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Endometriosis-Associated Ovarian Cancer: A Review of Pathogenesis

Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA
Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2013, 14(3), 5367-5379;
Received: 30 January 2013 / Revised: 21 February 2013 / Accepted: 26 February 2013 / Published: 6 March 2013
(This article belongs to the Special Issue Genes and Pathways in the Pathogenesis of Ovarian Cancer)


Endometriosis is classically defined as the presence of endometrial glands and stroma outside of the endometrial lining and uterine musculature. With an estimated frequency of 5%–10% among women of reproductive age, endometriosis is a common gynecologic disorder. While in itself a benign lesion, endometriosis shares several characteristics with invasive cancer, has been shown to undergo malignant transformation, and has been associated with an increased risk of epithelial ovarian carcinoma (EOC). Numerous epidemiologic studies have shown an increased risk of EOC among women with endometriosis. This is particularly true for women with endometrioid and clear cell ovarian carcinoma. However, the carcinogenic pathways by which endometriosis associated ovarian carcinoma (EAOC) develops remain poorly understood. Current molecular studies have sought to link endometriosis with EAOC through pathways related to oxidative stress, inflammation and hyperestrogenism. In addition, numerous studies have sought to identify an intermediary lesion between endometriosis and EAOC that may allow for the identification of endometriosis at greatest risk for malignant transformation or for the prevention of malignant transformation of this common gynecologic disorder. The objective of the current article is to review the current data regarding the molecular events associated with EAOC development from endometriosis, with a primary focus on malignancies of the endometrioid and clear cell histologic sub-types.

1. Introduction

Endometriosis is a common gynecologic disorder. The estimated frequency among women of reproductive age is 5%–10% and is particularly frequent among women with pelvic pain and infertility [13]. This disorder is classically defined as the presence of endometrial glands and stroma outside of the endometrial lining and uterine musculature [3,4]. The exact etiology of endometriosis has yet to be elucidated. Mechanistic theories include: the reflux of endometrial tissue through the fallopian tubes at the time of menstruation, coelomic metaplasia, embryonic cell rests, and lymphatic and vascular dissemination [58]. However, it is generally accepted that endometriosis has a multifactorial etiology, including genetic, hormonal and immunological factors [3,6].
Areas commonly affected by endometriosis include the surface of the ovaries and the pelvic peritoneum and can result in pelvic inflammation, adhesions, chronic pain and infertility [9]. While endometriosis is a benign lesion, it shares several characteristics with invasive cancer. Similar to cancer, endometriosis has the capacity to invade and spread distantly. Endometriosis can attach to, invade and damage affected tissues [1012]. In addition, numerous studies indicate that women with endometriosis have an increased risk of developing epithelial ovarian cancer (EOC) [11,1318].
Utilizing the national Swedish inpatient and cancer registry database, Brinton et al. reviewed the records of 20,686 women hospitalized with endometriosis between 1969 and 1983. Compared to age- and period-specific incidence rates from the Swedish population at that time, this cohort had an increased overall risk of cancer, with standardized incidence ratio (SIR) of 1.2, and 95% confidence intervals (CI) between 1.1 and 1.3. The risk of ovarian cancer (SIR, 95% CI; 1.9, 1.3–2.8) was also elevated and this was particularly pronounced among women with long-standing ovarian endometriosis (SIR, 95% CI; 4.2, 2.0–7.7) [14]. A follow-up to this study was conducted to determine whether these risk ratios were maintained in an extended study with longer follow-up. Between 1969 and 2000, 64,492 women were evaluated. While the overall risk of cancer was not elevated, the elevated risk of ovarian cancer previously reported was maintained (SIR, 95% CI; 1.43, 1.19–1.71). Again, women with a long-standing history of endometriosis had an even greater risk of ovarian cancer (SIR, 95% CI; 2.23, 1.36–3.44) [15].
Ovarian cancers do not exist as a homogeneous group of malignancies, but as several histologic sub-types with unique characteristics such as frequency, disease aggressiveness, sensitivity to chemotherapy, and factors contributing to malignant development. Studies have shown that the risk associated with endometriosis varies by histologic sub-type. The greatest risk is associated with malignancies of endometrioid and clear cell histology [13,19,20]. Brinton et al. evaluated a population-based cohort of women in Denmark between 1978 and 1998 and determined that women with endometriosis had a predisposition to ovarian cancer. However, this association was restricted to endometrioid (relative risk (RR) of 2.53, 95% CI; 1.19–5.38) and clear cell (RR, 95% CI; 3.37, 1.24–9.14) malignancies [19]. Similarly, Rossing et al. interviewed 812 women diagnosed with ovarian cancer. When compared to population-based controls, the risk of endometrioid/clear cell ovarian cancer for women with endometriosis was three-fold greater. In contrast, the risk associated with other histologic sub-types of EOC was not increased [20].
While epidemiologic studies have extensively evaluated the relationship between endometriosis and ovarian cancer, the underlying mechanism and factors involved with the malignant progression of endometriosis remain poorly understood. The objective of the current article is to review the current data regarding the genetic events and molecular changes for endometriosis-associated ovarian cancer (EAOC), with a primary focus on malignancies of the endometrioid and clear cell histologic sub-types.

