I’m working up a patient for erythrocytosis and I am a little stuck as to what my next step should be. His hgb has ranged from 17.5-21 and erythropoietin level has remained below 3 each time we’ve checked (3 or 4 times at this point). He is a smoker, and we have demonstrated elevated carboxyhemoglobin levels during my initial work up so I thought that was that until the erythropoietin came back low. His BMBx was mildly hypocellular at 20-40% for a 46yo (heavy EtOH use) and cytogenetics and myeloid NGS panel were normal and without mutations respectively. At this point I’m thinking about monitoring his counts and checking for hereditary erythrocytosis genes. Do you think his EtOH could be masking the expected panmyelosis of PV? Should I really be waiting until he is able to be clear of EtOH use for 6-8 weeks and repeat his marrow then thinking that this could be a triple negative MPN or do you think monitoring and looking for other explanations for his low-epo erythrocytosis is a decent path forward?
Interesting case. With low EPO level and persistent erythrocytosis, the differential is relatively narrow. PV is most likely with most patients have a JAK2 V617F mutation which you stated was negative (this is normally captured by NGS). JAK2 exon 12 mutations occur in about 3-4% of PV patients. Testing for this can be a bit trickier. JAK2 exon 12 mutations can be deletions, insertions, and duplications and may not be as reliably detected by NGS. I would recommend sending dedicated JAK2 exon 12 testing. For what it is worth JAK2 exon 12 mutations often results in more of an isolated erythrocytosis so you may not see the typical panmyelosis on bone marrow biopsy. You may also see mutations in LNK in triple negative MPNs but this typically leads to megakaryocyte hyperplasia and thrombocytosis. Unfortunately, LNK (SH2B3) mutations are often missed by NGS. The rarest cause of low EPO erythrocytosis is a mutation in the EPO-receptor. These are exceedingly rare and usually inherited, so you would expect to have some family history. Most of the other hereditary erythrocytosis genes lead to a high/normal EPO levels. I have not seen ETOH levels mask panmyelosis, but again, this may not be expected in JAK2 exon 12 driven erythrocytosis. In sum, I'd check JAK2 exon 12 mutations. Also consider checking JAK2 V617F mutation by PCR as low-level mutations may be missed by NGS that has higher sensitivities. Then, I'd query family history and consider sending secondary erythrocytosis panel (We've sent ours to Mayo Clinic, but I believe there are others). Within that panel, they will check for EPO-R mutations in addition to the other mutations in the oxygen sensing pathway. Certainly, I'd recommend alcohol cessation as it would be interesting to see what the bone marrow looks like once this confounder is removed. While I guess it is possible that ETOH could mask the panmyelosis, it wouldn't hide the JAK2 mutation. Thanks and let me know if any further question arise. Interesting case!