Endometriosis and ovarian cancer: potential benefits and harms of screening and risk-reducing surgery

Endometriosis and ovarian cancer: potential benefits and harms of screening and risk-reducing surgery

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Endometriosis and ovarian cancer: potential benefits and harms of screening and risk-reducing surgery Q12

Sun-Wei Guo, M.Med., Ph.D. Shanghai Obstetrics and Gynecology Hospital, Fudan University, Shanghai; Shanghai Key Laboratory of Female Reproductive Endocrine-Related Diseases, Fudan University; and Department of Biochemistry and Molecular Biology, Shanghai College of Medicine, Fudan University, Shanghai, People’s Republic of China

Although endometriosis is well recognized as a benign gynecologic condition, its association with ovarian cancer (OVCA) has frequently been reported. Review articles on this topic are voluminous, yet there seems to be no consensus as to whether endometriosis is truly a precursor of OVCA and whether any screening or risk-reducing surgery should be instituted, on the basis of our current knowledge. In this review, published data are compiled and critically appraised. Through this critical appraisal, it seems clear that the strongest evidence seems to come from prevalence data. This type of data also suggests a reduced risk of certain histotypes (mainly type II) of OVCA in women with endometriosis. This may explain the rather moderate increase in risk as shown in epidemiologic studies. Even with this moderate increase in OVCA risk, caution should be exercised because of apparent bias in favor of publication of positive results, extensive heterogeneities among prevalence estimates, and inverse relationship between estimates and sizes of the studies. Many molecular studies are conflicting, and earlier studies showing molecular aberrations involved in genomic instability and mutation that enable malignant transformation are not replicated in later studies. Given the low incidence of OVCA and the rather moderate increase in risk of mostly type I tumors, screening seems to be ill-advised, and risk-reducing surgery such as salpingectomy with or without oophorectomy does not seem to yield any substantial benefit Use your smartphone to women with endometriosis. (Fertil SterilÒ 2015;-:-–-. Ó2015 by American Society for to scan this QR code Reproductive Medicine.) and connect to the Key Words: Association, endometriosis, epidemiology, molecular, ovarian cancer, screening Discuss: You can discuss this article with its authors and with other ASRM members at http:// fertstertforum.com/guosw-endometriosis-ovarian-cancer/

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ndometriosis, defined as the presence of endometrial-like glands and stroma outside of the uterine cavity and featuring estrogen dependency and inflammation, affects approximately 10% of women of reproductive age and is a major contributor to infertility and dysmenorrhea (1). Although endometriosis is well recognized as a benign gynecologic condition, its association with ovarian cancer (OVCA) has been re-

ported frequently in the literature. Review articles on this topic abound, yet there is no consensus as to whether endometriosis is a precursor of OVCA (2). Some investigators think that the ovarian endometriomas ‘‘could be viewed as a neoplastic process,’’ considering the malignant transformation of endometriosis as rather obvious (3). Others are more cautious, however, arguing that, among the nine criteria of causality

Received June 18, 2015; revised August 3, 2015; accepted August 5, 2015. S.-W.G. has nothing to disclose. Supported, in part, by grants 81270676 and 81471434 from the National Science Foundation of China. The sponsors of the study had no role in study design, data collection, data analysis, data interpretation, or writing of this report. Reprint requests: Sun-Wei Guo, M.Med., Ph.D., Department of Gynecology, Shanghai Obstetrics and Gynecology Hospital, Fudan University, 419 Fangxie Road, Shanghai 200011, People's Republic of China (E-mail: [email protected]). Fertility and Sterility® Vol. -, No. -, - 2015 0015-0282/$36.00 Copyright ©2015 American Society for Reproductive Medicine, Published by Elsevier Inc. http://dx.doi.org/10.1016/j.fertnstert.2015.08.006

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proposed by Hill (4), many are still unfulfilled (5). Ovarian cancer is the second most common gynecologic malignancy in developed countries and by far the deadliest malignancy of the female reproductive system. Despite advances in radical surgery and chemotherapy, overall survival has changed very little in the last 30 years (6). With the advent of molecular biology, many efforts have been devoted to early detection, yet this attempt so far has not resulted in any tangible survival benefit to the patients. Faced with such an abject failure, it is important to identify the precursor(s) of OVCA, even for some specific histotypes. With this in perspective, it is perhaps understandable why there has been so much attention devoted to the endometriosis–OVCA link. However,

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how solid is the evidence for this link? Is the link causal? Does the evidence, accumulated so far, warrant any actionable measures such as screening and/or risk-reducing surgery? If screening and/or risk-reducing surgery are to be instituted, what are the potential benefits and harms? These are simple yet weighty issues that are worth careful evaluation. Whether to institute screening and/or risk-reducing surgery for women with endometriosis is a decision that gynecologists must make when caring for their patients with endometriosis. As with any decision making or policy making, it is essentially a matter of risk management. As such, the proper evaluation and handling of uncertainty in science is a prerequisite for sound decision making. This involves dealing with ambiguity (when we cannot place probabilities on outcomes), reducing or elaborating on uncertainties, and quantifying risks. Rational and sound decision making can benefit greatly from candid discourse on what is known, what is unknown, and more importantly, what is unknown or lacking now but could be known significantly better through more research. In this article I shall critically appraise the clinical, epidemiologic, and molecular evidence for the link, highlight the challenges in proving the causal link, and try to weigh the potential benefits/harms of screening and risk-reducing surgery accordingly. I shall also expose the current knowledge gap in our unraveling of the putative link, and in the end, sketch a way to solve this problem.

Evidence accumulated in the last 7–8 years indicates that there are two distinct types (types I and II) of epithelial ovarian carcinoma (EOC; EOC and OVCA will be used interchangeably hereafter), based on their distinctive clinicopathologic and molecular genetic features. Type I comprises low-grade serous, clear cell, endometrioid, and mucinous carcinomas, whereas type II includes mostly high-grade serous carcinoma, high-grade endometrioid carcinoma, and mixed histologies (19, 20). Type I EOC arises through well-recognized sequences from borderline serous tumors or putatively from endometriosis, and is frequently early stage and low-grade, with a relatively indolent disease course. Type II tumors are more common, present in advanced stage (stage II–IV) in more than 75% of cases, and is highly aggressive (20). They seem to originate from the fimbrial epithelium (20). The two types of EOC have distinctively different molecular genetic profiles. Type II tumors are chromosomally highly unstable, contain TP53 mutations in more than 95% of cases, and rarely harbor mutations found in type I tumors (20, 21). A substantial portion of type II tumors have aberrant expression of BRCA and its downstream genes due to either mutation or epimutation (22). Type I tumors, in contrast, are reported to have mutations in ARID1A, BCL2, BRAF, CTNNB1, ERBB2, KRAS, PIK3CA, PPP2R1A, PTEN, and ZNF217 (20).

WHAT IS KNOWN?

