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Home > Living Well > Health Library > Pheochromocytoma and Paraganglioma Treatment (PDQ®): Treatment - Health Professional Information [NCI]
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Pheochromocytomas and extra-adrenal paragangliomas are rare tumors arising from neural crest tissue that develops into sympathetic and parasympathetic paraganglia throughout the body.
In 2004, the World Health Organization classification utilized the term pheochromocytoma exclusively for tumors arising from the adrenal medulla, and the term extra-adrenal paraganglioma for similar tumors that arise from other locations.
Incidence and Mortality
The incidence of pheochromocytoma is 2 to 8 per million persons per year.[1,2] Pheochromocytoma is present in 0.1% to 1% of patients with hypertension,[3,4,5] and it is present in approximately 5% of patients with incidentally discovered adrenal masses. The peak incidence occurs in the third to fifth decades of life; the average age at diagnosis is 24.9 years in hereditary cases and 43.9 years in sporadic cases. The incidence is equal between males and females.
Pheochromocytomas and extra-adrenal paragangliomas arise from neural crest tissue. Neural crest tissue develops into sympathetic and parasympathetic paraganglia.
Sympathetic paraganglia include the following:
Parasympathetic paraganglia include the following:
No known environmental, dietary, or lifestyle risk factors have been linked to the development of pheochromocytoma.
Hereditary Predisposition Syndromes
Of all pheochromocytomas and extra-adrenal paragangliomas, 35% occur in the setting of a hereditary syndrome.[7,8,9] Major genetic syndromes that confer an increased risk of pheochromocytoma are included in Table 1.
Pheochromocytomas and extra-adrenal paragangliomas can also occur in the following two other very rare syndromes:
Genetic counseling and testing
It has been proposed that all patients diagnosed with a pheochromocytoma or paraganglioma should consider genetic testing because the incidence of a hereditary syndrome in apparently sporadic cases is as high as 25%.[7,8,23] Early identification of a hereditary syndrome allows for early screening for other associated tumors and identification of family members who are at risk. In addition, some patients with a hereditary syndrome are more likely to develop multifocal, malignant, or recurrent disease. Knowledge of the specific genetic mutation permits increased vigilance during preoperative localization or postoperative surveillance of such patients.
Certain subgroups of patients are at very low risk of having an inherited syndrome (e.g., <2% in patients diagnosed with apparently sporadic pheochromocytoma after age 50 years). Therefore, genetic testing for all patients diagnosed with a pheochromocytoma or paraganglioma may not be practical or cost effective from a population standpoint. It is currently recommended that every patient diagnosed with a pheochromocytoma or extra-adrenal paraganglioma should first undergo risk evaluation for a hereditary syndrome by a certified genetic counselor.
Genetic testing is often recommended in the following situations:
In patients with a unilateral pheochromocytoma and no personal or family history suggestive of hereditary disease, genetic testing can be considered if patients are between the ages of 40 years and 50 years, but genetic testing is generally not recommended if patients are older than 50 years. If a mutation is identified, predictive genetic testing should be offered to asymptomatic at-risk family members. (Refer to the PDQ summary on the Genetics of Endocrine and Neuroendocrine Neoplasias for more information.)
Patients with pheochromocytomas and sympathetic extra-adrenal paragangliomas may present with symptoms of excess catecholamine production, including the following:
These symptoms are often paroxysmal, although sustained hypertension between paroxysmal episodes occurs in 50% to 60% of patients with pheochromocytoma. Episodes of hypertension can be variable in frequency, severity, and duration and are often extremely difficult to manage medically. Hypertensive crisis can lead to cardiac arrhythmias, myocardial infarction, and even death.
Patients are often very symptomatic from excess catecholamine secretion. Symptoms of catecholamine excess can be spontaneous or induced by the following:
Phenoxybenzamine (an alpha-adrenergic receptor blocker) is an effective treatment for catecholamine excess and metyrosine (a catecholamine synthesis antagonist) can be added if needed.
