What Causes Borderline Ovarian Tumors?

What causes borderline ovarian tumors remains one of the most intriguing questions in gynecologic oncology research. While these rare tumors sit between benign and malignant ovarian growths, scientists are increasingly uncovering the complex web of genetic, hormonal, and environmental factors that contribute to their development.

Borderline ovarian tumors (BOTs), also known as borderline ovarian cancer, affect approximately 15 to 20% of all epithelial ovarian tumor cases, affecting roughly 2 to 5 women out of every 100,000 each year. 

Unlike their more aggressive counterparts, these tumors typically develop slowly and have a more favorable prognosis, but understanding what triggers their formation is crucial for prevention and early detection strategies. 

In this guide, we’ll explore the factors behind both major types of borderline ovarian tumors — serous and mucinous — and what current research reveals about their unique developmental pathways.

The Molecular Foundation: How Genetic Changes Drive BOT Development

Recent scientific breakthroughs have revealed that borderline ovarian tumors develop through specific molecular pathways that differ dramatically from high-grade ovarian cancers. The discovery of these genetic mechanisms has revolutionized our understanding of what causes borderline ovarian tumors.

Related reading: LGSOC vs HGSOC: Understanding the Two Faces of Ovarian Serous Carcinoma

KRAS and BRAF Mutations: The Early Triggers

Research has identified mutations in KRAS and BRAF genes as some of the earliest events in borderline ovarian tumor development, with one study finding that 88% of serous borderline tumors contained either BRAF or KRAS mutations. These mutations appear to occur very early in the process, even before the tumor becomes recognizable.

What makes this discovery particularly significant is that these mutations were found not only in the borderline tumors themselves but also in the adjacent, seemingly normal tissue. In 86% of cases, the same mutations detected in the borderline tumors were also present in the benign cystadenoma tissue nearby. This suggests that these genetic changes happen before the tumor develops its borderline characteristics.

The KRAS and BRAF genes work in the same cellular pathway, which explains why tumors rarely have mutations in both genes simultaneously. When one is mutated, it affects the RAS/RAF/MEK/MAPK signaling pathway, leading to uncontrolled cell growth.

Put simply, scientists have found that borderline ovarian tumors start with specific genetic damage that happens very early, often before any tumor is even visible. This genetic damage disrupts normal cell growth controls, and it’s different from the genetic changes seen in aggressive ovarian cancers, which helps explain why borderline tumors behave so differently.

The Two-Pathway Model of Ovarian Cancer Development

Scientists now recognize that borderline ovarian tumors develop through what’s called the “Type I pathway”—a slow, step-by-step progression from benign to borderline to low-grade invasive cancer. This contrasts sharply with high-grade serous ovarian cancers, which develop rapidly through a different “Type II pathway.”

Research shows that Type I tumors, including BOTs, are characterized by:

• KRAS and BRAF mutations
• Chromosomal instability on chromosome 1
• Slower growth patterns
• Better response to surgical treatment

This molecular distinction helps explain why borderline ovarian tumors behave so differently from aggressive ovarian cancers and why they typically have much better outcomes.

Reproductive and Hormonal Risk Factors

Understanding what causes borderline ovarian tumors extends beyond genetics to include reproductive and hormonal influences that can increase or decrease risk.

Pregnancy and Breastfeeding: Protective Factors

Some studies show that pregnancy and breastfeeding reduce borderline ovarian tumor risk. Research found that women who had given birth had a significantly lower risk compared to women who had never had children. 

This protection likely works by reducing lifetime ovulations and providing hormonal changes that give the ovaries periods of rest.

Oral Contraceptives and Hormone Use

Unlike with aggressive ovarian cancers, birth control pills don’t appear to protect against borderline tumors, with some studies showing no significant effect either way.

However, one study found that women using estrogen replacement therapy without progesterone (called “unopposed estrogen”) had about double the risk of developing serous borderline tumors specifically, compared to non-users. Women using estrogen with progesterone didn’t show this increased risk.

This finding is limited to one study and applies only to the serous subtype of borderline tumors, but it suggests that the balance between estrogen and progesterone may play a role in tumor development for some women.

Environmental and Lifestyle Factors

Beyond genetics and reproductive history, scientists have identified several environmental and lifestyle factors that appear to influence borderline ovarian tumor development.

Smoking: A Consistent Risk Factor

One of the most striking findings in borderline ovarian tumor research is the strong association with smoking. One study found that women with 20 or more pack-years of smoking had:

• 2.7 times higher risk for benign mucinous tumors
• 2.7 times higher risk for borderline mucinous tumors
• 2.1 times higher risk for invasive mucinous cancers

The consistency of this association across all stages of mucinous tumor development suggests that smoking may be involved in the fundamental mechanisms that initiate these tumors.

Learn more: Serous Borderline Tumor vs. Mucinous Borderline Tumor: What’s the Difference?

Other Lifestyle Factors Under Investigation

Research has examined various other potential risk factors, though most haven’t shown statistically significant associations. These include oral contraceptive use, age at first pregnancy, menstrual history, and family history of ovarian cancer. While these factors continue to be studied, the evidence for their role in borderline ovarian tumor development remains unclear.

What’s more established is that borderline tumors typically affect younger women than invasive ovarian cancers, with many cases diagnosed between ages 20 and 40, and that infertility appears to be more common among women who develop these tumors.

Age and Family History

Borderline ovarian tumors typically affect younger women than invasive ovarian cancers. The median age at diagnosis is approximately 45 years, with about one-third of patients diagnosed before age 40.

While borderline ovarian tumors can occur in families, they are less commonly associated with hereditary cancer syndromes than high-grade ovarian cancers. Family history of ovarian cancer has been studied as a potential risk factor, though the evidence for its role in borderline tumor development remains unclear.

The Appendix Connection: A Unique Aspect of Mucinous BOTs

One crucial discovery in borderline ovarian tumor research involves the appendix. Molecular studies have revealed that some mucinous borderline tumors of the ovary may actually represent metastases from primary appendiceal tumors.

This finding has important implications for treatment, as it means that appendectomy is now routinely performed when mucinous borderline tumors are diagnosed. This discovery also highlights how our understanding of what causes borderline ovarian tumors continues to evolve with new research.

What Causes Borderline Ovarian Tumors? What We Know and What We Don’t

What causes borderline ovarian tumors involves a complex interplay of genetic predisposition, hormonal influences, reproductive factors, and environmental exposures. While we’ve made significant progress in understanding the molecular mechanisms — particularly the role of KRAS and BRAF mutations — many questions remain.

For patients and families affected by borderline ovarian tumors, this growing understanding provides hope for better prevention strategies and more targeted treatments. As research continues, we will likely discover additional pieces of this complex puzzle.

At Not These Ovaries, we’re committed to funding research that will help answer these remaining questions about what causes borderline ovarian tumors. By supporting studies into the molecular mechanisms, risk factors, and prevention strategies for these rare tumors, we hope to improve outcomes for the young women most commonly affected by this disease.