Borderline ovarian tumors (BOTs), also known as tumors of low malignant potential (LMP), are ovarian growths classified between entirely benign cysts and fully invasive ovarian cancer. While they share some features with malignant disease, BOTs typically have a far more favorable outcome. Understanding the causes of these tumors involves examining their unique pathological classification, external risk factors, and underlying genetic changes.
Understanding the “Borderline” Classification
The “borderline” designation is a pathological classification distinguishing these tumors from both benign and malignant ovarian neoplasms. Pathologists recognize BOTs by abnormal cellular growth, including increased cell layers and mild nuclear atypia, where cell nuclei appear slightly irregular. This proliferation separates them from simple, non-threatening ovarian cysts.
The key feature preventing a BOT from being classified as invasive cancer is the absence of destructive stromal invasion. Although abnormal cells may push into the stroma, the underlying supportive tissue of the ovary, they do not break through and actively destroy it. This non-destructive growth pattern allows the tumors to grow slowly and is associated with excellent long-term survival rates.
Key Risk Factors and Epidemiological Links
BOTs often affect a younger population, with the mean age of diagnosis being approximately 45 years, about a decade younger than the average for invasive ovarian cancer. This earlier onset suggests that BOTs and aggressive ovarian cancers may follow different developmental pathways. Researchers examine various lifestyle, reproductive, and demographic factors to determine what increases the likelihood of developing these tumors.
Reproductive history is consistently studied, showing a nuanced relationship. Women who have never given birth (nulliparity) or who have low parity appear to have an increased risk for BOTs, particularly the serous subtype. This aligns with the theory that factors reducing ovarian surface disruption, such as pregnancy and lactation, offer a protective effect.
Hormonal factors, such as oral contraceptive use, show a less clear association compared to their protective effect against invasive ovarian cancer. Some studies suggest oral contraceptives do not confer the same protective benefit against serous BOTs as they do for invasive cancers. Conversely, hormonal situations where estrogen is unopposed by progesterone, such as certain hormone replacement therapies or obesity, may increase the risk for serous BOTs.
Smoking shows a strong link, particularly with the mucinous subtype of BOT. Women with a history of heavy smoking have a significantly higher risk for mucinous tumors compared to non-smokers. While family history is a major risk factor for invasive disease, the evidence is less definitive for BOTs, though a familial association between BOTs has been demonstrated.
Genetic and Molecular Mechanisms of Development
The cause of a borderline ovarian tumor lies in specific genetic changes within the ovarian epithelial cells. These tumors develop due to mutations that drive cell growth and proliferation, creating a cell that grows uncontrollably but still respects tissue boundaries. The most well-studied mutations involve the KRAS and BRAF genes, which are proto-oncogenes regulating cell signaling pathways.
These mutations are considered very early events in the formation of serous BOTs; one study found that over 80% of these tumors contained a mutation in either KRAS or BRAF. KRAS mutations are found in approximately 17% to 40% of serous BOTs, while BRAF mutations are present in a similar range of 23% to 48%. These genetic changes activate the Mitogen-Activated Protein Kinase (MAPK) signaling pathway, a master switch for cell division and growth.
The type of mutation may influence the tumor’s behavior, contributing to its “borderline” nature. For instance, BRAF mutations in serous BOTs are sometimes associated with cellular senescence, where cells stop dividing, potentially protecting against progression to invasive cancer. Conversely, KRAS mutations are more commonly seen in serous BOTs that eventually recur as a low-grade invasive carcinoma. Other subtypes, such as endometrioid BOTs, have distinct molecular drivers, frequently harboring mutations in the CTNNB1 gene, which is involved in growth signaling.