Endometriosis and Gynecological Cancer - Ingenta Connect

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Current Women’s Health Reviews, 2012, 8, 150-157

Endometriosis and Gynecological Cancer Mihai Emil Capilna*, Bela Szabo, Lucian Puscasiu, Aron Toma and Cosmin Rugina First Clinic of Obstetrics and Gynecology, University of Medicine and Pharmacy, Targu-Mures, Romania, EU Abstract: Objective: Endometriosis has been suspected of playing a role in the etiology of ovarian cancer. Design: This systematic review addresses the parallels and specific relationship of endometriosis and gynecological cancer regarding risk factors, histological data, genetic alterations, aberrant activation of oncogenic and antiapoptotic pathways, and options in clinical diagnosis. Data sources and eligibility criteria: We have performed a Pubmed search looking for all articles in English, using as key words “endometriosis”, “ovarian cancer”, “gynecologic cancer”, “pathogenesis”. Results: The evidence of the published studies suggests that ovarian tumors can arise from more than one potential source, endometriosis being one of these sources. Conclusion: Understanding the mechanism of the development of endometriosis and elucidating its pathogenesis and pathophysiology are intrinsic to the prevention of endometriosis associated ovarian cancer and the search for effective therapies.

Keywords: Endometriosis, epidemiology, molecular pathogenesis, ovarian cancer. INTRODUCTION Endometriosis is a common gynaecological disease. It is defined as the presence of endometrial-like glandular epithelium and stroma in ectopic locations. In addition to causing pain and infertility, endometriosis has been associated with an elevated risk for gynecologic cancer. The potential for neoplastic degeneration of endometriosis implants has been debated over the past decade from biological, epidemiological, and clinical perspectives [1-3]. This is a crucial issue given the high incidence of endometriosis, which affects an estimated 14 million women of reproductive age in the European Union alone. Endometriosis is often a progressive disease with an estimated prevalence of 10%; it is considered a benign disease, but it contains features similar to those found in malignancies, for example progressive growth, invasive growth, estrogendependent growth, recurrence and a tendency to metastasise [1]. There is increasing awareness that malignant transformation of endometriosis is a distinct entity. Although endometriosis cannot be termed a premalignant condition, epidemiologic, histopathologic, and molecular data suggest that endometriosis does have malignant potential. Three years after Sampson first described endometriosis, he postulated that adenocarcinoma of the ovary can arise from benign endometrial tissue in that organ [2]. Sampson’s criteria for cancer arising from ovarian endometriosis included: 1) the coexistence of carcinoma and endometriosis

*Address correspondence to this author at the First Clinic of Obstetrics and Gynecology, Str. Gh. Marinescu No. 50, 540136 Targu-Mures, Romania EU; Tel: +40744271539; Fax: +40265211600; E-mail: [email protected] 1875-6581/12 $58.00+.00

in the same ovary; 2) the presence of tissue resembling endometrial stroma surrounding characteristic epithelial glands; and 3) the exclusion of a second malignant tumor metastatic to the ovary. In 1953, Scott further refined this theory by stating that in addition to Sampson’s criteria the morphologic demonstration of benign endometriosis contiguous with the malignant tissue is a prerequisite for malignancy originating in endometriosis [3]. Since this time there have been a number of studies that described malignancy arising in both gonadal and extragonadal endometrial implants. This review addresses the parallels and specific relationship of endometriosis and gynecological cancer regarding risk factors, genetic alterations, aberrant activation of oncogenic and antiapoptotic pathways, and options in clinical diagnosis 1. EPIDEMIOLOGICAL DATA The exact incidence of endometriosis is unknown, because accurate diagnosis requires surgical intervention and, even then, depends on the indication for surgery, type of procedure, and thoroughness and familiarity of the surgeon with different appearances of endometriosis. The specific correlation of endometriosis and ovarian malignancy and their epidemiologic patterns have been extensively studied. There is suggestion of a common mechanism based on similar disease responses, such as the protective effects of tubal ligation, hysterectomy, oral contraceptives, number of pregnancies and lactation, increased risks with infertility, and early menarche, late menopause, and nulliparity for both ovarian cancer and endometriosis [1, 4, 38]. The prevalence of ovarian cancer developing in women with endometriosis is higher than sporadic ovarian cancer in © 2012 Bentham Science Publishers

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the general population. Several studies have specifically addressed the ovarian cancer risk in patients with endometriosis.

compared with 0,7 expected. But, the small number of cancers found in that population limits the proper statistically interpretation of this result [11].

