世界衛(wèi)生組織急性白血病分型2016版與2008版區(qū)別

楊曉陽，萬夢婕，陳方平

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·全科醫(yī)生知識窗·

世界衛(wèi)生組織急性白血病分型2016版與2008版區(qū)別

楊曉陽，萬夢婕，陳方平

時(shí)隔8年世界衛(wèi)生組織(WHO)對急性白血病分型進(jìn)行了修改，本文介紹了WHO急性白血病分型2016版與2008版的區(qū)別，結(jié)合細(xì)胞遺傳學(xué)和預(yù)后等分析了2016版對2008版進(jìn)行刪除或增加的原因。WHO急性白血病分型2016版能更好地結(jié)合和指導(dǎo)臨床。為了臨床醫(yī)生能及時(shí)掌握最新急性白血病分型，并積極為醫(yī)學(xué)創(chuàng)新做準(zhǔn)備，本文比較分析WHO急性白血病分型2016版與2008版的區(qū)別。

白血病；世界衛(wèi)生組織；分型

楊曉陽，萬夢婕，陳方平.世界衛(wèi)生組織急性白血病分型2016版與2008版區(qū)別[J].中國全科醫(yī)學(xué)，2016，19(26)：3253-3256.[www.chinagp.net]

YANG X Y，WAN M J，CHEN F P.Difference between the classification of acute leukemia by world health organization in 2016 and 2008 editions[J].Chinese General Practice，2016，19(26)：3253-3256.

世界衛(wèi)生組織(WHO)對急性白血病進(jìn)行分型后，明顯提高了對急性白血病的診斷和預(yù)后的認(rèn)識。但自2008年WHO急性白血病分型[1]公布后，對于急性白血病分型的認(rèn)識一直處于摸索和探討中，尤其是鑒于新一代基因測序技術(shù)的突飛猛進(jìn)。為能更準(zhǔn)確描述診斷和預(yù)后，2016年WHO又對急性白血病分型進(jìn)行了修改[2]。此次修改只是對于2008版的完善，此次工作是由100位病理學(xué)家、血液學(xué)家、腫瘤學(xué)者以及遺傳學(xué)者共同參與完成。由于對2008版比較熟悉，本文主要對2016版(見表1)和2008版的變化進(jìn)行闡述。

1　急性髓系白血病(AML)伴重現(xiàn)型遺傳異常

此種類型的白血病主要出現(xiàn)于兒童患者，此次修改主要是：

1.1MLL基因的命名更改為KMT2A，inv(3)(q21.3q26.2)或t(3;3)(q21.3;q26.2)不代表融合基因，而被定義為激活MECOM表達(dá)的遠(yuǎn)端GATA2增強(qiáng)子以及協(xié)同GATA2單倍劑量不足(haploinsufficiency)[3]。

1.2由于PML/RAR基因除了t(15;17)(q24.1;q21.2)外還有其他類型的染色體異常，故只保留了急性早幼粒細(xì)胞白血病伴PML/RAR，暫不對染色體異常進(jìn)行單列。

1.3臨時(shí)新增AML伴BCR-ABL1突變，此種疾病是新發(fā)現(xiàn)的AML，可以從絡(luò)氨酸激酶抑制劑的治療中獲益[4]。此種命名如缺乏病史，和慢性粒細(xì)胞白血病轉(zhuǎn)化的AML有時(shí)難以區(qū)分，僅有初步報(bào)道認(rèn)為有IGH、TCR、IKZF1和/或CDKN2A基因缺失，支持AML伴BCR-ABL1，可排除慢性粒細(xì)胞白血病轉(zhuǎn)化型[5]。

表1　世界衛(wèi)生組織急性白血病分型2016版

注：AML=急性髓系白血病，ALL=B淋巴細(xì)胞白血?。籥為新增加分型

1.4暫時(shí)新增AML伴RUNX1突變，因RUNX1突變與骨髓增生異常綜合征不具有相關(guān)性，但如初治的AML患者有該突變，常提示預(yù)后不良[6]。

