Thursday, September 7, 2017

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

Wednesday, June 14, 2017

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

Tuesday, September 13, 2016

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

Friday, July 1, 2016

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

Tuesday, March 29, 2016

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

Monday, June 29, 2015

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

Monday, February 2, 2015

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