{"paper_id":"cdbe0067-4d9b-40e8-8b8e-9db95b640d10","body_text":"201\nThis is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International  \n(CC BY-NC-SA 4.0). License (http://creativecommons.org/licenses/by-nc-sa/4.0/)\nREVIEW PAPER\nDOI: https://doi.org/10.5114/pm.2021.111276\nMenopause Rev 2021; 20(4): 201-206\nIntroduction\nEndometriosis is a complex and multifactorial dis-\nease, in which diagnosis, markers, and therapeutic \ntreatments remain unclear and somehow enigmatic [1]. \nThe fact that no single theory about the pathology and \ncauses of endometriosis is currently accepted [2, 3]\nexplains the lack of progress. For more details about \npathogenesis of endometriosis, see [4].\nCurrently, there is no doubt that endometriosis is a be-\nnign disease; however, more and more studies support the \nnotion that it may represent a condition that could lead \nto the development of pre-cancerous lesions. The first re-\nport of a suspected malignant change in endometriosis \noccurred almost 100 years ago [5] with the observation of \nmalignant changes in the endometrial tissue. This hypoth-\nesis was confirmed more than 25 years later [6]. Atypi-\ncal endometriosis is often considered a transitional form \nfrom benign disease to cancer [7]. However, the current \nclassification of endometriosis into typical and atypical is \nmore important for diagnosis than for clinical practice. The \nproblem is further elevated by the findings that the possi-\nble association between cancer and endometriosis varies \naccording to the histologic subtype of ovarian cancer [8].\nEndometriosis and gynaecological cancers:  \nmolecular insights behind a complex machinery\nVaclav Vetvicka1, Ludek Fiala2, Simone Garzon3, Giovanni Buzzaccarini4, Milan Terzic5,6,7,  \nAntonio Simone Laganà8\n1Department of Pathology, University of Louisville, Louisville, KY, United States \n2Institute of Sexology, First Faculty of Medicine, Charles University, Prague, Czech Republic \n3Department of Obstetrics and Gynecology, AOUI Verona, University of Verona, Verona, Italy \n4Department of Women and Children's Health, University of Padua, Padua, Italy\n5Department of Medicine, School of Medicine, Nazarbayev University, Nur-Sultan, Kazakhstan\n6Clinical Academic Department of Women's Health, National Research Center of Mother and Child Health, University Medical Center,  \n Nur-Sultan, Kazakhstan\n7Department of Obstetrics, Gynecology and Reproductive  Sciences, University of Pittsburgh School of Medicine,  Pittsburgh, PA, United States \n8Department of Obstetrics and Gynecology, \"Filippo Del Ponte\" Hospital, University of Insubria, Varese, Italy\nAbstract\nEndometriosis is described as the presence of both endometrial glandular and stromal cells outside the \nuterine cavity. A  major characterization of this disease is ectopic implantation of endometrial cells with in-\ncreased migration. It is one of the leading causes of morbidity among premenopausal women, with a preva-\nlence of 10–16% of women of reproductive age. Despite over century of intensive research, none of the current \ntreatment options represents a real cure. Based on the current knowledge, endometriosis, particularly its atypi-\ncal version, is considered to be a transitional form from benign disease to tumour. However, the exact mecha-\nnisms of this conversion are still not fully established.\nKey words: endometriosis, cancer, ovarian cancer. \nThis hypothesis is not only based on the known as-\nsociation between endometriosis and cancer, but also \non numerous common features shared by endometri-\nosis and cancer, such as the ability to evade apoptosis, \nstem cell-like dysregulation, neovascularization, can-\ncer-reminting implantation at distant sites, and strong \neffects on the immune system [4]. However, the ques-\ntion of whether atypical endometriosis really is a pre-\ncursor of future ovarian cancer has never been satis-\nfactorily answered. Lately, a discussion suggesting that \nendometriosis is not a benign disease but an invasive \none [9] occurred, but despite several points supporting \nthis option, it is still not accepted by the scientific com-\nmunity. Possible relationships between endometriosis \nCorresponding author: \nVaclav Vetvicka, Department of Pathology, University of Louisville, Louisville, KY, United States,  \ne-mail: Vaclav.vetvicka@louisville.edu\nSubmitted: 12.08.2021\nAccepted: 28.08.2021\nFig. 1. Possible relation between endometriosis and develop-\nment of ovarian cancer\nSimple\nEndometriosis\nHyperplasia Atypical\nComplex\nOvarian cancer\n\nMenopause Review/Przegląd Menopauzalny 20(4) 2021\n202\nand the development of ovarian cancer are shown in \nFigure 1.\nWomen with endometriosis appear to be more likely \nto develop certain types of cancer, particularly ovarian, \nnon-Hodgkin’s lymphoma, and brain tumours [10–12]. \nThe association between endometriosis and breast can-\ncer is still contradictory\n [11]. Similarly, a  review of the \nliterature suggested a link between endometriosis and \novarian cancer, but not breast and cervical cancer [13], \nso these possible links are even more questionable.