弥漫性大B细胞淋巴瘤免疫表型和预后的关系
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摘要
1研究背景
弥漫性大B细胞淋巴瘤(DLBCL)是一种高度异质性的非霍奇金淋巴瘤,约占成人非霍奇金淋巴瘤的30～40％,50％以上的DLBCL患者对蒽环类为基础的联合化疗有较好的治疗反应,但其余患者预后不佳。因此,需要寻找更为有效的预后参数,为临床诊断和个体化治疗提供依据。根据基因表达谱的研究可将DLBCL分成生发中心样亚型(Germinal central B cell like,GCB),外周活化B细胞样亚型(Activated B cell like, ABC),和第3型(type3);ABC型与type3预后相似,但都明显差于GCB型,故将type3与ABC放在一起称为非生发中心样型(Non-Germinal central B cell like, non-GCB).这种分型反映了DLBCL潜在的生物学行为的差异,但基因芯片检测费时且费用昂贵,不能广泛应用于临床。2004年Hans等以CD10、BCL-6、MUM1为标记物将DLBCL分成GCB型和non-GCB型两个亚型,与基因芯片的分型结果较一致,且免疫组化技术进行DLBCL分型有更好的实用价值。DLBCL是中国最常见的恶性淋巴瘤,近年来发病呈上升趋势,国内关于DLBCL的免疫分型及预后相关性研究较少。本研究收集了109例DLBCL病例,分析患者一般临床特征,国际预后指数(IPI),采用免疫组化方法检测CD10、BCL-6、BCL-2和MUM-1表达情况,并根据Hans模型分成GCB型和non-GCB型两个亚型,旨在探讨中国人群DLBCL的临床和预后特征、免疫学亚型及蛋白表达和预后的相互关系,为DLBCL预后判断及治疗方案选择提供依据。
2材料和方法
收集浙江省肿瘤医院2002年-2008年诊断的DLBCL病例,全部病例根据2008WHO淋巴造血系统肿瘤分类标准复习切片,补充必要的免疫组化以核实诊断,最后确诊为DLBCL, NOS (not otherwise specified,非特指型)的109例。免疫组织化学采用En Vision二步法,对资料完整的100例病例检测了CD20、CD3、CD10、BCL-6、MUM1、BCL-2的表达情况,根据Hans模型将患者区分为生发中心B细胞起源组(GCB)和非生发中心B细胞起源组(non-GCB),随访全部病例的预后情况。采用SAS 8.2分析统计学软件包对所得的资料进行X2检验、Cox风险回归分析及Kaplan-Meier生存分析。
3结果
3.1一般临床特点
本组病例以40岁以上的中老年人发病最多,中位发病年龄55岁,男女比例2.21：1。发病部位以原发淋巴结最为常见(66例,60.6％),结外发病部位以胃肠道最为多见(20例,18.3％)。临床Ann Arbor分期,Ⅰ～Ⅱ期病例占72％。Ⅲ～Ⅳ期病例约占28％。IPI低危组、中高危组的三年生存率分别为58.54％、28.57％。IPI低危组与中高危组相比较,生存率差异具有统计学意义(p<0.05)。
3.2免疫组化结果
100％(100例)CD3阴性；100％(100例)CD20阳性；68％(68例)BCL-2阳性；18％(18例)CD10阳性；59％(59例)BCL-6阳性；35％(35例)MUM-1阳性。
3.3 Hans模型分类结果
按照Hans模型进行分类,其中GCB起源组41％(41例),non-GCB起源组59％(59例),non-GCB起源组：GCB起源组=1.44：1。GCB起源组和non-GCB起源组3年生存率分别为45.71％和40.00％,Kaplan-Meier生存分析显示,两组长期生存状况无明显差异(p>0.05)。
3.4蛋白表达与预后
BCL-6阳性组长期生存状况明显优于BCL-6阴性组(p<0.05)；non-GCB组患者中BCL-2阳性组生存状况明显比阴性组差(p<0.05)；而GCB组患者中,BCL-2阳性组生存状况与阴性组相比无明显统计学差异(p>0.05)；MUM1、CD10与预后无明显相关性。
4结论
4.1弥漫性大B细胞淋巴瘤以中老年人发病为主,临床病程呈侵袭性。可分成GCB起源组(41％)和non-GCB起源组(59％),在我国non-GCB起源组较多。
4.2 BCL-6蛋白的表达和IPI指数为独立的预后相关因素,
4.3 BCL-2蛋白表达为non-GCB患者的不良预后指标。
Background:Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous entity of non-Hodgkin lymphomas (NHL), accounting for 30-40%of adult NHL. Although approximate 50%patients are potentially effective to anthracycline-based chemotherapy, more than half succumb to their disease with poor prognosis. Recently, the application of gene expression profiling(GEP) data had identified three distinct molecular groups:germinal centre B cell-like type(GCB), activated B cell-like type(ABC), and type 3. GCB type had the best prognosis in the three types; ABC and type 3 types had a similar poor outcome, so they were generally combined and categorized into a "non-germinal centre (non-GCB)"group. These molecular grouping reflects the biologic nature of DLBCL. Because the cDNA microarray study is expensive and requries fresh or frozen tissue, which may not be technically feasible in a clinical laboratory setting, Hans et al proposed that an immunostain panel of CD10, BCL-6 and MUM1 could be used to classify DLBCL into GCB and non-GCB, which showed prognostic significance equivalent to that of gene-expression profiling. In recent years the population of DLBCL in China has been increasing. Few studies are available about immunophenotype and prognosis in Chinese patients with DLBCL. The aims of our study were therefore, in Chinese population, to analyse the clinic, histologic and immunophenotypic characteristics of DLBCL patients, investigate their correlation to patient survival and define the applicability of identified immunohistochemical profiles. We intended to investigate more feasible and convenience parameter, to predict clinical prognosis and treatment.
