{"paper_id":"617e2fe3-32e3-43f4-89bf-64a1c0e988fc","body_text":"Abstract\n!\nEndometriosis is a common condition in women\nof reproductive age. According to several epide-\nmiological studies endometriosis may be associ-\nated with increased risk of various malignancies.\nHowever, endometriosis-associated malignancy\n(EAM) is defined by certain histological criteria.\nAbout 80 % of EAM have been found in the ovary,\nwhereas 20 % are localized in extragonadal sites\nlike intestine, rectovaginal septum, abdominal\nwall, pleura and others. Some authors suggest\nthat EAM arise from atypical endometriosis as an\nintermediate lesion between endometriosis and\ncancer. Moreover, a number of genetic alterations,\nlike loss of heterozygosity (LOH), PTEN, ARID1 A\nand p53 mutations have been found in both endo-\nmetriosis and EAM. Endometriosis-associated\novarian cancer (EAOC) is mostly a well or inter-\nmediately differentiated tumor of endometrioid\nor clear cell histological sub-type. Women af-\nfected by EAOC are on average five to ten years\nyounger than non-EAOC patients; in most of the\ncases EAOC is a low stage disease with favorable\nclinical outcome. Since EAM is a rare condition\nsystematic data on EAM are still missing. A sys-\ntematic retrospective study on endometriosis-as-\nsociated malignancies (EAM study) is currently\nbeing conducted by the Endometriosis Research\nFoundation together with the study groups on\novarian and uterine tumors of the working group\nfor gynecological oncology (AGO) (gyn@mlk-\nberlin.de).\nZusammenfassung\n!\nEndometriose stellt eine häufige, gutartige Er-\nkrankung der Frau im reproduktiven Alter dar.\nEpidemiologischen Studien zufolge gibt es eine\nAssoziation zwischen Endometriose und dem Ri-\nsiko, an verschiedenen Malignomen zu erkran-\nken. Die Diagnose von endometrioseassoziierten\nMalignomen (EAM) kann jedoch erst nach Erfül-\nlen einiger histologischer Kriterien erfolgen. Circa\n80 % der EAM entstehen im Ovar, während in 20 %\nder Fälle eine primär extragonadale Manifesta-\ntion möglich ist (Darm, rektovaginales Septum,\nBauchwand, Pleura u. a.). Eine der Entstehungs-\ntheorien besagt, dass EAM direkt aus der atypi-\nschen Endometriose entstehen. Darüber hinaus\nwurden bis dato zahlreiche Mutationen wie\nPTEN-, ARID1 A- oder p53-Mutationen sowie He-\nterozygotieverlust sowohl in der Endometriose\nals auch in EAM nachgewiesen. Ein endometrio-\nseassoziiertes Ovarialkarzinom (EAOC) stellt\nmeist ein gut oder mittelgradig differenziertes\nKarzinom vom endometroiden oder klarzelligen\nTyp dar. EAOC-Patientinnen sind durchschnittlich\n5–10 Jahre jünger als Frauen mit Nicht-EAOC; in\nden meisten Fällen wird das EAOC im frühen Sta-\ndium diagnostiziert und hat eine günstige Prog-\nnose. Aufgrund des seltenen Auftretens der EAM\nliegen in der Literatur nur wenige systematische\nStudien zu dieser Entität vor. Eine retrospektive\nStudie zur Charakterisierung endometrioseasso-\nziierter Malignome (EAM-Studie) wird aktuell\nvon der Stiftung Endometrioseforschung gemein-\nsam mit den Kommissionen Ovar und Uterus der\nArbeitsgemeinschaft Gynäkologische Onkologie\n(AGO) durchgeführt (gyn@mlk-berlin.de).\nEndometriosis-associated Malignancy\nEndometriose-assoziierte Malignome\nAuthors N. Krawczyk 1, M. Banys-Paluchowski 1, 4, D. Schmidt 2, U. Ulrich 3,T .F e h m1\nAffiliations 1 Department of Obstetrics and Gynecology, University of Düsseldorf, Düsseldorf\n2 Synlab MVZ Pathologie Mannheim GmbH, A2, 2, Mannheim\n3 Department of Obstetrics and Gynecology, Martin Luther Hospital, Berlin\n4 Department of Obstetrics and Gynecology, Marienkrankenhaus Hamburg, Hamburg\nKey words\nl\" endometriosis\nl\" ovarian cancer\nl\" endometriosis‑associated\nmalignancy\nl\" atypical endometriosis\nl\" malignant transformation\nSchlüsselwörter\nl\" Endometriose\nl\" Ovarialkarzinom\nl\" Endometriose‑assoziierte\nMalignome\nl\" atypische Endometriose\nl\" maligne Transformation\nreceived 17. 7. 2015\nrevised 13. 9. 2015\naccepted 18. 10. 