Endometriosis and endometriosis associated ovarian cancer

Endometriosis is defined by the presence of endometrial tissues outside of the endometrial cavity. I t is a benign condition and even though it’s patho genesis is not yet fully understood different theories, such as the Coelomic theory and the theory of Mullerian rest, have been proposed as possible explanations for the development of this pathology. E vidence suggests that women diagnosed with endometrios is presents an increased risk for developing ovarian cancers. Therefore, this review will explore the pathogensis of endometriosis, explore its association with the development of ovarian cancers and identify treatment

for managing lesions following malignant transformation.

Endometriosis, ovarian cancer, endometriosis associated ovarian cancer, ovarian clear cell carcinoma, endometrioid carcinoma 1. Introduction Endometriosis is defined by the presence of endometrial glands and stroma o utside the endometrial cavity. It is associated with pelvic pain, dysmenorrhea and female infertility [1]. Despite the fact that endometriosis is considered a benign condition, due to its normal histology, studies have shown that this disease is associated with increased risk for specific histotypes of ovarian carcinoma (endometrioid and clear cell ovarian cancer) [2, 3]. A combination of different factors may cumulatively lead to the malignant transformations in women diagnosed with endometriosis. Interpla y of inflammatory mediators, hormonal interactions and endometriosis induced changes within the pelvis may all ultimat ely lead to the development of malignancies. The presence of increase oestrogen may also influence malignant transformations [4, 5]. This literature review will therefore discuss the following 1) the pathogenesis of endometriosis, 2) the association between endometriosis and development of ovarian cancer and 3) potential treatment

for managing ovarian lesions following malignant traansformations. 2. Pathogenesis of Endometriosis Affecting 3–15% of premenopausal women, 3–5% of postmenopausal women [6], 25%-80% of infertile women and 40% -80% of women with pelvic pa in [7], endometriosis is an oestrogen - dependent condition defined by the presence and growth of endometrial-type mucosa outside the uterine cavity. Ectopic endometrial tissue may be present around pelvic organs such as the ovaries, in addition to other organs including the colon and bladder. Endometrio sis is mainly associated with inflammation, severe chronic pain, and infertility [8]. The diagnosis of endometriosis requires the presence of at least two of the following feat ures: 1) endometrial epithelial cells, 2) epithelium, 3) endometrial stromal cells 4) and signs of bleedi ng from endometrium-like tissue [9, 10]. Endometriosis accounts for three anatomical subtypes [11, 12]: 1) superficial peritoneal disease subtype defined by superficial implants, haemorrhagic lesions or white scarring, 2) ovarian disease subtype defined by superficial lesions on the surface of the ovary, or the presence of endo metriosis cysts inside the ovary commonly called endometriomas and 3) deep infiltrating disease subtype defined by lesions greater than 5 mm and the presence of formed connective tiss ue around the endometriosis stroma. Women diagnosed wit h endometriosis commonly report having pain and fertility issues. It is theorized that these two main symptoms are related to the pathogenesis of the disease which involves the influence of hormonal an d immunological factor s that leads to inflammation [13]. As a result of these discoveries, several concepts are now being explored to explain the pathogenesis of endometriosis. International Journal of Clinical Obstetrics and Gynaecology http://www.gynaecologyjournal.com ~ 34 ~ The implantation theory describes retrograde menstruation as a possible initia ting factor for the developme nt of endometriosis [14]. Retrograde menstruation involves the backward flow of menstrual contents, including endometri al tissue, through patent fallopian tubes into the peritoneal cavity [15]. It is believed that this retrograde flow occurs initially at birth; however, deposited endometrial tissues are not activated until puberty when the ovaries begin to produce sex hormones [16]. Ab normalities that may promote this occurrence include: congenital malformations of the female reproductive tract, the production of thick cervical mucus and the presence of a tight internal uterine cervix os 17. Evidence supports this theory as a higher prevalence of endometriosis has been observed in adolescent females presenting with congenital outf low tract obstruction [18] and the presence of outflow tract obstruction has been demonstrated to be associated with intra -peritoneal endometriotic lesions [19]. Following retrograde flow of menstrual contents into the peritoneal