Risk Factors for Endometriosis-Associated Ovarian Cancers

Key Takeaways:

• New 2024 data reveal a nearly 19-fold increased risk of Type 1 ovarian cancer for women with concurrent deep infiltrating endometriosis and ovarian endometriomas.
• While the absolute risk of ovarian cancer in women with endometriosis is low, specific subgroups – particularly those with large endometriomas, deep infiltrating disease, or ARID1A mutations – should be monitored more carefully.
• The progression to cancer is driven by a "two-hit" mechanism involving ARID1A mutations and oxidative stress, necessitating heightened surveillance in patients ages 48 to 51.

Endometriosis is a prevalent chronic gynecologic condition affecting approximately 10 percent of women of reproductive age. While predominantly benign, endometriosis shares important characteristics with cancer, such as its ability to invade tissues and spread to distant sites as well as undergo malignant transformation, potentially resulting in endometriosis-associated ovarian cancers (EAOC).

Although the overall absolute risk remains low – estimated at approximately 0.5 percent to 1 percent of cases – women with endometriosis exhibit a significantly elevated relative risk for specific ovarian cancer histotypes compared to the general population.^1-3

For healthcare providers managing patients with severe or long-standing disease, understanding the distinct clinical, histological, and molecular risk factors for EAOC is essential for risk stratification, counseling, and surveillance. Recent data from 2024 has further elucidated the hierarchy of risk associated with specific endometriosis subtypes, necessitating an update to clinical risk profiles.^4,5

Histological subtypes and disease severity

The association between endometriosis and ovarian cancer is not uniform across all cancer types. The risk is predominantly confined to Type 1 ovarian epithelial tumors, specifically endometrioid ovarian carcinoma (EnOC) and clear cell ovarian carcinoma (OCCC). Recent large-scale population studies have quantified these risks with greater precision.⁶

A pivotal 2024 cohort study published in JAMA analyzed over 78,000 women with endometriosis and found a 4.2-fold increased risk of overall ovarian cancer compared to unexposed controls.⁴

However, this risk stratification relies heavily on the phenotype of endometriosis:^4,5

• Ovarian endometriomas and deep infiltrating endometriosis (DIE) – The presence of these subtypes confers the highest risk. Women with concurrent deep infiltrating endometriosis and ovarian endometriomas face an adjusted hazard ratio (aHR) of 18.96 for Type 1 ovarian cancer compared to those without endometriosis.
• Superficial peritoneal endometriosis – This subtype is associated with a lower, though still elevated, risk profile compared to DIE or ovarian cystic disease.

Clinicians should note that the presence of ovarian endometriomas (>9 cm) is an independent predictor of ovarian cancer, suggesting that mass size and complexity are critical surveillance parameters.^3,6

Molecular and genetic pathogenesis

The malignant transformation of endometriosis is driven by a stepwise accumulation of genetic and epigenetic alterations, often exacerbated by the inflammatory, iron-rich, and oxidative microenvironment of the endometriotic cyst.^6-9

• ARID1A mutations – ARID1A, a subunit of the SWI/SNF chromatin remodeling complex, is thought to act as a tumor suppressor through its interaction with P53. Mutations in ARID1A – the most frequent molecular alteration in EAOC – drive the transition to malignancy and are found in approximately 50 percent of OCCC and 30 percent of EnOC. Crucially, these mutations often appear in benign endometriotic epithelium adjacent to the tumor, suggesting they are early events in oncogenesis.
• PI3K/AKT/mTOR pathway – Activation of this pathway, often via PIK3CA mutations or PTEN loss, frequently co-occurs with ARID1A mutations. This "two-hit" mechanism is central to the pathogenesis of clear cell and endometrioid carcinomas.
• Oxidative stress – The hemoglobin-rich fluid within endometriomas induces chronic oxidative stress, promoting DNA damage and subsequent mutations in epithelial cells.
• Inflammation – Endometriosis is a chronic inflammatory disease where ectopic implants trigger inflammation during each menstrual cycle. The resulting surge in inflammatory cytokines can interact with ARID1A, fueling the development of EAOC. This highlights inflammation as a potent driver of malignancy in endometriosis patients.

Clinical risk factors

Beyond histological and genetic markers, several clinical characteristics help identify the "at-risk" patient phenotype for EAOC.^2,3,6,7,10

• Advanced age and menopause – While endometriosis is a disease of reproductive age, the diagnosis of EAOC occurs later. The mean age at diagnosis for EAOC is approximately 48 to 51 years, which is significantly younger than the age of diagnosis for non-endometriosis-associated ovarian cancers. Postmenopausal status is a significant risk factor, particularly in women with persistent or untreated endometriomas.
• Duration of disease – Long-standing active disease is a critical factor. A history of endometriosis exceeding 10 to 15 years correlates with a higher likelihood of malignant transformation.
• Hyperestrogenism – Endometriosis itself creates a hyperestrogenic environment due to the level of aromatase in ectopic endometrial tissue. This hyperestrogenism supports cellular proliferation, and cellular proliferation increases the likelihood of DNA damage/mutations.
• Infertility – Infertility is a risk factor of endometriosis, likely due to the effects of hyperestrogenism and the severity of the disease.

Low risk, but high vigilance is needed

While the absolute risk of ovarian cancer in women with endometriosis is low, specific subgroups – particularly those with large endometriomas, deep infiltrating disease, or ARID1A mutations – should be monitored more carefully.^1,7

To date, no validated biomarkers have been identified that can reliably distinguish benign endometriosis from endometriosis-associated malignancy in a preoperative setting.⁶

Ultrasound imaging remains a critical tool for identifying endometriomas with malignant potential. Research indicates that the presence of mural (wall) nodules exceeding 1.5 cm in height is a significant morphological marker, effectively differentiating EAOC from benign endometriotic cysts.⁶

The 2024 data, highlighting the nearly 19-fold increased risk of type 1 cancers in women with severe combined phenotypes, underscores the need for personalized counseling. Clinicians should integrate these risk factors into long-term management strategies, maintaining a lower threshold for imaging and surgical evaluation in older patients with long-standing complex ovarian masses.⁴