Pheo and brown fat

Happy holidays!

Brown fat is a special fat that functions to generate heat for the body. Brown fat usually locates in the neck, shoulder, and along the spine. Brown fat is common in newborn babies and its purpose in babies is to protect babies from hypothermia. This is important as babies have a relatively larger body surface area and are more sensitive to ambient temperature. Brown fat is gradually lost as we become adults but persists in some. Brown fat is activated to produce heat when the body senses that its temperature may drop. The way the brown fat is activated to produce heat is by catecholamines.

In people with pheo, brown fat can be activated, likely due to the catecholamines released by pheo. The extent of brown fat activation is very variable. Most older people with pheo don’t show much brown fat activation. In young adults with pheo, brown fat activation can be extensive. Brown fat is very positive in FDG PET and somewhat positive on DOTATATE PET, so it can cause concern to those uninitiated on this phenomenon. Most radiologists can tell brown fat from pheo very readily. Thus brown fat activation associated with pheo is mostly an interesting observation; it can also help make the pheo diagnosis in a person with adrenal mass and brown fat activation.

Dr. Pheo

Late pheo metastasis

Some people with pheo will unfortunately develop metastasis. The most common organs that pheo metastasize to are the bones, liver, and lungs. There are a few predictors of pheo metastasis risk such as certain pheo-predisposing gene mutations (e.g. SDHB), primary tumor size, and histological findings (e.g. the PASS score). In clinical practice, the metastasis risk of an individual patient is pretty hard to predict. Some patients are followed for years after pheo resection. Shall we continue following them?

Once in a while, pheo metastasis is found many years after pheo resection. The record is 53 years. I have a patient who was found to have metastasis 52 years after pheo resection. It is not to say that the metastasis happens only after these many years. Based on studies of other cancers, metastasis likely happens before the pheo resection. The metastatic lesions remain microscopic and dormant. Years later, due to unclear reasons, the tiny lesions awaken and begin to grow, kind of like what happened in those dormant spy movies. Thus I favor continued pheo surveillance even in patients with a remote pheo history. I have diagnosed pheo metastasis in a couple of such patients.

Dr. Pheo

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

In case I missed your questions...

Only a few days ago, did I realize that I had missed several questions from the Dr. Pheo blog. I have not received any email alerts on new questions since late May 2018. Initially I thought perhaps it was summer time or perhaps readers found answers from previous posts. Then I saw a few comments on the blog a few days ago. That was strange because I was supposed to get email alters on new comments. I certainly did not change any settings and I checked again and found all the settings were the same.

Then I googled the problem. Wow, so many other bloggers had similar problems. It looked like Google Blogger required bloggers to re-consent receiving email alerts. The bottom line is that I can now receive email alerts of your questions. If you posted questions in late May or after, and did not receive answers from me, please post your questions again if you still need the answers.

Dr. Pheo

Incidental pheo (?) found by DOTATATE PET

Whenever a new imaging method is used widely, incidental findings from it are encountered. The new Ga-68 DOTATATE PET is no exception. It is well known that DOTATATE signals are normally found in the pituitary, salivary glands, thyroid, liver, spleen, and adrenal glands. Some people may also have signals in the pancreas.
      Although the adrenal glands are known to be lit up by DOTATATE PET, the signal from normal adrenal glands is usually low. A technical jargon called the standard uptake value (SUV) quantitatively describes the intensity of PET signals. Unfortunately, different machines give out different SUVs on the same organ of the same patient. The SUV thus has relative importance only in the same patient using the same machine.
      I saw a patient recently. She had another kind of neuroendocrine tumor and did a DOTATATE PET. The PET showed she had strong signal on one adrenal gland (SUV ~8) while the other adrenal gland had normal signal (SUV ~2). CT showed a tiny nodule in the adrenal gland with strong PET signal. Is this a metastatic lesion of the other neuroendocrine tumor? Or is it a tiny pheo that is incidentally found by the DOATATE PET? Either adrenal metastasis from neuroendocrine tumor or pheo is rare. Based on a variety of factors, I favor she has a tiny pheo. There are no convincing ways to prove either diagnosis. Only time will tell.