2. Malignant Transformation of Endometriosis

In 1925, Sampson was first to describe the malignant transformation of endometriosis to ovarian carcinoma [8]. It was not until 70 years later that the putative progression of endometriosis to an ovarian malignancy was supported by molecular evidence. Jiang et al. examined DNA from 40 cases of endometriosis to determine if these samples harbored alterations common to ovarian malignancies. Specifically, alterations in TP53 and RASK, as well as allelic losses at candidate ovarian tumor suppressor loci on chromosome arms 6q, 9p, llq, l7p, 17q and 22q, were evaluated. Though no mutations were detected in TP53 or RASK, loss of heterozygosity (LOH) at one or more of the evaluated loci was demonstrated in 11 of 40 cases (28%) [21]. In a similar study, Sato et al. evaluated the tumor suppressor gene PTEN/MMAC1, located on chromosome arm 10q (10q23.3) [22,23]. LOH at this site occurred in 8 of 19 ovarian endometrioid carcinomas (42.1%), 6 of 22 clear cell carcinomas (27.3%) and 13 of 23 solitary endometriotic cysts (56.5%). In addition, somatic mutations in PTEN were identified in 4 of 20 ovarian endometrioid carcinomas (20.0%), 2 of 24 clear cell carcinomas (8.3%), and 7 of 34 solitary endometriotic cysts (20.6%) [23].
Studies such as these support the theory that histologically benign endometriotic lesions may harbor genetic defects that are permissive for malignant transformation. This transformation is believed to progress in a step-wise fashion through an intermediary endometriotic lesion. Though the immediate precursor-lesion to EAOC has yet to be defined, several authors have evaluated potential targets that may represent the intermediary lesion. These include endometriosis contiguous with an ovarian malignancy and endometriosis displaying histologic features that distinguish it from completely benign and frankly malignant histology (i.e., “atypical endometriosis”). These histologic features, as defined by Czernobilsky and Morris [24] and LaGrenade and Silverberg [25], include large hyperchromatic or pale nuclei with moderate to marked pleomorphism; an increased nuclear-to-cytoplasmic ratio; and cellular crowding, stratification, or tufting. According to a study by Fukunaga et al., such atypical endometriosis was identified in 54% of clear cell and 42% of endometrioid ovarian carcinomas [26]. Separately, Ogawa et al. determined that in 37 cases of ovarian carcinomas with endometriosis, 22 cases showed transition from typical endometriosis to atypical endometriosis, and 23 cases showed transition from atypical endometriosis to carcinoma [17]. Ballouk et al. found that half of the endometriotic cysts with severe atypia showed DNA aneuploidy, suggesting the potential of invasive epithelial malignancies arise in these atypical endometriotic cysts [27].
In the previously mentioned study by Sato et al., synchronous endometriosis was identified in five cases of endometrioid and seven cases of clear cell carcinoma. In the five endometrioid carcinomas synchronous with endometriosis, three displayed LOH events common to both the carcinoma and the endometriosis. Among the seven clear cell carcinomas synchronous with endometriosis, three displayed LOH events common to both the carcinoma and the endometriosis [23]. Protein markers specific for ovarian malignancies have also been evaluated in the context of contiguous or atypical endometriosis. Hepatocyte nuclear factor-1β (HNF-1β) is a transcription factor that has been shown to be significantly up-regulated in ovarian clear cell carcinoma and rarely expressed in non-clear cell carcinoma specimens [28]. Evaluating HNF-1β, Kato et al. identified 17 clear cell tumors associated with endometriosis. Endometriotic epithelium was identified in 12 of these 17 cases, with a total of nine displaying expression of HNF-1β. Though histologically benign, the nine cases of endometriosis that displayed HNF-1β expression included five cases of reactive epithelium and four cases of “atypical endometriosis.” When a series of 40 cases of endometriosis not associated with a primary clear cell ovarian carcinoma were also evaluated, 16 (40%) of the cases displayed HNF-1β positivity. However, the authors noted that expression of HNF-1β was almost exclusively detected in the epithelium showing inflammatory atypia. Kato et al. thus concluded that some epithelial cells of ovarian endometriosis, including atypical endometriosis and endometriosis that undergoes repeated regenerative and inflammatory changes, have already acquired a clear cell phenotype [29].
Most recently, by transcriptomic sequencing, Wiegend et al. identified mutations of the tumor suppressor gene ARID1A that are common to endometrioid and clear cell ovarian carcinomas. Of 119 ovarian clear cell carcinomas and 33 endometrioid carcinomas, ARID1A mutations were present in 55 (46%) and 10 (30%) cases, respectively. Two sets of patient samples containing a clear cell carcinoma associated with contiguous atypical endometriosis were further evaluated. ARID1A mutations were found in the primary malignant lesion and the contiguous, atypical endometriosis. ARIDA expression was retained, however, in areas of endometriosis from sites distant from the primary malignant lesion [30]. In an immunohistochemical evaluation of ARID1A protein expression in 28 cases of endometriosis-associated clear cell carcinomas, Yamamoto et al. found that 17 cases (61%) were ARID1A negative. Within these cases, all atypical endometriosis and 86% of non-atypical endometriosis also lost ARID1A expression, suggesting that loss of ARID1A expression occurs as a very early event in the malignancy development [31].

3. Pathways of Carcinogenesis

Recent whole genome or targeted sequencing studies have identified frequent mutations of ARID1A and PIK3CA genes, and moderate mutations of PPP2R1A and KRAS in ovarian clear cell carcinomas [30,32,33], mutations of PTEN, CTNNB1 and KRAS in endometrioid cancer [34,35]. In combination with the results of gene expression profiling of these two tumor types [3639], activation of oncogenic KRAS and PI3K survival pathways, and inactivation of tumor suppressor genes PTEN and ARID1A are suggested for clear cell and endometrioid ovarian carcinomas, respectively. We emphasize here the significance of the following pathways in clear cell and endometrioid tumors in association with endometriosis.