The pathogenesis of endometriosis is an enigma. Although several theories have been proposed, none has been conclusively and unequivocally proven (23, 24). Currently the most widely accepted theory is the retrograde menstruation theory proposed by Sampson in the 1920s (23–25). There are no data showing the exact prevalence of endometriosis, owing to the invasive nature of the unequivocal diagnostic procedure, but the widely accepted number is approximately 10% (26). Endometriosis shares with OVCA many risk/protective factors, such as early menarche, incessant ovulation or menstruation due to either early menarche, late menopause, infertility, or nulliparity, tubal ligation, hysterectomy, multiple pregnancies, breast feeding, use of oral contraceptives, and recreational physical activity (27–29). As with OVCA, stress and surgical stress also could be risk factors for endometriosis, but there has been no epidemiologic evidence yet (30–32). Endometriosis also has its own risk and protective factors, such as shorter length of menstrual cycle, longer duration of flow, and smoking (27). Although dioxin exposure was reported to increase the risk of endometriosis (33), critical appraisal of published data does not support this notion (34, 35). Although family history is reported to be a risk factor (36), and numerous genetic association studies—many of them on a genome-wide scale—have identified various genetic variants that confer increased risk of endometriosis (37–39), it is yet to be determined whether these results can be consistently and robustly replicated, what the functional significance of the identified polymorphisms is, and how these genetic variants might be used to better understand the pathogenesis and pathophysiology (40, 41).

Ovarian Cancer: Basic Epidemiology and the Dualistic Model of Carcinogenesis

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The average lifetime risk of OVCA is reported to be approximately 1.4% in non-Hispanic white women in the United States, but there are women at substantially higher or lower risk (7). The risk is higher in developed countries. To round up and also to account for developing countries, the use of 1% as the lifetime risk for OVCA should be appropriate. The risk factors for OVCA are early menarche, family history, obesity, use of postmenopausal hormone therapy, carriers of BRCA1/2 mutations, and incessant ovulation or menstruation due to either early menarche, late menopause, infertility, or nulliparity, whereas protective factors include bilateral tubal ligation, hysterectomy, multiple pregnancies, breast feeding, use of oral contraceptives, and recreational physical activity (7–11). There may be other risk factors for OVCA. Chronic stress and surgical stress are biologically plausible risk factors for OVCA (12–15), although epidemiologic evidence is lacking. More than 90% of OVCAs arise from the surface epithelium (16). The most common histologic subtypes of epithelial ovarian carcinoma are serous (68%–71%), clear cell (12%– 13%), endometrioid (9%–11%), mucinous (3%), transitional (1%), and mixed (6%) (17). However, there may be substantial ethnic and/or racial difference in the composition of different histotypes. In the Japanese population, for example, the proportions of serous, clear cell, endometrioid, mucinous, transitional, and mixed type tumors are reported to be 35.4%, 23.8%, 16.9%, 10.9%, 0.2%, and 2.4%, respectively (18).

Endometriosis: Basic Epidemiology and its Enigmatic Pathogenesis and Pathophysiology

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WHAT IS UNCLEAR? REAPPRAISAL OF PUBLISHED DATA Early Criteria Sampson first proposed histopathologic criteria in 1925 for inferring that the malignancy arose from endometriosis, or the causal relationship between endometriosis and malignancy: [1] clear evidence of endometriosis close to the tumor (‘‘proximity’’); [2] the carcinoma must be seen to arise in endometriosis and not to be invading it from other sources (‘‘arising from endometriosis’’); and [3] presence of tissue resembling endometrial stroma surrounding characteristic glands (‘‘endometrial stroma plus glands’’) (42). Scott later added one more criterion: the demonstration of a histology-proven transition from benign endometriosis to cancer (‘‘transition’’) (43). Clearly, these criteria are all based on histologic evidence, which, in turn, is based on tissue samples taken from patients. Although the ‘‘proximity’’ and ‘‘endometrial stroma plus glands’’ criteria may be relatively easy to establish, the inference of ‘‘arising from endometriosis’’ and ‘‘transition’’ has, by necessity, to be based on a single snap shot, in contrast to serial observations, of the histologic images or morphologic features during a presumably long period of turmorigenesis, and as such can be challenging to establish. It is no wonder that these criteria, considered to be stringent, are rarely fulfilled (2, 44). The morphologic data can reveal something, but only to a certain extent. For example, OVCA was once regarded as a single disease because by morphology the tumor seemingly originated from ovary, but now a dualistic model of carcinogenesis seems to have replaced the older view (6, 20). Indeed, by morphology or histologic data alone, it would be very difficult to find that there are four main subtypes of breast cancer caused by different subsets of genetic and epigenetic abnormalities (45). In addition, because the choice of tissue sections entails a certain degree of selection, it may be susceptible to attribution error, especially when the pathologists are inexperienced.

Current Pieces of Evidence On the basis of the research methodology, the sources of current evidence in support of the endometriosis–OVCA link can be grouped into clinical prevalence reports, epidemiologic case–control and cohort studies, and molecular genetic studies. I shall evaluate these evidence category by category.

Prevalence Data: An Intimate Connection with the Odds Ratio

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The published clinical prevalence reports are predominantly prevalence of endometriosis in women with endometriosis. Two review articles have been published that compiled published prevalence of endometriosis in women with OVCA and provided an overview (46, 47). If we denote the lifetime risk of OVCA as P(O), the prevalence of endometriosis as P(E), the prevalence of women with both endometriosis and OVCA (often called endometriosis-associated ovarian cancer or EAOC) as P(E,O), and the proportion of women with OVCA having

endometriosis as the conditional probability as P(EjO), then the prevalence data shown in Table 1 represent estimates of P(EjO). Here the age-dependency is ignored for ease of exposition. Of course, the conditional probability could be more specific regarding the specific histotypes of OVCA. The relative risk (RR) of having OVCA in women with endometriosis vs. women without endometriosis (denoted as E), RR ¼ PðOjEÞ=PðO EÞ is the quantity that most epidemiologic studies attempt to estimate. We note that the RR also can be calculated from the prevalence data P(EjO) because RR ¼ Q3 P(EjO)/[1  P(EjO)]/(P(E)/[1  P(E)]). That is, RR depends only on the prevalence of endometriosis (of which we have a fairly good idea) and the prevalence of endometriosis among women with OVCA (which can be estimated from data, at least in theory). Note that this RR does not depend on the prevalence of OVCA. Hence we can calculate RR even for some specific histotypes of OVCA, such as clear cell or endometrioid OVCAs. It is noted that RR can be expressed in a more revealing form, as RR ¼ rO/r, where rO ¼ P(EjO)/[1  P(EjO)], the odds of having endometriosis given that the woman has OVCA, and r ¼ P(E)/[1  P(E)], the odds of having endometriosis in the general female population. For some interesting facts derived from this setup, see the Supplemental Materials (available online). In this review I expanded the list compiled by Van Gorp et al. (47), and the data are shown in Table 1, along with the summary data. It is noted that the compilation is important because very rarely can a single study provide enough sample size to estimate the proportion precisely. It can be seen that, whichever histotype or overall prevalence, there are tremendous heterogeneities among prevalence estimates (Table 1). Plotting the prevalence estimates against the square root of or log sample sizes revealed that for the overall prevalence and the prevalence of endometriosis in women with endometrioid carcinoma or clear cell and endometrioid carcinomas combined, there is an inverse linear relationship, suggesting that for these cancer types the estimates of endometriosis prevalence tend to decrease with larger sample sizes (Fig. 1). A more formal test using logit models confirmed this observation (Supplemental Materials). Several conclusions can be made from this analysis. First, there is indeed an excess of endometriosis in women with clear cell and endometrioid carcinomas. Assuming a 10% prevalence of endometriosis and using the pooled estimate of prevalence, the RR for clear cell and endometrioid carcinomas would be 3.59 and 1.98, respectively. However, the excess found in this analysis seems to be less than that reported by Somigliana et al. (44), who found the prevalence of endometriosis to be 35% and 27% in women with clear cell and endometrioid tumors, respectively. Second, there is an apparent deficit of endometriosis in women with serous carcinomas. The deficit found in this analysis agrees very well with that reported by Somigliana et al. (44), who reported the prevalence of endometriosis to be 5% and 4% in serous and mucinous tumors, respectively. The RR would be 0.55 if a 10% prevalence of endometriosis is assumed. This actually agrees with the dualistic model of OVCA carcinogenesis, because serous carcinomas, especially high-grade ones, are type II tumors (17). It is also consistent with the report that

