Histopathologic clues to mismatch repair deficiency in colon adenocarcinoma: the role of mucinous component and intratumoral/Crohn-like immune response.

BACKGROUND

Deficient mismatch repair (dMMR) identifies a biologically distinct subset of colon adenocarcinomas with important diagnostic, hereditary, prognostic, and therapeutic implications. This study investigated whether mucinous component and immune response pattern may serve as practical histopathologic clues to dMMR in routine pathology practice.

METHODS

This retrospective study included 222 consecutive colon adenocarcinoma resection cases with available mismatch repair (MMR) immunohistochemistry from 2022 to 2025. Clinicopathologic, histomorphologic, and immune response features were evaluated and compared according to MMR status. Multivariable logistic regression was performed to identify factors independently associated with dMMR.

RESULTS

Of 222 tumors, 29 (13.1%) were dMMR and 193 (86.9%) were proficient MMR. dMMR was significantly associated with age < 50 years (40.9% vs. 10.0%, p < 0.001), high grade (25.8% vs. 8.5%, p = 0.010), absence of lymph node metastasis (18.8% vs. 6.7%, p = 0.007), absence of perineural invasion (21.6% vs. 6.4%, p = 0.001), larger tumor size (p < 0.001), fewer metastatic lymph nodes (p = 0.038), and higher lymph node yield (p = 0.019). Intratumoral/Crohn-like immune response was strongly associated with dMMR (33.9% vs. 6.1%, p < 0.001). Tumors with a mucinous component showed a higher dMMR rate than those without (26.2% vs. 10.0%, p = 0.005). All associations that were significant in the unadjusted analyses remained significant after false discovery rate correction (q < 0.05). In the combined histopathologic clue analysis, the dMMR rate increased from 2.3% in tumors with no clue to 28.2% with one clue and 40.0% with both clues. In multivariable analysis, age < 50 years (OR 7.212, p = 0.002), intratumoral/Crohn-like immune response (OR 7.089, p < 0.001), and mucinous component (OR 6.067, p = 0.001) remained independently associated with dMMR.

CONCLUSIONS

Colon adenocarcinomas with a mucinous component and an intratumoral/Crohn-like immune response are enriched for dMMR, whereas tumors lacking both features show a low dMMR rate. These findings provide a detailed histopathologic characterization of a dMMR-enriched phenotype but should not be used to select cases for MMR testing or replace universal testing.