Pheochromocytoma: Diagnosis and Treatment

Adrenaline, noradrenaline (also known as epinephrine and norepinephrine) and dopamine (all three being types of catecholamines) are hormones that influence many normal functions of the body. Most notably, they regulate heart rate, blood pressure, breathing, digestion, sweating, urination, and sexual arousal. In times of stress or danger, catecholamines increase blood sugar to supply the brain and muscle with energy. Catecholamines control the “fight or flight” response, which allows the body to react to stressful situations. These substances are made by the adrenal glandsand in nerve tissue elsewhere in the body.

A pheochromocytoma is an adrenal tumor that makes and releases excess catecholamines.  These tumors can cause serious health problems including stroke, heart attack, and even death. Pheochromocytomas are quite rare and occur in about 2 to 8 out of every 1 million people. Catecholamine-producing tumors that grow outside of the adrenal glands are called “paragangliomas” and are discussed in more detail in that section. Approximately 95% of catecholamine-secreting tumors are located within the abdomen, and of these, 85 to 90% are in the adrenal glands. Approximately 10% of patients are found to have pheochromocytomas in both adrenal glands, which is most commonly seen in younger patients with pheochromocytoma-related genetic syndromes.

What is the chance that this is genetic?

As our understanding of human genetics increases, scientists have found that approximately 25 to 30% of all cases of pheochromocytoma are inherited. There are 4 main syndromes associated with pheochromocytoma:

von Hippel-Lindau Syndrome (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 can occur in up to 5% of people with NF1.  This syndrome is characterized by coffee-colored skin spots and tumors arising from nerve cells in the skin. These pheochromocytomas can be found in the adrenal and outside of the adrenal (paragangliomas) but are rarely seen in both adrenal glands at the same time.

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.

The two most common familial disorders associated with pheochromocytoma are vHL and MEN2A/2B. Many of the syndromes involving pheochromocytoma are “autosomal dominant”, which means that children have a 50% chance of having the disease. For patients with pheochromocytoma, genetic testing should be considered if a patient has one or more of the following:

   Diagnosis at 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, 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?

About 10% of pheochromocytomas are cancerous. Telling the difference between a benign and a cancerous pheochromocytoma may be difficult. The best predictor of cancer is whether or not there is spread to other organs (metastases), invasion of other organs, or recurrence after surgery.

Signs and Symptoms

Patients with pheochromocytoma present in one of 4 ways: classic symptoms (40%), in “pheo crisis” (10%), as an incidental finding (40%), or during screening for genetic or familial disease (10%).

Classic symptoms

High blood pressure is the most common symptom of pheochromocytoma. The high blood pressure can either be continuous (i.e. most of the time) or episodic (i.e. happens every once in a while). Although most patients will have high blood pressure, about 5 to 15% of patients present with normal blood pressure. In addition, the classic 3 symptoms or of pheochromocytoma are headaches, rapid heart rate, and sweating. Difficulty breathing, weakness, and panic attack-type symptoms can also occur in this classic presentation. Only about 40% of patients have the 3 classic symptoms. It is important to remember that high blood pressure is very common in general and does not necessarily mean that someone has a pheochromocytoma, even if the patient has headaches, palpitations, and sweating. Other less common signs and symptoms include: pale skin, low blood pressure, blurred vision, weight loss, increased thirst and urination, constipation, abdominal pain, elevated blood sugar, psychiatric disturbances, heart muscle dysfunction, and an elevated red and white blood cell count. When these symptoms occur during a procedure and following ingestion of certain food ingredients or drugs (e.g., phenylephrine, monoamine oxidase [MAO] inhibitors, tyramine), a prompt evaluation for pheochromocytoma should be performed.

Hypertensive (Pheo) Crisis

Approximately 10% of patients present in “pheo crisis”, which is a life-threatening release of adrenaline that can lead to stroke, heart attack, organ failure, coma, and even death.

Incidental finding

Approximately 40% of patients will be found to have a pheochromocytoma incidentally (i.e. during an imaging test being done for another reason). Occasionally, pheochromocytomas may be found by the medical examiner after someone has died. 

Screening for genetic or familial disease

Up to 10% of patients will be found to have a pheochromocytoma during genetic testing after another family member has been diagnosed with pheochromocytoma or one of the associated inherited diseases.

Diagnosis and Radiological Tests 

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

   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

When the diagnosis is confirmed with blood or urine tests, the patient should have a CAT scan or MRI to locate the pheochromocytoma. Pheochromocytomas usually have a very distinct appearance on CAT scan and MRI. These tests can also help determine if other organs are involved or if other tumors outside the adrenal glands (i.e. paragangliomas) exist.

When the adrenal glands appear normal on CAT scan or MRI, nuclear medicine imaging tests like an MIBG (metaiodobenzylguanidine) scan, FDG-PET (fluorodeoxyglucose positron emission 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 an adrenal tumor is discovered. This can be disastrous if the tumor is a pheochromocytoma. Adrenal masses should never be biopsied unless a pheochromocytoma/paraganglioma has been ruled out first. Even then, a biopsy is rarely helpful or necessary.

Treatment

Not treating a pheochromocytoma is incredibly dangerous and life-threatening. The best treatment for pheochromocytoma is to surgically remove the adrenal gland(s) with the tumor. 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 adrenaline 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 adrenaline 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 adrenaline. 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 pheochromocytoma 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 bleeding can occur during pheochromocytoma surgery, so it is important that the surgical and anesthesia team are experienced in treating this disease. Except for large tumors and those that are clearly cancerous, most operations for pheochromocytoma can be done through a minimally invasive approach.