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Author

Year of publication

Overall prevalence

Serous

Scully et al. (48) Scully and Barlow (49) Norris and Robinowitz (50) Aure et al. (51) Kurman and Craig (52) Rogers et al. (53) Fine et al. (54) Curling et al. (55) Doshi et al. (56) Eastwood (57) Russell (58) Klemi et al. (59) Klemi et al. (60) Shevchuk et al. (61) Yoonessi et al. (62) Snyder et al. (63) Tidy et al. (64) Brescia et al. (65) Crozier et al. (66) Jenison et al. (67) Kline et al. (68) DePriest et al. (69) Garzetti et al. (70) Vercellini et al. (71) Martin Jimenez et al. (72) McMeekin et al. (73) Sainz de la Cuesta et al. (74) Toki et al. (75) Chew et al. (76) Jimbo et al. (77) Fukunaga et al. (78) Erzen et al. (79) Komiyama et al. (80) Ogawa et al. (81) Vercellini et al. (82),a Takahashi et al. (83) Oral et al. (84) Deligdisch et al. (85) Dzatic-Smiljkovic et al. (86) Pearce et al. (87),b Pearce et al. (87) Pearce et al. (87) Pearce et al. (87) Pearce et al. (87) Pearce et al. (87)

1966 1967 1971 1971 1972 1972 1973 1975 1977 1978 1979 1979 1979 1981 1984 1988 1988 1989 1989 1989 1990 1992 1993 1993 1994 1995 1996 1996 1997 1997 1997 1998 1999 2000 2000 2001 2003 2007 2011 2012 2012 2012 2012 2012 2012

– –

– – – 0.0 (0/357) 5.9 (7/118) – – – – – 3.0 (7/233) – – – – – – – – 12.8 (7/55) – – – 3.6 (8/220) – – 0.0 (0/10) 10.2 (9/88) – 8.7 (8/92) 9.5 (6/63) 0.0 (0/31) – 6.7 (4/60) 3.3 (2/61) 6.7 (1/15) 4.3 (3/70) 4.5 (1/22) 3.5 (4/113) 6.7 (46/682) 1.0 (1/98) 1.3 (4/315) 6.1 (8/132) 7.9 (15/191) 10.6 (30/284)

4.2 (35/831) – – – – – – 11.3 (46/407) – – – – – – – – – – – – 11.1 (52/466) – – – – – 14.5 (25/172) 24.1 (54/224) – – 29.1 (37/127) 43.5 (91/209) – 7.7 (14/182) 52.6 (40/76) 11.0 (23/210) 8.7 (106/1221) 1.3 (3/227) 1.5 (8/540) 8.5 (28/329) 12.6 (47/374) 11.2 (66/590)

Mucinous – – – 0.5 (1/203) 4.3 (2/47) – – – – – 4.0 (3/69) – – – – – – – – – – – – 6.4 (6/94) – – 5.6 (1/18) 9.1 (3/33) – 2.9 (1/35) 5.7 (2/35) 0.0 (0/7) – 0.0 (0/17) 3.3 (1/30) 0.0 (0/13) 5.7 (2/35) – – 10.6 (5/47) 0.0 (0/27) 0.0 (0/50) 6.7 (2/30) 15.8 (3/19) 0.0 (0/22)

Clear cell – 53.6 (15/28) 25.0 (10/40) 23.7 (14/59) 7.1 (2/28) 9.5 (9/95) 43.8 (14/32) – 0.0 (0/15) 29.4 (5/17) 48.5 (16/33) – 44.4 (8/18) 28.6 (6/21) 45.5 (10/22) – – 66.7 (16/24) 22.0 (13/59) 59.1 (26/44) – – – 21.1 (8/38) – – 41.2 (7/17) 50.0 (22/44) 45.5 (5/11) 40.6 (13/32) 54.0 (27/50) 50.0 (1/2) 37.7 (20/53) 69.7 (30/43) 14.3 (5/35) 18.2 (2/11) 9.1 (1/11) 70.0 (7/10) 36.8 (7/19) 16.1 (15/93) 0.0 (0/6) 4.7 (2/43) 20.0 (6/30) 22.9 (8/35) 29.4 (10/34)

Endometrioid 23.5 (4/17) – – 9.4 (20/212) 10.8 (4/37) – – 25.0 (11/44) – – 27.7 (20/72) 8.7 (2/23) – – – 40.0 (4/10) 17.9 (7/39) 18.0 (11/61) – – 7.6 (11/145) 26.2 (11/42) 33.3 (3/9) 26.3 (30/114) 11.8 (2/17) 36.8 (32/87) 39.1 (9/23) 29.6 (16/54) 20.0 (4/20) 23.1 (3/13) 41.9 (13/31) 15.4 (2/13) – 42.9 (3/7) 19.7 (13/66) 40.0 (4/10) 22.2 (4/18) 72.5 (29/40) 31.6 (12/38) 11.8 (18/153) 0.0 (0/26) 1.4 (1/73) 14.3 (8/56) 18.9 (14/74) 17.3 (17/98)

Guo. Link of endometriosis with ovarian cancer. Fertil Steril 2015.

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TABLE 1

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473 474 475 476 477 478 479 480 481 482 483 484 485 486 487 488 489 490 491 492 493 494 495 496 497 498 499 500 501 502 503 504 505 506 507 508 509 510 511 512 513 514 515 516 517 518 519 520 521 522 523 524 525 526 527 528 529 530 531 VOL. - NO. - / - 2015

TABLE 1 Continued. Prevalence by histotype ID

Author

Year of publication

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HAW Pearce et al. (87) 2012 HOP Pearce et al. (87) 2012 MAY Pearce et al. (87) 2012 NCO Pearce et al. (87) 2012 NCI Pearce et al. (87) 2012 USC Pearce et al. (87) 2012 USC Pearce et al. (87) 2012 B13 Boyraz et al. (88) 2013 Q13 Qiu et al. (89) 2013 M15 Machado-Linde et al. (90) 2015 No. of studies Total no. of subjects Median sample size Range Median estimated prevalence (%) Range (%) Pooled estimate (%) 95% confidence interval (%) Heterogeneity G or c2 test (by Monte Carlo method, with B ¼ 10  106 replicates) Statistical significance

