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What does this patient have? Essential thrombocythemia, polycythemia vera, or masked polycythemia vera? The purpose of this talk is to get some definitions of polycythemia vera and the concept of masked polycythemia vera through a clinical presentation and looking at the specific importance of bone marrow morphology and, finally, the implications for revising diagnostic criteria.
To use a case, this is a patient who was referred after a long hospitalization who had a new myeloproliferative neoplasm diagnosis. It was identified when he was admitted to a trauma service after he was struck by a car and was found to have leukocytosis and thrombocytosis.
Despite a very life-threatening bleed, ultimately a nadir hemoglobin of 6.3, his initial hemoglobin had a white count of 25,000 that was left shifted, a hemoglobin of 16.6, and elevated platelet count. This was a patient who had an active smoking history and on exam his spleen was not palpable.
A bone marrow biopsy was done and was 70% cellular, and had areas that were more cellular than that. There was megakaryocytic atypia as we typically see in myeloproliferative neoplasms, and there was grade 2 fibrosis. There was no stainable iron, the karyotype was normal, the JAK-2 v617f mutation was detected, and this was actually interpreted by the pathologist as primary myelofibrosis.
From a clinical standpoint, particularly an asymptomatic patient who has vascular risk, this was a patient who had features of several different MPN subtypes. He had some polycythemia vera-like features, including a high hemoglobin, which we don't typically see in myelofibrosis, and normal spleen size, again atypical for myelofibrosis.
Fibrosis in his marrow was more typical of myelofibrosis, though not atypical in polycythemia vera, and I think we under-recognize the amount of fibrosis that can sometimes be seen in patients with polycythemia vera. And the leukocytosis is actually seen in both and may confer a high vascular risk.
Again, in this patient, one of my overarching concerns was reducing the risk of having future clots, including arterial clots and venous clots, and accurate subtyping of his MPN subtype can help to inform this. The patient does not have essential thrombocythemia based on bone marrow findings. Polycythemia vera, I would say he almost has all of the diagnostic features of that, although there is some overlap with primary myelofibrosis.
What is the entity of mass polycythemia vera? The diagnostic criteria of polycythemia vera as of 2008 include a hemoglobin cut-off that's quite high, and bone marrow morphology is only a minor criteria, and it ends up being a very specific diagnosis but a highly insensitive one. Our patient, for example, does not meet diagnostic criteria for polycythemia vera even though it sounds a bit like that.
Looking at the literature, there's been one case series that's been analyzed in patients with a high hemoglobin but not meeting diagnostic criteria, compared to those where diagnostic criteria were met. Looking at survival outcomes and risk, it found that mast polycythemia vera was associated with a less favorable survival, including thrombotic risk and probably a higher risk of progression of disease.
If you think about masked PV in the context of different MPN subtypes, we’re going to do a little linear concept of an evolving polycythemia vera, actual polycythemia vera, and then post-PV myelofibrosis iron deficiency, which used to be called masked PV, if they’re not meeting diagnostic criteria. But we see overlap with a number of different other diagnostic and proposed diagnostic entities, and masked PV can sometimes overlap all of these.
Masked PV should probably be treated as a variant of polycythemia vera, including phlebotomy and cytoreduction together with aspirin as indicated. Perhaps this lack of clarity in diagnosing some of these patients could be solved with revision of the diagnostic criteria.
In fact, that's what happened. The WHO classification in 2016 has now decreased the hemoglobin threshold, has included bone marrow biopsy as a major criteria, and probably will increase the sensitivity of patients, like this one, who appear to have at least all of the risks associated with polycythemia vera. By the 2016 WHO criteria, this patient has polycythemia vera and will be treated appropriately with phlebotomy, aspirin, and hydroxyurea.
Thank you for your attention and watching today.