cavity, other processes mu st follow in order for endometriosis to finally occur. This may involve the failure of the immune system to detect and eliminate ecto pic tissues, the attachment of ectopic tissues to the peritoneum or the development of local nerve and blood supply which s upports survival [17]. Another theory that has been developed to explain the pathogenesis of endometriosis is the Coelomic theory which involves the change or transformation of peritoneal tissue to ectopic endometrial tissue [20]. There are different fact ors that may influence these changes and endocrine disrupting chemicals (EDCs) have been proposed to play a potential role. It is also believed that endo genous agents such as hormonal or immunological factors may serve as inductive stimuli that ultimately support the changes or differentiation of normal peritoneal cells into endometrial cells 21,22. Furthermore, according to the theory of Mullerian rests, residual cells originating from th e embryonic Mullerian duct, migrate and maintain their ability to develop into endometriotic lesions in the presence of hormones such as oestrogen23. It has been postulated that extra -uterine ste m/progenitor cells such as cells from the bone marrow, may also play a role in the pathogenesis of endometriosis through the differentiation into endometrial tissue [24]. Endometriosis is now being observed as a pelvic inflammatory condition. In women diagnosed with this disease, examination of the peritoneal fluid demonstrates an alarming increase in the presence of activated macrop hages and alter ations in cytokine/chemokine profiles [25]. Cytokines or chemokines that are found to be increased in the peritoneal fluid of women suffering from endometriosis include: 1) macrophage migration inhibitory factor, 2) tumour necrosis factor (T NF) -α 3) interleukin (IL) -1β, 4) IL -6, 5) IL -8 and 6) m onocyte chemoattractant protein -1 (MCP -1). The reasons for this observation are yet to be determined 26. The peritoneum of women diagnosed with endometriosis usually has hi gh levels of prostaglandins which may account for the pathophysiology of the disease and its common presentation (pain and infertility). It is observed that the macrophages found in the peritoneum of endometriosis patients, possess higher levels of cyclo - oxygenase-2 (COX -2) and prod uce higher concentrations of prostaglandins as compared to macrophages found in healthy subjects. TNF -α stimulates endometrial cells to produce prostaglandin F2α (PG F2α) and prostaglandin E2 (PGE2). COX-2, which is activated by IL-1β, induces the production of PGE2 and this in turn stimulates steroidogenic acute regulatory (StAR) protein and aromatase. Oestrogen establishes a positive feedback loop through its up-regulation of PGE2 synthesis thus increasing the bioavailability of estradiol. This phenomenon explains the interconnection between oestrogen dependence and inflammation observed in endometriosis [20]. Furthermore, the protein hormone adiponectin has been explored for its pot ential role in the development of endometriosis. It regulates a variety o f metabolic processes in the body such as the catabolism of glucose and fatty acids. Adipose tissues secrete adiponectin and it has been noted that the serum and peritoneal fluid of w omen suffering from endometriosis exhibit decreased levels of this protei n hormone. Cultured endometrial stromal cells demonstrated a decrease in the secretion of IL -6, IL-8, and MCP -1 in the presence of adiponectin. This result shows the anti -inflammatory effects of this protein hormone on endometrial stromal cells, a protecti ve effect which is not present in patients suffering from endometriosis [27]. 3. Association between Endometriosis and the development of Ovarian Cancers A meta -analysis done by Kim et al . to assess the impact of endometriosis on the risk and prognosis o f ovarian cancer, concluded that there is a significant association between this pathology and the risk for developing ovarian cancers [28]. To date, the precise mechanism for malignant transformations of endometriosis is not fully known; however, differen t factors have been investigated for the role that they may play in this process [29]. Oxidative stress, possibly associated with genetic abnormalities, is an important mechanism commonly observed when investigating the association between endometriosis a nd the development of ovarian cancers [30]. The development o f epithelial ovarian cancer (EOC) is commonly associated with defects in β -catenin and P16, phosphatase and tensin homolog deleted on chromosome 10 (PTEN) gene suggesting an association with oestrogen [31, 30]. Clear cell carcinoma (CCC) is associated with the expr ession of fewer oestrogen receptors [30]. Oxidative stress, promoted by the presence of iron in the fluid of endometriotic cysts, potentially