Histopathological Identification of Colon Cancer with Microsatellite Instability

Abstract

and the Eastern Cooperative Oncology Group, ‡ Brookline, MassachusettesCancer with high levels of microsatellite instability (MSI-H) is the hallmark of hereditary nonpolyposis colorectal cancer syndrome, and MSI-H occurs in ϳ15% of sporadic colorectal carcinomas that have improved prognosis. We examined the utility of histopathology for the identification of MSI-H cancers by evaluating the features of 323 sporadic carcinomas using specified criteria and comparing the results to MSI-H status. Coded hematoxylin and eosin sections were evaluated for tumor features (signet ring cells; mucinous histology; cribriforming, poor differentiation, and medullary-type pattern; sponge-like mucinous growth; pushing invasive margin) and features of host immune response (Crohn's-like lymphoid reaction, intratumoral lymphocytic infiltrate, and intraepithelial T cells by immunohistochemistry for CD3 with morphometry). Interobserver variation among five pathologists was determined. Subjective interpretation of histopathology as an indication for MSI testing was recorded. We found that medullary carcinoma, intraepithelial lymphocytosis, and poor differentiation were the best discriminators between MSI-H and microsatellite-stable cancers (odds ratio: 37.8, 9.8, and 4.0, respectively; P ‫؍‬ 0.000003 to <0.000001) with high specificity (99 to 87%). The sensitivities, however, were very low (14 to 38%), and interobserver agreement was good only for evaluation of poor differentiation (kappa, 0.69). Mucinous histopathological type and presence of signet ring cells had low odds ratios of 3.3 and 2.7 (P ‫؍‬ 0.005 and P ‫؍‬ 0.02) with specificities of 95% but sensitivities of only 15 and 13%. Subjective interpretation of the overall histopathology as suggesting MSI-H performed better than any individual feature; the odds ratio was 7.5 (P < 0.000001) with sensitivity of 49%, specificity of 89%, and moderate interobserver agreement (kappa, 0.52). Forty intraepithelial CD3-positive lymphocytes/0.94 mm 2 , as established by receiver operating characteristic curve analysis, resulted in an odds ratio of 6.0 (P < 0.000001) with sensitivity of 75% and specificity of 67%. Our findings indicate that histopathological evaluation can be used to prioritize sporadic colon cancers for MSI studies, but morphological prediction of MSI-H has low sensitivity, requiring molecular analysis for therapeutic decisions.

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

“…12,32 However, immunohistochemistry cannot replace testing for microsatellite instability to identify microsatellite-unstable sporadic colorectal cancer, 33 and morphological prediction of microsatellite-unstable cancer has low sensitivity. 34 Thus, we emphasize that both hMLH1 immunohistochemistry and a histopathological evaluation can predict medullary-type carcinomas, but they may miss some cases. 32,33 Molecular analysis is required for therapeutic decisions.…”

“…32,33 Molecular analysis is required for therapeutic decisions. 34 Colorectal adenocarcinoma are graded predominantly on the basis of the extent of glandular appearances. 2,3 They are divided into well, moderately, and poorly differentiated, and in general the differentiation may reflect a biological behavior.…”

Genetic analysis of sinonasal adenocarcinoma phenotypes: distinct alterations of histogenetic significance

“…Analysis of K-ras, APC, and b-catenin gene mutation was carried out as previously described. 5 Immunohistochemistry for microsatellite analysis of markers hMLH1 and hMSH2 was carried out according to the method of Alexander et al 18 Immunohistochemistry for p53 protein was also performed according to previously published method. 19 Overexpression of p53 protein was considered to be present when more than 50% of the nuclei of tumor cells were strongly stained.…”

Survival in stage II/III colorectal cancer is independently predicted by chromosomal and microsatellite instability, but not by specific driver mutations

“…Th is phenotype can be assayed using either polymerase chain reaction polymerase chain reaction-based methods or immunohistochemistry for loss of MLH1 mismatch repair protein expression. Sporadic MSI + tumors occur more frequently proximal to the splenic fl exure and tend to show poor diff erentiation, mucinous histology and increased peritumoral lymphocytic infi ltration ( 4 ). Th ese tumors usually have near-diploid karyotypes and harbor a distinct set of driver mutations in genes such as BRAF and TGFBR2 ( 5,6 ).…”