Pheochromocytoma - Treatment and Diagnosis

Pheochromocytoma: Definition

Pheochromocytomas, sometimes simply referred to as “pheos”, are rare tumors that develop in the inner region (medulla) of the adrenal gland.

The adrenal medulla plays an instrumental role in synthesizing and secreting catecholamines – hormones such as epinephrine (adrenaline) and norepinephrine (noradrenaline). When the body is under stress, these hormones are released to initiate the “fight or flight” response which brings about rapid physiologic changes such as increased heart rate and an increase in the blood flow to essential organs. These hormonal effects take place within seconds. Pheochromocytomas overproduce catecholamines, upsetting the body’s normal balance of stress response hormones. Although most pheochromocytomas develop in the adrenal medulla, it is possible to encounter pheochromocytomas in other catecholamine-producing areas such as the abdomen, pelvis, chest, and neck.

Previously, many physicians referred to pheochromocytoma as “the 10 percent” tumor, meaning that 10% of cases were familial (inherited), 10% bilateral (affecting both right and left adrenal glands), 10% malignant (demonstrating cancerous metastases to other sites in the body), 10% in children, and 10% lying outside of the adrenal glands. Recent advances in our understanding of the genetics of pheochromocytoma have compelled physicians to abandon the 10% rule because it is an oversimplification (see “What causes pheochromocytoma” below).

How common are pheochromocytomas?

Pheochromocytomas arise in approximately 1–2 individuals per 100,000 adults per year. About 1 in 500 people with high blood pressure are eventually found to have pheochromocytomas. The most common age for people to develop pheochromocytomas is during the 40s and 50s. Men and women are affected equally.

Symptoms and signs

High blood pressure (hypertension) is the most common problem attributed to pheochromocytomas. This is a result of increased release of the catecholamines epinephrine and norepinephrine. Because each tumor is different from the next, patients with pheochromocytomas may experience either consistently high blood pressure (due to constant hormone release) or episodic peaks in blood pressure (due to random bursts of hormone release).

Symptoms of pheochromocytoma are often related to surges in blood pressure. People commonly report feeling a sudden “adrenaline rush” for no apparent reason, and this can happen up to several times per day. Many patients report that exercise may provoke pheochromocytoma “surges”. Typical symptoms include:

Severe Headache
Palpitations or rapid heart rate
Profuse sweating
Flushing or feeling hot
Chest pain or chest pressure

Are pheochromocytomas dangerous?

Yes. Catecholamines are among the most powerful hormones in the human body, and excessive amounts can be lethal. For this reason, pheochromocytomas are regarded as quite likely the single most high risk tumor that physicians treat. Because they are essential regulators of blood pressure, catecholamines are normally released as part of a delicate balance. The fluctuating catecholamine levels seen in pheochromocytoma patients can cause organ damage from dangerously high blood pressure, leading to:

Death
Heart attack
Stroke
Kidney failure

On the other side, some pheochromocytoma patients experience shock (dangerously low blood pressure) when catecholamine levels suddenly and unpredictably drop.

Prognosis

With modern medical and surgical techniques, most patients receiving specialty care at a center experienced in treating pheochromocytoma do very well. Published reports prior to 1960 demonstrated very high death rates, sometimes exceeding 50%, during treatment of pheochromocytoma. Now, the risk of death is less than 2% in expert hands. Untreated pheochromocytoma is frequently lethal. A small fraction of patients require further treatment for malignant pheochromocytoma after initial surgery (See below: How often are pheochromocytomas cancerous?).

What causes pheochromocytoma?

Most pheochromocytomas are sporadic, meaning that they occur at random for no identifiable reason. We do know that the tumors arise from chromaffin cells (specialized cells that take up catecholamine precursor amino acids), which are concentrated in the adrenal medulla but do exist in small collections outside of the adrenal glands. Very recent research (2003 and beyond) has clearly demonstrated that many more pheochromocytomas are familial (inherited or syndromic) than previously thought. Experts now believe that somewhere between 20% and 35% of pheochromocytomas are familial – hence the downfall of the 10% rule. Pheochromocytoma-associated mutations are passed on in an autosomal dominant fashion, meaning that all children of affected parents have a 50% chance of receiving the abnormal gene. Inherited syndromes that have been linked to pheochromocytoma include:

Multiple Endocrine Neoplasia type 2 (MEN-2, both type -2A and -2B)
Neurofibromatosis 1 (NF-1)
Von Hippel-Lindau Disease (VHL)
Familial pheochromocytoma/paraganglioma syndrome (SDHB, SDHD)

Special features of inherited pheochromocytomas

Patients with inherited pheochromocytoma syndromes possess unique characteristics. Because the mutation is present in every cell of the body, all chromaffin cells have a chance of growing into a pheochromocytoma tumor at some point during the life span. As one would expect, therefore, inherited pheochromocytoma patients are much more likely to develop multiple tumors and tumors lying outside of the adrenal gland. These must be carefully detected prior to any attempt at surgery.

Inherited pheochromocytoma syndromes are variably penetrant, meaning that only a fraction of people who carry the gene will eventually develop one or more pheochromocytoma tumors. Approximate penetrance rates are 40% for MEN-2, 1% for NF-1, 20% for VHL, and up to 80% for SDHB/SDHD.

How often are pheochromocytomas cancerous?

