WHAT IS

paraganglioma?

Paraganglioma (păr′ə-găng′glē-ō′mə) is a rare, usually noncancerous (benign), slow-growing tumor that is closely related to pheochromocytoma. It originates from outside the adrenal glands, specifically from the parasympathetic or sympathetic nervous system. Just like pheochromocytoma, paraganglioma is also characterized by the presence of an excess amount of hormones called catecholamines, which include norepinephrine (noradrenaline), epinephrine (adrenaline), and dopamine. It is these hormones that lead to persistent or episodic high blood pressure and other symptoms. Although it is rare, some paragangliomas do not produce any catecholamines, so common symptoms such as high-blood pressure, sweating or heart palpitations do not appear. These non-secreting paragangliomas are often found incidentally.

Paragangliomas are most often located in the head and neck region, chest, abdomen, or pelvis. Paraganglioma in the head and neck are less likely to be cancerous than tumors in the chest, abdomen and pelvis.

Paragangliomas, if detected early, can be successfully treated and managed in the vast majority of cases. If possible, the treatment of choice for the condition is surgery to remove the tumor(s), but there are other treatment options.  Surgical treatment usually alleviates symptoms.  Once diagnosed, it is recommended to be seen by a multi-disciplinary medical team with pheo para experience.

30-40% of pheochromocytomas and paragangliomas are hereditary.  If you are diagnosed with paraganglioma talk to your doctor about genetic testing.
Read more on our genetics page.

Watch videos on all pheo para topics presented by experts from 2019 Pheo Para Alliance Conference & our Facebook Live Webinar Series.

See the National Cancer Institutes Patient Guide to paraganglioma.

Go to our Research Articles page for the most recently published research on paraganglioma.

THE SYMPTOMS

signs to look for

Paraganglioma can occur at any age, but most commonly affects people between the ages of 20 and 50. While very rare, the illness often causes a range of symptoms that when recognized can help with diagnosis. Many of these symptoms can be caused by multiple other conditions as well.  Some paragangliomas do not cause any symptoms.

Signs and symptoms may occur weekly, several times daily, or once every few months. Most attacks last less than an hour, but rarely more than several days.

Signs + Symptoms
Triggers of Symptomatic Spells
When to see a Doctor
Signs + Symptoms
Signs or symptoms of paragangliomas may include:
  • Hypertension
  • Sustained hypertension
  • Paroxysmal hypertension
  • Orthostatic hypotension
  • Headache
  • Palpitations+/-tachycardia
  • Diaphoresis/sweating
  • Anxiety
  • Swelling at tumor site
Less common signs or symptoms may include:
  • Pallor
  • Flushing
  • Hyperglycemia
  • Vomiting
  • Abdominal/back pain
  • Nausea
  • Fatigue
  • Dyspnea
  • Dizziness
  • Visual symptoms
Triggers of Symptomatic Spells
Spells may occur spontaneously or may be triggered by such factors as:
  • Physical exertion
  • Anxiety or stress
  • Changes in body position
  • Bowel movement
  • Labor and delivery
  • Surgery and anesthesia
  • Caffeine
  • Certain drugs such as steroids, decongestants, psychiatric drugs such as phenelzine, tranylcypromine, and isocarboxazid
  • Stimulants, such as amphetamines or cocaine
Foods high in tyramine, a substance that affects blood pressure, also can trigger a spell. Tyramine is common in foods that are fermented, aged, pickled, cured, overripe or spoiled. These foods include:
  • Some cheeses
  • Some beers and wines
  • Dried or smoked meats
  • Avocados, bananas and fava beans
  • Pickled fish
  • Sauerkraut or kimchi
Certain medications that can trigger a symptomatic spell include:
  • Decongestants
  • Monoamine oxidase inhibitors (MAOIs), such as phenelzine (Nardil), tranylcypromine (Parnate) and isocarboxazid (Marplan)
  • Stimulants, such as amphetamines or cocaine
Medical procedures/treatments that can trigger a symptomatic spell include:
  • Intubation
  • Anesthesia
  • Endoscopy
  • Catheterization
  • Chemotherapy
 
