Endometriosis and Ovarian Cancer: Understanding the Connection

Endometriosis and ovarian cancer are two distinct gynecological conditions that can cause significant concerns for women’s health. While endometriosis is a benign disorder, it shares some similarities with ovarian cancer, leading many women to question the potential link between the two. 

In this article, we’ll explore the connection between endometriosis and ovarian cancer, examining the latest research, similarities and differences, as well as what you can do to stay informed and proactive about your health.

What is Endometriosis?

Endometriosis is a nonmalignant, chronic condition in which tissue similar to the lining of the uterus (endometrium) grows outside the uterus, often on the ovaries, fallopian tubes, and other pelvic structures. This misplaced tissue responds to hormonal changes throughout the menstrual cycle, causing inflammation, scarring, and pain.

According to WHO, endometriosis affects an estimated 10% of women of reproductive age worldwide, or approximately 176 million women. Despite its prevalence, endometriosis remains an often misunderstood and underdiagnosed condition.

Endometriosis Causes and Risk Factors

While the exact cause of endometriosis remains unknown, several theories attempt to explain its development:

• Retrograde menstruation: Menstrual blood containing endometrial cells flows back through the fallopian tubes and into the pelvic cavity, where the cells implant and grow.
• Immune system dysfunction: Alterations in the immune response may allow endometrial tissue to grow outside the uterus.
• Genetic factors: Endometriosis tends to run in families, suggesting a potential genetic predisposition.

Risk factors for endometriosis include:

• Never giving birth
• Starting menstruation at an early age
• Going through menopause at an older age
• Short menstrual cycles (less than 27 days)
• Heavy menstrual periods lasting more than 7 days
• Higher levels of estrogen in the body
• Low body mass index
• Alcohol consumption
• Family history of endometriosis

Common Endometriosis Symptoms

The most common symptoms of endometriosis include:

• Painful periods (dysmenorrhea)
• Pelvic pain and cramping, which may be chronic
• Pain during or after sexual intercourse (dyspareunia)
• Pain with bowel movements (dyschezia) or urination
• Excessive bleeding during or between periods
• Infertility

It’s important to note that the severity of symptoms does not necessarily correlate with the extent of endometriosis. Some women with mild endometriosis may experience severe pain, while others with advanced endometriosis may have minimal symptoms.

Overview of Ovarian Cancer

Ovarian cancer is a malignant growth that starts in the ovaries, the reproductive glands that produce eggs and female hormones. It is the fifth leading cause of cancer-related deaths among women in the United States; projections indicate nearly 12 million women will be diagnosed, and 8 million will die from ovarian cancer by 2050.

Several factors can increase a woman’s risk of developing ovarian cancer: 

• Older age (majority of cases occur after menopause)
• Family history of ovarian, breast, or colorectal cancer
• Inherited genetic ovarian cancer mutations (e.g., BRCA1 and BRCA2)
• Never having been pregnant
• Fertility treatment
• Hormone therapy after menopause
• Obesity
• Endometriosis (which we will discuss in more detail)

Symptoms of Ovarian Cancer

Early-stage ovarian cancer rarely causes noticeable symptoms, making it challenging to detect. As the disease progresses, women may experience: 

• Bloating or swelling of the abdomen
• Pelvic pressure or abdominal pain
• Difficulty eating or feeling full quickly
• Urinary urgency or frequency
• Change in bowel habits, such as constipation
• Unintentional weight loss

Is There a Link Between Endometriosis and Ovarian Cancer? 

The potential link between endometriosis and ovarian cancer has been a topic of interest for researchers and a concern for many women living with endometriosis. While the two conditions are distinct, there are some compelling reasons to investigate their relationship further. In the following sections, we’ll take a closer look at the current research on the connection between endometriosis and ovarian cancer, exploring the evidence, proposed mechanisms, and implications for women’s health.

Examining the Connection: What the Research Shows

While endometriosis is a benign condition, research has shown that women with endometriosis have a slightly increased risk of developing certain types of ovarian cancer, particularly endometrioid and clear cell carcinomas. 