results in genetic mutations. Repeated haemorrhage in endometriosis promotes iron-mediated oxidation. This combined with the expression of fewer oestrogen receptors, are proposed as a possible causes for the development of CCC in patients diagnosed with endometriosis [32]. The development of endomet riosis-associated clear cell carcinoma (EACCC) is strongly associated with AID1A (a tumour suppressor gene, encoding (BRG-associated factor 250a) BAF250a protein) mutations whereas mutations in PTEN, KRas and β -catenin genes are more commonly observed with the development of endometriosis -associated endometrioid carcinoma (EAEC) [30]. Research has shown that the expression of the ARID1A- encoded protein is reduced in ovarian CCC. In addition, decreased ARID1A gene function is observed in endometriotic lesions which are found within close proximity to the site of the primary lesion [33]. Mutations in this gene has been identified in 41 -57% of ovaria n CCC and 15 -20% of benign ovarian cysts and is it proposed that patients presenting with ARID1A mutations in benign endometriosis should be viewed as high risk for developing malignancies. Evidence suggests an association between ARID1A mutations and loss of expression of BAF250a. Loss of BAF250a combined with changes in γH2AX, pAKT activation and induction of pathways for apoptosis are observed as initial molecular events that occur in the development of EAOC [34]. ARID1A mutations with the loss of BAF250a protein expression has been identified as the most common occurrence in the development of CCC and International Journal of Clinical Obstetrics and Gynaecology http://www.gynaecologyjournal.com ~ 35 ~ endometrioid carcinoma (EC) [35]. The mechanism of DNA methylation has been observed for the role that it may play in the development of ovarian cancers in endometriosis. Some major genes that have been identified through research include genes that are inactivated through hyper-methylation including: 1) Runt-related transcription factor 3 (RUNX3) , 2) human mutL homolog 1 (hMLH1), 3) E - cadherin (CDH1),4) Ras-association domain family of gene 2 (RASSF2), 5) PTEN and genes activated by hypo -methylation such as: 1) long interspersed nuclear element -1 (LINE -1) and syncytin-1 [36]. Inactivation of RUNX3 through methylation is observed as an early molecular event in the development of EAOC [37] and it has been reported that higher frequencies of RUNX3 methylation and inactivation occur in patients suffering from endometriosis [38]. Hyper -methylation and inactivation of RUNX3 play a pivotal role in the development of malignant transformation in endometriosis. Hyper -methylation of RUNX3 affects both normal and abnormal endometrial tissues [30]. hMLH1 cor rects errors in DNA that may occur during replication. An absence in the expression of hMLH1 protein, due to promoter methylation and inactivation, has been demonstrated to play critical roles in the malignant transformation of ovarian endometrium [39]. Despite the potential risk for malignant transformation that presents with the presence of endometriosis, eivdence sugge sts that steps can be taken to reduce this risk in women presenting with this pathology [40, 41]. Evidence suggests that performing a hysterectomy while preserving the ovaries may help to prevent the development of o varian cancers in women. Report from Dixon-Suen et al . on a study carried out on 837 942 women from Western Australia, demonstrated that in women diagnosed with endometriosis or fibroids, a hysterectomy significantly reduced their overall risks for developing ovarian cancers (HR = 0.17, 95% CI = 0.12-0.24, and HR = 0.27, 95% CI = 0.20 -0.36, respectively) [42]. Furthermore, in some cases of endometriosis, cystectomies may also aid in preventing cancer development [43]. In addition, hormonal influences and reproductive factors, may also play potent ial roles in delaying or reducing malignant transformation in women diagnosed with endometriosis. Modugno et al . assessed the odds r atios of ovarian cancers in association with the use of oral contraceptives, childbearing, performance of a hysterectomy and tubal ligation in women presenting with or without a history of endometriosis. This study reported that the use of oral contracepti ves, childbearing and undergoing tubal ligation or a hysterectomy similarly decreased the risk for developing ovarian cancer s in women presenting with or without a diagnosis of endometriosis [44]. 