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World J Hematol. Aug 6, 2015; 4(3): 16-53
Published online Aug 6, 2015. doi: 10.5315/wjh.v4.i3.16
European vs 2015-World Health Organization clinical molecular and pathological classification of myeloproliferative neoplasms
Jan Jacques Michiels, Fransje Valster, Jenne Wielenga, Katrien Schelfout, Hendrik De Raeve
Jan Jacques Michiels, International Hematology and Bloodcoagulation Research Center, Goodheart Institute and Foundation in Nature Medicine, European Working Group on Myeloproliferative Neoplasms, 3069 AT Rotterdam, The Netherlands
Fransje Valster, Department of Internal Medicine, BRAVIS Hospital, 4624 VT Bergen op Zoom, The Netherlands
Jenne Wielenga, Department of Internal Medicine, Admiraal De Ruyter Hospital, 4382 EE Vlissingen, The Netherlands
Katrien Schelfout, Department of Pathology, BRAVIS Hospital, 4624 VT Bergen op Zoom, The Netherlands
Hendrik De Raeve, Department of Pathology OLV Hospital Aalst OLV Ziekenhuis, B-9300 Aalst, Belgium
Hendrik De Raeve, Department of Pathology, University Hospital, B-1090 Brussels, Belgium
Author contributions: Michiels JJ and De Raeve H designed the study and wrote the manuscript; Michiels JJ, Valster F and Wielenga J collected the clinical and molecular features of myeloproliferative neoplasms (MPN); Schelfout K and De Raeve H perfomed the pathology studies and interpreted the bone histology diagnostic findings in MPN of various molecular etiology.
Conflict-of-interest statement: The authors declare no conflicts of interest.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Correspondence to: Jan Jacques Michiels, MD, PhD, Investigator, Senior Internist, International Hematology and Bloodcoagulation Research Center, Goodheart Institute and Foundation in Nature Medicine, European Working Group on Myeloproliferative Neoplasms, Erasmus Tower, Veenmos 13, 3069 AT Rotterdam, The Netherlands.
Telephone: +31-62-6970534
Received: June 23, 2014
Peer-review started: June 23, 2014
First decision: August 14, 2014
Revised: March 14, 2015
Accepted: April 28, 2015
Article in press: April 30, 2015
Published online: August 6, 2015

The BCR/ABL fusion gene or the Ph1-chromosome in the t(9;22)(q34;q11) exerts a high tyrokinase acticity, which is the cause of chronic myeloid leukemia (CML). The 1990 Hannover Bone Marrow Classification separated CML from the myeloproliferative disorders essential thrombocythemia (ET), polycythemia vera (PV) and chronic megakaryocytic granulocytic myeloproliferation (CMGM). The 2006-2008 European Clinical Molecular and Pathological (ECMP) criteria discovered 3 variants of thrombocythemia: ET with features of PV (prodromal PV), “true” ET and ET associated with CMGM. The 2008 World Health Organization (WHO)-ECMP and 2014 WHO-CMP classifications defined three phenotypes of JAK2V617F mutated ET: normocellular ET (WHO-ET), hypercelluar ET due to increased erythropoiesis (prodromal PV) and ET with hypercellular megakaryocytic-granulocytic myeloproliferation. The JAK2V617F mutation load in heterozygous WHO-ET is low and associated with normal life expectance. The hetero/homozygous JAK2V617F mutation load in PV and myelofibrosis is related to myeloproliferative neoplasm (MPN) disease burden in terms of symptomatic splenomegaly, constitutional symptoms, bone marrow hypercellularity and myelofibrosis. JAK2 exon 12 mutated MPN presents as idiopathic eryhrocythemia and early stage PV. According to 2014 WHO-CMP criteria JAK2 wild type MPL515 mutated ET is the second distinct thrombocythemia featured by clustered giant megakaryocytes with hyperlobulated stag-horn-like nuclei, in a normocellular bone marrow consistent with the diagnosis of “true” ET. JAK2/MPL wild type, calreticulin mutated hypercellular ET appears to be the third distinct thrombocythemia characterized by clustered larged immature dysmorphic megakaryocytes and bulky (bulbous) hyperchromatic nuclei consistent with CMGM or primary megakaryocytic granulocytic myeloproliferation.

Keywords: Myeloproliferative disorders, Essential thrombocythemia, Primary megakaryocytic granulocytic myeloproliferation, Myelofibrosis, JAK2V617F mutation, MPL515 mutation, Calreticulin mutation, JAK2 wild type, Myeloproliferative neoplasm, Bone marrow pathology, Polycythemia vera

Core tip: The 2015 World Health Organization-Clinical Molecular and Pathological criteria define three phenotypes of JAK2V617F mutated myeloproliferative neoplasms (MPNs) essential thrombocythemia (ET), prodromal polycythemia vera (PV), prodromal PV, hypercellular megakaryocytic-granulocytic myeloproliferation and classical PV vs the JAK2 exon 12 mutated idiopathic eryhrocythemia and PV. MPL515 mutated JAK2 wild type ET and myelofibrosis is a distinct thrombocythemia without features of PV in blood and bone marrow. Calreticulin mutated JAK2/MPL wild type ET and myelofibrosis is the third thrombocythemia entity with characteristic features of primary megakaryocytic granulocytic myeloproliferation in the bone marrow, which are not seen in JAK2 and MPL mutated MPNs. MPN disease burden is best reflected by the degree of anemia and splenomegaly on top of mutation allele burden, bone marrow cellularity and increase of reticulin fibrosis.