{"paper_id":"fa43c2d4-1a6e-49ca-af21-775b576b1748","body_text":"~ 33 ~ \nInternational Journal of Clinical Obstetrics and Gynaecology 2021; 5(2): 33-38 \n \nISSN (P): 2522-6614 \nISSN (E): 2522-6622 \n© Gynaecology Journal \nwww.gynaecologyjournal.com \n2021; 5(2): 33-38 \nReceived: 20-02-2021 \nAccepted: 24-04-2021 \n \nCoumba Aicha Thiam \nDepartment of Obstetrics and \nGynaecology, Zhongnan Hospital, \nWuhan University, East Lake \nRoad, Wuhan, Hubei, China \n \nCai Hong Bing \nDepartment of Gynaecologic \nOncology, Zhongnan Hospital, \nWuhan University, East Lake \nRoad, Wuhan, Hubei, China \n \nMalyn MLK Antoine \nDepartment of Endocrinology, \nZhongnan Hospital, Wuhan \nUniversity, East Lake Road, \nWuhan, Hubei, China \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \nCorresponding Author: \nCoumba Aicha Thiam \nDepartment of Obstetrics and \nGynaecology, Zhongnan Hospital, \nWuhan University, East Lake \nRoad, Wuhan, Hubei, China \n \nEndometriosis and endometriosis associated ovarian \ncancer \n \nCoumba Aicha Thiam, Cai Hong Bing and Malyn MLK Antoine \n \nDOI: https://doi.org/10.33545/gynae.2021.v5.i3a.901 \n \nAbstract \nEndometriosis is defined by the presence of endometrial tissues outside of the endometrial cavity. I t is a \nbenign condition and even though it’s patho genesis is not yet fully understood different theories, such as \nthe Coelomic theory and the theory of Mullerian rest, have been proposed as possible explanations for the \ndevelopment of this pathology. E vidence suggests that women diagnosed with endometrios is presents an \nincreased risk for developing ovarian cancers. Therefore, this review will explore the pathogensis of \nendometriosis, explore its association with the development of ovarian cancers and identify treatment \nmethods for managing lesions following malignant transformation. \n \nKeywords: Endometriosis, ovarian cancer, endometriosis associated ovarian cancer, ovarian clear cell \ncarcinoma, endometrioid carcinoma \n \n1. Introduction  \nEndometriosis is defined by the presence of endometrial glands and stroma o utside the \nendometrial cavity. It is associated with pelvic pain, dysmenorrhea and female infertility [1]. \nDespite the fact that endometriosis is considered a benign condition, due to its normal histology, \nstudies have shown that this disease is associated  with increased risk for specific histotypes of \novarian carcinoma (endometrioid and clear cell ovarian cancer)  [2, 3]. A combination of different \nfactors may cumulatively lead to the malignant transformations in women diagnosed with \nendometriosis. Interpla y of inflammatory mediators, hormonal interactions and endometriosis \ninduced changes within the pelvis may all ultimat ely lead to the development of malignancies. \nThe presence of increase oestrogen may also influence malignant transformations  [4, 5]. This \nliterature review will therefore discuss the following 1) the pathogenesis of endometriosis, 2) the \nassociation between endometriosis and development of ovarian cancer and 3) potential treatment \nmethods for managing ovarian lesions following malignant traansformations. \n \n2. Pathogenesis of Endometriosis \nAffecting 3–15% of premenopausal women,  3–5% of postmenopausal women [6], 25%-80% of \ninfertile women and 40% -80% of women with pelvic pa in [7], endometriosis is  an oestrogen -\ndependent condition defined by the presence and growth of endometrial-type mucosa outside the \nuterine cavity. Ectopic endometrial tissue may be present around pelvic organs such as the \novaries, in addition to other organs including the colon and bladder. Endometrio sis is \nmainly associated with inflammation, severe  chronic pain, and infertility [8]. The diagnosis of \nendometriosis requires the presence of at least two of the following feat ures: 1) endometrial \nepithelial cells,  2) epithelium, 3) endometrial stromal cells 4) and signs of bleedi ng from \nendometrium-like tissue [9, 10]. Endometriosis accounts for three anatomical subtypes  [11, 12]: 1) \nsuperficial peritoneal disease subtype defined by superficial implants, haemorrhagic lesions or \nwhite scarring, 2) ovarian disease subtype defined by  superficial lesions on the surface of the \novary, or the presence of endo metriosis cysts inside the ovary commonly called endometriomas  \nand 3) deep infiltrating disease subtype defined by lesions greater than 5 mm and the