 
When to see a Doctor
The signs and symptoms of paraganglioma can be caused by a number of different conditions.
  • If any of the listed signs or symptoms come and go suddenly, you should see a doctor. It’s important to get a prompt diagnosis.
  • Although high blood pressure is a primary sign of a paraganglioma, most people with high blood pressure don’t have a paraganglioma, and not all patients with a paraganglioma have hypertension. Talk to your doctor if any of the following factors are relevant to you:
  • Difficulty controlling high blood pressure with current treatment plan
  • A family history of paraganglioma
  • A family history of a related genetic disorder: multiple endocrine neoplasia, type II (MEN II); von Hippel-Lindau disease; familial paraganglioma or neurofibromatosis 1 (NF1)

DIAGNOSIS

preparing for your appointment

If a para is suspected, you should be referred to a doctor who specializes in hormonal disorders (an endocrinologist).

Watch this video on diagnostics from our 2019 Pheo Para Conference.

Watch this video on biochemical testing. 

What you can do

Before your appointment, make a list that includes the following:

  • Signs or symptoms — or any changes from normal— that may be causing concern
  • A record of the frequency and duration of symptoms
  • Recent changes or stresses in your life
  • All medications — including over-the- counter drugs and dietary supplements — and doses you take.  This is very important because supplements and OTC drugs can affect test results.  Always consult your doctor before stopping medications.
  • A log of typical food and beverage consumption
  • Family history of medical conditions
The twenty-four hour urine and blood (plasma) tests are commonly used if pheochromocytoma or paraganglioma is suspected.

With both tests, catecholamines and metanephrines (which are metabolites of catecholamines) are measured.

Metanephrines are released continuously from the tumor, as opposed to catecholamines, which are usually released intermittently. This continuous release of metanephrines from the tumor explains why testing for metanephrines is preferred over testing for catecholamines. In rare cases, a paraganglioma, often in the head/neck, may not produce catecholamines or metanephrines. In these latter cases, an imaging test is the preferred method for diagnosis.

The 24-hour urine test and the blood plasma test are equally effective at measuring of free metanephrines and ultimately providing a diagnosis. Both tests are approximately 95% accurate. Some laboratories measure only total metanephrines and this is nearly as accurate as the measurements of free metanephrines. Determining which test to use is dependent on your and your doctor’s preference.

Twenty-four-hour urine test:

The 24-hr urine metanephrine test measures the free metanephrines in your urine. A 24-hour urine collection is done by collecting your urine in a special container over a full 24-hour period.  This may be less convenient than the blood test. When the 24-hr urine is incompletely collected, the test result may turn out to be false-negative (normal test result in a patient with a pheo).  True positive values (abnormal test result in a patient with pheo) are usually two or more times higher than the upper limit of normal.

Blood plasma test: 

Plasma free metanephrines test is a blood test that measures the amount of metanephrines in the blood.  This test compared to the 24-hour urine test can be more convenient since it is only a one-time blood draw.  The Endocrine Society Guideline suggests that blood be drawn after the patient has a brief rest and is supine (lying down on his/her back), but many labs do not follow this guideline. Patients with pheos or paras often have two or more times the upper limit of normal, so retesting in the supine position can be requested if your blood was drawn while you were sitting up and results are indeterminate.

3-Methoxytyramine 

3-methoxytyramine (3MT), which is the breakdown product of dopamine, is sometimes used for testing.  This is a blood test that can be moderately useful in patients with clear symptoms to confirm a pheo para diagnosis. It can also be helpful in identifying patients with head/neck paragangliomas. 3-MT may be measured in patients with genetic mutations, especially SDHB, which has a higher risk of metastatic disease.  Finally, it may be useful in the detection of metastatic disease.  3MT testing is however not available in most labs in the U.S.

False Negative/False Positive/Indeterminate Results 

Sometimes test results are false negative (normal test result in a patient with a pheo), a false positive (abnormal test result in patient with no pheo) or indeterminate (levels may be slightly higher than the upper limit of normal).  If this latter happens, your doctor may retest you or consider imaging.

