and their metabolites, which are called metanephrines (metanephrine, normetanephrine, methoxytyramine). Multiple studies at the National Institutes of Health (NIH) have demonstrated the utility of measuring metanephrines in the blood for the diagnosis of pheochromocytoma/paraganglioma.1 This method is often recommended as the first diagnostic test when there is suspicion for a pheochromocytoma/paraganglioma.

Tumors can also be found accidentally during non-related imaging studies. The location of a pheochromocytoma can be determined by using several imaging methods, including computed tomography (CT) and magnetic resonance imaging (MRI). CT scans use X-rays to produce detailed images of the inside of the body, while MRI uses magnetic waves to produce these pictures. A third imaging method that can be used to detect pheochromocytomas is MIBG (metaiodobenzylguanidine) scintigraphy. During this procedure, MIBG, a compound containing a small amount of radioactivity, is injected into a vein and is picked up by pheochromocytoma cells, but not normal cells.1 The body is scanned with a scanner that detects the MIBG. Any MIBG that is seen with the scanner can indicate the presence of pheochromocytoma cells.

Read more about getting an MIBG scan. (PDF - 636 KB)

Citations

  1. Pacak, K., & Eisenhofer G. (2007). An assessment of biochemical tests for the diagnosis of pheochromocytoma. Nature Clinical Practice Endocrinology & Metabolism. 3: 744-745.

Is there a cure for pheochromocytoma?

The success of pheochromocytoma treatment depends upon several factors; the most important include: presence of metastasis, genetics, location, and overall extent of the disease. Malignant pheochromocytoma can only be determined by the presence of metastasis or tumor spreading (tumors in locations such as the bone, liver, lungs, or lymph nodes).

The only curative treatment for pheochromocytoma is complete surgical removal of the tumor. The long-term prognosis of patients after resection of a single sporadic pheochromocytoma is excellent.

Even after tumor removal, there is still a risk that pheochomocytoma or paraganglioma might return (called recurrence). Recurrence is more likely for those with paraganglioma, those who are younger, those whose family members also have the disease, and those who had large tumors.1

There is currently no cure for malignant pheochromocytoma. Radiation therapy, or the use of radio waves to destroy tumors, can assist in shrinking some malignant tumors.2 Tumor shrinkage can lessen the clinical signs and symptoms of pheochromocytoma by reducing the production of hormones and in some cases may allow for surgery.

Although not curative, medications are used to control the clinical signs and symptoms of both benign and malignant pheochromocytoma.

Citations

  1. Amar, L., Lussey-Lepoutre, C., Lenders, J.W., Djadi-Prat, J., Plouin, P.F., & Steichen, O. (2016). MANAGEMENT OF ENDOCRINE DISEASE: Recurrence or new tumors after complete resection of pheochromocytomas and paragangliomas: a systematic review and meta-analysis. European Journal of Endocrinology. 2016. Oct;175(4):R135-45.
  2. Lenders, J.W., Eisenhofer, G. (2017). Update on Modern Management of Pheochromocytoma and Paragangliom. Endocrinology and Metabolism (Seoul, Korea). Jun;32(2):152-161. Retrieved May 16, 2018, from https://www.ncbi.nlm.nih.gov/pubmed/28685506

What are the treatments for pheochromocytoma?

Standard treatments for pheochromocytoma include1,2:

  • Surgical removal of the tumor
  • Medications (chemotherapy) designed to kill tumor cells
  • Radiotherapy: utilizing radio waves to destroy the tumors
  • Medications to control the signs and symptoms of the disease

Types of Therapies for Pheochromocytoma:

Ninety percent of patients are cured by surgery to remove benign pheochromocytoma tumors.3 Surgery for tumor removal is typically done by laparoscopy, during which a small incision is made in the abdomen.3,4 During surgery to remove the tumor, the physician will usually examine nearby organs to determine whether the pheochromocytoma has spread to other parts of the body.

Medications are prescribed to treat the clinical signs and symptoms of pheochromocytoma.

