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【检验临床面对面】急性髓系白血病伴CEBPA双等位基因突变1例

时间:2019-04-04       作者:检验视界网      浏览量:4213 次

作者:窦心灵  白  丹,甘肃省酒泉市人民医院


病例简介:


患者,女,27岁,主因“间断性双下肢皮肤紫癜3月余,咳嗽、咳痰、发热5天”就诊?;颊哂谌朐呵?月余无明显诱因出现双下肢皮肤紫癜,5天前患者受凉后出现间断性发热,体温最高39℃,伴有咳嗽、咳痰,就诊于当地私人诊所,给予抗感染治疗(具体不详),患者无明显缓解,并逐渐出现牙龈渗血、肿痛,左侧下颌部淋巴结肿大,遂前往当地市医院就诊,查血常规示:WBC 8.0×109/L,NE 5.0%(↓),LY 93.7%(↑,仪器分类),HGB 75g/L(↓),PLT 36×109/L(↓)。遂来我院就诊,门诊以“血细胞异常待查”收住我院血液科。


查体:T 36.8℃,贫血貌,神志清楚,精神欠佳,全身皮肤及粘膜无明显苍白,双下肢散在出血点及紫癜。左侧下颌部可触及约1×2cm大小淋巴结??诖郊凹状膊园?。双肺叩诊呈清音,听诊呼吸音粗,未闻及干湿性啰音及胸膜摩擦音。肝、脾肋下未触及。


实验室检查:


血常规:WBC 6.71×109/L,NE 1.8%(↓),LY 57.4%,MO 40.5%(↑,仪器分类),RBC 2.63×1012/L(↓),HGB 58g/L(↓),MCV 76.8fL(↓),MCH 22.1pg(↓),MCHC 287g/L(↓), PLT 35×109/L(↓)。血涂片镜下复检:可见较多原、幼单核细胞。


凝血+纤溶功能检测结果:PT 11.6s,INR 0.97,APTT 38.1s(↑),TT 16.9 s,Fbg 2.97g/L;D-dimer 0.42mg/L,FDP 1.80μg/mL,AT3:C 63.9%(↓)。


贫血五项:血清铁 4.05μmol/L(↓),铁蛋白 16.70ng/mL(↓),叶酸 20.05 nmol/L,维生素B12 189.0pmol/L,EPO 19.82mIU/ml(↑)。


外周血片所见如下:


1.jpg


骨髓涂片所见如下:

 

2.jpg

3.jpg


POX染色如下:


4.jpg


AS-DCE染色如下:



5.jpg


α-NBE染色如下:


6.jpg


α-NBE+NaF染色如下:


7.jpg


骨髓及外周血分类比例如下:


8.jpg


形态学特征及诊断意见如下:


9.jpg


流式细胞术分析结果如下:


10.jpg

11.jpg

12.jpg


骨髓活检结果如下:


13.jpg


染色体核型分析结果如下:


14.jpg


NPM1基因突变检测结果如下:


15.jpg


CEBPA基因突变检测结果如下:


16.jpg


综合诊断结论:


急性髓系白血病伴CEBPA双等位基因突变


文献复习:


急性髓系白血?。╝cute myeloid leukemia,AML)是一组异质性很强的恶性血液系统肿瘤,不同患者的形态学、免疫学、细胞遗传学、分子生物学和临床表现差异很大。目前对白血病的研究和应用已进入了“突变组”时代,基因突变检测可以指导临床对AML患者进行精确分层诊断、预后评估、靶向治疗或更合适的化疗方案的选择[1]。2016年WHO造血和淋巴组织肿瘤重新修订了AML的分型,已将AML伴CEBPA双等位基因突变列为独立的具有重现性细胞遗传学异常AML亚型之一。重现性细胞遗传学异常和基因突变进行整合能够提高AML的预后价值,从而确立了基因突变在AML预后中的重要性[1]。


