Endometriosis and Ovarian Cancer Risk

A new study tells us more

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Endometriosis is associated with an increased risk of ovarian cancer. While this has been known for some time, a new study provides us with more information, and it’s significant enough that I think it’s worth discussing. 

Some quick background: the lifetime risk of ovarian cancer is about 1.2%, and there are two main types of ovarian cancer: epithelial, which accounts for 95% of ovarian cancers, and non-epithelial, which represents the remaining 5%. Here, we will be discussing epithelial ovarian cancers. In addition, there are several types of epithelial ovarian cancers, and the two that are known to be associated with endometriosis are endometrioid and clear cell. About 5-10% of epithelial ovarian cancers are clear cell, so it’s not common, but the association with endometriosis is especially strong, and 50% of women who develop that cancer have a history of endometriosis.

Previous studies have suggested that the risk of ovarian cancer may be increased by 50-100% for women with endometriosis, which seems very scary. However, when you translate that into real-world numbers, it’s less alarming as the lifetime risk of ovarian cancer for women with endometriosis is believed to be between 1.8-2.4%. For perspective, we typically start considering removing the oviducts and ovaries (known as a risk-reducing bilateral salpingo-oophorectomy or RRSO) to reduce the risk of ovarian cancer when the risk of cancer is greater than 3-4%. As of now, the increased risk of endometriosis-associated ovarian cancer is something patients and providers should know about and should factor into the evaluation of cysts or other ovarian masses, but the risk hasn’t been significant enough for guidelines to recommend preventative surgery.

The New Study

Investigators used data from 1992-2019 from the Utah Population Database (UPDB), a comprehensive database, to identify women with endometriosis and a control group. They divided the women with endometriosis into categories based on whether their endometriosis was superficial or had invaded deeply into tissues (either deeply invasive endometriosis and/or endometriomas, which are cysts of endometriosis on the ovaries–to make it easier, I’ll refer to this group as having deep endometriosis). They grouped these women based on age, BMI, and other demographics and compared them with those without a diagnosis of endometriosis. They ended up with 450,906 women: 78,476 with endometriosis and  372,430 without. 

The investigators then identified the different types of epithelial ovarian cancer in a statewide cancer registry and linked those cases back to these two groups (there were 597 cases of ovarian cancer). They divided the ovarian cancers into type I (endometrioid, clear cell, mucinous, and low-grade serous) and type II (high-grade serous). 

The average length of follow-up in the study was 12 years. The average age of diagnosis of endometriosis was 36 years, which is sadly not uncommon. Overall, there was a 4.2x increased risk of ovarian cancer with endometriosis, which is higher than what we previously believed. 

The increased risk was driven in large part by type 1 cancers, as endometriosis was associated with a 7.5x increased risk of type 1 ovarian cancers. In contrast, the increased risk for type 2 cancers was 2.7x. Among the type 1 cancers, the most significant increase in risk was seen for clear cell cancer of the ovary–11.2x. 

The extent of the endometriosis also affected the relative risk of ovarian cancer. Deep endometriosis was associated with a 9.7x increased risk of ovarian cancer, but for those with superficial endometriosis, the risk only increased 2.8x. Deep endometriosis was associated with a staggering 19x increase in the risk of clear cell cancer of the ovary. 

Here is the graphic from the paper that was available to share as a PowerPoint slide:

Now, this is an observational study, so there are limitations. For many, the diagnosis of endometriosis was based on the surgical report, but without a biopsy, that diagnosis may be incorrect as visually identifying endometriosis can be inaccurate. Many women with endometriosis also go undiagnosed, so it’s possible that many with endometriosis were missed or were diagnosed before they came to Utah, and that information may not have been in the records. Some women may also have left the state for medical care. Some of the other data used was pulled from other record systems; for example, BMI came from the driver’s license, so there could be issues there. In addition, the prevalence of ovarian cancer over the duration of the study was 0.1%, which is significantly lower than the generally accepted lifetime risk of 1.2%. This could be because follow-up was not over a lifetime, and many were younger at enrollment, and follow-up may not have been long enough to capture all the cancers that might develop in the future. Some women with endometriosis who had their ovaries removed may have reduced their risk of cancer, and some women may have been using hormonal contraception, which lowers the risk of ovarian cancer (contraception data was not collected). And, of course, there may be other factors. This wasn’t a study designed to look at the lifetime prevalence of ovarian cancer, but I just thought it was an interesting point. 

However, the study's strengths include the sheer number of people, the length of follow-up, and the magnitude of the effect. 

What does this mean?