Overall prevalence

Serous

Mucinous

Clear cell

Endometrioid

11.2 (44/392) 9.3 (55/592) 10.6 (30/282) 10.7 (88/826) 8.3 (69/836) 17.2 (65/379) 9.8 (129/1323) 4.1 (45/1086) 7.5 (17/226) 5.4 (27/496) 26 12,623 385.5 76–1323 10.7 1.3–52.6 9.9 (9.3–10.4) 1237.0 P<2.2  1016

9.0 (15/167) 7.4 (22/298) 6.4 (11/171) 9.0 (42/468) 6.0 (28/468) 12.9 (25/194) 8.5 (45/527) 10.7 (6/562) 2.0 (3/153) – 31 6,318 153 10–682 6.1 0.0–12.9 5.8 (5.2–6.4) 138.2 P¼1.0  107

7.1 (3/42) 10.0 (3/30) 8.3 (1/12) 7.1 (3/42) 1.8 (1/55) 14.8 (4/27) 5.3 (6/113) 2.2 (4/186) 0.0 (0/7) – 28 1,345 34 7–203 4.8 0.0–15.8 4.2 (3.2–5.3) 43.7 P¼ .034

14.9 (7/47) 28.6 (14/49) 38.1 (8/21) 23/2 (19/82) 14.4 (16/111) 33.3 (12/36) 21.8 (19/87) 20.5 (17/83) 36.4 (8/22) 31.8 (7/22) 45 1,712 33 2–111 29.4 0.0–70.0 28.5 (26.3–30.6) 224.8 P¼1.0  107

21.7 (15/69) 7.4 (6/81) 15.2 (7/46) 12.8 (17/133) 12.6 (21/167) 29.9 (20/67) 14.4 (25/177) 9.3 (15/161) 35.3 (6/17) 28.9 (13/45) 43 2,705 45 7–212 20.0 0.0–72.5 18.0 (16.6–19.5) 239.9 P¼1.0  107

Note: Expanded from Table 2 in reference 48. Here, as in reference 48, endometriotic lesions found ipslateral or contralateral to the tumor site, in the pelvis, or in extra-gonadal locations were all included. Values are percentage (number), except where noted otherwise. a Only unilateral cancer and left-sided lesions were considered. b This study is a pooled analysis of 13 different studies. Given the apparent heterogeneity shown in the article, data from 13 studies are listed separately. Guo. Link of endometriosis with ovarian cancer. Fertil Steril 2015.

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Scatter plots showing the relationship between the prevalence of endometriosis in OVCA of all histotypes (A), in patients with serous tumors (B), mucinous tumors (C), clear cell tumors (D), endometroid tumors (E), and clear cell and endometroid tumors combined (F), and the measure of precision (either log- or square-root-transformed sample size). The alpha-numeric combinations are the IDs shown in Table 1, and each ID represents one study. In A, E, and F, the dashed line is the linear regression line, and the number is the Pearson's correlation coefficient. *P<.05; **P<.01; ***P<.001. CC ¼ clear cell; E ¼ endometrioid. Guo. Link of endometriosis with ovarian cancer. Fertil Steril 2015.

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serous and mucinous tumors and endometriotic lesions are physically separated and that the co-occurrence of the two diseases is simply coincidental (91). Third, the pooled overall prevalence estimate is very close to 10%, suggesting that the, from the increase in the risk of all histotypes of OVCA would be very small. Fourth, there are extensive heterogeneities among the prevalence estimates. Last, there are indications that smaller-sized studies tend to report more positive results. Incidentally, for the six studies compiled by Van Gorp et al. that reported the prevalence of OVCA among women with endometriosis (Table 3 , column B in reference 48), a similar trend also could be seen. It is unclear whether some seemingly high prevalence estimates are genuine or a result of ascertainment bias, population idiosyncrasy, or chance events.

Case–control Studies and Two-armed Cohort Studies The basic questions for case–control studies are the degree of association between risk for disease and the factor(s) under

investigation, the extent to which the observed association may result from bias, confounding, and/or chance, and the extent to which they may be described as causal (97). A case–control study compares cases (in our case, women with OVCA) and controls (women without OVCA, say) with respect to their exposure (or lack thereof) or levels of exposure to a suspecting risk factor (in our case, having endometriosis). As with the standardized incidence ratio (SIR) and RR used in cohort studies, the odds ratio (OR) or RR used in case–control studies are measures of association between disease and exposure. However, the association could be causal, but also could be merely a correlation. Several scenarios in which the association is shown but the association is causal or merely correlation are shown in Supplemental Figure 1. To appraise the epidemiologic evidence for the endometriosis–OVCA link, I extended the meta-analysis beautifully done by Kim et al. (98) by grouping case–control and twoarmed cohort studies together and also by contacting authors of published studies to get their unpublished data on the association of OVCA and endometriosis. By the inclusion of twoVOL. - NO. - / - 2015

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TABLE 2 Published case–control and two-armed cohort studies reporting OVCA risk in women with endometriosis. ID

Author

Year of publication

Adjusted RR/OR/hazard ratio

95% Confidence interval

N00 Z00 R01 O02 N02

Ness et al. (99) Ziogas et al. (100) Royar et al. (101) Olson et al. (102) Ness et al. (103)

2000 2000 2001 2002 2002

1.238 1.251 0.905 0.777 1.730

1.023–1.498 1.094–1.431 0.343–2.389 1.035–1.746 1.100–2.710

B04 G04 P04 B05 T05 R06 M08 m08 R08 C09 W09 A10 L10 N11 B11 V11 B11 P12

Borgfeldt et al. (104) Glud et al. (105) Pike et al. (106) Brinton et al. (107) Terry et al. (108) Risch et al. (109) Merritt et al. (110) Moorman et al. (111) Rossing et al. (112) Cunningham et al. (113) Wu et al. (114) Aris (115) Lurie et al. (116) Ness et al. (117) Balogun et al. (118) Vitonis et al. (119) Bodmer et al. (120) Pearce et al. (87)

2004 2004 2005 2005 2006 2008 2008 2008 2009 2009 2010 2010 2011 2011 2011 2011 2012

1.344 1.293 1.242 1.690 1.097 1.199 1.212 1.325 1.331 1.272 1.252 1.600 1.370 1.228 1.440 1.245 1.221 1.460

1.035–1.746 0.731–2.287 1.092–1.412 1.277–2.238 0.913–1.320 0.959–1.500 1.060–1.385 1.143–1.535 1.091–1.625 0.963–1.681 1.038–1.512 1.153–2.220 1.083–1.732 0.979–1.541 1.125–1.843 1.141–1.359 0.782–1.907 1.310–1.630

B13

Buis et al. (121)

2013

8.700

3.000–25.400

M13

Merritt et al. (122)

2013

1.365

(1.36–2.71)

2013 2014 2014 2015

3.110 3.280 5.620 4.560

1.130–8.570 1.370–7.850 3.460–9.140 1.720–12.11

S13 Stewart et al. (123) C14 Chang et al. (124) W14 Wang et al. (125) K15 Kok et al. (126) Summary Pooled estimate of RR Cochran's Q Higgin's I2

Remark

Originally considered infertility as a possible risk factor, but also looked at patients with infertility due to endometriosis

