Endometriosis, defined as the presence of endometrial-like glands and stroma in any extrauterine site, has markedly varied presentations, confounding the diagnosis.
Patients may be asymptomatic or, depending on the location of the lesions, may experience pelvic pain (particularly during menstruation), dyspareunia, and/or pain associated with urination or bowel movements. Infertility is a common consequence. Diagnosis has been limited to direct observation through surgery and may be further compromised by its “protean” or widely varied appearance. Thus, most patients are not diagnosed until symptoms are severe or during infertility workups, if at all. Hence, the reported prevalence of endometriosis in the reproductive age group varies between 2% and 10%, and it may be up to 30% in women with infertility.1
Although endometriosis cannot be termed a premalignant condition, epidemiologic, histopathologic, and molecular data suggest that endometriosis may be a precursor lesion to the specific subtypes of ovarian cancer.2 Furthermore, certain patients with endometriosis are at higher risk for malignancies, suggesting a potential benefit to selective patient surveillance.
Prevalence of Ovarian Cancer in Women With Endometriosis
The malignant transformation of endometriosis was first suggested by Sampson3 in 1925. Early epidemiologic studies suggested a link between endometriosis and invasive epithelial ovarian cancer, based on frequent co-occurrence in surgical specimens, particularly with the histologic subgroups endometrioid and clear cell ovarian carcinoma.
For example, in a large Swedish retrospective cohort study of 20,686 women hospitalized for endometriosis, Brinton et al4 found that patients with long-standing ovarian endometriosis (>10 years) had a highly relative risk (RR) for ovarian cancer [Standardized incidence ratio (SIR) = 4.2]. Melin et al5 later updated this report, supporting the results of the original study and finding that the highest risk was attributed to patients with ovarian endometriosis; there was no elevated risk for patients with adenomyosis. Similarly, the other factors associated with higher risk for ovarian cancer included long-standing endometriosis and endometriosis diagnosed at younger ages.
Throughout the early prevalence studies, when ovarian cancer was found, the endometrioid and clear cell histologic subtypes predominated. In a review of 15 published reports,6 the prevalence of endometriosis was 39.2% (198/505) for clear cell and 21.2% (147/694) for endometrioid ovarian malignancies, compared with 3.3% (39/1173) for serous type and 3.0% (13/436) for mucinous type of ovarian cancer. Similarly, Deligdisch et al7 found ovarian endometriosis present in 40 of 76 well staged I ovarian carcinoma cases. On further analysis, 71% (54/76) of the cases were nonserous cancers, and almost all were associated with endometriosis based on histologic examination.
Most recently, in a landmark study, Pearce et al8 from the Ovarian Cancer Association Consortium assessed the association between self-reported endometriosis and risk for ovarian cancer. Original data from 13 large case-control studies were pooled and, using logistic regression, were analyzed with respect to histologic subtypes, grade, and stage, among other variables. Overall, data were collected from 13,226 controls and 7911 women who had invasive ovarian cancer, of which 818 (6.14%) and 738 (9.33%) women, respectively, reported a history of endometriosis. Women with endometriosis had a significantly higher risk of developing ovarian cancer than the general population (odds ratio [OR], 1.46; 95% confidence interval [CI], 1.31–1.63; P < 0.0001). Self-reported endometriosis was associated with a significantly increased risk (P < 0.0001) for clear cell (OR, 3.05) and endometrioid (OR, 2.21) tumors. In addition, for the first time, there was a significant association between preexisting endometriosis and low-grade serous invasive ovarian cancers (OR, 2.21; P < 0.0001). There was no similar association between endometriosis and risk for high-grade serous invasive ovarian cancer (P = 0.13).
