Endometriosis-Associated Ovarian Cancer: The Origin and Targeted Therapy

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.

Keywords: chocolate cyst; clear cell carcinoma; endometrial cyst; endometrioid carcinoma; endometriosis; endometriosis-associated ovarian cancer; malignant transformation.

Figure 1

The actual cumulative curve for carcinogenesis from endometrial cysts. Graph showing that in 5945 women enrolled as endometriosis, 24 (0.4%) ovarian cancers developed within 30 days of enrollment. This figure was made by modifying a figure from BMC Cancer 2014 [27].

Figure 2

Mechanism of endometriosis-associated ovarian cancer carcinogenesis. Carcinogenesis requires an initiator and a promoter. Gene mutations occur frequently in endometrial glandular epithelial cells, but its mutations are often insufficient as initiators. Nonetheless, endometrial glandular epithelial cells with sufficient gene mutations cause carcinogenesis through the effect of the promoter. If they survive in the contralateral ovary or outside the ovary, they may not cause carcinogenesis, and such cells become endometriosis. This figure was made by modifying a figure from Clinical Gynecology and Obstetrics 2020 [69].