presence of \nformed connective tiss ue around the endometriosis stroma. Women diagnosed wit h \nendometriosis commonly report having pain and fertility issues. It is theorized that these two main \nsymptoms are related to the pathogenesis of the disease which involves the influence of hormonal an d \nimmunological factor s that leads to inflammation [13]. As a result of these discoveries,  several \nconcepts are now being explored to explain the pathogenesis of endometriosis. \n\n\nInternational Journal of Clinical Obstetrics and Gynaecology http://www.gynaecologyjournal.com \n~ 34 ~ \nThe implantation theory describes retrograde menstruation as a \npossible initia ting factor for the developme nt of endometriosis  \n[14]. Retrograde menstruation involves the backward flow of \nmenstrual contents, including endometri al tissue, through patent \nfallopian tubes into the peritoneal cavity  [15]. It is believed that \nthis retrograde flow occurs initially at birth; however, deposited \nendometrial tissues are not activated until puberty when the \novaries begin to produce sex hormones  [16]. Ab normalities that \nmay promote this occurrence include: congenital malformations \nof the female reproductive tract, the production of thick cervical \nmucus and the presence of a tight internal uterine cervix os 17. \nEvidence supports this theory as a higher prevalence of \nendometriosis has been observed in adolescent females \npresenting with congenital outf low tract obstruction  [18] and the \npresence of outflow tract obstruction has been demonstrated to \nbe associated with intra -peritoneal endometriotic lesions  [19]. \nFollowing retrograde flow of menstrual contents into the \nperitoneal cavity, other processes mu st follow in order for \nendometriosis to finally occur. This may involve the failure of \nthe immune system to detect and eliminate ecto pic tissues, the \nattachment of ectopic tissues to the peritoneum or the \ndevelopment of local nerve and blood supply which s upports \nsurvival [17].  \nAnother theory that has been developed to explain the \npathogenesis of endometriosis is the Coelomic theory which \ninvolves the change or transformation of peritoneal tissue to \nectopic endometrial tissue  [20]. There are different fact ors that \nmay influence these changes and endocrine disrupting chemicals \n(EDCs) have been proposed to play a potential role. It is also \nbelieved that endo genous agents such as hormonal or \nimmunological factors may serve as inductive stimuli that \nultimately support the changes or differentiation of normal \nperitoneal cells into endometrial cells 21,22. Furthermore, \naccording to the theory of Mullerian rests, residual cells \noriginating from th e embryonic Mullerian duct, migrate and \nmaintain their ability to develop into endometriotic lesions in the \npresence of hormones such as oestrogen23. It has been postulated \nthat extra -uterine ste m/progenitor cells such as cells from the \nbone marrow, may also play a role in the pathogenesis of \nendometriosis through the differentiation into endometrial tissue \n[24].  \nEndometriosis is now being observed as a pelvic inflammatory \ncondition. In women diagnosed with this disease, examination of \nthe peritoneal fluid demonstrates an alarming increase in the \npresence of activated macrop hages and alter ations in \ncytokine/chemokine profiles  [25]. Cytokines or chemokines that \nare found to be increased in the peritoneal fluid of women \nsuffering from endometriosis include: 1) macrophage migration \ninhibitory factor, 2) tumour necrosis factor (T NF) -α 3) \ninterleukin (IL) -1β, 4) IL -6, 5) IL -8 and 6) m onocyte \nchemoattractant protein -1 (MCP -1). The reasons for this \nobservation are yet to be determined 26. The peritoneum of \nwomen diagnosed with endometriosis usually has hi gh levels of \nprostaglandins which may account for the pathophysiology of \nthe disease and its common presentation (pain and infertility). It \nis observed that the macrophages found in the peritoneum of \nendometriosis patients, possess higher levels of cyclo -\noxygenase-2 (COX -2) and prod uce higher concentrations of \nprostaglandins as compared to macrophages found in healthy \nsubjects. TNF -α stimulates endometrial cells to produce \nprostaglandin F2α (PG F2α) and prostaglandin E2 (PGE2). COX-2, \nwhich is activated by IL-1β, induces the production of PGE2 and \nthis in turn stimulates steroidogenic acute regulatory (StAR) \nprotein and aromatase. Oestrogen establishes a positive feedback \nloop through its up-regulation of PGE2 synthesis thus increasing \nthe bioavailability of  estradiol. This phenomenon  explains the \ninterconnection between oestrogen dependence and \ninflammation observed in endometriosis [20].  \nFurthermore, the protein hormone adiponectin has been explored \nfor its pot ential role in the development of endometriosis. It \nregulates a variety o f metabolic processes in the body such as \nthe catabolism of glucose and fatty acids. Adipose tissues \nsecrete adiponectin and it has been noted that the serum and \nperitoneal fluid of w omen suffering from endometriosis exhibit \ndecreased levels of this protei n hormone. Cultured endometrial \nstromal cells demonstrated a decrease in the secretion of IL -6, \nIL-8, and MCP -1 in the presence of adiponectin.  This result \nshows the anti -inflammatory effects of this protein hormone on \nendometrial stromal cells, a protecti ve effect which is not \npresent in patients suffering from endometriosis [27].  \n \n3. Association between Endometriosis and the development \nof Ovarian Cancers \nA meta -analysis done by Kim et al . to assess the impact of \nendometriosis on the risk and prognosis o f ovarian cancer, \nconcluded that there is a significant association between this \npathology and the risk for developing ovarian cancers  [28]. To \ndate, the precise mechanism for malignant transformations of \nendometriosis is not fully known; however, differen t factors \nhave been investigated for the role that they may play  in this \nprocess [29].  \nOxidative stress, possibly associated with genetic abnormalities, \nis an important mechanism commonly observed when \ninvestigating the association between endometriosis a nd the \ndevelopment of ovarian cancers  [30]. The development o f \nepithelial ovarian cancer (EOC) is commonly associated with \ndefects in β -catenin and P16, phosphatase and tensin homolog \ndeleted on chromosome 10 (PTEN) gene suggesting an \nassociation with oestrogen [31, 30]. Clear cell carcinoma (CCC) is \nassociated with the expr ession of fewer oestrogen receptors  [30]. \nOxidative stress, promoted by the presence of iron in the fluid of \nendometriotic cysts, potentially results in genetic mutations. \nRepeated haemorrhage in endometriosis promotes iron-mediated \noxidation. This combined with the expression of fewer oestrogen \nreceptors, are proposed as a possible causes for the development \nof CCC in patients diagnosed with endometriosis [32]. \nThe development of endomet riosis-associated clear cell \ncarcinoma (EACCC) is strongly associated with AID1A (a \ntumour suppressor gene, encoding (BRG-associated factor 250a) \nBAF250a protein) mutations whereas mutations in PTEN, KRas \nand β -catenin genes are more commonly observed with the \ndevelopment of endometriosis -associated endometrioid \ncarcinoma (EAEC) [30]. Research has shown that the expression \nof the ARID1A- encoded protein is reduced in ovarian CCC. In \naddition, decreased ARID1A gene function is observed in \nendometriotic lesions which are found within close proximity to \nthe site of the primary lesion [33]. Mutations in this gene has been \nidentified in 41 -57% of ovaria n CCC and 15 -20% of benign \novarian cysts and is it proposed that patients presenting with \nARID1A mutations in benign endometriosis should be viewed \nas high risk for developing malignancies. Evidence suggests an \nassociation between ARID1A mutations and loss  of expression \nof BAF250a. Loss of BAF250a combined with changes in \nγH2AX, pAKT activation and induction of pathways for \napoptosis are observed as initial molecular events that occur in \nthe development of EAOC [34]. ARID1A mutations with the loss \nof BAF250a protein expression has been identified as the most \ncommon occurrence in the development of CCC and \n\nInternational Journal of Clinical Obstetrics and Gynaecology http://www.gynaecologyjournal.com \n~ 35 ~ \nendometrioid carcinoma (EC) [35].  \nThe mechanism of DNA methylation has been observed for the \nrole that it may play in the development of ovarian cancers in \nendometriosis. Some major genes that have been identified \nthrough research include genes that  are inactivated through \nhyper-methylation including: 1) Runt-related transcription factor \n3 (RUNX3) , 2) human mutL homolog 1 (hMLH1), 3) E -\ncadherin (CDH1),4)  Ras-association domain family of gene 2 \n(RASSF2), 5) PTEN and genes activated by hypo -methylation \nsuch as: 1) long interspersed nuclear element -1 (LINE -1) and \nsyncytin-1 [36]. Inactivation of RUNX3 through methylation is \nobserved as an early molecular event in  the development of \nEAOC [37] and it has  been reported that higher frequencies of \nRUNX3 methylation and inactivation occur in patients suffering \nfrom endometriosis  [38]. Hyper -methylation and inactivation of \nRUNX3 play a pivotal role in the development of malignant \ntransformation in endometriosis. Hyper -methylation of RUNX3 \naffects both normal and abnormal endometrial tissues [30]. \nhMLH1 cor rects errors in DNA that may occur during \nreplication. An absence in the expression of hMLH1 protein, due \nto promoter methylation and inactivation, has been demonstrated \nto play critical roles in the malignant transformation of ovarian \nendometrium [39]. \nDespite the potential risk for malignant transformation that \npresents with the presence of endometriosis, eivdence sugge sts \nthat steps can be taken to reduce this risk in women presenting \nwith this pathology  [40, 41]. Evidence suggests that performing a \nhysterectomy while preserving the ovaries may help to prevent \nthe development of o varian cancers in women.  Report from  \nDixon-Suen et al . on a study carried out on 837 942 women \nfrom Western Australia, demonstrated that in women diagnosed \nwith endometriosis or fibroids, a hysterectomy significantly \nreduced their overall risks for developing ovarian cancers (HR = \n0.17, 95% CI =  0.12-0.24, and HR = 0.27, 95% CI = 0.20 -0.36, \nrespectively) [42]. Furthermore, in some cases of endometriosis, \ncystectomies may also aid in preventing cancer development [43]. \nIn addition, hormonal influences and reproductive factors, may \nalso play potent ial roles in delaying or reducing malignant \ntransformation in women diagnosed with endometriosis. \nModugno et al . assessed the odds r atios of ovarian cancers in \nassociation with the use of oral contraceptives, childbearing, \nperformance of a hysterectomy and  tubal ligation in women \npresenting with or without a history of endometriosis. This study \nreported that the use of oral contracepti ves, childbearing and \nundergoing tubal ligation or a hysterectomy similarly decreased \nthe risk for developing ovarian cancer s in women presenting \nwith or without a diagnosis of endometriosis [44]. \n \n4. Management of Endometriosis -Associated Ovarian \nCancer \nOnce malignant transformation occurs and ovarian cancers \ndevelop, the primary management is surgery. Surgery is \nimportant for staging and debulking of tumours and can provide \na cure for lesions that hav e not yet metastasized. The extent of \nthe surgery required depends on the stage at which the cancer is \ndetected and its potential for malignant transformation  [45, 46]. In \nlate st age presentations and stage II cancers, chemotherapy \ntreatment is recommended following surgical resection of the \nmalignancy [47]. There still remains a need for the development \nof targeted therapies with the sole purpose of addressing the \ncommon genetic m utations of EAOC  [43]. Therefore, different \nforms of therapy have been studied for their potential application \nin the treatment of EAOC. \nSteps have alredy been taken to demonstrate the beneficial \neffects of immunotherapy in the management of EAOC. Clinical \ntrials exploring the use of immunotherapy for the management \nof ovarian cancers have already been undertaken. Hamanishi et \nal. investigated the safety and antitumor activity of nivolumab \n(an anti-PD-1 antibody that functions to inhibit PD -1 signalling) \nin patients presenting with platinum-resistant ovarian cancer and \nconcluded that the use of nivolumab was found to be relatively \nsafe and clinically effective; therefore, this intervention measure \ndefinitely warrants future attention. This study, which \ninvestigated 20 patients of interest, reported the occurrence of \nadverse events in two study participants and a 45% disease \ncontrol rate 48. Matulonis et al . examined two cohorts of study \nparticipants with advanced recurrent ovarian cancer (ROC) and \ndemonstrated that there was some degree of response (16%) to \nthe use of pembrolizumab as a single agent in patients with ROC \n[49]. In patients