At a Glance

Pheochromocytomas (PCC) are rare, potentially life threatening catecholamine secreting tumors of chromaffin cells, most often arising from the adrenal medulla (90%) but also sometimes from the extra-adrenal sympathochromaffin cells (10-15%; called paragangliomas in those sites; most often in the abdomen). Most PCCs (90%) are benign, but up to 10% may be malignant, metastasize, and recur. Most occur in adults between 40-50 years of age.

The most common associated symptom is hypertension (HT), classically described to be paroxysmal. However, patients with a PCC may be normotensive or have usual sustained HT. Their HT may also be labile and refractory. The classic triad of signs and symptoms along with HT is head ache, sweating, and tachycardia, but many patients do not have this complete triad. The classic paroxysms of HT associated with catecholamine release usually last less than 1 hour and may occur several times per day or only every several months. However, essential HT may also be paroxysmal and labile.

There is a wide range of symptoms associated with PCC, and many of these are non-specific, related to the pattern of catecholamine release, and seen more typically in other diseases. In fact, only 1 out of 300 people who are worked up for PCC actually have the tumor, but the consequences of missing the tumor are so severe and the differential diagnosis so wide (e.g., essential HT, stress, anxiety, thyroid disorders, and diabetes) that many people warrant laboratory screening. PCC is also a potentially curable form of HT.

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Most PCCs are sporadic, but certain familial syndromes are associated with PCC. These include MEN2a and 2b, Von Hippel Lindau syndrome, Neurofibromatosis Type 1, and succinate dehydrogenase mutations. Anyone with or having a family history of those syndromes should be periodically screened for PCC, since those patients are considered at high risk for the tumor. Younger adult patients with PCC symptoms may have one of these syndromes.

A number of PCCs are detected as part of a work-up for adrenal “incidentalomas,” detected on radiographic studies for other conditions. Some PCCs have also only been found incidentally at autopsy.

The range of signs and symptoms associated with PCC includes anxiety, tremor, fatigue, weight loss, pallor, dyspnea, nausea, papilledema, signs of glucose intolerance, polycythemia, leukocytosis, idiopathic dilated cardiomyopathy, and unusual blood pressure responses to certain stimuli. These latter stimuli include certain foods, drugs, anesthesia, surgery, medical procedures, exertion, torso twisting, straining, exertion, or coitus and may reflect stimulation of tumor catecholamine secretion. PCC patients may also have hypotension due to low blood volume or with surgery, anesthesia, or pregnancy. Some patients may show evidence of a local mass effect.

Finally, if a patient has a history of a treated PCC, he or she may have a recurrence or evidence of malignancy even years later. There is currently no histologic or biochemical way to distinguish benign from malignant tumors, but markers are being investigated.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

When ordering biochemical tests for PCC, it is important to consider the following:

Small or early tumors may not secrete excessive catecholamines, so repeat testing may be necessary.

Is the patient at high or low risk for PCC? High-risk patients should have the most sensitive test possible to avoid missing a diagnosis. Low-risk patients (i.e., most being tested) should have the most specific test to rule out the diagnosis and avoid false-positive results causing unnecessary work-ups.

Normal levels of catecholamines are age and sex dependent and depend on a patient’s condition (e.g., hypertension, stress, or medications). Any result must be compared to tables of expected results or “reference ranges” from the laboratory used.

Many medications may interfere with some test methods or raise or lower endogenous catecholamines, so, before ordering a test, check with the laboratory to see if a medication needs to be discontinued (not possible in all cases). Methods have improved to avoid some interference.

Rare tumors are nonsecretory, and there may be variability in the pattern of catecholamine secretion, including rare tumors that only secrete dopamine. Elevated levels of catecholamines or their metabolites may be continuous or only intermittent, so false-negative results may occur. Generally, the epinephrine and norepinephrine metanephrine metabolites are continuously produced, making them better screening choices.

Catecholamines are normally also produced in nontumor tissues, so tests specific for intratumor production or metabolism are best (e.g., plasma free/fractionated metanephrines).

High risk patients include those with:

familial syndromes associated with PCC or a family history of PCC

patients with prior PCC and symptoms suggesting recurrence

patients with very suspicious radiographic studies

Low risk patients are:

most patients screened because of HT and other nonspecific symptoms

patients having nonsuspicious, incidentally discovered adrenal masses

Given these factors, the two most highly recommended frontline tests are:

plasma free/fractionated metanephrines by HPLC/tandem mass spectroscopy for high risk patients or to confirm a positive test for #2, if necessary

urine free/fractionated metanephrines for low risk patients or to confirm a positive test for #1, if necessary

Plasma free/fractionated metanephrines are considered highly sensitive but less specific, so they may have more false-positive results and may result in more unnecessary follow-up testing. Twenty-four hour free/fractionated urinary metanephrines are more specific and are better for screening the majority of patients who do not have PCC. They can be followed by the plasma test, if necessary.

Each of the described tests may have special patient preparation and specimen procurement requirements, so one should check with the local or reference laboratory for those.

It may occasionally be indicated to perform a clonidine suppression test if results of both of the described tests are equivocal, but the clonidine suppression test requires special oversight and consideration of patient condition. Some PCCs may also result in false-negative suppression tests.

