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.
