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.
Paragangliomas are most often located in the head and neck region, chest, abdomen, or pelvis. They are more likely to be cancerous than pheochromocytomas except those in the head and neck region.
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 and to talk to your doctor about genetic testing.
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, pheochromocytoma 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:
- Sustained hypertension
- Paroxysmal hypertension
- Orthostatic hypotension
- Swelling at tumor site
Less common signs or symptoms may include:
- Abdominal/back pain
- 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
- 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:
- 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:
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)
preparing for your appointment
If a para is suspected, you should be referred to a doctor who specializes in hormonal disorders (an endocrinologist).
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
Tests that examine the blood and urine are used to detect (find) and diagnose paraganglioma.
The following tests and procedures may be used:
The twenty-four hour urine and blood catecholamine tests are commonly used first if para is suspected.
It is suggested to avoid coffee, tea, bananas, cocoa, citrus fruits, and vanilla for several days before being tested because these foods can cause higher than normal catecholamine levels.
Twenty-four-hour urine test:
A test in which urine is collected for 24 hours to measure the amounts of catecholamine 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 paraganglioma.
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.
This test compared to the 24-hour urine test can be more convenient since it includes only a one-time blood draw. It should be noted that the Endocrine Society Guidelines suggest that blood be drawn after the patient has a brief rest and is supine (lying down on his/her back). Patients with paraganglioma often have 2-4 times the normal range, so retesting in the supine position can be requested if you have indeterminate results.
Once the above tests indicate a pheo or para, imaging, outlined below, is often used to identify where, how many, and size of the tumor(s).
Sometimes these imaging techniques involve the use of molecular imaging (using radiation to take pictures of the body). Molecular imaging 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.
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).
What biochemical tests are used for diagnosis of pheochromocytomas and paragangliomas?
Biochemical tests used for diagnosis of pheochromocytomas and paragangliomas include measurements in blood or urine of the catecholamines and various breakdown products (metabolites) of the catecholamines. The metabolites most commonly measured include normetanephrine, the breakdown product of noradrenaline, and metanephrine, the breakdown product of adrenaline. These two metabolites, normetanephrine and metanephrine, are commonly referred to in the plural form as the “metanephrines”. It is incorrect to refer to these metabolites in their single form as “normetanephrines” and “metanephrines”. In addition to normetanephrine and metanephrine, some laboratories also measure methoxytyramine, which is the breakdown product of dopamine. Another biochemical test still offered by some laboratories involves measurements in urine of vanillymandelic acid (commonly referred to as VMA), which represents the final major breakdown product of both noradrenaline and adrenaline. Measurements of plasma chromogranin A (CgA) are another test sometimes used to diagnose pheochromocytomas and paragangliomas. Chromogranin A is not a catecholamine or a catecholamine metabolite, but is secreted by the same cells that secrete catecholamines.
SOURCE: Graeme Eisenhofer PhD, Professor & Chief, Division of Clinical
Neurochemistry, Institute of Clinical Chemistry & Laboratory Medicine
and Department of Medicine, University Hospital Dresden, Dresden, Germany
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
Somtaostatin Analogs (SSA's)
Tyrosine kinase inhibitor therapy
Surgical Resection (laparoscopic or open surgery)
Depending on the location of the tumor, the goal of surgery for paraganglioma is to completely remove the cancer, including tumors that have spread to distant parts of the body.
Before undergoing any surgical procedure, the patient must be adequately “blocked” with medication. The main goal of the administration of these medications is to normalize blood pressure and heart rate and to protect the patient from the effects of high levels of hormones (catecholamines) released during surgery. This usually involves taking an alpha blocking medication for at least 2 weeks before the surgery and monitoring the patient’s blood pressure carefully. The most common medication for alpha blocking patients is Phenoxybenzamine (Dibenzyline). Other alpha blocking medications can be used as well, sometimes in combination with calcium channel blockers. A beta-blocker may also be used in conjunction.