Dr. Pheo

Pheo still kills

Pheo very rarely causes death in modern times. Whenever a patient dies of pheo, the diagnosis and management of the patient’s pheo require detailed analysis. The lessons learned from such an unfortunate death are invaluable.

I run into a case report published earlier this year. A 61-year-old male suddenly developed fatigue, nausea, vomiting, and shortness of breath. He came to an emergency room 6 hours later. At the emergency room, he initially had high blood pressure and heart rate. His condition deteriorated quickly so that he was intubated. His markers of heart attack were elevated but his coronary arteries were normal. His left heart ventricle exhibited abnormal movement. He was diagnosed with takotsubo cardiomyopathy (a heart disease caused by extreme stress). Chest X-ray showed signs of heart failure and CT showed changes consistent with certain kind of pneumonia. 2 hours later, his blood pressure suddenly dropped and he suffered from cardiac arrest. He died shortly after. It was only 12 hours between the start of symptoms and death. Autopsy found a 4-cm hemorrhagic pheochromocytoma in the right adrenal gland.

This case is typical for pheo-related sudden death. He was apparently healthy before the onset of symptoms. He had no known pheo. His symptoms suggested heart or lung diseases. He initially had high blood pressure and heart rate. Testing and imaging showed he had normal coronary arteries but with other heart and lung abnormalities. He then suddenly developed low blood pressure and cardiac arrest and died quickly.

Was his death avoidable? It is hard to say. Were there potential opportunities to make an early diagnosis of pheo and to institute therapies? There probably were. In any patients with acute heart problems with normal coronary arteries, pheo should be considered. Pheo is a rare cause of heart problems but pheo-related heart problems are reversible. The probability of pheo is much higher after the coronary arteries are shown to be normal. Takotsubo cardiomyopathy cannot be reliably diagnosed without ruling out pheo. Therefore, pheo should be considered in this patient. A particularly odd thing in this case was that the chest CT did not mention the adrenal tumor. Chest CT should clearly see a 4-cm adrenal mass. A large adrenal mass and acute heart and lung problems without other plausible explanations only point to one disease, pheo-induced cardiomyopathy and pulmonary edema. He should have been diagnosed earlier and been treated with alpha blockade and aggressive cardiac support with all available devices. Believe it or not, even the sickest patient with pheo-induced cardiomyopathy can survive with early diagnosis and appropriate treatment.

Dr. Pheo

Targeted internal radiotherapies for malignant pheo

Treatment of malignant (metastatic) pheo is a big challenge. Malignant pheo has a very variable clinical course; some patients live with it for many years with high quality of life while some other patients can have a rapid deterioration of their conditions. Malignant pheo is exceedingly rare, making it hard for clinical trials to recruit patients. There have been no approved therapies for malignant pheo so far.

Two recent advances may offer hope. They are both “targeted internal radiotherapies”. The radiopharmaceuticals only go into certain cells of the body, malignant pheo cells in particular (hence “targeted”). The patients would receive intravenous infusions of the radiopharmaceuticals rather than getting radiation from an external source (hence “internal”).

The first one is carrier-free MIBG radiotherapy. We don’t have to go into the technical details of what is carrier-free but this new form of MIBG radiotherapy supposedly deliver more radiation to the tumors. The manufacturer released a press announcement this year, showing the effects of carrier-free MIBG radiotherapy in patients with malignant pheo. Older forms of MIBG radiotherapy have been used for years in clinical practice and in some clinical trials. It is hard to compare the therapeutic effects of the old and new MIBG radiotherapies. Generally the effects are comparable in my eyes. The carrier-free MIBG radiotherapy is tested in a prospective and more controlled manner, thus more convincing.

The second one is PRRT. Although the completed US clinical trial of PRRT is only for carcinoid, PRRT has been used in Europe and Australia for all kinds of neuroendocrine tumors, including malignant pheo. A recently published paper showed that PRRT helps control hypertension and reduce the size of malignant pheo. This study is a retrospective one so it is even harder to compare the carrier-free MIBG radiotherapy and PRRT. My own cursory reading convinces me that they have roughly similar efficacy.