2015\nBibliography\nDOI http://dx.doi.org/\n10.1055/s-0035-1558239\nGeburtsh Frauenheilk 2016; 76:\n176– 181 © Georg Thieme\nVerlag KG Stuttgart · New York ·\nISSN 0016‑5751\nCorrespondence\nDr. Natalia Krawczyk, MD\nDepartment of Obstetrics\nand Gynecology\nUniversity of Düsseldorf\nMoorenstraße 5\n40225 Düsseldorf\nNatalia_krawczyk@yahoo.de\n176\nKrawczyk N et al. Endometriosis-associated Malignancy Geburtsh Frauenheilk 2016; 76: 176 – 181\nGebFra Science\n\n\nAbbreviations\n!\nCCC Clear cell carcinoma\nDFS Disease-free survival\nEAM Endometriosis-associated malignancy\nEAOC Endometriosis-associated ovarian cancer\nHR Hazard ratio\nLOH Loss of heterozygosity\nOC Ovarian cancer\nOR Odds ratio\nOS Overall survival\nPTEN Phosphatase and tensin homolog\nRR Relative risk\nSIR Standardized incidence ratio\nIntroduction\n!\nEndometriosis is a common condition in women in which endo-\nmetrium-like tissue is detected outside the uterine cavity [1]. The\nincidence of the disease in females of reproductive age is esti-\nmated at 5 to 15 % [2]; the main symptoms are dysmenorrhea,\npelvic pain and infertility [3]. Despite extensive research in this\nfield, the exact pathogenesis of endometriosis remains not fully\nunderstood but one widely accepted hypothesis is the implanta-\ntion of endometrial tissue in the peritoneal cavity due to retro-\ngrade menstruation [4]. Although endometriosis is considered a\nbenign condition, it has been demonstrated to share some char-\nacteristics with malignant tumors such as tissue invasion and\ndamage, neoangiogenesis or spread to distant organs [5]. Current\nknowledge about endometriosis-associated malignancies will be\npresented in this review.\nEndometriosis and Cancer Risk – Epidemiological Data\n!\nAccording to several epidemiological studies endometriosis is as-\nsociated with increased risk of various malignancies with the best\nevidence for ovarian cancer [6–18]. Furthermore, a number of co-\nhort and case control studies demonstrated an epidemiological\nassociation of endometriosis with endometrial cancer, breast\ncancer, colorectal cancer, non-Hodgkin lymphoma and others [8,\n19, 20]. The clinical significance of the association between endo-\nmetriosis and non-gynecologic malignancies is poorly under-\nstood [21].\nThe majority of the published studies on endometriosis-associ-\nated ovarian cancer have reported that ovarian cancer (OC) risk\namong endometriosis patients is moderately increased (RR, SIR\nor OR 1.32 –1.92) ( l\n\" Table 1 ). The strongest association between\nOC and endometriosis was reported by Brinton et al. (SIR = 2.48)\n[8], Stewart et al. [22] (HR = 2.33) and Buis et al. [23] (HR = 12.4);\ninterestingly, these three studies included only women suffering\nfrom infertility, which may be a potential confounding factor for\ntheir results. Moreover, a remarkably high increase of ovarian\ncancer risk (SIR = 8.95) has been demonstrated by Kobayashi et\nal. [24]. In their retrospective cohort study ovarian cancer risk\nwas analysed in women with sonographically diagnosed endo-\nmetriomas based on time periods from first diagnosis of endo-\nmetrioma to first diagnosis of ovarian cancer. Since endometrio-\nmas were histologically confirmed in only one-third of the cases,\nwhereas the majority of diagnoses was made based on ultra-\nsound image, the ovarian cancer risk has been possibly overesti-\nmated in this analysis: some of ovarian cysts identified as endo-\nmetriomas might have been in fact ovarian cancers. In summary,\nthere are a number of epidemiological studies, in which at least a\nmodest association between endometriosis and ovarian cancer\nhas been consistently demonstrated. Despite epidemiological\nevidence, a direct causal association between endometriosis and\novarian cancer has not been elucidated so far [25].\nHistological Findings\n!\nThe histological link between endometriosis and cancer has first\nbeen postulated as early as 1925 [26]. Sampson et al., based on\nmicroscopic observations, speculated that endometrial ovarian\ncancer may develop from endometriotic tissue and described\nthe criteria for diagnosis of endometriosis-associated OC: (1) evi-\ndence of endometriosis close to the tumor, (2) exclusion of inva-\nsion from other sources, (3) presence of tissue resembling endo-\nmetrial stoma surrounding characteristic epithelial glands [26].