Parasympathetic extra-adrenal paragangliomas do not secrete catecholamines. These tumors usually present as a neck mass with symptoms related to compression or are incidentally discovered on an imaging study performed for an unrelated reason. In addition, approximately half of patients with pheochromocytoma are asymptomatic because their neoplasms are discovered in the presymptomatic state by either abdominal imaging for other reasons (e.g., adrenal incidentalomas) or genetic testing in at-risk family members.[20,26,27,28]
The diagnosis of pheochromocytoma is usually suspected by the presence of an adrenal mass or is discovered incidentally. Biochemical testing is done to document excess catecholamine secretion. Once the biochemical diagnosis of a catecholamine-secreting tumor is confirmed, localization studies should be performed. Controversy exists as to the optimal single test to make the diagnosis.
24-hour urine collection
A 24-hour urine collection for catecholamines (e.g., epinephrine, norepinephrine, and dopamine) and fractionated metanephrines (e.g., metanephrine and normetanephrine) has a relatively low sensitivity (77%–90%) but a high specificity (98%). Pretest probability is also important. The specificity of plasma-free fractionated metanephrines is 82% in patients tested for sporadic pheochromocytoma versus 96% in patients tested for hereditary pheochromocytoma.[29,30]
Plasma-free fractionated metanephrines
Measurement of plasma-free fractionated metanephrines appears to be an ideal case-detection test for patients at higher baseline risk of pheochromocytoma. Examples of these patients might include the following:
The test is associated with a relatively high false-positive rate in patients with a lower baseline risk of pheochromocytoma. Measurement of plasma-free metanephrines (e.g., metanephrine and normetanephrine) has a high sensitivity (97%–99%) but a relatively low specificity (85%).
In general, it is reasonable to use measurement of plasma-free fractionated metanephrines for initial case detection, which is followed by 24-hour measurement of urine-fractionated metanephrines and catecholamines for confirmation. Test results can be difficult to interpret because of the possibility of false-positive results. False-positive results can be caused by any of the following:[25,29]
A mildly elevated catecholamine or metanephrine level is usually the result of assay interference caused by drugs or other factors. Patients with symptomatic pheochromocytoma almost always have increases in catecholamines or metanephrines two to three times higher than the upper limits of reference ranges.
Provocative testing (e.g., using glucagon) can be dangerous, adds no value to other current testing methods, and is not recommended.
Computed tomography (CT) imaging or magnetic resonance imaging (MRI) of the abdomen and pelvis (at least through the level of the aortic bifurcation) are the most commonly used methods for localization. Both have similar sensitivities (90%–100%) and specificities (70%–80%). CT imaging provides superior anatomic detail compared with MRI.
Additional functional imaging may be necessary if CT imaging or MRI fails to localize the tumor. It might also be useful in patients who are at risk for multifocal, malignant, or recurrent disease. Iodine I 123 (123I)-metaiodobenzylguanidine (MIBG) scintigraphy coupled with CT imaging provides anatomic and functional information with good sensitivity (80%–90%) and specificity (95%–100%). 131I-MIBG can be used in the same way, but the image quality is not as high as with 123I-MIBG. Other functional imaging alternatives include gallium Ga 68 (68Ga)-DOTATATE and fluorine F 18-fludeoxyglucose positron emission tomography (PET), both of which can be coupled with CT imaging for improved anatomic detail.[35,36]
It is rare for localization of a catecholamine-secreting tumor to be unsuccessful if currently available imaging methods are used.
Prognosis and Survival
There are no clear data regarding the survival of patients with localized (apparently benign) disease or regional disease. Although patients with localized (apparently benign) disease should experience an overall survival approaching that of age-matched disease-free individuals, 6.5% to 16.5% of these patients will develop a recurrence, usually 5 to 15 years after initial surgery.[37,38,39]
Approximately 15% to 25% of patients with recurrent disease experience distant metastasis. The 5-year overall survival rates in those with metastatic disease range from 50% to 70%.[40,41,42,43] Carriers of SDHB pathogenic variants have an increased risk of developing metastatic disease of approximately 25% to 50%. The most commonly associated gene with metastatic pheochromocytoma and paraganglioma is SDHB (over 40% of cases).[45,46]
Long-term follow-up is essential for all patients with pheochromocytoma or extra-adrenal paraganglioma, even when initial pathology demonstrates no findings that are concerning for malignancy.
Other PDQ summaries containing information related to pheochromocytoma and paraganglioma include the following:
Pheochromocytoma and paraganglioma characteristically form small nests of uniform polygonal chromaffin cells ("zellballen"). A diagnosis of malignancy can only be made by identifying tumor deposits in tissues that do not normally contain chromaffin cells (e.g., lymph nodes, liver, bone, lung, and other distant metastatic sites).