Ness et al., [5] pooled 5.207 cases and 7.705 controls of eight case-control studies conducted in the United States, Denmark, Canada, and Australia to investigate the influence of infertility on ovarian cancer. Endometriosis was linked with a significantly increased ovarian cancer risk with an odds ratio (OR) of 1.73 (95% confidence interval (95% CI) 1.10–2.71). The only other type of infertility significantly linked to ovarian cancer was infertility of unknown cause (odds ratio 1, 5, 95% CI 1,3-1,7), a disorder that hormonal studies suggest may be closely related to endometriosis [6].

Olson et al., [13] completed the largest study that did not support the increased ovarian cancer risk in endometriosis patients. Analyzing a group of 37,434 postmenopausal women, a cohort of 1,392 postmenopausal patients who selfreported the diagnosis of endometriosis was isolated. After an average 13-year follow-up, no significant increased risk was found for all cancers, breast cancer, or ovarian cancer, but there was a significant association with increased risk of non-Hodgkin lymphoma, with an age-adjusted risk ratio of 1.8 (95% CI 1.0-3.0). This study involved acceptable longterm follow-up; however, several factors must be taken into account. The cohort was smaller, with only three ovarian cancer cases, making it underpowered. Furthermore, the endometriosis was not medically confirmed and, because all of the patients were postmenopausal, it is possible that younger patients may have already developed ovarian cancer and died.

Brinton et al., [7] reviewed 20,686 women hospitalized with endometriosis identified through the Swedish Inpatient Registry from 1969 to 1983 with a mean follow-up of 11.4 years. The cases of all incident cancers in this cohort were garnered through the National Swedish Cancer Registry, identifying 738 overall malignancies and 29 ovarian malignancies. Standardized incidence ratios (SIRs) with 95% confidence intervals (CIs) from this study showed an increased overall cancer risk of 1.2 (1.1-1.3), 1.9 (1.3-2.8) for ovarian cancer, 1.3 (1.1-1.4) for breast cancer, and 1.8 (1.0-1.8) for hematopoetic cancers. The incidence ratio for those with follow-up of 10 years increased to 2.5, and the highest cancer risk was among women with the longest history of endometriosis: SIR 4.2 (95% CI 2.0-7.7). This analysis may overestimate the cancer risk, because only hospitalized endometriosis patients were accounted for. Borgfeldt and Andolf [8] also identified a cohort of 28,163 endometriosis patients born before 1970 from the National Swedish Hospital Discharge Registry from 1969 to 1996 and matched each case with three controls. The cohort of endometriosis patients had an increased risk for ovarian cancer of 1.3 (95% CI 1.0-1.8) with a significantly lower mean age at diagnosis of 49 years versus 51.6 years in control population. Several retrospective studies in Japan also suggest that there may be an association between endometriosis and increased risk of ovarian cancer [9]. Another recent prospective study in Japan [10] directly showed that, during a follow up of up to 17 years of an ovarian endometrioma cohort (n= 6398), 46 incident ovarian cancers were identified, showing that the ovarian cancer risk was significantly elevated in patients with ovarian endometrioma (standardized incidence ratio SIR, 8.95; 95% confidence interval CI, 4.12 to 15.3). Advancing age (>40 years) and the size of endometriomas (>9cm) were independent predictors for the development of ovarian cancer. Of note, only approximately one-third of these patients had surgically confirmed endometriomas, with the remaining diagnoses made based on ultrasonographic findings and physical exam only. Furthermore, this study did not account for patients with extraovarian endometriosis. The possible relationship between infertility resulting from endometriosis and ovarian cancer was further assessed among 3800 women who sought infertilty evaluations [11, 12]. Eleven ovarian cancers were found, but none was detected among women with infertility from endometriosis,