Ness et al9 completed 2 case-control studies confirming the association between endometriosis and ovarian cancer.10 In a group of 767 women with ovarian cancer and 1367 control subjects, with adjustments made for age, parity, family history of ovarian cancer, race, oral contraceptive use, tubal ligation, hysterectomy, and breast-feeding, women with ovarian cancer were 1.7-fold more likely to report an endometriosis history.9 Furthermore, in a pooled study of 13,000 women, ovarian cancer was more likely among subfertile women, especially when infertility resulted from endometriosis, showing an OR of 1.9 (95% CI, 1.2–2.9), suggesting a role for specific biologic causes of infertility but not for fertility drugs in overall risk for ovarian cancer.2
Guo11 examined the link between endometriosis and cancer through a reanalysis of this and other epidemiologic studies and critically assessed the components of the measurements of the risk (RR, OR, and SIR) and the various confounding factors and discrepancies. He reported that all studies show the increase in risk for ovarian cancer particularly of clear cell, endometrioid, and low-grade serous subtypes in women with endometriosis. However, he pointed out that the results of these studies are not sufficient to establish causality between endometriosis and ovarian cancer. Alternatively, they may be the results of identical risk factors shared by both endometriosis and the subtypes of ovarian carcinoma.11
Pathogenetic Similarities Between Endometriosis and Ovarian Cancer
It is clear that endometriosis has mixed traits of both benign and malignant diseases. The pathogenesis of endometriosis involves limited loss of control of cell proliferation and is associated with local and distant spread. Endometriosis, however, does not cause catabolic disturbance, metabolic consequences, or death in humans.12
Genomic instability is a known characteristic of cancer cells. Similarly, endometriosis demonstrates somatically acquired genetic alterations, leading to clonal expansion of genetically abnormal cells. Endometriotic cysts are monoclonal13 and characterized by the loss of heterozygosity in 75% of endometriotic cysts with associated adenocarcinoma and even in 28% of cases without accompanying carcinoma.14 Although there are reports of Mendelian inheritance patterns of endometriosis, such as higher risk in first-degree relatives and twins, there is an increasing evidence that endometriosis is a complex genetic trait involving the interaction of multiple genes and environmental factors conferring disease susceptibility and malignant behaviors.15
Factors that predispose patients with endometriosis to develop ovarian cancer are unknown but involve genetic, epigenetic factors and/or the effects of the (micro) environment.16 Ovarian cancers and adjacent endometriotic lesions have shown common genetic alterations, such as PTEN gene mutations, suggesting a possible malignant genetic transition spectrum. Loss of heterozygosity at chromosome locus 10q23.3 occurs with high frequency in solitary endometrial cysts (56.5%), endometrioid carcinoma of the ovary (42.1%), and clear cell carcinoma of the ovary (27.3%), and a concentration of mutations in the PTEN gene exons encoding the phosphatase domain has been demonstrated in endometrial cysts and clear cell carcinomas of the ovary.17
Benign endometriosis-like lesions can develop within the normal ovarian surface epithelium (OSE) after expression of oncogenic K-ras; however, progression to endometrioid ovarian cancer necessitates inactivation of PTEN. Cheng et al18 demonstrated in an explant model of epithelial ovarian cancer that aberrant Hoxa10 expression along with Hoxa7 and Hoxa9 confer early endometrioid differentiation. The authors speculated that deregulated expression of HOX genes “tip the balance toward tumorigenicity” in “phenotypically uncommitted” OSE undergoing neoplastic transformation.
Wiegand et al19 found mutations in the tumor-suppressor gene ARID1A in endometrioid and clear cell carcinomas and showed the same mutation to be present in atypical endometriosis and associated ovarian carcinomas. The authors concluded that this may be an early event in the transformation of endometriosis to cancer.
Our group20 used immunohistochemistry to identify sequential or etiologic correlations between endometriosis and ovarian malignancies. We found alterations of bcl-2 and p53 in benign-appearing areas of malignant endometriotic cysts when compared with benign endometriotic cysts, suggesting that alterations in the expression of these 2 proteins may be involved in the malignant transformation of endometriotic cysts. Pearce et al8 speculated that the processes of endometriosis (and endosalpingiosis) result from an underlying host susceptibility to implantation of exfoliated Mullerian epithelial cells from both the endometrium and fallopian tube.
Angiogenic and Inflammatory Factors
Balkwill and Mantovani21 offer a keen description of the link between inflammation and cancer in general, “If genetic damage is the ‘match that lights a fire’ of cancer, some types of inflammation may provide the ‘fuel that feeds the flames.’”
