Intraepithelial lymphocytes are indicators of better prognosis in surgically resected endometrioid-type endometrial carcinomas at early and advanced stages

Background: Tumor-infiltrating lymphocytes (TILs) and tumor-associated macrophages (TAMs) may be useful prognostic indicators in endometrial cancer. However, standardized assessment methods and the prognostic roles of these cells in different stage groups are unclear.

Methods: Formalin-fixed paraffin-embedded tissue samples of 107 endometrioid-type endometrial carcinomas (EECs) comprising 60 stage IB and 47 stage IIIC or IVB cases were evaluated. CD3⁺ TILs, CD8⁺ TILs, CD68⁺ TAMs, and CD163⁺ TAMs were detected by immunohistochemistry, and their densities were evaluated by semiquantitative and quantitative methods. TILs within tumor epithelial cell nests (E-TILs) and those within the stroma at the invasive front (S-TILs) were evaluated separately for CD3⁺ and CD8⁺ cells. The "TIL score" was defined as the sum of semiquantitative scores of CD3⁺ E-TILs, CD3⁺ S-TILs, CD8⁺ E-TILs, and CD8⁺ S-TILs. For TAMs, the area of CD68⁺ and CD163⁺ cells in the invasive margin were semiquantitatively and quantitatively evaluated. Clinicopathological and prognostic implications of TILs and TAMs in stage IB and IIIC/IVB EECs were examined by Cox univariate and multivariate analyses.

Results: By Cox univariate analyses, semiquantitatively low CD3⁺ E-TILs, low CD8⁺ E-TILs, and low "TIL score" were significantly correlated with worse prognosis in stage IB patients (P = 0.011, 0.040, and 0.039, respectively). Likewise, low CD3⁺ E-TILs and low CD8⁺ E-TILs, by both semiquantitative (P = 0.011 and 0.0051) and quantitative evaluations (P < 0.0001, and P = 0.0015) and low "TIL score" (P = 0.020) were significantly correlated with worse prognosis in stage IIIC/IVB patients. By Cox multivariate analyses, semiquantitatively low CD3⁺ E-TILs and low CD8⁺ E-TILs, low "TIL score", and quantitatively low CD3⁺ E-TILs and low CD8⁺ E-TILs were independent worse prognostic factors in stage IIIC/IVB (P = 0.0011, 0.0053, 0.012, < 0.0001, and < 0.0001, respectively). CD68⁺ or CD163⁺ TAMs were not correlated with prognosis in any patients.

Conclusions: Both semiquantitatively and quantitatively low E-TILs, are correlated with worse prognosis in both early and advanced stage patients with EECs. In particular, CD3⁺ E-TILs and CD8⁺ E-TILs are potentially useful prognostic markers in patients with EEC regardless of the stage.