Uncommonly - fortunately, the majority of pheochromocytomas are benign. The likelihood of malignant pheochromocytoma appears to depend heavily on the underlying mutation. For most sporadic pheochromocytomas, less than 10% turn out to be malignant. The highest rate of malignancy is associated with the SDHB mutation (familial pheochromocytoma/paraganglioma syndrome) which may carry malignancy rates above 50%.

How are pheochromocytomas diagnosed?

Establishing the diagnosis of pheochromocytoma is dependent on the demonstration of significant catecholamine excess. Levels of epinephrine (adrenaline), norepinephrine (noradrenaline), and their metabolites (breakdown products of epinephrine and norepinephrine) can be measured in either urine or blood. Catecholamine metabolites include metanephrine, normetanephrine, dopamine, and vanillylmandelic acid (VMA). Because catecholamine relase varies throughout the day, the best method of diagnosing pheochromocytomas is using a 24-hour urine collection. This involves obtaining a special urine container, which has a small amount of preservative, from a medical laboratory and filling it with one entire day's worth of urine. The test is somewhat inconvenient but well worth the trouble due to its reliability and unrivaled specificity. Frequently, the 24-hour urine collection must be performed more than once to establish diagnostic certainty.

A 24-hour urine test for pheochromocytoma is considered positive if the catecholamine levels exceed two times the upper limit of normal. Many people, particularly those with hypertension, have mildly elevated catecholamine levels that are technically above what is considered the normal range, but fall below two times the upper limit. Virtually none of these people with mild catecholamine excess will turn out to have pheochromocytomas in the final analysis.

Can blood tests be used to diagnose pheochromocytomas?

Sometimes. Blood tests are available for metanephrine, normetanephrine, and chromogranin A. The most commonly ordered blood test for pheochromocytoma is the plasma free metanephrine test. Though more convenient to obtain than a 24-hour urine collection, plasma free metanephrine testing is plagued by frequent false positive results. In other words, the tests creates a false alarm where the patient appears to have a pheochromocytoma, but in reality s/he does not. False positive results like these are a frequent source of confusion for both patients and physicians alike. For this reason, 24-hour urine testing remains the gold standard.

How are pheochromocytomas located?

Imaging tests and scans Imaging should only be performed after the diagnosis of pheochromocytoma has been established with 24-hour urine testing. Several types of scans can be used to locate pheochromocytomas. These include cross-sectional scans, functional scans, and co-registered (hybrid cross-sectional and functional) scans. Cross-sectional scans yield detailed anatomic information, whereas functional scans utilize specific molecules (tagged with tiny amounts of a radioactive tracer) that target specific tumor properties.

Cross-sectional scans
Computed tomography (CT or CAT scan)
Magnetic resonance imaging (MRI)

Functional scans

¹³¹I-meta-iodobenzylguanidine scintigraphy (MIBG scan)
¹⁸F-deoxyglucose positron emission tomography (regular PET scan, also known as FDG-PET scan)

Co-registered scans

FDG-PET/CT scan
¹⁸F-DOPA PET/CT scan

Of the above, CT and MRI are most commonly used due to their wide availability. MIBG scanning is also frequently used, though the quality of the images depends highly on the experience of the center. MIBG scanning is highly specific for pheochromocytoma, and carries the added advantage of being able to locate multiple tumor areas (also known as foci). Regular FDG-PET is useful in identifying rapidly growing tumors that consume large amounts of glucose (sugar). It is capable of imaging a subset of pheochromocytomas.

¹⁸F-DOPA PET/CT scanning is the most advanced imaging technique listed above. This highly sensitive, co-registered scan merges anatomic definition and functional data into a single, three-dimensional landscape. It is very reliable in detecting multiple tumor foci and has surpassed MIBG scanning where available. ¹⁸F-DOPA PET/CT scan is only available at selected specialty centers such as the National Institutes of Health (NIH), UCLA, and a few sites in Europe.

How are pheochromocytomas treated?

The great majority of pheochromocytomas are successfully treated with surgery. Surgery can only be performed safely after the careful administration of alpha-blockers (medications such as phenxoybenzamine, which render the body less sensitive to catecholmine surges) for at least two to three weeks prior to surgery. The importance of meticulous pre-operative conditioning with alpha-blockers cannot be overemphasized. In fact, this single intervention is largely responsible for the improvements in outcome that pheochromocytoma patients have enjoyed over the past half-century. In select cases, beta-blockers (medications that slow the heart rate) may be added after adequate alpha-blockade has been established.

At expert centers, most pheochromocytomas are removed laparoscopically. This is true for most tumors arising from the adrenal glands, as well as select tumors arising elsewhere. The key to successful surgery is effective teamwork between the surgeon and anesthesiologist. In other words, both the surgeon and the anesthesiologist must be versed in pheochromocytoma treatment, and ideally the two will have performed a number of similar operations together previously.

After surgery, patients frequently require close monitoring in the intensive care unit. Most patients who undergo laparoscopic surgery stay one to two days in the hospital, after which they return to normal activities within one to two weeks.

What are the treatment options for malignant pheochromocytoma?

After aggressive surgery has been carried out, adjuvant treatment options include:

Combination chemotherapy
External beam radiation therapy
High-dose 131I-meta-iodobenzylguanidine (MIBG) radionuclide therapy

Of course, ongoing hormone excess must be treated with long-term alpha-blocker therapy in all cases where catecholamine levels remain demonstrably high after surgery. MIBG radionuclide therapy is available at a small number of centers in the United States, under a research protocol.