Older or other tests, such as urine for VMA or HVA, plasma or urine catecholamines, chromogranin A, and other provocative or suppression tests, are not sufficiently sensitive or specific compared to the frontline tests described for diagnosis but may be considered for equivocal cases to support a clinical impression or for monitoring of treated patients.

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications – OTC drugs or Herbals – that might affect the lab results?

The patient’s underlying medical or psychological situation can affect catecholamine secretion and sensitivity or specificity of tests as noted. Some test methods may also have drug or substance interferences, but newer HPLC/tandem mass spectroscopy methods can avoid those. One should check the information specific to the method and laboratory performing it.

Most metanephrines measured will be from intratumor metabolism, but some metabolism from peripheral catecholamine may occur, especially in conditions that raise catecholamine levels. These include:

monoamine oxidase inhibitor antidepressants and consumption of tyrosine rich foods, such as bananas, nuts, or cheese

cocaine, synthetic cocaines, and lidocaine that can inhibit re-uptake of catecholamines

some anesthetic gases

substance or drug withdrawal

Urine testing is preferred on a 24-hour collection, so that episodic symptoms with irregular secretion or metabolism can be captured. Reference ranges are age, sex, and condition dependent (e.g., higher with hypertension), so results must be interpreted according to those ranges. Ranges and cut-off points for diagnosis or further testing should be available from the performing laboratory.

Interferences or patient conditions affecting results should be available from the performing laboratory and may be method specific. Some potential factors to consider include:

patient condition and stress (e.g. hypertension, acute illness)

drugs, such as tricyclic antidepressants, L-Dopa, and acetaminophen

newer methods that eliminate the problems of many older interfering substances, such as acetaminophen

Small, early, asymptomatic, nonsecretory, or dopamine secreting tumors may be negative for the frontline tests and require periodic or sequential testing, depending on clinical suspicion. This is especially true for the familial syndromes.

What Lab Results Are Absolutely Confirmatory?

Values of plasma free/fractionated metanephrines exceeding four times the upper reference limit and urine 24-hour free/fractionated metanephrine values exceeding two to three times the upper reference limit are usually considered diagnostic or compatible with PCC; however, one should consult age, sex, and condition- associated reference ranges from the laboratory used.

Following biochemical confirmation of the diagnosis, CT or MRI testing for tumor localization is indicated. Additional radiographic studies for malignant tumors may be indicated. Suspected familial syndromes may warrant genetic testing.

What Confirmatory Tests Should I Request for My Clinical Dx? In addition, what follow-up tests might be useful?

If the two frontline tests are negative or equivocal and the clinical setting or suspicion for PCC is high, then the following tests may be considered for diagnosis, many of which may also be used to monitor treatment or long-term outcome:

Within urine fractionated/free catecholamines, specific elevated cut off levels may be difficult to assign and may affect the sensitivity or specificity of results. Catecholamines may have a number of factors affecting results. Plasma fractionated/free catecholamine assays are also available and share similar factors with the urine assay.

Chromogranin A is usually used to diagnose or track carcinoid tumors and can also be elevated in PCC and may help monitor treated PCC. It may supplement equivocal frontline testing or confirm a strong clinical suspicion.

Urine VMA or HVA testing is no longer felt to be sensitive or specific assays for PCC diagnosis, but it might be considered for equivocal frontline tests or to confirm a strong clinical suspicion of PCC.

Urine dopamine or plasma methoxytyramine testing may be considered for rare dopamine secreting PCCs.

For known or suspected familial syndromes, testing for known mutations associated with those syndromes should be considered. In patients younger than 40 years of age, it may be indicated to consider a familial syndrome predisposing to PCC.

What Factors, If Any, Might Affect the Lab Results? In particular, does your patient take any medications – OTC drugs or Herbals – that might affect the lab results?

Urine or plasma free/fractionated catecholamine assays are subject to the following factors:

Levels vary rapidly with changes in posture, environmental conditions, such as temperature and noise, and can reflect patient conditions, such as stress, hyper or hypotension, and hypoglycemia.

Nicotine, caffeine, or other foods can acutely affect levels.

Plasma levels may only episodically elevated.

Twenty-four-hour urine specimens are preferred to compensate for episodic catecholamine secretion.

Urine reference ranges are at least age related and may be related to gender or medical conditions, such as hypertension.

Plasma cut-off levels affect the sensitivity or specificity of the tests. Lower cut-offs yield less specific results.

A number of drugs or conditions can affect results, including monoamine oxidase inhibitors, such as antidepressants, cocaine, lidocaine, and similar drugs, some anesthetic gases, substance withdrawal, vasodilators or drugs that affect blood volume, and perhaps tricyclic antidepressants. L Dopa and drugs converted to catecholamines elevate results.

Newer methods may not have the number of interfering drugs as older methods, but, for questions, interferences for specific methods should checked.

Chromogranin A results may be:

elevated with proton pump (e.g., omeprazole) use because of neuroendocrine stimulation

affected by liver or renal disease, because its elimination depends on hepatic metabolism and renal clearance

subject to variations seen in different immunometric assays and show false-positive results due to heterophile antibodies or false-negative results due to a hook effect. Sequential testing should be run in the same laboratory.