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Learning about Pheochromocytomas

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The First International Symposium on Pheochromocytoma was held in Bethesda, Maryland, October 20-23, 2005. It is hard to believe that in 2005, this is the first international symposium ever held on this topic. [See Note 1] Drs. Graeme Eisenhofer and Karel Pacak of the U.S. National Institutes of Health co-chaired the meeting, bringing together 180 participants from all over the world. Forty patients and family members came from as far away as Texas, Michigan, and Oregon to be part of the experience.

Dr. William Manger of New York University opened the conference with this sobering thought: “Tragically up to 50% of pheochromocytomas are still discovered at autopsy, mainly because the diagnosis of this neuroendocrine tumor was not considered.” Families that know they may be at risk of a pheo should know the symptoms of a pheo so that they can help lead their doctors to this diagnosis.

“The very large variety of symptoms and signs encountered in patients with pheochromocytoma frequently suggests a number of other conditions and may mislead and confuse the physician and cause an erroneous diagnosis. This treacherous tumor has correctly earned the title of the “Great Masquerader.” Above all, it is essential when confronted with any manifestation of these conditions that the clinician be forever alert and think of pheochromocytoma!” It is also important for a family with VHL to suggest to their physicians that a pheo should be considered, and be prepared to give literature to their doctors to convey the best possible information – better than they remember from medical school. Alison’s story in the following article is a good demonstration of how a mother saved her children by pressing for the best answers and the best treatment.

In order to raise the rate of diagnosis, the conference focused on:

• Understanding the many ways pheos may present, to raise consciousness of these symptoms
• Agreeing on diagnostic criteria, especially agreeing on the tests needed to diagnose a pheo
• Agreeing on which biochemical tests are the most specific for pheo, and the most sensitive in finding even smaller tumors
• Agreeing on which imaging studies are the most effective in finding extra-adrenal pheos
• Agreeing on when patients should be screened for one or more of the genetic alterations that can result in a pheo.

Familial pheochromocytomas may occur in people with any one of six known genetic syndromes:

• Von Hippel-Lindau (VHL)
• Multiple Endocrine Neoplasia (MEN, especially type 1)
• Neurofibromatosis Type 1 (NF1)
• A newly recognized panel of genes referred to as SDHB, SDHC, and SDHD which cause head and neck paragangliomas

And at least 70% of pheos occur at random in the general population.

Pheochromocytomas (called “pheos” for short) were first described by Frankel in 1886. Dr. Von Euler won the 1946 Nobel prize for proving that norepinephrine (NE) was a neurotransmitter. But diagnosing and localizing or finding pheo within the body has been extremely difficult until recent advances in imaging and chemical diagnosis.

Pheos arise from chromaffin tissue in the sympathetic nervous system. 85% of pheos occur in the adrenal glands, but 15% occur outside the adrenals. These “extra-adrenal” pheos are called paragangliomas. For simplicity, the term “pheo” is here used to include these neuroendocrine tumors, wherever they occur in the body. The genetic factors involved in pheochromocytoma/ paraganglioma (Pheo/PGL) syndromes represent a perfect example for these exciting advances in modern biomedicine (4-7). Until recently, more than 90% of these rare but clinically important catecholamine-producing tumors were thought to occur as sporadic nonhereditary entities that should not need any genetic screening unless there was a family history of a certain form of multiple endocrine neoplasia. The last three years have seen mounting evidence that a substantial proportion of patients with these tumors have a definable genetic defect with potentially important clinical implications.

Debra Harlander, Pheochromocytoma Support

They are usually described as exhibiting a classic triad of symptoms: headache, palpitations, and sweating. But not everyone exhibits all three symptoms. Dr. Debbie Cohen of the University of Pennsylvania and others shared statistics for their patients that showed that approximately 60% of patients complain of headaches, about 50% have palpitations or panic attacks, and about 35% have sweating. Some have all three, but more often people exhibit one or two of these symptoms. And some have none of these three symptoms at all. Nearly 50% have normal blood pressure.

Pheos in pregnancy are often misdiagnosed as pre-eclampsia. Failure to recognize a pheo in pregnancy carries a high mortality rate for both the mother and the fetus. As long as the doctor knows about the pheo, especially early in the pregnancy, precautions can be taken to protect the mother and the child.

In studies of “incidental” findings of pheos (found while looking for something else), the pheos found in this way are generally large -- 5-11 cm (2-4.5 inches in diameter). Such a large tumor has likely been growing for a number of years, and has probably been causing symptoms for some years.

