Women with endometriosis appear to be more likely to develop certain types of cancer. What scientists know about the link - and why it might occur - were the focus of a session at the inaugural symposium of the Endometriosis Foundation of America. Chief of the Hormonal and Reproductive Epidemiology branch at the National Cancer Institute, Louise Brinton’s interest in the long-term effects of endometriosis led her to Sweden about 20 years ago. Using the country's national inpatient register, she identified more than 20,000 women who had been hospitalized for endometriosis. After an average follow-up of more than 11 years, the risk for cancer among these women was elevated by 90% for ovarian cancer, 40% for hematopoietic cancer (primarily non-Hodgkin's lymphoma), and 30% for breast cancer. Having a longer history of endometriosis and being diagnosed at a young age were both associated with increased ovarian cancer risk.
An increased risk for tumors with increasing years of follow-up was found. This made it unlikely that the ovarian cancer diagnoses were related to increased surveillance during endometriosis treatment. Also of special interest was the finding that women whose site of origin of endometriosis was the ovary had a particularly high risk for ovarian cancer. Dr. Brinton and colleagues published their research in 1997. A larger, more recent examination of the Swedish register, published in 2006 by Anna-Sofia Melin and colleagues, produced similar results.
These 2 studies indicate a high risk related to follow-up time and site of origin of endometriosis, which suggests a biologic effect between the 2 diseases. On the other hand, confounding factors could be at work. For example, women being treated for endometriosis are more likely to be experiencing infertility, which affects risk because childbearing offers some protection against ovarian cancer. A 2002 pooled case-control study by Roberta B. Ness and colleagues found that the odds of developing ovarian cancer were 50% higher among women diagnosed with endometriosis, even after adjusting for factors such as duration of oral contraception use and number of births. The risk was even higher -- a 3.5-fold increase -- for women with endometrioid or clear cell tumors, 2 subtypes of ovarian cancer. A 2005 case-control study by Brinton and colleagues also found a 2.5- to 3.5-fold increase in endometrioid and clear cell tumors among women with endometriosis.
The overall lifetime risk for ovarian cancer is 1.4%, according to the American Cancer Society. Endometriosis affects as many as 7% to 15% of women of reproductive age. Regarding the link between epithelial ovarian cancer and endometriosis, according to a 2000 study of women with ovarian cancer by Hiroyuki Yoshikawa and colleagues, endometriosis was present in 39% of the women with clear cell tumors and 21% of those with endometrioid tumors, vs just 3% of those with serous or mucinous tumors. Nezhat and colleagues also identified a link between endometriosis and ovarian cancer. A pathology review of samples from 76 patients with stage 1 ovarian cancer revealed that most were associated with endometriosis or endometrioma. Most patients presented with pelvic pain or adnexal mass, supporting the idea that healthcare providers should be alert to the possibility of ovarian cancer in women with a history of endometriosis.
Studies have been inconsistent on whether endometriosis is linked to breast cancer or non-Hodgkin's lymphoma. Anecdotal evidence has linked endometriosis to melanoma, brain and endocrine cancers, and thyroid cancer. Large epidemiologic studies are required to examine these associations.
The Pathogenesis of Endometriosis and Cancer
Both endometriosis and ovarian cancer are progressive diseases and depend on estrogen for their growth. Studies have shown that endometrial tissue shows elevated activity of aromatase, an enzyme used for a key step in the biosynthesis of estrogens.
Another factor that appears to play a role in both diseases is inflammation. Inflammation can cause cancer, as seen in hepatitis of the liver and asbestosis of the lung. Endometriosis is characterized by a chronic inflammatory state, which leads to the release of cytokine. These cytokines may promote the growth of tumours by causing unregulated mitotic division, growth, and differentiation. The combination of inflammation with estrogen can be a vicious circle.
The 2 diseases share numerous other characteristics. For example, both are related to early menarche and late menopause, infertility, and nulliparity. Factors that relieve or offer protection against both conditions include tubal ligation, oral contraceptives, hysterectomy, and progesterone exposure.
Mutations in genes that are known to suppress tumors, such as PTEN, p53, and bcl, have been found in both ovarian tumors and adjacent endometriotic lesions.
Of course, links between the 2 diseases don't prove that one causes the other. But there's reason to believe that endometriosis contributes to ovarian cancer, as evidenced by Dr. Brinton's finding that cancer risk increases with duration of endometriosis. If endometriosis does increase the risk for ovarian cancer, then treating it might reduce the risk
Advice to Surgeons and Patients
Surgeons who operate on women with endometriosis, which includes fertility specialists performing in vitro fertilization (IVF), need to be alert to the possibility of ovarian cancer. Ultrasound scanning should be carried out during the preoperative evaluation and the follow-up. Surgeons are also cautioned to biopsy any ovarian cysts instead of just draining them. Every adnexal mass has to be thoroughly evaluated.
Although the elevated risk for ovarian cancer appears to be real, women with endometriosis should not become too anxious about it. Even though a 2- to 3-fold increase in the risk for ovarian cancer is noted, it's still a very rare condition with the absolute risk being low.
References1. Brinton LA, Gridley G, Persson I, Baron J, Bergqvist A. Cancer risk after a hospital discharge diagnosis of endometriosis. Am J Obstet Gynecol. 1997;176:572-529. Abstract
2. Melin A, Sparén P, Persson I, Bergqvist A. Endometriosis and the risk of cancer with special emphasis on ovarian cancer. Hum Reprod. 2006;21:1237-1242. Abstract
3. Ness RB, Cramer DW, Goodman MT, et al. Infertility, fertility drugs, and ovarian cancer: a pooled analysis of case-control studies. Am J Epidemiol. 2002;155:217-224. Abstract
4. Brinton LA, Sakoda LC, Sherman ME, et al. Relationship of benign gynecologic diseases to subsequent risk of ovarian and uterine tumors. Cancer Epidemiol Biomarkers Prev. 2005;14:2929-2935. Abstract
5. US National Institutes of Health. National Cancer Institute Fact Sheet. BRCA1 and BRCA2: cancer risk and genetic testing. Available at: http://www.cancer.gov/cancertopics/factsheet/Risk/BRCA Accessed May 24, 2010.
6. Yoshikawa H, Jimbo H, Okada S, et al. Prevalence of endometriosis in ovarian cancer. Gynecol Obstet Invest. 2000;50(suppl 1):11-17. Abstract