Low-risk and high-risk pheo

Happy Thanksgiving! This will be the last piece for 2013. I wish everyone a great holiday season and a wonderful year of 2014!

When we, health care professionals and lay people alike, talk about pheo, we seem to assume all pheos are the same. In medical textbooks, pheo is mostly discussed in a way that gives the reader the impression that if one has a pheo, one will have all the classical signs and symptoms of pheo. In the lay communications, the heterogeneity of pheo is even less appreciated. One pheo, however, can be very different from another. I have written about clinically “silent” pheo, pheo associated with normal blood pressure, pheo that causes frank cardiovascular problems, small pheo, pheo caused by genetic mutations, etc. Understanding the heterogeneity of pheo is critical to tailor pheo management to an individual patient with a particular pheo.

Preoperative management of pheo has been controversial since the very beginning. I myself have advocated careful preoperative preparation for every patient with pheo. On the other hand, there are many different ways of preoperative preparation used by experts, all with similar excellent outcome. Recently, one review article proposes risk stratification for pheo, which may help reconcile the paradox.

The article divides pheos into 3 categories: low-, intermediate-, and high-risk, according to the risk of heart complications a particular pheo can impose on a patient. Low-risk pheos are those smaller than 3 cm in diameter. This article proposes that specific preoperative preparation is not needed for low-risk pheos. High-risk pheos are those that already cause obvious cardiovascular complications such as arrhythmia, heart attack, heart failure, or stroke. Careful preparation is needed for high-risk pheos and the doctors need to coordinate their care so that the preparation regimen is safe and effective. Intermediate-risk pheos are those that are none of the above. The preparation regimen should be individualized. The higher the relative risk of cardiovascular complications a pheo has, the more careful and longer the preparation it requires. 

It needs to be emphasized that this risk stratification is based on clinical observation and just a proposal. It has not been prospectively tested. What am I doing? I currently still carefully prepare everyone. If a patient does have a low-risk pheo, I am more relaxed with the regimen.

Dr. Pheo

Sorry but I missed many of you!

I just realized 2 days ago that my email software had placed all the alert messages from the Dr. Pheo blog in a strange new folder. You can see that obviously I am not very savvy on software stuff. I have been wondering lately why readers do not ask questions any more. At one time, I entertained thoughts that perhaps I had answered most questions so that readers wouldn't ask any more. Then 2 days ago, I tried to see the content of a strange folder in my email software and saw 30 questions from this blog.

I have since dutifully answered all of them but the answers are quite untimely. I apologize. The lesson learned is that if I do not see questions from this blog, I should check all the email folders.

Dr. pheo

Another "dopamine-producing" pheo

Some days ago, I got a call from a physician asking me for suggestions on how to proceed with a “dopamine-producing” pheo. The patient was an elderly man with labile blood pressure and varying heart rate. Pheo was suspected. Urine dopamine levels were >5000 mcg/24 hours (normal reference range: 60-450). But was it a pheo?

I usually get 1 or 2 calls on potential "dopamine-producing" pheo every year. True dopamine-producing pheos are extremely rare and do not cause clear symptoms. These tumors are usually localized outside the adrenal glands and may present as metastatic tumors. They are usually clinically silent until they grow very big and causing abdominal discomfort. Specifically they do not cause hypertension per se. Only about half of the patients have high dopamine only and the other half have high dopamine and high epinephrine or norepinephrine as well.

In any given situation, the most common cause of very high urine or plasma dopamine is the medication Carbidopa-Levodopa (Sinemet) for Parkinson disease. These patients usually have every high dopamine but normal or slightly elevated epinephrine or norepinephrine. Levodopa is presumably converted into dopamine which is then detected by the catecholamine measurement. Parkinson disease and related conditions such as multiple system atrophy often cause sympathetic instability in the forms of fluctuating blood pressure and heart rate, orthostatic hypotension, and syncope, all of which resemble pheo symptoms.

I therefore asked the physician if the patient had Parkinson disease. He was reasonably surprised and told me the patient did have Parkinson. I then asked if the patient took Sinemet. He checked the medication list but Sinemet was not on the list. I was not swayed. Many patients think Parkinson is a disease of old age and Sinemet some kind of food supplement so they do not tell their doctor they are taking it. Luckily the patient was still in the clinic. The physician told me he would ask the patient about Sinemet and call me back. He didn't call me back. I assumed the patient was taking Sinemet, as all of the patients I had been asked about are.

