Tubular adenomas with minor villous changes show molecular features characteristic of tubulovillous adenomas

Abstract

Advanced colorectal polyps are identified based on size ≥10 mm, high-grade dysplasia, and/or villous histology. A diagnosis of tubular adenoma (TA) is recommended if villous change occupies <20% of the lesion, or tubulovillous adenoma (TVA) is recommended if there is 20% to 80% villosity. We hypothesized that even subtle villous changes (1% to 20%) would correlate with advanced molecular features. Two hundred sixty-nine colorectal adenomas were examined for KRAS and BRAF mutation and immunohistochemical staining of β-catenin, O6-Methyl Guanine DNA Methyltransferase (MGMT), and p53. Adenomas were classified as TA1 (0% villosity, n=70), TA2 (1% to 20% villosity, n=81), or TVA (21% to 80% villosity, n=118). Clinical and molecular features were analyzed by univariate χ² and multivariate logistic regression. There was an incremental increase in KRAS mutation frequency with increasing villous compartment (17.9% TA1, 59.0% TA2, 78.4% TVA; P<0.001). MGMT was more frequently lost in TA2 (37.0%) than in TA1 (8.6%) (P<0.001) but did not differ from TVA (39.8%). p53 overexpression was more common in TA2 (38.3%) than in TA1 (10.0%) (P<0.001) but did not differ from TVA (32.2%). On multivariate analysis, TA2 adenomas were more likely to have a KRAS mutation [odds ratio (OR) 6.6, 95% confidence interval (CI), 3.0-14.2], MGMT loss (OR 6.2, 95% CI, 2.4-16.0), or p53 overexpression (OR 5.6, 95% CI, 2.3-13.7) than TA1. We have identified a subgroup of TAs based on subtle villous changes. These adenomas are more likely to show molecular features that are characteristic of TVAs than TAs. These data support the concept that any villous change may indicate increased malignant potential and may be useful to consider when assigning surveillance guidelines.