suffering from CCC the IL -6/JAK/STAT \npathway is observed to be active and IL -6 may be used as an \nindependent factor for predi cting poor prognoses in CCC \npatients [50]. A retrospective cohort study which enrolled 192 \nparticipants identified as having stage I CCC concluded that in \naddition to sub -stage classification, t he degree of IL -6 \nexpression can also serve as an excellent pr ognostic factor for \nCCC discovered at stage I and that the use of IL -6 molecular \nstratification may be useful in maximizing therapeutic methods \nand improving survival rates in these population o f patients [51]. \nFrom these findings the inhibition of this IL -6/JAK/STAT \npathway may promote improvement in treatment methods, and it \nhas already been demonstrated from animal studies that the use \nof anti-IL6 antibody in CCC potentially yields better prognoses  \n[52]. PIK3CA mutations are demonstrated in 33 -40% of pat ients \ndiagnosed with CCC  [53]. Mutations in this gene activate the \nPI3K/AKT/mTOR pathway. The use of inhibitors directly \ntargeting the PI3K/AKT/mTOR pathway may yield favourable \nresults for the manageme nt of CCC  [54, 55]. It has also been \nsuggested that th e use of Poly  ADP-ribose polymerase (PARP) \nmay serve potential benefits for the treatment of CCC when \nBRCA1/BRCA2 mutations are present [56].  \n A large percentage of women diagnosed with CCC expresses \nthe angiogenic factor, VEGF  (Vascular endothe lial growt h \nfactor) [54, 57]. Antibodies to VEGF are used for treating ovarian \ncancers and has also been recommended for the treatment of \nEAOC [58, 59, 60]. It is theorized that the use  of anti -VEGF \nantibodies along with other related drug therapies, may yield \nexcellent results for the future treatment of EAOC  [43]. The \ninhibition of VEGF receptors are also potentially excellent \ntherapy strategies for treating ovarian cancers. Sorafenib inhibits \nVEGF and RAF kinase which both act on the RTKs and the \nPAF/MEK/ERK pathw ay to initiate tumour angiogenesis 61. \nMatei et al. assessed the efficacy and tolerability of sorafenib in \npatients experiencing ROC or primary peritoneal \ncarcinomatosis. In this study 71 patients met the eligibility \ncriteria for inclusion. It was demonstrated from this investigation \nthat sorafenib exhibi ted some degree of antitumor activities, \nhowever, there were cases of significant toxicity - rashes (n = 7), \nhand-foot syndrome (n = 9), metabolic  (n = 10), GI (n = 3), \ncardiovascular (n = 2), and pulmonary ( n = 2 ) [62]. Chekerov et \nal. investigated the use of sorafenib in combination with \ntopotecan used for continued maintenance therapy for treating \nplatinum-refractory ovarian cancer. This study concluded that \nthe use of sorafenib combined with topotecan and as continued \nmaintenance therapy potentially provides significant clinical \nbenefits by improving survival rates in women presenting with \nplatinum-resistance ovarian cancer [63].  \nThe tumour microenvironment (TME) is greatly influenced by \n\nInternational Journal of Clinical Obstetrics and Gynaecology http://www.gynaecologyjournal.com \n~ 36 ~ \ntumour-associated macrophages (TAMs) and research has \nalready been undertaken to investigate the use of therapies that \ntarget TAM in the treatment of ovarian cancer  [64]. TAM \ntreatment strategies may inhibit the recruitment of macrophage s, \ndecrease the survival of TAM, enha nce the ability of M1 \nmacrophages to kill and destroy tumours and suppress the \nactivities of M2 macrophages, thus inhibiting tumour promoting \nactivities [65, 66].  \n \n5. Discussion \nEvidence suggests that women diagnosed with endometriosis \nexhibit an increase d risk for developing ovarian cancers \nespecially clear cell and endometrioid cancers. It is also \nobserved that women presenting with a long -standing history of \nendometriosis carry an even greater risk for developing these \ncancers [67, 68]. Brinton et al. carried out a study to determine the \nextent of association between endometriosis or uterine \nleiomyomas and the development of cancers and insinuated that \nthe presence of endometriotic lesions potentially influence the \ndevelopment of ovarian cancers, particu larly CCC and EC. It \nwas demonstrated from this study that following a period of  five \nyears or more with a diagnosis of endometriosis, the relative \nrisks (RRs) for developing EC were RR= 2.53; 95% CI, 