2　AML伴骨髓增生異常相關(guān)改變

與2008版相比,此種類型急性白血病未做更改，只是再次強(qiáng)調(diào)AML伴骨髓增生異常相關(guān)改變預(yù)后不良。而有NPM1或者等位基因CEBPA突變的急性白血病[7-8]，尚不能提示預(yù)后不好，即使有多系病態(tài)造血，亦不能歸為AML伴骨髓增生異常相關(guān)改變，應(yīng)歸為AML伴重現(xiàn)型遺傳異常類型。如果沒有以上基因的突變，形態(tài)學(xué)發(fā)現(xiàn)有兩系50%及以上的病態(tài)造血，取消了紅白血病的診斷，仍提示為AML伴骨髓增生異常相關(guān)改變，并且預(yù)后不良[2]。有骨髓增生異常綜合征相關(guān)的細(xì)胞基因?qū)W異?？梢詺w為AML伴骨髓增生異常相關(guān)改變，但是有del(9q)除外，因?yàn)锳ML伴骨髓增生異常相關(guān)改變常伴有NPM1或者等位基因CEBPA突變[9]。

3　治療相關(guān)性AML

與2008版相比,此種類型急性白血病未做更改。

4　非特異性AML

≥20%的髓系原始+幼稚細(xì)胞不屬于其他類型才能歸入此種分型[10]。非特異性AML分型僅有急性紅白血病有更改。急性紅白血病2008版歸為非特異性AML，目前屬于AML伴骨髓增生異常相關(guān)改變，其診斷標(biāo)準(zhǔn)為≥50%的骨髓幼紅細(xì)胞以及≥20%的髓系原始+幼稚細(xì)胞[11]。

5　急性混合細(xì)胞白血病

與2008版相比,此種類型急性白血病未做更改。2008年以來的臨床數(shù)據(jù)支持，有t(9;22)改變對絡(luò)氨酸激酶抑制劑有效[12]。

6　B淋巴細(xì)胞白血病(ALL)

6.1同以上AML分型，MLL基因的命名更改為KMT2A，即ALL/淋巴瘤伴t(v;11q23.3);KMT2A。

6.2暫時(shí)新增BCR-ABL1樣ALL。此種類型急性白血病常提示預(yù)后不良，部分患者對絡(luò)氨酸激酶抑制劑治療有效。對于此種類型急性白血病的定義仍存在困難，主要不同研究組分別報(bào)道了預(yù)后不良的ALL伴有與BCR-ABL1類似的基因表達(dá)[13-14]，但是不同研究組的定義規(guī)則，用于相同的疾病并不能得出相同的結(jié)果[15]。BCR-ABL1樣ALL共同的特性是包括其他的絡(luò)氨酸激酶易位，或者包括激酶受體樣因子2(CRLF2)易位，或者不常見的重排導(dǎo)致截短和紅細(xì)胞生成素受體激活[16-17]。出現(xiàn)基因易位的類型有包含絡(luò)氨酸激酶的ABL1基因(不含BCR基因)的突變，還有其他激酶如ABL2、PDGFRB、NTRK3、TYK2、CSF1R和AK2[18]。超過30種基因突變已經(jīng)被報(bào)道，其中有EBF1-PDGFRB易位，對于絡(luò)氨酸激酶抑制劑效果好，及時(shí)常規(guī)化療無效[19]。BCR-ABL1樣ALL常出現(xiàn)IKZF1和CDKN2A/B缺失，但是此種缺失在其他類型的ALL中亦有出現(xiàn)[15]。

6.3暫時(shí)新增ALL伴iAMP21。此種類型急性白血病主要是21染色體內(nèi)某一成分的擴(kuò)增，通過熒光原位雜交(FISH)探針探測RUNX1基因可以發(fā)現(xiàn)5個(gè)或者更多的基因復(fù)本，或者有3個(gè)及以上的不正常的21號染色體的額外復(fù)本產(chǎn)生[20]。此種類型急性白血病占兒童ALL的2%，尤其是年齡較大的兒童，臨床常有低白細(xì)胞計(jì)數(shù)。成年人中此種類型急性白血病并不多見。ALL伴iAMP21常提示預(yù)后不良，但對于部分患者，侵襲性的治療可能有效[20]。