Materials and methods:109 cases of Chinese DLBCL diagnosed according to the WHO Classification of Tumors of Haematopoietic and Lymphoid Tissues (2008) were collected from ZheJiang Cancer Hospital. The morphologic characteristics were studied under light microscopy, and the essential immunohistochemical staining were performed. Standard two-step En Vision method of immunohistochemical staining was used to detect the expression of CD20, CD3, CD 10, MUM-1, BCL-6, BCL-2. All cases were devided into GCB group and non-GCB group according to the Hans'algorithm. Data were analyzed with X2 test, Cox proportional hazard model and Kaplan-Meier analysis by the SAS 8.2 statistical package.
Result:Most of DLBCL patients were older than 40 ys, the middle age being 55 ys. The ratio of male to female was 2.21:1 approximately. Sixty-six cases (60.6%) primarily involved lymph nodes. The common extra-nodal organ involved was gastrointestinal tract (20 cases,18.3%). DLBCL patients were staged according to the Ann-Arbor Staging System.72%of patients presented at early stages (I and II), while 28%of patients at advanced stages (III and IV). The 3-year survival rate of IPI groups of low, moderate to high groups was 58.54%,28.57%, respectively. The survival analysis showed statistical significance between IPI groups low and moderate to high group. All of the 100 cases (100%) were CD3 negative and CD20 positive,68 cases (68%) were BCL-2 positive and 59 cases (59%) BCL-6 positive. CD 10 was expressed in 18 cases (18%).35 cases (35%) were MUM-1 positive. One hundred cases in this study can be classified according to Hans'algorithm.41 cases (41%) were classified as GCB subgroup, while 59 cases (59%) were non-GCB group. Non-GCB:GCB= 1.44:1.3 year-survival rate in GCB subgroup was 45.71%, while 40.00%of 3 year-survival rate in non-GCB subgroup. Life table survival analysis showed that survival status of the two subgroups according to Hans'model had no significant differences. The survival status of the BCI-6 positive group was superior to the BCL-6 negative group. There was no statistical significance in camparing survival status between BCL-2 positive group and BCL-2 negative group in GCB subgroup(p>0.05), while the survival status of BCL-2 negative group was better than BCL-2 positive group in non-GCB subgroup.
Conclusion:DLBCL is a highly aggressive disease which mainly involves the middle aged population, including GCB-DLBCL and non-GCB-DLBCL subtype. The non-GCB-DLBCL is more common in Chinese NHL. The International Prognostic Index (IPI) and BCL-6 expression are independent predictors of prognosis while the expression of CD 10 and MUM-1 showes no relationship with outcome. BCL-2 expression is predictors of poor prognosis of non-GCB subgroup.
