Pheochromocytoma - Treatment and Diagnosis
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).
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.
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
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:
- Heart attack
- Kidney failure
On the other side, some pheochromocytoma patients experience shock (dangerously low blood
pressure) when catecholamine levels suddenly and unpredictably drop.
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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
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)
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.
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%.
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.
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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.
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)
- 131I-meta-iodobenzylguanidine scintigraphy (MIBG scan)
- 18F-deoxyglucose positron emission
tomography (regular PET scan, also known as FDG-PET scan)
- 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.
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.
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.
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.
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.
After aggressive surgery has been carried out, adjuvant treatment options
- 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
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