Tumor immune microenvironment and epithelial-mesenchymal transition in recurrence of low-grade stage IA endometrial...

Low-grade, low-stage endometrial carcinomas are generally associated with an excellent prognosis. However, some of these tumors recur, although the prognostic factors are largely unknown. Recently, reports have described associations among tumor immune microenvironment (TIME), epithelial-mesenchymal transition (EMT), and circulating tumor cells (CTCs), factors that have also been reported to be associated with recurrence in endometrial carcinoma. Therefore, we conducted the present study to clarify the association between recurrence and TIME- and EMT-related factors in low-grade, low-stage endometrial carcinomas.

This study included 80 Japanese patients with low-grade, stage IA endometrial endometrioid carcinoma (20 in the recurrence group and 60 in the no-recurrence group). The institutional review board of Kyushu University approved this study (project number: 24101-00). The median follow-up was 94.5 months (range, 10-298). Immunohistochemistry was performed to evaluate regulatory T cells, marginal and intratumoral tumor-associated macrophages, and tumor cell expression of C-X-C motif chemokine ligand 12 (CXCL12) and Secreted Protein Acidic and Rich in Cysteine (SPARC).

In 13 of the 20 recurrent cases, recurrence occurred distant from the primary site, at lung or lymph nodes. Immunohistochemistry revealed that the numbers of FoxP3-positive cells, and marginal and intratumoral CD68-positive cells in the recurrence group were significantly higher than in the no-recurrence group. In addition, tumor cell expression of CXCL12, a chemokine involved in macrophage recruitment, was significantly higher in the recurrence group. Similarly, tumor cell expression of SPARC, an EMT-associated protein, was also significantly higher in the recurrence group. These findings suggest that a tumor microenvironment permissive of tumor cell dissemination may be associated with recurrence.

Recurrence in low-grade, stage IA endometrial carcinoma was associated with increased FoxP3-positive cells, increased marginal and intratumoral CD68-positive cells, and higher tumor cell expression of CXCL12 and SPARC. However, these findings suggesting a tumor microenvironment permissive of tumor cell dissemination should be interpreted as exploratory and hypothesis-generating, given that the involvement of CTCs was not directly evaluated in this study.