Original contributionHistologic features distinguish microsatellite-high from microsatellite-low and microsatellite-stable colorectal carcinomas, but do not differentiate germline mutations from methylation of the MLH1 promoter☆
Introduction
Microsatellite instability (MSI) occurs when tissues acquire numerical nucleotide variability in repetitive DNA sequences because of abnormalities in the mismatch repair proteins. Microsatellite instability is detected in 50% to 80% of tumors from patients with hereditary nonpolyposis colorectal cancer syndrome (HNPCC) [1], [2], [3] and is present in 15% to 20% of unselected colorectal cancer cases [4], [5], [6], some of which may be due to Lynch syndrome.
Lynch syndrome is defined as carcinoma having MSI due to a germline mutation in one of the DNA mismatch repair genes, MLH1, MSH2, MSH6, or PMS2. In sporadic colorectal cancer, MSI is related to epigenetic silencing of the MLH1 gene by hypermethylation of the promoter region [7]. The inability to repair somatic gene mutations raises the possibility that mutations will accumulate within a cell. These accumulated mutations are the underlying basis for cancer development.
Because most HNPCC-associated colorectal tumors also represent Lynch syndrome and have an analyzable gene defect, testing for MSI is an important screening/diagnostic tool. Microsatellite instability testing identifies patients and families who need a detailed study of germline DNA to confirm germline mutation to make the diagnosis of Lynch syndrome. The detection of MSI in sporadic colorectal carcinomas (CRCs) has prognostic value in that microsatellite-unstable cancers have an improved overall survival and may have a different response to adjuvant therapy [8], [9]. In addition, recent studies have suggested an association between low level of MSI and poor cancer-specific survival [10], [11].
Certain histologic features of microsatellite-unstable tumors have been described, including 2 patterns of adenocarcinoma. One pattern is a mucinous adenocarcinoma that is seen predominantly in the ascending colon. The tumors are well circumscribed, well to moderately differentiated with a prominent lymphocytic infiltrate and tumor-infiltrating lymphocytes (TIL) that may be evident in nonmucinous areas. The second pattern is a poorly differentiated adenocarcinoma with epithelium disposed in small clusters and irregular trabeculae or large aggregates. Tumors are well circumscribed and lack abundant desmoplastic stroma. Some tumors are peppered with TIL. A Crohn's-like lymphocytic reaction may also be present. This subtype has been described as medullary or undifferentiated, although most contains subclones in which glandular differentiation is evident [5], [12], [13], [14], [15], [16], [17]. Among the histologic features, mucinous histology and intraepithelial lymphocytosis correlate the most with MSI [5], [18], [19].
The aim of this study was to confirm the histologic features that are associated with MSI status. Furthermore, we wanted to evaluate if histologic features may help discriminate the between MSI-H and MSI-L tumors and between those with germline mutations or methylation of the MLH1 promoter.
Section snippets
Accrual of patients
Ours was a cohort of patients with newly diagnosed colorectal cancer enrolled in the Columbus metropolitan area HNPCC study regardless of age or family history. Clinical information, limited to age and tumor location, was obtained from surgical pathology reports.
Microsatellite instability analysis
A portion of tumor from each case was submitted for MSI analysis. For the determination of MSI status of the tumor, the genotypes of 5 to 6 polymorphic markers (BAT25, BAT26, D2S123, D5S346, D18S69, and/or D17S250) were determined in
Results
Of the 482 cases, 87 cases were MSI, with 69 (13.8%) MSI-H, 18 (3.6%) MSI-L, and 395 (82.6%) MSS. Sequence analysis of the mismatch repair genes in 86 of the 87 MSI cases showed 12 cases with germline mutations (all MSI-H). Among these cases, most involved the MSH2 gene (8), followed by the MLH1 gene (2), and 1 case each involved PMS2 and MSH6 genes. Ten additional cases were found to have a missense mutation of undetermined clinical significance. Of the 87 MSI cases, 82 had MLH1 promoter
Discussion
The National Cancer Institute Workshop on Hereditary Nonpolyposis Colorectal Cancer Syndrome defined a set of criteria that when met warrant MSI tumor testing. These criteria are known as the Bethesda guidelines. There is evidence that the Bethesda criteria are more sensitive (and less specific) than either the Amsterdam I or II criteria in identifying potential patients with Lynch syndrome and families with pathogenic mutations [3]. Included in the Bethesda criteria are certain histopathologic
Acknowledgments
The authors thank the Ohio State University human cancer genetics sample bank, the genotyping sequencing unit, the molecular pathology laboratory, and the Pathology Core Facility at the Ohio State University for their support.
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Lynch syndrome-associated colorectal carcinoma: Frequent involvement of the left colon and rectum and late-onset presentation supports a universal screening approach
2013, Human PathologyCitation Excerpt :More recently, Shia et al [14] compared 24 LS-associated colorectal carcinomas to 35 sporadic MSI-H colorectal carcinomas and found no difference in morphologic features, although LS-associated tumors more frequently displayed mucinous histology, but this was not statistically significant. Finally, Yearsley et al [17] studied 12 LS-associated carcinomas and 34 sporadic MSI-H colorectal carcinomas and identified no morphologic differences between these groups. The previous literature reports cited in Table 3 were all retrospective and contain a very high proportion of LS-associated colorectal carcinomas, indicating that they are vastly enriched for patients selected for analysis based on cancer-related personal or family history.
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This study was supported by grants CA16058 and CA67941 from the National Institutes of Health.