Overall, epidemiological studies showed inconclusive and contradictory results regarding a correlation between endometriosis and ovarian cancer. 2. HISTOLOGICAL DATA Reciprocal analysis of the prevalence of endometriosis found in ovarian cancer patients supports the correlation. In a review of 29 studies from 1973 to 2002 on the prevalence of endometriosis in epithelial ovarian cancers organized by location of disease, the following three groups were compiled: histologic proof of transition from ovarian endometriosis to cancer as defined by Sampson [2], ovarian cancers with endometriosis in the same ovary, and ovarian cancers with concomitant pelvic endometriosis. The second category was considered to be the best estimation of endometriosis in the different histologic subtypes, yielding a prevalence of 4.5% in serous, 1.4% in mucinous, 35.9% in clear-cell, and 19% in endometrioid carcinomas [1]. Among 22 cases of ovarian endometrioid adenocarcinomas of the ovary, Valenzuela et al., found three patients with concomitant endometriosis as defined by the Sampson criteria [14]. The review by Van Gorp et al., [1] calculated an ovarian cancer prevalence of 0.9% in all cases of endometriosis, 2.5% when present in the same ovary, and 4.5% when coexistent with any pelvic endometriosis. Malignant extraovarian endometriosis is estimated to account for 25% of all malignant transformations of endometriosis and 80% of the endometrioid subtype [15-17]. Heaps et al., [15] noted that 165 published cases showed malignant transformation by this definition, almost 80% occuring within ovarian endometriosis. The overall frequency of malignant transformations was estimated to be 0.3% to 0.8% [18]. Larger pathology series have found ovarian cancer in 5% to 10% of ovarian endometriotic lesions [19, 20]. Endometroid (up to 60% of lesions) and clear cell (up to 15%) tumors predominate in proportions higher than have

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been found among ovarian cancer in general (10%-20% and 3%-10%, respectively) [21], demonstrating the distinctive but not exclusive, relationship between endometroid and clear cell ovarian cancers and endometriosis. Sainz de la Cuesta et al., [22] found endometriosis among about 40% of women with stage I endometroid or clear cell ovarian carcinoma, about 1/3 of which were carcinomas arising out of endometriosis. Similar results have been found in 21% to 54% of clear cell and endometroid tumors and in 35 to 9% of serous, mucinous and other tumors [23-26]. Overall, embryologic, pathologic, and clinical data support the idea that malignant transformation may occur perhaps 5% to 10% of women found at surgery to have ovarian endometriosis. In comparison, the general population lifetime risk of ovarian cancer is only 1.5% [11]. Malignant change has also been diagnosed in extragonadal endometriosis. The majority of the tumors are located in the rectovaginal septum, but other locations include the vulva, vagina, cervix, uterine corpus (adenomyosis), fallopian tube, bladder, parametrium, uterosacral area, bowel, umbilicus, lymph node, pleura and retroperitoneal area. These locations parallel the frequency and distribution of benign extra-ovarian endometriosis [15, 27]. Malignant transformation of extra-ovarian endometriosis is thought to account for approximately 25% of all malignant transformations of endometriosis [15, 16]. However, most of the information about malignancy in extraovarian endometriosis is based on case reports. Moreover, several of these case reports are poorly documented and lack essential information regarding the histological transition between endometriosis and the malignant tumor. We are aware of only one study that described the frequency and made a comparison of both ovarian and extra-ovarian malignancies in endometriosis [28]. Malignant tissue was more commonly found in endometriomas (5.6%) than in extra-ovarian sites with endometriosis (1.6%) [1]. Endometrioid carcinomas or adenocarcinomas are the most frequently encountered histological subtype arising from extra-ovarian endometriosis, representing almost 80% of these tumors [15, 33, 35-37]. Besides the epithelial cancers other subtypes such as sarcomas, carcinosarcomas or adenosarcomas have been described [15, 27, 29, 31, 32, 34]. Non-epithelial tumors seem to be more often associated with extra-ovarian than with ovarian endometriosis and adenosarcomas are thought to be the second most common neoplasm arising in extraovarian endometriosis after endometrioid carcinomas [15, 27, 29]. Increases in cancer occurrence among women with endometriosis were also found in a study conducted by the Endometriosis Association. Compared with expected rates among women in the general population, the 4000 members completing a health survey reported cancer occurences that were 5-fold higher for ovarian cancer, 6-fold higher for breast cancer and 2.5-fold higher for non-Hodgkin’s lymphoma [30]. The relationship of endometriosis and ovarian cancer was further explored in terms of bias versus causality using the nine criteria proposed by Austin Bradford Hill which serve