4. Management of Endometriosis -Associated Ovarian Cancer Once malignant transformation occurs and ovarian cancers develop, the primary management is surgery. Surgery is important for staging and debulking of tumours and can provide a cure for lesions that hav e not yet metastasized. The extent of the surgery required depends on the stage at which the cancer is detected and its potential for malignant transformation [45, 46]. In late st age presentations and stage II cancers, chemotherapy treatment is recommended following surgical resection of the malignancy [47]. There still remains a need for the development of targeted therapies with the sole purpose of addressing the common genetic m utations of EAOC [43]. Therefore, different forms of therapy have been studied for their potential application in the treatment of EAOC. Steps have alredy been taken to demonstrate the beneficial effects of immunotherapy in the management of EAOC. Clinical trials exploring the use of immunotherapy for the management of ovarian cancers have already been undertaken. Hamanishi et al. investigated the safety and antitumor activity of nivolumab (an anti-PD-1 antibody that functions to inhibit PD -1 signalling) in patients presenting with platinum-resistant ovarian cancer and concluded that the use of nivolumab was found to be relatively safe and clinically effective; therefore, this intervention measure definitely warrants future attention. This study, which investigated 20 patients of interest, reported the occurrence of adverse events in two study participants and a 45% disease control rate 48. Matulonis et al . examined two cohorts of study participants with advanced recurrent ovarian cancer (ROC) and demonstrated that there was some degree of response (16%) to the use of pembrolizumab as a single agent in patients with ROC [49]. In patients suffering from CCC the IL -6/JAK/STAT pathway is observed to be active and IL -6 may be used as an independent factor for predi cting poor prognoses in CCC patients [50]. A retrospective cohort study which enrolled 192 participants identified as having stage I CCC concluded that in addition to sub -stage classification, t he degree of IL -6 expression can also serve as an excellent pr ognostic factor for CCC discovered at stage I and that the use of IL -6 molecular stratification may be useful in maximizing therapeutic methods and improving survival rates in these population o f patients [51]. From these findings the inhibition of this IL -6/JAK/STAT pathway may promote improvement in treatment methods, and it has already been demonstrated from animal studies that the use of anti-IL6 antibody in CCC potentially yields better prognoses [52]. PIK3CA mutations are demonstrated in 33 -40% of pat ients diagnosed with CCC [53]. Mutations in this gene activate the PI3K/AKT/mTOR pathway. The use of inhibitors directly targeting the PI3K/AKT/mTOR pathway may yield favourable

for the manageme nt of CCC [54, 55]. It has also been suggested that th e use of Poly ADP-ribose polymerase (PARP) may serve potential benefits for the treatment of CCC when BRCA1/BRCA2 mutations are present [56]. A large percentage of women diagnosed with CCC expresses the angiogenic factor, VEGF (Vascular endothe lial growt h factor) [54, 57]. Antibodies to VEGF are used for treating ovarian cancers and has also been recommended for the treatment of EAOC [58, 59, 60]. It is theorized that the use of anti -VEGF antibodies along with other related drug therapies, may yield excellent results for the future treatment of EAOC [43]. The inhibition of VEGF receptors are also potentially excellent therapy strategies for treating ovarian cancers. Sorafenib inhibits VEGF and RAF kinase which both act on the RTKs and the PAF/MEK/ERK pathw ay to initiate tumour angiogenesis 61. Matei et al. assessed the efficacy and tolerability of sorafenib in patients experiencing ROC or primary peritoneal carcinomatosis. In this study 71 patients met the eligibility criteria for inclusion. It was demonstrated from this investigation that sorafenib exhibi ted some degree of antitumor activities, however, there were cases of significant toxicity - rashes (n = 7), hand-foot syndrome (n = 9), metabolic (n = 10), GI (n = 3), cardiovascular (n = 2), and pulmonary ( n = 2 ) [62]. Chekerov et al. investigated the use of sorafenib in combination with topotecan used for continued maintenance therapy for treating platinum-refractory ovarian cancer. This study concluded that the use of sorafenib combined with topotecan and as continued maintenance therapy potentially provides significant clinical benefits by improving survival rates in women presenting with platinum-resistance ovarian cancer [63]. The tumour microenvironment (TME) is greatly influenced by International Journal of Clinical Obstetrics and Gynaecology http://www.gynaecologyjournal.com ~ 36 ~ tumour-associated macrophages (TAMs) and research has already been undertaken to investigate the use of therapies that target TAM in the treatment of ovarian cancer [64]. TAM treatment strategies may inhibit the recruitment of macrophage s, decrease the survival of TAM, enha nce the ability of M1 macrophages to kill and destroy tumours and suppress the activities of M2 macrophages, thus inhibiting tumour promoting activities [65, 66]. 