\nScott et al., in their analysis from 1953, added a fourth criterion:\nTable 1 Epidemiological studies on association between endometriosis and ovarian cancer.\nAuthor Type of study Number of\nendometriosis cases\nNumber of\ncancer cases\nNumber of\ncontrols\nOR, SIR, HR or RR\n(95 % CI)\nBrinton 1997 [8] cohort 20 686 29 1.92 (1.3 – 2.8)\nNess 2000 [10] case control 66 (85 CG) 767 1 367 1.7 (1.2 – 2.4)\nNess 2002 [11] case control 51 (39 CG) 5 207 7 705 1.73 (1.10 – 2.71)\nOlson 2002 [12] cohort 1 392 3 0.78 (0.25 – 2.44)\nBrinton 2004 [13] cohort 12 193 45 2.48 (1.3 – 4.2)\nBorgfeldt and Andolf 2004 [14] nested case control 28 163 81 84 489 1.34 (1.03 – 1.75)\nModugno 2004 [15] case control 177 (184 CG) 2 098 2 953 1.32 (1.06 – 1.65)\nMelin 2006 [16] cohort 64 992 122 1.43 (1.19 – 1.71)\nMelin 2007 [17] cohort 63 630 134 1.37 (1.14 – 1.62)\nKobayashi 2007 [24] cohort 6 398 46 8.95 (4.12 – 15.3)\nPearce 2012 [18] case control 738 (818 CG) 7 911 13 226 1.49 (1.24 – 1.65)\nStewart 2012 [22] cohort 2 978 38 2.33 (1.02 – 5.35)\nBuis 2013 [23] cohort 3 657 34 12.4 (2.8 – 54.2)\nKok 2015 [20] cohort 2 266 13 4.56 (1.72 – 12.11)\nCG: control group, RR: relative risk, OR: odds ratio, HR: hazard ratio, SIR: standardized incidence ratio\n177\nKrawczyk N et al. Endometriosis-associated Malignancy Geburtsh Frauenheilk 2016; 76: 176 – 181\nReview\n\n\n(4) histological proof of transition from benign changes in endo-\nmetriosis to malignant changes in cancer [27]; all four criteria are\nstill in use to define an endometriosis-associated malignancy\n(EAM).\nAbout 80 % of EAMs are localized in the ovary, whereas extrago-\nnadal sites are affected in one-fourth to one-fifth of all cases [9,\n28]. In two large reviews of endometriosis-related neoplasms\n(222 and 205 cases, respectively), extragonadal tumors were re-\nported in 21 –24 % of women [29, 30]. Since the malignant trans-\nformation can take place in every site affected by endometriosis,\nextragonadal EAMs can be found in the lower pelvis, gastrointes-\ntinal tract, abdominal wall, umbilicus, pleura and others [31]. The\nmost common localisations of extragonadal EAMs are the recto-\nsigmoid, colon, rectovaginal septum and pelvic peritoneum;\nthese sites are commonly involved by deep infiltrating endome-\ntriosis [31].\nBased on histopathology and molecular features, ovarian cancers\nare divided into five main categories: high-grade serous, endo-\nmetrioid, clear cell, mucinous, and low-grade serous carcinomas\n[32]. The most common subtype is the high-grade serous cancer\n(70 %), followed by the endometrioid (10 %) and clear cell (10 %)\ntype. Endometrioid and clear cell carcinomas usually present as\nlow-stage disease; the former is typically well differentiated\n[33]. Endometriosis-associated malignancies are most commonly\ncancers of these two histologic subtypes, rarely other ovarian ma-\nlignancy types like borderline tumors, endometrial stromal sar-\ncoma or adenosarcoma [18, 25, 28, 31]. Recently published pooled\nanalysis of case-controlled studies by Pearce et al. reported an in-\ncreased risk for low-grade serous ovarian cancer among endome-\ntriosis patients as well (RR 2.11; 95 % CI 1.39 –3.20, p < 0.0001)\n[18]. No association between endometriosis and high-grade se-\nrous ovarian cancer or mucinous ovarian cancer has been re-\nported to date [18, 28].\nTheories of Pathogenesis\n!