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as fundamentals of causal inference: strength of association, consistency, biologic gradient, specificity, temporality, biologic plausibility, experimental evidence, analogy, and coherence [39]. Based on the present analysis, the criterion of strength has not been fulfilled. There were insufficient or mixed data for four criteria (biological gradient, biological plausibility, analogy, coherence), and four criteria were fulfilled (consistency, temporality, specificity, experimental evidence in animal model). Their conclusions were that a causal relationship between endometriosis and specific histotypes of ovarian cancer should be recognized, but the low magnitude of the risk observed is consistent with the view that ectopic endometrium undergoes malignant transformation with a frequency similar to its eutopic counterpart. Atypical Endometriosis Epithelium in endometriosis occasionally shows metaplastic changes. Although metaplastic epithelia sometimes share morphological features with specific carcinoma, the biological significance of this metaplasia in tumor development is unclear [40]. Atypical endometriosis can probably be considered as a precancerous lesion. However, a spatial and chronological association between severe atypical endometriosis and ovarian cancer still had to be proven [1]. Once the altered epithelium shows “atypia”, it could be implicated in the malignant transformation of endometriosis. The term “atypia” refers to two pathological features: cytological atypia and hyperplasia (without atypia). Cytological atypia is almost always found in the epithelial lining of endometriotic cyst as a focal or multifocal lesion. It may be a reactive or degenerative change in most cases, and there is no realistic risk in clinical management. Nevertheless, there is evidence that atypical epithelia in endometriosis may be a precursor of malignancy. First, atypical endometriosis is far more frequently found in endometriosis accompanied by malignant tumors than in benign endometriotic cyst. Secondly, pathological reports have demonstrated a continous transition from benign endometriosis to carcinoma, and in these areas, atypical endometriosis is frequently observed [40]. Molecular analysis have also revealed that atypical endometriosis harbors various genetic events suggestive of the intermediate nature of this lesions between benign endometriosis and ovarian cancer. Given this evidence, atypical endometriosis is likely a lesion that represents a transition from benign endometriosis to carcinoma. However, this lesion is encountered only in occasional cases and its biological role in the malignant transformation of endometriosis remains unclear. Another type of atypical endometriosis is hyperplasia, with or without cytological atypia. It is less frequently observed than cytological atypia in endometriosis and is sometimes related to estrogenic stimuli or tamoxifen treatment. The precise relationship between hyperplasia and cancer development in endometriosis is not clear, but it may reflect a precancerous growth, because the synchronous presence of hyperplasia and carcinoma has been reported [40].


