Paraganglioma: Diagnosis and Treatment

Background

Noradrenaline and adrenaline are hormones that influence many normal functions of the body. They help regulate heart rate, blood pressure, breathing, digestion, sweating, urination, and sexual arousal. In times of stress or danger, they also increase blood sugar to supply the brain and muscle with energy. Adrenaline is said to control the “fight or flight” response, which gets your body ready to react to stressful situations.

A paraganglioma is a rare tumor of nerve tissue (located outside of the brain and spinal cord) that often makes and releases too much noradrenaline. Noradrenaline is only able to be turned into adrenaline within the adrenal gland or in specialized nerve tissue located along the lower part of the aorta. Paragangliomas outside of these two locations either do not make hormones or produce noradrenaline only. Paragangliomas are sometimes called “extra-adrenal pheochromocytomas”. Most (85-90%) paragangliomas are found along blood vessels in the abdomen or pelvis, but may also be found in the head, neck, or chest. These tumors can cause serious health problems including stroke, heart attack, and even death.

What is the chance that this is genetic?

Most paragangliomas are not inherited. However, certain hereditary syndromes such as von Hippel-Lindau syndrome (vHL), familial paraganglioma syndrome, and multiple endocrine neoplasia (MEN) type 2 can be associated with paragangliomas. Paragangliomas may also occur alongside adrenal pheochromocytomas and may occasionally occur as multiple tumors.

von Hippel-Lindau (vHL)

Patients with vHL can develop pheochromocytomas (often in both adrenal glands), paragangliomas, eye tumors, brain tumors, kidney cancers, kidney and pancreas cysts, pancreas tumors, and testicular tumors. In some families with vHL, pheochromocytoma is the only sign of the syndrome. Overall, about 10 to 20% of vHL patients will develop pheochromocytomas. Bilateral tumors may present at the same time or may be separated over the course of many years.

Multiple Endocrine Neoplasia Syndrome type 2A and 2B (MEN2A and MEN2B)

Mutations in the “RET” gene are responsible for tumor development in MEN2. There are two forms of MEN2:

In MEN2A syndrome, pheochromocytomas are usually found in both adrenal glands but may develop separately over time. They occur in about 50% of MEN2A patients and are associated with thyroid cancer and parathyroid disease.

In MEN2B syndrome, which accounts for 5% of MEN2 cases, pheochromocytomas are also often found in both adrenal glands. This syndrome is associated with thyroid cancer, bumps on the lips, tongue, and eyelids, thickened nerves over the front of the eye, benign intestinal tumors, and tall/thin (marfanoid) body stature.

Neurofibromatosis type 1 (NF1)

Pheochromocytoma/paraganglioma can occur in up to 5% of people with NF1.  This syndrome is characterized by darker colored (cafe au lait) skin spots and neurogenic tumors arising from nerve cells in the skin. 

Familial Paraganglioma Syndrome

Pheochromocytomas can rarely occur in association with familial paraganglioma syndromes. Genetic mutations in different parts of the “SDH” gene can lead to different forms of the disease.

Many of these syndromes involving paragangliomas are “autosomal dominant”, which means that children have a 50% chance of inheriting the mutation causing the disease. Genetic testing should be considered if a patient has one or more of the following:

    Diagnosis younger than 30 years old

    Bilateral pheochromocytomas

    Paraganglioma

    Family history of pheochromocytoma or paraganglioma

    Family history of the syndromes previously described

    Other signs or symptoms of the syndromes previously described

For family members of patients with pheochromocytoma or paraganglioma, genetic testing should only be done if the family member with the disease has a known genetic mutation. Genetic counseling is strongly urged to help families understand the implications of genetic testing, to coordinate testing of at-risk individuals, and to help families work through the psychological and social issues that may arise before, during, and after the testing process. Genetic testing is expensive and should be performed in a stepwise fashion (i.e. the patient should be tested to identify the genetic mutation and then other family members should be tested for only that genetic mutation) so as to decrease the number of tests performed.

What is the chance that this is cancer?

Compared to adrenal pheochromocytomas, paragangliomas have a higher chance of being cancerous (40-50% in some studies). Telling the difference between a benign and a cancerous paraganglioma may be difficult. The best predictor for malignancy is whether or not there is spread to other organs (metastases), invasion of other organs, or recurrence after surgery. Larger tumors (over 5 cm) are also more likely to be cancerous.

Signs and Symptoms

The signs and symptoms of paragangliomas can be similar to that of pheochromocytomas. When symptoms are present, they are usually due to the increased secretion of noradrenaline by the tumor, which may cause high blood pressure, headaches, rapid heartbeat, pounding in the chest, anxiety, and sweaty or clammy skin.

