title: Changing concepts of diagnostic criteria of myeloproliferative disorders and the molecular etiology and classification of myeloproliferative neoplasms: from Dameshek 1950 to Vainchenker 2005 and beyond.
abstract: The Polycythemia Vera Study Group (PVSG) and WHO classifications distinguished the Philadelphia (Ph(1)) chromosome-positive chronic myeloid leukemia from the Ph(1)-negative myeloproliferative neoplasms (MPN) essential thrombocythemia (ET), polycythemia vera (PV) and primary myelofibrosis (MF) or primary megakaryocytic granulocytic myeloproliferation (PMGM). Half of PVSG/WHO-defined ET patients show low serum erythropoietin levels and carry the JAK2(V617F) mutation, indicating prodromal PV. The positive predictive value of a JAK2(V617F) PCR test is 95% for the diagnosis of PV, and about 50% for ET and MF. The WHO-defined JAK2(V617F)-positive ET comprises three ET phenotypes at clinical and bone marrow level when the integrated WHO and European Clinical, Molecular and Pathological (ECMP) criteria are applied: normocellular ET (WHO-ET), hypercellular ET due to increased erythropoiesis (prodromal PV) and hypercellular ET associated with megakaryocytic granulocytic myeloproliferation (EMGM). Four main molecular types of clonal MPN can be distinguished: JAK2(V617F)-positive ET and PV; JAK2 wild-type ET carrying the MPL(515); mutations in the calreticulin (CALR) gene in JAK2/MPL wild-type ET and MF, and a small proportion of JAK2/MPL/CALR wild-type ET and MF patients. The JAK2(V617F) mutation load is low in heterozygous normocellular WHO-ET. The JAK2(V617F) mutation load in hetero-/homozygous PV and EMGM is clearly related to MPN disease burden in terms of splenomegaly, constitutional symptoms and fibrosis. The JAK2 wild-type ET carrying the MPL(515) mutation is featured by clustered small and giant megakaryocytes with hyperlobulated stag-horn-like nuclei, in a normocellular bone marrow (WHO-ET), and lacks features of PV. JAK2/MPL wild-type, CALR mutated hypercellular ET associated with PMGM is featured by dense clustered large immature dysmorphic megakaryocytes and bulky (cloud-like) hyperchromatic nuclei, which are never seen in WHO-ECMP-defined JAK2(V617F) mutated ET, EMGM and PV, and neither in JAK2 wild-type ET carrying the MPL(515) mutation. Two thirds of JAK2/MPL wild-type ET and MF patients carry one of the CALR mutations as the cause of the third distinct MPN entity. WHO-ECMP criteria are recommended to diagnose, classify and stage the broad spectrum of MPN of various molecular etiologies.
authors.affiliation: Department of Hematology, University Hospital Antwerp, Antwerp, The Netherlands.
authors.forename: Jan Jacques
authors.initials: JJ
authors.lastname: Michiels
authors.forename: Zwi
authors.initials: Z
authors.lastname: Berneman
authors.forename: Wilfried
authors.initials: W
authors.lastname: Schroyens
authors.forename: Hendrik
authors.initials: H
authors.lastname: De Raeve
mesh_terms: D001853:Bone Marrow / Q000473:pathology; D037282:Calreticulin / Q000235:genetics; D005091:Exons; D049673:History, 20th Century; D049674:History, 21st Century; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics; D009154:Mutation; D009196:Myeloproliferative Disorders / Q000175:diagnosis* / Q000235:genetics* / Q000266:history; D011087:Polycythemia Vera / Q000175:diagnosis / Q000235:genetics; D017410:Practice Guidelines as Topic; D055728:Primary Myelofibrosis / Q000175:diagnosis / Q000235:genetics; D053628:Receptors, Thrombopoietin / Q000235:genetics; D013920:Thrombocythemia, Essential / Q000175:diagnosis / Q000235:genetics
chemical_list: D037282:Calreticulin; D053628:Receptors, Thrombopoietin; C082218:MPL protein, human; D053614:Janus Kinase 2