For invasive OVCA

Invasive clear cell and endometrioid OVCAs Only those cases whose date of first diagnosis of endometriosis was at least 1 y before the OVCA diagnosis were included Low-grade serous, endometrioid/mixed, mucinous, and clear cell For nulliparous women

1.34 595.2, P<2.2  1016 95.3%

Note: Expanded based on Figure 1A in reference 51. Endo ¼ endometriosis. Guo. Link of endometriosis with ovarian cancer. Fertil Steril 2015.

armed cohort studies, which typically provide estimates of hazard ratio, which is approximately the RR, a more meaningful meta-analysis can be performed. Specifically, I updated Table 1A in reference 51 by adding studies published more recently, yielding Table 2. As expected, these studies vary in the types of OVCA and the selection of controls (women with endometriosis or endometriomas, or infertility). Regardless, the pooled RR estimate is 1.34 (Fig. 2A), suggesting that overall the RR is very moderate. In addition, there is great deal of heterogeneity (P<2.2  1016 for heterogeneity test). Some investigators invoked heterogeneity as an explanation for the low RR (125), using the example shown in the estimate of RR in reference 53: an RR estimate of 8.2 (95% confidence interval [CI] 3.1–

21.6) was found in women with endometriosis when the definition of endometriosis was based on self-report, medical records information at subfertility treatment, and/or a nationwide pathology database, but the estimate was increased to 12.4 (95% CI 2.8–54.2) in women with pathologically confirmed endometriosis after subfertility treatment. However, this increased precision in classification can go both ways. Indeed, the same study also reported an RR estimate of 8.7 (95% CI 3.0–25.4) when a more precise definition was used (i.e., when the first year after the diagnosis of endometriosis was excluded) (121). Figure 3 is a graphic rendition of the sensitivity analysis done in reference 54 (Table 4 in reference 54). One can see that once the cases who had at most 3, 5, or 10 years' interval between the diagnosis of

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TABLE 3 Published single-armed cohort studies reporting OVCA risk in women with endometriosis. ID B97 B04 M06 K07 M07

Author

Year of publication

Adjusted SIR

95% Confidence interval

Brinton et al. (92) Brinton et al. (93) Melin et al. (94) Kobayashi et al. (95) Melin et al. (96)

1997 2004 2006 2007 2007

1.921 2.500 1.434 5.599 1.370

1.031–3.577 0.904–6.911 1.087–1.891 2.243–13.973 1.276–2.531

Note: Based on Figure 1B in reference 51. Guo. Link of endometriosis with ovarian cancer. Fertil Steril 2015.

endometriosis and of OVCA were removed, the OR estimates shrank considerably. Perhaps one more plausible explanation for the low RR may be the deficit of serous and mucinous tumors in women with endometriosis, as shown above. The funnel plot of the log RRs from the 29 studies indicates that the plot also looks like an asymmetric funnel, with its tip pointing toward somewhere near log OR ¼ 0.29 (i.e., OR ¼ 1.34) (Fig. 2A). This is particularly so when the investigation of the endometriosis–OVCA link was the sole purpose of the published studies (studies marked in red in Fig. 2A). This seems to suggest publication bias may be present, favoring positive studies and higher estimates of RR.

Single-armed Cohort Studies Because no new study of this type has been published after the meta-analysis by Kim et al. (98), I just used their compiled

data (Table 3) and drew a funnel plot. When plotting the five log-transformed SIRs against their SEs in a funnel plot (Fig. 2B), one feature stood out. Indeed, the plot looks like an asymmetric funnel, with its tip gravitating toward somewhere near log SIR ¼ 0.59 (i.e., SIR ¼ 1.80). Because there is no indication of bias in inclusion criteria or heterogeneity, this suggests that there may be a publication bias toward favoring positive studies, and higher estimates of ORs may well be a chance variation.

Other Considerations Although the mean age at onset of OVCA is approximately 56 years (5), the onset of endometriosis occurs mostly and typically during women's reproductive age. This has been taken as support for the temporality requirement in Hill's nine criteria of causality (5). Indeed, the reported mean age

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(A) Funnel plot for the log RRs, using data extracted from Table 2. The dashed line represents RR ¼ 1.34. The alpha-numeric combinations are the IDs shown in Table 2, and each ID represents one study. The IDs shown in red are those studies devoted exclusively to the endometriosis–OVCA association, whereas those in blue are studies focusing on other risk factors. (B) Funnel plot for the log SIRs, using data extracted from Table 3. The dashed line represents SIR ¼ 1.797, as provided in reference 51. Guo. Link of endometriosis with ovarian cancer. Fertil Steril 2015.

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A graphic rendition of the sensitivity analysis for the association of endometriosis and risk of invasive OVCA, based on timing (time interval) of diagnosis between the two diseases, as reported by Pearce et al. (87) (their Table 4). When patients with endometriosis and OVCA diagnosed (Dx) within the time interval %3 years, 5 years, and 10 years are excluded, the decrease in the OR estimate is seen. Guo. Link of endometriosis with ovarian cancer. Fertil Steril 2015.

of EAOC cases is often significantly younger than OVCA patients without endometriosis but older than women with endometriosis alone (115). However, the case–control and the two-armed cohort studies published to date have not demonstrated a clear, graded temporal relationship between endometriosis and OVCA. Most epithelial tumors take a latent period of at least 15 years to develop (5). If endometriosis is a precursor of certain types of OVCA, then it should take a certain latent period, likely to be shorter than 15 years, for OVCA to develop. Even if the well-documented diagnostic delay in endometriosis (161, 162) is taken into account, there still should be considerable lead time between the first diagnosis of endometriosis and the diagnosis of OVCA. Consequently, one would see that after excluding some cases with endometriosis, say %3 years' interval between the diagnosis of endometriosis and of OVCA, the RR estimate would go up because this would effectively remove many ‘‘noisy’’ cases that would dilute the association signal. Unfortunately, this type of sensitivity analysis is not always performed, and even if it were, the results could be quite counterintuitive (Fig. 3). Another telling example is a recent study in which approximately half of the OVCA occurrence happened within the first 6 months of follow-up (Fig. 2 in reference 52). Removing these cases would likely knock down half the RR estimate. In addition, few, if any, studies provided information on the types of endometriosis (ovarian vs. peritoneal vs. deepinfiltrating endometriosis), whether there is concurrent adenomyosis or uterine fibroids, or its treatment modalities (surgery, pre- and postoperative medication, duration, etc., especially whether danazol is used). Although the presence

of ovarian endometriomas may conceivably generate a proinflammatory microenvironment that may be conducive to the development of OVCA, it is unclear as to whether peritoneal or vaginorectal deep-infiltrating endometriosis would also increase the risk of OVCA more than that of other gynecologic cancers. Nor is it clear as to whether the co-occurrence of adenomyosis and/or uterine fibroids with endometriosis would ever change the RR estimate. Few studies have taken pains to document and evaluate the effect of treatment of endometriosis on OVCA risk, but this would have obvious implications. In this sense, one recent study is of particular interest. By linkage to the National Swedish Cancer Register, Melin et al. (163) identified all women diagnosed with EOC at least 1 year after the endometriosis diagnosis (cases). Two controls per case with no OVCA before the date of cancer diagnosis of the case were randomly selected from the study base and matched for year of birth. The study found an OR of 0.30 (95% CI 0.12–0.74) for women who received a complete removal of all visible endometriosis (163). That is, for a woman with endometriosis, her risk of developing OVCA could be cut by 70% if she had all visible endometriotic lesions removed. It is worth noting that to date no other case–control studies have taken surgical completeness into consideration, because the study by Melin et al. strongly suggests this can be a protective factor.

