J J Michiels
Goodheart Institute, Netherlands
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
Biography
Biography: J J Michiels
Abstract
The Polycythemia Vera Study Group (PVSG) and WHO classifications distinguished the Philadelphia (Ph1) chromosome positive chronic myeloid leukemia from the Ph1 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.