Improvement of criteria for refractory cytopenia with multilineage dysplasia according to the WHO classification based on prognostic significance of morphological features in patients with refractory anemia according to the FAB classification

Matsuda, Akihisa; Germing, Ulrich; Jinnai, Itsuro; Iwanaga, Masako; Misumi, Motohiro; Kuendgen, Andrea; Strupp, Corinna; Miyazaki, Yasushi; Tsushima, Hiroyuki; Sakai, Mari; Bessho, Masami; Gattermann, Norbert; Aul, Carlo; Tomonaga, Masao

doi:10.1038/sj.leu.2404571

Cited by 52 publications

(40 citation statements)

References 11 publications

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Section: Discussionsupporting

confidence: 93%

“…We analyzed the interobserver concordance with a cutoff point of 40% dysplastic cells and found that the agreement improved in the megakaryocytic and granulocytic lineages but not in the erythroid lineage. These results agree with those of Matsuda et al 17 and Germing et al 28 who proposed raising (κ, 0.43; P<0.001). Most differences concerned the distinction of unilineage and multilineage dysplasia; consequently some patients were classified as having refractory anemia with ring sideroblasts or refractory cytopenia with multilineage dysplasia depending on the recognition of dysplasia in one or more myeloid lineages.…”

supporting

confidence: 93%

“…In this regard, Pseudo-Pelger-Huët anomaly in neutrophils and micromegakaryocytes has been correlated with overall survival. 17,24 Besides, several investigators consider that cases with multilineage dysplasia have a less favorable prognosis than those with only dyserythropoietic dysplasia. 10,[25][26] The WHO classification therefore separated cases with refractory anemia in the previous French-American-British classification into two categories depending on the presence or absence of multilineage dysplastic features.…”

Section: Discussionmentioning

confidence: 99%

“…For this purpose, we used the cutoff levels defined by the WHO classification and an additional cutoff level of 40% of dysplastic cells according to previous data. 17 To evaluate the concordance between observers in qualitative and categorized quantitative variables, the generalized kappa statistic for multiple raters (κ) was calculated. An ICC or generalized κ statistic value of 1 denotes complete agreement between the different observers, while an ICC value of 0 denotes agreement equivalent to chance.…”

mentioning

confidence: 99%

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Reproducibility of the World Health Organization 2008 criteria for myelodysplastic syndromes

et al. 2012

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ABSTRACTappropriate WHO morphological subtype (the number of blast cells in peripheral blood and bone marrow, percentage of ring sideroblasts in bone marrow and myelodysplastic features) was evaluated. Design and Methods Patients and samplesSamples of bone marrow aspirates and peripheral blood from 50 patients with a clearly established diagnosis of MDS according to WHO 2008 criteria and diagnosed at two of the participating centers (Hospital del Mar, Barcelona and Hospital Universitari i Politecnic La Fe, Valencia) were included in this retrospective analysis. In all instances the analyzed samples had been obtained at initial evaluation. The number of cases of the different WHO 2008 morphological subtypes selected for review was prefixed according to their expected incidence in previous studies. 4 Preference for inclusion in the study was given to cases diagnosed in more recent years and with good quality samples available. Table 2 summarizes the main characteristics of the patients. Morphological studiesFour smears from each patient included in the study were available for blind and independent microscopical review by four experienced cytologists from three centers. Two bone marrow and one peripheral blood May-Grünwald-Giemsa-stained smears were used for assessing percentages of blasts in peripheral blood and bone marrow and percentages of dysplastic cells of the three myeloid cell lines. An additional Prussian blue-stained bone marrow smear was used for assessing the percentage of ring sideroblasts. The cytologists had a meeting to discuss the evaluation of dysplasia and diagnosis using training slides. Blasts and ring sideroblasts were defined according to the recent consensus proposals of the International Working Group on Morphology of Myelodysplastic Syndromes (IWGM-MDS). 15 The WHO 2008 recommendations for evaluating the morphological diagnosis of MDS were followed strictly. Thus, bone marrow blast counts were calculated as percentages of all bone marrow nucleated cells. Peripheral blood and bone marrow differential counts were performed on at least 200 and 500 cells, respectively. The evaluation of dysplasia was based on morphological criteria described in the 2008 WHO publication. 4 Briefly, the following morphological features of dysplasia were evaluated: (i) dyserythropoiesis: nuclear budding, internuclear bridging, karyorrhexis, multinuclearity, nuclear hyperlobation, megaloblastic changes, basophil stippling, ring sideroblasts and vacuolization; (ii) dysgranulopoiesis: nuclear hypolobation (pseudo Pelger-Huët), irregular hypersegmentation, agranularity, pseudo Chediak-Higashi granules, Auer rods and Döhle bodies; and (iii) dysmegakaryocytopoiesis: micromegakaryocytes, nuclear hypolobation, and multinucleation. As defined in the WHO 2008 classification, the threshold used for considering a myeloid cell line as dysplastic was the presence of ≥10% abnormal cells in the corresponding myeloid lineage. To assess dysplasia at least 200 neutrophils, 200 erythroid precursors and 30 megakaryocytes were eval...

