Myelofibrosis 2012: it's complicated

Abstract

Major advances in myeloproliferative neoplasms in the last decade have cast light on their complexity. The identification of JAK2 (V617F) briefly promised a unifying mechanism of pathogenesis with a single pathway that could be efficiently targeted. Instead, there have been major advances in understanding acquired and background genetic and epigenetic contributors to this group of disorders, with refined risk prediction models and experimental therapeutics that have provided a more nuanced model of disease. In aggregate these observations likely explain the heterogeneity of these disorders and their generally unpredictable response to therapy. Molecular studies, beginning with the identification of JAK2 (V617F), have led to a concept of MPN subtypes existing on a continuum, and additional discoveries such as TET2 and EZH2 mutations have provided the molecular underpinnings to begin to explain overlapping phenotypes in myeloid malignancies more generally. In many ways the pace of molecular discovery is outstripping our ability to integrate these observations into clinical care, both in terms of molecular diagnostics and medical decision making. This review will attempt to summarize, within a clinical context, our evolving understanding of myeloproliferative neoplasms. It focuses on biology, histopathology, prognostic scoring systems, stem cell transplantation as well as selected clinical/preclinical therapeutic observations.

Keywords: JAK2 V617F; TET2; essential thrombocytosis; hematopoietic stem-cell transplantation; interferon; myelofibrosis; myeloproliferative neoplasms; polycythemia vera.

Figure 1.

Morphologic findings in essential thrombocytosis (ET) and myelofibrosis (MF). (A), (B) A 39-year-old woman with JAK2^V617F+ ET. Mildly hypocellular (50%) marrow (5× H&E) with balanced trilineage hematopoiesis featuring singly scattered and focally clustered normal sized and large megakaryocytes with widely spaced (‘staghorn’) nuclei (20× H&E). (C), (D) A 55-year-old woman with JAK2^V617F+ MF. Markedly hypercellular (95% cellularity) marrow (5× H&E) with granulocytic hyperplasia and prominent aggregates of smaller cytologically atypical megakaryocytes with hypolobated ‘cloudlike’ nuclei (20× H&E).

Figure 2.

Reversal of fibrosis following reduced intensity hematopoietic stem-cell transplantation (HSCT). A 63-year-old woman with primary myelofibrosis (PMF). Pre-transplant: H&E sections (5×) show markedly fibrotic marrow. While myelopoiesis and especially erythropoiesis are decreased, megakaryopoiesis is relatively increased and cytologically atypical (20×), with numerous clustered forms that range from small and hypolobated to large and bizarre. A reticulin stain (20×) highlights extensive diffuse reticulin fibrosis. Day 100 post-transplant: H&E sections (5×) show a substantial decrease in fibrosis, with marrow that is hypercellular for age (80%) and demonstrates normal trilineage hematopoiesis. Megakaryocytes are decreased in number and cytologically unremarkable (20×). A reticulin stain shows only mild and variable fibrosis (20×). One year post-transplant: H&E sections (5×) show marrow that is hypercellular for age (80%), with normal trilineage hematopoiesis (20×). A reticulin stain shows only mild and variable fibrosis (20×).