免疫母细胞形态和HANS分类方法预测弥漫大B细胞淋巴瘤的预后及疗效相关性分析

Prognostic Value of Morphology and Hans Classification in Diffuse Large B Cell Lymphoma

目的:明确免疫母细胞形态和HANS分类方法在预测弥漫大B细胞淋巴瘤(diffuse large B-cell lymphoma,DLBCL)中的价值。方法:回顾性分析2006年1月至2016年12月杭州市第一人民医院和杭州市西溪医院共诊断弥漫性大B细胞淋巴瘤病例249例的临床资料,根据其细胞形态分为免疫母细胞型(immunoblastic variant,IB)、中心母细胞型(centroblastic variant,CB)以及其他类型3组,根据CD10、BCL6及MUM1的表达将病例分为生发中心B细胞样(germinal center B-cell-like,GCB)型和非生发中心B细胞样(non-germinal center B-cell-like,non-GCB)型2种亚型(CD10^+、BCL6^(+-)、MUM1^(+-)/CD10^-、BCL6^+、MUM1^-为GCB型,CD10^-、BCL6^-、MUM1^(+-)/CD10^-、BCL6^+、MUM1^+为non-GCB型)。结果:单因素分析显示,年龄、LDH水平、IPI评分、IB型、non-GCB型、B症状以及利妥昔单克隆抗体的使用与否,对EFS和OS均有影响(P<0.05)。IB亚型的弥漫大B淋巴瘤CR率明显低于CB亚型(38.9%vs 68.3%)(P=0.02)。COX多因素分析显示,IPI评分和IB亚型是影响OS和EFS的独立预后因素。无论有没有使用美罗华,IB亚型是影响总生存期和无进展生存期的一个独立预后因素,EFS(P=0.000),OS(P=0.000)。BCL2和BCL6与预后有关,单用CHOP方案治疗时BCL6及BCL2对预后均无预测意义。其他的免疫标志(CD10、CD5、IRF/MUM1、HLA-DR、及Ki67增殖指数)对EFS、OS均无预测作用。接受美罗华治疗亚组中,GCB与non-GCB亚型分类对EFS及OS并无预测作用,未接受美罗华治疗的亚组中,GCB与non-GCB分类对预后有影响(EFS P=0.020;OS P=0.020)。GCB与non-GCB亚型间无明显差异(P=0.451)。此外,当分析CB亚组中GCB与non-GCB亚型对预后的影响时,亦未见明显差别。结论:无论使用或是不使用美罗华,IB型DLBCL均预示较差的预后,同时发现了IB亚型与non-GCB亚型具有明显相关性。

Objective： To investigate the prognostic value of morphology and Hans classification in diffuse large B cell lymphoma（ DLBCL）. Methods： Clinical data of 249 patients diagnosed with DLBCL in our hospital and Hangzhou Xixi hospital during Jan 2006 to Dec 2016 were analyzed retrospectively. These patients were classified into 3 groups：immunoblastic variant（ IB） group,centroblastic variant（ CB） group and others group according to the cell morphology.And DLBCL was also divided into GCB（ germinal center B-cell-like） or non-GCB（ non-germinal center B-cell-like）group by analyzing the expression of CD10,BCL6 and MUM1（ GCB： CD10＋,BCL6（＋-）,MUM1 （＋-）/CD10-,BCL6＋,MUM1-; non-GCB： CD10-,BCL6-,MUM1（＋-）/CD10-,BCL6＋,MUM1＋）. Results： The univariate analysis displayed that the age,LDH level,IPI,IB,non-GCB,B-symptoms and rituximab all could influence the OS and EFS,the CR rate of CB subtype patients was significantly higher than that of the patients with IB subtype（ 68. 3% vs 38. 9%）（ P= 0. 02）. IB subtype was the in dependent prognostic factor for both EFS and OS in the whole study. In multivariate analysis,IPI and IB were the independent prognostic factors for OS and EFS. IB subtype was also an independent prognostic factor in EFS and OS with or without rituximab. The expression of BCL2 and BCL6 was related with prognosis in R-CHOP,but not in CHOP treated patients. Other markers（ CD5,CD10,IRF4/MUM1,HLA-DR and Ki-67 proliferation index） were not of the significant prognostic value for DLBCL. When accepted rituximab,the GCB and non-GCB were not different significantly for prognosis. However,the non-GCB group showed a poor prognosis without using rituximab（ EFS P = 0. 020; OS P = 0. 020）. Multivariate Cox models showed that OS and EFS were not significantly different between GCB and non-GCB group,however,the IB subtype had a very significantly poor prognosis in OS and EFS（ P = 0. 001,P = 0. 002）. When the analysis was restricted to DLBCL with CB morphology only,no prognostic value was observed in Hans classification. Conclusion： The subtype of immunoblast is a major risk factor in patients treated with CHOP or R-CHOP. There is a significant association between the Hans classification and the morphologic subclassification. Results of this study have supplemented the data for the prognostic factor of DLBCL and demonstrated that the cytomorphologic diagnosis can be reproducible.