3. MOLECULAR PATHOGENESIS A variety of molecular alterations have been reported to be involved in the malignant transformation of endometriosis. These molecular events can be classified in three groups according to their nature and relevant stage of carcinogenesis. First, some events are common in endometriosis and cancers, suggesting they are primarily linked to the development of endometriosis or a very early stage of carcinogenesis. Second, some events are common and universal among various malignancies and are not specific to endometriosis associated ovarian cancer. These appear to be late events and include the activation of oncogenes and suppression of tumor-suppressor genes. Third, some events appear to be confined specifically to the malignant transformation of endometriosis, leading to the development of clear-cell or endometrioid cancer phenotype. However, in many cases, it is difficult to clearly define the role of each molecular event [40]. Molecular studies have provided the best support for a possible relationship between endometriosis and ovarian cancer. If one expects ovarian cancer to develop from endometriosis then one would expect common genetic alterations to exist for both benign and transformed malignant lesions [1]. Common pathogenetic factors were found both for endometriosis and for ovarian malignancy, like familial predisposition, genetic alterations, immunobiologic, cell adhesion, angiogenic, and hormonal factors. Genomic Instability and Mutations Although there are reports of mendelian inheritance patterns of endometriosis, such as an increased risk in first-degree relatives and twins, there is increasing evidence that endometriosis is inherited as a complex genetic trait involving the interaction of multiple genes and environmental factors conferring disease susceptibility and malignant behaviors [41]. Genomic instability is a known characteristic of cancer cells. Gene mutational and loss of heterozygosity (LoH) studies at different sites throughout the genome have been performed to address this issue. Endometriosis demonstrates somatically acquired genetic alterations similar to those found in cancer, leading to clonal expansion of genetically abnormal cells, as demonstrated in several studies [42, 43]. Endometriotic cysts are monoclonal and characterized by the loss of heterozygosity in 75% of endometriotic cyst cases with associated adenocarcinoma, and even in 28% of cases without accompanying carcinoma. Loss of heterozygosity at 5q, 6q, 9p, 11q, 22q, p16, and p53, indicating loss of tumor suppression genes, has been identified in endometriosis and endometriosis-derived cell lines [44]. Ovarian cancers and adjacent endometriotic lesions have shown common genetic alterations, such as PTEN gene mutations, suggesting a possible malignant genetic transition spectrum. K-ras mutation was found in 8.3% of endometrioid and 12.5% of clear cell carcinomas accompanied by endometriosis. In contrast, it was not found in benign endometriosis adjacent to carcinomas [40]. Loss of heterogenicity at 10q23.3 occurs with high frequency in solitary endometrial cysts (56.5%), endometrioid


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carcinoma of the ovary (42.1%), and clear cell carcinoma of the ovary (27.3%), and a concentration of mutations in the PTEN gene encoding the phosphatase domain has been demonstrated in endometrial cysts and clear cell carcinomas of the ovaries [45]. Mutation or loss of function of the tumor suppressor gene p53 is the most frequent and important event in the development of ovarian cancer. Although mutation or abnormal accumulation of p53 is rarely found in benign solitary endometriosis, it is sometimes detected in benignlooking or atypical endometriosis adjacent to ovarian cancer [40]. Undoubtedly, p53 play an important role in the malignant transformation of endometriosis, at least in some cases. The frequency of p53 mutation/accumulation in endometriosis associated ovarian cancer in some reports cited by Mandai [40] was around 40-50%, similar to, or somewhat less than, that in serous carcinoma of the ovary. Transitional Phenotype In the background of endometriosis, malignant progression at the ovary to endometrioid and clear cell carcinoma after severe atypia is a biologically plausible phenomenon of multidimensional molecular complexity. Malignant transformation of endometriosis was first reported by Sampson [2]. Many studies have confirmed histologic transition from endometriosis in direct continuity with tumor and malignant transformation of extraovarian endometriosis and cytologically “atypical” endometriosis. About 60%-80% of cases of endometriosis-associated ovarian cancers (EAOCs) arise in the presence of atypical endometriosis. Of these cases, 25% show direct continuity with the atypical ovarian endometriosis [19, 20]. Okamura and Katabuchi [46] presented evidence of direct transition from endometriotic gland to atypia to carcinoma in endometrioid carcinoma arising from an ovarian endometriotic cyst. As already mentioned, in more extensive studies of up to 1,000 cases, ovarian cancer was present in 5%-10% of ovarian endometriotic lesions. Regarding the exact histology of the tumors, ovarian cancers associated with endometriosis were up to 60% endometrioid and up to 15% clear cell, proportions much greater than the general make-up of the ovarian cancer population [22]. Inversely, 40% of 79 women with stage I ovarian cancer had associated endometriosis: 41% of the cases were endometrioid, 31% clear cell, and 18% mixed endometrioidclear cell. Out of the 22 cancer patients with endometriosis, seven (32%) had discernible tumors arising directly out of endometriosis lesions. Biologic Modulators The implantation of ectopic endometriosis on ovarian surface epithelium generates a distinct microenvironment in which regulatory signals from multiple cell types affect signaling pathways and integrated circuits of each cell type, changing the physiologic homeostasis under which these cells function in normalcy. The principal biologic


