Unique characteristics of Lynch syndrome-associated mismatch repair-deficient colorectal intramucosal carcinoma.

OBJECTIVES

Intramucosal carcinoma (IMC) of the colorectum is a rare and diagnostically challenging neoplasm frequently recognized in patients with Lynch syndrome (LS) recently. This study aimed to compare the clinicopathologic features and immunophenotypes of LS-associated mismatch repair-deficient (MMR-D) colorectal IMCs with mismatch repair-proficient (MMR-P) IMCs and sporadic MMR-D IMCs, as well as to examine APC pathway alterations in LS-associated MMR-D IMCs.

METHODS

Pathology archives from 2004 to 2024 were reviewed for colorectal IMC cases. Clinical, endoscopic, morphologic, immunohistochemical, and next-generation sequencing data were analyzed.

RESULTS

A total of 31 IMC cases were identified, including 9 LS-associated MMR-D, 5 sporadic MMR-D, and 17 MMR-P. Patients with LS who had MMR-D IMCs were significantly younger (P = .013), had more prior malignancies (P = .003), and had shorter colonoscopy intervals (P = .011) compared with patients with MMR-P and sporadic MMR-D. The LS-associated MMR-D IMCs were larger, more often infiltrated normal mucosa, and exhibited medullary and mucinous features more frequently than other IMCs. While expressing CDX2 and SATB2, LS-related MMR-D tumors showed less CK20 positivity than sporadic MMR-D and MMR-P IMCs (P = .003). Among LS-associated MMR-D IMCs, 37.5% exhibited nuclear β-catenin immunoreactivity, regardless of the specific MMR gene affected.

CONCLUSIONS

These findings suggest that LS-associated MMR-D IMCs have distinct clinicopathologic and immunophenotypic profiles compared with MMR-P and sporadic MMR-D IMCs, emphasizing the need for unique diagnostic and management strategies for these patients.