A meta-analysis of 20 case-control studies and 15 cohort studies found that women with endometriosis had a 1.42 times higher risk of ovarian cancer compared to women without endometriosis. This translates to a lifetime risk of ovarian cancer of 1.8% for women with endometriosis, compared to 1.3% for the general female population. 

Proposed Mechanisms Linking the Two Conditions

Recent research has revealed several key mechanisms that may explain the connection between endometriosis and ovarian cancer:

• Genetic mutations and progression: Studies have shown that cancer-associated mutations often occur in a specific sequence. While KRAS and PIK3CA mutations are common in both endometriosis and endometrial tissue, ARID1A mutations play a crucial role in cancer development. Research suggests that a “second hit” or additional mutation in ARID1A may be a key trigger in transforming benign endometriosis into cancer.
• Pathway alterations: The PI3K/AKT and RAS/MAPK pathways are frequently altered in both conditions. However, the frequency of these alterations differs between normal endometrium, endometriosis, and ovarian cancer, suggesting a complex progression of genetic changes during cancer development.
• Hormonal and inflammatory factors: The estrogen-dependent nature of endometriosis and chronic inflammation may create an environment that promotes additional genetic mutations. For example, KRAS mutations, which are common in endometriosis, have been associated with increased inflammation and may help endometriotic cells survive in the challenging environment of ovarian cysts.

This understanding of the molecular mechanisms has important implications for both monitoring and treating patients with endometriosis who may be at risk for ovarian cancer development.

Endometriosis vs. Ovarian Cancer

While endometriosis and ovarian cancer share some similarities, such as the potential to cause pelvic pain and the presence of tissue growth, they are ultimately distinct conditions with important differences. 

Understanding these differences is crucial for accurate diagnosis, appropriate treatment, and patient education. In the following section, we’ll explore the key distinctions between endometriosis and ovarian cancer, focusing on their unique symptoms, disease characteristics, and diagnostic challenges.

Key Differences in Symptoms and Disease Characteristics

While endometriosis and ovarian cancer share some symptoms, there are notable differences between the two conditions:

• Endometriosis symptoms are typically cyclical and related to menstrual periods, while ovarian cancer symptoms are generally persistent and unrelated to the menstrual cycle.
• Endometriosis is a benign condition, while ovarian cancer is a malignant growth that can metastasize (spread) to other parts of the body.
• Endometriosis is more common in women of reproductive age, while ovarian cancer is more frequently diagnosed in postmenopausal women.

Diagnostic Challenges: Is it Endometriosis or Ovarian cancer?

Distinguishing between endometriosis and ovarian cancer can be challenging, as both conditions can cause similar symptoms and appear as cysts or masses on imaging tests. Definitive diagnosis often requires surgical biopsy and histopathological examination.

Can Endometriosis Cause Ovarian Cancer?

Research has identified a specific type of ovarian cancer linked to endometriosis, now termed “Endometriosis-Associated Ovarian Cancer” (EAOC). 

While the overall lifetime risk of ovarian cancer is relatively low (1.8% for women with endometriosis compared to 1.3% for the general female population), understanding EAOC has become a critical area of research.

EAOC most commonly develops from endometriotic cysts in the ovaries (also known as “chocolate cysts” due to their dark, brown appearance). These cysts contain old blood and endometrial tissue, creating an environment that may promote malignant transformation. Two specific types of ovarian cancer — clear cell carcinoma and endometrioid carcinoma — are most strongly associated with endometriosis.

Several mechanisms have been proposed for how endometriotic cysts may lead to EAOC:

• The harsh environment within these cysts, including high levels of free iron from broken-down blood, can cause oxidative stress.
• The chronic inflammation associated with these cysts may trigger genetic mutations.
• Specific genetic alterations, particularly involving the ARID1A gene, appear to play a crucial role in the transformation from benign endometriosis to cancer

This understanding of EAOC has made it a priority in gynecologic cancer research, as identifying the precise mechanisms could lead to better prevention strategies and treatments.

