Endometriosis-associated ovarian carcinomas: insights into pathogenesis, diagnostics, and therapeutic targets-a narrative review

Abstract

Endometriosis is a benign gynecologic condition affecting up to one woman out of ten of reproductive age. It is defined by the presence of endometrial-like tissue in localizations outside of the uterine cavity. It often causes symptoms such as chronic pain, most frequently associated with the menstrual cycle, and infertility, but may also be oligo- or asymptomatic. There is evidence that some ovarian carcinoma (OC) histotypes, mainly the ovarian clear cell (OCCC) and endometrioid (EnOC) carcinoma, may arise from endometriosis. The most frequent genomic alterations in these carcinomas are mutations in the AT-rich interacting domain containing protein 1A (ARID1A) gene, a subunit of the SWI/SNF chromatin remodeling complex, and alterations in the phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR pathway, which frequently co-occur. In ARID1A deficient cancers preclinical experimental data suggest different targetable mechanisms including epigenetic regulation, cell cycle, genomic instability, the PI3K/AKT/mTOR pathway, inflammatory pathways, immune modulation, or metabolic alterations as potential precision oncology approaches. Most of these strategies are relying on the concept of synthetic lethality in which tumors deficient in ARID1A are more sensitive to the different compounds. Some of these approaches are currently being or have recently been investigated in early clinical trials. The remarkably frequent occurrence of these mutations in endometriosis-associated ovarian cancer, the occurrence in a relatively young population, and the high proportion of platinum-resistant disease certainly warrants further investigation of precision oncology opportunities in this population. Furthermore, advanced knowledge about oncogenic mutations involved in endometriosis-associated ovarian carcinomas may be potentially useful for early cancer detection. However, this approach may be complicated by the frequent occurrence of somatic mutations in benign endometriotic tissue as recent studies suggest. In this narrative review of the current literature, we will discuss the data available on endometriosis-associated ovarian carcinoma, with special emphasis on epidemiology, diagnosis and molecular changes that could have therapeutic implications and clinical applicability in the future.

Keywords: ARID1A mutations; Ovarian cancer; PI3K/AKT/mTor pathway; SWI/SNF transcription complex; clear cell ovarian carcinoma; endometrioid ovarian carcinoma; endometriosis; synthetic lethality; treatment.

Figure 1

Endometrioma of the left ovary. Endometrioma typically contain brown viscous content resembling to melted chocolate, reason why they are sometimes also called “chocolate cysts”. The surgical treatment of choice consists in the laparoscopic excision or fenestration and laser therapy of the cyst with preservation of the ovary (Image credits: with special thanks to Dr. Markus Eberhard, Schaffhausen, Switzerland).

Figure 2

Early ovarian clear cell carcinoma (OCC). Clear cell carcinoma of the right ovary, most probably originating from endometriosis. The macroscopic picture in the very early stage may be difficult to distinguish from a benign endometrioma or another benign ovarian tumor. The preoperative assessment including transvaginal sonography and tumor marker CA-125 is important in the risk assessment (e.g. according to the IOTA criteria) and crucial for the correct surgical therapy of the patient. Arrows: various peritoneal endometriotic lesions and old blood deposits.

Figure 3

Hypothetic model of pathogenesis of endometriosis-associated ovarian carcinoma. Reactive oxygen species (ROS) due to free heme and catalytic iron contained in the trapped blood in endometriomas may lead to increased oxidative stress and DNA damage in the epithelial layer of endometriomas. This may result in mutations and epigenetic changes, including mutations in the tumor suppressor gene ARID1A and possible second-hit mutations as well as activation of the PI3K-AKT-mTOR pathway to escape apoptosis caused by increased oxidative stress. The accumulation of oncogenic mutations in atypical endometriosis may ultimately lead to the development of endometriosis-associated ovarian clear cell (OCC) and endometrioid (EnOC) carcinomas (adapted from Vercellini et al., Hum Reprod, 2011 and Samartzis et al., GYNÄKOLOGIE, 2018).

Figure 4

Therapeutic targeting strategies in ARID1A deficient tumors. Since ARID1A mutations lead to a deficiency in the encoded protein, the strategies to target ARID1A mutated tumors use the principle of synthetic lethality. The main approaches are stated in circles and the examples of inhibitor families are listed next to the main groups.