We don’t know if we can apply the relative risk from this study to the general population, so it’s essential to be careful about extrapolating. But *if* the overall increased risk of ovarian cancer with endometriosis from this study were correct, meaning 4.2x. In that case, if the lifetime prevalence of ovarian cancer is 1.2%, that means the lifetime risk for women with endometriosis could be 4.8%. If the numbers for this study are correct (emphasis again on *if*), the 9.7x risk with deep endometriosis could translate to a lifetime risk of 11.6%. Still, with superficial endometriosis and a 2.7 x risk, that number is 3.24%. 

For comparison, the risk of ovarian cancer with a mother or sister who has that cancer is 3-4%, and risk-reducing surgery is generally not recommended. However, the risk of epithelial ovarian cancer with the BRCA2 variant is 11%–17% and risk-reducing surgery is definitely recommended. 

This is an observational study, and while it’s important information, it hasn’t yet been translated from information to actionable knowledge. If the results do turn out to apply to all women with endometriosis (again with the *if*), we don’t know the age when this risk starts to increase, and we don’t really know the effectiveness of risk-reducing surgery.

We also know that oral contraception reduces the risk of ovarian cancer by 28%, and the greatest benefit is seen for those who use oral contraceptives for five or more years. The protective effect lasts up to 35 years after stopping the pill. Unfortunately, this current study was not able to tell us anything about the use of oral contraception among the participants. Still, other research has suggested that the birth control pill may be associated with a reduced risk of ovarian cancer for those with endometriosis. 

What Are The Takeaways?

Ideally, I like to wrap up a post with a neat, actionable summary, but that isn’t always possible, especially with an observational study and the knowledge gaps we have with endometriosis.

Endometriosis is associated with an increased risk of ovarian cancer. This is well known, and this new study suggests the risk may be higher than previously thought, especially for women with deep endometriosis. While this is an observational study, this information might be considered when someone with endometriosis has a persistent mass on their ovaries, meaning do they feel comfortable following it with imaging studies, or is it better to remove it? These are personal decisions that will be important to discuss with a person’s healthcare provider. 

The information from this study might also weigh into decisions about surgery for endometriosis, specifically removing ovaries and oviducts, understanding that we don’t have great data on how well that might reduce the risk of cancer (not having great data doesn’t mean the decision to have the surgery would be right or wrong, just that we don’t have the data). This, of course, needs to be weighed against the risk of removing ovaries before menopause because we also don’t know the impact of menopausal hormone therapy on the risk of these cancers (I am working on a post about ovarian cancer and menopause hormone therapy). And we don’t know the age at which the risk for ovarian cancer increases for women with endometriosis. Also, oral contraception remains a way to reduce the risk of ovarian cancer. 

I suspect we will be seeing more studies on the cancer risk with endometriosis as there is far better machinery for cancer research than pain, so researchers should take advantage of this funding path. The more we learn about endometriosis, the better. However, I can’t help but add an exasperated asterisk that I believe it will be the link with cancer that likely propels research on endometriosis forward and not the fact that it causes pain and infertility. Of course, understanding the link between endometriosis and cancer is extremely valuable. I don’t mean to belittle that; it’s just after being in women’s health for 30 years it seems women’s pain has never been worthwhile. 

I am hopeful that we are on the cusp of a new era of endometriosis research, which will hopefully help us offer tailored care for preventing cancer as well as treating endometriosis-related pain and infertility. 

As always, the information here is not direct medical advice.

References

Kvaskoff M, Horne AW, Missmer SA. Informing women with endometriosis about ovarian cancer risk. Lancet 2017; 390: 2433-2434.

Ying L. Liu et al., Risk-Reducing Bilateral Salpingo-Oophorectomy for Ovarian Cancer: A Review and Clinical Guide for Hereditary Predisposition Genes. JCO Oncol Pract 18, 201-209(2022). DOI:10.1200/OP.21.00382

Hereditary breast and ovarian cancer syndrome. Practice Bulletin No.182. American College of Obstetricians and Gynecologists. Obstet Gynecol 2017:130:e110–26.

Barnard ME, Farland LV, Yan B, et al. Endometriosis Typology and Ovarian Cancer Risk. JAMA. Published online July 17, 2024. doi:10.1001/jama.2024.9210

Karlsson T, Johansson T, Höglund J, et al. Time-Dependent Effects of Oral Contraceptive Use on Breast, Ovarian, and Endometrial Cancers. Cancer Research. 2021; 81(4):1153-1162. Published online December 17, 2020. doi: 10.1158/0008-5472.CAN-20-2476.

Wentzensen  N, Poole  EM, Trabert  B,  et al.  Ovarian cancer risk factors by histologic subtype: an analysis from the ovarian cancer cohort consortium.   J Clin Oncol. 2016;34(24):2888-2898. doi:10.1200/JCO.2016.66.8178