\nThere are two main theories which attempt to explain the origin\nof endometriosis-associated malignancies. According to a num-\nber of histopathological studies endometriosis-associated ovar-\nian cancer (EAOC) may arise from atypical endometriosis of the\novary [34, 35]. This heterogeneous condition is histologically\ncharacterized by hyperplasia of endometrial glands with cytolog-\nical atypia or presence of atypical hobnail cells within ovarian en-\ndometriosis [25, 36, 37]. A direct association between atypical en-\ndometriosis and ovarian cancer was first demonstrated by La\nGrenade and Silverberg in 1988 [34]; in five cases of ovarian can-\ncer (three clear cell carcinomas and two endometrioid carcino-\nmas) accompanying atypical endometriosis was found in the ova-\nry and in four out of five cases atypical changes were in contigu-\nity with ovarian neoplasm [34]. Furthermore, a significantly\nhigher rate of cytological atypia within endometriotic lesion was\ndemonstrated in cases of EAOC compared with endometriosis\nalone [38]. Although the hypothesis that atypical endometriosis\nmay be a premalignant condition is supported by the fact that it\ncan be detected in up to 80 % of EAOC, there are still not enough\ndata proving this model [35, 39, 40].\nAccording to the other theory endometriosis is not a real precan-\ncerous lesion, but there is an indirect link involving common en-\nvironmental, histological, immunological and genetic factors.\nSeveral studies have demonstrated that microenvironment of en-\ndometriosis and EAOC share similar mediators and cytokines [40,\n41]. Whether EAM arise by malignant transformation of endo-\nmetriotic cells through intermediary lesions (atypical endome-\ntriosis) or similarity of microenviroment represents a link be-\ntween these both entities has not been definitely understood\n[40, 42].\nGenetic Alterations\n!\nIn the last two decades, evidence has been accumulated that en-\ndometriosis-associated malignancies may arise within ovarian\nendometriosis. Possibly, periodic hemorrhage in ovarian endo-\nmetriomas may lead to iron-triggered oxidative stress and thus\ninduce genetic alterations. Yamaguchi et al. reported that the\nconcentration of free iron in endometriotic cysts was over one\nhundred times higher than that in nonendometriotic cysts; the\nlevel of oxidative stress related markers, such as lactose dehydro-\ngenase, and antioxidants was higher as well [43].\nAccumulation of mutations in tumor suppressor genes and onco-\ngenes is a crucial step during tumor development. Interestingly,\nnumerous mutations in genes linked to carcinogenesis have been\nidentified in endometriotic lesions [44 –52]. Several studies have\nreported genetic aberrations in tumor suppression genes, such as\np53 and PTEN, in endometriosis specimens [53 –55]. Inactivation\nof DNA mismatch repair genes through hypermethylation has\nbeen observed in endometriotic tissue as well [53]. Furthermore,\ngenetic alterations associated with tumorigenesis are encoun-\ntered more frequently in benign endometriosis samples from pa-\ntients with synchronous ovarian cancer than in tumor-free pa-\ntients who were diagnosed with endometriosis alone. Prowse et\nal. performed microsatellite analysis in ten patients with ovarian\ncancer and coexisting endometriosis; the tumor and endometrio-\nsis samples were analysed for common molecular genetic altera-\ntions [56]. 63 events of loss of heterozygosity (LOH) were detected\nin cancer specimens; one-third of these was also identified in the\ncorresponding endometriosis samples, suggesting that endome-\ntriosis might be a clonal precursor to a subtype of ovarian cancer.\nHypothetically, endometriosis-associated and endometriosis-in-\ndependent ovarian cancer may develop through different molec-\nular pathways with distinct genetic alterations (l\n\" Table 2).\nRisk Factors\n!\nSeveral risk factors for EAM in patients with endometriosis have\nbeen reported to date. The size of endometrioma as well as post-\nmenopausal status were demonstrated to be independent pre-\ndictive factors for the development of ovarian cancer among en-\ndometriosis patients in the study by Kobayashi et al. [57]. In this\nprospective cohort trial which assessed the risk of ovarian cancer\nin 6398 women with ovarian endometriomas, tumor size ≥ 9c m\nin diameter was shown to be associated with increased OC risk.