5. Discussion Evidence suggests that women diagnosed with endometriosis exhibit an increase d risk for developing ovarian cancers especially clear cell and endometrioid cancers. It is also observed that women presenting with a long -standing history of endometriosis carry an even greater risk for developing these cancers [67, 68]. Brinton et al. carried out a study to determine the extent of association between endometriosis or uterine leiomyomas and the development of cancers and insinuated that the presence of endometriotic lesions potentially influence the development of ovarian cancers, particu larly CCC and EC. It was demonstrated from this study that following a period of five years or more with a diagnosis of endometriosis, the relative risks (RRs) for developing EC were RR= 2.53; 95% CI, 1.19 - 5.38 and for developing CCC were RR=3.37; 95% CI, 1.24-9.14 [8]. Elsewhere, it has been reported that women who carry a diagnosis of endometriosis carry a risk that is 2 to 3 times greater for developing ovarian cancers [69]. Kim et al . assessed the effects of endometriosis - associated genetic variation o n the risk for developing ovarian cancers reported a link between endometriosis- associated genetic variation and the development of ovarian cancers, parti cularly high-grade serous and CCC [28]. A meta-analysis which included 20 case -control and 15 cohort studies with a total of 444255 participants reported an increased risk for developing ovarian cancers in women diagnosed with endometriosis [70]. Based on evidence from the literature, EAOC most likely develops when the woman approaches her late 40s. It is however observed that if malignant trasnformation was not present before menopause, transformation following menopause is less likely [71, 72]. One study carried out in Japan by Kobayash et al . concluded that the presence of ovarian endometrioma increase s the risk for developing ovarian cancers. This study enrolled 6398 women who had a diagnosis of ovarian endometrioma. After observing this cohort for 17 years, it was noted that the presence of ovarian endometrioma increased the risk for ovarian cancer de velopment, as 46 cases of ovarian cancers were observed (SIR = 8.95, 95% CI = 4.12 -15.3). This study also demonstrated that the risk for occurrence of ovarian cancers was higher in women who rece ived a diagnosis of ovarian endometrioma at an older age [73]. Since the presence of endometriosis may be assocaited with an increased risk for malignant transformation, it is important that patients diagnosed with this pathology be closely monitored for this potential development. This can be achieved through the use of biological markers that can be used for the early identification of individuals that exhibit an increased risk for developing ovarian malignancies. Biomarkers are important as they can be used for early identification of high-risk cases and thus allow for the application of early intervention methods that may help in reducing the occurrence of EAOC, in addition to giving patients better prognoses [44]. Other methods that can be applied for the early identification of patients that carry increased ris ks for malignant transformations include the detection tumour DNA levels in the circulation or possibly screening for the presence of various mutations specific for different types of ovarian cancers. These advancements help clinicians in better diagnosing , treating and predicting disease outcomes [74, 75]. 6. Conclusion In conclusion, it is quite evident that there is some association between endometriosis and the development of ovarian cancers most commonly, CCC and EC. The exact mechanism for malignant transformation is not yet fully understood; however, different genes , proteins and receptors have been investigated for the role they may play in this process. The use of different surgical interventions like fallopian tube ligation and cystectomies in ad dition to the use of oral contraceptives may serve to delay or preven t malignant transformations in women diagnosed with endometriosis. Surgical intervention for tumour staging and debulking followed by chemotherapy treatment, depending on the stage of the disease, remain the main methods for successfully treating EAOC; how ever, other strategies are now being investigated for their potential effectiveness in treating this pathology. Declaration of Interest The authors of this paper declare no conflict of interest. 7. References 1. Kobayashi H. Potential scenarios leading to ovarian cancer arising from endometriosis. Redox Rep 2016;21(3):119-26. 2. Sampson JA. Endometrial carcinoma of the ovary arising in endometrial tissue in that organ. American Journal of Obstetrics & Gynecology 1925;9(1):111-4. 3. Melin A, Sparén P, Bergqvist A. 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