Pheochromocytoma forms in the adrenal gland.

Pheochromocytoma forms in the adrenal gland. 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 tumor of the adrenal medulla.

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. Some pheochromocytomas release extra adrenaline and noradrenaline into the blood and cause symptoms.

Paraganglioma forms in nerve tissue 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 extra adrenaline and noradrenaline into the blood may cause symptoms.

Pheochromocytoma and paraganglioma may be benign (not cancer) or malignant (cancer).

About half of all children with pheochromocytoma or paraganglioma have malignant pheochromocytoma or paraganglioma. This means that the tumor cells have spread to other parts of the body. Benign and malignant pheochromocytoma and paraganglioma require treatment because they can cause severe or life-threatening heart problems and affect many body functions.

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

Prognosis and treatment options depend on the following:

• Whether the cancer has just been diagnosed or has recurred (come back).

Pheochromocytoma is a type of neuroendocrine tumor that grows from cells called chromaffin cells. These cells produce hormones needed for the body and are found in the adrenal glands. The adrenal glands are small organs located in the upper region of the abdomen on top of the kidneys. About 80-85% of pheochromocytomas grow in the inner layer of the adrenal gland, called the adrenal medulla. About 15-20% of pheochromocytomas grow outside of this area and are called extra-adrenal pheochromocytomas or paragangliomas.

Most pheochromocytomas are benign, which means they are not cancer and do not spread to other parts of the body. Only about 10% of pheochromocytomas spread to other parts of the body.

Paraganglioma is a type of neuroendocrine tumor that forms near certain blood vessels and nerves outside of the adrenal glands. The adrenal glands are important for making hormones that control many functions in the body and are located on top of the kidneys. The nerve cells involved in paraganglioma are part of the peripheral nervous system, meaning the part of the nervous system outside of the brain and spinal cord. These tumors can also be called extra-adrenal pheochromocytomas.

Approximately 35-50% of paragangliomas may spread to other parts of the body.

Inheriting certain gene mutations (changes) increases the risk of pheochromocytoma and paraganglioma.

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

Having any of the following inherited syndromes or gene changes increases risk of pheochromocytoma and paraganglioma:

• Multiple endocrine neoplasia type 1 (MEN1) syndrome (tumors in the parathyroid gland, pituitary gland, or islet cells in the pancreas, and rarely, pheochromocytoma).
• Multiple endocrine neoplasia type 2A syndrome (pheochromocytoma, medullary thyroid cancer, and parathyroid gland disease).
• Multiple endocrine neoplasia type 2B syndrome (pheochromocytoma, medullary thyroid cancer, parathyroid hyperplasia, and other conditions).
• von Hippel-Lindau disease (VHL) (pheochromocytoma, paraganglioma, hemangioblastoma, clear cell renal carcinoma, pancreatic neuroendocrine tumors, and other conditions).
• Neurofibromatosis type 1 (NF1) (neurofibromas, brain tumors, pheochromocytoma, and other conditions).
• Carney-Stratakis dyad (paraganglioma and gastrointestinal stromal tumor [GIST]).
• Carney triad (paraganglioma, GIST, and pulmonary chondroma).
• Familial pheochromocytoma or paraganglioma.

More than half of the children and adolescents diagnosed with pheochromocytoma or paraganglioma have an inherited syndrome or gene change that increases the risk of cancer. Genetic counseling (a discussion with a trained professional about inherited diseases) and testing is an important part of the treatment plan.

Signs and symptoms of pheochromocytoma and paraganglioma occur if too much adrenaline or noradrenaline is released into the blood.

Some tumors do not make extra adrenaline or noradrenaline and do not cause symptoms. These tumors may be found when a lump forms in the neck or when a test 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, paraganglioma, or other conditions.

Check with your child's doctor if your child has any of the following:

• High blood pressure.
• Headache.
• Heavy sweating for no known reason.
• A strong, fast, or irregular heartbeat.
• Feeling shaky.
• Being extremely pale.
• Dizziness.
• Being irritable or nervous.

