Zeitschrift für Hämatologie und thromboembolische Erkrankungen
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2014 WHO Clinical Molecular and Pathological (WHO-CMP) Diagnostic Criteria for the Classification and Staging of Five Distinct JAK2, MPL and CALR Mutated Myeloproliferative Neoplasms

Jan Jacques Michiels1*, Karel Forstier2, Fransje Valster3, Vincent Potters3, Katrien Schelfout3 and Hendrik De Raeve4,5

Somatic mutations in the JAK2, MPL and calreticulin (CALR) genes are the driver causes of clonal myeloproliferative neoplasms (MPN). Applying the WHO Clinical, Molecular and Pathologic (WHO-CMP) classification of MPN, the JAK2V617F positive ET patients comprise three phenotypes of ET: normocellular ET, hypercellular ET due to increased erythropoiesis (prodromal PV) and ET with hypercellular megakaryocytic-granulocytic myeloproliferation (ET.MGM or masked PV). The percentage of JAK2V617F mutation load is low and stable in heterozygous normocellular ET and increasingly high in hetero/homozygous PV and masked PV. The JAK2V617F allele burden is related to MPN disease burden in terms of splenomegaly, constitutional symptoms and myelofibrosis. Five distinct clonal MPNs can be distinguished: JAK2V617F mutated ET and PV; JAK2 exon 12 PV and the JAK2 wild type ET and MF caused by the somatic mutations MPL515 or CALR. JAK2 mutated trilinear MPN reflects a broad spectrum of ET, prodromal or masked PV and classical PV, but the JAK2 wild type MPL or CALR positive ET and MF lack features of PV at diagnosis and during follow-up. Bone marrow features in JAK2V617F mutated ET and PV are similar and featured by medium sized to large (pleomorphic) megakaryocytes with only a few giant forms. Bone marrow histology in MPL515 mutated ET and MF is featured by clustered small and giant megakaryocytes with hyperlobulated stag-horn-like nuclei, in a normocellular bone marrow with no features of PV. Bone marrow histology in CALR mutated ET and MF is featured by dense clustered large immature dysmorphic megakaryocytes and bulky (cloude-like) hyperchromatic nuclei similar as described in primary megakaryocytic granylocytic myeloproliferation (PMGM), which are never seen in JAK2V617F, JAK2 exon 12 and MPL515 mutated MPN.