The carrier-free MIBG radiotherapy is seeking US approval. PRRT should be close to approval in the US but will very likely be approved for carcinoid only. Assuming both will be approved eventually, I imagine it will be interesting to how they are used for patients with malignant pheo. The use of PRRT will be “off-label”. Besides efficacy, availability, comorbidities, side effects, cost, and insurance coverage will also be factors that influence the decision to use one over the other. More interestingly, can the two radiotherapies be used in succession?  The best indication of the two radiotherapies should be assessed on a case-by-case basis.

Dr. Pheo

Do we need alpha blockade?

Traditionally, patients with pheo are treated with medications to block the alpha adrenergic receptor (alpha blockade) before surgical resection for longer than 2 weeks. alpha blockade has worked very well in the past 50 years to prepare patients for surgery. On the other hand, whether alpha blockade is really needed has been questioned for many years. Do we need alpha blockade?

Indeed, there has not been a randomized clinical trial comparing alpha blockade and another regimen without alpha blockade. Strictly speaking, the answer to the question whether we need alpha blockage is unknown. I believe in alpha blockade based on the long history of effective use, successful personal experience, and some evidence that alpha blockade reverses pheo-induced cardiomyopathy. In addition, I find 2 important flaws in the arguments against alpha blockade.

Flaw 1: Other medications control blood pressure just as well. As I explained in earlier posts, the goal of preoperative preparation is not just to control blood pressure but to treat and prevent pheo-induced cardiomyopathy. The most devastating complications of pheo are cardiovascular catastrophes such as congestive heart failure, cardiac arrest, severe arrhythmia, myocardial infarction, ventricular thrombosis, and stroke. Most patients who present with those complications have no history of hypertension but they are the ones who most need preoperative preparation.

Flaw 2: Nobody dies of pheo resection, regardless of the preoperative preparation regimen. Perioperative mortality is the wrong criterion for the success of pheo management. I have witnessed cases where omission of preoperative alpha blockade in normotensive patients led to severe postoperative complications and prolonged hospital stay. Postoperative length of stay, complications, and quality of life are much more meaningful criteria for the success of pheo medical management.

There is also a common issue in the arguments for and against alpha blockade. Both sides seem to consider all the pheos and the patients with pheo are the same. In reality, there is clear heterogeneity of pheo and the patients with this tumor. A 2-cm incidentally identified pheo is certainly different from a 7-cm one causing cardiac arrest. Likewise, a 30-year-old, otherwise healthy patient is obviously different from an 80-year-old patient with multiple comorbidities. Patients with low-risk pheo (< 3-cm) who are otherwise healthy and non-pregnant may probably undergo adrenalectomy safely without specific medical management. For the majority of patients with intermediate- and high-risk pheo, alpha blockade is probably the best initial treatment, until a randomized clinically trial demonstrates otherwise.

Dr. Pheo

Biochemical growth speed of pheo

A few years ago, I wrote on the growth speed of pheo. Pheo, contrary to conventional wisdom, grows slowly, at an average speed of one tenth of an inch (0.2 cm) every year. Recently, a study showed that the biochemical markers of pheo appear to also rise slowly. This study is interesting in a few aspects. It was based on the Department of Defense Serum Repository (DoDSR). The DoDSR is a large serum bank of all members of the US military forces and boasts of 50 million specimens. The specimens were collected on annual physicals. The authors used a smart research strategy. They identified people who had ever served in the US military and been diagnosed with pheo. They then tracked down the patients’ serum specimens and measured the metanephrine and normetanephrine levels in the specimens. For example, a person could be enrolled in military service at age 20 and diagnosed with pheo at age 40. All his serum specimens since he (most of the subjects were men, as expected) joined the military were available for testing. The authors actually picked only 3 specimens for testing.

The authors found out that the serum metanephrine or normetanephrine levels began to be elevated years before diagnosis. For example, the levels turned abnormal about 6 years before pheo diagnosis and were 3-fold elevated about 4 years before diagnosis. The average time of doubling of the marker levels was about 3 years. Individual patients had very wide differences in the rise of marker levels. For example, some patients had a doubling time less than 1 and half years, while some others had a doubling time more than 8 years. The authors thus concluded that a steady and slow rise of pheo marker levels is very suggestive of pheo. Because there were no imaging data, we don’t know if the rise of pheo marker levels is related to tumor growth, which is a limit of the study. Other studies do show parallel increase in pheo marker levels and tumor burden AFTER diagnosis.