MOLECULAR EVIDENCE: A CRITICAL SYNTHESIS There are already several excellent review articles on this aspect (8, 130,164–169). Instead of reviewing a roster of genes/phenotypes in OVCA that endometriotic lesions may or may not share, here I use the hallmarks of cancer elaborated by Hanahan and Weinberg (170) as a guide and examine some tumor-enabling characteristics of endometriosis. Tumorigenesis is a multistep process, in which normal cells acquire a succession of traits or hallmarks through chance events that enable them to survive, proliferate, and metastasize (170). The eight hallmarks (i.e., sustained proliferative signaling, resistance to cell death, induction of angiogenesis, replicative immortality, activation of invasion and metastasis, evasion of growth suppression, avoidance of immune destruction, and deregulation of cellular energetics) are regulated by several integrated biological circuits (170). These circuits include the proliferation circuit, in which growth factors and hormones play important roles and Ras and Myc are two critical factors, viability circuit, in which Bcl-2 is important, motility circuit, and cytostasis and differentiation circuit, in which transforming growth factor-b1 plays an important role (170). One critical component that does not belong to any of the above-mentioned circuits is the DNA-damage sensor, in which p53 is known to play a vital role. In addition, there are two enabling characteristics of cancer: [1] inflammation and [2] genomic instability and mutation. Analogous to the hallmarks of cancer, some notable features of endometriosis can be enumerated as in Figure 4A. Although some features are manifested at the cellular and/ or molecular levels (e.g., oxidative stress, tissue invasion),

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TABLE 4 Evidence for or against the existence of major molecular circuitry in endometriosis that regulates hallmark capabilities within cancer cells, and the presence or absence of two cancer-enabling characteristics in endometriosis. Category Proliferation circuit Estrogen dependency Angiogenesis Ras c-Myc Viability circuit Bcl-2 overexpression Motility circuit Epithelial–mesenchymal transition Decreased E-cadherin expression Cytostasis and differentiation circuit TGF-b1 signaling Two enabling characteristics Inflammation Proinflammatory cytokines/ chemokines Hypercoagulation Increased COX-2 expression and PGE2 production Genomic instability and mutation Oxidative stress Hypoxia Loss of heterozygosity PTEN mutation

Evidence in endometriosis (reference) Solidified (127) Solidified (128, 129) Conflicting (see (130)) Reported (131–133) Demonstrated (134, 135) Reported (136–139) Reported (140, 141) Reported (142, 143) Solidified Solidified (144–146) Reported (147, 148, 149) Demonstrated (150, 151) Controversial Solidified (152–158) Demonstrated (159, 160) Conflicting (see (130)) Conflicting (see (130))

Note: COX-2 ¼ cyclo-oxygenase 2; PGE2 ¼ prostaglandin E2; PTEN ¼ phosphatase and tensin homolog; TGF ¼ transforming growth factor. Guo. Link of endometriosis with ovarian cancer. Fertil Steril 2015.

Q6

other features, such as central sensitization, are manifested at the organismic level. It can be seen that several features, such as resistance to cell death, induction of angiogenesis, and avoidance of immune destruction, resemble, at least on the surface, certain hallmarks of cancer, whereas others, such as replicative immortality and evasion of growth suppression, are much less so (Table 4). This is of course due to the fact that, although cancer cells are aggressive in nature, endometriotic lesions can be viewed as wounds that undergo repeated tissue injury and repair, resulting ultimately in fibrosis (147,148,171). To put it differently, endometriotic lesions could be viewed as an organ, and many molecular aberrations that they display result from evolutionarily conserved mechanisms of tissue repair (171). Aside from these differences, one key distinction between the two types of lesions is the DNA-damage sensors that are apparently intact in endometriotic lesions but that apparently malfunction in cancer cells. In fact, although endometriosis has a strong component of inflammation, which is one driving force in promoting tumorigenesis (170), there are insufficient data showing that endometriosis also has another cancerenabling culprit, genomic instability and mutation. One earlier study showed a high rate of loss of heterozygosity (LOH) at 10q23.3 (i.e., 56.5% in endometriotic cysts [(172)], but later studies could not find such LOH [(173, 174)]). Mutations at the TP53 locus are often associated with the allelic loss at 17p13 and overexpression of p53 protein (130).

TP53 mutations and/or p53 protein expression are the most common alterations seen in serous OVCA but also in 30% of endometrioid and 10% of clear cell OVCA (175). Nakayama et al. (176) reported that 13 of 64 endometriotic tissues (20.3%) with or without synchronous OVCA were stained positive for p53, even though no TP53 mutation was found. However, no staining was found as reported in 54 (177), 66 (178), and 30 (179) samples of endometriotic lesions, and more recently 79 samples of ovarian cysts associated with OVCA (180). Assuming a p53 overexpression rate of 20.3%, then the chance of observing none in 54 þ 66 þ 30 þ 79 samples of four independent studies would be 2.6  1023. In other words, p53 positivity in endometriotic lesions would be an event of nearly infinitesimally small probability. Consistent with this notion, although Jiang detected one mutation among 14 endometriosis-associated OVCA, or a mutation rate of 0.071 (181), no other studies have replicated such a finding (130) to date. For K-Ras, the situation is similar. The strongest piece of Q7 evidence suggesting the involvement of K-Ras in the transition from endometriosis to OVCA came from an experiment using genetically engineered mice (182). Injection of an adenoviral Cre recombinase construct in the ovarian bursa resulted in the tissue-specific expression of active mutant K-Ras and led to lesions reminiscent of endometriosis (182). However, it is unclear whether such an animal model recapitulates its human version: first, the onset of endometriosis is very late in mouse (182), and second, to date three studies found have no mutation at K-ras (183–185). Although K-ras was detected in three of six endometriotic lesions adjacent to the site of OVCA (186), others could not find such an aberration in endometriotic lesions (186, 187). It is also unclear whether the two diseases occurred synchronously by chance, or whether endometriosis preceded the occurrence of OVCA (Fig. 4B). This brings us to an important question. Many published Q8 studies reported the co-occurrence of endometriosis and OVCA, and some even demonstrated a gradual transition from typical endometriotic lesions to atypical lesions, borderline carcinoma, and finally OVCA (164). As beautiful as these figures are, the cross-sectional nature of these studies cannot be taken as direct proof that endometriosis progresses to OVCA. At best, these data are only suggestive, because a rigorous proof would necessitate a clear demonstration of temporal changes from benign lesions to malignant ones. Given the limited space in the pelvic cavity, two unrelated conditions may still occur side by side simply by chance, and the cells in between may display morphologic or even molecular features that resemble, to some extent, two types of cells of the two conditions, yet also display some dissimilarities. Hence it is possible that when this happens, one may see transitional change in morphology.

