1、中國醫(yī)學(xué)科學(xué)院血液學(xué)研究所血液病醫(yī)院 秦鐵軍 電話骨髓增生異常綜合征,Tuesday, September 22, 2020,MDS的定義與最低診斷標準,定義 a group of clonal haematopoietic stem cell diseases characterized by cytopenia(s). dysplasia in one or more of the major myeloid cell lines. Ineffective haematopoiesis Increased risk of development of AML,Mo

2、nday, August 09, 2010,thresholds for cytopenias,Cytopenias Haemoglobin 100g/L Absolute neutrophil count (ANC)1.8xl09/L Platelets 100 xl09/L Definitive morphologic and/or cytogenetic findings support the diagnosis of MDS even if values above these thresholds,Monday, August 09, 2010,流行病學(xué)(Epidemiology)

3、,Median age 70 years incidence of 3-5/100 000 persons 20/100 000 among those over the age of 70 years male predominance,Clinical features,Symptoms related to cytopenia(s) Anemic and transfusion-dependent Neutropenia and/or thrombocytopenia -Less frequent Infrequently organomegaly,Monday, August 09,

4、2010,The morphological of MDS,principally based on percent of blasts in the BM and PB type and degree of the dysplasia presence of ring sideroblasts 500-cell differential of all nucleated cells in the BM smear 200-leukocyte differential in the PB necessity of high quality slide preparations and the

5、stain,Monday, August 09, 2010,骨髓和外周血涂片,高質(zhì)量的制片和染色 新鮮標本(抗凝標本不應(yīng)超過2小時) 計數(shù)500個細胞 粒紅比1:1時 計數(shù)500個非紅系細胞，不包括淋巴細胞、漿細胞、肥大細胞 原始細胞比例應(yīng)為非紅系比例 環(huán)形鐵粒幼細胞比例 15%時，即認為是紅系發(fā)育異常,Monday, August 09, 2010,Morphologic manifestation of dysplasia(1),Dyserythropoiesis Nuclear 核出芽(nuclear budding) 核間橋(internuclear bridging) 核破裂(Kar

6、yorrhexis) 多核(Multinuclearity) 核多分葉(nuclear hyperlobation) 巨幼樣變(megaloblastic changes) Cytoplasmic 環(huán)狀鐵粒幼紅細胞(Ring sideroblast) 空泡形成(Vacuolization) 糖原染色陽性(Periodic acid-Schiff positivity),Monday, August 09, 2010,Morphologic manifestation of dysplasia(2),Dysgranulopoiesis 細胞體積過小或過大(Small or unusually l

7、arge size) 核少分葉Nuclear hypolobation(pseudo Pelger-Huet; pelgeroid) 不規(guī)則的分葉過多(Irregular hypersegmentation) 少顆粒(Decreased granules; agranularity) Pseudo Chediak-Higashi granules 奧氏小體Auer rods,Monday, August 09, 2010,Morphologic manifestation of dysplasia(3),Dysmegakaryocytopoiesis 小巨核細胞(Micromegakaryoc

8、ytes) 核少分葉(Nuclear hypolobation in all size) Mutinucleation(normal megakaryocytes are uninucleate with lobulated nuclei) Multiple , widely-separated nuclei More readily appreciated in BM sections than smears,Monday, August 09, 2010,Recommended Qualifications of Dysplasia,Dyserythropoiesis and dysgra

9、nulopoiesis Requisite percentage of cells manifesting dysplasia 10% in the erythroid precursors and granulocytes Significant megakaryocyte dysplasia 10% dysplastic megakaryocytes based on evaluation of at least 30 megakaryocytes in smears or sections the most reliable dysplastic findings Micromegaka

10、ryocytes and multinucleate megakaryocytes,Monday, August 09, 2010,The relationship between cytopenias, type of dysplasia, and classification in MDS,General precautions,No MDS without the clinical and drug history Not reclassified while the patient is on growth factor therapy Cytopenia(s) in the abse

