Incidence

Parathyroid adenomas represent a common endocrine problem, whereas parathyroid carcinomas are very rare tumors. With an estimated incidence of 0.015 per 100,000 population and an estimated prevalence of 0.005% in the United States, parathyroid cancer is one of the rarest of all human cancers.[1,2] In Europe, the United States, and Japan, parathyroid carcinoma has been estimated to cause hyperparathyroidism (HPT) in 0.017% to 5.2% of cases; however, many series report this entity to account for less than 1% of patients with primary HPT.[1,3–5] The median age in most series is between 45 and 51 years.[1] The ratio of affected women to men is 1:1 in contrast to primary HPT in which there is a significant female predominance (ratio of 3–4:1).[5]

Anatomy and Histopathology

Operatively, parathyroid cancers may be distinguished from adenomas by their firm, stony-hard consistency and lobulation; adenomas tend to be soft, round, or oval in shape, and of a reddish-brown color.[5] In most series, the median maximal diameter of parathyroid carcinoma is between 3.0 cm and 3.5 cm compared with approximately 1.5 cm for benign adenomas.[1] In approximately 50% of patients, the malignant tumor is surrounded by a dense, fibrous, grayish-white capsule that infiltrates adjacent tissues.[5]

Histopathologically, as with other endocrine neoplasms, it is difficult to make the distinction between benign and malignant parathyroid tumors.[1,5,6] The extent to which capsular and vascular invasion appears to be unequivocally correlated with tumor recurrences and metastases makes a strong case for these findings to be considered the sole pathognomonic markers of malignancy.[6,7]

Risk Factors

The etiology of parathyroid carcinoma is unknown. However, an increased risk of parathyroid cancer has been associated with multiple endocrine neoplasia type 1 and with autosomal dominant familial isolated hyperparathyroidism.[8–10] Parathyroid cancer has also been associated with external radiation exposure; however, most reports describe an association between radiation and the more common parathyroid adenoma.[1,5]

Clinical Factors

Parathyroid cancer typically runs an indolent, albeit tenacious, course because the tumor has a rather low malignant potential. At initial presentation, few patients with parathyroid carcinoma have metastases either to regional lymph nodes (<5%) or distant sites (<2%).[1] In a National Cancer Database series of 286 patients, only 16 (5.6%) had lymph node metastases noted at the time of initial surgery.[2] A higher proportion of parathyroid cancers locally invade the thyroid gland, overlying strap muscles, recurrent laryngeal nerve, trachea, or esophagus. Some patients are not identified preoperatively or intraoperatively as having parathyroid carcinoma and undergo parathyroid procedures devised to treat parathyroid adenoma. Only after review of the postsurgical pathology, or when these patients experience local or distant recurrence, is a correct diagnosis of parathyroid carcinoma made.[1] Parathyroid carcinoma tends to be localized in the inferior parathyroid glands. One series reported that a primary tumor originating in the inferior parathyroid glands was found in 15 of 19 cases involving local invasion.[11,12]

Parathyroid cancers are hyperfunctional unlike other endocrine tumors that become less hormonally active when malignant.[1] The clinical features of parathyroid carcinoma are caused primarily by the effects of excessive secretion of parathormone (PTH) by the tumor rather than by the infiltration of vital organs by tumor cells. Serum PTH levels may be three to ten times above the upper limit of normal for the assay employed. This marked elevation is uncommon in primary HPT where serum PTH concentrations are typically less than twice that of normal.[5] Accordingly, signs and symptoms of hypercalcemia typically dominate the clinical picture and may include typical hyperparathyroid bone disease and features of renal involvement, such as nephrolithiasis or nephrocalcinosis.[1] Renal colic is a frequent presenting complaint of patients with parathyroid carcinoma.[5] In a study involving 43 cases, the prevalence of nephrolithiasis was reported to be 56%, and the prevalence of renal insufficiency was reported to be 84%.[13]

The prevalence of bone disease is much greater in patients with parathyroid carcinoma than it is in patients with parathyroid adenoma, with 70% or fewer patients manifesting symptoms related to calcium absorption with osteoporosis and bone pain.[14,15] In benign parathyroid disease, it is unusual to have both renal and bone symptomatology documented at the time of diagnosis.[16] These symptoms are present simultaneously at diagnosis in 50% or fewer patients with parathyroid cancer.[1] In contrast, simultaneous renal and overt skeletal involvement is distinctly unusual in primary HPT.[5] For more information about bone pain, see Cancer Pain.