These signs and symptoms may come and go, but high blood pressure is more likely to occur for long periods of time in young patients. These signs and symptoms may also occur with physical activity, injury, anesthesia, surgery to remove the tumor, eating foods such as chocolate and cheese, or while passing urine (if the tumor is in the bladder).

Tests and procedures used to diagnose and stage pheochromocytoma and paraganglioma depend on the patient's signs and symptoms and family history.

Tests are done to diagnose and stage cancer. After cancer is diagnosed, more tests are done to find out if cancer cells have spread to nearby areas or to other parts of the body. This process is called staging.

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 lumps or anything else that seems unusual. A history of the patient’s health habits and past illnesses and treatments will also be taken.
• Plasma-free metanephrines test: A blood test that measures the amount of metanephrines in the blood. Metanephrines are substances that are made when the body breaks down adrenaline or noradrenaline. Pheochromocytomas and paragangliomas can make large amounts of adrenaline and noradrenaline and cause high levels of metanephrines in both the blood and urine.
• Blood catecholamine studies: A procedure in which a blood sample is checked to measure the amount of certain catecholamines (adrenaline or noradrenaline) released into the blood. Substances caused by the breakdown of these catecholamines are also measured. An unusual (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 may be a sign of pheochromocytoma or paraganglioma.
• Twenty-four-hour urine test: A test in which urine is collected for 24 hours to measure the amounts of catecholamines (adrenaline or noradrenaline) or metanephrines in the urine. Substances caused by the breakdown of these catecholamines are also measured. An unusual (higher than normal) amount of a substance can be a sign of disease in the organ or tissue that makes it. Higher than normal amounts may be a sign of pheochromocytoma or paraganglioma.
• PET scan: A procedure to find malignant tumor cells in the body. A small amount of radioactive glucose (sugar) is injected into a vein. The PET scanner rotates around the body and makes a picture of where glucose is being used in the body. Malignant tumor cells show up brighter in the picture because they are more active and take up more glucose than normal cells do.

• CT scan (CAT scan): A procedure that makes a series of detailed pictures of areas inside the body, 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. This procedure is also called nuclear magnetic resonance imaging (NMRI).

• MIBG scan: A procedure used to find neuroendocrine tumors, such as pheochromocytoma and paraganglioma. A very small amount of a substance called radioactive MIBG is injected into a vein and travels through the bloodstream. Neuroendocrine tumor cells take up the radioactive MIBG and are detected by a scanner. Scans may be taken over 1-3 days. An iodine solution may be given before or during the test to keep the thyroid gland from absorbing too much of the MIBG.
• Somatostatin receptor scintigraphy: A type of radionuclide scan that may be used to find tumors. A very small amount of radioactive octreotide (a hormone that attaches to tumors) is injected into a vein and travels through the blood. The radioactive octreotide attaches to the tumor and a special camera that detects radioactivity is used to show where the tumors are in the body. This procedure is also called octreotide scan and SRS.
• Genetic testing: A laboratory test in which cells or tissue are analyzed to look for changes in genes or chromosomes. These changes may be a sign that a person has or is at risk of having a specific disease or condition. The following are genes that might be tested for in children with pheochromocytoma or paraganglioma: VHL, NF1, RET, SDHD, SDHB, SDHA, MAX, and TMEM127 genes.

KEY POINTS

• After pheochromocytoma or paraganglioma has been diagnosed, tests are done to find out if cancer cells have spread to nearby areas or to other parts of the body.
• There are three ways that cancer spreads in the body.
• Cancer may spread from where it began to other parts of the body.

After pheochromocytoma or paraganglioma has been diagnosed, tests are done to find out if cancer cells have spread to nearby areas or to other parts of the body.

The process used to find out if cancer has spread to nearby areas or to other parts of the body is called staging. There is no standard staging system for childhood pheochromocytoma and paraganglioma. The results of the tests and procedures done to diagnose cancer are used to help make decisions about treatment.

