About Pheochromocytoma and Paraganglioma
Because its symptoms are often mistaken for other conditions, pheochromocytoma is commonly referred to as "The Great Mimic." Less than one percent of high blood pressure cases are due to pheochromocytoma; therefore, it is considered a rare disease. Unfortunately, rare diseases are often misdiagnosed with dire consequences. This guide will explore the symptoms, genetic causes, diagnosis, and treatment options for pheochromocytoma and paraganglioma.
A Note About Pheo/Para and Pregnancy
This guide is offered strictly for informational purposes. Please contact your doctor for specific medical information and advice.
||First, A Little Background
Pheochromocytomas (pheos) and paragangliomas (paras) are neuroendocrine tumors. They occur in both men and women equally, they can occur at any age, and they affect every race of people. During embryonic development, neural crest tissue becomes our central nervous system, including ganglia and nerves, and medullary cells. This tissue contains chromaffin cells. Pheochromocytomas are tumors of the medulla (center part) of the adrenal glands: the two organs that sit directly on top of the kidneys. These tumors originate from the chromaffin cells inside the glands.
Sometimes pheo tumors occur elsewhere in the body. These are referred to as paragangliomas because they originate from the ganglion cells of the sympathetic nerve chain. Paragangliomas can also be called extra-adrenal pheochromocytomas.
The adrenal glands are responsible for generating the hormones adrenaline, noradrenaline, and dopamine, collectively referred to as catecholamines. They regulate the "fight or flight" response when the body is under stress. Pheochromocytoma tumors secrete higher than normal levels of adrenaline (epinephrine). Paragangliomas typically secrete noradrenaline (norepinephrine). To add to the complexity of pheo/para tumors, some of them are biochemically silent, meaning they do not secrete hormones and cannot be detected through standard lab tests.
In most cases (approximately 80%), a single adrenal pheo tumor presents itself in a patient and the underlying cause is unknown. Once the tumor is removed, catecholamine levels stabilize and the patient can resume normal life. When the origin of the tumor(s) is unknown and there is no known genetic mutation in the patient, the cause is referred to as sporadic. There is still a chance that the disease will return, so continued follow-up after the first tumor is vital.
Though it is even rarer than having a single pheo or para tumor, these tumors can be malignant (cancerous) and/or metastatic (in multiple locations). There is debate among medical professionals about benign versus malignant pheo/para tumors; however, it is generally believed that malignant pheo/para tumors occur mostly where chromaffin tissue does not exist in the body (such as the liver, lungs, and bones). Malignant and metastatic pheo/para tumors are usually associated with a genetic mutation in the patient; however, sporadically occurring disease may also be malignant and/or metastatic.
There are many symptoms associated with pheo/para tumors, but it is important to note that a patient may exhibit only some of the symptoms listed here.
- Heart palpitations
- Racing heart rate, even while resting
- High blood pressure
- Excessive sweating
- Attacks similar to panic/anxiety attacks (these may occur in response to exercise or for no apparent reason)
- Chest/Abdominal pain
- Muscle weakness
- Visual disturbances
Most pheochromocytoma tumors are sporadic, meaning their cause is unknown, but there are genetic diseases that are known to produce these tumors. Paragangliomas have a higher association with genetic mutations than pheochromocytomas. Testing for genetic mutations simply involves drawing blood and sending it to a lab. There are several factors that may lead doctors to perform genetic testing, including early age of onset, family history of tumors, having multiple tumor locations, and having head and neck paraganglioma(s).
- Multiple Endocrine Neoplasia Type 2 (MEN2A and MEN2B)
Patients with MEN2 have a mutation in the RET gene. MEN2A is characterized by medullary thyroid cancer, parathyroid adenoma or hyperplasia, and pheochromocytoma tumors. Patients with MEN2A have an increased risk of having bilateral pheochromocytomas.
In addition to having a high risk of developing pheo tumors, MEN2B is characterized by mucosal neuromas and marfanoid habitus (Marfan's Syndrome).
MEN2 is autosomal dominant, which means there is a 50% chance that children of an affected parent will have the mutation. The mutation can also occur sporadically in an individual where there is no family history of disease.
- Neurofibromatosis Type 1
This disease is caused by a mutation in the NF-1 gene. Symptoms and severity of the disease can vary; however, characteristics include changes in skin pigmentation (caf� au lait spots) and the development of neurofibromas, which are tumors arising from nerves. They are typically benign, but these tumors can cause complications depending on which structures of the body they are growing near. Patients with NF-1 also have an increased risk (over the general population) of developing pheochromocytoma tumors.
NF-1 is autosomal dominant, which means there is a 50% chance that children of an affected parent will have the mutation. The mutation can also occur sporadically in an individual where there is no family history of disease.
- SDH Mutations (Succinate Dehydrogenase Subunits A, B, C, and D) and SDHAF2
These mutations occur in the SDHA, SDHB, SDHC, SDHD, and SDHAF2 genes, which are all tumor suppressor genes. Carriers of mutations in SDHB and SDHD have a high risk of developing adrenal pheochromocytoma tumors, and are also likely to develop paragangliomas. SDHB patients have an increased risk of developing malignant paraganglioma. Carriers of SDHC and SDHAF2 mutations are most likely to develop paragangliomas. For SDHD patients, these occur most frequently in the head and neck area and may be bilateral. Mutations of SDHAF2 were discovered in 2009 and currently appear to cause paragangliomas only.
