1、中国医学科学院血液学研究所血液病医院秦铁军 电话：13332095356,骨髓增生异常综合征,Sunday, July 29, 2018,MDS的定义与最低诊断标准,定义a group of clonal haematopoietic stem cell diseasescharacterized bycytopenia(s).dysplasia in one or more of the major myeloid cell lines. Ineffective haematopoiesisIncreased risk of development of AML,Monday, August
2、 09, 2010,thresholds for cytopenias,Cytopenias Haemoglobin 100g/LAbsolute neutrophil count (ANC)1.8xl09/LPlatelets 20/100 000 among those over the age of 70 yearsmale predominance,Clinical features,Symptoms related to cytopenia(s)Anemic and transfusion-dependentNeutropenia and/or thrombocytopenia -L
3、ess frequentInfrequently organomegaly,Monday, August 09, 2010,The morphological of MDS,principally based onpercent of blasts in the BM and PBtype and degree of the dysplasiapresence of ring sideroblasts500-cell differential of all nucleated cells in the BM smear 200-leukocyte differential in the PBn
4、ecessity of high quality slide preparations and the stain,Monday, August 09, 2010,骨髓和外周血涂片,高质量的制片和染色新鲜标本(抗凝标本不应超过2小时) 计数500个细胞 粒红比1:1时计数500个非红系细胞，不包括淋巴细胞、浆细胞、肥大细胞原始细胞比例应为非红系比例环形铁粒幼细胞比例 15%时，即认为是红系发育异常,Monday, August 09, 2010,Morphologic manifestation of dysplasia(1),DyserythropoiesisNuclear核出芽(nucle
5、ar budding)核间桥(internuclear bridging)核破裂(Karyorrhexis)多核(Multinuclearity)核多分叶(nuclear hyperlobation)巨幼样变(megaloblastic changes)Cytoplasmic环状铁粒幼红细胞(Ring sideroblast)空泡形成(Vacuolization)糖原染色阳性(Periodic acid-Schiff positivity),Monday, August 09, 2010,Morphologic manifestation of dysplasia(2),Dysgranulop
6、oiesis细胞体积过小或过大(Small or unusually large size)核少分叶Nuclear hypolobation(pseudo Pelger-Huet; pelgeroid)不规则的分叶过多(Irregular hypersegmentation)少颗粒(Decreased granules; agranularity)Pseudo Chediak-Higashi granules奥氏小体Auer rods,Monday, August 09, 2010,Morphologic manifestation of dysplasia(3),Dysmegakaryocy
7、topoiesis小巨核细胞(Micromegakaryocytes)核少分叶(Nuclear hypolobation in all size)Mutinucleation(normal megakaryocytes are uninucleate with lobulated nuclei)Multiple , widely-separated nucleiMore readily appreciated in BM sections than smears,Monday, August 09, 2010,Recommended Qualifications of Dysplasia,Dy
8、serythropoiesis and dysgranulopoiesisRequisite percentage of cells manifesting dysplasia 10% in the erythroid precursors and granulocytesSignificant megakaryocyte dysplasia 10% dysplastic megakaryocytes based on evaluation of at least 30 megakaryocytes in smears or sectionsthe most reliable dysplast
9、ic findingsMicromegakaryocytes 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 historyNot reclassified while the patient is on growth factor therapyCyto
