WHAT IS

paraganglioma?

Paraganglioma (păr′ə-găng′glē-ō′mə) is a 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 (defined by 1,2-dihydroxybenzene group-not methylated hydroxyl groups), which include norepinephrine (noradrenaline), epinephrine (adrenaline), and dopamine. It is these hormones that lead to persistent or episodic high blood pressure and other symptoms. Some pheochromocytomas or paragangliomas, although very few, can be biochemically silent, thus do not produce any catecholamines.

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.

THE SYMPTOMS

signs to look for

The most common sign of paraganglioma is uncontrolled hypertension.

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
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 are paroxysmal, 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)

SOURCE: https://www.mayoclinic.org/

Our Doctor Tracker is a great resource if you’re looking for a trusted pheochromocytoma specialist.

 

DIAGNOSIS

preparing for your appointment

You’re likely to start by seeing your family doctor or a general practitioner. However, you may then 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
  • 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:

Physical exam and 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 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 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 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).

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

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. They can be categorized into two groups: local therapy (resection, radiation, radio-frequency ablation, transarterial embolism) and systemic therapy (radionuclide therapy [MIBG and radiolabeled somatostatin analogs], octreotide, cytoxic chemotherapy, molecular targeted therapy).

Treatment OPTIONS

Surgery
Radiation therapy
Radio Frequency Ablation (RFA)
Transarterial embolization (TAE)
MIBG (I-131 metaiodobenzylguanidine)
Radiolabeled Somatostatin Analogues
Octreotide
Cytoxic Chemotherapy
Molecular Targeted Therapy
New types of treatment are being tested in clinical trials
Surgery
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 Surgery

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
Radiation therapy

External beam radiation has been successful in treating a variety of cancers, but it has mixed results with paraganglioma tumors. It can be effective as a method of pain control, but it may not eliminate the tumor cells. In some cases, it may stabilize disease at the treated site.  Side effects include fatigue, skin burns at the site of radiation, nerve damage, and arthritis (long term).

 
Radio Frequency Ablation (RFA)
Radio Frequency Ablation (RFA)

RFA is a relatively new procedure that involves inserting a needle directly into the tumor and destroying the cells with radio waves. This procedure is not effective on large tumors. RFA should not be used on tumors in the head and neck or near nerves because of potential damage to surrounding structures. As with surgery, the patient must be blocked with an alpha blocker for at least 2-3 weeks before the procedure. Side effects include pain and swelling at the site of the procedure.

Transarterial embolization (TAE)
Transarterial embolization (TAE)

TAE is used for liver tumors that are too large for RFA (typically over 5cm). In this procedure, a catheter (a thin, flexible tube) is put into an artery through a small cut in the inner thigh and threaded up into the hepatic artery in the liver. A dye is usually injected into the bloodstream at this time to

MIBG (I-131 metaiodobenzylguanidine)
MIBG (I-31 metaiodobenzylguanidine)

This is the same molecule that is used during scans to locate tumors, but attached to a more toxic radioactive iodine. In order to receive MIBG as a therapy, the paraganglioma tumor must be MIBG positive, meaning it will absorb, or “take up,” the tracer. Precautions must be taken to protect the patient’s thyroid. Side effects of this treatment include fatigue, nausea, and a decrease in blood platelets, especially in high-dose treatments or with several treatments over time.

Radiolabeled Somatostatin Analogues
Radiolabeled Somatostatin Analogues

Symptomatic improvement may occur with all of the various (111)In, (90)Y, or (177)Lu-labeled somatostatin analogues that have been used. Since tumor size reduction was seldom achieved with (111)Indium labeled somatostatin analogues, radiolabelled somatostatin analogues with beta-emitting isotopes like (90)Y and (177)Lu were developed. Reported anti-tumor effects vary considerably between various studies. The side effects include fatigue, nausea and a decrease in blood counts, among others. However, like MIBG, the tumors must be receptive to the agents being considered for use. Not all patients will be candidates for these therapies because their tumor cells won’t “take up” the tracer elements.

Octreotide
Octreotide

Octreotide is a synthetic octapeptide that mimics somatostatin but is a more potent inhibitor of growth hormone, glucagon, and insulin than natural somatostatins. Like the radio labeled somatostatin analogues, Octreotide can also be labeled with a variety of radionuclides, such as yttrium-90 or lutetium-177, to enable peptide receptor radionuclide therapy (PRRT) for the treatment of unresectable paraganglioma.

