错配修复蛋白缺失相关子宫内膜癌的病理特征及其临床意义

Clinicopathological characteristics and clinical significance of mismatch repair protein deletion-related endometrial carcinoma

目的探讨错配修复蛋白缺失相关子宫内膜癌(dMMR-EC)的病理特征及其临床意义。方法选取2014年6月至2017年6月宁波市临床病理诊断中心诊断的子宫内膜癌(EC)患者294例,收集其临床病理资料,复阅病理切片并分析肿瘤组织学类型、肌层浸润、淋巴结转移及国际妇产科协会(FIGO)分级分期等临床病理特征。采用免疫组化法检测肿瘤组织中人体碱基错配修复(MMR)蛋白(包括MLH1、PMS2、MSH2和MSH6)的表达,采用二代测序方法检测部分病例肿瘤组织MMR基因突变频谱,分析MMR蛋白阴性率与临床病理特征的相关性。结果294例EC患者中有62例(21.1%,62/294)为dMMR-EC,其中40例(13.6%,40/294)MLH1和(或)PMS2阴性,22例(7.5%,22/294)MSH2和(或)MSH6阴性。MMR蛋白阴性率与患者年龄、组织学类型、肌层浸润深度、淋巴结转移情况和FIGO分级分期均无明显相关性(均P>0.05)。非II型高级别ECMMR蛋白阴性率为35.5%,明显高于II型高级别EC的11.6%,差异有统计学意义(P<0.05)。随机选取21例dMMR-EC患者进行二代测序检测MMR基因突变频谱,16例出现MMR基因突变。62例dMMR-EC患者均进行随访,随访时间25~62个月,有效随访52例,其中无病生存49例,远处转移2例,病死1例,失访10例。结论推荐所有初次确诊EC的患者进行免疫组化初筛Lynch综合征相关子宫内膜癌,其中非II型高级别EC是重点筛查对象;采用免疫组化筛查高级别dMMR-EC,有助于高级别EC的预后预测并指导疾病的治疗和管理。

Objective To investigate the clinicopathological characteristics of mismatch repair protein deletion-related endometrial carcinoma(dMMR-EC).Methods A total of 294 endometrial carcinoma(EC)patients diagnosed by Ningbo Clinical Pathological Diagnosis Center from June 2014 to June 2017 were enrolled.The pathological sections were reviewed,and the clinicopathological characteristics of patients,including histological type,myometrial infiltration,lymph node metastasis,and grade and stage of the tumor were analyzed.The expression of mismatch repair(MMR)proteins MLH1,PMS2,MSH2 and MSH6 was detected by immunohisto-chemistry.The mutation spectrum of MMR gene was detected by next generation sequencing.The relationship between the expression of MMR protein and the clinicopathological characteristics of patients was analyzed.Results There were 62 cases(21.1%,62/294)of dMMR-EC,among which MLH1 and/or PMS2 expression deletion was detected in 40 cases(13.6%)and MSH2 and/or MSH6 expression deletion was detected in 22 cases(7.5%).The rate of loss of MMR protein expression was not related to age,histological type,the depth of myometrial infiltration,lymph node metastasis,tumor grade and staging(all P>0.05).The loss rate of MMR protein in non-type II high-grade EC patients was higher than that in type II high-grade EC patients(35.5%vs.11.6%,P<0.05).Twenty-one cases of dMMR-EC were randomly selected for next-generation sequencing and 16 cases had MMR gene mutations.Fifty-two cases were followed up for 25-62 months,49 cases were disease-free,2 cases had distant metastasis,and 1 case died.Conclusion It is recommended that patients diagnosed with EC for the first time should be screened for Lynch syndrome-related EC by immunohistochemistry,particularly for non-type II high-grade EC.Using immunohistochemistry to screen high-grade dMMR-EC can help to predict the prognosis and treatment of high-grade EC.