ESTABLISHING THE PHYLOGENETIC RELATIONSHIP: ONE LAST RESORT? To date, epidemiologic studies have not convincingly demonstrated a temporal relationship between endometriosis and OVCA. Obviously, serial observations made through VOL. - NO. - / - 2015

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(A) Diagram showing various features of endometriosis. The phrases in blue are features manifested at the organismic level, whereas those in other colors are features manifested at the cellular and molecular levels. The phrases in red are features that are comparable with, but not necessarily identical to, certain hallmarks of cancer as elaborated in reference 66. (B) The comparison of molecular circuitry in endometriosis and cancer. Although endometriotic lesions may appear to have sets of circuitry similar to that of cancer, the components (genes and their products) and the wiring (signaling networks) of these circuitries may be different, and this is shown in different shades of color. More importantly, the DNAdamage sensors in endometriosis appear to be intact, but show dysfunction in cancer. Guo. Link of endometriosis with ovarian cancer. Fertil Steril 2015.

following up women with endometriosis are simply out of the question. Because it is now well documented that, similar to cancer, endometriotic lesions are monoclonal in origin

(188), one possible approach to the establishment of the temporal relationship and to providing a convincing proof that OVCA originates from endometriosis is to reconstruct a

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phylogenetic trees delineating the genetic relationship between endometriotic lesions and OVCA based on a molecular clock (189). The idea is simple: a human body contains approximately 3.7  1012 cells, all descended, thorough numerous and successive cell divisions, from a single fertilized egg or zygote. Each cell has one set of genomes, which is identical to that of the zygote, more or less. Although cell division has a very high fidelity in duplicating the genome of the parental cell, mutation is bound to occur. For a given base pair, the mutation rate is estimated to be approximately 108 to 107. Although extremely low in frequency, given the size of the human genome, which has 3.23  109 base pairs, the probability of having at least one mutation somewhere in the genome is 100%. Because the probability of having the reversal mutation (i.e., the original mutation was, say, C/T, and the second mutation was T/C) at exactly the same base pair is infinitesimally small and can thus be practically ignored, once a particular mutation occurs in a cell, then all its descendant cells will carry the same mutation. Thus, two cells sharing more mutations would be genetically or phylogenetically closer than the two that share less or no mutation. In other words, the replication errors during cell divisions surreptitiously record divisions and ancestry and can be used to reconstruct a genealogic tree that originates from the zygote and ends with present-day cells (190). Consequently, given the current genomes (or sequence data), statistical methods can be used to infer the phylogeny of the existing cells. Because the epimutation rate is three to four orders of magnitude higher than that of DNA mutation, and a higher mutation rate (akin to higher reference or calibration frequency for a wristwatch) is better for the reconstruction of the phylogenic tree, nowadays epigenome data are used. Note that although genetic and physical distance or proximity may potentially encode ancestry, cancer genomes can become increasingly numerous, polymorphic, and physically separated after transformation. By necessity, daughter cells are initially adjacent, and thus geographic or physical proximity can be used to calibrate genetic proximity. Hence if an OVCA lesion arises from an endometriotic lesion, they may be both genetically and physically close. Yet physical proximity alone may not necessarily imply genetic closeness, because when cancer growth ceases and cell division is balanced by cell death due to selection pressure, physical distances can become relatively static but genetic distances still increase, potentially reducing correlations between physical and genetic differences. Therefore, adjacent cells, such as OVCA tumor cells and neighboring endometriotic cells, may or may not be closely related, whereas cells from different sides of an OVCA lesion likely shared a common ancestor near the time of transformation (190). A proof-of-concept study demonstrating the utility of the molecular clock in reconstructing the geologic relationship among pieces of endometrial fragments demonstrates that the phylogenetic approach is feasible using today's genetic technology (191). By establishing the phylogenetic relationship between OVCA cells and their adjacent endometriotic lesions and other nonendometriotic tissues using either DNA mutation or epimutation data, the issue of whether OVCA truly originates from endometriotic lesions can be unequivo-

cally resolved. Such an approach has been successfully used to elucidate the complex patterns of metastatic spread in prostate cancer (192). The timing for doing so may be especially ripe because the cost for whole-genome sequencing is well within the reach of many research laboratories.

SHOULD ANY ACTION BE TAKEN? Given the somewhat consistent but rather moderate increase in RR, some investigators believe that OVCA originates from endometriosis, at least for clear cell carcinoma and endometrioid adenocarcinoma (193), hence screening, laboratory, and imaging evaluation should be ‘‘recommended for early detection of malignant disorders in women with endometriosis’’ (194). Some even show that patients with EAOC actually had a more favorable prognosis (195–197). However, other studies do not find such evidence (198, 199). Because of the low incidence of OVCA and the rather moderate increase in risk, extreme caution needs to be exercised when conveying the message to the public and also in the context of screening. For all types of OVCA, the incidence of new cases is reported to be 12.1 per 100,000 women per year (Surveillance Epidemiology and End Results: http:// seer.cancer.gov/statfacts/html/ovary.html, accessed June 15, 2015). Using the numbers provided in reference 17, the incidence of new cases of clear cell or endometrioid tumors would be approximately 3 per 100,000 women per year, but this number will be considerably lower in women without endometriosis. Using the highest RR estimate in Table 1 (i.e., 8.7) and assuming, perhaps too optimistically, that a screening test exists that is 99% sensitive and 99% specific, the corresponding positive predictive value is a disheartening 2.5%. In other words, even with this rather rosy scenario, out of 100 women who have tested positive, fully 97 would have a false-positive result and be likely to be subjected to invasive procedures. Therefore, given the low incidence and also the moderate increase in RR, it is perhaps premature to talk about screening. Given that screening is out of the question for now, what about risk-reducing surgery such as salpingectomy with or without oophorectomy? This has been proposed as a regional initiative for low-risk women (200) and also for women with endometriosis who have had children (167). Cost-effective analysis, based on statistical simulation, suggests that the procedure will reduce OVCA risk at acceptable cost and is a cost-effective alternative to tubal ligation for sterilization, as compared with hysterectomy (201). The procedure, however, costs far more than tubal ligation but gains an average of 1 week (201). It is also unclear whether it is still cost-effective when cardiovascular disease, osteoporosis, and quality of life are also taken into account. Granted, salpingectomy can indeed reduce the risk of OVCA, of hydrosalpinx, tubal ligation failure, and ectopic pregnancies. For patients with endometriosis, it should be noted that the risk of type II OVCA does not seem be elevated. In other words, the majority of prevented OVCA by this procedure would be type II; that is, the most effective riskreducing surgery would be effective mostly on non–endometriosis-associated OVCA. Therefore, any risk-reduction VOL. - NO. - / - 2015

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surgery for women with endometriosis would be primarily clear cell and endometrioid tumors, because type I lowgrade serous tumors are very rare and would be of marginal importance as far as prevention is concerned. Additionally, to achieve the full potential for the procedure, it has to include bilateral oophorectomy (i.e., bilateral salpingectomy and oophorectomy [BSO]). Given the lifetime risk of 1.4% and that approximately 24% of OVCA are clear cell and endometrioid tumors, the lifetime risk would be 0.34% in the general population and approximately 1% in women with endometriosis (assuming, conservatively, an RR of 3). Hence the reduction in risk as a result of the procedure would be 0.66%. It should be noted, however, that the risk reduction does not necessarily translate into reduction in mortality, because women with endometriosis-associated OVCA have a better overall survival than those with non–endometriosis-associated OVCA (98). There is a considerable downside to BSO. With BSO there would be reduced quality of life and increased risk of cardiovascular diseases and of osteoporosis associated with menopause. Given such a low risk, it is questionable to institute a riskreducing surgery such as BSO. As a contrast, the lifetime risk for breast cancer and prostate cancer is 9 and 10 times higher than that of OVCA, yet nobody advocates prophylactic mastectomy and prophylactic prostatectomy in the general population. Thus, although BSO as risk-reducing surgery may be of value for older women with atypical endometriosis, which is rare, its effectiveness in reducing the overall risk of mortality is questionable. In lieu of the surgical procedure, there is reason to believe that oral contraceptives should be considered as an alternative to surgery as a risk-reducing medical intervention in women with a previous diagnosis of endometriosis.

