Endometriosis-associated Malignancy

! Endometriosis is a common condition in women of reproductive age. According to several epide- miological studies endometriosis may be associ- ated with increased risk of various malignancies. However, endometriosis-associated malignancy (EAM) is defined by certain histological criteria. About 80 % of EAM have been found in the ovary, whereas 20 % are localized in extragonadal sites like intestine, rectovaginal septum, abdominal wall, pleura and others. Some authors suggest that EAM arise from atypical endometriosis as an intermediate lesion between endometriosis and cancer. Moreover, a number of genetic alterations, like loss of heterozygosity (LOH), PTEN, ARID1 A and p53 mutations have been found in both endo- metriosis and EAM. Endometriosis-associated ovarian cancer (EAOC) is mostly a well or inter- mediately differentiated tumor of endometrioid or clear cell histological sub-type. Women af- fected by EAOC are on average five to ten years younger than non-EAOC patients; in most of the cases EAOC is a low stage disease with favorable clinical outcome. Since EAM is a rare condition systematic data on EAM are still missing. A sys- tematic retrospective study on endometriosis-as- sociated malignancies (EAM study) is currently being conducted by the Endometriosis Research Foundation together with the study groups on ovarian and uterine tumors of the working group for gynecological oncology (AGO) (gyn@mlk- berlin.de). Zusammenfassung ! Endometriose stellt eine häufige, gutartige Er- krankung der Frau im reproduktiven Alter dar. Epidemiologischen Studien zufolge gibt es eine Assoziation zwischen Endometriose und dem Ri- siko, an verschiedenen Malignomen zu erkran- ken. Die Diagnose von endometrioseassoziierten Malignomen (EAM) kann jedoch erst nach Erfül- len einiger histologischer Kriterien erfolgen. Circa 80 % der EAM entstehen im Ovar, während in 20 % der Fälle eine primär extragonadale Manifesta- tion möglich ist (Darm, rektovaginales Septum, Bauchwand, Pleura u. a.). Eine der Entstehungs- theorien besagt, dass EAM direkt aus der atypi- schen Endometriose entstehen. Darüber hinaus wurden bis dato zahlreiche Mutationen wie PTEN-, ARID1 A- oder p53-Mutationen sowie He- terozygotieverlust sowohl in der Endometriose als auch in EAM nachgewiesen. Ein endometrio- seassoziiertes Ovarialkarzinom (EAOC) stellt meist ein gut oder mittelgradig differenziertes Karzinom vom endometroiden oder klarzelligen Typ dar. EAOC-Patientinnen sind durchschnittlich 5–10 Jahre jünger als Frauen mit Nicht-EAOC; in den meisten Fällen wird das EAOC im frühen Sta- dium diagnostiziert und hat eine günstige Prog- nose. Aufgrund des seltenen Auftretens der EAM liegen in der Literatur nur wenige systematische Studien zu dieser Entität vor. Eine retrospektive Studie zur Charakterisierung endometrioseasso- ziierter Malignome (EAM-Studie) wird aktuell von der Stiftung Endometrioseforschung gemein- sam mit den Kommissionen Ovar und Uterus der Arbeitsgemeinschaft Gynäkologische Onkologie (AGO) durchgeführt ([email protected]). Endometriosis-associated Malignancy Endometriose-assoziierte Malignome Authors N. Krawczyk 1, M. Banys-Paluchowski 1, 4, D. Schmidt 2, U. Ulrich 3,T .F e h m1 Affiliations 1 Department of Obstetrics and Gynecology, University of Düsseldorf, Düsseldorf 2 Synlab MVZ Pathologie Mannheim GmbH, A2, 2, Mannheim 3 Department of Obstetrics and Gynecology, Martin Luther Hospital, Berlin 4 Department of Obstetrics and Gynecology, Marienkrankenhaus Hamburg, Hamburg Key words l" endometriosis l" ovarian cancer l" endometriosis‑associated malignancy l" atypical endometriosis l" malignant transformation Schlüsselwörter l" Endometriose l" Ovarialkarzinom l" Endometriose‑assoziierte Malignome l" atypische Endometriose l" maligne Transformation received 17. 7. 2015 revised 13. 9. 2015 accepted 18. 10. 2015

DOI http://dx.doi.org/ 10.1055/s-0035-1558239 Geburtsh Frauenheilk 2016; 76: 176– 181 © Georg Thieme Verlag KG Stuttgart · New York · ISSN 0016‑5751 Correspondence Dr. Natalia Krawczyk, MD Department of Obstetrics and Gynecology University of Düsseldorf Moorenstraße 5 40225 Düsseldorf [email protected] 176 Krawczyk N et al. Endometriosis-associated Malignancy Geburtsh Frauenheilk 2016; 76: 176 – 181 GebFra Science Abbreviations ! CCC Clear cell carcinoma DFS Disease-free survival EAM Endometriosis-associated malignancy EAOC Endometriosis-associated ovarian cancer HR Hazard ratio LOH Loss of heterozygosity OC Ovarian cancer OR Odds ratio OS Overall survival PTEN Phosphatase and tensin homolog RR Relative risk SIR Standardized incidence ratio