Diagnosis

The following signs and symptoms of the hyperparathyroid state associated with parathyroid cancer may be found at diagnosis:[1,5]

For more information about some of these symptoms, see Cancer Pain, Nutrition in Cancer Care (for weight loss information), and Nausea and Vomiting Related to Cancer Treatment.

Certain clinical features may help distinguish parathyroid carcinoma from parathyroid adenoma.

Parathyroid carcinoma should be suspected clinically if the patient presents with the following diagnostic features:[1,5,17,18]

Clinical Treatment and Management

The medical management of hypercalcemia, particularly in patients with unresectable disease or without measurable disease, is critical and must be the initial treatment goal in all patients with HPT. Conventional treatment with intravenous fluids, diuretics, and antiresorptive agents such as bisphosphonates, gallium, or mithramycin may help control the hypercalcemia.[12] Calcimimetic agents that directly block secretion of the parathyroid hormone from the glands may offer an important approach to medical therapy of primary HPT associated with parathyroid cancer.[19,20]

Surgery is the only effective therapy for parathyroid carcinoma.[1,5,6] Preoperative suspicion and intraoperative recognition of parathyroid carcinoma is critical to achieve a favorable outcome, which involves en bloc resection of the tumor with all potential areas of invasion at the initial operation.[12,21,22]

One analysis of the literature indicated a local recurrence rate of 8% after an en bloc resection and 51% after a standard parathyroidectomy.[23] En bloc excision during the initial procedure for parathyroid cancer may involve resection of the recurrent laryngeal nerve because the nerve is at risk for invasion by any residual tumor and subsequent loss of function. The increased potential for long-term local control achieved by en bloc excision outweighs the complication of postoperative vocal cord paralysis, which can be improved with techniques such as Teflon injection into the paralyzed cord. Cervical lymph node dissection should be performed only for enlarged or firm nodes, particularly those found in the level VI paratracheal nodes and levels III and IV internal jugular nodes.[1]

Because of the fairly indolent biology of this cancer, the management of recurrent or metastatic disease is primarily surgical. Significant palliation may result from the resection of even very small tumor deposits in the neck, lymph nodes, lungs, or liver.[2,13,16,24,25] Accessible distant metastases should be resected when possible.[5] Localization studies performed before the first operation or reoperation may include technetium Tc 99m-sestamibi (MIBI) scan, single photon emission computed tomography, computed tomography (CT)-MIBI image fusion, ultrasound, CT, selective angiogram, and selective venous sampling for PTH.[3] CT and magnetic resonance imaging are useful imaging adjuncts for the localization of distant metastases.[5,26]

Nonsurgical forms of therapy for parathyroid carcinoma generally have poor results.[1,5,6,11] Some investigators have advocated the use of adjuvant radiation therapy to decrease the local recurrence rate.[27,28] Patients with this disease should be monitored for life because they may be at a relatively high risk of multiple relapses over prolonged periods of time.[11] Patients rarely die of the tumor itself; rather, they die of the metabolic complications of uncontrolled HPT.

Follow-Up and Survivorship

Approximately 40% to 60% of patients experience a postsurgical recurrence, typically within 2 to 5 years after the initial resection.[17,21] In most cases, hypercalcemia precedes physical evidence of recurrent disease. The location of recurrence is typically regional, either in the tissues of the neck or in cervical lymph nodes, and accounts for approximately two-thirds of recurrent cases.[18] Often, local recurrences in the neck are difficult to identify because they may be small and multifocal, and they may involve scar tissue from a previous surgical procedure. Use of ultrasonography, sestamibi-thallium scanning, and positron emission tomography may help to identify difficult-to-detect recurrent disease.[29–31]

In older studies, distant metastases were reported in 25% of patients, primarily in the lungs but also in the bone and liver.[18,32] Other series indicate that the incidence of recurrence may be higher, possibly because of more accurate pathological diagnoses that exclude patients with atypical adenomas.[1] Because of its low malignant potential, the morbidity and mortality associated with parathyroid cancer primarily result from the metabolic consequences of the disease and not directly from malignant growth.[11,32] In a National Cancer Database series of 286 patients, the 10-year survival rate was approximately 49%.[2] A smaller series reported a 10-year survival rate of 77%, which might be related to improvements in supportive medical care and in the prevention of fatal hypercalcemia.[11]

Localized Parathyroid Cancer

Localized parathyroid cancer is disease that involves the parathyroid gland with or without invasion of adjacent tissues.