3.1. Oxidative Stress

Oxidative stress has been implicated in the development of numerous human disorders. These include cancer, atherosclerosis, diabetes, cardiovascular disease, neurodegenerative diseases, pulmonary fibrosis, liver diseases, AIDS and aging [40]. As mentioned previously, endometriosis is defined as the occurrence of endometrial tissue outside of the uterus, often on the surface of the ovaries and the pelvic peritoneum [9]. Repetitive hemorrhage and the accumulation of heme and free iron within endometriotic lesions are believed to play a pivotal role in the development of ovarian carcinoma through the formation of reactive oxygen species (ROS) [4143]. Yamaguchi et al. evaluated the contents of 21 endometriotic cysts, 4 clear cell carcinomas, and 11 non-endometriotic cysts to determine the concentrations of free iron and several stress-related factors (e.g., lactose dehydrogenase, potential antioxidant lipid peroxide, and 8-hydroxy-2′-deoxyguanosine). When compared to non-endometriotic cysts, the concentration of free iron in endometriotic cysts was significantly higher (p < 0.01). In addition, the average concentration of the evaluated stress-related factors was significantly greater in endometriotic cysts, when compared to non-endometriotic cysts. In vitro analyses showed that the contents of endometriotic cyst could produce more ROS and could induce gene mutations more frequently than the contents in the other cysts [42]. Similarly, Sanchez et al. found that markers of oxidative damage, such as strand breakage, DNA adducts and lipid peroxidation products could all be detected in ovarian cancer tissue [44].
Ultimately, oxidative stress results when the production of ROS exceeds the capacity of cellular antioxidant defenses to remove toxic ROS [45,46]. Excess ROS can result in oxidative stress-related damage to proteins, lipids, DNA and the cell membrane through numerous carcinogenic DNA mutations or losses [47,48]. The theory that oxidative stress is implicated in the development of ovarian carcinoma, specifically clear cell carcinoma, is further supported by microarray gene-expression profiling [29,49]. Fifty-four genes have been found to be highly up-regulated in ovarian clear cell carcinoma. Of these 54 genes, 47 (87%) are redox-related genes, including oxidative and detoxification enzymes [43]. The subsequent carcinogenic pathways remain poorly understood but HNF-1β appears to play a key role as 22 (40.7%) of the 54 up-regulated genes are downstream targets of HNF-1β [4951].
HNF-1β is a transcription factor that targets genes encoding proteins vital to cell proliferation, differentiation, gluconeogenesis and glycogen synthesis [52]. The relationship between HNF-1β and oxidative stress has been studied in the context of viral hepatitis infection. Hepatitis C virus (HCV) infection induces oxidative stress during replication and/or protein expression, and chronic HCV infection in human liver, as well as in different experimental models, is associated with excess oxidative stress [5355]. Adaptive responses to the increased oxidative burden include the activation of detoxification pathways via activation of HNF [5557]. With respect to ovarian carcinoma, the oxidative stress related HNF-1β pathways remain largely unexplored. However, an interesting study conducted by Liu et al. revealed that down-regulation of HNF-1β by shRNA strategy sensitized ovarian cancer cells to cisplatin- or paclitaxel-induced cytotoxicity both in vitro and in vivo[58].

3.2. Inflammation

In 1863, Rudolf Virchow observed leukocytes in neoplastic tissues and made a connection between inflammation and cancer. He suggested that the “lymphoreticular infiltrate” reflected the origin of cancer at sites of chronic inflammation [46]. Both acute and chronic inflammations are classic features of endometriosis and a growing body of literature now supports the conceptualization of endometriosis as a pelvic inflammatory condition [59,60]. In women with endometriosis, the peritoneal fluid often contains an increased number of activated macrophages [61]. In addition, several important cytokines and chemokines are present in increased concentrations. These include TNF-α, IL-1β, IL-6, IL-8, regulated on activation normal T cell expressed and secreted (RANTES), and monocyte chemotactic protein-1. The latter three are chemoattractants, which facilitate the recruitment of macrophages [6265].
Similar to results in endometriosis, numerous studies suggest inflammatory mediators and several cytokines (e.g., TNF-α, IL-1β, IL-6) promote the development, growth and progression of EOC [66,67]. Szlosarek et al. explored the role of TNF-α in the development of ovarian carcinoma. Within a cancer profile array including serous and clear cell ovarian carcinoma, the expression of TNF-α was increased when compared to the level of expression within normal ovarian tissue. Further, cultured ovarian cancer cells expressed up to 1000 times more TNF-α mRNA than cultured normal ovarian surface epithelium [68]. A follow-up study from the same group showed that elevated TNF network gene expression in the tumor microenvironment resulted in increased signaling related to angiogenesis, cell adhesion, cell cycle, inflammation, as well as NOTCH signaling [69]. In another microarray expression profiling study of endometriosis-associated endometrioid ovarian cancer, the expression of small inducible cytokine A2 (SICA2) and small inducible cytokine subfamily A, member 14 (CCL14) were the most up-regulated genes in endometriosis-associated endometrioid ovarian tumors when compared with benign ovaries and endometrioid cases not associated with endometriosis, suggesting that inflammatory cytokines are important in the etiology of endometriosis and associating endometrioid tumors [36]. Finally, prostaglandin E2 (PGE2) is a central mediator of the inflammatory response but has also been shown to regulate vital processes related to tumor growth, including angiogenesis, proliferation and inhibition of apoptosis [70,71].

3.3. Estrogen

Numerous studies have demonstrated an association between hyperestrogenism and gynecologic malignancies. These include cancers of the breast, endometrium and ovary [7274]. Specific to EAOC, hyperestrogenism has been associated with the malignant transformation of endometriotic cysts and the micro-environment provided by endometriosis facilitates the accumulation of excess estrogen through several mechanisms [75,76]. For example, the enzyme aromatase is normally absent in eutopic endometrial tissue, but present in high levels within endometriotic tissue [77]. This enzyme catalyzes the conversion of androstenedione and testosterone, derived from ovarian and adrenal sources, to estrone and estradiol (E2), respectively [78]. In endometriotic tissue, this results in the constitutive expression of E2[79]. Next, endometriotic tissues lack the enzyme 17β-hydroxysteroid-dehydrogenase (17β-HSD) type 2, which is present in eutopic endometrial tissue and serves to convert E2 to estrone, which is a less potent estrogen [80]. In contrast, 17β-HSD type 1 converts estrone to the more potent E2 and this enzyme can be found in endometriotic tissue with the cumulative effect of increasing the local concentration of highly estrogenic E2 through increased production and decreased inactivation [78,80].
Excess E2 can result in cellular proliferation through the stimulation of cytokine production, specifically IL-8 and RANTES [81]. In addition, E2 stimulates the production of PGE2. As previously mentioned, PGE2 promotes tumor growth, but also serves to stimulate the activity of aromatase, thereby resulting in a positive feedback loop in favor of continuous estrogen formation in endometriosis [77,78]. In sum, the micro-environment in endometriotic tissue is marked by proliferative pressure with an enhanced level of reparative activity and thus, a higher chance for DNA damage and mutations.
Among EAOC, expression of estrogen receptor (ER) and progesterone receptor (PR) is predominantly found in the endometrioid sub-type. The clear cell sub-type typically does not express ER or PR [82]. The previously described events, mediated by oxidative stress and inflammation secondary to the repeated hemorrhage from endometriosis, result in DNA methylation that has been linked to decreased ER expression [83,84]. Some investigators have postulated a dualistic model for the development of EAOC, in which the loss of ER expression marks a pivotal point in the carcinogenic pathway separating the development of estrogen-dependent carcinomas (i.e., endometrioid) from estrogen-independent carcinomas (i.e., clear cell) [85,86]. While the separation of estrogen-dependent and estrogen-independent EAOC is supported on the basis of morphology and genomics, the details of both pathways remain areas of further investigation [85,86].

