Histopathological identification of colon cancer with microsatellite instability

Cancer with high levels of microsatellite instability (MSI-H) is the hallma rk of hereditary nonpolyposis colorectal cancer syndrome, and MSI-H occurs in similar to 15% of sporadic colorectal carcinomas that have improved prog nosis. We examined the utility of histopathology for the identification of MSI-H cancers by evaluating the features of 323 sporadic carcinomas using s pecified criteria and comparing the results to MSI-H status. Coded hematoxy lin and eosin sections were evaluated for tumor features (signet ring cells ; mucinous histology; cribriforming, poor differentiation, and medullary-ty pe pattern; sponge-like mucinous growth; pushing invasive margin) and featu res of host immune response (Crohn's-like lymphoid reaction, intratumoral l ymphocytic infiltrate, and intraepithelial T cells by immunohistochemistry for CD3 with morphometry), Interobserver variation among five pathologists was determined. Subjective interpretation of histopathology as an indicatio n for MSI testing was recorded. We found that medullary carcinoma, intraepi thelial lymphocytosis, and poor differentiation were the best discriminator s between MSI-H and microsatellite-stable cancers (odds ratio: 37,8, 9,8, a nd 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 interob server agreement was good oily for evaluation of poor differentiation (kapp a, 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 specifici ties of 95% but sensitivities of only 15 and 13%, Subjective interpretation of the overall histopathology as suggesting MSI-H performed better than an y individual feature; the odds ratio was 7.5 (P < 0.000001) with sensitivit y of 49%, specificity of 89%, and moderate interobserver agreement (kappa, 0.52), Forty intraepithelial CD3-positive lymphocytes/0.94 mm(2), as establ ished by receiver operating characteristic curve analysis, resulted in an o dds 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 predi ction of MSI-H has low sensitivity, requiring molecular analysis for therap eutic decisions.