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Abstract
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 JAK2 V617F 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 JAK2 V617F allele burden is related to MPN disease burden in terms of splenomegaly, constitutional symptoms and myelofibrosis. Five distinct clonal MPNs can be distinguished: JAK2 V617F mutated ET and PV; JAK2 exon 12 PV and the JAK2 wild type ET and MF caused by the somatic mutations MPL 515 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 JAK2 V617F 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 JAK2
Highlights
Polycythemia vera (PV) are described by Vaquez [1], Osler [2,3] and essential thrombocythemia (ET) and PV has been delineated as distinct clinical disease entities when the 1980 Rotterdam Clinical and Pathological (RCP) criteria are applied (Table 1) [4,5]
The JAK2V617F mutation load in gramulocytes is usually low in heterozygous ET, less that 10 to maximal 50% and either low with less than 50% or high between 50 to 100% in PV [40,41]
Patients with hypercellular ET, masked PV and PV homozygous for the JAK2V617F mutation patients are at high risk for myeloid metaplasia of the spleen with splenomegaly and bone marrow transformation into myelofibrosis (MF) [42]
Summary
Polycythemia vera (PV) are described by Vaquez [1], Osler [2,3] and essential thrombocythemia (ET) and PV has been delineated as distinct clinical disease entities when the 1980 Rotterdam Clinical and Pathological (RCP) criteria are applied (Table 1) [4,5]. The 1975 PVSG diagnostic criteria of PV did not use bone marrow histology and excluded by definition the erythrocythemic stage 1 PV (idiopathic erythrocythemia: IE) with normal platelets, leukocytes and spleen size [11,12,13]. Between 1975 and 1980, we routinely used bone marrow histopathology and erythrocyte count above 6 x 1012/L according to Dameshek in 1940 [9] as specific clues to the diagnosis of PV to clearly differentiate PV from all variant of primary and secondary erythrocytosis (Table 1). Idiopathic erythrocythemia (IE) is featured by increased red cell mass, normal spleen size, normal leukocyte and platelet counts and no clinical or laboratory evidence of primary or secondary erythrocytosis and a typical PV bone marrow histology (Table 1). The WHO Clinical, Molecular and Pathological (2014-CMP) classification of Michiels et al of the myeloproliferative neoplasms extended the CMGM concept of Georgii et al and replaced the term CMGM by primary megakaryocytic granulocytic myeloproliferation (PMGM, Figure 1) [32,33]
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