Dr. Pheo

P.S. I have not written about pheo for 7 months for various reasons. My job is more demanding, to be sure. Also, there has not been a major advancement in the pheo field in the last 7 months, in my opinion. 

Pheo and heart II

I first wrote about pheo and heart 4 years ago (April 2009). At that time, my instinct was that heart damage is a key issue for pheo. Over the years, after seeing more patients with heart complications caused by pheo and discussing with colleagues about the issue, I increasingly appreciate the intricacies of pheo-induced cardiomyopathy.

Pheo-induced cardiomyopathy is not a new finding. The first two cases of pheo known to medicine were both about pheo-induced cardiovascular collapse in modern terms. The correlation of pheo and cardiomyopathy was clearly and convincingly reported in the 1960s. Hundreds of case reports of pheo-induced cardiomyopathy have been published in the last 50 years. The problem is that pheo is very rare and pheo-induced cardiomyopathy is even rarer. Many cardiologists and endocrinologists simply are not aware of the concept of pheo-induced cardiomyopathy. Part of the reason why pheo-induced cardiomyopathy is not well known is that there are few, if any, systemic studies on pheo-induced cardiomyopathy.

In the last year, two very similar systemic studies were published on pheo-induced cardiomyopathy. Both studies were retrospective review of experience of a large single medical center (in Prague and Los Angeles, respectively). In both studies, the authors focused on patients without known history of pheochromocytoma but presenting with cardiovascular complications such as arrhythmia, heart attack, heart failure, or stroke. Their results were strikingly similar as well. The Prague study included 145 patients, 28 of them (19%) presented with cardiovascular complications. The Los Angeles study was about half the size with 76 patients, but still 9 of them (12%) presented with heart complications. Because both medical centers are large tertiary referral centers and tend to see sicker patients, the incidence of cardiovascular complications may be overestimated but the 12-19% incidence is at least true in large hospitals. Both studies showed that there are no good predictors on which patients will get cardiovascular complications. Specifically, most patients with cardiovascular complications do not have hypertension. There may be a higher risk for cardiovascular complications if the pheo is biochemically very active and large. I have mentioned in a previous post that pheos smaller than 3 cm do not cause cardiovascular complications. Both studies showed that once correctly diagnosed and managed, the pheo-induced cardiomyopathy is reversible. The moral of the studies is that if a patient presents with cardiovascular complications, pheo is a possibility, even if the patient has no history of hypertension. It is also reassuring that the cardiomyopathy is reversible after pheo removal.

Dr. Pheo

Alternative medicine and pheo

Happy holidays!

This is a long overdue topic suggested by a reader. I’ve been thinking about it for months. The reason for the long thinking process is mostly because I want to give alternative medicine in pheo management a fair and clear evaluation. Here are my opinions on alternative medicine.

Luckily, most patients with pheo do not need alternative medicine. For the majority of patients, preoperative preparation and surgical removal are sufficient and definitive management of pheo. We don’t have to invoke alternative medicine for them.

Patients may be interested in ways to prevent pheo recurrence if they have had pheo, or ways to prevent pheo emergence if they are carriers of mutations or have family members with pheo. As the exact molecular pathogenesis of pheo has not been worked out yet, there is no reliable knowledge on specific ways to prevent pheo recurrence or emergence. Patients and their family members should follow a healthy life style and appropriate surveillance.

Patients with metastatic pheo may have hard-to-control symptoms, develop adverse effects from treatment, or be resistant to therapies. For those patients, alternative medicine may have a role but the patients and their mainstream physicians need to be very cautious and act on good common sense. Alternative medicine won’t shrink the tumors or magically make the tumors disappear but it may make the patients feel somewhat better. The patients should let their mainstream doctors know that they are seeking alternative medicine or under alternative medicine treatment. The exact alternative medicine treatment should be known to the mainstream doctors and should not be outrageous or dangerous. The alternative medicine practitioner should not make grandiose claims about the regimen, should have a good reputation, and should know when to stop the regimen. I frankly don’t recommend alternative medicine to my patients in most situations.

Dr. Pheo

The story of Para and Poly: Are they related?

