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

Five years!

On March 19, 2009, when I started the blog, I was really not sure how it would do in the long term. With the enthusiastic support from readers all over the world, the blog has been running for exactly 5 years. I will keep the blog running as long as someone has a question on pheo but cannot find the answer elsewhere.

Thank you very much for your support!

Dr. Pheo

Tis the season to be false positive

If the interpretation of pheo marker results is already complicated, our current season adds one more variable for us to consider.

A seasonable paper on seasonal variations of pheo marker levels was just published. The researchers charted pheo blood marker levels in each month of the entire year in people without pheo. They found that the normetanephrine levels were about 20% higher in wintertime than in summertime. The normetanephrine levels did not vary between seasons in patients with pheo. As you probably have guessed, the study was done in the Netherlands and Germany (one city in each country) where there are big temperature differences between winter and summer. Actually, during the same wintertime, the normetanephrine levels are a little higher in the colder city. To prove that the cold temperature causes elevation of normetanephrine levels, the researchers warmed the forearms where blood was drawn and found the levels dropped.

The 20% higher blood normetanephrine levels in wintertime do not sound too much but can make a result from high normal to borderline abnormal. We already know that anxiety, stress, sleep apnea, hypertension, older age, and some medications are associated with higher normetanephrine levels. All these factors, including wintertime, need to be weighed before a decision is made about the lab results. As I have reiterated many times before, the pheo diagnosis should not be based on a single lab test but should be based on the totality of the patient’s condition. Clinical presentation, lab results, and imaging characteristics are all important.

It would be interesting to do the same study in a tropical area like Hawaii. We would predict that the blood normetanephrine levels in people without pheo remain similar throughout the year.

The new wintertime confounding factor in pheo test result interpretation reminds us once again that a test result is influenced by many factors. Simply calling a test result positive or negative will result in misdiangosis. 

Dr. Pheo