4. Conclusions

The association between endometriosis and EOC has been supported by years of epidemiologic research. Our current knowledge of this association at the molecular level remains an area of great interest and worthy of future studies as the carcinogenic mechanisms and pathways remain poorly defined. Future studies will clarify the roles of oxidative stress, inflammation and estrogen in the development of EAOC. At this point, we know that the micro-environment of endometriosis and EAOC share similar cytokines and mediators. Whether this similarity represents a link between endometriosis and EAOC or simply an employment of common signaling molecules to two separate lesions remains to be seen. Studies evaluating the possible intermediary lesion of EAOC (both contiguous and “atypical” endometriosis) appear promising in strengthening the link between endometriosis and ovarian carcinoma. These studies may also aid in identifying endometriotic lesions at greatest risk of malignant transformation. However, most of the specimens harboring these features are in formalin-fixed, paraffin-embedded (FFPE) form, which presents a challenge for successful molecular profiling and analysis. In conclusion, EAOC represents a poorly understood consequence of a common gynecologic disorder (i.e., endometriosis). A greater understanding of the pathogenesis of EAOC would potentially allow for preventative strategies for those women with endometriosis at greatest risk of developing EAOC, as well as novel treatment approaches for women already diagnosed with EAOC.


We gratefully thank the generous support to the Laboratory of Gynecologic Oncology by the Ruth N. White Gynecologic Oncology Research Fellowship, the Deborah First Fund, the Sperling Family Fund Foundation, the Women’s Cancer Program and the Gillette Center for Women’s Cancer from the Dana-Farber Cancer Institute, the Ovarian Cancer Research Foundation, the Adler Foundation Inc. and the Friends of Dana Farber Cancer Institute Foundation.

Conflict of Interest

The authors declare no conflict of interest.