modulators localized within this microenvironment are growth factors inducing proliferation, cytokines promoting cell activation and proliferation, hormones inducing nuclear factors and inflammatory mediators, and chemokines inducing chemotaxis and cell migration. Based on existing observations it is increasingly evident that within the endometriosis-ovarian cancer entity, these molecular mediators, along with genetic factors, confer cellular capabilities toward the acquisition of a malignant phenotype. The features of the malignant phenotype were recently outlined by the landmark publication of Hanahan and Weinberg on the hallmarks of cancer [47]. Accordingly, a cancer cell must have self-sufficiency in growth signals, insensitivity to antiproliferative signals, resistance to apoptosis, sustained angiogenesis, tissue invasion and metastasis, and genomic instability. Green and Evan theorized that “deregulation of proliferation, together with a reduction of apoptosis, creates a platform that is both necessary and sufficient for cancer” [48]. The subsequent molecular aberrations of endometriosis may explain the possibility of malignant transformation at the ovarian endometriosis foci within this context. Furthermore, it is widely accepted that the OSE harbors pleuripotential embryonic properties, including a capacity to undergo an epithelial-mesenchymal conversion as well as differentiation along the mullerian duct pathway, with characteristics of metaplasia [49]. As noted for centuries, inflammation may be central to tumorigenesis. Inflammation is considered to be a hallmark of endometriosis, with local and systemic implications [50]. Local inflammatory reactions at the endometriotic implant site elicit proinflamatory protein secretion by associated immune cells as well as cells integral to the implant. The orchestrated aberrant expression of proinflammatory IL-1, IL-6, IL-8, and TNF-a alter several physiologic processes leading to cell survival at the endometriosis-ovarian junction. Growth Factors Increased estrogen levels associated with the proximity of endometriotic cells may trigger up-regulation of insulinlike growth factor (IGF)-binding proteins in OSE cells, leading to estrogen-induced growth [56]. Moreover, IGF-1 signaling in these cells may be altered by the higher levels of plasma IGF-1 shown in severe cases of endometriosis [57] and the higher levels of IGF-1 in the peritoneal fluid of women with endometriosis [58]. In addition to IGF-1, the peritoneal fluid of women with endometriosis contains significantly higher levels of several other growth factors compared with patients without endometriosis. Platelet-derived growth factor also has been identified in the peritoneal fluid of women with endometriosis [59], and this growth factor significantly enhances the proliferation of human OSE cells in a dose-dependent manor [60]. Endocrine Factors Several studies have suggested that unopposed estrogens, including internal production in obese women, is also associated with malignant transformation of endometriotic cyst or of the residual endometriosis even after total abdominal hysterectomy and bilateral oophorectomy [40].