Why false negative?
  • very small tumors
  • tumors that aren’t producing catecholamines
  • incomplete urine collections
Why false positive?
  • Blood was drawn in the seated position. The Endocrine Society Guideline suggests that blood be drawn after the patient has a brief rest and is supine (lying down on his/her back), but many labs do not follow this guideline.
  • severe pain, heart failure or acute physical or emotional stress.
  • supplements, prescribed medications, over-the-counter or illicit drugs, see below for a list that may affect results. This depends however on the technical procedure used to measure.

Tell your doctor about all prescribed and over-the-counter medications, supplements and illicit drugs you are taking.  Do not stop taking prescribed medications without consulting your doctor first.  Here is a list of medications/substances that may affect test results:

Acetaminophen, sympathomimetics, tricyclic antidepressants, selective serotonin reuptake,  serotonin norepinephrine reuptake inhibitors, cyclobenzaprine, levodopa, monoamine oxidase inhibitors, some beta-blockers, some alpha blockers (phenoxybenzamine), marijuana, illicit drugs

Imaging 

Imaging, taking pictures of the inside of the body, is often used once biochemical tests indicate a pheo or para.  Imaging will help to identify where, how many, and size of the tumor(s).  CT/MRI are often used first, before functional imaging is used.

Functional imaging means imaging involving the use of a radioactive substance to take pictures of the body.  Some of these radioactive substances can also be used for treatment of metastatic pheo para and this can be confusing. The Society of Nuclear Medicine and Molecular Imaging has many online resources to explain the use of both and address issues about radiation exposure.

CT scan (CAT scan): 

A CT scan takes a series of detailed pictures inside the body in places such as the neck, chest, abdomen, and pelvis.  The pictures, taken at various angles, are made by a computer linked to an x-ray machine. A dye may be injected into a vein  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): 

An MRI 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).

Functional imaging:

Functional imaging allows physicians to see how the body is functioning and to measure its chemical and biological processes.  For pheo paras, functional imaging may include 123I-MIBG, 18F-FDG-PET/CT, 18F-DOPA-PET/CT or 68GaDOTATATE PET/CT scan.  A small amount of a radiopharmaceutical is injected into the patient and detected by special types of cameras to provide very precise pictures of the area of the body being imaged.

Functional imaging can be used to identify if a disease has progressed to other parts of the body (metastatic), and where the tumors are located.  Because the cost of these scans can be prohibitive, they are not widely available, and they may not be covered by insurance.

Treatment Overview

exploring your options

Paragangliomas, if detected early, can be successfully treated and managed in the vast majority of cases. If possible, the treatment of choice for the condition is paraganglioma surgery, either open or laparoscopic.

When surgery is not an option due to multiple tumor sites, metastatic disease, or the location of the paraganglioma, the treatment will depend on several factors and is best determined by doctors who are experienced with pheo/para tumors. The following treatments have been used for these tumors with variable outcomes.

Below details treatment options as presented at the 2019 Pheo Para Conference.  To see the full video, click on the links below.

Slide credit: Dr. Joseph Dillon, University of Iowa

 

Treatment OPTIONS

Surgery
Radiation therapy
Somtaostatin Analogs (SSA's)
Chemotherapy
Ablation therapy
Embolization therapy
Tyrosine kinase inhibitor therapy
Clinical Trials
Surgery
Surgery

Surgery to remove a paraganglioma is the preferred treatment option. During surgery, the tissue and lymph nodes close to the tumor may 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, the blood or urine are checked to ensure metanephrine levels and subsequently, catecholamine levels have returned to normal. Normal metanephrine levels are a sign that all the paraganglioma cells were removed, if the tumor was secreting catecholamines.

If you have surgery scheduled, you can participate in pheo para research and be a part of finding new treatments or a cure by donating your tumor tissue to research.  It is quick and easy to consent.  You can learn more here.

Before Surgery

Before surgery the patient must be adequately “blocked” with medication. Going under anesthesia without being blocked is very dangerous. Anesthesia can cause tumors to release massive amounts of catecholamines. Manipulation of the tumor during surgery can also cause this release, which may result in a hypertensive crisis and even death. This is why it is not recommended for patients to have a biopsy of the tumor if pheo or para is suspected.