Indeed, inflammation is considered to be a hallmark of endometriosis, with local and systemic implications.12 Local inflammatory reactions at the endometriotic implant site elicit proinflammatory protein secretions by associated immune cells and cells integral to the implant itself; elevated levels of proinflammatory tumor necrosis factor α, interleukin 1 (IL-1), IL-2, IL-6, IL-8, and interferon γ have been recorded in the peritoneal fluid in women with endometriosis.22 Recently, NF-κB and its activating kinases IKKα and IKKβ have been shown to have a central role in linking cancer to inflammation by differential regulation of cell survival and production of proinflammatory cytokines.23,24
In ovarian cancer, the hypothesis has been put forth that inflammation acts as an intermediary between an extrinsic factor such as infection or physical or chemical stimuli. Ovarian carcinogenesis has been linked to inflammatory mediators, cytokines, eicosanoids, and immune cells. Prolonged exposure to these factors that aim to degrade noxious stimuli may lead to increased oxidative stress, disruption of homeostasis, genomic instability and, consequently, to abnormal proliferation.
Higher intraperitoneal macrophage activity may play a role in optimizing endometriosis development by a release of angiogenic factors, leading to increased microvascularization of the parietal peritoneum. Integrins allow cells to attach to components of extracellular matrix and cell-cell adhesion. Thus, a stressful change in the microenvironment may contribute to the malignant transformation of endometriomas.
Both endometriotic cell components and OSE can become prolific in response to endocrine-mediated growth factors. In that respect, an important aberration of ectopic endometrial cells, namely, the pathologic expression of P450 aromatase, triggers constitutive synthesis of estradiol (E2).25 A second anomaly of this tissue is the lack of the enzyme 17β-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 E production, which in turn stimulates further aromatase activity contributing to the constitutive production of E2. This prostaglandin is itself implicated in tumor progression, and ovarian tumors are shown to contain increased levels.26 Thus, estrogen itself is a potent mitogenic factor that can increase the risk for both ovarian cancer and endometriosis.
Progesterone is a natural antagonist of estrogen that reduces cell proliferation and may induce apoptosis.27 In fact, a marked reduction in expression of the 2 progesterone receptor isoforms is noted in ovarian cancer specimens, thus increasing the possibility for proliferation.28 Given the well-documented anti-inflammatory qualities of progesterone, its attenuated action in endometriostic cells may enhance proinflammatory environment.
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 ovarian surface. This suggests a proliferation with an enhanced level of DNA synthesis and repair 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 nonphysiologic hormonal conditions may lead to further progression to malignancy.
Dual Model of Ovarian Carcinogenesis and Endometriosis
More recently, our knowledge of pathogenesis of ovarian cancer has critically evolved. Molecular genetic studies have led to a new paradigm based on a dualistic model of ovarian carcinogenesis. Based on this new model, epithelial ovarian cancer is divided in 2 categories, namely, types I and II. Type I tumors are low-grade serous, endometrioid, clear cell, or mucinous and typically have KRAS or BRAF mutations.29 Type II carcinomas are high-grade serous carcinomas, presenting at advanced stage, characterized by TP53 mutations. Both type I and II tumors seem to have extra ovarian origin. Type I tumors are thought to arise from the epithelium of distal fimbriated part of the fallopian tubes, whereas type II tumors may originate from displaced endometrial tissue- endometriosis. According to this paradigm, type I endometrioid and clear cell carcinomas develop via malignant transformation of the endometrial tissue deposited on the ovarian surface via retrograde menstruation.30
Clinical Implications and Future Directions
Ovarian cancer is the deadliest gynecologic malignancy in developed countries. In the United States, approximately 22,000 new cases and 14,000 cancer-related deaths are expected from ovarian cancer in 2013. The lifetime risk of developing ovarian cancer is 1 in 70, and the average age at diagnosis of ovarian cancer in the United States is 63 years old.31 Secondary to its insidious nature, ovarian cancer is usually diagnosed in stage III/IV. Early stages of the disease are diagnosed in only 15% to 20% of women, with a 5-year survival of greater than 90%, whereas stage III disease has a 5-year survival rate of 46%. Approximately 80% of all malignancies associated with endometriosis are identified in the ovary; 20% of those are extragenital.32 Although the most common histologies are endometrioid and clear cell carcinomas, other histologies, such as carcinosarcomas and adenocarcinoma have also been reported.33,34
