Progression in Ph-Chromosome-Negative Myeloproliferative Neoplasms: An Overview on Pathologic Issues and Molecular Determinants

SIMPLE SUMMARY: The present review is meant to provide an updated overview on the progressions in Ph-chromosome negative MPN, with major focus on the histopathological changes identifiable in routine diagnostic practice on bone marrow biopsies. It integrates these issues with clinical parameters that define the risk of progression and the molecular determinants that are potentially involved in the transformation. The fibrotic and accelerated/leukemic types of progression are defined by the Who Classification, but laboratory changes may occur during the course of the disease, such as monocytosis or leukocytosis. These can impact on morphology and challenge the histologic diagnosis with potential risk of reclassification. Molecular investigations are becoming relevant for the management of these patients and profoundly changing and challenging our diagnostic approach, but histology remains a turning point for the diagnosis and classification of Ph-negative MPN and should remain the reference also in the event of unusual or discordant molecular findings. ABSTRACT: Progression in Ph-chromosome-negative myeloproliferative neoplasms (MPN) develops with variable incidence and time sequence in essential thrombocythemia, polycythemia vera, and primary myelofibrosis. These diseases show different clinic-pathologic features and outcomes despite sharing deregulated JAK/STAT signaling due to mutations in either the Janus kinase 2 or myeloproliferative leukemia or CALReticulin genes, which are the primary drivers of the diseases, as well as defined diagnostic criteria and biomarkers in most cases. Progression is defined by the development or worsening of marrow fibrosis or the progressive increase in the marrow blast percentage. Progression is often related to additional genetic aberrations, although some can already be detected during the chronic phase. Detailed scoring systems for clinical usage that are mostly applied in patients with primary myelofibrosis have been defined, and the most recent ones include cytogenetic and molecular parameters with prognostic significance. Additional different clinic-pathologic changes have been reported that may occur during the course of the disease and that are, at present, classified as WHO-defined types of progression, although they likely represent such an event. The present review is meant to provide an updated overview on progression in Ph-chromosome-negative MPN, with a major focus on the pathologic side.