Hereditary paraganglioma-pheochromocytoma is an inherited condition characterized by the growth of tumors in structures called paraganglia. Paraganglia are groups of cells that are found near nerve cell bunches called ganglia. A tumor involving the paraganglia is known as a paraganglioma. A type of paraganglioma known as a pheochromocytoma develops in the adrenal glands, which are located on top of each kidney and produce hormones in response to stress. Other types of paraganglioma are usually found in the head, neck, or trunk. People with hereditary paraganglioma-pheochromocytoma develop one or more paragangliomas, which may include pheochromocytomas.

Pheochromocytomas and some other paragangliomas are associated with ganglia of the sympathetic nervous system. The sympathetic nervous system controls the "fight-or-flight" response, a series of changes in the body due to hormones released in response to stress. Sympathetic paragangliomas found outside the adrenal glands, usually in the abdomen, are called extra-adrenal paragangliomas. Most sympathetic paragangliomas, including pheochromocytomas, produce hormones called catecholamines, such as epinephrine (adrenaline) or norepinephrine. These excess catecholamines can cause signs and symptoms such as high blood pressure (hypertension), episodes of rapid heartbeat (palpitations), headaches, or sweating.

Most paragangliomas are associated with ganglia of the parasympathetic nervous system, which controls involuntary body functions such as digestion and saliva formation. Parasympathetic paragangliomas, typically found in the head and neck, usually do not produce hormones. However, large tumors may cause signs and symptoms such as coughing, hearing loss in one ear, or difficulty swallowing.

Paragangliomas and pheochromocytomas are typically considered an undetermined tumor type, meaning they can be noncancerous (benign) or become cancerous (malignant) and spread to other parts of the body (metastasize). Extra-adrenal paragangliomas become malignant more often than other types of paraganglioma or pheochromocytoma.

Researchers have identified several types of hereditary paraganglioma-pheochromocytoma. Each type is distinguished by its genetic cause. People with types 1, 2, and 3 typically develop paragangliomas in the head or neck region. People with type 4 usually develop extra-adrenal paragangliomas in the abdomen and are at higher risk for malignant tumors that metastasize. The other types are very rare. Hereditary paraganglioma-pheochromocytoma is typically diagnosed in a person's 30s.

Paragangliomas and pheochromocytomas can occur in individuals with other inherited disorders, such as von Hippel-Lindau syndrome, Carney-Stratakis syndrome, and certain types of multiple endocrine neoplasia. These other disorders feature additional tumor types and have different genetic causes. Some paragangliomas and pheochromocytomas occur in people with no history of the tumors in their families and appear not to be inherited. These cases are designated as sporadic.

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).

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.

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. 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. Malignant pheochromocytomas may spread, or metastasize, to the liver, lungs, bone, and lymph nodes.

Hereditary paraganglioma-pheochromocytoma occurs in approximately 1 in 1 million people.

Mutations in at least four genes increase the risk of developing the different types of hereditary paraganglioma-pheochromocytoma. Mutations in the SDHD gene predispose an individual to hereditary paraganglioma-pheochromocytoma type 1; mutations in the SDHAF2 gene predispose to type 2; mutations in the SDHC gene predispose to type 3; and mutations in the SDHB gene predispose to type 4.

The SDHB, SDHC, and SDHD genes provide instructions for making three of the four subunits of an enzyme called succinate dehydrogenase (SDH). In addition, the protein made by the SDHAF2 gene is required for the SDH enzyme to function. The SDH enzyme links two important cellular pathways called the citric acid cycle (or Krebs cycle) and oxidative phosphorylation. These pathways are critical in converting the energy from food into a form that cells can use.

As part of the citric acid cycle, the SDH enzyme converts a compound called succinate to another compound called fumarate. Succinate acts as an oxygen sensor in the cell and can help turn on specific pathways that stimulate cells to grow in a low-oxygen environment (hypoxia).

Mutations in the SDHB, SDHC, SDHD, and SDHAF2 genes lead to the loss or reduction of SDH enzyme activity. Because the mutated SDH enzyme cannot convert succinate to fumarate, succinate accumulates in the cell. As a result, the hypoxia pathways are triggered in normal oxygen conditions, which lead to abnormal cell growth and tumor formation.

Hereditary paraganglioma-pheochromocytoma is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to increase the risk of developing tumors. An additional mutation that deletes the normal copy of the gene is needed to cause the condition. This second mutation, called a somatic mutation, is acquired during a person's lifetime and is present only in tumor cells.

The risk of developing hereditary paraganglioma-pheochromocytoma types 1 and 2 is passed on only if the mutated copy of the gene is inherited from the father. The mechanism of this pattern of inheritance is unknown. The risk of developing types 3 and 4 can be inherited from the mother or the father.