Metastatic Parathyroid Cancer

Metastatic parathyroid cancer is disease that spreads beyond the tissues adjacent to the involved parathyroid gland(s). Parathyroid carcinoma most frequently metastasizes to regional lymph nodes and lungs, and it may involve other distant sites, such as liver, bone, pleura, pericardium, and pancreas.[4]

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.

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.

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.

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of parathyroid cancer. 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 reviewer for Parathyroid Cancer Treatment is:

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 Parathyroid Cancer Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/parathyroid/hp/parathyroid-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389236]

Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.

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Based on the strength of the available evidence, treatment options may be described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.

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Pheochromocytoma and paraganglioma are rare tumors that come from the same type of tissue.

Paragangliomas form in nerve tissue in the adrenal glands and near certain blood vessels and nerves. Paragangliomas that form in the adrenal glands are called pheochromocytomas. Paragangliomas that form outside the adrenal glands are called extra-adrenal paragangliomas. In this summary, extra-adrenal paragangliomas are called paragangliomas.

Pheochromocytomas and paragangliomas may be benign (not cancer) or cancer.

Pheochromocytoma is a rare tumor that forms in the adrenal medulla (the center of the adrenal gland).

Pheochromocytoma forms in the adrenal glands. There are two adrenal glands, one on top of each kidney in the back of the upper abdomen. Each adrenal gland has two parts. The outer layer of the adrenal gland is the adrenal cortex. The center of the adrenal gland is the adrenal medulla.

Pheochromocytoma is a rare tumor of the adrenal medulla. Usually, pheochromocytoma affects one adrenal gland, but it may affect both adrenal glands. Sometimes there is more than one tumor in one adrenal gland.

The adrenal glands make important hormones called catecholamines. Adrenaline (epinephrine) and noradrenaline (norepinephrine) are two types of catecholamines that help control heart rate, blood pressure, blood sugar, and the way the body reacts to stress. Sometimes a pheochromocytoma will release extra adrenaline and noradrenaline into the blood and cause signs or symptoms of disease.

Enlarge

Paragangliomas form outside the adrenal gland.

Paragangliomas are rare tumors that form near the carotid artery, along nerve pathways in the head and neck, and in other parts of the body. Some paragangliomas make extra catecholamines called adrenaline and noradrenaline. The release of these extra catecholamines into the blood may cause signs or symptoms of disease.

Enlarge

Some inherited disorders and changes in certain genes increase the risk of pheochromocytoma or paraganglioma.

Anything that increases your chance of getting a disease is called a risk factor. Having a risk factor doesn’t mean that you will get cancer; not having risk factors doesn’t mean that you will not get cancer. Talk to your doctor if you think you may be at risk.

The following inherited syndromes or gene changes increase the risk of pheochromocytoma or paraganglioma:

Signs and symptoms of pheochromocytoma and paraganglioma include high blood pressure and headache.

Some tumors do not make extra adrenaline or noradrenaline and do not cause signs and symptoms. These tumors are sometimes found when a lump forms in the neck or when a test or procedure is done for another reason. Signs and symptoms of pheochromocytoma and paraganglioma occur when too much adrenaline or noradrenaline is released into the blood. These and other signs and symptoms may be caused by pheochromocytoma and paraganglioma or by other conditions. Check with your doctor if you have:

The most common sign is high blood pressure that may be hard to control. Very high blood pressure can cause serious health problems such as irregular heartbeat, heart attack, stroke, or death.

Signs and symptoms of pheochromocytoma and paraganglioma may occur at any time or be brought on by certain events.

Signs and symptoms of pheochromocytoma and paraganglioma may occur when one of the following events happens:

Tests that examine the blood and urine are used to diagnose pheochromocytoma and paraganglioma.