10、penia(s) in the absence of dysplasia should not be interpreted as MDSNo dysplasia + certain cytogenetic abnormalities -presumptive MDSPersistent cytopenia(s) + No dysplasia +No specific cytogenetic abnormalities =ICUS,Monday, August 09, 2010,The significance of the Auer rod,Virtually diagnostic of A
11、ML for several decade Evidence of a high-grade MDS (RAEBT) in the FAB classification(1982), irrespective of the blast percentage in the PB or BMEvidence of RAEB-2 regardless of the blast percentage in the 2001 WHO classification The concept is retained in the present classificationCases of MDS with
12、5% blasts in the 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 disordermyelodysplasia due to a clonal disorderthe result of some other factorsEssential element defl
13、cienciesexposure to heavy metals,particularly arsenic and several commonly used drugs and biologic agents磺胺甲基异恶唑-marked neutrophil nuclear hypolobationCongenital haematological disorders such as congenital dyserythropoietic anemia,组织病理学及免疫组织化学Histopathology and immunohistochemistry,骨髓涂片混血时可与AML鉴别与低增
14、生AML鉴别与AA鉴别发现CD34+祖细胞多灶性聚集发现CD34+祖细胞异常定位，ALIP发现巨核细胞异常形态及聚集显示骨髓纤维化显示血管新生诊断低增生MDS显示细胞遗传学标记诊断共发骨髓细胞肿瘤(如肥大细胞增多症、淋巴瘤等),MDS中推荐的免疫组化标记物,流式细胞术在MDS中的应用,MDS中重现的异常免疫表型,流式细胞术在MDS中的应用,MDS中重现的异常免疫表型（续）,流式细胞术在MDS中的应用,Determining the size and immunophenotype of the blast populationGenerally good correlation between
15、Percentage of blasts as determinedBy morphologic examination of routine smearBy imprintBy immunohistologic preparationsPercentage of CD34+ cells determined by flow cytometry (FC)FC percentages of CD34+ cells cannot replace differential counts on smearsMF, haemodilute,流式细胞术在MDS中的应用,Abnormal phenotype
16、s of CD34+ cellsEvidence of dysplasiaEmerging pathological population of CD34 or CD117 cells In low-grade MDS Suggest evolution of the disease,流式细胞术在MDS中的应用,Assessing the maturation pattern of the myeloid cell populationflow cytometry results correlate well with morphology and cytogenetics in MDSsin
17、gle aberrant features by FC are not significantborderline dysplasia by morphology no cytogenetic abnormalitiesOnly if there are three or more aberrant features in erythropoietic,granulocytic or monocytic maturationFC results are highly suggesitve for MDS,MDS染色体核型分析,传统核型分析：G带、Q带、R带。荧光原位杂交（FISH）：探针应包括
18、5q31, CEP7, 7q31, CEP8, 20q, CEPY, p53。克隆：两个骨髓细胞获得相同的染色体物质或具有同样结构的变异，或者三个骨髓细胞丢失同样的染色体。亚克隆：一个克隆中的至少两个或三个细胞出现新的染色体变异。复杂染色体核型：至少在两个细胞中出现三个或三个以上不同的染色体变异。复杂核型同样具有亚克隆，复杂核型组的MDS患者可能由不同复杂程度的亚群构成，可能具有不同的预后。当怀疑MDS进展时，核型分析有助于发现克隆进展的细胞遗传学证据。,Genetics of MDS,Clonal cytogenetic abnormalities in -50% of MDSIsolate
