Friday, June 11, 2010

The Link Between Endometriosis and Cancer

Endometriosis and Cancer Risk

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.

"We've got pretty good evidence that there's some increase in the risk for ovarian cancer" with endometriosis, said Louise Brinton, PhD, Chief of the Hormonal and Reproductive Epidemiology branch at the National Cancer Institute, in an interview with Medscape following the session. "But there are still other cancers that need further study."

Dr. 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.

"We found an increased risk for tumors with increasing years of follow-up," said Dr. Brinton, "making 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.

"The 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," said Dr. Brinton. 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.

Farr Nezhat, MD, Chief of Gynecologic Minimally Invasive Surgery and Robotics at St. Luke's and Roosevelt Hospitals in New York City and Professor of Obstetrics and Gynecology at Columbia University, spoke on the pathogenesis of endometriosis and ovarian cancer. Dr. Nezhat also cited research on 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.

Dr. Nezhat's own research with Liane DeLigdisch 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
What do endometriosis and ovarian cancer have in common? A lot, it turns out.

"Both of these diseases are progressive and depend on estrogen for their growth," said Dr. Nezhat. 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. "We know that inflammation can cause cancer, as in hepatitis of the liver and asbestosis of the lung," said Dr. Nezhat. Endometriosis is characterized by a chronic inflammatory state, which leads to the release of cytokine. These cytokines may promote the growth of tumors by causing unregulated mitotic division, growth, and differentiation.

"If you combine inflammation with estrogen, it's going to be a vicious circle," said Dr. Nezhat.

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 Dr. Nezhat said 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. "Endometrial implants produce estrogen and inflammation," he said. "So if you remove the endometriosis, you should theoretically reduce the risk for cancer."

Advice to Surgeons and Patients
Dr. Nezhat said that 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. "Do an ultrasound during the preoperative evaluation and during the follow-up," he told Medscape. He also cautioned surgeons to biopsy any ovarian cysts instead of draining them. "Every adnexal mass has to be thoroughly evaluated," he said.

Although the elevated risk for ovarian cancer appears to be real, Dr. Brinton emphasized that women with endometriosis should not become anxious about it. "Even though we see a 2- to 3-fold increase in the risk for ovarian cancer, it's still a very rare condition," she said. "The absolute risk is low."