Commonly prescribed medications include the following1:

  • Alpha-adrenergic blockers to lower blood pressure
  • Beta blockers for controlling rapid, irregular pulse

For tumors that are successfully removed, blood pressure and hormone levels usually return to normal over the weeks immediately following surgery.

Citations

  1. National Cancer Institute. (2012). Pheochromocytoma and paraganglioma treatment (PDQ). Retrieved March 7, 2012, from http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0033247/
  2. Waguespack, S. G., Rich, T., Grubbs, E., Ying, A. K., Perrier, N. D., Ayala-Ramirez, M., et al. (2010). A current review of the etiology, diagnosis, and treatment of pediatric pheochromocytoma and paraganglioma. Journal of Clinical Endocrinology and Metabolism. 95(5), 2023–2037. PMID 20215394
  3. National Organization for Rare Diseases (2011). Pheochromocytoma. https://rarediseases.org/rare-diseases/pheochromocytoma/
  4. Lentschener, C., Gaujoux, S., Tesniere, A., & Dousset, B. (2011). Point of controversy: Perioperative care of patients undergoing pheochromocytoma removal—time for a reappraisal? European Journal of Endocrinology, 165(: 365-373.

Pheochromocytoma and Paraganglioma: NICHD Research Goals

The NICHD supports research on pheochromocytoma with the goal of increasing the understanding of the disease and improving disease management. Research supported by the Institute is intended to lead to better methods of diagnosis, treatment, and overall understanding of the illness. To achieve these goals, the Institute bases its strategy on multidisciplinary collaborations with investigators from several NIH Institutes and outside medical centers.

Outcomes of NICHD-supported research on pheochromocytoma-associated genes may improve the diagnosis of the disease through the discovery of better genetic testing methods. NICHD-supported pheochromocytoma research also leads to the better care and treatment of diagnosed women and their children.

To advance research on pheochromocytoma, the NICHD links patient-oriented studies with laboratory or "bench-level" studies. Patient-oriented studies in medical neuroendocrinology help guide the Institute's future hypotheses and discoveries. Bench-level studies include tumor pathology and chemistry research that apply the technologies of basic research to the development of new clinical therapies.

NICHD-funded studies include efforts to:

  • Define the molecular and genetic bases of the disease and transfer this knowledge to better diagnosis and treatment of malignant pheochromocytoma.
  • Develop highly effective therapeutic strategies in order to improve the patient's quality of life and prognosis.
  • Facilitate interdisciplinary research through new collaborations among researchers.
  • Produce better diagnostic and detection methods in order to help improve diagnosis of pheochromocytoma and determine tumor location(s).
  • Understand the significance of differences in clinical presentation among patients, which are thought to be due to molecular and cellular differences among patients.

Pheochromocytoma and Paraganglioma: Research Activities and Scientific Advances

Institute Activities and Advances

Research on pheochromocytoma and paraganglioma is conducted through the NICHD’s Division of Intramural Research (DIR), in the Pacak Lab , within the Program in Reproductive and Adult Endocrinology (PRAE) and the Loh Lab , in the Program on Developmental Neuroscience :

  • Gene Mutations That Are Associated with Early Malignant Pheochromocytoma
    Researchers examine the genetics of pheochromocytoma to help characterize the disease. In current studies on the genetics of pheochromocytoma, researchers are attempting to identify genes that are associated with malignancy, which is known to substantially shorten patient survival.

    In one DIR study, researchers examined the age of initial diagnosis (when the patient’s first tumor was found) of patients who had metastatic disease (the presence of tumors in tissues such as the bone, lungs, liver, or lymph nodes). Researchers looked at all individuals evaluated who had metastatic disease and determined when they were first diagnosed (either in childhood/adolescence or in adulthood) and then determined whether or not they had a genetic predisposition to disease. It was discovered that the majority of those patients whose first tumor developed in childhood or adolescence and later developed metastatic disease had a mutation in the SDHB gene.