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

The following tests and procedures may be used:

• Physical exam and health history: An exam of the body to check general signs of health, including checking for signs of disease, such as high blood pressure or anything else that seems unusual. A history of the patient’s health habits, diet, and past illnesses and treatments will also be taken.
• Twenty-four-hour urine test: A test in which urine is collected for 24 hours to measure the amounts of catecholamines in the urine. Substances caused by the breakdown of these catecholamines are also measured. An unusual (higher or lower than normal) amount of a substance can be a sign of disease in the organ or tissue that makes it. Higher-than-normal amounts of certain catecholamines may be a sign of pheochromocytoma.
• Blood catecholamine studies: A procedure in which a blood sample is checked to measure the amount of certain catecholamines released into the blood. Substances caused by the breakdown of these catecholamines are also measured. An unusual (higher than or lower than normal) amount of a substance can be a sign of disease in the organ or tissue that makes it. Higher-than-normal amounts of certain catecholamines may be a sign of pheochromocytoma.
• CT scan (CAT scan): A procedure that makes a series of detailed pictures of areas inside the body, such as the neck, chest, abdomen, and pelvis, taken from different angles. The pictures are made by a computer linked to an x-ray machine. A dye may be injected into a vein or swallowed to help the organs or tissues show up more clearly. This procedure is also called computed tomography, computerized tomography, or computerized axial tomography.
• MRI (magnetic resonance imaging): A procedure that uses a magnet, radio waves, and a computer to make a series of detailed pictures of areas inside the body such as the neck, chest, abdomen, and pelvis. This procedure is also called nuclear magnetic resonance imaging (NMRI).

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 may be recommended by a genetic counselor for patients who:

• Have a personal or family history of traits linked with inherited pheochromocytoma or paraganglioma syndrome.
• Have tumors in both adrenal glands.
• Have more than one tumor in one adrenal gland.
• Have signs or symptoms of extra catecholamines being released into the blood or malignant (cancerous) paraganglioma.
• Are diagnosed before age 40.

Genetic testing is sometimes recommended for patients with pheochromocytoma who:

• Are aged 40 to 50 years.
• Have a tumor in one adrenal gland.
• Do not have a personal or family history of an inherited syndrome.

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.

Treatment Option Overview

KEY POINTS

• There are different types of treatment for patients with pheochromocytoma or paraganglioma.
• Patients receive medication to treat the signs and symptoms of pheochromocytoma and paraganglioma.
• The following types of treatment are used:
  • Surgery
  • Radiation therapy
  • Chemotherapy
  • Ablation therapy
  • Embolization therapy
  • Targeted therapy
• New types of treatment are being tested in clinical trials.
• Treatment for pheochromocytoma and paraganglioma may cause side effects.
• Patients may want to think about taking part in a clinical trial.
• Patients can enter clinical trials before, during, or after starting their cancer treatment.
• Follow-up tests will be needed.

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:

• Drugs that keep the blood pressure normal. For example, one type of drug called alpha-blockers stops noradrenaline from making small blood vessels more narrow. Keeping the blood vessels open and relaxed improves blood flow and lowers blood pressure.
• Drugs that keep the heart rate normal. For example, one type of drug called beta-blockers stops the effect of too much noradrenaline and slows the heart rate.
• Drugs that block the effect of extra hormones made by the adrenal gland.

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

The following types of treatment are used:

Surgery

Surgery to remove pheochromocytoma is usually an adrenalectomy (removal of one or both adrenal glands). During this surgery, the tissues and lymph nodes inside the abdomen will be checked and if the tumor has spread, these tissues may also be removed. Drugs may be given before, during, and after surgery to keep blood pressure and heart rate normal.

After surgery to remove the tumor, catecholamine levels in the blood or urine are checked. Normal catecholamine levels are a sign that all the pheochromocytoma cells were removed.

If both adrenal glands are removed, life-long hormone therapy to replace hormones made by the adrenal glands is needed.

Radiation therapy

Radiation therapy is a cancer treatment that uses high-energy x-rays or other types of radiation to kill cancer cells or keep them from growing. There are two types of radiation therapy:

• External radiation therapy uses a machine outside the body to send radiation toward the area of the body with cancer.
• Internal radiation therapy uses a radioactive substance sealed in needles, seeds, wires, or catheters that are placed directly into or near the cancer.

The way the radiation therapy is given depends on the type of cancer being treated and whether it is localized, regional, metastatic, or recurrent. External radiation therapy and 131I-MIBG therapy are used to treat pheochromocytoma.

Metastatic pheochromocytoma is sometimes treated with 131I-MIBG, which carries radiation directly to tumor cells. 131I-MIBG is a radioactive substance that collects in certain kinds of tumor cells, killing them with the radiation that is given off. The 131I-MIBG is given by infusion. Not all pheochromocytomas take up 131I-MIBG, so a test is done first to check for this before treatment begins.