Regional or distant metastatic disease is documented on initial pathology in only 3% to 8% of patients; thus, an attempt has been made to identify tumor characteristics associated with future malignant behavior. Pathologic features associated with malignancy include the following:
In the absence of clearly documented metastases, no combination of clinical, histopathologic, or biochemical features has been shown to reliably predict the biologic behavior of pheochromocytoma. If no definite malignancy is identified, pathology generally provides insufficient prognostic information regarding the likelihood of recurrence or metastasis. These tumors cannot be considered benign by default; patients require continued lifelong surveillance.[1,2,3,4,5,6,7]
AJCC Stage Groupings and TNM Definitions
The American Joint Committee on Cancer (AJCC) has designated staging by TNM (tumor, node, metastasis) classification to define pheochromocytoma and paraganglioma. Although the AJCC staging system does not account for the unique characteristics of these tumors, it could increase the understanding of prognostic indicators for survival.
Only limited data are available from phase II clinical trials to guide the management of patients diagnosed with pheochromocytoma or paraganglioma. There are no phase III trials. Everything is based on case series, and the impact of survival is not known.
Localized and Regional Pheochromocytoma
Definitive treatment for localized and regional pheochromocytoma, including localized disease recurrence, consists of alpha- and beta-adrenergic blockade followed by surgery.
For patients with unresectable or metastatic pheochromocytoma, treatment may include a combination of the following:
Treatment for patients with localized, regional, metastatic, or recurrent pheochromocytoma is summarized in Table 2.
Preoperative Medical Preparation
Surgery is the mainstay of treatment for most patients; however, preoperative medical preparation is critical. Alpha-adrenergic blockade should be initiated at the time of diagnosis and maximized preoperatively to prevent potentially life-threatening cardiovascular complications, which can occur as a result of excess catecholamine secretion during surgery. Complications may include the following:
Phenoxybenzamine (a nonselective alpha-antagonist) is the usual drug of choice; prazosin, terazosin, and doxazosin (selective alpha-1-antagonists) are alternative choices.[1,2] Prazosin, terazosin, and doxazosin are shorter acting than phenoxybenzamine, and therefore, the duration of postoperative hypotension is theoretically less than with phenoxybenzamine; however, there is less overall experience with selective alpha-1-antagonists than with phenoxybenzamine.
A preoperative treatment period of 1 to 3 weeks is usually sufficient; resolution of spells and a target low normal blood pressure for age indicate that alpha-adrenergic blockade is adequate. During alpha-adrenergic blockade, liberal salt and fluid intake should be encouraged because volume loading reduces excessive orthostatic hypotension both preoperatively and postoperatively. If tachycardia develops or if blood pressure control is not optimal with alpha-adrenergic blockade, a beta-adrenergic blocker (e.g., metoprolol or propranolol) can be added, but only after alpha-blockade. Beta-adrenergic blockade must never be initiated before alpha-adrenergic blockade; doing so blocks beta-adrenergic receptor-mediated vasodilation and results in unopposed alpha-adrenergic receptor-mediated vasoconstriction, which can lead to a life-threatening crisis.
Standard Treatment Options for Localized Pheochromocytoma
Standard treatment options for localized pheochromocytoma include the following:
Surgical resection (i.e., adrenalectomy) is the definitive treatment for patients with localized pheochromocytoma. A minimally invasive adrenalectomy is generally the preferred approach if the following conditions can be met:
Both anterior transabdominal laparoscopic adrenalectomy and posterior retroperitoneoscopic adrenalectomy have been demonstrated to be safe for most patients with a modestly sized, radiographically benign pheochromocytoma.[1,2] If preoperative imaging suggests malignancy, or if the patient has an extra-adrenal paraganglioma or multifocal disease, an open approach is generally preferred.
Intraoperative hypertension can be controlled with intravenous infusion of phentolamine, sodium nitroprusside, or a short-acting calcium-channel blocker (e.g., nicardipine). Tumor removal may be followed by a sudden drop in blood pressure that may require rapid volume replacement and intravenous vasoconstrictors (e.g., norepinephrine or phenylephrine). Postoperatively, patients should remain in a monitored environment for 24 hours. Postoperative hypotension is managed primarily by volume expansion, and postoperative hypertension usually responds to diuretics.