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Endometriosis has been shown to respond in a variable degree to the stimulation from endogenous and exogenous steroid hormones. This hormonal sensitivity might lead to malignant transformation of endometriosis. However, malignant transformation is reported to occur most often with unopposed estrogens and tamoxifen, and rarely when progestins were used [1]. Both endometriotic cell components and ovarian surface epithelium have the capacity to undergo proliferation in response to endocrine and growth factors. In that respect an important aberration of ectopic endometrial cells, namely, the pathologic expression of P450 aromatase, triggers constitutive expression of E2 [51]. A second anomaly of this tissue is the lack of the enzyme 17b-HSD-2, which converts E2 to estrone, leading to further accumulation of E2. Elevated estrogen levels stimulate COX-2 production in these cells, leading to an increase of prostaglandin-E2 production, which in turn stimulates further aromatase activity contributing to the constitutive production of E2. Prostaglandin-E2 is itself implicated in tumor progression, and ovarian tumors are shown to contain increased levels of this prostaglandin [52]. Additionally, ectopic endometriotic cells express low levels of the progesterone receptor isoform A and none of isoform B, rendering these cells unresponsive to progesterone and prone to proliferation, thus increasing levels of E2 in the microenvironment [52]. A marked reduction in expression of the two progesterone receptor isoforms is also noted in ovarian carcinoma specimens, leading to unresponsiveness of those cells to progesterone and thus increasing the possibility for proliferation [53, 53]. The estrogen-rich environment created by endometriotic cells may also trigger increased responsiveness to E2 in malignant ovarian epithelia via altered expression of estrogen receptors in those cells [54], thus further promulgating growth of malignant cells. Clearly, high estrogen levels persist in the microenvironment created by the presence of an endometriotic implant at the ovary, generating a highly altered physiologic milieu surrounding the OSE, which suggests proliferative pressure with enhanced level of reparative activity, and thus a higher chance of DNA damage and mutations. Specific changes in hormone receptors and enzyme expressions in transformed OSE cells continually exposed to non-physiologic hormonal conditions may lead to further progression to malignancy [55]. In summary, these key inflammatory modulators, hormones, and growth factors are maintained at high levels by immune and endometriotic cells at the ovarian endometriosis foci. The resulting microenvironment is similar to that found in ovarian cancer, and malignant OSE cells are shown to use these modulators for proliferation, evasion of apoptosis, and evasion of immune surveillance. It is reasonable to surmise that sustained elevation of these biologic modulators in the ovarian endometriosis microenvironment may promote malignant transformation in susceptible OSE cells. Another hypothesis suggests another mechanism that may contribute to malignant transformation: the epithelial cells in the endometriotic cysts are exposed to a stressful microenvironement (lactose-dehydrogenase LDH, potential antioxidant PAI, lipid peroxidase LPO, all elevated


in the endometriotic cyst) and this persistent oxidative stress may lead to carcinogenesis [67]. 4. CLINICAL IMPLICATIONS Diagnosis of Endometriosis Owing to its malignant potential, endometriosis requires particular vigilance during diagnosis and treatment. Routine imaging studies have not been able to diagnose either endometriosis or malignant transformation of endometriotic disease. However, recently, magnetic resonance imaging evidence of malignant transformation within an endometrioma has been suggested. The finding that was most important for a diagnosis of malignant change was the presence of one or more contrast material-enhanced mural nodules within a cystic mass. Enlargement of the endometrioma and the disappearance of shading within the mass on T2-weighted images may be suggestive of malignant transformation [61]. Diagnosis has thus far been limited to direct observation through surgery; the appearance of endometriosis has been described as having a protean, or widely varied, appearance, making a gold standard for diagnosis difficult. Proteomic techniques are now being used to identify proteins that are potential biomarkers for the disease. This strategy uses mass spectrometry to identify, purify, and sequence proteins directly rather than through mRNA and complementary DNA intermediates. It has been noted that glycodelin-A biosynthesis is reduced in endometriosis compared with unaffected cycle-matched control subjects. Identifying an accurate marker will be challenging, owing to the likely multifactorial etiology of endometriosis and the variations between individuals and varying influences of steroid hormones during the menstrual cycle. However, proteomic profiling in combination with bioinformatics software has the potential for major diagnostic contributions for the endometriosis disease process [62]. These updated techniques may have a complementary role in diagnosing patients with endometriosis, and thus a population with an increased cancer risk. Prognosis of Endometriosis-Associated Ovarian Carcinoma Although case reports and small studies had suggested that endometriosis-associated ovarian carcinoma (EAOC) might represent a distinct clinical entity [31, 36, 37, 60], it wasn’t until 1995 that McMeekin et al., performed the first cohort study to investigate this systematically [63]. These authors compared 28 (31%) EAOC and 63 (69%) nonendometriosis associated ovarian carcinomas (NEAOC) out of a cohort of 91 endometrioid carcinomas (four of these developed in extra-ovarian endometriosis). EAOC was associated with an age at diagnosis of less than 55 years; nulliparity; stage I or II disease and a longer disease-free survival. However, this association was not found for use of unopposed estrogens, endometrial hyperplasia, tumor grade and survival. Komiyama and colleagues performed a similar cohort study that consisted of 53 clear-cell carcinomas (20 clear-cell carcinomas associated with endometriosis and 33 not associated with endometriosis) [64]. Like McMeekin et al., they found patients with EAOC to be more often nulliparous,


