Endometriosis is one of the most common gynaecological disorders. It affects 10–15% of all women in the reproductive years [
The aim of this paper is to systematically review the literature evidence of a correlation between endometriosis and ovarian cancer.
A protocol-driven systematic review was conducted in accordance with the Centre for Reviews and Dissemination (CRD) guidance. [
Seven reviews were found in the literature [
A summery of the reviews’ findings.
Review | Language of literature searched | Type of studies included | Quality assessment tool used in the review | Overall results | Application of results |
---|---|---|---|---|---|
Ness 2003 [ | English | In vitro, animal, clinical, and epidemiologic studies | Not specified | Consistent with the association between endometriosis and ovarian cancer. | Possible chemoprevention for women with endometriosis. |
Somigliana et al. 2006 [ | English | Observational, cohort, and case-control | Studies have been critically analysed. | Increased risk of ovarian cancers: effect size: 1.3–1.9. | Modifications of the standard treatment options for the disease are not justifiable. |
Vigano et al. 2007 [ | English | Observational, cohort, and case-control epidemiologic, biological, and genetic studies | Nineriteria, by Austin Bradford Hill [ | The criterion of strength has not been fulfilled. There were insufficient data for four criteria, and four criteria were fulfilled. | 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. |
Nezhat et al. 2008 [ | English | Observational, cohort, and case-control epidemiologic, histopathological, and molecular studies | Not specified | Histological transition from benign endometriosis to ovarian malignancy. | The malignant potential of endometriosis holds serious implications for management. |
Baldi et al. 2008 [ | English | Not specified | Not specified | Further epidemiological and genetic studies are required. | Appropriate physical screening and imaging testing are recommended. |
Vlahos et al. 2010 [ | No search criteria specified | No search criteria specified | Not specified | Endometriosis is associated with specific types of ovarian cancer (endometrioid and clear cell). | More studies are needed to establish the risk factors that may lead to malignant transformation. |
Kobayashi 2010 [ | English | Studies on screening, epidemiology, clinical diagnosis, natural history, preclinical and clinical trials, and promising molecular targets on epithelial ovarian cancer (EOC). | Not specified | Ovarian endometrioma could be viewed as a neoplastic process. | Understanding the mechanisms of endometriosis development and elucidating its pathogenesis and pathophysiology are intrinsic to prevention. |
In our review, 11 studies were identified, which addressed the association between endometriosis and ovarian cancer [
A Forest pilot summarises the eight studies’ effect size. Effect size was measured in odd ratio (OR), standardized incidence ratio (SIR), or relative risk (RR). The 95% confidence interval is represented by the horizontal line, and the dimensions of the boxes are proportional to the sample size.
In epidemiological terms, when the RR is less than 2, a careful assessment of the confounding factors must be conducted before any conclusion of causality can be made [
Summary the types, sample size, followup time, confounding factors, and limitation of each one of the eight studies included in our review.
Name of study | Type | Mean of followup (years) | Size of endometriosis cohort | Ovarian cancer cases identified in the cohort | Confounding factors considered | Main limitations |
---|---|---|---|---|---|---|
Aris 2010, Canada [ | Retrospective cross-sectional | 9 | 2521 | 41 | Age, pregnancies, family history, race, oral contraceptive, tubal ligation, hysterectomy and breastfeeding | Retrospective collection of data using a coded computerised system. Selection bias |
Borgfeldt and Andolf 2004, Sweden. [ | Case-control | 10 | 28,163 | 81 | Age and parity | Use of cohort of women discharged from hospital with a diagnosis of endometriosis. This may lead to including women with moderate and severe endometriosis (hospital stay patients) without minimal and mild cases. This may overestimate the risk ratio. Selection bias. |
Brinton et al. 1997, Sweden. [ | Retrospective cohort study | 11.4 | 20,686 | 29 | Age and length of history of endometriosis | |
Melin et al. 2006, Sweden. [ | Retrospective cohort study | 12.7 | 64,492 | 122 | Age and type of surgery performed. | |
Melin et al. 2007, Sweden. [ | Retrospective cohort study | 13.4 | 63 630 | 134 | Age, parity, and type of surgery performed | |
Modugno et al. 2004, USA. [ | Case-control | 177 | Age, parity, oral contraceptive use, tubal ligation, family history of ovarian cancer, and study site, gynaecological surgical procedures | Recall and selection bias, as the authors pooled data on the history of endometriosis reported by patients. | ||
Ness et al. 2000. USA. [ | Case-control | 66 | Age, history of ovarian cancer, parity, breastfeeding, type and length of each contraceptive, tubal ligation, hysterectomy, ovarian operations. | Data was collected by case interviews. Recall bias. Low participation rates among cases and controls. | ||
Olsen et al. 2002, USA [ | Prospective cohort study. | 13 | 1,392 | 3 | Age, education, marital status, alcohol intake, physical activity, smoking, parity, oral contraceptive use, HRT, history of hysterectomy or dilatation and curettage, BMI and waist to hip ratio. | Reliance on self-reports of endometriosis in this cohort (a questionnaire). Recall bias. The number of women who developed ovarian cancer is quite limited. |
Despite the studies presented, the risk of ovarian cancer among patients with endometriosis has always been
In our review we have found another group of eight epidemiologic studies that correlated endometriosis with endometrioid and/or clear-cell ovarian carcinoma as a specific histological subtype [
In a previous review, Somigliana et al. included two other studies which assessed the risk of endometriosis on ovarian cancer in infertile patients [
Additionally, we have excluded another study conducted by Kobayashi et al.’s in Japan. They documented only endometriomas and evaluated the risk of ovarian cancer based on varying time periods from time of diagnosis of endometrioma [
Many genetic, biological, and immunological studies have tried to address the causal relationship between endometriosis and ovarian cancer. Different types of genomic instability and mutations have been shown to occur in endometriosis and ovarian cancer [
A vital factor in the development of both endometriosis and malignancy is considered to be angiogenesis. In a study by Hayrabedyan et al., the expression of several angiogenic factors (interleukin-1 alpha (IL-1 alpha), Fibroblast growth factor FGF-1, and S100A13) and a common pan-ovarian carcinoma antigen were investigated, in several cases of adenomyosis and ovarian endometriosis [
Recently, Wiegand et al. published new data implicating ARID1A (AT-rich interactive domain-containing protein 1A) as a tumor-suppressor gene frequently disrupted in ovarian clear-cell and endometrioid carcinomas [
It seems, from the previous discussion, that there is insufficient evidence to suggest a specific gene mutation or a specific biological pathway that predisposes endometriosis patients to ovarian cancer. There is good evidence, however, to demonstrate the potential transformation from endometriosis to ovarian endometriosis cell and clear-cell carcinoma. The association between the two entities with an effect size of 1.32–1.9 may be due to sharing similar risk factors, rather than a causal relation.
There is increased risk of ovarian cancers, specifically endometrioid and clear-cell carcinoma, in women with endometriosis. The estimated effect size, however, is modest varying between 1.32 and 1.9. A causative relationship between the two incidences cannot be confirmed. However, there is increasing evidence on the role of genetic mutations in ovarian clear-cell and endometrioid carcinoma developing from endometriosis. There are few gene mutations involved, and yet more evidence is needed before generalising any mutation screening test or changing the treatment of endometriosis to include radical excision in case of a positive genetic mutation.