Dr. Pheo

Seasonal variations not found in a third study

I wrote 2 years ago on the seasonal variations of plasma normetanephrine levels in patients without pheo. In early 2014, a paper reported that the normetanephrine levels are 20% higher in wintertime than in summertime in the Netherlands and Germany, and a second study showed that normetanephrine levels are 40% higher in wintertime than in summertime in Los Angeles, USA. As the Netherlands and Germany have temperate climate and Los Angeles has Mediterranean climate, higher normetanephrine levels in wintertime seem to be pretty universal. At that time, I suggested a similar study in a tropical area like Hawaii with minimal temperature differences throughout the year. One would predict that the plasma normetanephrine levels in people without pheo remain unchanged throughout the year in Hawaii.

A third study is indeed done, although not in Hawaii, and published recently. It is done in the West of Ireland. Ireland has a temperate oceanic climate. The average summertime and wintertime temperatures are 14.3 and 5.8 °C respectively in the West of Ireland. The temperature difference of 8.4 °C in the West of Ireland is very similar to that in Los Angeles (8.6 °C), although it is generally much cooler in the West of Ireland (average Los Angeles summertime and wintertime temperatures are 23.2 and 14.6 °C respectively). The seasonal temperature differences are much smaller in the West of Ireland and Los Angeles than those in the Netherlands and Germany (17 °C). Unlike in Los Angeles, there is, however, no difference in the plasma normetanephrine levels between the summertime and wintertime in the West of Ireland.

There could be multiple potential explanations of the different result obtained from the third study. An obvious issue is that all three studies are retrospective ones which can lead to certain biases. The most important lesson, however, is that medical studies need to be reproduced in different settings. We cannot assume that results from a previous study should be readily applied to another setting.

Dr. Pheo

Pheo spillage?

Although I am not a surgeon, I am often asked by patients about surgical approaches. One of the common questions is how laparoscopic pheo resection can completely remove the tumor. The ports look small; how can a tumor 5-cm large pass through the ports? Even if the tumor can squeeze through the ports, will that cause fragmentation of the tumor or cause tumor spillage?  I usually ask the patients to direct the questions to the surgeons but I do wonder if tumor spillage can actually happen.

Then I saw a case report published this year. It described a 64-year-old woman with a large (12-cm) pheo. The pheo was resected laparoscopically. The tumor was completely removed but the tumor capsule ruptured. Tumor histology showed relatively high cell division rate but otherwise there was no suggestion that the tumor was malignant. Several months later, the pheo recurred at the primary site and the abdominal wall where the laparoscopic ports were. The tumor progressed quickly and the patient unfortunately died of it.  

The references cited in the case report listed an older study published in 2001. Three patients with single pheos 5.5-6.5-cm large had small multiple recurrent pheos at the same site of the original pheos 3-4 years after laparoscopic resection. In all three cases, tumor spillage was suspected by the surgeons. No abdominal wall seeding was found in the 3 cases.

In retrospect, the case reported this year probably had malignant pheo while the 3 earlier cases probably had benign pheo. At any rate, pheo spillage indeed appears possible during laparoscopic resection but should be very uncommon.

Dr. Pheo

A non-genetic risk factor for pheo?

Patients with pheo often ask “why do I have pheo?” I usually assure them that nothing we know of, other than genetic risks, causes pheo. There is no clear evidence that common risk factors such as smoking, obesity, diet, infection, and exposure to environmental toxins are associated with higher pheo risk. There is also no clear evidence that other diseases the patient has, other than those that are part of a genetic syndrome, are associated with higher pheo risk.

An interesting paper published online last month seems to suggest that cyanotic congenital heart diseases may predispose people to develop pheo. The idea that hypoxia may lead to pheo is not too new now. About half of the genes that cause pheos when mutated are involved in making molecules carrying energy. As making energy molecules requires oxygen, the mutated genes mislead the cell into thinking that it lacks oxygen supply (hypoxia). The cellular processes that try to cope with hypoxia, over time, can result in pheos. It has been reported that people living in high altitude (thus low oxygen levels) tend to have more neck paras and perhaps pheos. The new paper now shows that people with cyanotic congenital heart disease may also tend to have more pheos.