6.4刪除Burkitt白血病，即FAB L3，將其歸入其他類型ALL。

7　T淋巴細(xì)胞白血病

7.1暫時(shí)新增早期前T細(xì)胞淋巴細(xì)胞白血病(ETP ALL)，此種類型急性白血病大多預(yù)后不良，但有部分研究得到可喜的治療效果[21-22]。其有特征性改變，如表達(dá)CD7、CD2和胞質(zhì)CD3，缺少CD1a和CD8，有1個(gè)或多個(gè)髓系或者干細(xì)胞標(biāo)記，比如CD34、CD117、HLADR、CD13、CD33、CD11b或者CD65，CD5經(jīng)常陰性表達(dá)[23]，常有髓系相關(guān)基因突變，如FLT3、NRAS/KRAS、DNMT3A、IDH1和IDH2等[23]，亦可表現(xiàn)T淋巴細(xì)胞白血病基因突變，如NOTCH1或CDKN1/2[23]。

當(dāng)許多臨床醫(yī)生對WHO急性白血病分型2008版還未完全應(yīng)用時(shí)，最新的2016版又出現(xiàn)在我們面前。更好地給患者提高診療和判斷預(yù)后，是每個(gè)醫(yī)務(wù)工作者不可推脫的責(zé)任和義務(wù)。此文只是拋磚引玉，希望我國的醫(yī)務(wù)工作者，能為下一次WHO急性白血病分型更新添磚加瓦。

作者貢獻(xiàn)：楊曉陽進(jìn)行課題設(shè)計(jì)與實(shí)施、資料收集整理、撰寫論文、成文并對文章負(fù)責(zé)；萬夢婕、陳方平進(jìn)行課題實(shí)施、評估、資料收集；陳方平進(jìn)行質(zhì)量控制及審校。

本文無利益沖突。

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(本文編輯：陳素芳)

Difference between the Classification of Acute Leukemia by World Health Organization in 2016 and 2008 Editions

YANGXiao-yang，WANMeng-jie，CHENFang-ping.DepartmentofHematology,CentralSouthUniversityXiangyaSchoolofMedicineAffiliatedHaikouHospital,HaikouPeople′sHospital,Haikou570208,China

Correspondingauthor：YANGXiao-yang，DepartmentofHematology,CentralSouthUniversityXiangyaSchoolofMedicineAffiliatedHaikouHospital,HaikouPeople′sHospital,Haikou570208,China；DepartmentofHematology,XiangyaHospitalCentralSouthUniversity，Changsha410008,China；E-mail:y108108@126.com

After eight years,the World Health Organization(WHO) has made amendments on the classification of acute leukemia.The differences between classification of acute leukemia by WHO in 2016 and 2008 editions are introduced in this paper.The reasons for deleting or adding contents in the 2016 edition based on the 2008 edition are analyzed in combination with cytogenetics and prognosis.The classification of acute leukemia by WHO in the 2016 edition can better combine and guide clinical practices.The differences between the classification of acute leukemia by WHO in the 2016 and 2008 editions are reviewed to help clinical doctors understand the latest types of acute leukemia and prepare for medical innovation.

Leukemia；World health organization；Classification

570208海南省?？谑校心洗髮W(xué)湘雅醫(yī)學(xué)院附屬?？卺t(yī)院暨海口市人民醫(yī)院血液科(楊曉陽，萬夢婕)；中南大學(xué)湘雅醫(yī)院血液科(楊曉陽，陳方平)；中南大學(xué)湘雅三醫(yī)院血液科(陳方平)

楊曉陽，570208海南省?？谑校心洗髮W(xué)湘雅醫(yī)學(xué)院附屬?？卺t(yī)院暨?？谑腥嗣襻t(yī)院血液科，中南大學(xué)湘雅醫(yī)院血液科；E-mail：y108108@126.com

R 733.7

A

10.3969/j.issn.1007-9572.2016.26.026

2016-06-06；

2016-07-20)