Srivastava Amitabh, Redston Mark, Farraye Francis A, Yantiss Rhonda K, Odze Robert D
Department of Pathology, Dartmouth-Hitchcock Medical Center, Lebanon, NH-03755.
Am J Surg Pathol. 2008 Feb;32(2):296-303. doi: 10.1097/PAS.0b013e318150d51b.
Herein, we describe the clinical, pathologic, immunohistochemical, and molecular features of 3 unique patients with long standing inflammatory bowel disease, all of whom developed numerous discrete hyperplastic/serrated colonic polyps similar to those described in the hyperplastic/serrated polyposis syndrome. The 3 patients (2 with ulcerative colitis and 1 with Crohn ileo-colitis) were evaluated for a variety of clinical, histologic (including the type, location and number of polyps in the colon), and immunohistochemical features [MLH-1, MSH-2, MGMT (O(6)-methylguanine-DNA methyltransferase), beta-catenin, and p53]. KRAS and BRAF mutation analysis was also performed on a subset of polyps from 2 patients. All patients had moderate-severe pancolitis of more than 10 years duration and had >20 colonic polyps. None had polyps in the upper gastrointestinal tract. Pathologically, a combination of conventional hyperplastic polyps and sessile serrated polyps (adenomas) were present in the 3 cases. In addition, serrated adenomas were present in 2 and conventional adenomas in 1. Two patients also had synchronous adenocarcinoma. All 3 cases showed retention of MLH-1 and MSH-2, and a membranous beta-catenin staining pattern. However, 2 cases showed loss of MGMT in several serrated polyps, and one also in adjacent colitic mucosa. KRAS mutations were detected in 5/11 serrated polyps. However, BRAF mutations were not present in any of the polyps tested. These findings suggest the possibility of a serrated pathway of carcinogenesis in inflammatory bowel disease characterized by silencing of MGMT, most likely by gene promoter methylation, KRAS mutations, and possibly other, as yet, uncharacterized molecular alterations, resulting eventually in progression to adenocarcinoma.
在此，我们描述了3例患有长期炎症性肠病的独特患者的临床、病理、免疫组化和分子特征，所有患者均出现了大量散在的增生性/锯齿状结肠息肉，类似于增生性/锯齿状息肉病综合征中所描述的息肉。对这3例患者（2例溃疡性结肠炎和1例克罗恩回结肠病）进行了多种临床、组织学（包括结肠息肉的类型、位置和数量）和免疫组化特征[MLH-1、MSH-2、MGMT（O(6)-甲基鸟嘌呤-DNA甲基转移酶）、β-连环蛋白和p53]的评估。还对2例患者的一部分息肉进行了KRAS和BRAF突变分析。所有患者均患有中度至重度全结肠炎，病程超过10年，且结肠息肉>20个。上消化道均无息肉。病理上，3例均存在传统增生性息肉和无蒂锯齿状息肉（腺瘤）的组合。此外，2例存在锯齿状腺瘤，1例存在传统腺瘤。2例患者还同时患有腺癌。所有3例均显示MLH-1和MSH-2保留，以及β-连环蛋白膜性染色模式。然而，2例在多个锯齿状息肉中显示MGMT缺失，1例在相邻的结肠炎黏膜中也显示MGMT缺失。在11个锯齿状息肉中的5个检测到KRAS突变。然而，在所检测的任何息肉中均未发现BRAF突变。这些发现提示炎症性肠病中存在一种锯齿状致癌途径的可能性，其特征为MGMT沉默，最可能是通过基因启动子甲基化、KRAS突变以及可能的其他尚未明确的分子改变，最终导致进展为腺癌。