1.19 -\n5.38 and for developing CCC were RR=3.37; 95% CI, 1.24-9.14 \n[8]. Elsewhere, it has been reported that women who carry a \ndiagnosis of endometriosis carry a risk that is 2 to 3 times \ngreater for developing ovarian cancers  [69]. Kim et al . assessed \nthe effects of endometriosis - associated genetic variation o n the \nrisk for developing ovarian cancers reported a link between \nendometriosis- associated genetic variation and the development \nof ovarian cancers, parti cularly high-grade serous and CCC  [28]. \nA meta-analysis which included 20 case -control and 15 cohort \nstudies with a total of 444255 participants reported an increased \nrisk for  developing ovarian cancers in women diagnosed with \nendometriosis [70].  \nBased on evidence from the literature, EAOC most likely \ndevelops when the woman approaches her late 40s. It is however \nobserved that if malignant trasnformation was not present before \nmenopause, transformation following menopause is less likely  \n[71, 72]. One study carried out in Japan by  Kobayash et al . \nconcluded that the presence of ovarian endometrioma increase s \nthe risk for developing ovarian cancers. This study enrolled \n6398 women who had a diagnosis of ovarian endometrioma. \nAfter observing this cohort for 17 years, it was noted that the \npresence of ovarian endometrioma increased the risk for ovarian \ncancer de velopment, as 46 cases of ovarian cancers were \nobserved (SIR = 8.95, 95% CI = 4.12 -15.3). This study also \ndemonstrated that the risk for occurrence of ovarian cancers was \nhigher in women who rece ived a diagnosis of ovarian \nendometrioma at an older age [73].  \nSince the presence of endometriosis may be assocaited with an \nincreased risk for malignant transformation, it is important that \npatients diagnosed with this pathology be closely monitored for \nthis potential development. This can be achieved through the use \nof biological markers that can be used for the early identification \nof individuals that exhibit an increased risk for developing \novarian malignancies. Biomarkers are important as they can be \nused for early identification of high-risk cases and thus allow for \nthe application of early intervention methods that may help in \nreducing the occurrence of EAOC, in addition to giving patients \nbetter prognoses [44]. Other methods that can be applied for the \nearly identification of patients that carry increased ris ks for \nmalignant transformations include the detection tumour DNA \nlevels in the circulation or possibly screening for the presence of \nvarious mutations specific for different types of ovarian cancers. \nThese advancements help clinicians in better diagnosing , \ntreating and predicting disease outcomes [74, 75].  \n \n6. Conclusion \nIn conclusion, it is quite evident that there is some association \nbetween endometriosis and the development of ovarian cancers \nmost commonly, CCC and EC. The exact mechanism for \nmalignant transformation is not yet fully understood; however, \ndifferent genes , proteins and receptors have been investigated \nfor the role they may play in this process. The use of different \nsurgical interventions like fallopian tube ligation and \ncystectomies in ad dition to the use of oral contraceptives may \nserve to delay or preven t malignant transformations in women \ndiagnosed with endometriosis. Surgical intervention for tumour \nstaging and debulking followed by chemotherapy treatment, \ndepending on the stage of the  disease, remain the main methods \nfor successfully treating EAOC; how ever, other strategies are \nnow being investigated for their potential effectiveness in \ntreating this pathology.  \n \nDeclaration of Interest  \nThe authors of this paper declare no conflict of interest. \n \n7. References \n1. Kobayashi H. Potential scenarios leading to ovarian cancer \narising from endometriosis. Redox Rep 2016;21(3):119-26.  \n2. Sampson JA. Endometrial carcinoma of the ovary arising in \nendometrial tissue in that organ. American Journal of \nObstetrics & Gynecology 1925;9(1):111-4.  \n3. Melin A, Sparén P, Bergqvist A. The risk of cancer and the \nrole of parity among women with endometriosis. Hum \nReprod 2007;22(11):3021-6.  \n4. Zanetta GM, Webb MJ, Li H, Keeney GL. \nHyperestrogenism: a relevant risk factor f or the \ndevelopment of cancer from endometriosis. 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