Bone marrow histology is a pathognomonic clue for hematopathologists to accurately distinguish the BCR/ABL negative chronic Myeloproliferative Disorders(CMPD) Essential thrombocythemia (ET) and polycythemia vera (PV) from BCR/ABL positive chronic myeoid leukemia (CML) and ET, and from thrombocythemia associated with myelodyspastic syndromes in RARS-T and 5q-minus syndrome. The 2008 European Clinical Molecular and Pathological (2008 ECMP) classifications distinguish three distinct clonal myeloproliferative neoplasms (MPN) of JAK2V617F mutated ET, JAK2 wild type MPL mutated ET and JAK2/MPL wild type ET. The 2008 ECMP criteria could delineate three prefibrotic stages JAK2V617F mutated ET as normocellular ET, ET with features of early PV (prodromal PV), and ET with hypercellular megakaryocytic granulocytic myeloproliferation (EMGM) and 6 clinical stages of PV, which have important prognnostic and therapeutic implications. Spontaneous EEC and low serum erythropoietin (EPO) levels are highly specific for JAK2V617F mutated ET, prodromal PV, masked PV and classical PV. The quantitation of JAK2V617F mutation allele burden plays a key-role in the diagnostic work-up and staging of ET, PV and MF patients. The JAK2V617F mutation allele burden in heterozygous mutated ET is low but high in combined heterozygous - homozygous or homozygous mutated PV and EMGM. The combined use of JAK2V617F mutation load, spleen size are of major prognostic significance in terms of critical care medicine on top of pre-treatment bone marrow histopathology. This has important therapeutic implications for the first, second and third line treatment options in prodromal, classical and masked PV. JAK2 wild type ET carrying the MPL515 mutation is a separate and distinct MPN entity without features of PV in blood (normal serum EPO) and bone marrow at diagnosis and during follow-up. JAK2/MPL wild type ETis associated with primary megakaryocytic granulocytic myeloproliferation (PMGM) and appears to be the third distinct MPN entity first definde as chronic granulocytic megakarycytic myeloproliferation in the 1990 Hannover Bone Marrow classification of CMPD. Myelofibrosis (MF) is not a disease but a secondary response to cytokines released from the clonal granulocytic and megakaryocytic proliferative cells in MPNs of various molecular etiology. Large Prospective Unmet Need (PUN) studies of treated and newly diagnosed MPN patients are warranted to delineate the natural history and outcome of MPN of various molecular etiology during long-term or life long follow-up
