骨髓增生异常综合征患者病态造血及细胞遗传学变化及其与预后的关系

目的探讨骨髓增生异常综合征(MDS)患者造血细胞中病态造血状况与骨髓单个核细胞遗传学异常变化特征,判断其在该类疾病诊断及预后中的作用和价值。方法经骨髓涂片检查及骨髓组织切片活检确诊的57例MDS患者同时进行骨髓单个核细胞直接培养法R带显带技术进行染色体核型分析,并观察该类患者骨髓造血细胞病态造血、染色体核型异常与患者生存期关系。结果 MDS的病态造血以三系病态造血为多见,其骨髓活检阳性检出率高,尤其对巨核细胞病态造血检出更突出。MDS患者多易出现染色体异常,常见为5 q-、11 q-、20 q-、+8、-7和染色体异位、复杂异常核型,复杂异常染色体核型患者生存期明显缩短。结论骨髓活检是准确反映MDS患者病态造血的特异性检查方法。三系病态造血及复杂异常染色体患者转为急性白血病概率大、生存期短,预后差。     

结合WHO诊断标准浅谈骨髓细胞形态学在骨髓增生异常综合征诊断中的意义

按照WHO标准,主要依靠外周血细胞减少、细胞形态学(骨髓细胞病态造血、环形铁粒幼红细胞计数、原始细胞比例)、细胞遗传学核型分析,对骨髓增生异常综合征(MDS)进行诊断和分型。重要的辅助诊断包括骨髓病理活检或(和)免疫组织化学、流式细胞免疫表型和MDS相关基因突变的检测。病态造血是MDS诊断分型的形态学基础,原始细胞不增多的MDS主要依靠病态造血进行诊断分型。病态造血巨核细胞≥10%或环状铁粒幼红细胞≥15%,对MDS具有较确定性的诊断意义。部分MDS-SLD及MDS-MLD,巨核细胞系无病态造血,仅有红细胞系和(或)粒细胞系病态造血细胞的比例≥10%,属于真正意义上的MDS最低诊断标准,在实际操作起来难以准确把握,诊断MDS时应慎重,并需排除反应性病态造血。该文详细介绍了细胞形态学对MDS的诊断意义,详细解读了各系病态造血的细胞形态学特征以及笔者的经验和体会,分析总结了MDS的诊断思路,阐述了MDS诊断中应注意的问题,对于MDS的精准诊断及防止误诊具有建设性意义。     

骨髓增生异常综合征的免疫表型分析

目的:探索骨髓增生异常综合征(MDS)的特征性免疫表型,评估流式细胞术(FCM)在其诊断中的价值。方法:采用FCM检测20例MDS患者及10例对照骨髓单个核细胞的免疫表型。结果:①MDS患者CD34+细胞比例明显增加,且高度MDS患者CD34+细胞比例高于低度患者,而低度MDS患者CD34+细胞比例与对照组相近。②MDS患者粒系SSC的平均荧光强度明显低于对照组。③MDS患者粒细胞CD13/CD16分布明显异常,且与形态学粒系病态造血无关。④MDS患者粒细胞CD56表达频率增高。⑤MDS患者红系CD71平均荧光强度低于对照组。⑥MDS患者红系CD71/GlyA分布可见明显异常,且与形态学红系病态造血无关。结论:FCM在MDS的诊断方面有着重要意义,可以作为重要的补充手段。     

世界卫生组织2016年骨髓增生异常综合征分类更新解读

2016 年,世界卫生组织(WHO) 对骨髓增生异常综合征(MDS) 的细胞形态学重现性特征细化,并综合染色体、 分子生物学变化及临床预后,对MDS 分类进行了修订。取消以血细胞减少系列的名称,代以MDS 伴相应病态造血、 原始细胞和细胞遗传学异常。骨髓原始细胞比例以全髓有核细胞计,取消既往的“非红系”计算,使得过去符合急性 红白细胞白血病再分类为MDS-EB。del(5q) 预后良好,除外单体7 和del(7q),再伴有1 个额外核型异常亦不影响预后。 在原始细胞增多和出现MDS 典型染色体时,不需要形态学病态造血指标达标即可诊断MDS。SF3B1 突变与MDS- 环状铁幼粒红细胞(RS) 关系紧密,使RS 阈值降至5%。TP53 突变或缺失则预后不良。NPM1 和MLL 阳性提示进 展为AML。     