In addition to asking about your personal and family health history and doing a physical exam to check for signs of disease, such as high blood pressure, your doctor may perform the following tests and procedures:

Genetic counseling is part of the treatment plan for patients with pheochromocytoma or paraganglioma.

All patients who are diagnosed with pheochromocytoma or paraganglioma should have genetic counseling to find out their risk for having an inherited syndrome and other related cancers.

Genetic testing is often recommended by a genetic counselor for patients who:

Genetic testing is sometimes recommended for patients with pheochromocytoma who:

When certain gene changes are found during genetic testing, the testing is usually offered to family members who are at risk but do not have signs or symptoms.

Genetic testing is not recommended for patients older than 50 years.

Certain factors affect prognosis (chance of recovery) and treatment options.

The prognosis and treatment options depend on:

After pheochromocytoma and paraganglioma have been diagnosed, tests are done to find out if the tumor has spread to other parts of the body.

The process to find out if cancer has spread to other parts of the body is usually called staging. It is important to know whether the cancer has spread in order to plan treatment. The following tests and procedures may be used to determine if the tumor has spread to other parts of the body:

There are three ways that cancer spreads in the body.

Cancer can spread through tissue, the lymph system, and the blood:

Cancer may spread from where it began to other parts of the body.

When cancer spreads to another part of the body, it is called metastasis. Cancer cells break away from where they began (the primary tumor) and travel through the lymph system or blood.

The metastatic tumor is the same type of cancer as the primary tumor. For example, if pheochromocytoma spreads to the bone, the cancer cells in the bone are actually pheochromocytoma cells. The disease is metastatic pheochromocytoma, not bone cancer.

Pheochromocytoma and paraganglioma are described as localized, regional, or metastatic.

There are different types of treatment for patients with pheochromocytoma or paraganglioma.

Different types of treatments are available for patients with pheochromocytoma or paraganglioma. Some treatments are standard (the currently used treatment), and some are being tested in clinical trials. A treatment clinical trial is a research study meant to help improve current treatments or obtain information on new treatments for patients with cancer. When clinical trials show that a new treatment is better than the standard treatment, the new treatment may become the standard treatment. Patients may want to think about taking part in a clinical trial. Some clinical trials are open only to patients who have not started treatment

Patients receive medication to treat the signs and symptoms of pheochromocytoma and paraganglioma.

Drug therapy begins when pheochromocytoma or paraganglioma is diagnosed. This may include:

Drug therapy is often given for one to three weeks before surgery.

The following types of treatment are used:

New types of treatment are being tested in clinical trials.

For some people, joining a clinical trial may be an option. There are different types of clinical trials for people with cancer. For example, a treatment trial tests new treatments or new ways of using current treatments. Supportive care and palliative care trials look at ways to improve quality of life, especially for those who have side effects from cancer and its treatment.

You can use the clinical trial search to find NCI-supported cancer clinical trials accepting participants. The search allows you to filter trials based on the type of cancer, your age, and where the trials are being done. Clinical trials supported by other organizations can be found on the ClinicalTrials.gov website.

Learn more about clinical trials, including how to find and join one, at Clinical Trials Information for Patients and Caregivers.

Treatment for pheochromocytoma and paraganglioma may cause side effects.

For information about side effects caused by treatment for cancer, visit our Side Effects page.

Follow-up care will be needed.

Some of the tests that were done to diagnose the cancer or to find out the extent of the cancer may be repeated. Some tests will be repeated to see how well the treatment is working. Decisions about whether to continue, change, or stop treatment will be based on the results of these tests.

Some of the tests will continue to be done after treatment has ended. The results of these tests can show if your condition has changed or if the cancer has recurred (come back). These tests are sometimes called follow-up tests.

For patients with pheochromocytoma or paraganglioma that causes symptoms, catecholamine levels in the blood and urine will be checked on a regular basis. Catecholamine levels that are higher than normal can be a sign that the cancer has come back.

For patients with paraganglioma that does not cause symptoms, follow-up tests, such as CT, MRI, or MIBG scan should be done every year.

For patients with inherited pheochromocytoma or paraganglioma, catecholamine levels in the blood and urine will be checked on a regular basis. Other screening tests will be done to check for other tumors that are linked to the inherited syndrome.