Standard Treatment Options for Inherited Pheochromocytoma
Standard treatment options for inherited pheochromocytoma include the following:
The surgical management of pheochromocytoma in patients with the hereditary syndromes multiple endocrine neoplasia type 2 (MEN2) or von Hippel-Lindau (VHL) disease has been controversial. In both of these syndromes, pheochromocytoma is bilateral in at least 50% of patients; however, malignancy is very uncommon. Bilateral total adrenalectomy commits all patients to lifelong steroid dependence, and up to 25% of patients will experience Addisonian crisis (acute adrenal insufficiency).[3,4]
Current recommendations generally favor preservation of adrenal cortical tissue in patients with MEN2 or VHL when possible. Patients who initially present with unilateral pheochromocytoma should undergo unilateral adrenalectomy, and patients who present with bilateral pheochromocytomas or who develop pheochromocytoma in their remaining adrenal gland should undergo cortical-sparing adrenalectomy, when technically feasible.
A similar approach may be reasonable in other hereditary pheochromocytoma-paraganglioma syndromes that are characterized by benign disease, but there are currently insufficient data upon which to base unequivocal recommendations. (Refer to the PDQ summary on the Genetics of Endocrine and Neuroendocrine Neoplasias for more information on the treatment of inherited pheochromocytoma.)
Current Clinical Trials
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
Standard Treatment Options for Regional Pheochromocytoma
Standard treatment options for regional pheochromocytoma include the following:
Surgical resection is the definitive treatment for pheochromocytoma or extra-adrenal paraganglioma that is regionally advanced (e.g., from direct tumor extension into adjacent organs or because of regional lymph node involvement). Data to guide management are limited because regional disease is diagnosed in very few patients who present with pheochromocytoma. However, aggressive surgical resection to remove all existing disease can render patients symptom free. Surgical management of these patients may require en bloc resection of all or part of adjacent organs (e.g., kidney, liver, inferior vena cava) along with extended lymph node dissection. Patients who have undergone complete resection of regional pheochromocytoma require lifelong monitoring for disease recurrence.
Standard Treatment Options for Metastatic Pheochromocytoma
Standard treatment options for metastatic pheochromocytoma include the following:
The most common sites of metastasis for pheochromocytoma or extra-adrenal paraganglioma are lymph nodes, bones, lungs, and liver. Patients with known or suspected malignancy should undergo staging with computed tomography or magnetic resonance imaging as well as functional imaging (e.g., with iodine I 123-metaiodobenzylguanidine [MIBG]) to determine the extent and location of disease. Patients are often very symptomatic from excess catecholamine secretion. Phenoxybenzamine is effective, and metyrosine, which is a drug that blocks catecholamine synthesis, can be added if needed.
If all identifiable disease is resectable, including a limited number of distant metastases, surgery can provide occasional long-term remission. If disease is unresectable, surgical debulking will not improve survival; however, it is occasionally indicated for symptom palliation.
Chemotherapy has not been shown to improve survival in patients with metastatic pheochromocytoma; however, chemotherapy can be attempted for the palliation of symptoms.
The best-established chemotherapy regimen is a combination of cyclophosphamide, vincristine, and dacarbazine (the Averbuch protocol).
Several other chemotherapy regimens have been used in small numbers of patients, but the overall results were disappointing.[4,5]
Novel targeted therapies are emerging as potential treatment strategies for metastatic pheochromocytoma. Disappointing initial results were reported with the mammalian target of rapamycin (mTOR) inhibitor everolimus, but results from a very small number of patients treated with the tyrosine kinase inhibitors sunitinib, axitinib, and cabozantinib have been more promising.[7,8][Level of evidence: 3iiiDiv]
Iodine I 131 (131I)-MIBG radiation therapy has been used for the treatment of patients with MIBG-avid metastases.[9,10] Approximately 60% of metastatic pheochromocytoma or paraganglioma sites are MIBG-avid; protocol-based treatment with other experimental radiolabeled agents, such as radiolabeled somatostatin, can be considered for metastases that do not take up MIBG.
Evidence (radiation therapy):
Iobenguane I 131 (Azedra) is a high-specific-activity 131I-MIBG agent made of labeled MIBG molecules that allows lower mass doses of MIBG to be administered for adult and pediatric patients (age >12 years) with advanced unresectable disease. It has been shown to be safe and generally well tolerated and was approved by the U.S. Food and Drug Administration via fast track designation in July 2018.