\nHowever, as mentioned before, one of the limitations of this\nstudy is that endometriomas were diagnosed mostly by sonogra-\nphy, and therefore some of the larger tumors might in fact have\nbeen ovarian cancers [57]. Another risk factor for EAM is hyper-\nestrogenism, both endo- and exogenous: in the study by Zanetta\net al. obesity as well as therapy with unopposed estrogens after\nhysterectomy were shown to be a significant risk factor for the\ndevelopment of EAM [58]. Similar effects of estrogen were dem-\nonstrated by others [40]. On the other hand, hormonal contra-\nception, childbearing, tubal ligation or hysterectomy were found\n178\nKrawczyk N et al. Endometriosis-associated Malignancy Geburtsh Frauenheilk 2016; 76: 176 – 181\nGebFra Science\n\n\nto reduce the ovarian cancer risk among patients with endome-\ntriosis [15, 59].\nClinical Implications\n!\nEAOC is characterized by an early onset of the disease: Aris et al.\nreported in their retrospective cohort trial that the mean age of\nwomen with EAOC was 48.3 ± 10.8, on average 5.5 years lower\nthan in non EAOC patients (p = 0.003) [60]. In a retrospective\nstudy by Orezzoli et al. patients with endometriosis-associated\nclear cell cancer (CCC) of the ovary were even 10 years younger\ncompared with those with non-endometriosis-associated CCC\n(95 % CI 0.6–18 years; p < 0.05) [61].\nInterestingly, EAOC is commonly a low-stage and low-grade dis-\nease usually without ascites at initial presentation [62, 63]. Fur-\nthermore, several authors reported that EAOC is associated with\nsignificantly better prognosis (DFS and OS) compared with non-\nEAOC, suggesting that EAOC represents a biologically distinct en-\ntity [28, 61, 64, 65]. However, these findings have not been con-\nfirmed by others: after controlling for stage, age, grade and treat-\nment no difference in overall survival between these two patient\ngroups could be demonstrated [62, 66, 67]; thus, better clinical\noutcome of EAOC might be explained by a high rate of well-dif-\nferentiated early-stage tumors rather than by an association with\nendometriosis per se [62, 63, 67].\nBased on existing data on incidence and risk factors of EAM, the\npossibility of malignant transformation should be included in di-\nagnostic considerations for patients with endometriosis [21], es-\npecially in postmenopausal women who present a sudden recur-\nrence of symptoms. Because of the malignant potential, endome-\ntriosis patients should, if indicated, receive a combined estrogen-\nprogestin therapy (HRT, hormone replacement therapy) or tibo-\nlone even after hysterectomy; unopposed estrogens should gen-\nerally be avoided in these patients [21, 68, 69]. Clinicians should\nbe aware of the increased risk of specific subtypes of ovarian car-\ncinoma in endometriosis patients. A modest increase in cancer\nrisk should be discussed with these patients [70]. The risk of\novarian cancer is highest in women with endometriosis and pri-\nmary infertility [13]. However, there are currently no diagnostic\noptions to predict the risk of malignant transformation in an in-\ndividual patient. Future studies should aim at understanding the\nmechanisms underlying this phenomenon so as to identify pa-\ntients who are most at risk for developing endometriosis-related\nmalignancy.\nSince EAM are mostly low-grade tumors, there is the question of\nthe efficacy of chemotherapy in EAOC patients [29]. However, in\nthe study by Davis et al. no difference in response to chemother-\napy in EAOC patients compared with controls with papillary se-\nrous ovarian cancer has been found [62]. Due to the lack of appro-\npriate data postoperative treatment of EAOC follows the standard\nchemotherapy guidelines for ovarian cancer [71]. In case of extra-\ngonadal EAM, especially of rectum or rectovaginal septum, how-\never, surgical resection followed by radiotherapy may be the\ntreatment of choice [29, 31, 65].