\nSome cases, despite usually being case reports, \nunderline the complexity of the endometriosis-cancer \nrelationship. A  case of primary endometrioid carcino-\nma arising from deep infiltrating endometriosis 6 years \nafter diagnosis of ovarian cancer [14] can serve as an \nexample. Similar case reports do not provide any mean-\ningful information about the mechanisms of action or \npathology of cancer development, but strongly suggest \nthe need for long-term follow-up for survivors of ovari-\nan cancer with co-existent endometriosis.\nEpigenetic changes such as the presence of some \nmRNAs or DNA methylation have been suggested. One \nof the possible triggers of conversion from benign to \nmalignant disease might be microRNAs (miRNAs) [15]. \nOne of the suggestions was offered by Nakamura et al. \n[16]. However, even though a high level of miR-486-5p \nin serum and its upregulation causing migration and \nproliferation of ovarian endometrioma cells seems to \nsupport their hypothesis, the real proof was missing. \nAnother study found 23 individual miRNAs expressed \ndifferently in healthy women and in women with endo-\nmetriosis and/or ovarian cancer [17].\nComprehensive miRNA profiling from ovarian can-\ncer and its associated endometriosis showed that the \nexpressions of miRNAs were significantly different [18]. \nBased on similar studies, miRNAs have been suggested as \na marker of either disease or endometriosis-cancer pro-\ngression. With limited information and a high number of \nindividual miRNAs, it is not currently possible to ascertain \nwhether miRNAs are really relevant and if so, which ones.\nMutation of ARID1A, which is a tumour suppressor \ngene involved in endometriosis-cancer transformation \n[10]. The fact that tumours with a mutated ARID1A gene \noften have a better higher survival rate might explain \nwhy endometrium-associated ovarian cancer often \nhas lower mortality than other types of ovarian cancer.  \nThe relatively wide range of this mutation in ovarian en-\ndometroid carcinoma (30–48%) might explain the often \ncontradictory results of numerous studies. Additional \nstudies have suggested the role of CTNNB1 and PTEN \ngenes, PIK3-AKT-mTOR pathway, methylation of the  \nER promoter, high levels of oestrogen, and inflamma-\ntion [19, 20]. \nOvarian cancer\nThe association between endometriosis and cancer \nis focused mostly on ovarian cancer, most of all en-\ndometroid and clear-cell ovarian cancer subtypes [21–25]. \nBasic types of ovarian cancer are shown in Figure 2.\nMost studies agree that endometriosis and ovari-\nan cancer are somehow linked, but the relationship is \nnot clear and is often controversial. A study of operated \novarian cancer patients showed 10% with coexisting \novarian endometriosis. This number increased to 36.8% \nin patients with clear cell ovarian cancer \nHistopathological studies have suggested that atyp-\nical endometriosis is a  transition between endome-\ntriosis and cancer [26].\n If true, endometriosis is a pre-\nmalignant condition. This hypothesis is supported by \nthe fact that almost 70% of endometriosis-associated \novarian carcinomas occur in the presence of atypical \novarian endometriosis. Clinically significant similarities \nbetween endometriosis and ovarian cancer exist, some \nof which can influence the incidence rate of cancer. In-\nfertility or late menopause can serve as examples of \nclinical manifestations related to increased risk [27]. On \nthe other hand, factors such as hysterectomy, use of \noral contraceptives, or tubal ligation surprisingly result \nin lower risk of cancer development [28].\nOne of the new areas is focused on the possibility \nthat endometrial cysts might be the origin of endometri-\nosis-associated ovarian cancer (EAOC), but this hypoth-\nesis is only discussed rather than confirmed. The cur -\nrent hypothesis assumes that the process involves DNA \ndamage and instability in endometrial cysts followed \nby selection of cells with high antioxidant capacity [29]. \nThe evidence of resistance of ovarian cancer to oxidative \nstress is lacking. Some studies have suggested that this \ntype of cancer is probably caused by eutopic endometrial \nglandular cells with oncogenic mutation upon engrafting \nin the ovary and not by endometrial cysts undergoing \noncogenic mutations [30]. Most of the research believes \nthat endometrial cysts are not the cause of ovarian can-\nFig. 2. Basic types of ovarian cancer\nEpithelial cancer\nStromal cell cancer Germ cell cancer\n\nMenopause Review/Przegląd Menopauzalny 20(4) 2021\n203\ncer. Possible steps involved in changes from endometri-\nosis to EAOC are summarized in Figure 3.