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.
Hello Dr. Pheo,
ReplyDeleteVery interesting post. I have to admit that I don't understand why a gene that two women have will help in the treatment of paraganglioma.
All my best,
Frances
PS. I don't know anyone named Poly, but I'll ask around.
Dear frances,
DeleteIf HIF2A hyperactivity is confirmed in more patients with paraganglioma or polycythemia, HIF2A may be used as a drug therapy target.
Dr. Pheo
Dear Dr. Pheo,
ReplyDeleteThank you.
Frances
Dear Dr. Pheo.
ReplyDeleteMy tumor slides were tested at NIH for HIFa2. Slides came back negitive. As well neg for SDH B.C and D. My family back ground is mostly unavailable so there are no relatives or health issues to compare with. I was wondering if these patients were somatic, would that gene defect be able to be passed down to their children. I am working on getting tested for VHL since there has been a documented case of Chuvash and VHL. My children have not been tested for anything yet, but youngest daughter has been told by 2 drs that she has a visible mass behind her left eye. She is awaiting a mri. She has a lot of the same symptoms as I do.
Thank you
Dear lori,
DeleteIt all depends on which organs are involved. If the somatic mutation occurs very early during embryonic development, the germ cells in the ovary and testis may be involved. If it occurs late, the chance that germ cells are affected is lower. In the paper, the white blood cells do not have the mutation, suggesting that the somatic mutation occurs pretty late. The best way is test the mutation in the offspring.
Dr. Pheo
Hi Dr Pheo -- I know you're busy and really appreciate your continued posts on this blog.
ReplyDeleteI had an apparently sporadic 5cm Pheo removed 2.5 years ago, and as recommended have continued to get scans and plasma-free metanephrine levels checked about every six months. Based on these tests, there's been no sign of recurrence.
That said, my Normatanephrine level has increased each time from .28 (at the 6 month follow-up) to .48 (at 1 year) to .51 (at 1.5 years), and now .53 (at 2.5 years). While all of those readings are within the reference range (of <.90), I'm concerned that they seem to be creeping up. (Metanephrine remains unchanged at <.20)
While I recognize that the difference in the more recent readings isn't that great, I'd be a lot more comfortable if the trend over the last two years didn't see them consistently rising.
I was curious what you might say to a patient of yours with similar concerns. Thank you again!
Gooch
Dr. Pheo, I have a couple of random questions. I had a 8cm x 5cm retrocardiac paraganglioma removed in June that was locally invasive to the left atrium and pulomary vein. It was fed by two of the main arteries of the heart. The pathology report states the tumor has prominent nuclear pleomorphism. What does that mean and is it a common feature of paragangliomas? I did not test positive for SDHx deletions or mutations. Should I pursue other genetic testing?
DeleteDear Gooch,
DeleteCan you tell me your age and sex?
Your plasma normetanephrine levels, which can fluctuate in the same person, are not alarming. If your scans are normal, I would not think there is any evidence of recurrence.
Dr. Pheo
Dear cardiacpara2012,
DeleteCan you tell me your age and sex? The age and sex are important information to make a recommendation.
Large pheos/paras often have nuclear pleomorphism. By itself, the nuclear pleomorphism is not sufficient to tell anything about the tumor. The genetic testing strategy depends on your individual situation.
Dr. Pheo
Dr. Pheo,
DeleteThank you for your response. I am a 34 year old male. I am currently a patient of the NIH pheo/para protocol and will be returning in November. There is no other known family history of this specific tumor. My father was adopted, however it appears that from what I've pieced together from his side, my paternal grandfather had "multiple abdominal tumors" (as described by the VA) and died from tonsilar cancer. He (my grandfather) had high blood pressure and suffered his first stoke at the age of 43. I am just really curious as to whether I should push for other genetic testing when I go up there. Thanks!
Dear cardiacpara2012,
DeleteYou most likely have a genetic predisposition to pheo/para. The matter is what genes to screen for next. The NIH group has a nice algorithm for screening. I would go by their recommendations. RET mutation is an obvious one.
Dr. Pheo
Thank you Dr. Pheo! I will bring that up when I see them in November.
DeleteDr. Pheo,
DeleteWhat characteristics about the RET mutation would make it an obvious one to test for next?
Thank you!
Dear cardiacpara2012,
DeleteTwo reasons: it is one of the more common mutations, and it is known to cause cardiac pheo.
Dr. Pheo
Again, thank you so much! I will try to get that set up.
DeleteThank you as always for your response, Dr Pheo. I'm a 41 year old male (Pheo was removed when I was 38).
ReplyDeleteAnd while I understand that normetanephrine levels can fluctuate, it does concern me that they've only gone up over the last 2.5 years.
My fear, of course, is that this is a sign of a developing recurrence.
Thank you again,
Gooch
Dear Gooch,
DeleteI am very certain that with normal normetanephrine levels, any apparent symptoms or signs of pheo are actually not caused by pheo recurrence. I would continue biochemical and imaging follow-up.
Dr. Pheo
Hi Dr. Pheo.
ReplyDeleteI wanted to let you know that I am still interested in what you have to say on alternative and holistic healing. I have a 15 years old daughter with SDHB mutation and PCOS. I am ready to give her herbal supplements to try to help balance her. It seems this would be better than synthetic hormones. I believe a paleo diet would be best, but she will not cooperate. I also take super greens to support my adrenal function. And occasionaly licorice root or b vitamins to help with anxiety. I just wanted to encourge you to write on this topic when you have time. Thanks for your work in this area.
Dear Team Burns,
DeleteI will write on that topic soon.
Dr. Pheo
Hello Dr Pheo,
ReplyDeleteA question has come up in regards to the possibility of pheochromocytoma causing an increase in the production of cortisol by the adrenal glands. I know pheos produce catecholamines, but can they also push the rest of the gland to produce more of its various hormones? The question stems from the presence of bone pains that turn out to be osteoporosis, as well as diagnosis of diabetes which immediately disappears on resection of the tumour. Thank you for your time and attention.
Dear Danielle,
DeleteDiabetes and osteoporosis are both rare complications of pheo. The cause of diabetes is usually attributed to catecholamines. The cause of osteoporosis is not as clear. Pheo can cause high cortisol in rare cases but diabetes and osteoporosis are generally thought not through high cortisol.
Dr. Pheo
Dr. Pheo,
ReplyDeleteI just got back from NIH and was curious about some results. The team there now want to test me for SDHA, HIF, and MAX mutations. I now know I am negative for SDHB, C and D as well as VHL. I understand these are all fairly new. Can you explain them more for your readers?
Also, I had a few new areas show up on an FDG scan. The first area is described as being in the location of the old tumor, being photopenic and having a hypermetabolic ring. There are also areas around the paratracheal region, ascending aorta, and right bifurcation, and adjacent to the right side of the thyroid. Could all these areas be scar tissue or should I have a follow up FDG scan in a few months?
As always, thank you for your input.
Dear cardiacpara2012,
DeletePlease see my earlier posts on the MAX mutations, etc. SDHA is a protein similar to other SDHs in that it plays a role in regulating energy balance inside a cell.
You should do neck and chest MRI to examine the areas where the FDG PET is positive.
Dr. Pheo