Xia Michelle, Singhi Aatur D, Dudley Beth, Brand Randall, Nikiforova Marina, Pai Reetesh K
Departments of *Pathology †Internal Medicine, Division of Gastroenterology, University of Pittsburgh Medical Center, Pittsburgh, PA.
Appl Immunohistochem Mol Morphol. 2017 Jul;25(6):399-406. doi: 10.1097/PAI.0000000000000389.
Universal screening for Lynch syndrome has been advocated for colorectal carcinoma but its utility in small bowel adenocarcinoma has not been reported. We analyzed a consecutive series of 71 small bowel adenocarcinomas identified over an 8-year period for DNA mismatch repair (MMR) protein expression to (1) compare the clinicopathologic features of small bowel adenocarcinoma stratified into MMR-deficient (MMRD) and MMR-proficient (MMRP) groups and (2) examine the patterns of MMR protein expression in small bowel adenocarcinoma compared with colorectal carcinoma. Six of 71 (8.5%) small bowel adenocarcinomas and 149 of 1291 (11.5%) colorectal carcinomas demonstrated MMRD. The 6 MMRD small bowel adenocarcinomas had the following expression pattern: 3 with concurrent loss of MSH2 and MSH6, 1 with isolated loss of MSH6, and 2 with concurrent loss of MLH1 and PMS2 in patients with a family history suggestive of genetic cancer susceptibility. Histopathology suggestive of MMR protein deficiency as proposed by the revised Bethesda guidelines was commonly seen in both MMRP (63%) and MMRD (67%) small bowel adenocarcinomas (P>0.05). MMRD small bowel adenocarcinoma more frequently demonstrated abnormalities of MSH2 and/or MSH6 (4/6, 67%) compared with MMRD colorectal carcinoma (23/149, 15%) (P=0.01). None of the MMRD small bowel adenocarcinomas harbored the BRAF V600E mutation, whereas 60% of MMRD colorectal carcinomas were positive for BRAF V600E with concurrent loss of MLH1 and PMS2 expression. Small bowel adenocarcinoma more frequently harbored Lynch syndrome-associated MMRD compared with colorectal carcinoma, providing support for screening of small bowel adenocarcinoma to identify patients at risk for Lynch syndrome. In contrast to colorectal carcinoma, sporadic MLH1 deficiency is not seen in small bowel adenocarcinoma. Clinicopathologic and histologic features do not distinguish between MMRP and MMRD small bowel adenocarcinoma indicating that universal screening in small bowel adenocarcinoma is necessary to detect patients at risk for Lynch syndrome.
针对林奇综合征进行结直肠癌的普遍筛查已得到提倡，但尚未见其在小肠腺癌中的应用报道。我们分析了连续8年中确诊的71例小肠腺癌，检测其DNA错配修复（MMR）蛋白表达情况，目的是（1）比较分为错配修复缺陷（MMRD）组和错配修复功能正常（MMRP）组的小肠腺癌的临床病理特征，以及（2）研究与结直肠癌相比，小肠腺癌中MMR蛋白的表达模式。71例小肠腺癌中有6例（8.5%）表现为MMRD，1291例结直肠癌中有149例（11.5%）表现为MMRD。6例MMRD小肠腺癌具有以下表达模式：3例同时缺失MSH2和MSH6，1例单独缺失MSH6，2例在有遗传癌症易感性家族史的患者中同时缺失MLH1和PMS2。按照修订的贝塞斯达指南提出的提示MMR蛋白缺陷的组织病理学表现，在MMRP（63%）和MMRD（67%）小肠腺癌中均较为常见（P>0.05）。与MMRD结直肠癌（23/149，15%）相比，MMRD小肠腺癌更常出现MSH2和/或MSH6异常（4/6，67%）（P=0.01）。MMRD小肠腺癌均未检测到BRAF V600E突变，而60%的MMRD结直肠癌BRAF V600E呈阳性，同时伴有MLH1和PMS2表达缺失。与结直肠癌相比，小肠腺癌更常伴有林奇综合征相关的MMRD，这为筛查小肠腺癌以识别林奇综合征高危患者提供了依据。与结直肠癌不同，小肠腺癌中未发现散发性MLH1缺陷。临床病理和组织学特征无法区分MMRP和MMRD小肠腺癌，这表明对小肠腺癌进行普遍筛查对于检测林奇综合征高危患者是必要的。