  1. Eskenazi, B.; Warner, M.L. Epidemiology of endometriosis. Obstet. Gynecol. Clin. N. Am 1997, 24, 235–258. [Google Scholar]
  2. Bulun, S.E. Endometriosis. N. Engl. J. Med 2009, 360, 268–279. [Google Scholar]
  3. Giudice, L.C.; Kao, L.C. Endometriosis. Lancet 2004, 364, 1789–1799. [Google Scholar]
  4. Olive, D.L.; Schwartz, L.B. Endometriosis. N. Engl. J. Med 1993, 328, 1759–1769. [Google Scholar]
  5. Pearce, C.L.; Templeman, C.; Rossing, M.A.; Lee, A.; Near, A.M.; Webb, P.M.; Nagle, C.M.; Doherty, J.A.; Cushing-Haugen, K.L.; Wicklund, K.G.; et al. Association between endometriosis and risk of histological subtypes of ovarian cancer: A pooled analysis of case-control studies. Lancet Oncol 2012, 13, 385–394. [Google Scholar]
  6. Gazvani, R.; Templeton, A. New considerations for the pathogenesis of endometriosis. Int. J. Gynaecol. Obstet 2002, 76, 117–126. [Google Scholar]
  7. Halme, J.; Hammond, M.G.; Hulka, J.F.; Raj, S.G.; Talbert, L.M. Retrograde menstruation in healthy women and in patients with endometriosis. Obstet. Gynecol 1984, 64, 151–154. [Google Scholar]
  8. Sampson, J.A. Metastatic or embolic endometriosis, due to the menstrual dissemination of endometrial tissue into the venous circulation. Am. J. Pathol. 1927, 3. [Google Scholar]
  9. Sainz de la Cuesta, R.; Eichhorn, J.H.; Rice, L.W.; Fuller, A.F., Jr; Nikrui, N.; Goff, B.A. Histologic transformation of benign endometriosis to early epithelial ovarian cancer. Gynecol. Oncol. 1996, 60, 238–244. [Google Scholar]
  10. Jiang, Q.Y.; Wu, R.J. Growth mechanisms of endometriotic cells in implanted places: A review. Gynecol. Endocrinol 2012, 28, 562–567. [Google Scholar]
  11. Vlahos, N.F.; Economopoulos, K.P.; Fotiou, S. Endometriosis, in vitro fertilisation and the risk of gynaecological malignancies, including ovarian and breast cancer. Best Pract. Res. Clin. Obstet. Gynaecol 2010, 24, 39–50. [Google Scholar]
  12. Vlahos, N.F.; Kalampokas, T.; Fotiou, S. Endometriosis and ovarian cancer: A review. Gynecol. Endocrinol 2010, 26, 213–219. [Google Scholar]
  13. Kobayashi, H.; Sumimoto, K.; Moniwa, N.; Imai, M.; Takakura, K.; Kuromaki, T.; Morioka, E.; Arisawa, K.; Terao, T. Risk of developing ovarian cancer among women with ovarian endometrioma: A cohort study in shizuoka, japan. Int. J. Gynecol. Cancer 2007, 17, 37–43. [Google Scholar]
  14. Brinton, L.A.; Gridley, G.; Persson, I.; Baron, J.; Bergqvist, A. Cancer risk after a hospital discharge diagnosis of endometriosis. Am. J. Obstet. Gynecol 1997, 176, 572–579. [Google Scholar]
  15. Melin, A.; Sparen, P.; Persson, I.; Bergqvist, A. Endometriosis and the risk of cancer with special emphasis on ovarian cancer. Human Reprod 2006, 21, 1237–1242. [Google Scholar]
  16. Vercellini, P.; Parazzini, F.; Bolis, G.; Carinelli, S.; Dindelli, M.; Vendola, N.; Luchini, L.; Crosignani, P.G. Endometriosis and ovarian cancer. Am. J. Obstet. Gynecol 1993, 169, 181–182. [Google Scholar]
  17. Ogawa, S.; Kaku, T.; Amada, S.; Kobayashi, H.; Hirakawa, T.; Ariyoshi, K.; Kamura, T.; Nakano, H. Ovarian endometriosis associated with ovarian carcinoma: A clinicopathological and immunohistochemical study. Gynecol. Oncol 2000, 77, 298–304. [Google Scholar]
  18. Kumar, S.; Munkarah, A.; Arabi, H.; Bandyopadhyay, S.; Semaan, A.; Hayek, K.; Garg, G.; Morris, R.; Ali-Fehmi, R. Prognostic analysis of ovarian cancer associated with endometriosis. Am. J. Obstet. Gynecol. 2011, 204, 63 e61–e67. [Google Scholar]
  19. Brinton, L.A.; Sakoda, L.C.; Sherman, M.E.; Frederiksen, K.; Kjaer, S.K.; Graubard, B.I.; Olsen, J.H.; Mellemkjaer, L. Relationship of benign gynecologic diseases to subsequent risk of ovarian and uterine tumors. Cancer Epidemiol. Biomark. Prev 2005, 14, 2929–2935. [Google Scholar]
  20. Rossing, M.A.; Cushing-Haugen, K.L.; Wicklund, K.G.; Doherty, J.A.; Weiss, N.S. Risk of epithelial ovarian cancer in relation to benign ovarian conditions and ovarian surgery. Cancer Causes Control 2008, 19, 1357–1364. [Google Scholar]
  21. Jiang, X.; Hitchcock, A.; Bryan, E.J.; Watson, R.H.; Englefield, P.; Thomas, E.J.; Campbell, I.G. Microsatellite analysis of endometriosis reveals loss of heterozygosity at candidate ovarian tumor suppressor gene loci. Cancer Res 1996, 56, 3534–3539. [Google Scholar]
  22. Li, J.; Yen, C.; Liaw, D.; Podsypanina, K.; Bose, S.; Wang, S.I.; Puc, J.; Miliaresis, C.; Rodgers, L.; McCombie, R.; et al. Pten, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 1997, 275, 1943–1947. [Google Scholar]
  23. Sato, N.; Tsunoda, H.; Nishida, M.; Morishita, Y.; Takimoto, Y.; Kubo, T.; Noguchi, M. Loss of heterozygosity on 10q23.3 and mutation of the tumor suppressor gene pten in benign endometrial cyst of the ovary: Possible sequence progression from benign endometrial cyst to endometrioid carcinoma and clear cell carcinoma of the ovary. Cancer Res 2000, 60, 7052–7056. [Google Scholar]
  24. Czernobilsky, B.; Morris, W.J. A histologic study of ovarian endometriosis with emphasis on hyperplastic and atypical changes. Obstet. Gynecol 1979, 53, 318–323. [Google Scholar]
  25. LaGrenade, A.; Silverberg, S.G. Ovarian tumors associated with atypical endometriosis. Hum. Pathol 1988, 19, 1080–1084. [Google Scholar]
