Management of Myeloproliferative Neoplasms: A Focus on Polycythemia Vera and Myelofibrosis - Episode 2

Differentiating Between Myeloproliferative Neoplasms


Harry P. Erba, MD, PhD: Mary Frances, how do we distinguish between the pH-negative classical MPNs [myeloproliferative neoplasms], such as ET [essential thrombocythemia], PV [polycythemia vera], and MF [myelofibrosis]?

Mary Frances McMullin, MD, FRCP, FRCPath: We have diagnostic criteria that have evolved over time. The WHO [World Health Organization] has specific criteria. Other groups have refinements of those, but basically, we’re looking at people with a raised blood count, a marker for a clonal disorder, like a JAK mutation, MPL, or CALR mutation, and then the bone marrow changes. The specific criteria for each disorder are set out and you distinguish between them on the level of the platelet count, the finding of the mutation, and the bone marrow appearances. Therefore, they clearly fall into the group of ET, PV, or myelofibrosis.

Harry P. Erba, MD, PhD: One of the things I find challenging about taking care of patients with MPNs is that sometimes the pathologist says the marrow looks like A, but clinically, they’re behaving like C. For example, the marrow looks like ET or prefibrotic MF, but they have a high red blood cell count and microcytic indices making me think of a PV. Have you seen this? The other part of this is, can patients go from 1 subtype to another?

Mary Frances McMullin, MD, FRCP, FRCPath: Yes. At the end of the day, these are specific diagnostic criteria where, at this point in time, it’s been said that this is what you need for PV or that’s what you need for ET. That has changed, over time the levels have gone down. The other point you make is that of what the bone marrow pathology shows. I, in the United Kingdom, get the job of reporting the bone marrows as well, as our training is different, but I think you have to accept that there’s no absolute marker when you look down a microscope that says, “This is ET,” or “This is polycythemia vera.” Their appearance is consistent with that, and it can be very difficult to distinguish that. One could even argue, to make a diagnosis of polycythemia vera, do you need a bone marrow if you have a JAK2 mutation on somebody with a markedly elevated hemoglobin? Does adding a bone marrow add anything further to that?

I think the final point you’re alluding to is, are these actually totally separate diseases, or is this a continuum? I’m interested in what we call diagnostic criteria and what we need to make a diagnosis, and where we are now. At the moment, we accept the criteria we have, but the big change in this area, of course, was finding the clonal mutations, and what we’re actually describing are acquired clonal diseases. Is the distinction valid between ET and PV? Time will tell.

Harry P. Erba, MD, PhD: I know Ruben and Rami want to make comments, but I want to come back to a very important comment that you made about our training. In the days of the Giants in the United States, we actually did look at bone marrows as well. I just want to make that clear. Ruben?

Ruben A. Mesa, MD, FACP: I think Mary Frances brought up several important points, but a key one is that the diagnosis of your MPN is not solely on the shoulders of the pathologist. It really is both a mixture of the clinical features, the phenotype, and the pathology. I find to do that well, it’s really an active conversation between the pathologist and the treating hematologist, if they’re not 1 person in the same, to most accurately classify the diseases. All of the other parts of molecular phenotype and all of those factors, increasingly, will add to that understanding, but the clinical phenotype and presentation is really key, both for initial diagnosis and also for the issue of progression.

Rami Komrokji, MD: The other challenge that I wanted to add is basically in distinguishing those from other diseases, such as myelodysplastic syndrome [MDS]. Often, the megakaryocytic atypia or proliferation sometimes describes as dysplasia. We have a lot of patients who are referred for MDS, but when our hematopathologist would look at those slides, they would say, “This is classical megakaryocytic proliferation. This is not megakaryocytic dysplasia.” They are often, especially if the patients present with cytopenia, labeled as MDS rather than MPN. I totally agree with the point. The clinical phenotype we see is probably a reflection of the molecular phenotype that we started learning about, and it’s probably the combination of mutations. Their sequence is what determines the clinical behavior that we see for those patients.

Harry P. Erba, MD, PhD: Exactly, and that’s one of the things I find most challenging. It was William Dameshek, MD, who, many years ago, when he saw these patients with myeloproliferative disorders, said, “Some day we’re going to find out that these are due to abnormalities in the normal signaling patterns that govern hematopoiesis.” We’ve done that. Quite frankly, the list of mutations is pretty similar in each of the diseases, although the frequencies might change a little bit. Do we really have an understanding of how these mutations lead to the different phenotypes? Is there any understanding there, or are we still learning?

Ruben A. Mesa, MD, FACP: In many ways, we’re still learning. Calreticulin may behave pathogenetically in a slightly different fashion than JAK2 V617F, but of course, we could see it in patients with early ET or advanced MF. We’re learning parts, but I don’t think we necessarily have found how the mutations fit into this issue of progression.

Rami Komrokji, MD: Obviously, it’s very challenging to understand, because I think the process is very complex, but there is definitely a clinical phenotype that’s a reflection for some of those mutations or the sequence of those mutations. I think there have been some studies where the TET2 happens before the JAK2 mutation. You’d see a certain clinical phenotype versus the other way, whether it’s a homozygotic or mutation in the JAK2. We’ve been looking recently to try to see whether we can distinguish or classify the patients based on the mutation alone, without the clinical phenotype. I don’t think we are there. Then there is, for example, the entity we talk about now as triple negative. Are those really true MPNs? Could those be an overlap of MDS and MPN? We are not there yet, but definitely have better understanding than we had a few years ago.

Harry P. Erba, MD, PhD: I think we call them triple negatives because we want to be as cool as the breast cancer doctors.

Transcript Edited for Clarity