! Endometriosis is a common condition in women in which endo- metrium-like tissue is detected outside the uterine cavity [1]. The incidence of the disease in females of reproductive age is esti- mated at 5 to 15 % [2]; the main symptoms are dysmenorrhea, pelvic pain and infertility [3]. Despite extensive research in this field, the exact pathogenesis of endometriosis remains not fully understood but one widely accepted hypothesis is the implanta- tion of endometrial tissue in the peritoneal cavity due to retro- grade menstruation [4]. Although endometriosis is considered a benign condition, it has been demonstrated to share some char- acteristics with malignant tumors such as tissue invasion and damage, neoangiogenesis or spread to distant organs [5]. Current knowledge about endometriosis-associated malignancies will be presented in this review. Endometriosis and Cancer Risk – Epidemiological Data ! According to several epidemiological studies endometriosis is as- sociated with increased risk of various malignancies with the best evidence for ovarian cancer [6–18]. Furthermore, a number of co- hort and case control studies demonstrated an epidemiological association of endometriosis with endometrial cancer, breast cancer, colorectal cancer, non-Hodgkin lymphoma and others [8, 19, 20]. The clinical significance of the association between endo- metriosis and non-gynecologic malignancies is poorly under- stood [21]. The majority of the published studies on endometriosis-associ- ated ovarian cancer have reported that ovarian cancer (OC) risk among endometriosis patients is moderately increased (RR, SIR or OR 1.32 –1.92) ( l " Table 1 ). The strongest association between OC and endometriosis was reported by Brinton et al. (SIR = 2.48) [8], Stewart et al. [22] (HR = 2.33) and Buis et al. [23] (HR = 12.4); interestingly, these three studies included only women suffering from infertility, which may be a potential confounding factor for their results. Moreover, a remarkably high increase of ovarian cancer risk (SIR = 8.95) has been demonstrated by Kobayashi et al. [24]. In their retrospective cohort study ovarian cancer risk was analysed in women with sonographically diagnosed endo- metriomas based on time periods from first diagnosis of endo- metrioma to first diagnosis of ovarian cancer. Since endometrio- mas were histologically confirmed in only one-third of the cases, whereas the majority of diagnoses was made based on ultra- sound image, the ovarian cancer risk has been possibly overesti- mated in this analysis: some of ovarian cysts identified as endo- metriomas might have been in fact ovarian cancers. In summary, there are a number of epidemiological studies, in which at least a modest association between endometriosis and ovarian cancer has been consistently demonstrated. Despite epidemiological evidence, a direct causal association between endometriosis and ovarian cancer has not been elucidated so far [25]. Histological Findings ! The histological link between endometriosis and cancer has first been postulated as early as 1925 [26]. Sampson et al., based on microscopic observations, speculated that endometrial ovarian cancer may develop from endometriotic tissue and described the criteria for diagnosis of endometriosis-associated OC: (1) evi- dence of endometriosis close to the tumor, (2) exclusion of inva- sion from other sources, (3) presence of tissue resembling endo- metrial stoma surrounding characteristic epithelial glands [26]. Scott et al., in their analysis from 1953, added a fourth criterion: Table 1 Epidemiological studies on association between endometriosis and ovarian cancer. Author Type of study Number of endometriosis cases Number of cancer cases Number of controls OR, SIR, HR or RR (95 % CI) Brinton 1997 [8] cohort 20 686 29 1.92 (1.3 – 2.8) Ness 2000 [10] case control 66 (85 CG) 767 1 367 1.7 (1.2 – 2.4) Ness 2002 [11] case control 51 (39 CG) 5 207 7 705 1.73 (1.10 – 2.71) Olson 2002 [12] cohort 1 392 3 0.78 (0.25 – 2.44) Brinton 2004 [13] cohort 12 193 45 2.48 (1.3 – 4.2) Borgfeldt and Andolf 2004 [14] nested case control 28 163 81 84 489 1.34 (1.03 – 1.75) Modugno 2004 [15] case control 177 (184 CG) 2 098 2 953 1.32 (1.06 – 1.65) Melin 2006 [16] cohort 64 992 122 1.43 (1.19 – 1.71) Melin 2007 [17] cohort 63 630 134 1.37 (1.14 – 1.62) Kobayashi 2007 [24] cohort 6 398 46 8.95 (4.12 – 15.3) Pearce 2012 [18] case control 738 (818 CG) 7 911 13 226 1.49 (1.24 – 1.65) Stewart 2012 [22] cohort 2 978 38 2.33 (1.02 – 5.35) Buis 2013 [23] cohort 3 657 34 12.4 (2.8 – 54.2) Kok 2015 [20] cohort 2 266 13 4.56 (1.72 – 12.11) CG: control group, RR: relative risk, OR: odds ratio, HR: hazard ratio, SIR: standardized incidence ratio 177 Krawczyk N et al. Endometriosis-associated Malignancy Geburtsh Frauenheilk 2016; 76: 176 – 181 Review (4) histological proof of transition from benign changes in endo- metriosis to malignant changes in cancer [27]; all four criteria are still in use to define an endometriosis-associated malignancy (EAM). About 80 % of EAMs are localized in the ovary, whereas extrago- nadal sites are affected in one-fourth to one-fifth of all cases [9, 28]. In two large reviews of endometriosis-related neoplasms (222 and 205 cases, respectively), extragonadal tumors were re- ported in 21 –24 % of women [29, 30]. Since the malignant trans- formation can take place in every site affected by endometriosis, extragonadal EAMs can be found in the lower pelvis, gastrointes- tinal tract, abdominal wall, umbilicus, pleura and others [31]. The most common localisations of extragonadal EAMs are the recto- sigmoid, colon, rectovaginal septum and pelvic peritoneum; these sites are commonly involved by deep infiltrating endome- triosis [31]. Based on histopathology and molecular features, ovarian cancers are divided into five main categories: high-grade serous, endo- metrioid, clear cell, mucinous, and low-grade serous carcinomas [32]. The most common subtype is the high-grade serous cancer (70 %), followed by the endometrioid (10 %) and clear cell (10 %) type. Endometrioid and clear cell carcinomas usually present as low-stage disease; the former is typically well differentiated [33]. Endometriosis-associated malignancies are most commonly cancers of these two histologic subtypes, rarely other ovarian ma- lignancy types like borderline tumors, endometrial stromal sar- coma or adenosarcoma [18, 25, 28, 31]. Recently published pooled analysis of case-controlled studies by Pearce et al. reported an in- creased risk for low-grade serous ovarian cancer among endome- triosis patients as well (RR 2.11; 95 % CI 1.39 –3.20, p < 0.0001) [18]. No association between endometriosis and high-grade se- rous ovarian cancer or mucinous ovarian cancer has been re- ported to date [18, 28]. Theories of Pathogenesis ! There are two main theories which attempt to explain the origin of endometriosis-associated malignancies. According to a num- ber of histopathological studies endometriosis-associated ovar- ian cancer (EAOC) may arise from atypical endometriosis of the ovary [34, 35]. This heterogeneous condition is histologically characterized by hyperplasia of endometrial glands with cytolog- ical atypia or presence of atypical hobnail cells within ovarian en- dometriosis [25, 36, 37]. A direct association between atypical en- dometriosis and ovarian cancer was first demonstrated by La Grenade and Silverberg in 1988 [34]; in five cases of ovarian can- cer (three clear cell carcinomas and two endometrioid carcino- mas) accompanying atypical endometriosis was found in the ova- ry and in four out of five cases atypical changes were in contigu- ity with ovarian neoplasm [34]. Furthermore, a significantly higher rate of cytological atypia within endometriotic lesion was demonstrated in cases of EAOC compared with endometriosis alone [38]. Although the hypothesis that atypical endometriosis may be a premalignant condition is supported by the fact that it can be detected in up to 80 % of EAOC, there are still not enough data proving this model [35, 39, 40]. According to the other theory endometriosis is not a real precan- cerous lesion, but there is an indirect link involving common en- vironmental, histological, immunological and genetic factors. Several studies have demonstrated that microenvironment of en- dometriosis and EAOC share similar mediators and cytokines [40, 41]. Whether EAM arise by malignant transformation of endo- metriotic cells through intermediary lesions (atypical endome- triosis) or similarity of microenviroment represents a link be- tween these both entities has not been definitely understood [40, 42]. Genetic Alterations ! In the last two decades, evidence has been accumulated that en- dometriosis-associated malignancies may arise within ovarian endometriosis. Possibly, periodic hemorrhage in ovarian endo- metriomas may lead to iron-triggered oxidative stress and thus induce genetic alterations. Yamaguchi et al. reported that the concentration of free iron in endometriotic cysts was over one hundred times higher than that in nonendometriotic cysts; the level of oxidative stress related markers, such as lactose dehydro- genase, and antioxidants was higher as well [43]. Accumulation of mutations in tumor suppressor genes and onco- genes is a crucial step during tumor