11、nce of dysplasia should not be interpreted as MDS No dysplasia + certain cytogenetic abnormalities -presumptive MDS Persistent cytopenia(s) + No dysplasia +No specific cytogenetic abnormalities =ICUS,Monday, August 09, 2010,The significance of the Auer rod,Virtually diagnostic of AML for several dec

12、ade Evidence of a high-grade MDS (RAEBT) in the FAB classification(1982), irrespective of the blast percentage in the PB or BM Evidence of RAEB-2 regardless of the blast percentage in the 2001 WHO classification The concept is retained in the present classification Cases of MDS with 5% blasts in the

13、 BM and 1 % in the PB may rarely have Auer rods. Associated with an adverse prognosis,Differential diagnostic considerations,dysplasia is not in itself definitive evidence of a clonal disorder myelodysplasia due to a clonal disorder the result of some other factors Essential element deflciencies exp

14、osure to heavy metals,particularly arsenic and several commonly used drugs and biologic agents 磺胺甲基異惡唑-marked neutrophil nuclear hypolobation Congenital haematological disorders such as congenital dyserythropoietic anemia,組織病理學(xué)及免疫組織化學(xué)Histopathology and immunohistochemistry,骨髓涂片混血時可與AML鑒別 與低增生AML鑒別 與

15、AA鑒別 發(fā)現(xiàn)CD34+祖細胞多灶性聚集 發(fā)現(xiàn)CD34+祖細胞異常定位，ALIP 發(fā)現(xiàn)巨核細胞異常形態(tài)及聚集 顯示骨髓纖維化 顯示血管新生 診斷低增生MDS 顯示細胞遺傳學(xué)標記 診斷共發(fā)骨髓細胞腫瘤(如肥大細胞增多癥、淋巴瘤等),MDS中推薦的免疫組化標記物,流式細胞術(shù)在MDS中的應(yīng)用,MDS中重現(xiàn)的異常免疫表型,流式細胞術(shù)在MDS中的應(yīng)用,MDS中重現(xiàn)的異常免疫表型（續(xù)）,流式細胞術(shù)在MDS中的應(yīng)用,Determining the size and immunophenotype of the blast population Generally good correlation betwe

16、en Percentage of blasts as determined By morphologic examination of routine smear By imprint By immunohistologic preparations Percentage of CD34+ cells determined by flow cytometry (FC) FC percentages of CD34+ cells cannot replace differential counts on smears MF, haemodilute,流式細胞術(shù)在MDS中的應(yīng)用,Abnormal

17、phenotypes of CD34+ cells Evidence of dysplasia Emerging pathological population of CD34 or CD117 cells In low-grade MDS Suggest evolution of the disease,流式細胞術(shù)在MDS中的應(yīng)用,Assessing the maturation pattern of the myeloid cell population flow cytometry results correlate well with morphology and cytogeneti

18、cs in MDS single aberrant features by FC are not significant borderline dysplasia by morphology no cytogenetic abnormalities Only if there are three or more aberrant features in erythropoietic,granulocytic or monocytic maturation FC results are highly suggesitve for MDS,MDS染色體核型分析,傳統(tǒng)核型分析：G帶、Q帶、R帶。 熒

19、光原位雜交（FISH）：探針應(yīng)包括5q31, CEP7, 7q31, CEP8, 20q, CEPY, p53。 克?。簝蓚€骨髓細胞獲得相同的染色體物質(zhì)或具有同樣結(jié)構(gòu)的變異，或者三個骨髓細胞丟失同樣的染色體。 亞克?。阂粋€克隆中的至少兩個或三個細胞出現(xiàn)新的染色體變異。 復(fù)雜染色體核型：至少在兩個細胞中出現(xiàn)三個或三個以上不同的染色體變異。 復(fù)雜核型同樣具有亞克隆，復(fù)雜核型組的MDS患者可能由不同復(fù)雜程度的亞群構(gòu)成，可能具有不同的預(yù)后。 當懷疑MDS進展時，核型分析有助于發(fā)現(xiàn)克隆進展的細胞遺傳學(xué)證據(jù)。,Genetics of MDS,Clonal cytogenetic abnormalities

