Pheo functional transformation

 It is well known that most pheos in the adrenal glands are functional in that they produce excess catecholamines. About half of paras are functional and the other half non-functional in this sense. Whether a non-functional para can turn into a functional one is not clear. 

Functional transformation (from a non-functional tumor to a functional tumor) is well known in other neuroendocrine tumors. To be clear, pheos are a subtype of neuroendocrine tumors. For example, a non-functional pancreatic neuroendocrine tumor can suddenly produce a myriad of hormones, causing ectopic Cushing’s syndrome, hypoglycemia, or hypercalcemia. 

A case report is just published describing a young man with cyanotic congenital heart disease who has a para that was initially not functional. In a matter of a few years, the para grew in size and began to produce large amounts of catecholamines, even resulting in cardiomyopathy. The patient’s heart function recovered well after the para was removed. The case report reviews the literature and finds 2 precedent cases. In all three cases including the one just published, the functional transformation is associated with either tumor growth or metastasis. 

Pheo functional transformation is thus possible and should be suspected when new symptoms arise.

Dr. Pheo

Pheo in cyanotic congenital heart disease

In a post I wrote almost 8 years ago (“A non-genetic risk factor for pheo?” in February 2015), I described an article that suggests cyanotic congenital heart diseases may predispose people to develop pheo. Since then, a few seminal papers have provided insights into that phenomenon. In my own practice, I have taken care of several patients with cyanotic congenital heart disease who develop pheo at young ages.

In 2018, a paper showed for the first time that 4 out 5 patients with pheo and cyanotic congenital heart disease had somatic mutations in the gene EPAS1 (which encodes hypoxia-inducible factor 2-alpha) in their pheo tumors. These mutations are not inherited but develop spontaneously. Similar mutations are also responsible for the polycythemia-paraganglioma-somatostatinoma syndrome (see post “The story of Para and Poly: Are they related?” in September 2012). The difference is that the EPAS1 mutations in the pheo of people with cyanotic congenital heart disease appear to only happen in the cells that give rise to pheo (paraganglia cells, including cells of the adrenal medulla). In this year (2022), a larger study confirmed the findings. It is thus pretty clear that hypoxia favors the proliferation of paraganglia cells that harbor EPAS1 mutations, resulting in pheo formation.

In my experience, people with cyanotic congenital heart disease often have frequent imaging evaluations so that a pheo or para can be easily seen so long as the doctors have a high alertness about those tumors. It is not unusual for a small tumor to be omitted first but re-discovered years later. The typical locations and imaging features of the tumors make the diagnosis quite straightforward. It is not easy, however, to determine if the tumors are functional in that whether they secrete catecholamines, because people with cyanotic congenital heart disease often have slightly high pheo marker levels in the absence of such tumors. Timing of surgical removal of the tumors is also quite complicated. A tumor with clear evidence of catecholamine secretion should be removed as soon as possible.

Dr. Pheo

Pheochromocytomatosis

Most people probably have not heard of the term “pheochromocytomatosis.” Pheochromocytoma itself is already an odd word, let alone pheochromocytomatosis. The more I practice medicine, the more evident is to me that a disease’s presentation and natural history could be affected by medicine itself. Even 30 years ago, pheochromocytoma was still mostly suspected based on clinical symptoms; with the wide use of imaging, most cases of pheochromocytoma nowadays are found incidentally by imaging. Pheochromocytomatosis is likely a modern phenomenon associated with laparoscopic adrenalectomy.   

A pheochromocytoma is surrounded by a fibrous capsule. During a surgical operation, the surgeon separates the pheochromocytoma from the normal tissue and organs and removes the tumor with the capsule intact, so that no tumor is left behind. That usually did not pose a problem in the era of open operation to remove the pheochromocytoma. During a laparoscopic operation, inexperience in surgical skills or accidents can result in rupture of the capsule and tumor cell spillage into the abdomen. The spilled tumor cells can form numerous tiny tumors that may grow to a few centimeters, which is called pheochromocytomatosis. It is not clear how often tumor capsule rupture occurs during adrenalectomy and how often pheochromocytomatosis occurs in those with tumor capsule rupture.

Once pheochromocytomatosis happens, it becomes an incurable problem. Pheochromocytomatosis, however, is indolent and may manifest itself years after the original operation. As pheochromocytomatosis is very rare, we are not sure how to best control it. Reoperation is usually done to remove visible gross tumors. Patients are then monitored. If the tumors grow again, MIBG radiotherapy or PRRT can be tried. If the tumors are still growing after the radiotherapies, somatostatin analogs and other agents may be used.

Dr. Pheo

Telemedicine for pheo

I hope everyone has been as safe and healthy as possible during the COVID-19 pandemic!