胸骨穿刺对髂骨增生低下骨髓增生异常综合征诊断意义探讨

目的:探讨胸骨骨穿对于骨髓增生异常综合征(MDS)的诊断意义。方法:分析我院31例经胸骨骨穿诊断的MDS,对同期的髂骨和胸骨骨髓像进行对比研究。结果:31例经胸骨诊断为MDS的患者髂骨穿刺及髂骨活检表现为增生低下,按WHO分型均为MDS-RCMD;31例髂骨骨髓增生低下患者粒系、红系少见病态造血,粒系仅6.5%(2例)出现巨幼样变,12.9%(4例)患者出现核浆发育失衡,红系仅6.5%(2例)患者出现巨幼样改变,巨核细胞少见,仅3.2%(1例)患者见到4个巨核细胞,未见到病态巨核细胞;相反,同期的胸骨骨髓均表现为增生活跃或明显活跃,三系病态造血明显,在粒系病态造血表现中54.8%(17例)出现双核粒,71.0%(22例)出现了巨幼样粒细胞,93.5%(29例)出现了核浆发育失衡粒细胞,22.6%(7例)出现了假性派胡细胞;红系病态造血表现中,35.5%(11例)患者出现三核红细胞,77.4%(24例)患者出现巨幼样红细胞;87.1%(27例)患者巨核系统出现病态造血,其中小巨核、单圆核、双圆核、三圆核巨核出现的比例分别为19.4%(6例)、77.4%(24例)、35.5%(11例)、35.5%(11例)。结论:部分MDS患者表现为髂骨增生低下,髂骨穿刺发现病态造血的概率低,胸骨穿刺能有效地发现具有重要意义的病态造血表现,为诊断提供明确的依据,是诊断此类MDS的重要方法。     

骨髓增生异常综合征45例患者的染色体核型研究

目的:探讨骨髓增生异常综合征(MDS)患者染色体异常克隆与WHO分型及临床转归的关系。方法:采用骨髓短期培养和G显带技术对45例MDS患者进行染色体核型分析,同时追踪其临床病情进展情况。结果:45例MDS患者中有27例(60%)检出异常克隆。在异常染色体核型中 8和高度复杂异常最多,其次为-7/7q-和复杂异常。难治性贫血(RA)异常核型检出率33.3%,难治性血细胞减少伴多系增生异常(RCMD)异常核型检出率66.6%,难治性贫血伴原始细胞增多(RAEB)异常核型检出率75%。45例患者经追踪观察,16例(35.5%)患者转化为急性白血病,其中复杂和高度复杂核型异常7例,3例 8患者,2例-7/7q-患者,4例在初诊时核型正常。国际预后评分系统(IPSS)评分中低危组和中危1组白血病转化率为0,中危2组白血病转化率为18.2%,高危组为70%,明显高于其他3组,差异有统计学意义。结论:染色体核型分析在MDS的预后评估中有重要价值。     

骨髓增生异常综合征的病态造血表现

骨髓增生异常综合征 (MDS)是一组获得性造血功能严重紊乱、造血干细胞克降性的疾病。目前认为 MDS是健康人发展成白血病 (A1)的中间阶段 ,也是血液学研究的重要课题。 MDS的细胞学特点是病态造血和原始细胞量改变 ,病态造血对 MDS的诊断、治疗及预后判断具有重要意义 ,现对MDS患者的病态造血表现进行总结。1　 MDS患者的血象和骨髓象特点1.1　血象　 1粒细胞系统 :主要表现是幼稚粒细胞增多 ,细胞核浆发育不平衡 ,可见环形杆状核及双核杆状核细胞 ,成熟粒细胞有分叶过多现象 ,Pelger- Huet畸形大于 5 % ;有的粒细胞浆内颗粒减少或…     

老年骨髓增生异常综合征患者染色体核型及临床研究

目的探讨骨髓增生异常综合征（MDS）患者染色体异常克隆与WHO分型及临床转归的关系，以及老年MDS患者国际预后积分系统（IPSS）分组特点。方法采用骨髓短期培养和G显带技术对48例MDS患者进行染色体核型分析，同时追踪其临床病情进展情况。结果48例MDS患者中，老年患者28例，占58．3％。IPSS评分中危2组和高危组老年患者为21例，占75％，非老年患者11例，占55％。在48例患者中有28例检出异常克隆，以高度复杂异常和＋8最多。难治性贫血（RA）异常核型检出率29．4％，难治性血细胞减少伴多系增生异常（RCMD）异常核型检出率66．6％，难治性贫血伴原始细胞增多（RAEB）异常核型检出率76％。48例患者经追踪观察，17例（11例为老年患者）转化为急性白血病，其中复杂和高度复杂核型异常者8例。IPSS评分中高危组白血病转化率为71．4％，明显高于其它组。结论老年MDS患者中，中高危患者比例高，染色体核型分析在MDS的预后评估中有重要价值。     