Cytoxic Chemotherapy
Cytoxic Chemotherapy

The type of chemotherapy used for paraganglioma tumors is a mix of three drugs: Cyclophosphamide (Cytoxan), Vincristine, and Dacarbozine (DTIC). This type of chemo is referred to as CVD. Typically, patients will remain on CVD for an extended period of time. A common error with this therapy is to stop the therapy too soon, resulting in further tumor growth. Once CVD chemotherapy has been stopped it typically cannot be started again. It is recommended that patients stay on chemo for 20 or more rounds. An experienced physician should manage this protocol. Patients with the SDHB mutation in particular seem to respond well to this treatment. Side effects include fatigue, nausea, hair loss, decreased white and red blood cell counts, and low platelets. If the patient has bone metastases, a bone-strengthening drug (bisphosphonate) may also be administered with the chemo.

Molecular Targeted Therapy
Molecular Targeted Therapy

Understanding the molecular pathway changes responsible for metastatic paragannglioma will hopefully guide future molecular-targeted therapies. These therapies work by interfering with specific molecular targets along the signaling pathways in the cell that are responsible for carcinogenesis and tumor growth. To date, both benign and malignant paraganglioma gene mutations are part of two distinct molecular pathways leading to tumorigenesis:

  • Cluster 1 includes mutations of VHL, SDHB, SDHC and SDHD and is associated with pseudohypoxia and aberrant VEGF signaling, leading to abnormal hypoxia inducible factor (HIF) activation and overexpression of angiogenic factors.
  • Cluster 2 includes mutations of RET, NF1, TMEM12, and MAX and is associated with abnormal activation of kinase-signaling pathways such as PI3kinase/AKT, RAS/RAF/ERK, and mTOR1/p70s6K, leading to abnormal cell growth and lack of apoptosis capacity.

This all sounds complex, and it is, but what researchers are attempting to do is keep these cells from malfunctioning by interfering with their abnormal activities somewhere along these pathways.

HIF1a inhibitors are drugs targeted at interfering with HIF hypoxia-driven transcription pathway. These agents have shown marked anti-tumor activity in mice models and seem to be promising for malignant paras, but more studies are needed.

The mTOR inhibitor everolimus (RAD001) in combination with octreotide LAR has been evaluated for low- and intermediate-grade neuroendocrine tumors, with good results. However, when everolimus was evaluated in malignant para patients, all patients experienced disease progression. Researchers concluded that further studies on the PI3K/AKT/mTOR pathway have to be conducted to find a more specific molecular target in its signaling.

Several studies have demonstrated overexpression in malignant paraganglioma of angiogenic molecules, such as VEGF, angiopoietin-2, and the endothelin receptors ETA and ETB, suggesting that targeting this pathway with antiangiogenic therapies could represent a new promising treatment option. As a result, sunitinib, a receptor tyrosine kinase inhibitor that acts on several targets (VEGF, PDGF, and c-KIT), and has antiangiogenic and antitumor activity, has been used in the treatment of malignant paragangliomas, with mixed but promising results.

Imatinib, another tyrosine kinase inhibitor already used for hematologic and gastrointestinal stromal tumors, has not been found effective for malignant paraganglioma treatment.

Thalidomide, by targeting VEGF and basic fibroblast growth factor, is an antiangiogenic agent that has been evaluated in combination with Temozolomide in neuroendocrine tumors. Although there was an objective biochemical response rate (40%) and a radiologic response rate in 33% of malignant paragangliomas, lymphopenia occurred in about 70% of treated patients.

Activators of prolyl hydroxylase (PHD) (such as ERBB2 inhibitors) are now being evaluated as promising antineoplastic therapies. These molecules decrease the expression levels of some angiogenic factors, such as VEGF, acting on HIF pathway, by activating the PHD, thus increasing HIF hydroxylation, and promoting its degradation. More studies are required on these agents.

Molecular targeted therapies are promising strategies, but, due to the complexity of the tumor pathogenesis, further studies on tumor biology, discovery of novel targeted drugs, and new trials are needed to achieve more effective treatments.

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

Information about clinical trials is available from the NCI website: https://www.cancer.gov/about-cancer/treatment/clinical-trials/search

GENETIC COMPONENT

why and how

Up to about 35% of patients with paraganglioma will have a family member with the same condition.

It has been suggested that all patients diagnosed with a paraganglioma be urged to consider genetic testing. Testing for genetic mutations simply involves a blood test and sending the sample to a lab. Historically, there were several factors that lead doctors to perform genetic testing, including early age onset; family history of tumors; having multiple tumor locations; and having head and neck paraganglioma(s). These factors all increase the chances of a hereditary syndrome being involved.

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.

Source- MayoClinic.org
Source: National Cancer Institute: https://www.cancer.gov/types/pheochromocytoma

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