Going under anesthesia without being blocked is highly dangerous for paraganglioma patients. The anesthesia drugs can have a negative influence on the tumors and cause them 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. It is extremely important that the practitioners involved in the care of the patient have experience with pheochromocytoma/paraganglioma surgery and that patients be “blocked” for the best possible outcome.
After Surgery: Follow-Up
Urine and/or plasma tests should be repeated 4-8 weeks after surgery to check for any remaining disease. Long-term regular follow-up is recommended for all patients after that. Yearly urine or plasma tests for paraganglioma should be performed for life to detect remaining disease or the return of the disease. For many patients, follow-up CT or MRI may not be needed if urine and plasma test results are normal.
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.
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.
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.
I-131 is also an MIBG therapy that has been used off-label for many years to treat pheo para.
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 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 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 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.
New types of treatment are being tested in clinical trials
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.
The prognosis for metastatic patients is dependent on a number of factors including the location of the tumors and genetic status. If tumors have spread to the liver and lungs, a patient may have a significantly shorter lifespan than those with tumors in the bones. There are currently no cures for cancerous paraganglioma. However, existing treatment options may reduce the tumors and prolong survival.
why and how
Approximately 35% of pheo paras are hereditary.
Recent research has indicated that people who know they have a genetic mutation, have less metastatic disease, lower likelihood of complications and better overall health outcomes. Regular annual biochemical screening can catch tumors before they are symptomatic.
All patients diagnosed with a paraganglioma should talk to their doctor about genetic testing. Testing for genetic mutations simply involves a blood test and sending the sample to a lab. Historically, there were several factors that led doctors to perform genetic testing, including early age onset; family history of tumors; having multiple tumor locations; and having head and neck paraganglioma(s).
Currently, there are approximately 20 genetic mutations identified that can be attributed to a greater risk of developing pheo para, and geneticists believe more genes will be discovered in the near future. It is important to get genetic testing to identify current genetic mutations associated with pheo para as well as yet to be discovered mutations.
If you have a pheo para genetic mutation, your children have a 50/50 chance of inheriting the genetic mutation, although there are two exceptions. (Please see below for more information).
To find a genetic counselor near you go to findageneticcounselor.com.
The NIH has an excellent online source of information on Hereditary Pheochromocytoma and Paraganglioma: Your Guide to Understanding Genetic Conditions: Hereditary paraganglioma-pheochromocytoma.
This podcast about PPGL and SDHx mutations, by the Life Raft Group, is very informative, as well.
Here is a list of genetic mutations commonly associated with pheo para.
NF1, VHL, RE, SDHD, SDHC, SDHB, SDHAF2, TMEM127, SDHA, PHD2, MAX, HIF2A, HRAS, FH, PHD1, MDH2, ATRX, CSDE1 UBTF-MAML3, FOT2, IRP1, DNMT3A, DLST & Chromatin remodeling genes.
The following inherited syndromes or gene changes increase the risk of pheochromocytoma:
Multiple endocrine neoplasia 2 syndrome, types A and B (MEN2A and MEN2B)
Multiple endocrine neoplasia, type II (MEN II) is a disorder resulting in tumors in more than one part of the body’s hormone-producing (endocrine) system. The locations of other tumors associated with MEN II include the thyroid, parathyroid, lips, tongue and gastrointestinal tract.
Multiple Endocrine Neoplasia, Type 2 (MEN2) is an inherited condition that is caused by genetic mutations in the RET gene on chromosome 10. When normal, these genes signal when to turn on cell growth and division. A mutation in RET causes the cell growth and division signal to always be on, which increases the risk for specific types of tumors.
MEN2 is classified into three subtypes: MEN2A and MEN2B. All subtypes involve high risk for development of medullary carcinoma of the thyroid and an increased risk for pheochromocytoma; MEN2A has an increased risk for parathyroid adenoma or hyperplasia (excessive growth). Additional features in MEN2B include bumps (neuromas) of the lips and tongue; enlarged lips; and ganglioneuromas (a specific type of polyp within the gastrointestinal tract). In addition, patients with MEN2B tend to be slender with long limbs. About 5% of MEN2A patients and 50% of MEN2B patients have the disease because of a de novo (new) mutation that was not inherited from their parents. If an individual has a RET mutation, then each of his or her children will have a 50% chance of having MEN2, as well. Visit the AMEND support group for more information on MEN2 and the RET gene.
von Hippel-Lindau (VHL) syndrome
Von Hippel-Lindau disease can result in tumors at multiple sites, including the central nervous system, endocrine system, pancreas and kidneys.
