Features of Colorectal Cancers with High-Level Microsatellite Instability Occurring in Familial and Sporadic Settings

Abstract

High-level microsatellite instability (MSI-H) is demonstrated in 10 to 15% of sporadic colorectal cancers and in most cancers presenting in the inherited condition hereditary nonpolyposis colorectal cancer (HNPCC). Distinction between these categories of MSI-H cancer is of clinical importance and the aim of this study was to assess clinical, pathological, and molecular features that might be discriminatory. One hundred and twelve MSI-H colorectal cancers from families fulfilling the Bethesda criteria were compared with 57 sporadic MSI-H colorectal cancers. HNPCC cancers presented at a lower age (P < 0.001) with no sporadic MSI-H cancer being diagnosed before the age of 57 years. MSI was less extensive in HNPCC cancers with 72% microsatellite markers showing band shifts compared with 87% in sporadic tumors (P < 0.001). Absent immunostaining for hMSH2 was only found in HNPCC tumors. Methylation of hMLH1 was observed in 87% of sporadic cancers but also in 55% of HNPCC tumors that showed loss of expression of hMLH1 (P = 0.02). HNPCC cancers were more frequently characterized by aberrant beta-catenin immunostaining as evidenced by nuclear positivity (P < 0.001). Aberrant p53 immunostaining was infrequent in both groups. There were no differences with respect to 5q loss of heterozygosity or codon 12 K-ras mutation, which were infrequent in both groups. Sporadic MSI-H cancers were more frequently heterogeneous (P < 0.001), poorly differentiated (P = 0.02), mucinous (P = 0.02), and proximally located (P = 0.04) than HNPCC tumors. In sporadic MSI-H cancers, contiguous adenomas were likely to be serrated whereas traditional adenomas were dominant in HNPCC. Lymphocytic infiltration was more pronounced in HNPCC but the results did not reach statistical significance. Overall, HNPCC cancers were more like common colorectal cancer in terms of morphology and expression of beta-catenin whereas sporadic MSI-H cancers displayed features consistent with a different morphogenesis. No individual feature was discriminatory for all HNPCC cancers. However, a model based on four features was able to classify 94.5% of tumors as sporadic or HNPCC. The finding of multiple differences between sporadic and familial MSI-H colorectal cancer with respect to both genotype and phenotype is consistent with tumorigenesis through parallel evolutionary pathways and emphasizes the importance of studying the two groups separately.

Hypermethylation of the hMLH1 promoter with absent hMLH1 expression in medullary-type poorly differentiated colorectal adenocarcinoma in the elderly

“…13,23 Consequently, medullarytype carcinomas in the elderly may be induced by an epigenetic event within the hMLH1 gene, whereas hereditary nonpolyposis colorectal cancer results from germ-line mutation of the mismatch repair gene with occasional hypermethylation of the hMLH1 promoter. 24 In the present study, medullary-type carcinomas accumulated with advancing age. The spread of methylation in the hMLH1 promoter in the normal colonic mucosa was closely associated with age and with the development of sporadic colorectal cancers with microsatellite instability.…”

Should the grading of colorectal adenocarcinoma include microsatellite instability status?

“…In our study, adenocarcinomas were graded according to the area showing the least differentiated component which had to be present in at least one field at magnification x40. Using these criteria may have resulted in a Heterogeneity is frequently observed in MSI carcinomas but usually by the frequent occurrence of minor mucinous carcinoma components in an otherwise low-grade adenocarcinoma [14,21]. The difference in proportions of high-grade adenocarcinomas is likely to be explained by the inclusion of tumors with overall <50% gland formation (i.e.…”

Expression of MUC2, MUC5AC, MUC5B, and MUC6 mucins in colorectal cancers and their association with the CpG island methylator phenotype

“…Tumor budding was assessed using the criteria described by Ueno et al 32 (Z10 foci of isolated tumor cells or clusters of fewer than five tumor cells at the invasive margin within a  25 microscopic field). Peritumoral lymphocytes (a mantle or cap of lymphoid cells at the deepest point of direct spread), Crohn's-like lymphocytic reaction (at least three nodular lymphoid aggregates deep to the invasive margin in a  4 field), and tumor-infiltrating lymphocytes (at least four intraepithelial lymphocytes per  40 field) were scored using the criteria described previously by Young et al 33 Tumors in the ileocecal junction, cecum, ascending colon, hepatic flexure, and transverse colon were grouped as right-sided (proximal) colon cancers (ICD-O-3 codes C180, C182, C183, and C184), 34 whereas those in the splenic flexure (C185), descending colon (C186), sigmoid colon (C187), recto-sigmoid junction (C199) and rectum (C209) were grouped as left-sided (distal).…”