Endometriosis as a Risk Factor vs. Cause

The relationship between endometriosis and ovarian cancer is more complex than initially understood. While endometriosis has traditionally been viewed as one of the risk factors for ovarian cancer, some research suggests that atypical endometriosis may be a precursor lesion to certain types of ovarian cancer, particularly clear cell and endometrioid carcinomas.

However, this potential progression from atypical endometriosis to cancer remains a subject of debate in the medical community. Several challenges exist:

• The definition and identification of atypical endometriosis need more standardization among pathologists.
• More research is needed to fully understand the progression from endometriosis to cancer.
• Other factors, such as genetic predisposition and environmental influences, likely play important roles in determining which cases of endometriosis may progress to cancer.

This uncertainty highlights the importance of continued research and the need for more standardized pathology reporting to better understand the relationship between endometriosis and ovarian cancer.

The Role of Genetics, Inflammation, and Hormones

As mentioned earlier, genetic mutations, chronic inflammation, and hormonal factors may contribute to the link between endometriosis and ovarian cancer. However, more research is needed to fully understand the complex interplay of these factors and their role in the development of ovarian cancer in women with endometriosis.

Comparing the Epidemiology and Risk Factors

Endometriosis and ovarian cancer share some risk factors, including:

• Nulliparity: medically defined as having never given birth to a pregnancy that reached 24 weeks or beyond, whether the outcome was a live birth or stillbirth.
• Early menarche: the onset of menstrual periods at a young age, typically before the age of 12.

However, there are also notable differences in their epidemiology:

• Endometriosis affects approximately 10% of women of reproductive age, while ovarian cancer is relatively rare, with a lifetime risk of about 1.3%.
• Endometriosis is typically diagnosed in women aged 25-35 years, while ovarian cancer is more commonly detected in postmenopausal women, with a median age at diagnosis of 63. 

Both conditions present significant diagnostic challenges. Ovarian cancer is difficult to detect in its early stages due to the lack of specific symptoms and effective screening methods. 

Similarly, while endometriosis symptoms can be suggestive of the condition, the only way to definitively diagnose endometriosis is through surgery, typically a laparoscopy, where a surgeon can visually confirm and biopsy endometrial tissue growing outside the uterus.

These diagnostic challenges can impact patient care in different ways:

• For ovarian cancer: While more prevalent in older women, it can affect women of any age, making it crucial to evaluate persistent symptoms promptly, regardless of age.
• For endometriosis: Although symptoms may strongly suggest the condition, many patients face delays in receiving a definitive diagnosis due to the requirement for surgical confirmation.

This underscores the importance of awareness among both healthcare providers and patients and the need for careful evaluation of persistent gynecological symptoms, particularly in cases where endometriosis is suspected or ovarian cancer risk factors are present.

Recent research has also revealed critical immunological connections between endometriosis and ovarian cancer, particularly in the development of endometriosis-associated ovarian cancers (EAOCs). Studies show that endometriosis increases the risk approximately 3-fold for specific subtypes of epithelial ovarian carcinoma:

• Clear cell carcinoma
• Endometrioid carcinoma
• Low-grade serous tumors

The connection between endometriosis and low-grade serous tumors is a relatively recent finding. Unlike high-grade serous tumors (which show no association with endometriosis), low-grade tumors typically develop from a malignant transformation process. These tumors show distinct genetic patterns, with mutations in KRAS and BRAF genes and overexpression of hormone receptors, rather than the TP53 mutations commonly seen in high-grade serous carcinomas.

The underlying mechanisms linking these conditions involve:

• Chronic inflammation and oxidative stress, particularly from iron overload in endometriotic cysts.
• Hormonal factors, especially elevated estrogen activity.
• Immune system dysregulation, including altered macrophage function and inflammatory cytokine production.
• Shared genetic alterations, particularly in the ARID1A gene, in both atypical endometriosis and clear cell carcinoma.

These shared biological mechanisms help explain why certain types of ovarian cancers are more likely to develop in women with endometriosis, though the absolute risk remains relatively low.