\nOn the one hand, a large case-control study demon-\nstrated that the lifetime chance of ovarian cancer was \n50% higher among women suffering from endometri-\nosis, but the possible triggering mechanisms such as \noral contraception use or the number of births showed \nno effects. A subsequent review study revealed up to  \n3.5-fold higher development of endometrioid and clear \ncell tumours among these women [31]. On the oth-\ner hand, a  systematic review of 25 years of studies \nshowed only modest effects, ranging between 1.3 and \n1.9 [32]. The largest study completed by Olson [33] with \nan average 13-year follow-up did not find any differ -\nence in ovarian cancer occurrence between normal pa-\ntients and patients with endometriosis. A recent review \ncomparing individual studies showing either high or no \nincidence of endometriosis-ovarian cancer relation was \ndone by Pejovic et al. [34].\nDespite often cited relations between endometrio-\nsis and ovarian cancer, the overall frequency was found \nto be 0.3 to 0.8% [35]. Conversely, numerous other stud-\nies found much higher risk – from 19% [36] to a 4-fold \nincrease [37]. More detailed studies tried to elucidate \nthe reasons behind these contradictory results. An eval-\nuation of 200,000 patients showed that higher risk is \nassociated with greater age, pelvic inflammatory prob-\nlems, and being childless [38]. A retrospective study of \nmalignancy risks in endometriosis found than not only \novarian cancer, but also cervical, breast, and thyroid \ncancer have higher incidence [39]. If confirmed, can-\ncer screening might be beneficial to all women over  \n40 years of age originally diagnosed with endometri-\nosis. However, other studies found no increased coin-\ncidence of breast cancer [20]. Strangely, the associa-\ntion, often significant, has been found in older studies, \nwhereas the newest population-based cohort studies \nfound no association [19, 40].\nAnother controversy exists with prognosis. Ovarian \ncancer has the highest mortality of all gynaecological \ncancers, but several studies found that patients with \nboth endometriosis and ovarian cancer have better \nprognosis [41]. Even more studies, however, did not \nconfirm these findings. The problems might be caused \nby a low number of patients in the studies and over-re-\nliance on self-reporting. To answer this question, a large \ncohort study evaluating over 32,000 women with a di-\nagnosis of ovarian cancer over a 25-year interval was \nperformed. The results confirmed that patients with \nhistologically confirmed endometriosis and ovarian \ncancer have a longer overall survival rate [21, 22]. Be-\ncause the aim of this study was to find only possible \ndifferences in prognosis, we still have no clue about the \npossible mechanisms. Clearly, more studies are nec-\nessary. Possible stratification by endometriosis status \nmight help to elucidate the role of endometriosis.\nAnother unclear association is the survival prognosis. \nIndeed, ovarian cancer resulting from endometriosis has \nsome special characteristics such as having endometroid \nor clear cell histology and a better prognosis [42]. How-\never, the question of endometriosis being a prognostic \nfactor for cancer survival is not clear. On the one hand, \nsome studies found no definitive association between \nthe presence of endometriosis and survival [43]. On \nthe other hand, another study found significantly bet-\nter survival in women with endometriosis than for all \nmalignancies combined [44]. From the genetic point of \nview, the malignant transformation of endometriosis \nto ovarian cancer might be triggered by some essential \ngenes. A recent study used RNA sequencing of several \ntypes of tissues ranging from normal endometriosis to \natypical endometriosis and ovarian cancer and found \nsignificant significantly increased levels of mRNA of tet-\nraspanin 1 [45]. These data were confirmed by evalua-\ntion of tetraspanin 1 protein levels. The authors suggest \nthat overexpression of this gene enhanced cell prolifer-\nation and invasion, probably via increasing activity of \nAMP-activated protein kinase. If confirmed, tetraspanin \n1 might be used first as a marker in screening for the risk \nof endometriosis-ovarian cancer conversion and later as \na therapeutic target. The additional 13 genes regulated \nduring the transition phases might also be important, \nbut their possible role is still unclear. The most important \ngenes involved in development of endometriosis, EAOC, \nand ovarian cancer are shown in Figure 4.\nAnother possibility might be the recently reported \nmolecular pathways associated with ARID1A mutations, \nwhich might be involved in the progression from en-\ndometriosis to atypical endometriosis and subsequent \nEAOC [46]. This hypothesis is based on the finding of \nARID1A mutation occurring in app. 50% of endometri-\nosis-associated ovarian cancer [47]. A  meta-analysis \nof 984 endometriosis-related genes identified 39 key \nendometriosis-related genes, which might be involved \nwith tumour formation [48]. If confirmed, the shared \ngenetic mechanism of cancer and endometriosis might \nopen a new window for diagnosis, risk evaluation, and \neven treatment.