国人弥漫大B细胞淋巴瘤P53表达的判读标准及预后价值探讨

Investigation for pathological interpretation criteria and its prognostic value for P53 expression in Chinese diffuse large B-cell lymphoma

目的探索在国人弥漫大B细胞淋巴瘤(DLBCL)中免疫组织化学染色(IHC)检测P53蛋白表达状态预测TP53基因突变风险的能力,以及P53表达差异的预后评估价值。方法收集北京高博博仁医院2021年1月至2021年12月同时进行二代测序(NGS)和IHC检测的DLBCL病例51例,依据P53的IHC染色将P53蛋白表达状态分为缺失(<1%)、弥漫(>80%)和不均一(1%~80%)3组,将缺失及弥漫表达归为TP53突变高风险组;与NGS结果对比分析IHC预测TP53突变风险的敏感性和特异性。收集北京大学肿瘤医院2016年6月至2019年9月有完整随访资料的DLBCL患者131例,制作组织芯片并通过IHC检测P53表达,评估P53表达差异的预后价值。结果51例同时行IHC和NGS检测的病例中,TP53突变高风险23例(7例缺失,16例弥漫),NGS证实22例存在TP53突变;TP53突变低风险组28例,仅1例证实有TP53突变。IHC预测TP53突变风险敏感性95.7%,特异性96.4%。NGS共检出26个TP53突变位点,等位基因突变频率为61.57%(13.41%~86.25%),P53弥漫组检出16个错义突变、2个剪切位点突变;缺失组检出6个截短突变、1个剪切位点突变;不均一组检出1个截短突变。纳入预后分析的131例DLBCL患者中,IHC显示29.0%(38/131)为TP53突变高风险(17例弥漫、21例缺失)。多因素分析显示TP53突变高风险(HR=2.612,95%CI 1.145~5.956,P=0.022)是影响总生存的独立危险因素。结论IHC检测P53蛋白表达缺失(<1%)或弥漫(>80%)TP53突变风险高,IHC预测TP53突变的敏感性与特异性高,TP53突变高风险是预后不良的独立影响因素。

Objective To explore the feasibility of predicting TP53 mutation risk by immunohistochemical staining(IHC)pattern of P53 in Chinese diffuse large B-cell lymphoma(DLBCL)and its correlation with a prognostic difference.Methods Between January 2021 and December 2021,51 DLBCL cases at Beijing Boren Hospital were gathered.These cases had both IHC and next-generation sequencing(NGS)results.IHC classified the P53 protein expression pattern into a loss(<1%),diffuse(>80%),and heterogeneous(1%-80%).The sensitivity and specificity of the predicting TP53 mutation by IHC were assessed by comparing the results of the NGS,and the TP53 high mutation risk group included both loss and diffuse expression of P53.From June 2016 to September 2019,Peking University Cancer Hospital collected 131 DLBCL cases with thorough clinicopathological and follow-up data.From their tumor blocks,tissue microarray blocks were made for IHC evaluation of P53 expression pattern,and prognosis effect of P53 studies.Results Among 51 cases with both IHC and NGS results,23 cases were classified as TP53 high mutation risk(7 cases loss and 16 cases diffuse),22/23 cases were proved with mutated TP53 by NGS.Only 1 of the 28 cases classified as TP53 low mutation risk was proved with mutated TP53 by NGS.IHC had a sensitivity and specificity of 95.7%and 96.4%for predicting TP53 mutation.NGS identified a total of 26 TP53 mutations with a mutation frequency of 61.57%(13.41%-86.25%).In the diffuse group,16 missense mutations and 2 splice mutations were detected;6 truncating mutations and 1 splice mutation were detected in the loss group;1 truncating mutation was detected in the heterogeneous group.Multivariate analysis demonstrated that TP53 cases with high mutation risk have impartial adverse significance for the 131 patients included in survival analysis(HR=2.612,95%CI 1.145-5.956,P=0.022).Conclusion IHC of P53 exhibiting loss(<1%)or diffuse(>80%)pattern indicated TP53 high mutation risk,IHC can predict TP53 mutation with high specificity and sensitivity.TP53 high mutation risk is an independent predictor for adverse survival.