Women with endometriosis have a significantly increased ovarian cancer risk, study finds

By Dr. Sushama R. Chaphalkar, PhD.Reviewed by Danielle Ellis, B.Sc.Jul 22 2024

In a recent population-based cohort study published in the Journal of the American Medical Association (JAMA), researchers from the United States of America investigated the potential association between different subtypes of endometriosis and the incidence of ovarian cancer.

They found that women with ovarian endometriomas and/or deep infiltrating endometriosis had a significantly higher risk of ovarian cancer, especially type I ovarian cancer, compared to women without endometriosis.

Background

Endometriosis affects approximately 11% of reproductive-aged women, including a significant proportion of those with pelvic pain or infertility. It is associated with an increased risk of ovarian cancer, with women having nearly twice the risk compared to those without endometriosis. A recent meta-analysis found strong associations between endometriosis and certain ovarian cancer histotypes, such as clear cell, endometrioid, and low-grade serous cancers. However, no consistent associations were found for high-grade serous or mucinous tumors.

Additionally, the relationship between endometriosis subtypes (superficial peritoneal endometriosis, ovarian endometriomas, and deep infiltrating endometriosis) and ovarian cancer histotypes remains to be explored thoroughly. Understanding these associations could inform new etiologic pathways and influence clinical decision-making. Therefore, researchers in the present study investigated the potential association between endometriosis and its subtypes with the incidence of overall ad histotype-specific ovarian cancer.

About the study

A retrospective cohort study (1992-2019) was created within the Utah Population Database (UPDB). Researchers identified women aged 18 to 55 with at least one endometriosis diagnosis, resulting in a prevalence of 6.3%. Endometriosis diagnoses were obtained from various health records and subtyped into five categories: superficial peritoneal endometriosis, ovarian endometriomas, deep infiltrating endometriosis, concurrent ovarian endometriomas, and deep infiltrating endometriosis, and other.

The study included 78,893 women with endometriosis ("exposed") and matched them 1:5 to 379,043 women without endometriosis ("unexposed") by birth year and birthplace. The mean age of the participants was 36 years, and the average follow-up period was 12 years.

Ovarian cancer cases (n = 597) in that period were identified via the Utah Cancer Registry using International Classification of Diseases (ICD) codes and classified according to 2020 World Health Association (WHO) guidelines. The most common histotypes—high-grade serous, low-grade serous, endometrioid, mucinous, and clear cell—matched previous distributions. For analysis, cases were grouped into type I (endometrioid, clear cell, mucinous, low-grade serous) and type II (high-grade serous) categories.

Demographic data included sex, race, ethnicity, birth and death information, and residence type. Health data covered reproductive and surgical histories, including body mass index (BMI) from driver's licenses and smoking from ICD codes. Statistical analysis involved the use of Cox proportional hazards models with robust variance estimation, Kolmogorov-type supremum tests, generalized linear models, and probabilistic bias analysis.

Results and discussion

About 75% of participants had borne children (parous), with 6% having undergone surgical removal of both ovaries at follow-up. Women with endometriosis were more likely to have not borne children (31% vs. 24%) and to have had a surgical removal of the uterus (39% vs. 6%) compared to those without endometriosis.

Endometriosis was found to be associated with an increased risk of all ovarian cancer histotypes, with adjusted hazard ratios (aHRs) ranging from 2.70 for high-grade serous ovarian cancer to 11.15 for clear cell carcinoma, compared to women without endometriosis. Overall, the ovarian cancer risk was 4.20 times higher in women with endometriosis. The highest ovarian cancer risk was observed in women with deep infiltrating endometriosis and/or ovarian endometriomas (aHR, 9.66), with the highest risk for deep infiltrating endometriosis alone followed by deep infiltrating endometriosis with ovarian endometriomas.

Deep infiltrating endometriosis and/or ovarian endometriomas were found to be strongly associated with type I ovarian cancer (aHR, 18.96). Risk differences indicated an excess of 9.90 ovarian cancer cases per 10,000 women with endometriosis over 12 years. Quantitative bias analysis suggested that the true associations might be stronger than observed, with bias-adjusted HRs of 8.29 overall, 20.2 for type I, and 3.9 for type II ovarian cancers.

The strength of the study lies in its large, population-based design. However, the study is limited by potential misclassification of endometriosis due to diagnostic challenges, possible misclassification of ovarian cancer histotypes, possible misclassification of BMI and smoking, incomplete data on hysterectomies and oophorectomies, and missing data on oral contraceptives and agonists of GnRH (short for gonadotropin hormone-releasing hormone), which could have underestimated the true associations.

Conclusion

The present study suggests that endometriosis is associated with a significantly increased risk of ovarian cancer, particularly type I ovarian cancer. Women with deep infiltrating endometriosis and/or ovarian endometriomas have nearly 19 times the risk of type I ovarian cancer compared to those without endometriosis.

The study emphasizes the urgent need for studies in the future to understand better the biological mechanisms underlying these associations to improve ovarian cancer screening and prevention strategies, especially for women with severe endometriosis and genetic risk factors, and to identify new molecular targets for ovarian cancer treatments.