白血病中常见的基因突变按功能主要可分为3类:I类主要指激酶通路信号转导分子突变,为细胞提供增殖优势;II类主要为转录因子突变,导致细胞的分化和凋亡异常;Ⅲ类主要为表观遗传调控分子突变,可使多种基因表达调控异常、细胞分化和功能紊乱。王芳[1]等的研究显示:各种基因突变在初诊AML患者中的发生频率由高到低依次为CEBPA、FLT3、NPM1、TET2、KIT、DNMT3A、PHF6、IDH1、IDH2、ASXL1;按检测到的突变数计算,最常发生突变的基因依次是CEBPA、FLT3-ITD、NPM1TET2,所有基因均存在与其他一种或多种基因同时发生突变的情况。


CEBPA基因位于染色体19q13,编码一个长为356个氨基酸残基的蛋白质,属于髓系特异性的碱性区域/亮氨酸拉链(bZIP)家族,是维持造血系统粒系增殖与分化平衡的重要转录因子。研究发现CEBPA突变绝大多数见于AML,占AML的6%~15%,占标危组AML的15%~18%,多见于FAB分型的M1或M2,多数同时具有N端和C端双侧突变,且分布在不同的等位基因上。研究显示,CEBPA基因突变(尤其CEBPA双等位基因突变)是正常核型AML患者预后好的指标,其CR率、DFS率及OS率均明显优于无突变者,且CEBPA基因双侧突变患者才具有良好预后,而单侧突变与无突变患者预后大致相当,但其预后意义还受共同存在的FLT3-ITD等其他基因突变的显著影响,显示同时进行多种基因突变检测的重要性[1-2]。Kurosawas等发现在AML化疗缓解后期,CEBPA双等位基因突变患者预后较好,支持继续化疗,而CEBPA单等位基因突变或野生型患者预后差,化疗缓解后需行自体干细胞移植(auto-HCT)。Ahn JS等的一项多因素分析发现CEBPAdm是AML获得完全缓解后的一项预后较好独立危险因素,40个月的随访资料发现CEBPAdm与CEBPA野生型相比,其OS、EFS较高,RI较低;完全缓解后CEBPAdm组巩固化疗较auto-HCT组重要,auto-HCT组的EFS和RI较低,非复发死亡率较高,但两组的OS无显著差异。我国的相应研究也发现了CEBPA突变的CR、OS较高,预后较好,同时伴有高WBC计数和Hb,CD7和HLA-DR高表达,CD34和CD56低表达。Lavallée和Maxson等的研究均表明CEBPA突变与JAK-STAT通路调控因子继发突变高度一致,尤其是粒细胞集落刺激因子3受体(CSF3R)突变,因此针对CEBPAdm患者的JAK-STAT通路抑制剂的靶向治疗已进入临床试验[2]。


参考文献:

[1] 王芳,张阳,陈雪,等. 初诊急性髓系白血病患者十种常见突变基因的突变组分析[J]. 白血病?淋巴瘤,2015,24(3):161-164.

[2] 喻雕,胡兰,周涛. 急性髓细胞白血病基因突变对预后的影响[J]. 吉林医学,2017,38(8):1568-2570.


17.jpg

窦心灵,副主任检验师,现担任世界华人检验与病理医师协会康复医学检验专家委员会委员,甘肃省老年病基因健康管理专委会委员,君安医学细胞平台副总台长兼血液(骨髓)1台总台长,细胞形态学那些事微信群群主,检验视界网及君安医学细胞平台公众号特约作者。就职于甘肃省酒泉市人民医院检验科,从事血液病骨髓形态学及综合诊断工作十多年,先后在中国医学科学院血液学研究所、甘肃省人民医院及宁夏医科大学总医院进修学习。主持完成酒泉市科技进步奖3项,发表检验医学及血液病学相关专业论文十余篇,参编《医学细胞彩图精选》专著1部。2004年和2008年分别被酒泉市人民医院和酒泉团市委授予“青年岗位能手”荣誉称号,在“2015年甘肃省职工技能大赛临床检验医学专业省级决赛”中荣获团体及个人一等奖,并被甘肃省总工会、甘肃省人社厅、甘肃省科技厅等五部门联合授予“甘肃省技术标兵”荣誉称号。2017和2018年度分别被君安医学细胞平台管委会授予“优秀台长”和“杰出贡献奖”荣誉称号。


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