Talk to your doctor about which tests should be done and how often. Patients with pheochromocytoma or paraganglioma need lifelong follow-up.

Localized Pheochromocytoma and Paraganglioma

Treatment of localized benign pheochromocytoma or paraganglioma is usually surgery to completely remove the tumor. If the tumor is in the adrenal gland, the entire adrenal gland is removed.

Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.

Inherited Pheochromocytoma

In patients with inherited pheochromocytoma linked to multiple endocrine neoplasia (MEN2) or von Hippel-Lindau (VHL) syndrome, tumors often form in both adrenal glands. The tumors are usually benign.

These surgeries may help patients avoid life-long hormone replacement therapy, acute adrenal insufficiency, and health problems due to the loss of hormones made by the adrenal gland.

Regional Pheochromocytoma and Paraganglioma

Treatment of pheochromocytoma or paraganglioma that has spread to nearby organs or lymph nodes is surgery to completely remove the tumor. Nearby organs that the cancer has spread to, such as the kidney, liver, part of a major blood vessel, and lymph nodes, may also be removed.

Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.

Metastatic Pheochromocytoma and Paraganglioma

Treatment of metastatic pheochromocytoma or paraganglioma may include:

Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.

Recurrent Pheochromocytoma and Paraganglioma

Treatment of recurrent pheochromocytoma or paraganglioma may include:

Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.

Pregnant women with pheochromocytoma need special care.

Although it is rarely diagnosed during pregnancy, pheochromocytoma can be very serious for the mother and fetus. Women who have an increased risk of pheochromocytoma should have prenatal testing. Pregnant women with pheochromocytoma should be treated by a team of doctors who are experts in this type of care.

Signs of pheochromocytoma in pregnancy may include:

The diagnosis of pheochromocytoma in pregnant women includes testing for catecholamine levels in blood and urine. See the General Information section for a description of these tests and procedures. An MRI can be done to safely find tumors in pregnant women because it does not expose the fetus to radiation.

Treatment of pregnant women with pheochromocytoma may include surgery.

Treatment of pheochromocytoma during pregnancy may include:

About PDQ

Physician Data Query (PDQ) is the National Cancer Institute’s (NCI’s) comprehensive cancer information database. The PDQ database contains summaries of the latest published information on cancer prevention, detection, genetics, treatment, supportive care, and complementary and alternative medicine. Most summaries come in two versions. The health professional versions have detailed information written in technical language. The patient versions are written in easy-to-understand, nontechnical language. Both versions have cancer information that is accurate and up to date and most versions are also available in Spanish.

PDQ is a service of the NCI. The NCI is part of the National Institutes of Health (NIH). NIH is the federal government’s center of biomedical research. The PDQ summaries are based on an independent review of the medical literature. They are not policy statements of the NCI or the NIH.

Purpose of This Summary

This PDQ cancer information summary has current information about the treatment of pheochromocytoma and paraganglioma. It is meant to inform and help patients, families, and caregivers. It does not give formal guidelines or recommendations for making decisions about health care.

Reviewers and Updates

Editorial Boards write the PDQ cancer information summaries and keep them up to date. These Boards are made up of experts in cancer treatment and other specialties related to cancer. The summaries are reviewed regularly and changes are made when there is new information. The date on each summary (“Updated”) is the date of the most recent change.

The information in this patient summary was taken from the health professional version, which is reviewed regularly and updated as needed, by the PDQ Adult Treatment Editorial Board.

Clinical Trial Information

A clinical trial is a study to answer a scientific question, such as whether one treatment is better than another. Trials are based on past studies and what has been learned in the laboratory. Each trial answers certain scientific questions in order to find new and better ways to help cancer patients. During treatment clinical trials, information is collected about the effects of a new treatment and how well it works. If a clinical trial shows that a new treatment is better than one currently being used, the new treatment may become “standard.” Patients may want to think about taking part in a clinical trial. Some clinical trials are open only to patients who have not started treatment.

Clinical trials can be found online at NCI’s website. For more information, call the Cancer Information Service (CIS), NCI’s contact center, at 1-800-4-CANCER (1-800-422-6237).

Permission to Use This Summary

PDQ is a registered trademark. The content of PDQ documents can be used freely as text. It cannot be identified as an NCI PDQ cancer information summary unless the whole summary is shown and it is updated regularly. However, a user would be allowed to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks in the following way: [include excerpt from the summary].”

