Sex-related differences in pathological characteristics of colorectal cancer: a retrospective study

Colorectal cancer (CRC) exhibits substantial sex-related differences in incidence, prognosis, and clinicopathological features. However, existing evidence on these disparities remains limited and inconclusive. This study aimed to investigate sex-specific patterns in tumor differentiation, metastasis, and mismatch repair (MMR) status, and to determine whether these associations persist after adjustment for clinicopathological covariates.

A retrospective cohort study was conducted in 2,912 patients who underwent surgery for CRC at West China Hospital between November 2008 and June 2023. Sex differences were assessed across subgroups stratified by tumor differentiation grade, metastatic status, and age at onset. Three multivariable Firth penalized logistic regression models were constructed to assess whether sex remained an independent predictor of metastasis, deficient MMR (dMMR), and poor differentiation (G3) after adjustment for age, body mass index (BMI), stage, tumor location, and relevant molecular markers.

Significant sex-related differences were observed in tumor differentiation, metastasis, and MMR status. Female patients had higher rates of poorly differentiated (G3) tumors, dMMR, and metastasis. However, these differences were markedly heterogeneous and were most evident in moderately differentiated (G2) tumors, late-onset CRC, and non-metastatic disease, whereas no significant sex differences were identified in early-onset disease. In multivariable analysis, female sex remained an independent predictor of metastasis (adjusted OR 1.36, 95% CI 1.04-1.79, P = 0.024), but not of dMMR (adjusted OR 1.28, P = 0.108) or G3 differentiation (adjusted OR 1.15, P = 0.146), suggesting that the latter associations were largely explained by tumor location.

Sex-related differences in CRC are context-dependent and vary according to tumor differentiation, metastatic status, and age at diagnosis. The higher metastatic risk observed in female patients appears to be an independent association, whereas differences in dMMR and tumor grade mainly reflect the greater prevalence of right-sided tumors in women. These findings support the incorporation of sex as a biological variable in metastatic risk stratification, while highlighting the importance of accounting for anatomical confounding when interpreting molecular and histological sex differences.