Abstract
Endometrial cysts (ECs) are thought to be the origin of endometriosis-associated ovarian cancer (EAOC). A hypothesis that the oxidative stress of iron in cysts causes “malignant transformation of ECs” has been proposed, but this has not been verified. Several population-based studies showed that endometriosis was a risk factor but did not reflect the “malignant transformation of ECs”. A review showed that most patients were diagnosed with EAOC early in monitoring following detection of ECs, and that these cases might have been cancer from the start. Epidemiologically, EAOC was reduced by hysterectomy rather than by cystectomy of ECs. Gene mutation analyses identified oncogenic mutations in endometriosis and normal endometrium and revealed that the same mutations were present at different endometriotic lesions. It was also shown that most of the gene mutations found in endometriosis occurred in normal endometrium. Taking together, EAOC might be caused by eutopic endometrial glandular epithelial cells with oncogenic mutations that have undergone menstrual blood reflux and engrafted in the ovary, rather than by low-risk ECs acquiring oncogenic mutations and becoming malignant. This review discusses the mechanisms of EAOC development and targeted therapy based on genetic variation in EAOC with a focus on eutopic endometrium.
Highlights
Endometriosis is a disease in which the endometrium or similar tissue develops outside the original uterine cavity [1]
As described above, there was no increase in the incidence of ovarian cancer after menopause related to a history of endometriosis. These results suggest that the reflux of eutopic endometrial glandular epithelial cells through the fallopian tube might be involved in the development of Endometriosis-associated ovarian cancer (EAOC), and not through the endometriotic lesions gradually turning into cancer
Basic and epidemiological data suggesting that genetic mutations in the eutopic endometrium may be responsible for EAOC have been accumulating
Summary
Endometriosis is a disease in which the endometrium or similar tissue develops outside the original uterine cavity [1]. Endometriosis-associated ovarian cancer (EAOC) is thought to develop from ovarian endometrial cysts (ECs) [4]. EAOC is mainly endometrioid or clear cell carcinoma. Ovarian endometrioid carcinoma (OEC) is the most common type of EAOC, occurring in approximately 75% of cases [5]. In Japan, ovarian clear cell carcinoma (OCCC), which is refractory to chemotherapy and has a poor prognosis, is more prevalent, accounting for approximately a quarter of all epithelial ovarian cancers [6]. Regarding the management of endometriosis, the European Society of Human Reproduction and Embryology (ESHRE) guidelines recommend that even if endometriosis increases the risk of developing ovarian cancer, there is no way to reduce it, and its management should not be changed with concern for the ovarian cancer [7]. We discuss the mechanisms of EAOC development and targeted therapy according to genetic variations in EAOC based on the evidence to date, with a focus on eutopic endometrium
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