What is endometriosis?

Endometriosis is a chronic gynaecological condition where endometrial (uterus-like) tissue grows in other places, such as the ovaries, fallopian tubes, and tissue lining the pelvis (Figure 1). Normally, endometriosis tissue breaks down and sheds with each menstrual cycle, but if it grows in abnormal places, it can no longer shed.

This can cause cysts to develop in the ovaries, and surrounding tissue to become irritated. This leads to scar tissue formation, which can cause pelvic tissue and organs to stick together. Endometriosis is characterised by chronic pain, especially during your period, and can sometimes cause infertility. In the UK, around 1.5 million people assigned female at birth (AFAB) are living with endometriosis.

Figure 1: Illustration of endometriosis. (Image created in BioRender.com)

Causes of endometriosis 

Unfortunately, the exact cause of endometriosis is unclear. However, there are many theories and hypotheses as to the origin. Some of these are:¹

• Retrograde menstruation
• Genetic predisposition 
• Lymphatic or circulatory spread of endometrial tissue
• Immune dysfunction
• Environmental exposures
• Metaplasia - change from one cell type to another 

The most prevailing theory is retrograde menstruation. This is where menstrual blood flows backwards towards the fallopian tubes into the pelvic cavity, instead of out of the vagina. Most people AFAB experience retrograde menstruation but have a more efficient ability to clear the tissue and prevent deposition around organs than people with endometriosis.

Many healthcare providers believe retrograde menstruation puts individuals at a higher risk of endometriosis. However, it fails to explain why endometriosis has developed after a hysterectomy, or in people assigned male at birth (AMAB) who have been exposed to oestrogen through drug treatments.¹

Overview of cancer types associated with endometriosis

Some studies have linked endometriosis to an increased likelihood of developing different types of cancer. However, there is a difference in opinions as to the extent to which endometriosis impacts the risk of getting cancer.

Ovarian cancer

There are several types of epithelial ovarian cancers and only some are associated with an increased likelihood of endometriosis. The major subgroups of ovarian cancer are:²

• High-grade serous - sometimes known as high-grade carcinoma is the most common type of ovarian cancer and originates from the fallopian tube 
• Low-grade serous - sometimes known as low-grade carcinoma is a rare and slow-growing form that tends to affect younger people AFAB
• Endometrioid - accounts for approximately 20% of cases of ovarian cancer
• Clear cell - sometimes known as clear cell carcinoma is another rare type of ovarian cancer 
• Mucinous - these are benign (non-cancerous tumours)
• Undifferentiated/unclassified - doesn’t fit into any of the other categories 

Endometrioid and clear-cell ovarian cancers are associated with endometriosis. There is also some evidence to suggest low-grade serous ovarian cancer is linked to endometriosis. It has been found that atypical endometriosis, where cells appear enlarged or deformed, can be a precursor to these tumour types.³ Although the precise mechanism by which endometriosis leads to these types of epithelial ovarian cancer is still unclear, there are some indications of their origin. 

For example, endometrial cysts in the ovaries can develop into endometriosis-associated ovarian cancer.³ Only in 0.5-1% of cases do endometrial cysts develop into ovarian cancer.⁴ There have been several suggestions on how ovarian cysts become cancerous. These are based on their ability to damage DNA, a characteristic of cancer. These factors are:^3,4

• Oxidative stress
• Mutations (change) in DNA
• Microenvironmental factors, such as inflammation and tumour immunity 

A study analysing individuals' genomes (all their DNA) showed a genetic predisposition to endometriosis increases the risk of these ovarian cancers.⁵ Together, these different factors can increase the risk of ovarian cancer in people with endometriosis. However overall in the general population, there is a 1.3% chance an individual AFAB will develop ovarian cancer whereas the risk of ovarian cancer for people AFAB with endometriosis is 1.8%.⁶ Since the relative difference is small, and the likelihood is still relatively low, it shouldn’t be a major concern for people with endometriosis. 

Other gynaecological cancers

Endometriosis and endometrial cancer are two distinct conditions; in endometrial (uterus) cancer, the cells grow abnormally, and uncontrollably, unlike in endometriosis. Some studies have shown a link as people AFAB are more likely to experience endometrial cancer or breast cancer if they have endometriosis.⁷ It is difficult to say for sure if there is a direct link since many people AFAB with endometriosis may also happen to have cancer because they are both common conditions. This means it is often difficult to determine if the cancer was directly caused by endometriosis. 