As presented previously, most of early ovarian carcinomas are of endometrioid and clear cell type, with a background of endometriosis.7,8,35,36 Whereas endometriosis is a relatively common diagnosis, endometriosis-associated cancers are relatively uncommon. Given this discrepancy of prevalence and absence of a sensitive test to predict which patient with endometriosis will develop ovarian cancer, the question arises as how to use this information in clinical practice. In women with BRCA1 or BRCA2 mutation, the lifetime risk for ovarian cancer is 12% to 46%, whereas in Lynch syndrome, the lifetime risk is 3% to 14% (compared with 1.8% in the general population).37,38 Obviously, unlike women with BRCA mutation where prophylactic bilateral salpingo-oophorectomy, by the age of 40 years or after the conclusion of childbearing, is recommended,39–42 it is not rational to suggest such radical procedure in every patient with pelvic endometriosis. However, the available information may be used in clinical practice to decrease the potential risk of malignant transformation or association. The important clinical questions to answer are the following.
1. Identifying patients who may be at an increased risk for ovarian cancer.
Both the gynecologist and the general practitioner should pay special attention to patients with endometriosis and the following history:
* Long-standing endometriosis
* Endometriosis diagnosed at an early age
* Endometriosis associated with infertility and/or history of infertility treatment
* Patients with ovarian endometriomas
2. What screening opportunities are available to practitioners for women with endometriosis?
The dualistic model of ovarian carcinogenesis allows for more rational screening methods for ovarian cancer. Type II high-grade serous carcinomas are associated with TP53 mutations, and BRCA-related DNA repair defects may be amenable to mutation screening; however, type I cancers such as clear cell and endometrioid do not have clearly identifiable genetic hereditary component, and no genetic testing is available to screen for “high-risk endometriotic lesions.” Population screening of women with endometriosis does not seem to be necessary or justified presently. At the same time, careful follow-up of women at risk, as identified, might be prudent. To that goal, several methods have been proposed. For example, CA-125 has been shown to be a poor screening modality for endometriosis-associated ovarian cancers and nonendometriosis ovarian cancers. Wang et al43 found that CA-125 levels were lower in endometriosis-associated ovarian carcinoma compared with those of patients with nonendometriosis ovarian carcinoma (mean, 122.9 vs 1377.5, respectively). Lim et al44 found that 32.6% of patients with early-stage endometriosis-associated ovarian carcinoma demonstrated normal CA-125 levels.
Sonography is useful in the identification of ovarian endometrioma with homogeneous hypoechogenic cystic features (Fig. 1) and those with mural malignant changes (Fig. 2). However, it is difficult to detect relatively small endocystic echogenic components with this modality.45 Magnetic resonance imaging (MRI) may be more useful to both visualize endometriomas and possibly detect malignant transformation. Hyperdense mural nodules within the ovary and rapid growth of an endometrioma can be visualized on MRI; these have been associated with malignant transformation.46 In a cohort study comparing MRI findings of 10 patients with ovarian adenocarcinoma with those of 10 patients with benign endometriomas, Tanaka et al45 found mural nodules in all 10 malignancies but in only 3 of the benign cases. Long-term follow-up is necessary to understand the timeline of transformation in patients with mural nodules and the predictive value of such a discovery.
In addition, Deligdisch et al7 showed the value of evaluating women with endometriosis as well as with abnormal vaginal bleeding owing to the association of endometriosis with ovarian endometrioid carcinoma and with concomitant endometrial diseases such as polyps, hyperplasia, and carcinoma. In their study, of 76 consecutive cases of stage I ovarian cancer, all nonserous ovarian carcinomas have been diagnosed from associated symptoms, such as pelvic pain with endometriosis/adnexal masses or vaginal bleeding associated with underlying endometrial pathology. Therefore, careful evaluation of the endometrium of symptomatic patients with endometriosis is of importance in the early detection of ovarian and endometrial malignancy.