Dr. Marta Barontini from Argentina shared her study spanning her 40-year career in pediatric medicine. She finds that pheos in children have more severe and more sustained symptoms than in adults. It is especially important to do genetic studies in children with pheos, as a higher percentage of them have a genetic syndrome. She has stayed in touch with all her patients, and has recalled them for genetic screening as additional genetic information has become available.

Dr. Henri Timmers of the Netherlands did a review of 141 papers in the medical literature on pheos in pregnancy, reporting a total of 174 cases. Only 7% of these had previously been treated for pheo, and only 17% of them had any history of high blood pressure. The initial diagnosis was wrong in 31% of these cases. The risks to the mother were highest in cases of incorrect diagnosis. The outcome for both mother and child were largely dependent upon timely recognition of the problem, and appropriate treatment. Things tended to go best when the pheo was removed earlier than 24 weeks of pregnancy, or if the pregnancy was carefully managed to term and the pheo was removed after delivery. It is critically important to inform the obstetrician if the patient might be at risk of a pheo so that the mother and child can be diagnosed early and treated carefully.

How is it that six different genes can all cause a pheo? Dr. William Kaelin presented the work he published in Cancer Cell. Mutations in VHL, RET, NF1, SDHB, SDHC, and SDHD can give rise to pheochromocytoma/paraganglioma. These different genetic lesions may all act by decreasing the activity of a 2-oxoglutarate-dependent oxygenase, SM-20/EglN3/PHD3, resulting in reduced apoptosis of neural crest cells during development.” [3]

There are a number of checks and balances in the cell that verify that cells are proceeding properly. If they are badly formed, the body’s normal protective mechanisms kill off the badly formed cell and make a new one. This is a process called apoptosis. In the case of pheos, cells that would normally have been killed off go on to become tumors. These genes interfere with the normal process of apoptosis and allow the cell to become a pheo or paraganglioma. The most important messages for people with familial syndromes that may cause pheos is to keep strong, to monitor for early detection, and do what you have to do to get appropriate treatment. Read, learn, and help to bring your doctors up to speed on pheos. Remember that you can’t protect yourself if you don’t know you are at risk. Make it your business to find out whether you may be at risk, and take responsibility for your own health and that of your children.

Dr. Hartmut Neumann of Germany planing the violin at dinner, a tradition at VHL meetings. Photo by Debra Harlander.

Since knowledge about pheochromocytoma/paraganglioma syndromes is so scarce among the vast majority of physicians and health practitioners, the conference participants asked that recommendations and updated treatment guidelines should be posted on the PRESSOR website (www.pressor.org) along with a list of centers with a satisfactory level of experience in treating pheochromocytoma. This information will be developed over the coming year. The formal Proceedings of this conference will be published in the Annals of the New York Academy of Sciences, forecasted for October 2006.

See related family story next

See Ask the Experts follow-up in April 2006 issue

Notes: Our thanks to Prof Stefan R. Bornstein, University of Dresden, Germany, Debra Harlander, and Jo Ann Monroe of the Pheochromocytoma Support Board for their assistance in the preparation of this report.

1. An earlier meeting broke ground for this effort atCold Spring Harbor NY in November 2003. For the results of that conference, see Endocrine-Related Cancer (2004) 11: 423-436.

2. Finding a pheo or paraganglioma is best done with CT or MRI, or an MIBG. An MIBG test is a nuclear medicine procedure using a radioactive isotope or tracer, which is absorbed by pheochromocytoma tissue. Meta-Iodo-Benzyl-Guanidine (MIBG) is injected into the patient before the scan is performed, making the pheo stand out clearly on the diagnostic pictures. There are two radioisotopes used for this purpose, 131-MIBG or 123-MIBG. 123-MIBG is far superior, but has a shorter half-life and must be used within hours of being made up. Nonetheless it is becoming more available because of its greater ability to seek out pheos and paragangliomas wherever they are hiding in the body.

3. S. Lee, W. Kaelin, et al., Neuronal apoptosis linked to EglN3 prolyl hydroxylase and familial pheochromocytoma genes: developmental culling and cancer. Cancer Cell. 2005 Aug;8(2):155-67. The quote is from the commentary in the same issue by Dr. Patrick Maxwell, A common pathway for genetic events leading to pheochromocytoma. Cancer Cell. 2005 Aug;8(2):91-3.

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As printed in the VHL Family Forum 13:6, December 2005. For permission to reprint, please contact VHL Family Alliance, editor@vhl.org.

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