development. Interestingly, numerous mutations in genes linked to carcinogenesis have been identified in endometriotic lesions [44 –52]. Several studies have reported genetic aberrations in tumor suppression genes, such as p53 and PTEN, in endometriosis specimens [53 –55]. Inactivation of DNA mismatch repair genes through hypermethylation has been observed in endometriotic tissue as well [53]. Furthermore, genetic alterations associated with tumorigenesis are encoun- tered more frequently in benign endometriosis samples from pa- tients with synchronous ovarian cancer than in tumor-free pa- tients who were diagnosed with endometriosis alone. Prowse et al. performed microsatellite analysis in ten patients with ovarian cancer and coexisting endometriosis; the tumor and endometrio- sis samples were analysed for common molecular genetic altera- tions [56]. 63 events of loss of heterozygosity (LOH) were detected in cancer specimens; one-third of these was also identified in the corresponding endometriosis samples, suggesting that endome- triosis might be a clonal precursor to a subtype of ovarian cancer. Hypothetically, endometriosis-associated and endometriosis-in- dependent ovarian cancer may develop through different molec- ular pathways with distinct genetic alterations (l " Table 2). Risk Factors ! Several risk factors for EAM in patients with endometriosis have been reported to date. The size of endometrioma as well as post- menopausal status were demonstrated to be independent pre- dictive factors for the development of ovarian cancer among en- dometriosis patients in the study by Kobayashi et al. [57]. In this prospective cohort trial which assessed the risk of ovarian cancer in 6398 women with ovarian endometriomas, tumor size ≥ 9c m in diameter was shown to be associated with increased OC risk. However, as mentioned before, one of the limitations of this study is that endometriomas were diagnosed mostly by sonogra- phy, and therefore some of the larger tumors might in fact have been ovarian cancers [57]. Another risk factor for EAM is hyper- estrogenism, both endo- and exogenous: in the study by Zanetta et al. obesity as well as therapy with unopposed estrogens after hysterectomy were shown to be a significant risk factor for the development of EAM [58]. Similar effects of estrogen were dem- onstrated by others [40]. On the other hand, hormonal contra- ception, childbearing, tubal ligation or hysterectomy were found 178 Krawczyk N et al. Endometriosis-associated Malignancy Geburtsh Frauenheilk 2016; 76: 176 – 181 GebFra Science to reduce the ovarian cancer risk among patients with endome- triosis [15, 59]. Clinical Implications ! EAOC is characterized by an early onset of the disease: Aris et al. reported in their retrospective cohort trial that the mean age of women with EAOC was 48.3 ± 10.8, on average 5.5 years lower than in non EAOC patients (p = 0.003) [60]. In a retrospective study by Orezzoli et al. patients with endometriosis-associated clear cell cancer (CCC) of the ovary were even 10 years younger compared with those with non-endometriosis-associated CCC (95 % CI 0.6–18 years; p < 0.05) [61]. Interestingly, EAOC is commonly a low-stage and low-grade dis- ease usually without ascites at initial presentation [62, 63]. Fur- thermore, several authors reported that EAOC is associated with significantly better prognosis (DFS and OS) compared with non- EAOC, suggesting that EAOC represents a biologically distinct en- tity [28, 61, 64, 65]. However, these findings have not been con- firmed by others: after controlling for stage, age, grade and treat- ment no difference in overall survival between these two patient groups could be demonstrated [62, 66, 67]; thus, better clinical outcome of EAOC might be explained by a high rate of well-dif- ferentiated early-stage tumors rather than by an association with endometriosis per se [62, 63, 67]. Based on existing data on incidence and risk factors of EAM, the possibility of malignant transformation should be included in di- agnostic considerations for patients with endometriosis [21], es- pecially in postmenopausal women who present a sudden recur- rence of symptoms. Because of the malignant potential, endome- triosis patients should, if indicated, receive a combined estrogen- progestin therapy (HRT, hormone replacement therapy) or tibo- lone even after hysterectomy; unopposed estrogens should gen- erally be avoided in these patients [21, 68, 69]. Clinicians should be aware of the increased risk of specific subtypes of ovarian car- cinoma in endometriosis patients. A modest increase in cancer risk should be discussed with these patients [70]. The