E first trimester of pregnancy.MPDs [13]. The JAK2 V617F mutation clearly represents a new molecular marker for the Ph-negative patients. Initially described in PV patients, where it has been observed in 65 to 97 of the cases [1,14-17], this mutation has also been detected in subsets of each of the other Ph-negative MPDs: in 23 to 57 of ET and 43 to 67 of IMF patients, as well as in some Ph-negative CML and MDS [18,19]. The presence or absence of the V617F mutation does not strictly correlate with any phenotype of Ph-negative MPD recognized according to either the PVSG criteria or the WHO classification. As the absence of the mutation has been repeatedly confirmed in more than 50 of ET patients, the diagnosis of ET presently remains a mixture of: 1) positive non specific arguments in favor of a Ph-negative MPD, including the JAK2 mutation and the bone marrow (BM) biopsy findings and 2) elimination of PV and IMF according to their currently used and phenotypically based definitions [12,13,20].Arguments supporting the diagnosis of Ph-negative MPD ?Standardized histological BM features have been introduced in the WHO diagnostic criteria for Ph-negative MPDs. The diagnostic target of histopathology in patients presenting an elevated platelet count according to this classification may be twofold:1) To confirm the presence of a Ph-negative MPD and exclude long lasting reactive thrombocytoses (Rth). This step can be achieved through a systematic analysis of: a) megacaryocytopoiesis, focusing especially on the proportion of giant vs. small forms, nuclear lobulation, maturation MG-132 cost defects, cluster formation by megacaryocytes; b) BM cellularity; c) degree of expansion and of left shifting of granulocyte and erythrocyte lineages; d) densification of the reticulin network and presence of collagen fibrosis in the BM stroma [7,21,22]. 2) To offer a specific morphologic description of each of the Ph-negative MPDs. For instance in ET, megakaryocytopoiesis is characterized by the presence of large to giant cells with a predominance of hyperlobulated staghorn nuclei loosely clustered throughout the BM. Cellularity in ET is not significantly increased compared with age-matched normal samples, and neutrophil granulopoiesis and erythropoiesis display no significant change in the distribution and proliferation of both cell lineages. In true ET there is no collagen fibrosis and no increase in reticulin fibers of the myeloid stroma [22]. The relevant parameters in BM introduced by the WHO classification to eliminate not only classical forms of PV or IMF but mainly prefibrotic early stages of IMF or/and early or latent PV will be described conjointly with the differential diagnosis of the other Ph-negative MPDs.Diagnostic PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/27488460 criteriaDue to the lack of a specific molecular marker, the diagnosis of ET can only be settled after a step-by-step elimination of the other clinical situations associated with a protracted elevation of the platelet number. The criteria of this stepwise elimination were initially proposed by the PVSG [12]. More recently, the World Health Organisation (WHO) has proposed an improved new set of criteria where specific abnormalities of megacaryocytopoiesis associated with other bone marrow biopsy findings were proposed as a common positive marker of Ph-negativePage 3 of(page number not for citation purposes)Orphanet Journal of Rare Diseases 2007, 2:http://www.OJRD.com/content/2/1/?The unique, acquired, clonal, somatic mutation of JAK2 occurring.