Immunohistochemical Assessment of MLH1, MSH2, MSH6, and PMS2 Expression and Mismatch Repair Deficiency in Surgically Resected Colorectal Carcinomas

Abstract Deficiency of DNA mismatch repair (dMMR) in colorectal cancer (CRC) predicts prognosis and guides' therapy. Data on dMMR prevalence and predictors in Brazil remain limited. To estimate the prevalence of dMMR in CRC resections and identify independent clinical-pathological predictors. We retrospectively analyzed 330 adults who underwent resection for primary colorectal adenocarcinoma between January 2008 and December 2024 at a public hospital and a private clinic in Campinas, in the state of São Paulo, Brazil. The exclusion criteria were non-adenocarcinoma histology, complete pathologic response to neoadjuvant therapy, inflammatory bowel disease-associated CRC, polyposis syndromes, and inadequate tissue. Immunohistochemistry (IHC) for MLH1, MSH2, MSH6, and PMS2 was centralized; complete loss of any protein indicated dMMR. We recorded age, sex, tumor site, histological grade, and nodal status. Univariate analyses used the Fisher's exact and Mann-Whitney tests, and a multivariable logistic regression was conducted to identify independent dMMR predictors (p < 0.05). The dMMR prevalence was 12.7% (42/330). In the multivariable analysis, proximal location (odds ratio [OR]: 2.51; 95%CI: 1.26–4.99; p = 0.009) and high grade (OR: 3.79; 95%CI: 1.40–6.24; p = 0.008) were independently associated with dMMR, but age was not (p = 0.441). Node-positive tumors had higher dMMR rates than node-negative cases (17.1 % versus 11.0 %; p = 0.045). The predominant IHC profile was MLH1 + PMS2 co-loss (47.6 % of dMMR cases). Approximately one in eight CRCs in this Brazilian cohort is positive for dMMR. Tumor phenotype (proximal site, poor differentiation), rather than age, predicts dMMR.