Other palliative treatment modalities include external-beam radiation therapy (e.g., for palliation of bone metastases) and embolization, radiofrequency ablation, or cryoablation (e.g., for palliation of bulky hepatic metastases or isolated bony metastases).
Pheochromocytoma and paraganglioma often express the somatostatin receptor proteins SSTR2 and SSTR3 which may allow for targeted treatment with somatostatin receptor agonists.[13,14] A meta-analysis of studies involving advanced or metastatic pheochromocytoma and paraganglioma patients treated with peptide receptor radionuclide therapy showed that 89.8% of pooled patients had achieved disease stabilization or a partial response.[Level of evidence: 3iiiDiv]
Standard Treatment Options for Recurrent Pheochromocytoma
Standard treatment options for recurrent pheochromocytoma include the following:
After resection of a localized pheochromocytoma presumed to represent a benign tumor and documented normal postoperative biochemical testing, disease recurrence occurs in 6.5% to 16.5% of patients, and 50% of patients with disease recurrence develop metastatic disease.[1,2,3] Insufficient data exist to determine recurrence rates after complete surgical resection of regional or metastatic disease.
Treatment for recurrent disease involves appropriate medical management (i.e., alpha-adrenergic blockade) followed by complete surgical resection, when possible.
Palliation of symptoms, including those related to catecholamine excess and local mass effect, is the primary focus of treatment for disease that is not resectable.
The following are options for patients with local-regional or metastatic disease who are not considered candidates for surgical resection:
(Refer to the Metastatic Pheochromocytoma Treatment section of this summary for more information.)
Treatment Options for Inherited Pheochromocytoma or Paraganglioma
Patients with inherited pheochromocytoma or paraganglioma are at risk of recurrent disease in the form of additional primary tumors. Follow-up evaluation and management of additional primary tumors in such patients is essential. (Refer to the Localized Pheochromocytoma Treatment section of this summary for more information.)
Pheochromocytoma diagnosed during pregnancy is extremely rare (0.007% of all pregnancies).[1,2] However, women with hereditary conditions that increase the risk of developing pheochromocytoma are often also of childbearing age, and the outcome of undiagnosed pheochromocytoma during pregnancy can be catastrophic.
Prenatal diagnosis clearly results in decreased mortality for both mother and fetus. Prior to 1970, a prenatal diagnosis of pheochromocytoma was made in only approximately 25% of cases, and the mortality rate for both mother and fetus was around 50%.[4,5] The prenatal diagnosis rate rose to greater than 80% through the 1980s and 1990s, and decreased maternal and fetal mortality rates were 6% and 15%, respectively.[4,6]
The diagnosis of pheochromocytoma should be suspected in any pregnant woman who develops hypertension in the first trimester, paroxysmal hypertension, or hypertension that is unusually difficult to treat.[2,7] Normal pregnancy does not affect catecholamine levels. Thus, the usual biochemical tests are valid. Magnetic resonance imaging is the localization method of choice because it does not expose the fetus to ionizing radiation.
Phenoxybenzamine use is safe in pregnancy, but beta-adrenergic blockers should be initiated only if needed because their use has been associated with intrauterine growth restriction.[9,10] Resection of the tumor can often be performed safely during the second trimester, or tumor resection can be combined with cesarean delivery for patients diagnosed later in pregnancy. Case reports have documented successful outcomes in the rare circumstance when surgical resection was delayed until a short time after vaginal delivery. The successful management of pheochromocytoma in pregnancy depends on careful monitoring and the availability of an experienced team of specialists.
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
This summary was comprehensively reviewed and extensively revised.
This summary is written and maintained by the PDQ Adult Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.
Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of pheochromocytoma and paraganglioma. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.
Reviewers and Updates
This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewers for Pheochromocytoma and Paraganglioma Treatment are:
Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.
Levels of Evidence
Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.
Permission to Use This Summary
PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as "NCI's PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary]."
The preferred citation for this PDQ summary is:
PDQ® Adult Treatment Editorial Board. PDQ Pheochromocytoma and Paraganglioma Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/pheochromocytoma/hp/pheochromocytoma-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389312]
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Last Revised: 2021-09-30
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