Finding Elusive Pheochromocytomas Review of studies by Graeme Eisenhofer, Ph.D. A newly developed blood test to detect potentially deadly tumors that form in the adrenal glands has been shown to be significantly more sensitive than traditional diagnostic tests. The new test provides earlier and more accurate diagnoses of these tumors in patients with an inherited predisposition to develop them, possibly preventing complications or death. The study, led by researchers at the U.S. National Institute of Neurological Disorders and Stroke (NINDS) and the National Cancer Institute (NCI), appeared in the June 17, 1999, issue of The New England Journal of Medicine. "Although rare, these tumors are clinically important because they must be excluded as a surgically curable cause of hypertension in many of the people who develop high blood pressure," says Graeme Eisenhofer, Ph.D., a researcher in the Clinical Neurocardiology Section of the NINDS, and lead author of the study. "If the tumors are not diagnosed and removed, they can have potentially catastrophic consequences for the patient." The mainly benign tumors, called pheochromocytomas (pheos), are sometimes found in patients with von Hippel-Lindau (VHL), a familial cancer syndrome with neurologic complications in which affected individuals inherit a predisposition to develop tumors in a number of organs, including the adrenal glands that sit atop the kidneys. "Pheochromocytoma can occur in VHL patients as young as 4 years of age. Deaths from unsuspected adrenal gland tumors have been reported in young children in these families and it is important to make the diagnosis early so that surgical intervention can be performed," said W. Marston Linehan, M.D., NCI’s Chief of Urologic Surgery. A patient who develops pheos for any reason is at risk for dangerous and unpredictable surges in blood levels of certain adrenal gland hormones that regulate blood pressure and which are responsible for the so-called "fight or flight" responses to stress. The surges in hormones and resulting spikes in blood pressure put the patient at risk for heart attack, stroke, hemorrhage, or sudden death. Currently, the most reliable tests for pheos use imaging technologies, such as CT (computed tomoraphy) or MRI (magnetic resonance imaging), which can be time-consuming and expensive and which do not necessarily identify a tumor as a pheo. Confirmatory biochemical tests are required for accurate diagnosis. Several biochemical tests are available which measure blood and urine levels of the adrenal gland hormones. But in many cases these tests are not accurate, because some pheos do not release the adrenal hormones regularly or in significant amounts. These tests depend upon catching the pheo during an active episode. Drs. Eisenhofer, Linehan, and their colleagues studied enzymes important in catecholamine production that may have altered activity in pheos in contrast to normal adrenal tissue. Metanephrines are produced mostly by pheos, not normal tissue. Dr. Eisenhofer and colleagues found that measurements of blood levels of these chemicals makes it easier to differentiate secretion of normal tissue versus pheo. Thus these measurements give a more accurate diagnosis of pheos. A person with a normal plasma concentration of metanephrine and normetanephrine can be fairly confident of not having a pheo. Because of the high reliability of this tests, additional tests are not needed to rule out a pheo, significantly reducing costs. Altogether, they measured the amounts of normetanephrine and metanephrine in 26 patients with VHL and 9 patients with multiple endocrine neoplasia type 2 (MEN2), another rare genetic disease characterized by pheochromocytomas. Use of the new test detected 97 percent of the tumors, whereas the other tests detected only 47 to 74 percent of tumors. Although particularly useful in diagnosis of tumors in VHL and MEN2, the test also shows promise for improved diagnosis of pheos in the much larger population of patients with high blood pressure where the tumor needs to be excluded. Symptoms. Pheochromocytomas are usually benign. They may occur in or near the adrenal glands, or anywhere along the sympathetic nervous system roughly from the base of the skull to the bladder. The most apparent symptom, caused by the increased secretion of epinephrine and norepinephrine, is hypertension, or high blood pressure. This hypertension may be constant or intermittent. Attacks may occur every few months or several times daily, and typically last less than five minutes. Physical and emotional stresses can initiate an attack. During severe attacks, patients may experience headache, sweating, apprehension, palpation, tremor, pallor or flushing of the face, nausea and vomiting, pain in the chest and abdomen. There may be a tingling, burning, or crawling sensation on the skin of arms or legs or urinary difficulties. Testing options. The most commonly used test for a pheo is a 24-hour urine collection. All the urine is collected for a 24-hour period, kept refrigerated, and then analyzed for levels of catecholamines and epinephrine. Patients are