Clinicopathological Characteristics and Outcomes of Colorectal Cancer With Heterogenous Staining of Mismatch Repair Protein

BACKGROUND:Scant data are available on heterogenous staining of mismatch repair protein in colorectal cancer. OBJECTIVE:This study aimed to improve insights into clinicopathologic features and prognosis of colorectal cancer harboring heterogenous mismatch repair protein staining. DESIGN:A single-center retrospective observational study. SETTING:This study was conducted in a tertiary referral center in China between 2014 and 2018. PATIENTS:Patients with colorectal cancers with heterogenous staining of mismatch repair protein were included. MAIN OUTCOME MEASURES:Clinicopathologic and molecular features and survival outcomes were analyzed. RESULTS:A total of 151 of 6721 colorectal cancers (2.2%) exhibited heterogenous staining for at least 1 mismatch repair protein, with intraglandular heterogeneity being the most common pattern (89.4%). Heterogenous mutL homolog 1 staining was significantly associated with distant metastasis (p = 0.03), whereas heterogenous mutS homolog 2 staining was associated with left-sided (p = 0.03) and earlier pT stage tumors (p = 0.02). The rates of microsatellite instability-high, K-ras and BRAF mutation were 12.6%, 47.3%, and 3.4%, respectively. Microsatellite instability-high was significantly associated with higher intraglandular mutS homolog 6 heterogeneity frequency (p < 0.001) and decreased mutS homolog 6 expression level (<27.5%, p = 0.01). BRAF mutation was associated with the coexistence of intraglandular and clonal heterogeneity (p = 0.003) and decreased PMS1 homolog 2 expression level (p = 0.01). Multivariable analysis revealed that progression-free survival was significantly associated with tumor stage (p = 0.003), stroma fraction (p = 0.004), and heterogenous PMS1 homolog 2 staining (p = 0.02). Overall survival was linked to tumor stage (p = 0.006) and BRAF mutation (p = 0.01). LIMITATIONS:The limitations of this study include the absence of testing for mutL homolog 1 promoter methylation and mismatch repair gene mutations, its retrospective design, and insufficient data related to direct comparison with deficient mismatch repair and proficient mismatch repair colorectal cancer. CONCLUSIONS:Heterogenous mismatch repair protein staining in colorectal cancer exhibits distinct associations with tumor location, stage, microsatellite instability, BRAF mutation, and prognosis. It is recommended to report mutS homolog 6 heterogeneity as it may indicate microsatellite instability-high.