  26. Fukunaga, M.; Nomura, K.; Ishikawa, E.; Ushigome, S. Ovarian atypical endometriosis: Its close association with malignant epithelial tumours. Histopathology 1997, 30, 249–255. [Google Scholar]
  27. Ballouk, F.; Ross, J.S.; Wolf, B.C. Ovarian endometriotic cysts. An analysis of cytologic atypia and DNA ploidy patterns. Am. J. Clin. Pathol 1994, 102, 415–419. [Google Scholar]
  28. Tsuchiya, A.; Sakamoto, M.; Yasuda, J.; Chuma, M.; Ohta, T.; Ohki, M.; Yasugi, T.; Taketani, Y.; Hirohashi, S. Expression profiling in ovarian clear cell carcinoma: Identification of hepatocyte nuclear factor-1 beta as a molecular marker and a possible molecular target for therapy of ovarian clear cell carcinoma. Am. J. Pathol 2003, 163, 2503–2512. [Google Scholar]
  29. Kato, N.; Sasou, S.; Motoyama, T. Expression of hepatocyte nuclear factor-1beta (hnf-1beta) in clear cell tumors and endometriosis of the ovary. Mod. Pathol 2006, 19, 83–89. [Google Scholar]
  30. Wiegand, K.C.; Shah, S.P.; Al-Agha, O.M.; Zhao, Y.; Tse, K.; Zeng, T.; Senz, J.; McConechy, M.K.; Anglesio, M.S.; Kalloger, S.E.; et al. Arid1a mutations in endometriosis-associated ovarian carcinomas. N. Engl. J. Med 2010, 363, 1532–1543. [Google Scholar]
  31. Yamamoto, S.; Tsuda, H.; Takano, M.; Tamai, S.; Matsubara, O. Loss of arid1a protein expression occurs as an early event in ovarian clear-cell carcinoma development and frequently coexists with pik3ca mutations. Mod. Pathol 2012, 25, 615–624. [Google Scholar]
  32. Jones, S.; Wang, T.L.; Shih Ie, M.; Mao, T.L.; Nakayama, K.; Roden, R.; Glas, R.; Slamon, D.; Diaz, L.A., Jr; Vogelstein, B.; et al. Frequent mutations of chromatin remodeling gene arid1a in ovarian clear cell carcinoma. Science 2010, 330, 228–231. [Google Scholar]
  33. Yanaihara, N.; Caplen, N.; Bowman, E.; Seike, M.; Kumamoto, K.; Yi, M.; Stephens, R.M.; Okamoto, A.; Yokota, J.; Tanaka, T.; et al. Unique microrna molecular profiles in lung cancer diagnosis and prognosis. Cancer Cell 2006, 9, 189–198. [Google Scholar]
  34. Kolasa, I.K.; Rembiszewska, A.; Janiec-Jankowska, A.; Dansonka-Mieszkowska, A.; Lewandowska, A.M.; Konopka, B.; Kupryjanczyk, J. Pten mutation, expression and loh at its locus in ovarian carcinomas. Relation to tp53, k-ras and brca1 mutations. Gynecol. Oncol 2006, 103, 692–697. [Google Scholar]
  35. Palacios, J.; Gamallo, C. Mutations in the beta-catenin gene (ctnnb1) in endometrioid ovarian carcinomas. Cancer Res 1998, 58, 1344–1347. [Google Scholar]
  36. Banz, C.; Ungethuem, U.; Kuban, R.J.; Diedrich, K.; Lengyel, E.; Hornung, D. The molecular signature of endometriosis-associated endometrioid ovarian cancer differs significantly from endometriosis-independent endometrioid ovarian cancer. Fertil. Steril 2010, 94, 1212–1217. [Google Scholar]
  37. Madore, J.; Ren, F.; Filali-Mouhim, A.; Sanchez, L.; Kobel, M.; Tonin, P.N.; Huntsman, D.; Provencher, D.M.; Mes-Masson, A.M. Characterization of the molecular differences between ovarian endometrioid carcinoma and ovarian serous carcinoma. J. Pathol 2010, 220, 392–400. [Google Scholar]
  38. Stany, M.P.; Vathipadiekal, V.; Ozbun, L.; Stone, R.L.; Mok, S.C.; Xue, H.; Kagami, T.; Wang, Y.; McAlpine, J.N.; Bowtell, D.; et al. Identification of novel therapeutic targets in microdissected clear cell ovarian cancers. PLoS One 2011, 6, e21121. [Google Scholar]
  39. Tothill, R.W.; Kowalczyk, A.; Rischin, D.; Bousioutas, A.; Haviv, I.; van Laar, R.K.; Waring, P.M.; Zalcberg, J.; Ward, R.; Biankin, A.V.; et al. An expression-based site of origin diagnostic method designed for clinical application to cancer of unknown origin. Cancer Res 2005, 65, 4031–4040. [Google Scholar]
  40. Cerutti, P.A. Oxy-radicals and cancer. Lancet 1994, 344, 862–863. [Google Scholar]
  41. Kobayashi, H.; Yamada, Y.; Kanayama, S.; Furukawa, N.; Noguchi, T.; Haruta, S.; Yoshida, S.; Sakata, M.; Sado, T.; Oi, H. The role of iron in the pathogenesis of endometriosis. Gynecol. Endocrinol 2009, 25, 39–52. [Google Scholar]
  42. Yamaguchi, K.; Mandai, M.; Toyokuni, S.; Hamanishi, J.; Higuchi, T.; Takakura, K.; Fujii, S. Contents of endometriotic cysts, especially the high concentration of free iron, are a possible cause of carcinogenesis in the cysts through the iron-induced persistent oxidative stress. Clin. Cancer Res 2008, 14, 32–40. [Google Scholar]
  43. Kajihara, H.; Yamada, Y.; Kanayama, S.; Furukawa, N.; Noguchi, T.; Haruta, S.; Yoshida, S.; Sado, T.; Oi, H.; Kobayashi, H. Clear cell carcinoma of the ovary: Potential pathogenic mechanisms. Oncol. Rep 2010, 23, 1193–1203. [Google Scholar]
  44. Sanchez, M.; Torres, J.V.; Tormos, C.; Iradi, A.; Muniz, P.; Espinosa, O.; Salvador, A.; Rodriguez-Delgado, J.; Fandos, M.; Saez, G.T. Impairment of antioxidant enzymes, lipid peroxidation and 8-oxo-2′-deoxyguanosine in advanced epithelial ovarian carcinoma of a spanish community. Cancer Lett 2006, 233, 28–35. [Google Scholar]
  45. Limon-Pacheco, J.; Gonsebatt, M.E. The role of antioxidants and antioxidant-related enzymes in protective responses to environmentally induced oxidative stress. Mutat. Res 2009, 674, 137–147. [Google Scholar]
