BRAF-Mutant Colon Cancers with and without High-Level Microsatellite Instability Are Distinguished by Histology and Methylation Phenotype
Bryan W Steussy, Andrew M Bellizzi. University of Iowa Hospitals and Clinics, Iowa City, IA
Background: The histologic features (fx) of high-level microsatellite unstable (MSI-H) colorectal cancers (CRCs) are well-characterized, and these tumors are associated with a relatively favorable prognosis. Most are sporadic and believed to arise from BRAF-mutant sessile serrated polyps (SSP). Somewhat surprisingly, BRAF mutation in CRC has repeatedly been shown to adversely affect prognosis. Recently, it was shown that this is explained by the especially poor prognosis of BRAF-mutant, non-MSI-H tumors; the histologic features of this group of tumors has not been characterized.
Design: Cases were selected from a population-based cohort of CRCs based on the presence of BRAF mutation and available H&E slide(s) of primary tumor. MSI-H was defined as instability at ≥40% of loci tested. CpG island methylator phenotypes (CIMP) were defined as follows: CIMP-0, 0/8 methylation-positive loci; CIMP-L 1-5/8; CIMP-H ≥6/8. Age, sex, and tumor location (right, left) were recorded and the following assessed: tumor type (adenocarcinoma [adca], mucinous [muc] adca, medullary [med] carcinoma [ca]); presence of any muc, med, or signet-ring fx; grade (high, low); tumor border (pushing, infiltrative); tumor budding (bud); tumor infiltrating lymphocytes (TIL) per high-power field (HPF); and Crohn-like reaction (CLR). Fisher's exact test was used to analyze categorical data and the Mann-Whitney test for age and TIL counts (significant at p<0.05).
Results: There are 50 MSI-H (47%) and 56 non-MSI-H CRCs, occurring at median ages of 66 and 67 (p=0.54), and with median TIL counts of 11 and 1.3 (p <0.0001). While all MSI-H tumors are CIMP-H, the non-MSI-H tumors are 16% CIMP-0, 41% CIMP-L, and 43% CIMP-H. Categorical data are shown in the Table.
|MSI-H (%)||non-MSI-H (%)||p|
|Any Muc Differentiation (Dif)||62||46||0.12|
|Any Med Dif||30||8.9||0.0066|