CONCLUSIONS Through this critical appraisal of published clinical, epidemiologic, and molecular data showing the link between endometriosis and OVCA, it seems clear that although clinical and epidemiologic studies have provided evidence for a consistent but rather moderate increase in the risk of developing OVCA in women with endometriosis, and that the elevated risk is most prominent in some histoypes of OVCA, caution should be exercised when interpreting these results. The strongest evidence seems to come from prevalence data (i.e., reporting the prevalence of endometriosis in women with OVCA, either overall or in certain histotypes). At the same time, this type of data also suggests a reduced risk of certain histotypes (mainly more prevalent type II) of OVCA in women with endometriosis. This may explain the rather moderate increase in risk (OR in the neighborhood of 1.34 or SIR approximately 1.80) as shown in case–control and cohort studies. Additionally, even with this moderate increase in OVCA risk, caution should also be exercised because of, first, apparent bias in favor of publication of positive results and, second, conspicuous and extensive heterogeneities among prevalence estimates and inverse linear relationship between prevalence estimates and the sample sizes of the studies. The evidence for such a causal relationship attempted to be demonstrated by molecular studies is sometimes tantalizing but only suggestive. In fact, many published studies are

conflicting, and earlier studies showing LOH in endometriosis and p53 aberration in EAOC, that is, genes involved in genomic instability and mutation that enable malignant transformation, are not replicated in later studies. All studies failed to show an unequivocal temporal relationship between endometriosis and the subsequent OVCA onset, and rarely investigated the effect of endometriosis subtypes and treatment modality and radicality on the OVCA risk. In view the low incidence of OVCA and the rather moderate increase in risk, screening would seem to be ill-advised. Given that endometriosis only increases a moderate risk of type I OVCA, risk-reducing surgery such as salpingectomy with or without oophorectomy does not seem to yield any substantial benefit to women with endometriosis. From the funnel plots for the RRs reported from case– control and two-armed cohort studies and the SIRs from cohort studies, it seems that there may be a publication bias toward favoring positive studies. In addition, these plots seem to suggest that the true effect size is very moderate. Given the excess in clear cell and endometrioid OVCA but also deficit in perhaps high-grade serous and mucinous OVCA, which seems to dovetail with the prevalent dualistic model of OVCA tumorigenesis (20), the moderate risk of OVCA seems to be logical. Yet the vast variation in the prevalence data is somewhat puzzling. It is unclear exactly what factors contributed to the wide variation, but there is tantalizing evidence for the negative correlation between the estimated prevalence and the sample size (Fig. 1). Why this is the case? Is it because of ascertainment or selection bias, sampling errors, or preference for astounding findings by the authors or journal editors? Or is it simply the result of falling into the trap of attribution error? There is no answer as of now, and addressing these questions would warrant further studies. Humans are very good at making inferences from limited, sometimes ambiguous information, searching insatiably for meaning, but quite often the inference may lead us astray, especially when the available information is ambiguous or simply incomplete. In many ways, the data in support either for or against the causal endometriosis–OVCA link are somewhat not fully sufficient, in fact often are ambiguous. Before more thorough investigations are carried out, it may be hazardous to jump to certain conclusions. Although the presence of ovarian endometriomas can generate a proinflammatory microenvironment that may be conducive to the development of OVCA, it is noted that most, if not all, diseases, especially those associated with pain, have signs of inflammation. Even obesity has signs of inflammation. What is unclear is how the proinflammatory milieu in endometriosis per se leads to OVCA. It is also unclear whether peritoneal or deep-infiltrating endometriosis would also increase the risk of OVCA more than other gynecologic cancers. Moreover, the failure in providing or adjustment for information on treatment in many published epidemiologic studies raises the question of whether a surgery or drug treatment can actually reduce the risk of OVCA. It also raises the question of whether the use of danazol, an androgenic agent and once a popular therapeutic for endometriosis, could increase the risk of OVCA, or whether endometriosis

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Q9

removal surgery itself may increase the risk of OVCA. Finally, owing to the nature of case–control studies, the possibility cannot be ruled out that the elevated risk may be attributable, in part, to shared risk factors because both endometriosis and OVCA (especially clear-cell or endometrioid type) may simply share some common risk and/or protective factors—such as ‘‘incessant menstruation’’ and oral contraceptive use, or factors yet to be identified. The finding reported by Melin et al. (163) that the risk of OVCA in women with endometriosis could be cut by 70% if she had all visible endometriotic lesions removed is particularly interesting. To date almost all other published case–control studies failed to control the effect of surgical treatment on the endometriosis–OVCA association, even though the diagnosis of endometriosis is usually established by laparoscopic visualization of lesions, which are almost always removed surgically thereafter. Of course, some subtypes of endometriotic lesions, such as deep-infiltrating endometriosis, can be challenging to remove completely; but does this mean that those women who had complete removal of all visible lesions are those who had less-severe endometriosis? How does this surgical completeness or radicality interact with the extensiveness or severity of endometriosis and impact the risk of developing OVCA? There are no data to answer these questions. In summary, although published clinical, epidemiologic, and molecular studies strongly implicated the risk, though moderate, of developing certain histotypes of OVCA in women with endometriosis, many stones are still left unturned. Future studies need to demonstrate a clear temporal relationship. In addition, further research is warranted to investigate the extent and scope of genomic instability and mutation, either genetically and epigenetically, that is, aberrations that enable malignant transformation. Given the moderate association and the relatively low baseline risk, it is perhaps premature to institute any actionable measures as of now. The evidence for instituting risk-reducing surgeries such as BSO is also insufficient and should be more carefully investigated in the future, in confusion with other aspects, such as risk of cardiovascular diseases and of osteroporosis and quality of life. Future molecular studies also need to establish the phylogenetic relationship between OVCA and its adjacent endometriotic lesions, providing an unequivocal piece of evidence, once and for all, for or against the endometriosis–OVCA link. Acknowledgment: The author thanks Professor Paolo Vercellini for stimulating discussion and for sharing his views on the topic during preparation of this article; two anonymous reviewers and the editor, who provided constructive comments on an earlier version of the manuscript; and Professor Yuedong Wang for his technical assistance on mixed models. The author apologizes for omission of some related work owing to space constraints.

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