Cyanotic congenital heart disease is a congenital condition in which the abnormal heart structure causes mixing of blood from the two sides of heart, thus low oxygen levels in the artery and tissue. The new paper shows that people with cyanotic congenital heart disease have a 6-fold risk of having a pheo diagnosis, compared with those without, during their hospitalization for whatever causes. In the same paper, the authors also identified 20 patients with congenital heart disease and pheo, 18 of them having cyanotic disease, 2 having aortic coarctation. The 18 patients with cyanotic congenital heart disease were younger than the average patients with pheo and tend to have multiple tumors. Unfortunately, the paper does not specify the 18 patients were out of how many patients with cyanotic congenital heart disease so that we don’t know the incidence of pheo in those patients.

As the authors prudently cautioned, their study only establishes an association between pheo and cyanotic congenital heart disease but not a causal effect of chronic cyanosis. One other potential bias is from ascertainment. If more patients with cyanotic congenital heart disease are tested for pheo, more pheos will be diagnosed. Nonetheless, I will ask my next patient with suspected pheo whether she/he has a history of congenital heart disease, especially a cyanotic one.  

Dr. Pheo

Report from ISP 2014

The 4th International Symposium on Pheochromocytoma (“ISP 2014”) was held in Kyoto, Japan, September 17-20. I just returned from the meeting. This time, I was too tired to write a meeting report during the meeting but I did take extensive notes.

Public transportation was amazing there. The meeting organizers provided detailed instructions on using public transportation which I took seriously. Upon landing at Osaka airport, I bought an IC card with a little Hello-Kitty on the face. The IC card apparently was for foreign travelers only (they wrote down my passport number and name). The card could be used on trains and subways and in some shops. It gave discount price for round trip between the airport and the Kyoto train station. Very handy! I could have returned the card and got some refund but I kept it as a souvenir because I liked it so much. A high-speed rail (JR “Haruka”) took me from the Osaka airport in 75 minutes to the Kyoto station. Then a 5-minute walk took me to the meeting venue.

The meeting was wonderful. I attended every single lecture and discussion except for those on the last day. I also presented a poster. The meeting featured many Japanese speakers who shared their experience on pheo. It turned out that the diagnosis and treatment of pheo in Japan were a little different from those in US and Europe. I was surprised to know that metanephrines testing was not available in Japan but some Japanese doctors were developing the assay there. Interestingly Japanese surgeons had to send in 20 videos of their laparoscopy operations to be certified. The first-time pass rate was only about 40%!

The following is a list of major new things I learned from the meeting:

1. Two more new genes were added to the list of pheo-predisposing genes. I will write about them after the papers are published. So now a total of 17 genes are known to be associated with pheo.

2. A new syndrome, paraganglioma-somatostatinoma-polycythemia was established. The syndrome is caused by activating mutations in the gene HIF2alpha in some but not all cells of the body. I was fortunate enough to have an extensive discussion with one of the lead authors of the paper to understand how they went through the thinking process. This syndrome is particularly interesting to me as I also have interests in somatostatinoma and other pancreatic or duodenal neuroendocrine tumors.

3. Prediction of malignancy may be possible now. A famous Japanese pathologist literally used the Obama’s “Yes we can” in describing the scheme that will tell a malignant pheo from a benign one. This scheme was discussed 3 years ago at the previous meeting but was met with more skepticism than support. This year, the same scheme seemed to have garnered more support than skepticism. I, among others, would like to see how the scheme would pan out in the hands a practicing pathologist.

4. Whole-genome sequencing seemed to very popular now. A few famous researchers were sold on the whole-genome sequencing idea. Quite a few others and I viewed the whole-genome sequencing with guarded optimism. I don’t see much value of whole-genome sequencing in routine clinical care.

5. A plenary session speaker described the status quo and predicted future directions of pheo and pheo research. This speaker thought that routine pheo diagnosis and treatment should be pretty straightforward if a doctor knew the right stuff. Future research should address the treatment of malignant pheo and the role of genetic testing in the care of patients with pheo. I agreed with the speaker full-heartedly.