骨髓增生异常综合征MIC异常和临床特点

目的：研究骨髓增生异常综合征（MDS）形态学、免疫学、遗传学（MIC）异常变化及临床特点.方法：对65例MDS患者的血液学、免疫学、遗传学异常改变资料进行了回顾性分析.结果：65例中外周血象全血细胞减少36例（55.4%），2系细胞减少19例（29.2%），分类可见幼红细胞35例（53.8%），幼粒细胞27例（41.5%）.贫血60例（92.3%），以中重度为主58例（89.2%），表现为大细胞或正细胞性贫血.白细胞异常56例（86.2%），以减少为主45例（69.2%）.血小板减少41例（63.1%）.65例行骨髓细胞学检查：增生活跃至极度活跃55例（84.6%），1系或1系以上病态造血54例（83.1%），11例难治性质血患者病态造血不明显（16.9%）.59例行骨髓病理学检查：3系不同程度病态造血30例（50.8%），粒系幼稚前体细胞异常定位（ALIP）29例（49.2%）.45例行骨髓细胞流式细胞仪（FCM）免疫表型测定，表现2系或2系以上异常40例（88.9%）.41例做FCM-DNA倍体分析，检出DNA非整倍体26例（63.4%）.32例做骨髓细胞染色体分析，发现异常克隆13例（40.6%）.结论：MDS临床表现不典型，血液学改变复杂，缺乏特异性，部分RA病态造血不明显，仅依靠形态学难以做出正确诊断，应提倡MIC分型诊断。     

骨髓增生异常综合征病理机制及靶向药物治疗

骨髓增生异常综合征（MDS）是起源于造血干/祖细胞（HSPC）的克隆性、髓系肿瘤性疾病,临床表现异质性强,骨髓发育异常导致的形态学表现（病态造血）及无效造血、染色体核型异常、急性髓系白血病（AML）转化是最突出的临床特征。MDS治疗药物适应证目前只有7种被美国食品药品监督管理局（FDA）批准,但是,近年来靶向药物研发态势迅猛,初步临床研究疗效有前景。文章在此对MDS病理机制研究及靶向药物临床研究进展做一全面梳理。     

Prognostic implications of morphology and karyotype in primary myelodysplastic syndromes

Forty-nine patients with primary myelodysplastic syndromes (MDS) were subclassified according to French-American-British (FAB) Cooperative Group criteria. Eight patients had acquired idiopathic sideroblastic anemia (AISA), ten had chronic myelomonocytic leukemia (CMMoL), 14 had refractory anemia (RA), nine had refractory anemia with excess blasts (RAEB), and five had refractory anemia with excess blasts in transformation (RAEB-T); three patients could not be subclassified. The actuarial median survival for patients with AISA or with RA had not been reached at 60 months of follow-up. The median survival times for patients with CMMoL, RAEB, and RAEB-T were 25, 21, and 16 months, respectively. The percentages of patients with each subtype who developed ANLL were none in AISA, 20% in CMMoL, 7% in RA, 56% in RAEB, and 40% in RAEB-T. Patients with CMMoL had a poor prognosis independent of transformation to acute nonlymphocytic leukemia (ANLL), whereas patients with RAEB and RAEB-T had a high incidence of transformation and short survival times. Clonal chromosomal abnormalities were present in bone marrow cells from 19 patients at the time of diagnosis, and two others developed an abnormal karyotype at the time of leukemic transformation. The most frequent abnormalities, including initial and evolutionary changes, were trisomy 8 (9 patients), deletion of 5q (4 patients), and deletion of 20q (4 patients). The median survival times were 32 months for patients with an abnormal karyotype, and 48 months for those with a normal karyotype (P = 0.2). Specific chromosomal abnormalities were not associated with particular histologic subtypes; however, a high percentage of patients with RAEB and RAEB-T had an abnormal clone (89% and 80%, respectively). The percentages of patients with clonal abnormalities were 13% for AISA, 20% for CMMoL, and 29% for RA. The MDS transformed to ANLL in 42% of patients with an abnormal karyotype, compared to 10% of those with an initially normal karyotype (P less than .01). Among patients with RA, RAEB, and RAEB-T, the risk of leukemic transformation was confined to those with an abnormal karyotype (P less than .01). Thus, in the present study, morphology and karyotype combined were the best indicators of outcome in patients with MDS.     