Polycythemia (Poly), a pathological increase of red blood cell count, is a well-recognized paraneoplastic syndrome. Many types of tumors are associated with polycythemia. The mechanism for the connection is generally thought to be tumor-elaborated erythropoietin (EPO), which stimulates red blood cell generation. Pheo and paraganglioma (Para) are both known to be associated with polycythemia. The polycythemia usually resolves after pheo or para resection. In some cases, the polycythemia can persist even after tumor resection, and in some others, polycythemia occurs long before pheo/para is diagnosed, suggesting that the polycythemia may not be necessarily caused by the pheo or para but they may have a common cause. Indeed, it was reported in 2009 that an inherited mutation in the gene PHD2 is associated with paraganglioma and polycythemia.

In this week’s New England Journal of Medicine, researchers at the National Institute of Health (NIH) reported two patients with paraganglioma and polycythemia who do not have PHD2 mutations. Both patients are female, 30- and 18-year-old respectively. The older patient also has somatostatinomas (duodenal or pancreatic neuroendocrine tumors secreting somatostatin). Through biochemical analysis, the NIH researchers found that the two patients have enhanced signaling of HIF2A (hypoxia-induced factor 2alpha, regulated by PHD2) in their paragangliomas. The researchers sequenced the tumor HIF2A gene and found 2 heterozygous mutations in it. Interestingly the two mutations are very closely spaced on the gene. Both mutations are activating; that is, the normal HIF2A function is heightened by the mutations. The patients’ parents do not have the mutations so the mutations are “somatic” (which occur by chance after the patients were conceived).

So now a novel cause of the syndrome of pheo/para and polycythemia has been discovered. And yes, Para and Poly are related. It is somewhat intriguing that inherited HIF2A mutations have not been found in patients with pheos in the past. It is also not clear how frequent the HIF2A somatic mutations are in the pheo/para tumors of all comers. From a practical point of view, we should screen for PHD2 and HIF2A mutations in patients with both pheo/para and polycythemia, especially if the polycythemia does not resolve after pheo/para resection, or is diagnosed long before the pheo/para is found. Novel treatment of these two disorders may now be possible. Keep tuned.

Dr. Pheo

P.S. Both Para and Poly are girl names. Para means "supreme". I don't know the origin of Poly. If you know girls named Poly, please ask them what it means. Thanks.

Small and very small pheos

As the readers may have guessed, I have been extremely busy (due to increased workload) in the last few months. That’s why I haven’t written anything in the last 4 months. I found some time at the Memorial Day weekend to write this post.  

An interesting study was published in May about small pheos. Small pheos are more commonly seen in these days. In the last year alone, at least 5 physician colleagues discussed with me about small pheos. There is no official definition of a “small” pheo but the authors call anything less than 3 cm in diameter as small. I actually agree with the authors in the 3 cm cutoff. In the past, I reviewed the literature on pheo-induced cardiomyopathy and noted all the tumors that cause cardiomyopathy are equal or larger than 3 cm. An inquisitive reader may wonder why doctors only use one dimension in describing tumor size. On one hand, doctors are lazy and one dimension is easier to remember; on the other hand, most pheos are nice and round. I have yet to see an odd-shaped pheo, say one resembling the shape of a cucumber. Of course you never know.

There are 3 main findings in the paper. First, about 1/3 of all pheos in the last 15 years are “small” (<3 cm). Second, small pheos do not usually cause hypertension or other classical pheo symptoms but some small pheos ironically cause hypertensive crisis during an unrelated surgical procedure. So if one has a small pheo and hypertension, the hypertension unlikely gets better after pheo removal. I recently had a patient with small pheo whose blood pressure actually got worse after pheo removal. Third, small pheos have typical appearance on CT/MRI but the biochemical test results can be borderline or in the cases of very small pheos (i.e. <1 cm), even normal. In my earlier posts, I emphasized that most borderline test results are false positive. That statement is still correct but I need to add some qualifications now. If an adrenal tumor is small but has typical pheo appearance on CT/MRI, and the test results are borderline, it has a good chance to be a real (small) pheo!

Pheo is a humbling tumor. The more I know about it, the more careful I become when I make a diagnosis. I begin to question myself whether I was absolutely right when I told my patients with normal biochemical test results “You don’t have pheo.” They might still have a very small pheo. Now I use a buzz phrase “clinically significant pheo.” I tell my patients if they likely or unlikely have a “clinically significant pheo” rather than if they have pheo or not. Nobody can say for sure whether a patient has a very small pheo. The good news is that very small pheos are clinically insignificant.

Dr. Pheo