\nFig. 3. Possible steps involved in changes from endometriosis \nto endometriosis-associated ovarian cancer\nEndometriosis\nDAMPs\nInflammation\n↑ Inflamma some – related genes\n↑ Oncogenes\nEAOC\n\nMenopause Review/Przegląd Menopauzalny 20(4) 2021\n204\nOne of the newest suggestions is focused on Notch \nsignalling, but again, the few studies on this subject \nyielded controversial results [49]. These differences \nmight be caused by different experimental approaches.\nSome interesting hypotheses about the endometri-\nosis-related ovarian cancer have been proposed [50]. \nOne involves extracellular haemoglobin, iron, and heme \ncausing cellular oxidative damage via increased reac-\ntive oxygen species with subsequent DNA damage and \nsubsequent mutations. This hypothesis is based on the \nincessant menstruation theory. The second one sug-\ngested the opposite and involves increased production \nof antioxidants, which might favour a tumour-potenti-\nating environment. Both options are based on the idea \nof the double-edged sword of redox imbalance [51]. Ad-\nditional risk factors might involve age over 42 years and \npost-menopause status [52]. The authors underline the \nneed for better evaluation of these risks. Age is clearly \nthe main risk factor.\nAnother possibility involves the immune system. En-\ndometriosis-related cancers often have distinct immune \nprofiles that significantly differ from de novo tumours. \nAt the same time, many aspects of the defence system \nare changed in endometriosis, including macrophages, \nlymphocytes, and natural killer cell functions [53], lead-\ning to the hypothesis of the involvement of a changed \nimmune system in ovarian cancer progression. Howev-\ner, it is still not fully established whether immunological \nchanges found in patients with endometriosis are the \ncause or a secondary result.\nEndometrial cancer\nEndometrial cancer is common but has better prog-\nnosis, with the overall 5-year survival rate reaching al-\nmost 85% [54]. Some studies, similarly to ovarian can-\ncer, suggest an association between endometriosis and \nendometrial cancer with a possible significantly higher \nrate [34].\nIn endometrial cancer, apoptosis is often considered \nto be responsible for the development of this type of \ncancer. With a rate 3 times above control values, KARAS \nLC56 polymorphism might be one of the factors in-\nvolved in the development and progression of this dis-\nease [55], but the low numbers of patients evaluated in \nthis study make any conclusion questionable. A recent \nstudy showed that apoptosis inducer apoptosis-stimu-\nlating p53 protein 2 (ASPP2) might be strongly involved \nbecause its suppression promoted malignancy. The ex-\nact mechanism of action showed that ASPP2 acts via \nYes-associated protein and lipolysis-stimulated lipopro-\ntein receptor [56]. If these in vitro experiments are fur -\nther confirmed, ASPP2 might be developed into a ther -\napeutic target. However, new diagnostic or therapeutic \nprocesses are lacking [6].\nConclusions\nBoth endometriosis and ovarian cancer are multi-\nfactorial diseases, so it is not surprising that even af-\nter decades of intensive research, more questions than \nanswers remain. The evidence suggesting that patients \nwith endometriosis have a  higher risk of developing \novarian cancer is interesting but unclear because the \ndata are often contradictory. One of the reasons for \nsuch a discrepancy might be the fact that most of the \nresults are from retrospective cohort studies of hospi-\ntalized patients. The vast amount of these studies of-\nfers little actual information because the results differ \nwidely based on exclusion criteria.\nThe mechanisms resulting in malignant transforma-\ntion are unclear, and the fact that benign or at least \nbenign-appearing ovarian masses are often detected \nseveral years before cancer diagnosis [57] makes the \nsituation more problematic. Even more inconclusive \nis the question of the extent to which endometrio-\nsis-ovarian cancer is causative. Somatic mutations \nof PIK3CA, PTEN, and ARID1A might play a role in the \ndisease progression and malignant transformation. \nFig. 4. Genes involved in development of endometriosis, endometriosis-associated ovarian cancer, and ovarian cancer\nEndometriosis\nEndometriosis\nAtypical \nendometriosis\nOvarian \nendometriosis Ovarian cancerEAOC\nPTEN\nBRCA\nPIK\nPTEN\nPIK\nCTNNB\nBRCA\nKRAS\nEAOC\nPTEN\nARIDA\nPIK\nCTNNB\nBRCA\nKRAS\nOvarian cancer\nBRCA ½\nBRAF\nKRAS\nPTEN\nPIK\nBRAF\nMET\n\nMenopause Review/Przegląd Menopauzalny 20(4) 2021\n205\nThe list of potential molecules that might be involved \nis rather long but is almost always based on a simple \ncomparison of the levels of expression in patients with \nendometriosis and ovarian (or other) cancer. To some \nextent, it is almost certain that a  detailed study will \nfind differences in the levels of some molecules, mak-\ning these results interesting but clinically questionable. \nThe possible mechanisms of action remain, however, at \nthe theoretical level only. At present, not a single mark-\ner can be used for diagnosis, let alone treatment. 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