It is extremely important that practitioners involved in the care of the patient have experience with pheo para surgery and that patients be “blocked” for the best possible outcome. Alpha and beta-blockers are prescribed to normalize blood pressure and heart rate, which protect the patient from the effects of high levels of hormones (catecholamines) released during surgery.  First, an alpha blocking medication is prescribed for at least 2 weeks before the surgery. Phenoxybenzamine(Dibenzyline) is commonly prescribed.  Doxazosin, prazosin and terazosin are also used. Once blockage has been obtained, a beta-blocker is prescribed, sometimes in combination with calcium channel blockers. A high salt diet may be recommended, as well.

After Surgery: Follow-Up

Urine or plasma tests should be repeated 2-8 weeks after surgery to check for any remaining disease. Long-term regular follow-up is recommended for all patients. Yearly urine or plasma tests for paraganglioma should be performed for life to detect remaining disease, return of the disease, or the development of metastases. For most people, follow-up CT or MRI is not needed if urine and plasma test results are normal.  Exceptions to this may include the identification of a genetic mutation or if the primary tumor was large.  Read more about genetic mutations on this page.

Radiation therapy
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 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 radiation therapy is given depends on the type of cancer being treated and whether it is localized, regional, metastatic, or recurrent. 

Molecular imaging (using radiation to take pictures of the body) and nuclear medicine (using radiation to treat an illness) can be confusing.  The Society of Nuclear Medicine and Molecular Imaging has many online resources to explain the use of both and address issues about radiation exposure.

MIBG Therapy

Paraganglioma can be treated with MIBG, which is a therapy that is injected into the patient’s bloodstream.  It travels to and binds to the tumor delivering a targeted high dose of radiation directly to the cancer cells.  Not all paras take up MIBG, so a test is done first to check for this before treatment begins.  Approximately 60% of tumors are MIBG active.

Azedra (iobenguane 131) is an MIBG therapy and is the only FDA approved treatment for metastatic pheo para.  This treatment requires a 3-4 day hospital stay and sterilization precautions to limit radiation exposure of those in contact with you.  Side effects can include nausea, myelosuppression (fewer white/red blood cells and platelets measured in blood) and fatigue.

Azedra can only be administered at certain hospitals in the U.S.  Financial compensation may be available for patients who are traveling to receive treatment or to help with out of pocket costs.  For more information visit https://azedra.com/support-program/.

PRRT Therapy

PRRT (Peptide Receptor Radionuclide Therapy) is a therapy that when injected into the patient’s bloodstream travels to and binds to the tumor delivering a targeted high dose of radiation directly to the cancer cells.  A Gallium DOTATE  or NETSPOT PET/CT scan is done first to check if the tumor will respond to PRRT.

Lutathera (lutetium Lu 177 dotatate) is used off-label to treat pheo para.  Lutathera does not usually require a hospital stay and minimal sterilization precautions are required to limit radiation exposure to those in contact with you.

Some clinical trials are available at the University of Iowa, the NIH, and Cincinnati Children’s Hospital for PRRT.  More information can be found at clinicaltrials.gov or by reaching out directly to the institution.

Somtaostatin Analogs (SSA's)

Somatostatin is a naturally occurring hormone that acts by binding to somatostatin receptor (SSTR), a receptor that is overexpressed in pheo para.  SSA’s such as octreotide and lanreotide work by activating SSTR’s, which can slow tumor growth.  Studies have produced mixed results on the effectiveness of SSA’s.  Octreotide and lanreotide are administered intravenously (by a needle into the body).

Chemotherapy
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). When chemotherapy is placed directly into the cerebrospinal fluid, an organ, or a body cavity such as the abdomen, the drugs mainly affect cancer cells in those areas (regional chemotherapy). Combination chemotherapy is treatment using more than one anticancer drug. The way the chemotherapy is given depends on the type of cancer being treated and whether it is localized, regional, metastatic, or recurrent. 

Chemotherapy drugs that may be used can include cyclophosphamide, vincristine, dacarbazine, and temozolomide monotherapy in malignant pheos for SDHB genetic mutations.

Ablation therapy
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

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.

Tyrosine kinase inhibitor therapy
Tyrosine kinase inhibitor therapy

TKI is a targeted therapy treatment that uses drugs or other substances to identify and attack specific cancer cells without harming normal cells. 

