Comparative study of the endometrial microenvironment's immunohistochemical profile in pre-tumour and tumour conditions: endometrial hyperplasia, endometrioid carcinoma, and serous carcinoma.

BACKGROUND

Endometrial carcinogenesis involves complex interactions between hormonal signaling and the local immune microenvironment. While atypical endometrial hyperplasia is a recognized precursor to carcinoma, the spatial and phenotypic evolution of immune and hormonal markers during progression remains incompletely characterized.

METHODS

A retrospective cohort of 150 endometrial specimens, including hyperplasia without atypia (n=40), hyperplasia with atypia (n=40), endometrioid carcinoma (n=40), and serous carcinoma (n=30), was analyzed using immunohistochemistry for CD3, CD4, CD8, FOXP3, CD68, CD163, estrogen receptor (ER), and progesterone receptor (PR). Digital whole-slide imaging and QuPath were applied to quantify immune cell densities in intratumoral and peritumoral compartments. Correlations between immune markers and hormonal receptors were evaluated, and a subgroup of 27 paired hyperplasia-carcinoma cases was analyzed separately.

RESULTS

CD3+ and CD8+ T-cell densities increased progressively from hyperplasia to carcinoma (P<0.001), with hyperplastic lesions demonstrating predominant peritumoral localization consistent with immune exclusion. FOXP3+ regulatory T cells were enriched in neoplastic lesions, particularly in ER/PR-positive tumors. CD8+ intratumoral and peritumoral densities showed significant inverse correlations with ER and PR expression (both r=-0.76, P<0.001), whereas FOXP3+ infiltration correlated positively with ER and PR (r=0.64, P<0.001). M2 CD163+ macrophages demonstrated an inverse association with ER (r=-0.49, P<0.01), while M1 CD68+/iNOS macrophages showed no statistically significant correlations. In the paired subgroup, higher peritumoral than intratumoral CD8+ densities persisted, indicating residual immune exclusion despite malignant transformation.

CONCLUSIONS

Endometrial neoplastic progression is characterized by a transition from peritumoral immune exclusion in hyperplasia to increased intratumoral immune infiltration in carcinoma, although this shift is not universal. Hormone receptor-positive tumors exhibit enrichment of FOXP3+ regulatory T cells and CD163+ macrophages, suggesting hormone-linked immune suppression. These findings highlight combined immune-hormonal biomarkers as potential indicators of progression risk and support further investigation of integrated immunomodulatory and hormone-targeted therapeutic strategies.