\nSeveral epidemiological studies, case reports and case series on\nEAM have been published in the literature to date. However, a\nsystematic analysis of a large population of patients with EAM is\nstill missing. Thus, a systematic retrospective study on endome-\ntriosis-associated malignancies (EAM study) is currently being\nconducted by the Endometriosis Research Foundation together\nwith the study groups on ovarian and uterine tumors of the\nworking group for gynecological oncology (AGO). Histopatholog-\nical second opinion by pathology reference laboratory is the core\nTable 2 Genetic alterations associated with endometriosis and endometriosis-related malignancies.\nFactor Genetic\nalteration\nCurrent data\nOxidative\nstress\n8-OHdG 8-Oxo-2 ′-deoxyguanosine is a marker of oxidative DNA damage. Endometriosis-related ovarian cancer show significantly\nstronger staining of 8-OHdG than ovarian cancers not accompanied by endometriosis [43]. Endometriotic cysts and atyp-\nical endometriosis also stain positive for this marker. 8-OHdG seems to play a role in pathogenesis of ovarian cancer and was\nlinked to poor prognosis [44].\nTumor\nsuppressor\ngenes\nPTEN Phosphatase and tensin homolog is mutated in many cancer entities, particularly in endometrial and endometrioid ovarian\ncancer; its inactivation occurs early during tumorigenesis [53]. PTEN somatic mutations are frequently found in endo-\nmetriotic cysts [45].\np53 As a negative cell-cycle regulator, p53 is involved in tumorigenesis of different malignancies. Several studies showed no\nexpression in benign endometriosis but high expression in benign endometriotic lesions next to the endometrioid or clear\ncell carcinoma [54].\nARID1A ARID1A mutations are significantly more common in two ovarian cancer subtypes associated with endometriosis (clear-\ncell and endometrioid). In case of endometriosis synchronous with ovarian cancer, mutation was more frequent in clones\nderived from endometriosis samples directly adjacent of the tumor than in those from distant endometriotic lesions [46].\nDNA repair hMLH1 hMLH1 corrects errors in DNA replication; hypermethylation of its promoter occurs early in endometrial malignant trans-\nformation and can be identified in 10 % of typical and in 33 % of atypical endometrial hyperplasias [47]. Abnormal methyl-\nation can be observed in endometriosis as well [53].\nOncogene Bcl-2 Expression of this anti-apoptotic protein is significantly higher in endometriosis accompanying cancer (42 – 73 %) than in\nbenign endometriosis (23 %) [54], suggesting its role in the early steps of tumorigenesis.\nKRAS KRAS mutations are significantly more common in endometriosis-associated endometrioid adenocarcinomas (29 %) than\nin tumors not associated with endometriosis (3 %) [48].\nChromosomic\naberrations\nAneuploidy Aneuploidic frequency seems higher in endometriosis specimen from patients with advanced endometriosis when com-\npared to the background frequency observed in normal specimens, particularly with regard to chromosome 17, on which\ntumor suppressor gene p53 is located [49, 50].\nLoss of\nheterozygosity\n(LOH)\nA trend of increasing LOH frequencies has been described between solitary endometriosis lesions, endometriosis-associ-\nated carcinoma and endometrioid ovarian cancer, respectively [51, 52]. Common LOH events can be identified in endo-\nmetriosis synchronous with ovarian cancer [45, 56].\n179\nKrawczyk N et al. Endometriosis-associated Malignancy Geburtsh Frauenheilk 2016; 76: 176 – 181\nReview\n\n\ncomponent of this study (for more information: gyn@mlk-berlin.\nde).\nConflict of Interest\n!\nNone.\nReferences\n1 Vignali M, Infantino M, Matrone R et al. Endometriosis: novel etiopa-\nthogenetic concepts and clinical perspectives. Fertil Steril 2002; 78:\n665–678\n2 Sayasneh A, Tsivos D, Crawford R. Endometriosis and ovarian cancer: a\nsystematic review. ISRN Obstet Gynecol 2011; 2011: 140310\n3 Berkley KJ, Rapkin AJ, Papka RE. The pains of endometriosis. Science\n2005; 308: 1587 –1589\n4 Gazvani R, Templeton A. New considerations for the pathogenesis of\nendometriosis. Int J Gynaecol Obstet 2002; 76: 117 –126\n5 Siufi Neto J, Kho RM, Siufi DF et al. Cellular, histologic, and molecular\nchanges associated with endometriosis and ovarian cancer. 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