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but no statistical difference was found for age and stage of disease. Although they found no difference in 5-year survival for stage III disease, they did find a difference for stage I disease. The lack of statistical difference for several characteristics in this study could be explained at least partially by the small size of the studied cohort, which had a very small number, or even absence, of stage IB, II and IV disease. Toki et al., studied 235 ovarian carcinomas of different histological types for their baseline characteristics and found patients with EAOC to be younger with significant earlier clinical stage disease than those without endometriosis. Survival also appeared to be significantly different in favour of the former but this difference disappeared when the tumors were compared within their stage [65]. Erzˇen and co-authors [66] performed an age-matched nested case-control study of 290 ovarian tumors (all histological types). Each EAOC was matched with four NEAOC and a difference in stage, grade, overall survival and histological type was found between both groups, with a significant lower stage and grade and a better survival (OR 2.89, 95% CI 1.56-5.34) for EAOC. In a study cited by Kobayashi [67], on 18 patients with a history of ovarian endometriomas who developed ovarian cancer, mean age at presentation of malignant transformation was 45.2 years (range, 36 to 66 years), and 78 % of women were premenopausal. The pattern of spread was local in 16 (89%), regional in 2(11%) and distant in 0. Characteristic histological findings showed that 61% of the tumors were clear cell carcinomas. Endometriosis-associated malignancies have a favorable prognosis. The patients showed long latency intervals before developing ovarian cancer (mean, 4.5 years; range 1-16 years). Survival also seemed to differ when age groups and histological subtypes were analysed separately, albeit not always significantly for all age and histological subgroups. Like Toki et al., Erzˇen et al., found no difference in stagespecific survival, attributing the increased survival of EAOC to a predominance of early-stage disease. When they compared all of the NEAOC in the cohort without matching according to age to the EAOC, they also found a significant younger patient population in the EAOC group. According to the epidemiological data from the above studies, EAOC appears to have a different biological behaviour. The tumors seem to occur in younger and nulliparous patients; they are well-differentiated, low-stage carcinomas that result in a better survival. 5. CONCLUSIONS The accumulated data suggest that endometriosis is a neoplastic disease and should be managed as such. Though the precise molecular mechanisms are still to be elucidated, some recent data suggest that microenviromental factors such as oxidative stress and inflammation play an important role in the carcinogenesis and phenotype of carcinoma occurring from endometriosis. Endometriosis is a risk factor for ovarian cancer, even after menopause. There is a genuine link between endometriosis and endometrioid and clear cellcarcinomas; these results cannot be explained by shared risk


factors alone. But, such a view does not explain the great majority of cases of ovarian cancer in which ovarian endometriosis cannot be demonstrated, even if allowance is made for the fact that a small focus of endometriosis could well have been obliterated by the tumor. Overall, the evidence of the published studies suggests that ovarian tumors can arise from more than one potential source, endometriosis being one of these sources. Understanding the mechanism of the development of endometriosis and elucidating its pathogenesis and pathophysiology are intrinsic to the prevention of endometriosis associated ovarian cancer and the search for effective therapies. In particular, further elucidation of the involved genetic and immune mechanisms of endometriosis is necessary. Advancements in more precise diagnostic, prognostic, and treatment options for endometriosis are needed to address early ovarian cancer. CONFLICT OF INTEREST

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Revised: January 01, 2012

Accepted: January 23, 2012