Current diagnostic criteria for the chronic myeloproliferative disorders (MPD) essential thrombocythemia (ET), polycythemia vera (PV) and chronic idiopathic myelofibrosis (CIMF)Critères diagnostiques actuels des syndromes myéloprolifératifs (SMP), thrombocytémie essentielle (TE), polyglobulie de Vaquez (PV) et myélofibrose idiopathique (MFI)☆
Introduction
In 1950, William Dameshek presented an original view on the physiopathology and course of polycythemia vera (PV) [1]. He described PV as a chronic disorder of the bone marrow characterized by excessive production of blood cells by the marrow elements i.e. the nucleated red cells the granulocytes and the megakaryocytes. Not only is PV a chronic disorder without any evidence of invasiveness but it is a total marrow disorder in which erythrocytosis, leukocytosis and thrombocytosis are all simultaneously present [1]. In PV, all “stops” to blood production in the bone marrow seem to have been pulled out. The marrow is crowded with great numbers of nucleated red cells and granulocytes in all stages of maturation with marked hyperplasia and clustering of enlarged mature megakaryocytes. Some cases however show only a moderate elevation of erythrocytes with an extreme degree of thrombocytosis, while in others the leukocyte counts may be at or close to leukemic levels, with only slight increase in red cells or platelets. As to the etiology of trilinear myeloproliferation in PV, Dameshek proposed two highly speculative possibilities one, the presence of excessive bone marrow stimulation by an unknown factor or factors and two, a lack or a diminution in the normal inhibitory factor or factors [1]. This original view and hypothesis of Dameshek is recently confirmed by the discovery of the JAK2 V617F mutation by James, Ugo, Casadevall and Vainchenker in Paris, France [2] demonstrating that the V617F mutation induces a loss of inhibitory activity of the JH2 pseudokinase part on the JH1 kinase part of JAK2 leading to enhanced activity of the normal JH1 kinase activity of JAK2, which makes the mutated hematopoietic stem cells hypersensitive to hematopoietic growth factors TPO EPO, IGF1, SCF and GCSF resulting in trilinear myeloproliferation.
Section snippets
The concept of PV as a trilinear MPD
Wasserman proposed in 1954 a hypothetical concept for the course of PV[3], [4]. Accordingly PV is characterized by initial erythrocytosis (erythrocythemia), which is usually accompanied by leukocytosis of normal mature granulocytes (leukocythemia) with increased leukocyte alkaline phosphatase score, by thrombocytosis (thrombocythemia), splenomegaly, and plethora. Wasserman distinguished at least five subsequent stages in the natural history of PV (Fig. 1) [3], [4]:
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stage 1). Pure erythrocythemia
Clinical, laboratory and pathological features of the MPDs
In the 1980s and 1990s the German pathologists Burkhardt et a1 [8], Georgii et al. [9], [10], [11], [12] and Thiele et al. [13], [14], [15], [16], [17], [18] have described typical histopathological features from bone marrow biopsy material for the diagnosis and classification of each of the 3 different Ph-negative MPDs essential thrombocythemia (ET), PV and AMM. Georgii et al. [9], [10] and Thiele et al. [13], [14] drew attention to an authentic chronic megakaryocytic granulocytic
WHO pathological criteria for the diagnosis of ET, PV and CIMF
A typical bone marrow picture according to the WHO [24] for true ET affects mainly of megakaryocytic cell lineage, shows increased numbers of loosely clustered enlarged, mature megakaryocytes with hyperploid staghorn-like nuclei together with normal cellularity, normal erythropioesis, and normal granulopoiesis, no increase of reticulin fibrosis, and there is no peripheral blood, bone marrow and cytogenetic evidence of typical and atypical chronic myeloid leukemias (CML), PV, myelodysplastic
Current clinical and pathological criteria for the diagnoses of ET PV and CIMF
Since 1975 the minimum criterion of the Polycythemia Vera Study Group (PVSG) for the diagnosis of ET was 1000 × 109/l (1 million) [37]. In 1985, we demonstrated that the majority of symptomatic ET patients diagnosed by increase and clustering of enlarged megakaryocytes in bone marrow biopsies, had platelet counts between 400 and 1000 × 109/l (below 1 million). This prompted the PVSG to lower the platelet count for the diagnosis of ET to the arbitrary minimum of 600 (Table 3) [38]. We could
Myelofibrosis (MF) versus chronic idiopathic myelofibrosis (CIMF)
Prefibrotic CIMF according to WHO [24] and ECP [25] is a dual mixed proliferation of increased granulopoiesis and megakaryopoiesis dominated by immature giant megakaryocytes which are conspicuously enlarged due to increase of nuclear as well as cellular size with bulky and irregular roundish-shaped nuclei, so-called cloud-like nuclei, which are never seen in ET and PV (Table 2) [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36]. The PVSG criteria for the
The molecular etiology of the MPDs ET PV and MF
As to the etiology of trilinear myeloproliferation in PV, Dameshek proposed in 1950 two highly speculative possibilities: the presence of excessive bone marrow stimulation by an unknown factor or factors, and a lack or a diminution in the normal inhibitory factor or factors [1]. The JAK2 V617F mutation reflects a gain of function mutation, which is in line with the concept of Dameshek [1] that all “stops” to blood production in the bone marrow seem to have been pulled out, which now appears to
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2020, Blood Cells, Molecules, and DiseasesCitation Excerpt :The diagnosis of PV uses clinical and biological criteria defined by either the Polycythemia Vera Study Group or the World Health Organization (WHO) [4]. With advancements in molecular and cytogenetic testing, PV diagnostic criteria are continually evolving to incorporate molecular studies into MPN diagnostic algorithms [5,6]. The 2008 WHO MPN diagnostic criteria revision added JAK2 mutation status into the major diagnostic criteria [7–9].
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2010, Biochimica et Biophysica Acta - Reviews on CancerCitation Excerpt :Cytoplasmatic STATs, of which 7 family members are known in mammals, are activated upon tyrosine phosphorylation, which lead to their dimerization, nuclear translocation and regulation of target genes expression [21]. Mutations and translocations in the JAK genes (e.g. JAK2V617F) leading to constitutively active JAK proteins are associated with a variety of haematopoietic malignancies, including acute myeloid and lymphoblastic leukemias (JAK1 and JAK2), acute megakaryoblastic leukemia (JAK2 and JAK3), T-cell precursor acute lymphoblastic leukemia (JAK1), MPD and polycythemia vera (JAK2) [22–24]. Aberrant STAT activation has been observed in several leukemias as well (reviewed in [25]).
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Lecture International Symposium on The V616F JAK2 mutation: A major step forward in the pathogenesis and management of myeloproliferative disorders, November 18, 2005, Hopital Avicenne and Paris 13 University.