Comparison of the Mutational Profiles of Primary Myelofibrosis, Polycythemia Vera, and Essential Thrombocytosis

Jinming Song, MD, PhD; Mohammad Hussaini, MD; Hailing Zhang, MD; Haipeng Shao, MD; Dahui Qin, MD, PhD; Xiaohui Zhang, MD, PhD; Zhenjun Ma, PhD; Syeda Mahrukh Hussnain Naqvi, MD, MPH; Ling Zhang, MD; Lynn C. Moscinski, MD


Am J Clin Pathol. 2017;147(5):444-452. 

In This Article

Abstract and Introduction


Objectives: To compare the mutational profiles of patients with primary myelofibrosis (PMF), polycythemia vera (PV), and essential thrombocytosis (ET).

Methods: Next-generation sequencing results of 75 cases of PMF, 33 cases of PV, and 27 cases of ET were compared.

Results: Mutation rates of ASXL1 and SRSF2 were significantly higher in PMF than in PV or ET. ASXL1 mutations appeared to be more frequently associated with risk of transformation to acute myeloid leukemia than JAK2 or TET2 mutations. The most common mutation-cytogenetic combinations in myeloproliferative neoplasm (MPN) were mutations of JAK2 or ASXL1 with del(20q) and were more common in patients with PMF and PV than in patients with ET. Differences were also found between patients with PMF and PV.

Conclusions: PMF, PV, and ET show different mutational profiles, which may be helpful in resolving the differential diagnosis between MPNs. Due to the relatively small number of cases and variable testing over time, larger controlled studies are necessary to confirm the findings.


Primary myelofibrosis (PMF), polycythemia vera (PV), and essential thrombocytosis (ET) are common Philadelphia chromosome–negative chronic myeloproliferative neoplasms (MPNs), characterized by cytoses, splenomegaly, and hypercellular bone marrows with proliferation of myeloid, erythroid, and/or megakaryocytic lineages. In early stage disease, PMF usually presents with leukocytosis, PV with increased hemoglobin level, and ET with thrombocytosis. However, it is a challenge to distinguish between ET and prefibrotic/early myelofibrosis, as well as initial cases of PV from ET or even PMF.[1–3] The differential diagnosis at the intermediate stage is easier but could still be a pathologic challenge. The relevance of differentiating between these entities lies beyond an academic exercise given the different natural histories and treatment approaches for each. Survival is longest in ET (median survival of 20 years), intermediate in PV (14 years), and shortest in PMF (6 years).[1,4] The goal of therapy in PV and ET is aimed more at supportive care and prevention of thrombocytosis than curing disease. In contrast, for patients with genetically and clinically high-risk PMF, stem cell transplant is the treatment of choice.[1,4] Different prognostic systems are also used for these three identities.[1,4] Therefore, there is clinical utility in identifying unique nonmorphologic features that may help to distinguish between these three entities. As these diseases progress, they all may potentially develop diffuse bone marrow fibrosis and present with cytopenia(s). At the terminal fibrotic stage, marrow morphologies can be very similar between advanced PMF and post-ET/PV myelofibrosis, making them hard to distinguish and posing a real and common diagnostic challenge to the pathologist. However, the prognosis and the treatment may be similar between these entities at this stage.[5]

With rapid progress in the sequencing technology due to next-generation sequencing (NGS), somatic mutations in growing numbers of genes, with pathogenetic and prognostic significance, have been identified in myeloid neoplasms. Key MPN-specific driver mutations have been well characterized—namely, JAK2, CALR, and MPL—and these are usually mutually exclusive.[6] JAK2 is the most frequent mutation in Philadelphia chromosome–negative MPN, with frequencies of approximately 95% to 98% in PV, 50% to 60% in ET, and 55% to 65% in PMF.[4] CALR and MPL mutations are typically absent in patients with PV with rare exception. CALR mutations are present in approximately 20% to 25% of ET or PMF cases, while MPL mutations are present in 3% to 4% of ET cases and 6% to 7% of PMF cases.[4]

It has been previously shown that an MPN can be initiated from a single hematopoietic stem cell expressing the canonical JAK2 V617 mutation.[7] Furthermore, JAK2 inhibitors have shown promising activity in controlling constitutional symptoms and splenomegaly in PMF[8] and PV but have not been shown to be disease modifying. Patients with CALR mutations have been reported to have lower risk of thrombosis in ET and better overall survival in PMF compared with JAK2-mutated patients.[9] Among patients with ET, those with MPL mutations show significantly inferior overall survival.

Of note, approximately 10% to 15% of patients with PMF or ET do not express any of the three (JAK2, CALR, MPL) mutations. However, with the widespread research and clinical application of NGS, mutations in additional genes and other nondriver mutations have been identified in MPN, and their clinical and prognostic significance is under intensive studies.[10] Given the growing body of genomic data, it has been suggested that MPNs may better be categorized based on their mutational bases rather than morphologic differences with regard to clinical outcomes.[11]

In this study, we analyzed the mutational profiles and cytogenetic abnormalities of 135 patients with PMF, PV, or ET with the aim of uncovering molecular and/or cytogenetic profiles that may facilitate the distinction between and understanding of these three entities.