Diagnosis and Radiological Tests

In patients who are thought to have a paraganglioma, laboratory tests (blood and/or urine) should be done to measure the levels of hormones that are produced during the normal production and processing of adrenaline (noradrenaline, metanephrines, normetanephrines, and dopamine). Certain medications and conditions can lead to false positive laboratory results (i.e. positive test in someone who does not have a paraganglioma):

   Tricyclic antidepressants (including cyclobenzaprine hydrochloride)

   Levodopa

   Alcohol (ethanol) withdrawal

   Withdrawal from certain medications (i.e. clonidine)

   Withdrawal from illicit drugs

   Antipsychotics, buspirone hydrochloride, and bupropion hydrochloride

   Amphetamines

   Prochlorperazine

   Reserpine

   Major physical stress (i.e. surgery, stroke)

   Obstructive sleep apnea

The diagnosis of a paraganglioma should be suspected in any patient in whom imaging reveals a tumor that is located next to the spine or aorta within the abdomen. When the diagnosis is confirmed with blood or urine tests, the patient should have a CAT scan or MRI to locate the paraganglioma, if not already performed. Paragangliomas usually have a very distinct appearance on CT scan and MRI. Since patients can have multiple paragangliomas, it is recommended to use a number of tests to localize the disease, especially in cases of familial paraganglioma syndrome. Nuclear medicine tests like an MIBG (metaiodobenzylguanidine) scan, FDG-PET CT (fluorodeoxyglucose positron emission computed tomography) scan, or Dotatate PET scan can be helpful. These radioisotope scans may also be useful in detecting small paragangliomas, cancer spread, and recurrent disease.

Do I need a biopsy?

One common mistake is to perform a biopsy when a tumor is found to be located near the spine or aorta within the abdomen. This can be disastrous if the tumor is a paraganglioma. Suspicious masses should never be biopsied unless a paraganglioma/pheochromocytoma has been ruled out first. Even then, a biopsy is rarely helpful or necessary.

Treatment

Not treating a paraganglioma is incredibly dangerous and life-threatening. The best treatment for paraganglioma is to surgically remove the tumor(s). This is true for almost all patients except for those with such severe other medical issues that they would not survive an operation. Medical therapy to block the effects of noradrenaline excess is available but is not nearly as effective as surgery.

Preparing for an operation

Before surgery, you must be appropriately prepared with medications that will block the effects of noradrenaline during the start of anesthesia and during the operation. This preparation must be carried out under the supervision of a doctor (an endocrinologist, endocrine surgeon, or hypertension specialist) with expertise in managing patients with pheochromocytoma/paraganglioma. Medication (alpha-blockers) will be given in increasing doses over 10 to 14 days prior to surgery to block the effects of excess adrenaline production. This preparation helps avoid wide swings in blood pressure during removal of the tumor. These medications will slowly relax blood vessels that have clamped down because of the increased adrenaline levels. As the medication dose is increased, you may start to have symptoms like a stuffy nose, tiredness, and lightheadedness when standing up quickly. In fact, the specialist will look for these signs to make sure that the medication is adequate. A few days before surgery, an additional medication (ß-blocker) may be started to help slow a fast heart rate. Calcium channel blockers, which also relax blood vessels and slow the heart rate, may also be given either instead of or in addition to alpha and ß-blockers.

In addition to blocking the effects of adrenaline, it is equally important to fix the dehydration associated with increased noradrenaline. As adrenaline causes the blood vessels to tighten, the body tries to keep the blood pressure normal by getting rid of fluid in the body through your urine. This means that actually become dehydrated over time. Once the paraganglioma is removed, the blood pressure can be dangerously low if the dehydration is not fixed. As the medications start to relax the blood vessels prior to surgery, it is important to replace the lost fluid. During this time, it is important to drink plenty of extra fluid and take a little extra salt in the diet.

Surgery

Surgery is performed under general anesthesia with you completely asleep and relaxed. Blood pressure swings, abnormal heart rhythms, and excessive bleeding can occur during paraganglioma surgery. Most paragangliomas are removed through a traditional “open” operation due to their relationship to important blood vessels in the abdomen and their increased risk of being cancerous. However, several groups have described successful removal of paraganglioma using a minimally invasive or laparoscopic approach. The advantages of laparoscopic surgery may include a shorter length of hospitalization, less postoperative pain, and a faster recovery. However, if the tumor has invaded into the surrounding tissue or spread to lymph nodes, then the tumor should be removed through an open operation.