  46. Balkwill, F.; Mantovani, A. Inflammation and cancer: Back to virchow? Lancet 2001, 357, 539–545. [Google Scholar]
  47. Storz, G.; Imlay, J.A. Oxidative stress. Curr. Opin. Microbiol 1999, 2, 188–194. [Google Scholar]
  48. Barnouin, K.; Dubuisson, M.L.; Child, E.S.; Fernandez de Mattos, S.; Glassford, J.; Medema, R.H.; Mann, D.J.; Lam, E.W. H2O2 induces a transient multi-phase cell cycle arrest in mouse fibroblasts through modulating cyclin d and p21cip1 expression. J. Biol. Chem 2002, 277, 13761–13770. [Google Scholar]
  49. Yoshida, S.; Furukawa, N.; Haruta, S.; Tanase, Y.; Kanayama, S.; Noguchi, T.; Sakata, M.; Yamada, Y.; Oi, H.; Kobayashi, H. Theoretical model of treatment strategies for clear cell carcinoma of the ovary: Focus on perspectives. Cancer Treat. Rev 2009, 35, 608–615. [Google Scholar]
  50. Kobayashi, H.; Yamada, Y.; Kanayama, S.; Furukawa, N.; Noguchi, T.; Haruta, S.; Yoshida, S.; Sakata, M.; Sado, T.; Oi, H. The role of hepatocyte nuclear factor-1beta in the pathogenesis of clear cell carcinoma of the ovary. Int. J. Gynecol. Cancer 2009, 19, 471–479. [Google Scholar]
  51. Kobayashi, H.; Kajiwara, H.; Kanayama, S.; Yamada, Y.; Furukawa, N.; Noguchi, T.; Haruta, S.; Yoshida, S.; Sakata, M.; Sado, T.; et al. Molecular pathogenesis of endometriosis-associated clear cell carcinoma of the ovary (review). Oncol. Rep 2009, 22, 233–240. [Google Scholar]
  52. Parviz, F.; Matullo, C.; Garrison, W.D.; Savatski, L.; Adamson, J.W.; Ning, G.; Kaestner, K.H.; Rossi, J.M.; Zaret, K.S.; Duncan, S.A. Hepatocyte nuclear factor 4alpha controls the development of a hepatic epithelium and liver morphogenesis. Nat. Genet 2003, 34, 292–296. [Google Scholar]
  53. Okuda, M.; Li, K.; Beard, M.R.; Showalter, L.A.; Scholle, F.; Lemon, S.M.; Weinman, S.A. Mitochondrial injury, oxidative stress, and antioxidant gene expression are induced by hepatitis c virus core protein. Gastroenterology 2002, 122, 366–375. [Google Scholar]
  54. Liu, C.; Zhu, H.; Tu, Z.; Xu, Y.L.; Nelson, D.R. Cd8+ T-cell interaction with hcv replicon cells: Evidence for both cytokine- and cell-mediated antiviral activity. Hepatology 2003, 37, 1335–1342. [Google Scholar]
  55. Qadri, I.; Iwahashi, M.; Capasso, J.M.; Hopken, M.W.; Flores, S.; Schaack, J.; Simon, F.R. Induced oxidative stress and activated expression of manganese superoxide dismutase during hepatitis c virus replication: Role of jnk, p38 mapk and ap-1. Biochem. J 2004, 378, 919–928. [Google Scholar]
  56. Qadri, I.; Iwahashi, M.; Kullak-Ublick, G.A.; Simon, F.R. Hepatocyte nuclear factor (hnf) 1 and hnf4 mediate hepatic multidrug resistance protein 2 up-regulation during hepatitis c virus gene expression. Mol. Pharmacol 2006, 70, 627–636. [Google Scholar]
  57. Guo, H.; Wei, J.; Inoue, Y.; Gonzalez, F.J.; Kuo, P.C. Serine/threonine phosphorylation regulates hnf-4alpha-dependent redox-mediated inos expression in hepatocytes. Am. J. Physiol. Cell Physiol 2003, 284, C1090–C1099. [Google Scholar]
  58. Liu, P.; Khurana, A.; Rattan, R.; He, X.; Kalloger, S.; Dowdy, S.; Gilks, B.; Shridhar, V. Regulation of hsulf-1 expression by variant hepatic nuclear factor 1 in ovarian cancer. Cancer Res 2009, 69, 4843–4850. [Google Scholar]
  59. Burney, R.O.; Giudice, L.C. Pathogenesis and pathophysiology of endometriosis. Fertil. Steril 2012, 98, 511–519. [Google Scholar]
  60. Ness, R.B.; Modugno, F. Endometriosis as a model for inflammation-hormone interactions in ovarian and breast cancers. Eur. J. Cancer 2006, 42, 691–703. [Google Scholar]
  61. Rana, N.; Braun, D.P.; House, R.; Gebel, H.; Rotman, C.; Dmowski, W.P. Basal and stimulated secretion of cytokines by peritoneal macrophages in women with endometriosis. Fertil. Steril 1996, 65, 925–930. [Google Scholar]
  62. Kats, R.; Collette, T.; Metz, C.N.; Akoum, A. Marked elevation of macrophage migration inhibitory factor in the peritoneal fluid of women with endometriosis. Fertil. Steril 2002, 78, 69–76. [Google Scholar]
  63. Eisermann, J.; Gast, M.J.; Pineda, J.; Odem, R.R.; Collins, J.L. Tumor necrosis factor in peritoneal fluid of women undergoing laparoscopic surgery. Fertil. Steril 1988, 50, 573–579. [Google Scholar]
  64. Harada, T.; Yoshioka, H.; Yoshida, S.; Iwabe, T.; Onohara, Y.; Tanikawa, M.; Terakawa, N. Increased interleukin-6 levels in peritoneal fluid of infertile patients with active endometriosis. Am. J. Obstet. Gynecol 1997, 176, 593–597. [Google Scholar]
  65. Akoum, A.; Lemay, A.; McColl, S.; Turcot-Lemay, L.; Maheux, R. Elevated concentration and biologic activity of monocyte chemotactic protein-1 in the peritoneal fluid of patients with endometriosis. Fertil. Steril 1996, 66, 17–23. [Google Scholar]
  66. Nowak, M.; Glowacka, E.; Szpakowski, M.; Szyllo, K.; Malinowski, A.; Kulig, A.; Tchorzewski, H.; Wilczynski, J. Proinflammatory and immunosuppressive serum, ascites and cyst fluid cytokines in patients with early and advanced ovarian cancer and benign ovarian tumors. Neuro Endocrinol. Lett 2010, 31, 375–383. [Google Scholar]