3. What preventative measures can be offered to women with endometriosis?
Although our knowledge about the association of ovarian cancer with endometriosis continues to broaden, it is safe to say that vast majority of women with endometriosis will not develop ovarian cancer. Although screening and preventative measures are not justified at the level of population, a woman and her physician may discuss the options including surgery and hormonal treatment of symptoms and prevention.
When endometriosis is diagnosed, surgical resection remains the most effective treatment.47,48 Interestingly, Melin et al49 showed that women who underwent unilateral oophorectomy for endometriosis had a significantly reduced risk of later development of ovarian cancer, with an OR of 0.19 (95% CI, 0.08–0.46) compared with controls. In addition, ovarian cancer was significantly less likely to develop in women who underwent radical surgical excision of all visible endometriosis, with an OR of 0.30 (95% CI, 0.12–0.74).
Hormonal therapy induces a decrease in the severity and recurrence rate of endometriomas.50 Most endometriomas are composed of endometrial implants, which invade a functional cyst as reported by the Nezhats.51 Ovarian suppression and elimination of functional cyst formation will decrease the incidence of endometriomas, thereby preventing a large proportion of potentially premalignant lesions. Hormonal therapy alone, however, often fails to cause a total regression of endometriomas52 and is most effective after a thorough surgical excision of endometriomas and associated endometriosis. A review of the literature by Vercellini et al50 comparing diligent postoperative oral contraceptive versus sporadic use demonstrated a pooled OR of 0.21 (95% CI, 0.11–0.40) for ovarian endometrioma recurrence. Koga et al53 presented similar findings, with gonadotropin-releasing hormone agonists, oral contraceptive pills, levonorgestrel intrauterine device, and pregnancy.
4. How should we approach treatment options for women with endometriosis who are determined to be at an increased risk for ovarian cancer?
Treatment options for women with endometriosis include observation, hormonal therapy, surgical therapy, or a combination of the latter two. The treatment plan for each patient should be individualized based on her symptoms, age, desire for childbearing, and family history.
A large proportion of patients with endometriosis and endometriomas may be surgically treated. To decrease the rate of recurrence, a complete resection of the endometrioma with the cyst wall is recommended.54 Unfortunately, the recurrence of the endometrioma without adjuvant therapy is common, with reported incidence of 11% to 50% within 5 years.52,53 The decision to perform a complete resection of the endometrioma or endometriotic tissue versus an oophorectomy will be highly individual. It is important to consider whether the patient is premenopausal or postmenopausal, her childbearing status and wishes, and her family history. In the absence of any future fertility issues, bilateral salpingectomy should be considered as it could prevent high-grade serous carcinoma, by targeting the site of origin. Removal of fallopian tubes may also decrease the risk of endometrioid and clear cell carcinoma by obstructing the carcinogenic pathway from endometrium and vagina, reducing the risk of peritoneal inflammation and endometriosis.55
In summary, a comprehensive approach to women with endometriosis should include (i) identification of women with endometriosis, either surgically documented or self-reported by symptoms; (ii) careful follow-up of ovarian endometriomas with imaging studies, particularly MRI, to detect any characteristics changes such as mural formation; (iii) complete surgical resection of all endometriotic foci in women undergoing surgical treatment, with tissue evaluation of ovarian endometriomas to rule out malignancy; and (iv) hormonal treatment aimed at reducing the risk for recurrent endometriosis and endometriomas.
In the future, efforts should be directed toward biomarker discovery to identify women at risk of developing cancers and to develop preventative strategies and curative therapies for endometriosis.
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0. For a full list of references, contact: FNezhat@chpnet.org.
Keywords:© 2014 by the International Gynecologic Cancer Society and the European Society of Gynaecological Oncology.
Clinical implications; Endometriosis; Ovarian carcinoma subtype