Elsevier

Pathologie Biologie

Volume 55, Issue 2, March 2007, Pages 92-104
Pathologie Biologie

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)

https://doi.org/10.1016/j.patbio.2006.06.002Get rights and content

Abstract

The clinical criteria for the diagnosis of essential thrombocythemia (ET) according to the polycythemia vera study group (PVSG) do not distinguish between ET and thrombocythemia associated with early stage PV and prefibrotic chronic idiopathic myelofibrosis (CIMF). The clinical criteria of the PVSG for the diagnosis of polycythemia vera (PV) only detects advanced stage of PV with increased red cell mass. The bone marrow criteria of the World Health Organization (WHO) are defined by pathologists to explicitly define the pathological criteria for the diagnostic differentiation of ET, PV, and prefibrotic and fibrotic CIMF. As the clinical PVSG and the pathological WHO criteria show significant shortcomings, an updated set of European Clinical and Pathological (ECP) criteria combined with currently available biological and molecular markers are proposed to much better distinct true ET from early PV mimicking ET, to distinguish ET from thrombocythemia associated with prefibrotic CIMF, and to define the various clinical and pathological stages of PV and CIMF that has important therapeutic and prognostic implications. Comparing the finding of clustered giant abnormal megakaryocytes in a representative bone marrow as a diagnostic clue to MPD, the sensitivity for the diagnosis of MPD associated with splanchnic vein thrombosis was 63% for increased red cell mass, 52% for low serum EPO level, 72% for EEC, and 74% for splenomegaly indicating the superiority of bone marrow histopathology to detect masked early and overt MPD in this setting. The majority of PV and about half of the ET patients have spontaneous EEC, low serum EPO levels and PRV-1 over-expression and are JAK2 V617F positive. The positive predictive value for the diagnosis of PV of spontaneous growth of endogenous erythroid colonies (EEC) of peripheral blood (PB) and bone marrow (BM) cells is about 80–85% when either PB or BM EEC assays, and up to 94% when BM and PB EEC assays were performed. The diagnostic impact of low serum EPO levels (ELISA assay) in a large study of 186 patients below the normal range (< 3.3 IU/l) had a sensitivity specificity and positive predictive value of 87%, 97% and 97.8%, respectively, for the diagnosis of PV. There is a significant overlap of serum EPO levels in PV versus control and controls versus SE. The specificity of a JAK2 V617F PCR test for the diagnosis of MPD is high (near 100%), but only half of ET and MF (50%) and the majority of PV (up to 97%) are JAK2 V617F positive. The use of biological markers including JAK2 V617 PCR test, serum EPO, PRV-1, EEC, leukocyte alkaline phosphatase score and peripheral blood parameters combined with bone marrow histopathology has a high sensitivity and specificity (almost 100%) to diagnose the early and overt stages of ET, PV and CIMF in JAK2 V617F positive and negative MPDs.

Résumé

Les critères cliniques de diagnostic de la thrombocytémie essentielle (TE) développés par le PVSG ne permettent pas de distinguer les TE des formes débutantes avec thrombocytose de PV et de MFI. Ces critères ne permettent par ailleurs que le diagnostic de formes patentes de PV, avec une claire augmentation du volume globulaire. Les critères OMS de diagnostic des SMP incluent la biopsie médullaire, avec des critères définis par les pathologistes pour clairement différencier TE, PV, MFI au stade préfibrotique ou fibrotique. Nous proposons une mise à jour des critères diagnostiques utilisant les marqueurs biologiques et moléculaires actuellement disponibles, dans le but de distinguer des TE pures les formes débutantes de PV et de MFI mimant les TE, et de définir les stades cliniques et anatomopathologiques de PV et MFI, ce qui a d'importantes conséquences pronostiques et thérapeutiques. Sont notamment discutés, la valeur des données morphologiques sur la biopsie de moelle osseuse, du dosage d'érythropoïétine, de l'existence de colonies érythroïdes ou mégacaryocytaires spontanées, de l'hyperexpression du gène PRV-1, et de la mutation V617F de JAK2. L'utilisation de ces marqueurs en association avec les données morphologiques de la moelle osseuse permet de diagnostiquer avec une haute sensibilité et spécificité (proches de 100 %) les stades patents mais aussi précoces de TE, PV et MFI, qu'ils soient V617F JAK2 positifs ou négatifs.

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]:

  • 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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