Cytogenetic and morphological abnormalities in paroxysmal nocturnal haemoglobinuria

Paroxysmal nocturnal haemoglobinuria (PNH) is characterized by the expansion of a haematopoietic stem cell clone with a PIG-A mutation (the PNH clone) in an environment in which normal stem cells are lost or failing: it has been hypothesized that this abnormal marrow environment provides a relative advantage to the PNH clone. In patients with PNH, generally, the karyotype of bone marrow cells has been reported to be normal, unlike in myelodysplastic syndrome (MDS), another clonal condition in which cytogenetic abnormalities are regarded as diagnostic. In a retrospective review of 46 patients with a PNH clone, we found a karyotypic abnormality in 11 (24%). Upon follow-up, the proportion of cells with abnormal karyotype decreased significantly in seven of these 11 patients. Abnormal morphological bone marrow features reminiscent of MDS were common in PNH, regardless of the karyotype. However, none of our patients developed excess blasts or leukaemia. We conclude that in patients with PNH cytogenetically abnormal clones are not necessarily malignant and may not be predictive of evolution to leukaemia.     

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目的分析30例特纳综合征(Turner综合征)的核型、临床表现及其关系。方法1991～2004年于汕头大学医学院第二临床学院诊治30例Turner综合征患者,行外周血淋巴细胞培养常规检查染色体,G显带、R显带技术分析核型。记录每例的核型及临床表现并进行分析。结果Turner综合征的核型可分为4类,即单一型、嵌合型、X染色体结构异常及含Y染色体核型;绝大多数为嵌合型。核型异常越明显,性发育不全等症状越典型。结论典型Turner综合征患者有身材矮小、闭经及性发育不全、特殊体型等表现,不同核型的临床表现取决于核型异常的程度及异常核型和正常核型细胞系的比例。含Y染色体者多有两性畸形,应早期行预防性性腺切除术。     

Myelodysplastic syndrome with karyotype abnormality is associated with elevated F-cell production

A sensitive F-cell assay has been used to examine the production of fetal haemoglobin (Hb F) in a group of 77 adult patients with myelodysplastic syndrome (MDS), and a control group composed of 100 normal blood donors. Although the mean F-cell percentage in the MDS group (6.0%) is not statistically different from that in the normal blood donors (3.1%), a higher proportion of myelodysplastic patients have elevated F-cell values and the magnitude of the increases is greater than that observed in blood donors. In order to investigate the association further, the karyotypes of the MDS patients have been examined. 13/21 (61.9%) of the MDS patients with karyotypic abnormalities have F-cell values >5%, compared to only 6/56 (10.9%) of the MDS patients with a normal karyotype and 11/100 (11%) of the blood donors. The observed difference in the distributions of F cells between the two subgroups of patients with MDS is highly significant ( P  < 0.0001).     

DNA image cytometry in MDS bone marrow smears

The nuclear DNA content, defined as DNA index (DI) in blasts/promyelocytes (bla/pro), were determined on Feulgen-stained bone marrow smears from 39 patients with myelodysplastic syndromes (MDS) and eight control subjects by the use of image cytometry (ICM). The DI in patients was compared to that of corresponding normal cell types, and to cytogenetic data available in 32/39 patients. The mean DI in bla/pro of patients with MDS was significantly (P < 0.01) lower compared to corresponding cell types in control subjects. By ICM, a DNA aneuploidy in bla/pro was found in 67% of the MDS patients, and 59% expressed DNA hypodiploidy. By cytogenetics, an abnormal karyotype was found in 31%, and 6/9 MDS patients with a 'hypodiploid' abnormal karyotype showed DNA hypodiploidy. Of patients with a normal karyotype (69%), seven (32%) showed a normal, 12 (55%) a lower, and three (14%) a higher DI compared to controls. No difference between groups of MDS patients was found. DNA hypodiploidy is suggested to be a common feature in MDS without a relationship to cytogenetics.     