弥漫性大B细胞淋巴瘤(DLBCL)是一种高度异质性的非霍奇金淋巴瘤,约占成人非霍奇金淋巴瘤的30～40％,50％以上的DLBCL患者对蒽环类为基础的联合化疗有较好的治疗反应,但其余患者预后不佳。因此,需要寻找更为有效的预后参数,为临床诊断和个体化治疗提供依据。根据基因表达谱的研究可将DLBCL分成生发中心样亚型(Germinal central B cell like,GCB),外周活化B细胞样亚型(Activated B cell like, ABC),和第3型(type3);ABC型与type3预后相似,但都明显差于GCB型,故将type3与ABC放在一起称为非生发中心样型(Non-Germinal central B cell like, non-GCB).这种分型反映了DLBCL潜在的生物学行为的差异,但基因芯片检测费时且费用昂贵,不能广泛应用于临床。2004年Hans等以CD10、BCL-6、MUM1为标记物将DLBCL分成GCB型和non-GCB型两个亚型,与基因芯片的分型结果较一致,且免疫组化技术进行DLBCL分型有更好的实用价值。DLBCL是中国最常见的恶性淋巴瘤,近年来发病呈上升趋势,国内关于DLBCL的免疫分型及预后相关性研究较少。本研究收集了109例DLBCL病例,分析患者一般临床特征,国际预后指数(IPI),采用免疫组化方法检测CD10、BCL-6、BCL-2和MUM-1表达情况,并根据Hans模型分成GCB型和non-GCB型两个亚型,旨在探讨中国人群DLBCL的临床和预后特征、免疫学亚型及蛋白表达和预后的相互关系,为DLBCL预后判断及治疗方案选择提供依据。
2材料和方法
收集浙江省肿瘤医院2002年-2008年诊断的DLBCL病例,全部病例根据2008WHO淋巴造血系统肿瘤分类标准复习切片,补充必要的免疫组化以核实诊断,最后确诊为DLBCL, NOS (not otherwise specified,非特指型)的109例。免疫组织化学采用En Vision二步法,对资料完整的100例病例检测了CD20、CD3、CD10、BCL-6、MUM1、BCL-2的表达情况,根据Hans模型将患者区分为生发中心B细胞起源组(GCB)和非生发中心B细胞起源组(non-GCB),随访全部病例的预后情况。采用SAS 8.2分析统计学软件包对所得的资料进行X2检验、Cox风险回归分析及Kaplan-Meier生存分析。
3结果
3.1一般临床特点
本组病例以40岁以上的中老年人发病最多,中位发病年龄55岁,男女比例2.21：1。发病部位以原发淋巴结最为常见(66例,60.6％),结外发病部位以胃肠道最为多见(20例,18.3％)。临床Ann Arbor分期,Ⅰ～Ⅱ期病例占72％。Ⅲ～Ⅳ期病例约占28％。IPI低危组、中高危组的三年生存率分别为58.54％、28.57％。IPI低危组与中高危组相比较,生存率差异具有统计学意义(p<0.05)。
3.2免疫组化结果
100％(100例)CD3阴性；100％(100例)CD20阳性；68％(68例)BCL-2阳性；18％(18例)CD10阳性；59％(59例)BCL-6阳性；35％(35例)MUM-1阳性。
3.3 Hans模型分类结果
按照Hans模型进行分类,其中GCB起源组41％(41例),non-GCB起源组59％(59例),non-GCB起源组：GCB起源组=1.44：1。GCB起源组和non-GCB起源组3年生存率分别为45.71％和40.00％,Kaplan-Meier生存分析显示,两组长期生存状况无明显差异(p>0.05)。
3.4蛋白表达与预后
BCL-6阳性组长期生存状况明显优于BCL-6阴性组(p<0.05)；non-GCB组患者中BCL-2阳性组生存状况明显比阴性组差(p<0.05)；而GCB组患者中,BCL-2阳性组生存状况与阴性组相比无明显统计学差异(p>0.05)；MUM1、CD10与预后无明显相关性。
4结论
4.1弥漫性大B细胞淋巴瘤以中老年人发病为主,临床病程呈侵袭性。可分成GCB起源组(41％)和non-GCB起源组(59％),在我国non-GCB起源组较多。
4.2 BCL-6蛋白的表达和IPI指数为独立的预后相关因素,
4.3 BCL-2蛋白表达为non-GCB患者的不良预后指标。
Background:Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous entity of non-Hodgkin lymphomas (NHL), accounting for 30-40%of adult NHL. Although approximate 50%patients are potentially effective to anthracycline-based chemotherapy, more than half succumb to their disease with poor prognosis. Recently, the application of gene expression profiling(GEP) data had identified three distinct molecular groups:germinal centre B cell-like type(GCB), activated B cell-like type(ABC), and type 3. GCB type had the best prognosis in the three types; ABC and type 3 types had a similar poor outcome, so they were generally combined and categorized into a "non-germinal centre (non-GCB)"group. These molecular grouping reflects the biologic nature of DLBCL. Because the cDNA microarray study is expensive and requries fresh or frozen tissue, which may not be technically feasible in a clinical laboratory setting, Hans et al proposed that an immunostain panel of CD10, BCL-6 and MUM1 could be used to classify DLBCL into GCB and non-GCB, which showed prognostic significance equivalent to that of gene-expression profiling. In recent years the population of DLBCL in China has been increasing. Few studies are available about immunophenotype and prognosis in Chinese patients with DLBCL. The aims of our study were therefore, in Chinese population, to analyse the clinic, histologic and immunophenotypic characteristics of DLBCL patients, investigate their correlation to patient survival and define the applicability of identified immunohistochemical profiles. We intended to investigate more feasible and convenience parameter, to predict clinical prognosis and treatment.
