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弥漫性大B细胞淋巴瘤
Diffuse Large B-Cell Lymphoma


Laurie H. Sehn ... 肿瘤 • 2021.03.04
相关阅读
• tisagenlecleucel治疗成人复发性或难治性弥漫性大B细胞淋巴瘤 • axicabtagene ciloleucel CAR T细胞疗法治疗难治性大B细胞淋巴瘤

据估计,全世界每年约有15万例新发大B细胞淋巴瘤,约占所有非霍奇金淋巴瘤病例的30%。患者通常表现为进行性淋巴结肿大、淋巴结外病变或两者兼有,并且需要治疗。虽然大多数患者就诊时已为晚期,但60%以上可通过R-CHOP(利妥昔单抗、环磷酰胺、多柔比星、长春新碱和泼尼松)免疫化疗方案治愈(图1A)。R-CHOP治疗失败的患者通常结局不良(尤其是一线或后续方案难治性患者),但有一些患者可达到持久缓解,并且经过二线治疗后可治愈。过去20年间,我们对大B细胞淋巴瘤的流行病学、预后因素和生物学异质性有了深入了解,因此完善了疾病分类并开发出了新疗法。

 

图1. 弥漫性大B细胞淋巴瘤(DLBCL)的结局、危险因素和生物学特征

图A显示了在加拿大不列颠哥伦比亚省,接受R-CHOP(利妥昔单抗、环磷酰胺、多柔比星、长春新碱和泼尼松)治疗的所有新诊断的DLBCL患者的Kaplan-Meier生存期估计值(2001—2019年)。至进展的时间(TTP)指的是从诊断至疾病进展或因淋巴瘤死亡的时间(将无关原因死亡删失)。该曲线凸显出DLBCL进展风险在2年内最高,之后长达10年间的进展风险较低。无进展生存期(PFS)指的是从诊断至进展或任何原因死亡的时间。鉴于DLBCL患者的中位年龄为65岁上下,因此TTP和PFS曲线之间的差异反映出无关原因死亡的竞争性风险。PFS和总生存期(OS)曲线之间的微小差异反映出二线疗法治愈的患者数量有限,尽管新疗法可能延长总生存期。图B显示发生DLBCL的危险因素。图C显示我们在过去20年间了解到的异质性生物学特征。基因表达谱最初说明了两种分子亚型(生发中心B细胞样和活化B细胞样),我们认为它们起源于B细胞淋巴样分化的不同阶段(起源细胞),并且基因表达类似于正常B细胞1。目前已在这两个亚型内发现不同的功能特征和遗传畸变,而这些亚型内的异质性也已得到确认。基于深入的基因组分析结果,人们提出了新的DLBCL分类方法,即LymphGen分型2和DLBCL集群3。这些分类法进一步完善了DLBCL基因组分类,并且可能更好地说明不同的生物学实体。起源细胞的分子亚型和这些新的基因组实体之间的假定联系用实线箭形表示,表明强关联;虚线箭形表示较弱关联或不明确关联。基于反复出现的基因组畸变和所致遗传通路下调的遗传标志已在实体中确定,这些遗传标志与不同预后相关。伴有MYC重排,并同时出现BCL2、BCL6或这两者重排的DLBCL(双打击[DH]或三打击[TH]淋巴瘤)目前被归类为高级别B细胞淋巴瘤(HGBCL-DH/TH)。HGBCL-DH/TH病例以及带有MYC DH基因标签的EZB亚型(EZB-MYC+)病例2,4大多与EZB亚型聚类,并具有与不良临床结局相关的生物学特征。BCR表示B细胞受体,CNS表示中枢神经系统,EBV表示EB病毒,HHV8表示人类疱疹病毒8型,HIV表示人类免疫缺陷病毒,HL表示霍奇金淋巴瘤,miR-17-92表示微RNA集群17-92,NF-κB表示核因子κB,PI3K表示磷脂酰肌醇3-激酶,SLE表示系统性红斑狼疮,TNF/LTA表示肿瘤坏死因子/淋巴因子α。

 

病理特征和分子分类


大B细胞淋巴瘤的诊断依赖于对肿瘤组织的详细检查,最好由血液病理学专家对切除的活检标本进行评估5。除形态学特征之外,对淋巴瘤的准确分类需要特殊检查,包括免疫组化、流式细胞术、荧光原位杂交(FISH)和分子检测。细针穿刺活检标本不足以进行病理学评估。虽然粗针穿刺活检标本常用,但它们往往不足以进行完整评估,而且只有在切除活检不可行的情况下,才应进行粗针穿刺活检。

世界卫生组织(WHO)最新分类法完善了大B细胞淋巴瘤的分类;大B细胞淋巴瘤是临床病理实体的异质集合(表1)6,其中非特指弥漫性大B细胞淋巴瘤(DLBCL,NOS)最常见。关于每种疾病的详细综述超出了本文的范围,周到的治疗往往需要咨询性综述(consultative review)。





作者信息

Laurie H. Sehn, M.D., M.P.H., and Gilles Salles, M.D., Ph.D.
From the BC Cancer Centre for Lymphoid Cancer and the University of British Columbia, Vancouver, Canada (L.H.S.); and the Lymphoma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York (G.S.). Address reprint requests to Dr. Sehn at the BC Cancer Centre for Lymphoid Cancer, 600 W. 10th Ave., Vancouver, BC V5Z 4E6, Canada, or at lsehn@bccancer.bc.ca.

 

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