Sometimes childhood pheochromocytoma or paraganglioma recurs (comes back) after treatment. It may come back in the place it first formed or in 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:

• Tissue. The cancer spreads from where it began by growing into nearby areas.
• Lymph system. The cancer spreads from where it began by getting into the lymph system. The cancer travels through the lymph vessels to other parts of the body.
• Blood. The cancer spreads from where it began by getting into the blood. The cancer travels through the blood vessels to other parts of the body.

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.

• Lymph system. The cancer gets into the lymph system, travels through the lymph vessels, and forms a tumor (metastatic tumor) in another part of the body.
• Blood. The cancer gets into the blood, travels through the blood vessels, and forms a tumor (metastatic tumor) in another part of the body.

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.

Treatment Option Overview

KEY POINTS

• There are different types of treatment for children with pheochromocytoma or paraganglioma.
• Children with pheochromocytoma or paraganglioma should have their treatment planned by a team of doctors who are experts in treating childhood cancer.
• Four types of standard treatment are used:
  • Surgery
  • Chemotherapy
  • High-dose 131I-MIBG therapy
  • Targeted therapy
• New types of treatment are being tested in clinical trials.
• Treatment of 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 may be needed.

There are different types of treatment for children 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.

Because cancer in children is rare, taking part in a clinical trial should be considered. Some clinical trials are open only to patients who have not started treatment.

Children with pheochromocytoma or paraganglioma should have their treatment planned by a team of doctors who are experts in treating childhood cancer.

Treatment will be overseen by a pediatric oncologist, a doctor who specializes in treating children with cancer. The pediatric oncologist works with other pediatric health professionals who are experts in treating children with cancer and who specialize in certain areas of medicine. This may include the following specialists and others:

• Pediatrician.
• Pediatric surgeon.
• Pathologist.
• Pediatric endocrinologist.
• Pediatric nurse specialist.
• Social worker.
• Rehabilitation specialist.
• Psychologist.
• Child-life specialist.

Four types of standard treatment are used:

Surgery

Surgery to remove the tumor is the main treatment for pheochromocytoma and paraganglioma. For several days before surgery, your child may need to take blood pressure medicine to lower the risk of complications during and after surgery.

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).

High-dose 131I-MIBG therapy

131I-MIBG therapy is a treatment with high-dose radioactive iodine. The radioactive iodine is given through an intravenous (IV) line and enters the bloodstream which carries radiation directly to tumor cells. Radioactive iodine collects in pheochromocytoma and paraganglioma cells and kills them with the radiation that is given off.

Targeted therapy

Targeted therapy is a type of treatment that uses drugs or other substances to identify and attack specific cancer cells. Targeted therapies usually cause less harm to normal cells than chemotherapy or radiation therapy do.

• Angiogenesis inhibitor drugs prevent the growth of new blood vessels needed for tumors to grow. Sunitinib is an angiogenesis inhibitor used to treat pheochromocytoma and paraganglioma.

New types of treatment are being tested in clinical trials.

Treatment of 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 may be needed.

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

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

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. Talk to your child’s doctor about which tests should be done and how often.

Patients with pheochromocytoma or paraganglioma need lifelong follow-up.

Treatment of Childhood Pheochromocytoma and Paraganglioma

Treatment of newly diagnosed pheochromocytoma and paraganglioma in children may include the following:

• Surgery to completely remove the tumor.
• Combination chemotherapy, high-dose 131I-MIBG therapy, or targeted therapy for tumors that have spread to other parts of the body.

Before surgery, drug therapy with alpha-blockers to control blood pressure and beta-blockers to control heart rate are given. If both adrenal glands are removed, life-long hormone therapy to replace hormones made by the adrenal glands is needed after surgery.

Treatment of Recurrent Childhood Pheochromocytoma and Paraganglioma

Treatment of recurrent pheochromocytoma and paraganglioma may include the following:

• A clinical trial that checks a sample of the patient's tumor for certain gene changes. The type of targeted therapy that will be given to the patient depends on the type of gene change.
• A clinical trial of 131I-MIBG therapy.
• A clinical trial of a new chemotherapy drug (guadecitabine).