The best way to cite 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: /types/pheochromocytoma/patient/pheochromocytoma-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389499]

Images in this summary are used with permission of the author(s), artist, and/or publisher for use in the PDQ summaries only. If you want to use an image from a PDQ summary and you are not using the whole summary, you must get permission from the owner. It cannot be given by the National Cancer Institute. Information about using the images in this summary, along with many other images related to cancer can be found in Visuals Online. Visuals Online is a collection of more than 3,000 scientific images.

Disclaimer

The information in these summaries should not be used to make decisions about insurance reimbursement. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.

Contact Us

More information about contacting us or receiving help with the Cancer.gov website can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the website’s E-mail Us.

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,[3–5] and it is present in approximately 5% of patients with incidentally discovered adrenal masses.[6] 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.[7] The incidence is equal between men and women.[8]

Anatomy

Pheochromocytomas and extra-adrenal paragangliomas arise from neural crest tissue. Neural crest tissue develops into sympathetic and parasympathetic paraganglia.

Sympathetic paraganglia include:

Parasympathetic paraganglia include:

Risk Factors

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 patients with a hereditary cancer syndrome.[7–9] Major genetic syndromes that confer an increased risk of pheochromocytoma are included in Table 1.

Pheochromocytomas and extra-adrenal paragangliomas can also occur in two other very rare syndromes:

Clinical Features

Patients with pheochromocytomas and sympathetic extra-adrenal paragangliomas may present with symptoms of excess catecholamine production, including:

These symptoms are often paroxysmal, although sustained hypertension between paroxysmal episodes occurs in 50% to 60% of patients with pheochromocytoma.[25] 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:

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.[17,26–28]

Diagnostics

The diagnosis of pheochromocytoma is usually preceded 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.

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.[37–39]

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%.[40–43] Carriers of SDHB pathogenic variants have an increased risk of developing metastatic disease of approximately 25% to 50%.[44] The most commonly associated gene with metastatic pheochromocytoma and paraganglioma is SDHB (over 40% of cases).[45,46]

Follow-Up Evaluation

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.[5]

Pathological Classification

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. Pathological features associated with malignancy include:

In the absence of clearly documented metastases, no combination of clinical, histopathological, or biochemical features has been shown to reliably predict the biological 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.[1–7]

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.[1] 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.

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.

Metastatic Pheochromocytoma

For patients with unresectable or metastatic pheochromocytoma, treatment may include a combination of:

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:

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.

Treatment Options for Localized Pheochromocytoma

Treatment options for localized pheochromocytoma include:

Treatment Options for Inherited Pheochromocytoma

Treatment options for inherited pheochromocytoma include:

Current Clinical Trials

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Treatment Options for Regional Pheochromocytoma

Treatment options for regional pheochromocytoma include:

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.[1] However, aggressive surgical resection to remove all existing disease can render patients symptom free.[2] 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.

Current Clinical Trials

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Treatment Options for Metastatic Pheochromocytoma

Treatment options for metastatic pheochromocytoma include:

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.

Current Clinical Trials

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Treatment Options for Recurrent Pheochromocytoma

Treatment options for recurrent pheochromocytoma include:

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.[1–3] Insufficient data exist to determine recurrence rates after complete surgical resection of regional or metastatic disease.

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. For more information, see the Treatment of Localized Pheochromocytoma section.

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.

Diagnosis

Prenatal diagnosis clearly results in decreased mortality for both mother and fetus.[3] 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.[8] 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.

Treatment Options for Pheochromocytoma During Pregnancy

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.[2] Case reports have documented successful outcomes in the rare circumstance when surgical resection was delayed until a short time after vaginal delivery.[11] The successful management of pheochromocytoma in pregnancy depends on careful monitoring and the availability of an experienced team of specialists.

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.

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 reviewer for Pheochromocytoma and Paraganglioma Treatment is:

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: /types/pheochromocytoma/hp/pheochromocytoma-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389312]

Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.

Disclaimer

Based on the strength of the available evidence, treatment options may be described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.

Contact Us

More information about contacting us or receiving help with the Cancer.gov website can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the website’s Email Us.

