Compartment-Specific Immunohistochemical Alterations Along the Colorectal Adenoma-Carcinoma Continuum

Colorectal cancer (CRC) progresses through the adenoma-carcinoma sequence, yet the contribution of tumor microenvironment (TME) alterations remains unclear. This study investigated whether the distribution of CD204-positive macrophages, COL11A1-positive stromal cells, and MFAP5 expression patterns differed across colorectal lesion categories and evaluated the diagnostic relevance of integrated TME biomarkers. Expression patterns of CD204, COL11A1, MFAP5, and p53 were analyzed across stages of CRC polyp progression.

A total of 154 CRC lesions-low-grade dysplasia (LGD), high-grade dysplasia (HGD), adenomas with intramucosal carcinoma (IMC), and malignant polyps (MP)-were retrospectively examined. Immunohistochemistry assessed CD204-positive tumor-associated macrophages within lesions (iCD204) and in the perilesional TME (pCD204), COL11A1 (cancer-associated fibroblasts), MFAP5 (ECM integrity), and p53 (epithelial genomic instability). Statistical, trend, correlation, and ROC analyses were performed.

Significant differences in TME-related marker distributions were observed across the LGD-HGD-IMC-MP spectrum. While iCD204 showed minimal variation, pCD204 density increased progressively with dysplasia grade (p < 0.001) and demonstrated superior discriminatory performance in ROC analyses, particularly for LGD vs. HGD and IMC vs. MP (p < 0.05). MFAP5 expression inversely correlated with dysplasia (p < 0.001), was preserved in pseudoinvasion, and markedly reduced in true invasion. COL11A1 showed variable expression without a consistent stage-related trend; however, moderate positive correlations between COL11A1 and both intralesional and perilesional CD204-positive macrophages were observed only in the HGD subgroup. p53 positivity increased significantly with lesion grade (p < 0.001) and positively correlated with pCD204.

TME-specific immunohistochemical marker distributions differed across colorectal lesion categories. Perilesional CD204-positive macrophage counts demonstrated discriminatory ability in several lesion-group comparisons, whereas MFAP5 expression showed distinct staining patterns between pseudoinvasive and invasive lesions. COL11A1 expression did not demonstrate a consistent category-associated trend but showed moderate correlations with CD204-positive macrophage counts in the HGD subgroup. These findings should be considered exploratory and require validation in larger independent cohorts.