Age-stratified impact of microsatellite instability on lymph node positivity and survival in stage I-III colon cancer

Microsatellite instability-high/deficient mismatch repair (MSI-H/dMMR) colon cancers are associated with reduced lymph node (LN) metastasis and improved outcomes in early-stage disease; however, whether these associations vary by patient age remains unclear.

Using the National Cancer Database (2018-2021), we identified 116,623 patients with stage I-III colon adenocarcinoma undergoing upfront surgery and stratified them by age (<65 vs. ≥65 years) and MSI status (MSI-H/dMMR vs. microsatellite stable). Multivariable linear regression assessed LN positivity and lymph node ratio, and Cox proportional hazards models evaluated overall survival, including an interaction term between age and MSI status.

MSI-H tumors were more common in older patients (24.9% vs. 13.6%). MSI-H status was independently associated with 0.53 fewer positive lymph nodes (95% CI -0.73 to -0.34), and older age was associated with 0.37 fewer positive lymph nodes (95% CI -0.47 to -0.28). A significant interaction between age and MSI status demonstrated attenuation of the MSI-associated nodal protection in older adults. In node-negative disease, MSI-H was associated with improved overall survival in younger but not older patients, whereas in stage III disease MSI-H was associated with worse survival in older patients. The age-MSI interaction remained significant in adjusted survival models.

These findings suggest that the prognostic and biologic implications of MSI-H in stage I-III colon cancer are meaningfully modified by age and should be interpreted within an age-specific context.