    While it is well-established that SDHB mutations lead to aggressive tumors, this study helped further describe the clinical presentation of SDHB-related pheochromocytoma/paraganglioma. This study may also help direct genetic testing (testing for SDHB mutations in patients with early tumor development and metastatic disease) and proper follow up (tumor screening for metastatic disease in patients with SDHB mutations and early tumor development). PMID: 21969497)
  • A Novel Marker for Metastatic Pheochromocytomas
    Measurement of higher than normal catecholamine levels is used in the diagnosis of pheochromocytoma. Catecholamines are transformed in the body into several products called metabolites, which can also be measured to diagnose pheochromocytoma. Benign pheochromocytoma can often be cured by tumor removal, but malignant pheochromocytoma, which spreads to other parts of the body, cannot be cured. The discovery of methods to identify patients who have early malignant pheochromocytoma is important to address shorter survival in these patients.1

    This study examined whether catecholamine-related metabolites could be used to diagnose malignant pheochromocytoma. The researchers found that patients with higher than normal levels of one metabolite, methoxytyramine, had malignant pheochromocytoma. Methoxytyramine could be used to identify patients with malignant pheochromocytoma and tailor treatment for malignancy. (PMID: 22036874)
  • Proteins in Blood Can Indicate Pheochromocytoma Type
    Approximately one-third of pheochromocytoma cases are associated with familial inheritance of a mutated gene.2 Pheochromocytoma cases are often distinguished by the presence of different mutations. These hereditary mutations are passed from parents to their children. Catecholamines and their related metabolites are measured to diagnose pheochromocytoma. Recently, there has been an interest in diagnosing a patient's mutations through measurement of higher than normal catecholamines and related metabolites. Knowledge of specific disease predisposing mutations can help care providers personalize the required treatment and follow up. The most common mutations found in patients with pheochromocytoma include VHL, SDHB, SDHD, MEN2, and NF1.

    This study examined whether various metabolites of catecholamines could help distinguish various hereditary forms of the tumor. The researchers examined pheochromocytoma patients who had mutations in the VHL, SDHB, SDHD, MEN2, or NF1 genes. The researchers were able to group patients according to their gene mutations based on the amount of the different metabolites measured in their blood. These findings show that the distinct patterns of blood levels of different metabolites can be a cost-effective method (versus full genetic testing) to determine a patient's mutations. PMID: 21262951)
  • A Gene Mutation is Associated with Tumor Growth 
    NICHD researchers analyzed tumors from two patients who had paragangliomas. Analysis of the tumor tissue revealed that it contained an alteration in one of the family of genes called hypoxia-inducible factors (HIFs). HIFs have been implicated in the development of tumors and the progression of cancers. The researchers found that the altered HIF2A gene generated proteins that were broken down more slowly than the typical form of the gene. In the presence of these proteins, the researchers also documented increased levels of a hormone that stimulates the production of red blood cells.

    HIF genes are most active in conditions of low oxygen, such as in tumor tissue. The researchers concluded that the mutation may have altered gene activity in a way that led to more tumors growing in the bodies of the patients they examined. The discovery may help clarify how some tumors generate a new blood supply to sustain their growth. The finding could lead to information on how to hinder the growth of tumors and treat cancers associated with excessive production of red blood cells. (PMID: 22931260)

Other Activities and Advances

Conferences

  • The International Patient Symposium on Pheochromocytoma: Working Together Today For a Better Tomorrow, held June 28–29, 2012, in Washington, DC, brought together leading clinicians from around the world to educate patients and primary care physicians about pheochromocytoma. Researchers presented the latest information on the diagnosis, genetics, and treatments of pheochromocytoma, and patients had the opportunity to ask questions and interact with experts in this disease.
  • The 3rd International Symposium on Pheochromocytoma, held September 14–17, 2011, in Paris, France, brought together investigators and health care professionals from around the world who have a common interest in pheochromocytoma.

Citations

  1. Blake, M. A. (2011). Pheochromocytoma. Retrieved April 5, 2012, from http://emedicine.medscape.com/article/124059-overview External Web Site Policy
  2. Karasek, D., Shah, U., Frysak, Z., Stratakis, C., Pacak, K. (In press). An update on the genetics of pheochromocytoma. Journal of Human Hypertension, doi:10.1038/jhh.2012.20.
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