During the early days of the pandemic, I saw most patients by telemedicine in the form of a video visit. I did see quite a few pheo patients by telemedicine as well. My experience with telemedicine for pheo patients and my interaction with readers on this blog convince me that pheo is the model disease for telemedicine.

As physical examination, a key part of patient visit, rarely contributes to the diagnosis and treatment of pheo, telemedicine for pheo does not lose much compared with traditional patient visit. History taking and review of laboratory test results and imaging studies are the same in telemedicine and in traditional patient visit. The time and cost saved by telemedicine on the patient’s part can be tremendous. With telemedicine, a patient can access a pheo expert much more easily even if the expert is in another city.

Of course, nothing can replace the personal touch, the body language, and the many subtle details during an in-person visit. For the purpose of pheo diagnosis and treatment, however, the convenience of telemedicine offsets its shortcomings. Many of my colleagues feel that telemedicine will be here to stay as an important alternative to in-person visit. For patients with suspected or known pheo, telemedicine will continue allowing them to access pheo experts not locally available.

Dr. Pheo

Why are the repeat test results different?

Happy Holidays!

For a serious diagnosis like pheo, repeat testing of pheo markers is generally a good idea. Pheo test results from the same patient even within a few days or weeks can be quite different at times. Patients having acute illness, anxiety attack, or any emotional or physical stress would have higher pheo marker levels than when they are healthy and restful. The position (sitting or lying) of patients getting blood draw matters. Random variations are always possible. Laboratory errors do happen as well. If the two test results are concordant (which fortunately are more common), we can confidently say whether the patient has normal or abnormal pheo marker levels. If, however, the two test results are discordant (one abnormal and one normal, or one very high and one only slightly high), what shall we do?

There are several factors to consider. First, we need to see the quantitative differences between the two results. If one result is in the high normal range and the other slightly abnormal, they are essentially similar and concordant results. Second, we need to delve into the details on the patient’s mental and physical condition when the tests are done. If the patient is seriously ill when one test is taken, the result is likely higher and does not necessarily suggest pheo. Third, we need to ask ourselves the likelihood of this patient’s having pheo is high or not, based on the grounds why we test for pheo in the first place. Of course the more suspicion we have, the more likely the abnormal result is true. Fourth, past research has shown that if there are no laboratory errors, a single normal test result rules out pheo in most patients. Thus a negative pheo test result should be given more weight in general. Last, when we are really not sure, imaging is needed to give us more information.

Dr. Pheo

Ten years and going strong!

I started the Dr. Pheo blog on March 19, 2009. At that time, I was not certain how long the blog would last. Today, exactly 10 years later, I am pleased to see the blog is still going and going strong! I thank my family, friends, colleagues, patients, and especially readers for your support and encouragement in all these years.

      Pheo is a fascinating but challenging disease. In the last 10 years, we witnessed the explosive growth in pheo genetics and pathogenesis. Genetic tests for pheo are now widely available. We also observed the unraveling of the natural history of pheo and the understanding of pheo-induced heart problems. More doctors now recognize that small pheos exhibit features distinct from those of large pheos. The diagnosis of pheo progressed right in front of our eyes. Metanephrines are now accepted by most doctors as the best tests and are more available world-wide. The imaging characteristics of pheo were firmly established with the emergence of many nuclear imaging tools. In spite of the advancements, two major challenges still face us: misdiagnosis of pheo and management of malignant pheo.

      I will continue the blog as long as I can. I will remain anonymous.  

   

Dr. Pheo

Plasma or urine metanephrines?

I have discussed plasma versus urine metanephrines in the past. Recently a few doctors asked me this question again. I figure that if some doctors are not clear whether to order plasma or urine metanephrines, patients probably also want to know the pros and cons of plasma and urine metanephrines.

      First of all, both tests are great. If your local area only offers one of them, take it. If your local area offers both tests, which one is better? Shall you do both? My personal preference is plasma metanephrines. The plasma test is convenient and can be done to any patient at any time. The only small drawback is the blood draw itself. If you really hate needles, the plasma test could be an issue. The urine test offers no practical advantage over the plasma test. In theory and in earlier reports, the urine test is less prone to false positive results. In real clinical practice, the urine test and the plasma test perform similarly. The urine test is laborious to collect (24-hour urine is required), not reliable in patients with kidney problems, and hard to do in children. Lastly, the urine test results have to be corrected by urine creatinine. I have seen patients who passed ~5 liters of urine in 24 hours; of course the metanephrines levels are higher simply because of the large urine volume. The results usually are more accurate after they are divided by the total amount of creatinine in the urine. Again I want to emphasize that I personally don’t see why one would need the urine metanephrines for pheo diagnosis if plasma test is available. There is also no need to do both tests.

       

Dr. Pheo