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Section: Discussionsupporting

confidence: 93%

supporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Reproducibility of the World Health Organization 2008 criteria for myelodysplastic syndromes

et al. 2012

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“…At the same time it is associated with a poor prognosis of the disease. 30,31 Similarly, multiple reports continue to show that thrombocytopenia is also associated with both a worse outcome and decreased survival in MDS, 8,[32][33][34] even among low-risk MDS cases. 35 In our series, megakaryocytic dysplasia was not seen to have a significant impact on the outcome of MDS patients.…”

Section: Discussionmentioning

confidence: 98%

Altered immunophenotypic features of peripheral blood platelets in myelodysplastic syndromes

Sandes¹,

Yamamoto²,

Matarraz³

et al. 2012

Haematologica

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BackgroundMultiparameter flow cytometric analysis of bone marrow and peripheral blood cells has proven to be of help in the diagnostic workup of myelodysplastic syndromes. However, the usefulness of flow cytometry for the detection of megakaryocytic and platelet dysplasia has not yet been investigated. The aim of this pilot study was to evaluate by flow cytometry the diagnostic and prognostic value of platelet dysplasia in myelodysplastic syndromes. Design and MethodsWe investigated the pattern of expression of distinct surface glycoproteins on peripheral blood platelets from a series of 44 myelodysplastic syndrome patients, 20 healthy subjects and 19 patients with platelet alterations associated to disease conditions other than myelodysplastic syndromes. Quantitative expression of CD31, CD34, CD36, CD41a, CD41b, CD42a, CD42b and CD61 glycoproteins together with the PAC-1, CD62-P, fibrinogen and CD63 platelet activation-associated markers and platelet light scatter properties were systematically evaluated. ResultsOverall, flow cytometry identified multiple immunophenotypic abnormalities on platelets of myelodysplastic syndrome patients, including altered light scatter characteristics, over-and under expression of specific platelet glycoproteins and asynchronous expression of CD34; decreased expression of CD36 (n=5), CD42a (n=1) and CD61 (n=2), together with reactivity for CD34 (n=1) were only observed among myelodysplastic syndrome cases, while other alterations were also found in other platelet disorders. Based on the overall platelet alterations detected for each patient, an immunophenotypic score was built which identified a subgroup of myelodysplastic syndrome patients with a high rate of moderate to severe alterations (score>1.5; n=16) who more frequently showed thrombocytopenia, megakaryocytic dysplasia and high-risk disease, together with a shorter overall survival. ConclusionsOur results show the presence of altered phenotypes by flow cytometry on platelets from around half of the myelodysplastic syndrome patients studied. If confirmed in larger series of patients, these findings may help refine the diagnostic and prognostic assessment of this group of disorders.

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Myelodysplastic Syndromes

2014

Morphology of Blood Disorders

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FAS gene, a direct target for NFκB transcription factor, is repressed in solid tumors including colon carcinomas. We have previously reported that, while overexpressed in low risk myelodysplastic syndromes (MDS), the Fas death receptor becomes undetectable on CD34 + progenitors when the disease progresses to secondary acute myeloid leukaemia (sAML). This study aimed at investigating the interplay between NFκB and Fas during MDS progression. We first observed that Fas was inducible by TNFα in the HL60 cell line. In these cells, p65/RelA bound to the chromatin at FAS promoter, while inhibition of NFκB pathway by IKKα inhibitor BAY11-7082 or lentiviral expression of a non-degradable mutant of IκBα, IκSR blocked the expression of Fas. By contrast, TNFα failed to induce Fas expression in the colon carcinoma cell line SW480, due to hypermethylation of the FAS promoter. In vitro use of azacitidine rescued p65/RelA binding on FAS promoter and, subsequently Fas expression in SW480 cells. We also show that, inhibition of NFκB pathway decreased the expression of Fas in MDS CD45 lo CD34 + bone marrow cells. However, despite of the nuclear expression of p65/RelA, Fas was often low on CD45 lo CD34 + AML cells. TNFα failed to stimulate its expression, while azacitidine efficiently rescued p65/RelA binding and Fas reexpression. Our data suggest that DNA methylation at NFκB sites is responsible for FAS gene silencing. Rescuing FAS gene expression by azacitidine could contribute to slacken the progression to leukaemia.

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Improvement of criteria for refractory cytopenia with multilineage dysplasia according to the WHO classification based on prognostic significance of morphological features in patients with refractory anemia according to the FAB classification

Cited by 52 publications

References 11 publications

Reproducibility of the World Health Organization 2008 criteria for myelodysplastic syndromes

Reproducibility of the World Health Organization 2008 criteria for myelodysplastic syndromes

Altered immunophenotypic features of peripheral blood platelets in myelodysplastic syndromes

Myelodysplastic Syndromes

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