Extra gynaecological cancers

Besides ovarian cancer, endometrial, and breast cancer, there is no strong evidence to suggest endometriosis is linked to any non-gynaecological cancers. However, the potential links highlight the importance of vigilance when watching out for symptoms of cancer particularly if you have endometriosis. 

Clinical implications

Since there is an association between endometriosis and ovarian cancer, treatment approaches for endometriosis must consider the potential cancer risk. It is important to attend regular screenings and implement early detection strategies. This may involve:

• Routine pelvic exams
• Transvaginal sonography
• Ultrasounds

This is especially important if you have a severe presentation of the disease, a long history of endometriosis or are above the age of 49. This is because age is a key predictor of malignant (cancerous) transformation of endometriosis with two-thirds of endometriosis-associated ovarian cancers being reported in individuals AFAB over 50.^8,9

Biomarkers, like CA-125 (proteins in the blood), are used to monitor for signs of ovarian cancer and the effectiveness of treatment. However, one study found for endometriosis-associated ovarian cancer, CA-125 levels do not indicate malignancy and CA-125 levels are at a normal level.¹⁰ This means CA-125 biomarkers shouldn’t be solely used for a definitive diagnosis of ovarian cancer in patients with endometriosis. Instead, other biomarkers or diagnostic techniques would be better to use.⁸ 

Sonography can be used to identify the nature of the ovarian cysts/tumours. This is significant as individuals with endometriosis-associated ovarian cancer have larger cysts with more solid components present than people AFAB with endometriosis whose cysts are benign.¹¹ Therefore if a patient has a tumour with these characteristics it indicates malignancy to your physician. 

Depending on whether the ovarian cyst is benign or malignant, different surgical removal strategies will be used. If benign, the cyst can be excised, and fertility is maintained using fenestration and laser ablation (a minimally invasive technique using lasers to destroy tumour cells). If the tumour is malignant it must be managed by complete salpingo-oophorectomy, whereby ovaries and fallopian tubes are removed. This is done to avoid the dissemination of malignant cells around the body, but compromises an individual’s fertility. Often, this requires referral to a centre specialised in gynaecologic oncology.¹²

Prevention strategies

Neither endometriosis nor ovarian cancer can be prevented, although there are some risk reduction strategies.

Ways to reduce the risk of ovarian cancer:

Oral contraception 

As well as reducing the risk of ovarian cancer, oral contraceptives lower oestrogen levels, which leads to shrinking of the endometrium tissue reducing pain from endometriosis. The combined oral contraceptive pill has been discussed as an early prevention strategy for adolescents with dysmenorrhoea (period pain), an indicator of early-onset endometriosis. Therefore, long-term use of oral contraceptives might be a suitable preventer of endometriosis-associated ovarian cancer by limiting the progression of endometriosis.⁹

However, it is also known that long-term use of oral contraceptives increases the risk of breast cancer, especially if you have a family predisposition. This is why using oral contraception is an individualistic decision that you should discuss with your physician to weigh up the benefits and risks.

Pregnancy

Having more children has been suggested to reduce the risk of ovarian cancer, especially if you give birth under the age of 26. The risk is hypothesised to decrease with pregnancy as pregnant people typically do not ovulate (releasing eggs). However, more research is required to confirm this link.

Breastfeeding

Breastfeeding is also associated with a lower risk of ovarian cancer. The longer a person AFAB breastfeeds the lower the risk of developing ovarian cancer. Again, this is thought to occur due to the delay in ovulation.

Nevertheless, it is important to note, that these prevention strategies are not specific to endometrioid and clear cell epithelial ovarian cancer, and so may not specifically reflect the chance of endometriosis becoming cancerous. Moreover, pregnancy and breastfeeding will not completely guarantee you will not develop ovarian cancer.

Arguably, the most important preventive strategy is the early detection of cancer. As previously mentioned, it is crucial for people AFAB to attend regular checkups and be aware of the symptoms of cancer, especially if they have endometriosis. 

Summary 

Endometriosis has been linked to an increased risk of epithelial ovarian cancer, in particular endometrioid and clear cell ovarian cancer. While the general population has a 1.3% risk of ovarian cancer, people AFAB with endometriosis have a 1.8% risk. Regular screenings and early detection strategies are essential for managing this risk. Preventative measures include oral contraception, which reduces endometriosis symptoms and ovarian cancer risk. Although endometriosis increases the risk, it is still relatively low, and not much greater than the general population, so it doesn’t pose a major concern to individuals with endometriosis.