19、d del(5q)primarily in womenmegakaryocytes with non-Iobated or hypolobated nuclei,refractory macrocytic anaemianormal or increased platelet counta favourable clinical course17p-pseudo Pelger-Huet anomaly and small vacuolated neutrophilsTP53 mutationunfavourable clinical coursemost common in therapy-r
20、elated 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 megakaryocytesinv(3)(q21q26.2) or t(3:3)(q21:q26.2)increase
21、d abnormal megakaryocytes,Genetics of MDSRecurring chromosomal abnormalities,Genetics of MDSRecurring chromosomal abnormalities,Prognosis and predictive factorsof MDS,Prognosis of morphologic subtypesThe low-risk groups RCUD and RARSThe intermediate-risk groupsRCMD with or without ring sideroblasts
22、and RAEB-1the high-risk groupRAEB-2,Prognosis and predictive factorsof MDS,Prognosis of cytogeneticsGoodnormal, -Y, del(5q), del(20q)PoorComplex karyotypes (3 abnormalities) -7/del(7q)IntermediateOther abnormalities,lnternational Prognostic Scoring System (IPSS) for MDS,*This group is recognized as
23、AML in the WHO classification.#Cytopenias:Haemoglobin 100g/L;ANC1.8xl09/L;Platelets 100xl09/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,说明,RCUD中可有2系血细胞减少，全血细胞减少者应诊断为MDS-U骨髓中原始细胞5%,外周血原始细胞2%4%,应诊断RAEB-1其他标准符合RCMD或RCUD，但外周血原始细胞1%,应诊
24、断MDS-U骨髓Auer小体阳性，外周血原始细胞5%,骨髓原始细胞10%, 应诊断RAEB-2,低增生性MDS (Hypoplastic MDS),10% MDS难以与AA鉴别AA治疗方案（如ATG）对部分患者有效注意与中毒性骨髓病(toxic myelopathy)及自身免疫性疾病鉴别,MDS with myelofibrosis,约10%的MDS伴明显的骨髓纤维化大多数患者原始细胞增多且进展迅速(aggressive)仅凭骨髓涂片易误诊为低危组MDS原始细胞检测需结合骨髓活检病理及免疫组织化学,MDS最低诊断标准,意义未明的特发性血细胞减少（ICUS）,分子分型及点突变分析在MDS的应用,
25、分子分型 有助于明确是否存在克隆型疾病与辅助诊断标准中的其他实验一起判断“高度怀疑MDS”将来有助于预测对治疗的反应 点突变分析MDS怀疑伴有系统性肥大细胞增多症时，检测KIT基因 D816V点突变MDS伴有显著血小板增多时，检测Jak-2基因V671F点突变,MDS的危险积分系统,目前：国际预后积分系统（IPSS ）有提议将LDH水平纳入IPSS即将：WHO修正的预后积分系统（WPSS） 将输血依赖作为一个重要指标,MDS的非强烈治疗及疗效反应标准,非强烈治疗 适合低危MDS及不适合强烈治疗的高危MDS者治疗目标：维持生活质量（QOL）及防治输血相关的发病及死亡 祛铁治疗：适应于长期输血的M
26、DS患者 EPO或EPO+G-CSF：作为低危或输血依赖但内源EPO水平不高且输血频率低的INT-1患者标准治疗方案 G-CSF/GM-CSF：适用于反复或难治的中性粒细胞减少所致感染的患者 TPO/IL-11：不作为MDS标准治疗方案,MDS的非强烈治疗及疗效反应标准,建议修订的IWG改变MDS自然病程疗效判定标准,MDS的非强烈治疗及疗效反应标准,建议修订的IWG改变MDS自然病程疗效判定标准（续）,MDS的非强烈治疗及疗效反应标准,建议修订的IWG血液学改善疗效判定标准,MDS的强烈治疗,选择强烈治疗需考虑以下几点：造血干细胞移植（SCT）仅适用于少数患者，其具有相对高风险的移植相关发病
27、率及死亡率强烈多药化疗能恢复部分患者的多克隆造血，但只有少数患者能获得长期无病生存，大多数患者会在一段时间内复发即使是高危组MDS的自然病程也不尽相同，生存期从几个月到数年不等合并疾病、年龄及其他个体因素可能会影响SCT和强烈化疗的结果。高危组MDS移植后复发率仍达1040%,MDS患者是否需要治愈性的治疗手段？,MDS的强烈治疗,大部分化疗方案类似于AML患者大约50%能达到CR达到CR的年轻患者，可考虑SCT作为巩固治疗,MDS的强烈治疗,待解决的问题：SCT合适时机合适的预处理方案自体SCTSCT后复发,免疫抑制剂、新的靶向药物及姑息治疗,免疫抑制剂（ATGCsA）适用于年轻、低危MDS
28、（RA、IPSS中危1组） HLA-DR15、PNH克隆、低增生性MDS的反应更好雷利度胺成为MDS伴有5q-治疗的一线药物去甲基化剂（5-氮杂胞苷、地汐他滨）部分中心已考虑将其作为高危组MDS未来的标准治疗方案姑息治疗白细胞增高时，应用羟基脲,2018/7/29,Thank You !,Erythroid karyorrhexis in myelodysplasia:bone marrow aspirate,骨髓原始细胞,两类：无嗜天青颗粒的原始粒细胞有嗜天青颗粒的原始粒细胞出现清晰可辨的核旁高尔基区时则划分为早幼粒细胞,铁粒幼红细胞,1型，5个铁颗粒型，5个铁颗粒但不呈核周分布型 为环状铁粒幼红细胞，5个绕核周分布的铁颗粒(常13核周),