Chemotherapy

Chemotherapy is a cancer treatment that uses drugs to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. When chemotherapy is taken by mouth or injected into a vein or muscle, the drugs enter the bloodstream and can reach cancer cells throughout the body (systemic chemotherapy). Combination chemotherapy is treatment using more than one anticancer drug. Systemic chemotherapy is used to treat pheochromocytomas and paragangliomas.

Ablation therapy

Ablation is a treatment to remove or destroy a body part or tissue or its function. Ablation therapies used to help kill cancer cells include:

• Radiofrequency ablation: A procedure that uses radio waves to heat and destroy abnormal cells. The radio waves travel through electrodes (small devices that carry electricity). Radiofrequency ablation may be used to treat cancer and other conditions.
• Cryoablation: A procedure in which tissue is frozen to destroy abnormal cells. Liquid nitrogen or liquid carbon dioxide is used to freeze the tissue.

Embolization therapy

Embolization therapy is a treatment to block the artery leading to the adrenal gland. Blocking the flow of blood to the adrenal glands helps kill cancer cells growing there.

Targeted therapy

Targeted therapy is a type of treatment that uses drugs or other substances to identify and attack specific cancer cells. Tyrosine kinase inhibitors (TKIs) block signals needed for tumors to grow. Sunitinib, axitinib, and cabozantinib have been used as palliative therapy for metastatic and recurrent pheochromocytoma.

Treatment for pheochromocytoma and paraganglioma may cause side effects.

Patients may want to think about taking part in a clinical trial.

For some patients, taking part in a clinical trial may be the best treatment choice. Clinical trials are part of the cancer research process. Clinical trials are done to find out if new cancer treatments are safe and effective or better than the standard treatment.

Many of today's standard treatments for cancer are based on earlier clinical trials. Patients who take part in a clinical trial may receive the standard treatment or be among the first to receive a new treatment.

Patients who take part in clinical trials also help improve the way cancer will be treated in the future. Even when clinical trials do not lead to effective new treatments, they often answer important questions and help move research forward.

Patients can enter clinical trials before, during, or after starting their cancer treatment.

Some clinical trials only include patients who have not yet received treatment. Other trials test treatments for patients whose cancer has not gotten better. There are also clinical trials that test new ways to stop cancer from recurring (coming back) or reduce the side effects of cancer treatment.

Follow-up tests 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, 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.

Treatment of Pheochromocytoma and Paraganglioma

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.

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.

• Treatment for inherited pheochromocytoma that forms in one adrenal gland is surgery to completely remove the gland.
• Treatment for inherited pheochromocytoma that forms in both adrenal glands or later forms in the remaining adrenal gland may be surgery to remove the tumor and as little normal tissue in the adrenal cortex as possible.

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.

Metastatic Pheochromocytoma and Paraganglioma

Treatment of metastatic pheochromocytoma or paraganglioma may include the following:

• Surgery to completely remove the cancer, including tumors that have spread to distant parts of the body.
• Palliative therapy, to relieve symptoms and improve the quality of life, including:
  • Surgery to remove as much cancer as possible.
  • Combination chemotherapy.
  • Radiation therapy with 131I-MIBG.
  • External radiation therapy to areas (such as bone) where cancer has spread and cannot be removed by surgery.
  • Embolization (treatment to block an artery that supplies blood to a tumor).
  • Ablation therapy using radiofrequency ablation or cryoablation for tumors in the liver or bone.
  • Targeted therapy (tyrosine kinase inhibitors).

Recurrent Pheochromocytoma and Paraganglioma

Treatment of recurrent pheochromocytoma or paraganglioma may include the following:

• Surgery to completely remove the cancer.
• When surgery to remove the cancer is not possible, palliative therapy to relieve symptoms and improve the quality of life, including:
  • Combination chemotherapy.
  • Targeted therapy.
  • Radiation therapy using 131I-MIBG.
  • External radiation therapy to areas (such as bone) where cancer has spread and cannot be removed by surgery.
  • Ablation therapy using radiofrequency ablation or cryoablation.

KEY POINTS

• Pregnant women with pheochromocytoma need special care.
• Treatment of pregnant women with pheochromocytoma may include surgery.

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 any of the following:

• High blood pressure during the first 3 months of pregnancy.
• Sudden periods of high blood pressure.
• High blood pressure that is very hard to treat.

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 the following:

• Surgery to completely remove the cancer during the second trimester (the fourth through the sixth month of pregnancy).
• Surgery to completely remove the cancer combined with delivery of the baby by cesarean section for patients diagnosed later in pregnancy.