Materials and methods:109 cases of Chinese DLBCL diagnosed according to the WHO Classification of Tumors of Haematopoietic and Lymphoid Tissues (2008) were collected from ZheJiang Cancer Hospital. The morphologic characteristics were studied under light microscopy, and the essential immunohistochemical staining were performed. Standard two-step En Vision method of immunohistochemical staining was used to detect the expression of CD20, CD3, CD 10, MUM-1, BCL-6, BCL-2. All cases were devided into GCB group and non-GCB group according to the Hans'algorithm. Data were analyzed with X2 test, Cox proportional hazard model and Kaplan-Meier analysis by the SAS 8.2 statistical package.
Result:Most of DLBCL patients were older than 40 ys, the middle age being 55 ys. The ratio of male to female was 2.21:1 approximately. Sixty-six cases (60.6%) primarily involved lymph nodes. The common extra-nodal organ involved was gastrointestinal tract (20 cases,18.3%). DLBCL patients were staged according to the Ann-Arbor Staging System.72%of patients presented at early stages (I and II), while 28%of patients at advanced stages (III and IV). The 3-year survival rate of IPI groups of low, moderate to high groups was 58.54%,28.57%, respectively. The survival analysis showed statistical significance between IPI groups low and moderate to high group. All of the 100 cases (100%) were CD3 negative and CD20 positive,68 cases (68%) were BCL-2 positive and 59 cases (59%) BCL-6 positive. CD 10 was expressed in 18 cases (18%).35 cases (35%) were MUM-1 positive. One hundred cases in this study can be classified according to Hans'algorithm.41 cases (41%) were classified as GCB subgroup, while 59 cases (59%) were non-GCB group. Non-GCB:GCB= 1.44:1.3 year-survival rate in GCB subgroup was 45.71%, while 40.00%of 3 year-survival rate in non-GCB subgroup. Life table survival analysis showed that survival status of the two subgroups according to Hans'model had no significant differences. The survival status of the BCI-6 positive group was superior to the BCL-6 negative group. There was no statistical significance in camparing survival status between BCL-2 positive group and BCL-2 negative group in GCB subgroup(p>0.05), while the survival status of BCL-2 negative group was better than BCL-2 positive group in non-GCB subgroup.
Conclusion:DLBCL is a highly aggressive disease which mainly involves the middle aged population, including GCB-DLBCL and non-GCB-DLBCL subtype. The non-GCB-DLBCL is more common in Chinese NHL. The International Prognostic Index (IPI) and BCL-6 expression are independent predictors of prognosis while the expression of CD 10 and MUM-1 showes no relationship with outcome. BCL-2 expression is predictors of poor prognosis of non-GCB subgroup.
引文
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