asked to avoid caffeine, bananas, vanilla, chocolate and a lengthy list of other foods for two days before the test. Many foods can cause false positives, but caffeine is the most frequent cause of false negative results. The test is somewhat inconvenient, as you have to keep a jug of urine in the refrigerator, and you have to remember to save all urine for this period, even if you wake in the middle of the night. This test is even more difficult to perform reliably with a small child. Pheos that occur in the adrenal glands themselves are usually the easiest to find. They usually appear quite clearly on a CT or MRI, even when they are quite small. CT and MRI are equally good at showing them. The hardest ones to find are those which occur outside the adrenal glands, in the tissue of the sympathetic nervous system, anywhere from the base of the skull to the bladder. Dr. Eisenhofer and his colleagues compared the normetanephrine and metanephrine levels in the blood against the blood levels of catecholamines (epinephrine and norepinephrine) and the levels of these and other chemicals in the urine. They found that the blood test was 97% accurate in detecting the presence of pheo tumors, while the other biochemical tests were only 47% to 74% accurate. All patients with MEN-2 had high blood concentrations of metanephrine, while the patients with VHL had almost exclusively high blood plasma concentrations of only normetanephrine. One person with VHL had a normal plasma level of normetanephrine. This patient had a very small adrenal tumor (less than 1 cm.) The higher the sensitivity of measurements of plasma normetanephrine and metanephrine, the more accurate the test in finding pheos. The study recommends use of HPLC measurements of plasma free normetanephrine and metanephrine as the initial biochemical test of choice. To avoid false-positive results, a list of any drugs the patient may be taking should also be considered, and the patient must be cautioned not to take acetaminophen in any form (e.g. Tylenol, Excedrin, or as an ingredient in cold medications) for at least five days before the sample is drawn. It is best if the sample is obtained in the morning after an overnight fast (water and non-caffeinated soft drinks are permissible). Caffeinated or even decaffeinated coffee should be avoided for at least 24 hours before the test, and the doctor should be told if these have been taken, as they can cause higher levels of dihydrocaffeic acid in the bloodstream and reduce the accuracy of the test. If plasma free metanephrines have been run, and they are well within the normal range, then it is highly unlikely that the patient has a pheo and there is little need for further tests. On the other hand, blood or urine catecholamines, even when performed in combination, may yield normal results when there is in fact a pheo present. Locating the tumor. In most cases of positive biochemical results, CT or MRI scan of the entire abdomen will usually locate the tumor. However, in many cases it is also appropriate to follow up with MIBG scintigraphy -- preferably using the 123-iodine labeled compound rather than the 131-iodine labeled compound -- to establish more reliably that a located mass is a pheochromocytoma, or to locate an extra-adrenal pheo. 123-iodine is ten times as sensitive as 131-iodine. It tends to be less available because it has a much shorter half-life and therefore has to be used within 24 hours of preparation. It is most available near large university centers where they are able to do the "labeling" process in their own research facilities. MIBG-131 finds only 60% of pheos in VHL; MIBG-123 finds in the range of 95%. Treatment. The treatment of choice whenever possible is laparoscopic adrenal sparing surgery. Since VHL patients often have bilateral pheos in the course of their lifetime, it is important to retain as much adrenal function as possible even when dealing with a single pheo. 1. Eisenhofer, G.; Lenders, J.W.M.; Linehan, W.M.; Walther, M.M.; Goldstein, D.S.; Keiser, H.R. "Plasma normetanephrine and metanephrine for detecting pheochromocytoma in Von Hippel-Lindau disease and multiple endocrine neoplasia type 2." N.E.J.M. 340:24 (1999) 1872-1879. 2. Eisenhofer, G; Walther, W.M., et al, "Plasma Metanephrines: Novel and Cost Effective Test for Pheochromocytoma," Proceedings of the 1st International Meeting on Adrenal Diseases, Brazilian Journal of Medical and Biological Research, September 7, 1999. 3. Sources of testing for plasma metanephrines: (1) Clinical testing with a 2-day turn-around is available from the Mayo Clinic by calling 1-800-533-1510 or +1 (507) 266-5700. The published fee as of 8 Nov 1999 was $122.50. CPT code 82491. Please ask for information on blood drawing, shipping instructions, and patient instructions. Our thanks to Dr. Walther, Dr. Eisenhofer, Debra Harlander and Mary Peebels and the Pheochromocytoma Support Group for their assistance with this article and for their ongoing partnership in support of people with pheos. See http://members.aol.com/ThreePeb/indexpheo1.html As printed in the VHL Family Forum 7:4, December 1999.