risk of ovarian cancer is highest in women with endometriosis and pri- mary infertility [13]. However, there are currently no diagnostic options to predict the risk of malignant transformation in an in- dividual patient. Future studies should aim at understanding the mechanisms underlying this phenomenon so as to identify pa- tients who are most at risk for developing endometriosis-related malignancy. Since EAM are mostly low-grade tumors, there is the question of the efficacy of chemotherapy in EAOC patients [29]. However, in the study by Davis et al. no difference in response to chemother- apy in EAOC patients compared with controls with papillary se- rous ovarian cancer has been found [62]. Due to the lack of appro- priate data postoperative treatment of EAOC follows the standard chemotherapy guidelines for ovarian cancer [71]. In case of extra- gonadal EAM, especially of rectum or rectovaginal septum, how- ever, surgical resection followed by radiotherapy may be the treatment of choice [29, 31, 65]. Several epidemiological studies, case reports and case series on EAM have been published in the literature to date. However, a systematic analysis of a large population of patients with EAM is still missing. Thus, a systematic retrospective study on endome- triosis-associated malignancies (EAM study) is currently being conducted by the Endometriosis Research Foundation together with the study groups on ovarian and uterine tumors of the working group for gynecological oncology (AGO). Histopatholog- ical second opinion by pathology reference laboratory is the core Table 2 Genetic alterations associated with endometriosis and endometriosis-related malignancies. Factor Genetic alteration Current data Oxidative stress 8-OHdG 8-Oxo-2 ′-deoxyguanosine is a marker of oxidative DNA damage. Endometriosis-related ovarian cancer show significantly stronger staining of 8-OHdG than ovarian cancers not accompanied by endometriosis [43]. Endometriotic cysts and atyp- ical endometriosis also stain positive for this marker. 8-OHdG seems to play a role in pathogenesis of ovarian cancer and was linked to poor prognosis [44]. Tumor suppressor genes PTEN Phosphatase and tensin homolog is mutated in many cancer entities, particularly in endometrial and endometrioid ovarian cancer; its inactivation occurs early during tumorigenesis [53]. PTEN somatic mutations are frequently found in endo- metriotic cysts [45]. p53 As a negative cell-cycle regulator, p53 is involved in tumorigenesis of different malignancies. Several studies showed no expression in benign endometriosis but high expression in benign endometriotic lesions next to the endometrioid or clear cell carcinoma [54]. ARID1A ARID1A mutations are significantly more common in two ovarian cancer subtypes associated with endometriosis (clear- cell and endometrioid). In case of endometriosis synchronous with ovarian cancer, mutation was more frequent in clones derived from endometriosis samples directly adjacent of the tumor than in those from distant endometriotic lesions [46]. DNA repair hMLH1 hMLH1 corrects errors in DNA replication; hypermethylation of its promoter occurs early in endometrial malignant trans- formation and can be identified in 10 % of typical and in 33 % of atypical endometrial hyperplasias [47]. Abnormal methyl- ation can be observed in endometriosis as well [53]. Oncogene Bcl-2 Expression of this anti-apoptotic protein is significantly higher in endometriosis accompanying cancer (42 – 73 %) than in benign endometriosis (23 %) [54], suggesting its role in the early steps of tumorigenesis. KRAS KRAS mutations are significantly more common in endometriosis-associated endometrioid adenocarcinomas (29 %) than in tumors not associated with endometriosis (3 %) [48]. Chromosomic aberrations Aneuploidy Aneuploidic frequency seems higher in endometriosis specimen from patients with advanced endometriosis when com- pared to the background frequency observed in normal specimens, particularly with regard to chromosome 17, on which tumor suppressor gene p53 is located [49, 50]. Loss of heterozygosity (LOH) A trend of increasing LOH frequencies has been described between solitary endometriosis lesions, endometriosis-associ- ated carcinoma and endometrioid ovarian cancer, respectively [51, 52]. Common LOH events can be identified in endo- metriosis synchronous with ovarian cancer [45, 56]. 179 Krawczyk N et al. Endometriosis-associated Malignancy Geburtsh Frauenheilk 2016; 76: 176 – 181 Review component of this study (for more information: gyn@mlk-berlin. de). Conflict of Interest ! None.

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