The SDH mutations are autosomal dominant, which means the children of an affected parent have a 50% chance of inheriting the mutated gene. However, SDHD and SDHAF2 mutations do not generally cause tumors when inherited from the mother (although a mother can pass the mutation on to her children, and her son's children will again be at risk). Mutations can also occur sporadically in individuals with no family history of disease.
SDHD and SDHAF2 mutations show very high penetrance, which means that most mutation carriers will develop a tumor by the age of 70 (~80 and ~100%, resp.). SDHB mutations show incomplete penetrance, and current estimates indicate that only 25% or less of all mutation carriers will develop the disease in their lifetime. SDHA and SDHC mutation carriers are too few in number to allow reliable estimates of penetrance.
- Von-Hippel Lindau (VHL)
The VHL gene regulates cell growth. When a patient has a mutated VHL gene, the likelihood of developing tumors is very high. Hemangioblastomas (overgrowth of blood vessels) may develop in the cerebellum, spinal cord, kidney, and retina. Cysts may also develop in the areas of the hemangioblastomas. Complications include blindness, damage to affected cellular structures, and kidney cancer. About 20% of VHL patients will get pheochromocytoma. The severity of symptoms varies widely between individuals.
VHL is autosomal dominant. Children of an affected parent have a 50% chance of inheriting the defective gene. The mutation also occurs sporadically in people with no family history of disease.
- Carney Triad and Carney-Stratakis Diad
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.
Carney-Stratakis Diad is similar to Carney Triad; however, gene mutations causing this condition have been identified. Patients with the condition have been found to have mutations in the SDHB, SDHC, and SDHD genes. The condition is characterized by paraganglioma tumors and GIST (no pulmonary chondromas as with Carney Triad). Carney-Stratakis Diad is autosomal dominant.
Tumors may be detected using a variety of scans. Simple lab tests for pheochromocytoma will determine if scans are necessary. If there is an active, secreting pheo or para tumor, the catecholamine levels in the body will be elevated. Generally, two tests are used to measure the levels of catecholamines.
Certain foods and drugs may affect the outcome of these tests. Patients should avoid caffeine, bananas, chocolate, and acetaminophen (Tylenol) for at least 24 hours before the test (and during the collection). If the catecholamine levels measured in these tests are elevated, an MIBG scan may be ordered to locate a possible tumor. There are several types of scans used to detect pheochromocytoma and paraganglioma tumors, including CT, MRI, PET, and MIBG. MIBG is a special type of scan that involves injecting the patient with a radioactive tracer. Pheo and para tumors will absorb the tracer and light up on the scan. Please note that non-functioning (biochemically silent) tumors may not show up on an MIBG scan.
- Fractionated plasma metanephrines - This test measures catecholamine levels in the blood. For best results, the patient should lie supine for 30 minutes prior to the blood draw.
- Twenty-four hour urinary metanephrines - This test measures catecholamine levels in the urine. Patients will collect their urine for 24 hours and return it to the lab.
While there is no known preventative measure for pheochromocytoma or paraganglioma, there are many effective treatment options once a tumor has been discovered. If the tumor can be surgically removed, either open or laparoscopically, it is the preferred method of treatment. Before undergoing any surgical procedure, the patient must be adequately "blocked" with medication. This involves taking an alpha blocking medication for at least 2-3 weeks prior to the surgery and monitoring the patient's blood pressure carefully. The most common medication for blocking patients is Phenoxybenzamine (Dibenzyline). A beta blocker may be used in conjunction. Going under anesthesia without being blocked is highly dangerous for pheo/para 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 this practice is followed for the best possible outcome.
When surgery is not an option due to multiple tumor sites, malignant disease, or the location of a tumor, the treatment depends on several factors and is best determined by doctors who are experienced with pheo/para tumors. The following treatments have been used for pheo/para tumors with variable outcomes.
Even though it is rare for pheochromocytoma tumors to recur, patients should continue to have follow-up lab tests periodically throughout their lifetime, especially if they have a known genetic mutation.
- MIBG (I-131 metaiodobenzylguanidine)
This is the same radioactive tracer that is used during scans to locate tumors but in a much higher dose. In order to receive MIBG as a therapy, the pheo/para tumors must be MIBG positive, meaning they 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.
External beam radiation has been successful in treating a variety of cancers, but it has mixed results with pheo/para tumors. It can be effective as a method of pain control, but it may not eliminate the tumor cells. Side effects include fatigue, skin burns at the site of radiation, nerve damage, and arthritis (long term).
The type of chemotherapy used for pheo para 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. 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.
- 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 prior to the procedure. Side effects include pain and swelling at the site of the procedure.
||Pregnancy and Pheo/Para
Having a pheochromocytoma or 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, or cause premature labor. During the stress of labor, a pheo or para tumor can release massive amounts of catecholamines that may cause hypertensive crisis in the mother and/or complicate the delivery. Therefore, patients with a suspected pheo/para tumor should be monitored closely during pregnancy and have their blood pressure controlled with medication.
Information last updated: November 2010.
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