Intervention

Screening, usually at age 6 months, for urine vanillylmandelic acid and homovanillic acid, which are metabolites of the hormones, norepinephrine and dopamine.

Benefits

Based on solid evidence, screening for neuroblastoma does not lead to decreased mortality.

Harms

Based on solid evidence, screening infants for neuroblastoma leads to an increase in incidence of early-stage neuroblastoma. There is no concurrent decrease in incidence in children who are screened for advanced-stage disease, which typically has a poor outcome, or in children older than 1 year. The cases identified by screening almost exclusively have biologically favorable properties.

Based on solid evidence, screening infants for neuroblastoma results in overdiagnosis (diagnosis of some neuroblastomas detectable by mass screening that would not have been clinically diagnosed later). This leads to unnecessary diagnostic and therapeutic procedures with consequent physical and psychological morbidity, including death from treatment complications.

Incidence and Mortality

About 7% of all malignancies in children younger than 15 years are neuroblastomas. About one-quarter of cancers in the first year of life are neuroblastomas, making this the most frequent histological type of infant cancer.[1,2] The incidence rate of the disease in children younger than 1 year is about 35 per million but declines rapidly with age to about 1 per million between ages 10 and 14 years.[3] Males appear to be affected slightly more commonly than females, with about five cases occurring in boys to every four occurring in girls.

Screening Method and Sensitivity

The risk factors for and causes of neuroblastoma have not been established, and therefore it is not possible to provide information or advice for the primary prevention of this disease. It is generally thought that many neuroblastomas are present and detectable at birth, thereby allowing for detection of tumors by a single, once-in-a-lifetime screening test, such as those used for neonatal screening for noncancerous conditions (e.g., phenylketonuria). Screening is performed through biochemical tests for metabolites of norepinephrine and dopamine (i.e., vanillylmandelic acid [VMA], and homovanillic acid [HVA]). Seventy-five percent to 90% of cases of neuroblastoma excrete these substances into the urine, which can be measured in urine specimens.[4] There is no known optimal age for screening, but the most commonly discussed and studied age for a one-time screen has been 6 months. Screening at 12 months has also been evaluated in a population-based study in Germany.[5] Approximately 65% of cases are present before 6 months.[6] Furthermore, the clinical significance of screen-detected neuroblastomas is in question since stage I and II localized tumors less than 5 cm have been observed to regress without treatment in an observational study.[7]

Testing of liquid urine samples or of samples collected on filter paper for VMA and HVA is possible.[8] The first attempts to conduct mass screening through urinary testing occurred in Japan in the early 1970s.[9] The VMA and HVA levels are usually measured by gas chromatography, thin layer chromatography, and/or high performance liquid chromatography.

There are no standard cutoff levels between positive and negative VMA and HVA tests. One recommendation is to use a VMA cutoff level of 25 μg/mg creatinine and an HVA cutoff level of 32 μg/mg creatinine. Alternatively, individual laboratories use a level of two standard deviations above that laboratory’s age-specific mean to identify specimens for reanalysis. On reanalysis, a level of three standard deviations above the mean is used to determine the need for diagnostic evaluation.[10]

The sensitivity of the screening procedure used in different studies ranges from 40% to 80%.[10–13] False-positives results can be caused by dietary agents such as bananas and vanilla [14] but are rare with quantitative assays such as gas chromatography (specificity approximates 99.9%).[12,15] Because of the low prevalence of the disease, even in the Quebec Neuroblastoma Screening Project in which the specificity of the test was extremely high, the positive-predictive value was only 52%,[11] i.e., for every two children identified by screening as being likely to have neuroblastoma, only one was actually affected. In the German Neuroblastoma Screening Project, the positive-predictive value has been reported as only 8.4%.[5] False-positive cases are generally followed for prolonged periods with serial noninvasive testing before a definitive diagnosis excluding cancer can be offered to the parents.[16]

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about neuroblastoma screening. 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 Screening and Prevention 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.

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 Screening and Prevention 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® Screening and Prevention Editorial Board. PDQ Neuroblastoma Screening. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/neuroblastoma/hp/neuroblastoma-screening-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389460]

Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.

Disclaimer

The information in these summaries should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.

Contact Us

More information about contacting us or receiving help with the Cancer.gov website can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the website’s Email Us.