Histological Subtypes of Ovarian Cancer Linked to Endometriosis

Endometriosis is most strongly associated with two subtypes of epithelial ovarian cancer: endometrioid and clear cell carcinomas. These subtypes are less common than high-grade serous ovarian cancer but tend to be diagnosed at an earlier stage.

Studies have shown that endometriosis-associated ovarian cancers may have a better prognosis than non-endometriosis-associated ovarian cancers. This may be due to the earlier stage at diagnosis and the favorable histological subtypes associated with endometriosis.

Latest Research on the Endometriosis and Ovarian Cancer Link

Recent research has revealed important breakthroughs in understanding the molecular and immunological connections between endometriosis and ovarian cancer, particularly in identifying potential ovarian cancer biomarkers and treatment targets.

Recent studies have provided key insights:

• Research has identified specific genes (ITGA7, ITGBL1, and SORBS1) that may help explain the invasive nature of endometriosis and its potential progression to cancer. These genes are involved in cell adhesion and share similar expression patterns in both conditions.
• Immunological studies have shown that both conditions share similar inflammatory responses and immune system mobilization. The chronic inflammation and oxidative stress in endometriosis, particularly from iron overload in endometriotic cysts, may contribute to cancer development.
• Investigation into tumor-associated macrophages (TAMs) has revealed their crucial role in both conditions, with M2 macrophages potentially contributing to disease progression and worse outcomes.
• A 2024 JAMA study found that women with endometriosis had a 4.2-fold higher overall ovarian cancer risk, with those having ovarian endometriomas and/or deep infiltrating endometriosis showing a dramatic 9.7-fold increased risk, particularly for type I ovarian cancers (endometrioid, clear cell, mucinous, and low-grade serous).

Ongoing Efforts to Unravel the Relationship 

Researchers are focusing on several promising areas:

• Studying the role of oxidative stress, inflammation, and hyperestrogenism in the development of endometriosis-associated ovarian cancers (EAOCs)
• Identifying biomarkers that could help detect premalignant lesions in endometriosis patients
• Exploring immunotherapy approaches, including targeting specific immune checkpoints and investigating anti-inflammatory agents
• Developing drugs that target shared molecular pathways between the two conditions

The key goal is to develop better interventions to decrease the incidence of EAOCs while improving treatments for both conditions. This includes finding non-invasive diagnostic methods and clarifying the genetic and environmental factors that influence disease progression.

The Importance of Early Detection and Prevention

Given the potential link between endometriosis and ovarian cancer, early detection and prevention strategies are crucial. Regular gynecologic exams and awareness of ovarian cancer symptoms can help detect the disease at an earlier, more treatable stage.

Currently, there is no recommended screening test for ovarian cancer in women with endometriosis. However, women with endometriosis should discuss their risk factors with their healthcare provider and develop a personalized monitoring plan.

Meanwhile, women with endometriosis who experience persistent or worsening symptoms should consult their healthcare provider promptly. Warning signs that may indicate ovarian cancer include: 

• Persistent bloating or abdominal distension
• Pelvic or abdominal pain
• Feeling full quickly or having difficulty eating
• Urinary changes, such as urgency or frequency

The Bottom Line on Endometriosis and Ovarian Cancer

While research has shown an association between endometriosis and ovarian cancer, it is essential to understand that the overall risk remains low. The majority of women with endometriosis will not develop ovarian cancer, and having endometriosis does not necessarily mean that a woman will develop ovarian cancer. 

Increased awareness and early intervention are crucial for both endometriosis and ovarian cancer. Women should be proactive about their gynecologic health, reporting any unusual symptoms to their healthcare provider and undergoing regular check-ups.

Non-profit organizations like Not These Ovaries work tirelessly to fund research and clinical trials to support ovarian cancer patients and improve outcomes. By raising awareness and supporting ongoing research efforts, we can work towards better prevention, early detection, and treatment strategies for both endometriosis and ovarian cancer.

In conclusion, while the link between endometriosis and ovarian cancer is a cause for concern, it is essential to approach the topic with a balanced perspective. By staying informed, engaging in open communication with healthcare providers, and supporting research efforts, women with endometriosis can take proactive steps to manage their health and well-being.