The Clinical Management of Primary Myelofibrosis - Episode 3
Harry Erba, MD, PhD:This is a very typical case of primary myelofibrosis, and it brings us to the discussion of how exactly this is diagnosis made. Now you would think that seeing fibrosis in the marrow would make the diagnosis. That is clearly not the case. There are multiple things that can cause reactive fibrosis of the bone marrow: other malignancies, carcinomas, hairy cell leukemia lymphomas, infections and granuloma in this disease, drug reactions can do it. Even autoimmune disease has been associated with an autoimmune myelofibrosis. And so, the mere fact that there’s fibrosis doesn’t mean that the patient has primary myelofibrosis.
In fact, morphologically what the pathologists hang their hat on in terms of this diagnosis is the megakaryocytic hyperplasia and atypia with hyperchromatic, very folded and low-beta nuclei, and the clustering of those megakaryocytes. It’s really the megakaryocytic abnormalities that lead to the consideration of myelofibrosis as the diagnosis. And in fact, there is a prefibrotic myelofibrosis that’s characterized by those same megakaryocytic changes, but without the grade 2 or 3 myelofibrosis that’s seen then.
So, the second criteria then are to rule out other myeloproliferative neoplasms and other myeloid malignancies. And the third is to find some evidence of clonality. Now in 90% of patients, there will be mutation inJAK2, the V617F, as in this patient, or in calreticulin, orCALR, or inMPL. Those are the 3 genes that are most commonly mutated in myelofibrosis. The other 10% of patients have what is called triple-negative myelofibrosis. A number of other mutations have been associated with myelofibrosis such asASXL1and others likeTET2, for example. That’s important because not only can a broader myeloid gene panel make the diagnosis if you don’t findJAK2, calreticulin, or MPL, this more extended gene panel can help with the diagnosis by showing clonality, but also, it’s prognostically important. So, patients withASXL-mutated myelofibrosis, especially if they don’t have a calreticulin mutation, have a worse outcome.
If you don’t find evidence of clonality based on the mutation analysis, then you have to be certain to rule out all of the reactive causes of myelofibrosis. You have to have all 3 of those major criteria: megakaryocytic hyperplasia and atypia, the ruling out of other myeloid malignancies, and finally, evidence of clonality by mutational analysis, or at least ruling out other reactive cause of myelofibrosis.
There are 5 minor criteria, you only have to have 1 of those: a leukocytosis with a white count over 11,000so, it’s different than the staging system—anemia hemoglobin under 10, elevated LDH, splenomegaly, and the final one is a leucoerythroblastic picture—immature white cells, nuclei red blood cells, teardrop cells, and giant platelets. Those are things that you might see in a patient in the peripheral blood of a patient with primary myelofibrosis.
What’s interesting about the morphologic classification, how you make the pathologic diagnosis, the splenomegaly is a minor criteria, but the degree of splenomegaly actually has not been associated with prognosis in the prognostic schemes. Even in the revised International Prognostic Scoring System and the revised Dynamic International Prognostic Scoring System, splenomegaly isn’t included. What’s included would be if a patient has thrombocytopenia, if the patient has certain poor-risk cytogenetic changes requiring transfusions. And in fact, anemia is doubly weighted in those more recent classification systems.
So, this is a challenging diagnosis. Patients with myeloid fibrosis, I truly believe their marrows need to be seen by hematopathologists who are experts in the diagnosis of myeloid neoplasms. Distinguishing the myeloproliferative neoplasms from each other pathologically is quite a challenge. Even grading the degree of fibrosis is something that is not tremendously well standardized, and there can be disagreements between pathologists. So, I do recommend getting a second opinion from a hematopathologist who specializes in myeloid malignancies.
Transcript edited for clarity.