Dr. Pheo

The Endocrine Society Guideline on pheo

The Endocrine Society, the world's largest scholarly society on endocrine diseases, just released its clinical practice guideline on pheo and para (http://www.endocrine.org/education-and-practice-management/clinical-practice-guidelines). The writing committee includes leading international experts on pheo and para.

Before the publication of this guideline, the North American Neuroendocrine Tumor Society (NANETS) published a guideline in 2010, and the First International Symposium on pheo published another guideline in 2007. The authors of the 3 guidelines overlap significantly. I am very familiar with the two previous guidelines.

I have read the new guideline in detail and am pleased to find that some of my own work is cited. Overall, the Guideline is thoughtful, up-to-date, succinct, and clear. I congratulate the writing committee on its completing such a wonderful piece. It has 6 parts: biochemical testing, imaging, genetic testing, perioperative management, surgery, and personalized approach. The Guideline is a great resource for physicians and patients. If the Guideline is followed, the majority of clinical scenarios will be covered very well and the clinical decisions will be correct most of the times. For non-specialists, the Guideline is a great resource for decision making regarding pheo.

I like the Guideline so much that I cannot think of almost anything that I have to change if I had been involved in the writing. As a pheo specialist, I do find a few places in the Guideline where some discussions are worthwhile. You can call me nitpicker but you will see why the following issues can actually matter in clinical practice.

Table 1. I would add heart problems without clear causes as another indication for testing. Over 10% of patients with pheo present with cardiovascular complications. Most patients with heart disease, indeed, do not have pheo, but those without clear common causes should be tested for pheo. For example, most patients with heart failure do not have pheo and pheo testing is not needed if a clear cause such as severe coronary heart disease is present. A young patient with heart failure of unknown (“idiopathic”) causes, however, should be tested for pheo. Pheo-induced cardiomyopathy is reversible upon pheo removal so that it is worthwhile to test for pheo in patients with heart problems without clear causes.

1.4. “All positive results require follow-up.” This recommendation is not incorrect but deserves some comments. In real world, most positive results are false alarms. In my experience, more than 50% of patients with positive results can be safely reassured that they don’t have pheo and further testing is not needed. A common example is an elderly patient with hard-to-control hypertension who has a slight elevation of pheo test results. I would be very comfortable in telling the patient that further testing for pheo is not needed. The Guideline goes on to say that the ways of follow-up should be determined by the pre-test probability and by clinical judgment, and that clinical follow-up (i.e. without further testing or imaging) is appropriate in select cases.

4.2. “We recommend preoperative medical treatment for 7 to 14 days to allow adequate time to normalize blood pressure and heart rate.” This recommendation is the only one that I have serious issues with. 1) This recommendation assumes that all pheos are the same and gives a general recommendation without considering the individual perioperative risks of each pheo. An incidentally found 1-cm pheo and a 7-cm pheo causing cardiac arrest are certainly different and should be prepared differently. 2) It perpetuates a long-held but likely incorrect notion that the goal of preoperative preparation is to normalize blood pressure and heart rate. Not uncommonly, patients with very active pheos have normal blood pressure and heart rate. An un-experienced doctor may feel that preoperative preparation is not needed because those patients already “achieve” the goals of preoperative preparation. Normal blood pressure and heart rate are important before operation but they should not be the goals of preoperative preparation. The real goal should be to revert or prevent pheo-induced cardiomyopathy.

A major challenge in writing clinical guidelines is to make balanced recommendations covering both common and uncommon clinical situations. A guideline will become too long and cumbersome if it tries to cover all situations. The Endocrine Society Guideline on pheo did a great job in balancing the common and uncommon situations. When we read guidelines, we should bear in mind that they are intended as “guidelines” and it is up to us to apply the guidelines to each unique patient. In other words, the physicians and patients should make the final clinical decisions, using the guidelines as a reference but not the only reference. Clinical experience and literature review are perhaps more important than following guidelines. As the Endocrine Society Guideline on pheo emphasizes, a multi-disciplinary team on pheo is the key to optimal pheo diagnosis and management.

Dr. Pheo