20、 in -50% of MDS Isolated del(5q) primarily in women megakaryocytes with non-Iobated or hypolobated nuclei, refractory macrocytic anaemia normal or increased platelet count a favourable clinical course 17p- pseudo Pelger-Huet anomaly and small vacuolated neutrophils TP53 mutation unfavourable clinica

21、l course most common in therapy-related MDS,Genetics of MDS,Some clonal cytogenetic abnormalities are not definitive evidence for MDS in the absence of morphological criteria -Y, +8, del(20q),Genetics of MDS,isolated del(20q) morphologic abnormalities of erythroid cells and megakaryocytes inv(3)(q21

22、q26.2) or t(3:3)(q21:q26.2) increased abnormal megakaryocytes,Genetics of MDSRecurring chromosomal abnormalities,Genetics of MDSRecurring chromosomal abnormalities,Prognosis and predictive factorsof MDS,Prognosis of morphologic subtypes The low-risk groups RCUD and RARS The intermediate-risk groups

23、RCMD with or without ring sideroblasts and RAEB-1 the high-risk group RAEB-2,Prognosis and predictive factorsof MDS,Prognosis of cytogenetics Good normal, -Y, del(5q), del(20q) Poor Complex karyotypes (3 abnormalities) -7/del(7q) Intermediate Other abnormalities,lnternational Prognostic Scoring Syst

24、em (IPSS) for MDS,*This group is recognized as AML in the WHO classification. #Cytopenias:Haemoglobin 100g/L;ANC1.8xl09/L;Platelets 100 xl09/L,Prognosis and predictive factorsof MDS,* In the absence of therapy,2008 WHO MDS分型,2008 WHO MDS分型,2008 WHO MDS分型,說明,RCUD中可有2系血細胞減少，全血細胞減少者應(yīng)診斷為MDS-U 骨髓中原始細胞5%,

25、外周血原始細胞2%4%,應(yīng)診斷RAEB-1 其他標準符合RCMD或RCUD，但外周血原始細胞1%,應(yīng)診斷MDS-U 骨髓Auer小體陽性，外周血原始細胞5%,骨髓原始細胞10%, 應(yīng)診斷RAEB-2,低增生性MDS (Hypoplastic MDS),10% MDS 難以與AA鑒別 AA治療方案（如ATG）對部分患者有效 注意與中毒性骨髓病(toxic myelopathy)及自身免疫性疾病鑒別,MDS with myelofibrosis,約10%的MDS伴明顯的骨髓纖維化 大多數(shù)患者原始細胞增多且進展迅速(aggressive) 僅憑骨髓涂片易誤診為低危組MDS 原始細胞檢測需結(jié)合骨髓活檢

26、病理及免疫組織化學(xué),MDS最低診斷標準,意義未明的特發(fā)性血細胞減少（ICUS）,分子分型及點突變分析在MDS的應(yīng)用,分子分型 有助于明確是否存在克隆型疾病 與輔助診斷標準中的其他實驗一起判斷“高度懷疑MDS” 將來有助于預(yù)測對治療的反應(yīng) 點突變分析 MDS懷疑伴有系統(tǒng)性肥大細胞增多癥時，檢測KIT基因 D816V點突變 MDS伴有顯著血小板增多時，檢測Jak-2基因V671F點突變,MDS的危險積分系統(tǒng),目前：國際預(yù)后積分系統(tǒng)（IPSS ） 有提議將LDH水平納入IPSS 即將：WHO修正的預(yù)后積分系統(tǒng)（WPSS） 將輸血依賴作為一個重要指標,MDS的非強烈治療及療效反應(yīng)標準,非強烈治療 適合低危MDS及不適合強烈治療的高危MDS者 治療目標：維持生活質(zhì)量（QOL）及防治輸血相關(guān)的發(fā)病及死亡 祛鐵治療：適應(yīng)于長期輸血的MDS患者 EPO或EPO+G-CSF：作為低?；蜉斞蕾嚨珒?nèi)源EPO水平不高且輸血頻率低的INT-1患者標準治療方案 G-CSF/G