Clinicopathological correlations of endometrioid and clear cell carcinomas in the uterus and ovary

Abstract

Endometrioid carcinoma (EC) and clear cell carcinoma (CC) are associated with endometrial tissue hyperplasia and endometriosis, and they occur in the endometrium and ovaries. However, detailed differences between these tumors based on immunostaining are unclear; therefore, in this study, we aimed to analyze the clinicopathological correlations between these tumors using immunostaining and to develop new treatments based on histological subtypes. Immunohistochemistry was used to investigate differentially expressed hypoxia-associated molecules (hypoxia-inducible factor-1 subunit alpha [HIF-1α], forkhead box O1, prostate-specific membrane antigen, signal transducer and activator of transcription 3 [STAT3], hepatocyte nuclear factor 1β [HNF-1β], aquaporin-3, and vimentin [VIM]) between these carcinomas because of the reported association between CC and ischemia. Immunostaining and clinicopathological data from 70 patients (21 uterine endometrioid carcinomas [UECs], 9 uterine cell carcinomas, 20 ovarian endometrioid carcinomas [OECs], and 20 ovarian cell carcinomas [OCCs]) were compared. HIF-1α and prostate-specific membrane antigen expression levels were higher in UEC and OCC than in uterine cell carcinomas and OEC. STAT3 was slightly overexpressed in UEC. Additionally, forkhead box O1 expression was either absent or significantly attenuated in all ECs. VIM and AQ3 were highly expressed in UEC, whereas HNF-1β expression was higher in OCC. UEC, OEC, and OCC were more common in the uterine fundus, left ovary, and right ovary, respectively. Ovarian endometriosis was strongly associated with EC. Our findings suggest that UEC and OCC share a carcinogenic pathway that involves HIF-1α induction under hypoxic conditions via STAT3 expression, resulting in angiogenesis. Furthermore, the anatomical position of carcinomas may contribute to their carcinogenesis. Finally, aquaporin-3 and VIM demonstrate strong potential as biomarkers for UEC, whereas HNF-1β expression is a crucial factor in CC development. These differences in tumor site and histological subtypes shown in this study will lead to the establishment of treatment based on histological and immunohistological classification.

Figure 1.

Endometrioid carcinoma of the uterus (A) and ovary (B) and clear cell carcinoma of the uterus (C) and ovary (D) share similar morphological features.

Figure 2.

HIF-1α (×40) (A), STAT3 (×40) (B), and HNF-1β (×40) (C) expression in tumor nuclei. The neovascular cytoplasm of the tumor appears positive for PSMA (D) (×40). The tumor cytoplasm also appears positive for VIM (E) and AQP3 (F). FOXO1 (G) (×40) expression appears either absent or reduced in all cancers. AQP3 = aquaporin-3; FOXO1 = forkhead box O1; HIF-1α = hypoxia-inducible factor-1 subunit alpha; HNF-1β = hepatocyte nuclear factor-1 beta; PSMA = prostate-specific membrane antigen; STAT3 = signal transducer and activator of transcription 3; VIM = vimentin.

Figure 3.

Schema of the histological tumor differences and tumor locations. The prevalence of endometriosis in the left ovary is explained by the presence of the sigmoid colon, which delays the spread of retrograde menstrual blood, resulting in weak and slowed fluid flow in the left hemipelvis. Endometriosis of the right ovary is more severe than that of the left ovary, and obliteration of the pouch of Douglas occurs more frequently in the right ovary. This may increase the severity of hypoxia, leading to higher ovarian clear cell carcinoma occurrence in the right ovary. Uterine endometrioid carcinomas (particularly early lesions) were found more frequently in the uterine fundus than uterine clear cell carcinomas, which is likely because the fundus is more hypoxic than other parts of the uterus.