  67. Clendenen, T.V.; Lundin, E.; Zeleniuch-Jacquotte, A.; Koenig, K.L.; Berrino, F.; Lukanova, A.; Lokshin, A.E.; Idahl, A.; Ohlson, N.; Hallmans, G.; et al. Circulating inflammation markers and risk of epithelial ovarian cancer. Cancer Epidemiol. Biomark. Prev 2011, 20, 799–810. [Google Scholar]
  68. Szlosarek, P.W.; Grimshaw, M.J.; Kulbe, H.; Wilson, J.L.; Wilbanks, G.D.; Burke, F.; Balkwill, F.R. Expression and regulation of tumor necrosis factor alpha in normal and malignant ovarian epithelium. Mol. Cancer Ther 2006, 5, 382–390. [Google Scholar]
  69. Kulbe, H.; Hagemann, T.; Szlosarek, P.W.; Balkwill, F.R.; Wilson, J.L. The inflammatory cytokine tumor necrosis factor-alpha regulates chemokine receptor expression on ovarian cancer cells. Cancer Res 2005, 65, 10355–10362. [Google Scholar]
  70. Munkarah, A.R.; Morris, R.; Baumann, P.; Deppe, G.; Malone, J.; Diamond, M.P.; Saed, G.M. Effects of prostaglandin e(2) on proliferation and apoptosis of epithelial ovarian cancer cells. J. Society Gynecol. Investig 2002, 9, 168–173. [Google Scholar]
  71. Murakami, M.; Kudo, I. Recent advances in molecular biology and physiology of the prostaglandin e2-biosynthetic pathway. Prog. lipid Res 2004, 43, 3–35. [Google Scholar]
  72. Beresford, S.A.; Weiss, N.S.; Voigt, L.F.; McKnight, B. Risk of endometrial cancer in relation to use of oestrogen combined with cyclic progestagen therapy in postmenopausal women. Lancet 1997, 349, 458–461. [Google Scholar]
  73. Collaborative group on hormonal factors in breast cancer. Breast cancer and hormone replacement therapy: Collaborative reanalysis of data from 51 epidemiological studies of 52,705 women with breast cancer and 108m411 women without breast cancer. Lancet 1997, 350, 1047–1059.
  74. Morch, L.S.; Lokkegaard, E.; Andreasen, A.H.; Kruger-Kjaer, S.; Lidegaard, O. Hormone therapy and ovarian cancer. JAMA 2009, 302, 298–305. [Google Scholar]
  75. Heaps, J.M.; Nieberg, R.K.; Berek, J.S. Malignant neoplasms arising in endometriosis. Obstet. Gynecol 1990, 75, 1023–1028. [Google Scholar]
  76. Oxholm, D.; Knudsen, U.B.; Kryger-Baggesen, N.; Ravn, P. Postmenopausal endometriosis. Acta Obstet. Et Gynecol. Scand 2007, 86, 1158–1164. [Google Scholar]
  77. Zeitoun, K.M.; Bulun, S.E. Aromatase: A key molecule in the pathophysiology of endometriosis and a therapeutic target. Fertil. Steril 1999, 72, 961–969. [Google Scholar]
  78. Munksgaard, P.S.; Blaakaer, J. The association between endometriosis and ovarian cancer: A review of histological, genetic and molecular alterations. Gynecol. Oncol 2012, 124, 164–169. [Google Scholar]
  79. Ness, R.B. Endometriosis and ovarian cancer: Thoughts on shared pathophysiology. Am. J. Obstet. Gynecol 2003, 189, 280–294. [Google Scholar]
  80. Zeitoun, K.; Takayama, K.; Sasano, H.; Suzuki, T.; Moghrabi, N.; Andersson, S.; Johns, A.; Meng, L.; Putman, M.; Carr, B.; et al. Deficient 17beta-hydroxysteroid dehydrogenase type 2 expression in endometriosis: Failure to metabolize 17beta-estradiol. J. Clin. Endocrinol. Metab 1998, 83, 4474–4480. [Google Scholar]
  81. Khorram, O.; Taylor, R.N.; Ryan, I.P.; Schall, T.J.; Landers, D.V. Peritoneal fluid concentrations of the cytokine rantes correlate with the severity of endometriosis. Am. J. Obstet. Gynecol 1993, 169, 1545–1549. [Google Scholar]
  82. Soslow, R.A. Histologic subtypes of ovarian carcinoma: An overview. Int. J. Gynecol. Pathol 2008, 27, 161–174. [Google Scholar]
  83. Suzuki, F.; Akahira, J.; Miura, I.; Suzuki, T.; Ito, K.; Hayashi, S.; Sasano, H.; Yaegashi, N. Loss of estrogen receptor beta isoform expression and its correlation with aberrant DNA methylation of the 5′-untranslated region in human epithelial ovarian carcinoma. Cancer Sci 2008, 99, 2365–2372. [Google Scholar]
  84. Ottaviano, Y.L.; Issa, J.P.; Parl, F.F.; Smith, H.S.; Baylin, S.B.; Davidson, N.E. Methylation of the estrogen receptor gene cpg island marks loss of estrogen receptor expression in human breast cancer cells. Cancer Res 1994, 54, 2552–2555. [Google Scholar]
  85. Mandai, M.; Yamaguchi, K.; Matsumura, N.; Baba, T.; Konishi, I. Ovarian cancer in endometriosis: Molecular biology, pathology, and clinical management. Int. J. Clin. Oncol 2009, 14, 383–391. [Google Scholar]
  86. Tanase, Y.; Yamada, Y.; Shigetomi, H.; Kajihara, H.; Oonogi, A.; Yoshizawa, Y.; Furukawa, N.; Haruta, S.; Yoshida, S.; Sado, T.; et al. Modulation of estrogenic action in clear cell carcinoma of the ovary (review). Exp. Ther. Med 2012, 3, 18–24. [Google Scholar]

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Worley, M.J., Jr.; Welch, W.R.; Berkowitz, R.S.; Ng, S.-W. Endometriosis-Associated Ovarian Cancer: A Review of Pathogenesis. Int. J. Mol. Sci. 2013, 14, 5367-5379.

AMA Style

Worley MJ Jr., Welch WR, Berkowitz RS, Ng S-W. Endometriosis-Associated Ovarian Cancer: A Review of Pathogenesis. International Journal of Molecular Sciences. 2013; 14(3):5367-5379.

Chicago/Turabian Style

Worley, Michael J., Jr., William R. Welch, Ross S. Berkowitz, and Shu-Wing Ng. 2013. "Endometriosis-Associated Ovarian Cancer: A Review of Pathogenesis" International Journal of Molecular Sciences 14, no. 3: 5367-5379.

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