Myelodysplastic features in patients with long-term HIV infection and haemophilia

HIV-related bone marrow changes are consistent with myelodysplastic features (MDF). Their pathogenesis may differ from primary myelodysplastic syndromes (MDS) and is associated with various factors including the virus itself or the antiretroviral therapy. In order to evaluate the differences between HIV-related MDF and MDS, the morphological changes in peripheral blood and bone marrow, cytogenetic analysis and the response to anaemia treatment were studied in 158 HIV+ patients with haemophilia and the results were compared with those of 61 patients with primary MDS (31 with RA, 10 with RARS, 11 with RAEB, three with RAEB-t and six with CMML). The eligibility criteria for patients with MDS were primary MDS, Hb levels < 10 g dL(-1), and no significant organ disease. The peripheral blood and bone marrow examination revealed MDF in 44 HIV-infected haemophilic patients (27.8%). The median time from seroconversion was 12.5 years and the mean time under AZT therapy was 44.1 months. Nineteen of these patients (43.1%) had Hb levels < 10 g dL(-1), while neutropenia and thrombocytopenia were observed in 29.5% and 25%, respectively. Every patient of this study with Hb < 10 g dL(-1) received erythropoietin (Epo). There were statistically significant morphological alterations between HIV-related MDF and MDS: hypocellularity, plasmatocytosis and eosinophilia were more pronounced in HIV haemophiliacs with MDF, while dysplasia of erythroblasts, megakaryocytes and granulocytes was more frequent in MDS patients. No HIV haemophilic patient with MDF had more than 5% blasts in the bone marrow nor did any develop RAEB or acute leukaemia during the period of this study. The cytogenetic analysis was normal in HIV-infected patients with haemophilia whereas 42.6% of patients with MDS had an abnormal karyotype. Complete erythroid response was achieved with Epo administration in 84.2% of HIV+ haemophilic patients with anaemia compared to 19.7% of patients with MDS. These data suggest that bone marrow changes in long-term HIV patients have different characteristics from primary MDS and constitute the entity for which the name HIV-myelopathy has been proposed in the literature.     

Detection of latent subclones with abnormal karyotypes by long-term bone marrow cultures in cases of myelodysplastic syndrome

Cytogenetic studies on non-adherent cells from long-term bone marrow cultures (LTBMC) were done for 23 patients with myelodysplastic syndrome (MDS) and compared with the karyotypes detected during their clinical courses. Of 14 cases with normal karyotype before culture, abnormal karyotypes were detected first in LTBMC from seven. Novel abnormal karyotypes were observed after LTBMC in two of four cases which had had both normal and abnormal karyotypes before culture. Abnormal karyotypes were also newly detected in four of five cases with only abnormal karyotypes before culture. Among 13 cases in which abnormal karyotypes were observed during the cultures, three patients showed the same karyotypes 1-11 months later in their clinical courses. These findings suggest that our LTBMC might be useful for evaluating the prognosis and choice of treatment for MDS patients.     

骨髓增生异常综合征99例临床分析

目的探讨骨髓增生异常综合征(MDS)患者WHO亚型分布、细胞遗传学特点及其与MDS诊断分型、疾病进展和预后的关系。方法回顾性分析2001年1月至2007年12月安徽医科大学附属安徽省立医院血液科收治的99例成人原发MDS患者的染色体核型、WHO分型及预后情况,随访观察并进行相关性研究。结果99例MDS患者难治性贫血(RA)型26例(26.26%);难治性贫血伴环形铁幼粒细胞增多(RAS)型6例(6.06%);难治性贫血伴多系发育异常(RCMD)型23例(23.23%);难治性贫血伴原始细胞增多(RAEB)型44例(44.44%)。按IPSS预后分组,中危Ⅱ和高危组的染色体核型异常检出率明显高于低危和中危Ⅰ组(χ2=17.88,P<0.01);中危Ⅱ和高危组患者进展为急性白血病的发生率明显高于低危和中危Ⅰ组(χ2=40.22,P<0.01)。按IPSS染色体核型分组,预后好、中、差的患者中位存活期分别为45(95%CI:39~51)、37(95%CI:25~49)和23(95%CI:13~31)个月,Log-rank检验三组总体生存(OS)率差异有统计学意义(P=0.010)。结论中国有别于西方国家MDS患者的WHO亚型分布,染色体核型分析是MDS诊断分型及预后评估的重要指标。