Kuan Shih-Fan, Ren Bing, Brand Randall, Dudley Beth, Pai Reetesh K
Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA 15213.
Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA 15213.
Hum Pathol. 2017 May;63:33-39. doi: 10.1016/j.humpath.2017.02.003. Epub 2017 Feb 21.
Universal screening using immunohistochemistry for DNA mismatch-repair proteins (MLH1, MSH2, MSH6, and PMS2) is advocated by major professional medical organizations to identify Lynch syndrome-associated colorectal carcinoma. Loss of MSH6 expression independent of MSH2 expression has been reported in microsatellite-stable (MSS) colorectal carcinoma after neoadjuvant therapy. The mechanism remains unclear. We studied the immunohistochemical expression of MSH2, MSH6, and Ki-67 in MSS colorectal carcinoma with (n=50) or without (n=64) preoperative neoadjuvant therapy and Lynch syndrome-associated colorectal carcinoma with confirmed MSH6 germline mutation (n=3). Twelve of 50 MSS colorectal carcinoma postneoadjuvant resections demonstrated reduced MSH6 expression, with loss of expression ranging from 20% to 100% of tumor cells. Eight of 64 MSS colorectal carcinomas without neoadjuvant therapy also exhibited reduced MSH6 expression but to a lesser degree (10%-50% of tumor cells with loss of expression). In both subgroups, concomitant loss of MSH6 and Ki-67 expressions was demonstrated in the same tumor areas in consecutive tissue sections. However, 3 cases of Lynch syndrome-associated colorectal carcinoma due to germline MSH6 mutation revealed complete loss of MSH6 expression with discordant positive Ki-67 staining in the tumor cells. The MSH2-independent, Ki-67-related expression of MSH6 in colorectal carcinoma helps to explain the heterogeneous MSH6 staining in MSS colorectal carcinoma with or without neoadjuvant therapy.
主要专业医学组织提倡使用免疫组织化学方法对DNA错配修复蛋白（MLH1、MSH2、MSH6和PMS2）进行全面筛查，以识别林奇综合征相关的结直肠癌。新辅助治疗后，微卫星稳定（MSS）的结直肠癌中已报道MSH6表达缺失且不依赖于MSH2表达。其机制仍不清楚。我们研究了术前接受新辅助治疗（n = 50）或未接受新辅助治疗（n = 64）的MSS结直肠癌以及确诊为MSH6种系突变的林奇综合征相关结直肠癌（n = 3）中MSH2、MSH6和Ki-67的免疫组织化学表达。50例接受新辅助治疗后切除的MSS结直肠癌中有12例显示MSH6表达降低，肿瘤细胞表达缺失范围为20%至100%。64例未接受新辅助治疗的MSS结直肠癌中有8例也表现出MSH6表达降低，但程度较轻（10% - 50%的肿瘤细胞表达缺失）。在这两个亚组中，连续组织切片的同一肿瘤区域均显示MSH6和Ki-67表达同时缺失。然而，3例因种系MSH6突变导致的林奇综合征相关结直肠癌显示MSH6表达完全缺失，而肿瘤细胞中Ki-67染色呈不一致的阳性。结直肠癌中MSH6不依赖于MSH2、与Ki-67相关的表达有助于解释接受或未接受新辅助治疗的MSS结直肠癌中MSH6染色的异质性。
