Low density of intratumoral M1-macrophage infiltration may correlate with worse prognosis in low-grade early-stage uterine endometrioid carcinoma

Michiko Nagamine; Hiroshi Ogi; Maki Hirai; Ikoi Omatsu; Sanzo Moriwaki; Saya Shibata; Satoru Yasukawa; Kaori Yoriki; Motohiro Kojima; Taisuke Mori; Kyoko Itoh; Eiichi Konishi

doi:10.1016/j.gore.2025.101758

Low density of intratumoral M1-macrophage infiltration may correlate with worse prognosis in low-grade early-stage uterine endometrioid carcinoma

Gynecol Oncol Rep. 2025 May 10:59:101758. doi: 10.1016/j.gore.2025.101758. eCollection 2025 Jun.

Authors

Michiko Nagamine^{1

2}, Hiroshi Ogi^{3

4}, Maki Hirai³, Ikoi Omatsu¹, Sanzo Moriwaki^{3

4}, Saya Shibata³, Satoru Yasukawa⁵, Kaori Yoriki⁶, Motohiro Kojima¹, Taisuke Mori⁶, Kyoko Itoh⁴, Eiichi Konishi^{1

7}

Affiliations

¹ Department of Surgical Pathology, Kyoto Prefectural University of Medicine, Kyoto, Japan.
² Department of Pathology and Clinical Laboratories, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa, Chiba 277-8577, Japan.
³ Innovation Development, SCREEN Holdings Co., Ltd., Kyoto, Japan.
⁴ Department of Pathology and Applied Neurobiology, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan.
⁵ Department of Pathology, Japanese Red Cross Kyoto Daini Hospital, Kyoto, Japan.
⁶ Department of Obstetrics and Gynecology, Kyoto Prefectural University of Medicine, Kyoto, Japan.
⁷ Department of Pathology, Kyoto Saiseikai Hospital, Kyoto, Japan.

Abstract

Objective: Low-grade type 1 endometrial carcinoma generally has a favorable prognosis if diagnosed in the early stage. However, a small proportion of the patients experience recurrence, which becomes a significant clinical challenge. Our objective was to explore the differences in tumor immune microenvironment (TIME) between recurrent and cured low-grade early-stage endometrioid carcinoma cases.

Methods: We retrospectively examined the TIME in recurrent (n = 11) and non-recurrent (cured, n = 10) cases of low-grade, early-stage endometrioid carcinoma. Cases treated with preoperative or postoperative chemotherapy or radiotherapy were excluded. Multiplex immunohistochemistry was performed on tissue microarrays constructed from formalin-fixed paraffin-embedded tissue blocks of primary surgical specimens and, when available, recurrent lesions. TIME was evaluated by the densities (cell count/mm²) of CD68-positive macrophages, M1 (CD80- or CD86-positive) and M2 (CD206-positive) macrophages, CD15-positive neutrophils, and CD3-positive lymphocytes. Intraluminal areas were evaluated separately. In addition, clusters of foam cells in the stroma were visually examined.

Results: Compared with the cured group, the primary tumor of recurrent group demonstrated significantly lower densities of CD68-positive macrophages and M1 macrophage. Moreover, analysis of matched primary versus recurrent lesions in a subset of recurrent cases revealed similar immune cell infiltration profiles, suggesting temporal stability of TIME of recurrent cases. Notably, although foam cell clusters were present in both groups with similar frequencies, M1 macrophages were detected exclusively in the cured group, whereas a small number of M2 macrophages were occasionally present in the recurrent group.

Conclusions: These findings underscore the potential prognostic value of an activated, pro-inflammatory immune response in early-stage endometrial carcinoma and warrant further investigation into the mechanisms underlying tumor recurrence.

Keywords: Foam cells; Macrophages; Multiplex immunohistochemistry; Tumor immune microenvironment; Uterine endometrioid carcinoma.