VHL is an inherited condition caused by genetic mutations in the VHL gene on chromosome 3. When normal, this gene helps stop tumors from developing. A mutation in the VHL gene increases the risk for many types of benign and cancerous tumors in the brain, spinal cord, eye, ear, kidneys, adrenal glands, and other parts of the body. If an individual has a VHL mutation, each of his or her children will have a 50% chance of having VHL as well. Over 90% of patients with this genetic mutation will develop disease by the age of 65. Approximately 20% of VHL patients will develop pheochromocytoma. Some mutations in the VHL gene primarily increase the risk for developing Pheo. The severity of symptoms varies widely between individuals. Visit the NIH online for more information on VHL.
Neurofibromatosis type 1 (NF1)
Neurofibromatosis 1 (NF1) results in multiple tumors in the skin nerves or deeper nerves in the body (neurofibromas), pigmented skin spots and tumors of the optic nerve.
NF1 is an inherited condition caused by genetic mutations in the NF1 gene on chromosome 17. When normal, these genes help stop tumors from developing. A mutation in NF1 increases the risk for multiple café au lait spots; axillary and inguinal freckling; multiple cutaneous (skin) neurofibromas; and iris Lisch nodules. Learning disabilities are present in at least 50% of individuals with NF1. Less common but potentially more serious manifestations include plexiform neurofibromas; optic nerve and other central nervous system gliomas; malignant peripheral nerve sheath tumors; scoliosis; tibial dysplasia; and vasculopathy.
If an individual has an NF1 mutation, each of his or her children will have a 50% chance of having NF1 as well. Visit the NIH online for more information on NF1.
Hereditary Pheochromocytoma Syndrome
Hereditary Pheochromocytoma Syndrome is an inherited disorder that result in pheochromocytoma and can be associated with tumors in the kidney and GI tract as well.
Mutations in the Succinate Dehydrogenase Subunit Genes (SDH) increase risk of developing pheochromocytoma. These genes have a role in the energy cycle in our cells and typically act to prevent tumors from forming but when mutated, can lead to tumor formation. Patients with mutations in any of the SDH genes are at increased risk for pheochromocytoma and also increased risk of cancerous tumors in the kidney and GI tract.
Other genetic causes of pheochromocytoma and paraganglioma are being studied. For example, germline mutations in the gene TMEM127 and MAX have been shown to increase risk of developing pheochromocytoma.
Other genes are currently being studied to see if they too may cause pheos and paras. Researchers are still studying the hereditary patterns and penetrance of these mutations. The Genetics Home Reference page is a good resource to find updated information on new genes as it becomes available.
Carney-Stratakis dyad (paraganglioma and gastrointestinal stromal tumor [GIST]) and Carney triad (paraganglioma, GIST, and pulmonary chondroma):
Carney Triad is a rare disease that causes three different tumor types to develop: functioning paragangliomas, pulmonary chondromas (benign cartilaginous lung tumors), and GISTs (gastrointestinal stromal tumors). GISTs may occur anywhere inside the digestive tract, but the stomach is the most common area; they may be multifocal. Carney Triad affects more women than men; up to 80% of patients are women. Even though a gene mutation has not been discovered, it is strongly suspected that Carney Triad is genetic.
Other genetic causes
Other genetic causes of paraganglioma are being studied. For example, germline mutations in the gene TMEM127 and MAX have been shown to increase risk of developing paraganglioma.
The Genetics Home Reference page is a good resource to find updated information on new genes as it becomes available.
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.
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.
Source: National Cancer Institute: https://www.cancer.gov/types/pheochromocytoma