Sunitinib and cabozantinib are types of TKI therapy that can be prescribed off-label and are currently being studied in clinical trials. 

Clinical Trials
New types of treatment are being tested in clinical trials

Information about clinical trials is available from the NCI website or at clinicaltrials.gov.

Participation in clinical trials for those with progressive disease is critical to finding better treatments for pheo para.  It is important to note, that placebos are rarely used in cancer treatment clinical trials.  For pheo para, they may be used in a clinical trial that compares standard treatment plus a placebo, with standard treatment plus a new treatment.  So, everyone participating in a clinical trial will receive, at least, the standard treatment commonly used for pheo para.

Cancerous Paraganglioma

Rarely, paraganglioma can spread to other organs.

The prognosis for these patients is highly variable and can be based on the location of the tumors, genetic status, among other factors.  It is highly encouraged for metastatic patients to receive treatment from an experienced, multi-disciplinary pheo para team.  There are currently no cures for cancerous paraganglioma. However, existing treatment options may reduce the tumors and prolong survival.

Metastatic

There is no test to determine if a paraganglioma is malignant.  The disease is cancerous (malignant/metastasized) if it has spread to other parts of the body.  This happens in approximately 15-25% of pheo para cases.

It is highly recommended for metastatic patients to receive treatment from an experienced, multi-disciplinary pheo para team.  In addition, everyone who has metastatic para should have genetic testing.  Knowing your genetic status will help your medical team determine an appropriate course of treatment.  Read more on the genetics page.

There are currently no cures for metastatic paraganglioma. However, existing treatment options may reduce the tumors and prolong survival.  Some patients live for decades with metastatic paraganglioma.  The prognosis is highly variable and is dependent upon the size of the primary tumor (tumors larger than 5-6 cm are more likely to metastasize), levels of methoxytyramine (a metabolite of the neurotransmitter dopamine which can be measured in the blood), and genetic status.  Paras that are originally in the head and neck are less likely to metastasize than paras that develop in other areas.  Patients with the SDHB and SDHA genetic mutations are more likely to develop malignant para. You can read more about each genetic mutation and its prognosis on the genetics page.  Metastatic para often spreads to the bone and sometimes to the lymph nodes, lungs and liver.  Please see the treatment portion of this page for further information about treating metastatic para.

Participation in clinical trials for those with progressive disease is critical to finding better treatments for pheo para.  It is important to note that placebos are rarely used in cancer treatment clinical trials.  For pheo para, participants in a clinical trial receive standard treatment plus a placebo or standard treatment plus a new treatment.  So, everyone participating in a clinical trial will receive, at least, the standard treatment commonly used for pheo para.

Information about clinical trials is available from the NCI website or at clinicaltrials.gov.

Pregnancy + PARA

what you need to know.

Having a paraganglioma tumor during pregnancy can be dangerous for the mother-to-be and the baby. Uncontrolled high blood pressure can damage the kidneys, restrict oxygen to the baby and/or cause premature labor. During the stress of labor, a paraganglioma can release massive amounts of catecholamines that may cause hypertensive crisis in the mother and/or complicate the delivery. Therefore, patients with a suspected paraganglioma should be monitored closely during pregnancy and have their blood pressure controlled with medication and ideally managed in centers which have experience with the diagnosis and treatment of pheo or para in pregnancy. Consultation with a paraganglioma expert is essential for the best possible outcome.

If you or your partner have a genetic form of pheo para, your child will have a 50/50 chance of inheriting the genetic mutation.  If you or your partner have one of the genetic mutations associated with pheo para, pre-implantation genetic diagnostic (PGD) testing can be used with In Vitro Fertilization (IVF). PGD tests the embryos prior to implantation to only implant embryos that do not have the genetic change seen in you or your partner.  You can read more about genetics here.

If a woman is already pregnant, and prenatal genetic testing is desired, consultation with a prenatal genetic counselor (findageneticcounselor.com) is recommended. There are genetic testing options using chorionic villus sampling (CVS) and/or amniocentesis at various points in the pregnancy that can be performed, and a full consultation should occur with a specialist.

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