Ovarian cancer is said to “whisper,” because the symptoms are seldom obvious. The most frequent symptoms seen in women diagnosed with ovarian cancer are abdominal bloating, pelvic or abdominal pain, difficulty eating/feeling full fast, or urinary symptoms. These are often passed off as nothing other than symptoms of getting older, gaining weight, or related to menopause. However, this whispering disease is the most lethal of all the breast and gynecologic cancers and accounts for more deaths than any other cancer of the female reproductive system.1
The American Cancer Society estimates that about 22,280 women will be diagnosed with ovarian cancer in 2012, and 15,500 women will die of ovarian cancer.1 Approximately 75% of women will survive 1 year after diagnosis and treatment. The 5-year survival rate is 46%, an increase of less than 10% since 1974, when the survival rate was 37%. Those diagnosed at an early stage (stage I) have a 5-year survival rate of 94%; however, only about 15% of all ovarian cancers are diagnosed at this early stage.
One in 71 women will have a diagnosis of ovarian cancer in her lifetime, representing about 3% of all cancers that occur in women. It is the ninth most frequent type of cancer diagnosed in American women (Table 1). Ovarian cancer is more common in women over 50 to 60 years of age (depending on the source), and uncommon in women younger than 40 years.
Types of Ovarian Cancer
Epithelial ovarian cancer is the most frequently diagnosed type of ovarian cancer, accounting for approximately 90% of ovarian cancers.2 The epithelium is the covering of the ovary. As the tumor grows on the surface of the ovary and becomes larger, it can shed cells like seeds directly into the abdominal cavity, a process called seeding. The shed cells can implant or seed themselves into other tissue and organs in the abdominal and pelvic cavities and form new tumors in these sites.
Germ cell ovarian tumors grow in the egg-producing cells of the ovary. These tumors are uncommon, seen approximately 5% of the time, and often benign. Germ cell tumors occur most often in girls, teenagers, and young women. If the germ cell tumor is cancerous, a high percentage of patients can be cured with surgery and chemotherapy.
Sex cord tumors form in the connective or stromal tissue cells of the ovaries. Sex cord tumors generally occur in women younger than 40 years but can occur in older women. These tumors are generally slower growing and do not spread rapidly.
Risk Factors of Ovarian Cancer
Although the causes of epithelial ovarian cancer are still being uncovered, researchers have identified a number of factors that increase a woman’s odds of developing epithelial ovarian cancer. Much less is known about risk factors for germ cell and stromal tumors.
Risk factors for epithelial ovarian cancer can be divided into 3 categories: genetic factors, age, and hormonal/reproductive factors.
Genetic Risk Factors
The most significant risk factor for ovarian cancer is having an inherited mutation in 1 or both of 2 genes called breast cancer gene 1 (BRCA1) and breast cancer gene 2 (BRCA2). These genes were originally identified in families with multiple cases of breast cancer, which is how they got their name; they are responsible for about 10% of ovarian cancers.3
The second genetic link that increases the risk of developing ovarian cancer involves an inherited syndrome called hereditary nonpolyposis colorectal cancer (HNPCC). Individuals in HNPCC families are at increased risk for cancers of the uterus, colon, ovary, stomach, and small intestine.
Age as a Risk Factor
The risk of ovarian cancer increases with age, with a median age at diagnosis of 63 years.1
Hormonal and Reproductive Risk Factors
One of the leading causation theories of ovarian cancer is that of incessant ovulation.3 When the ovum leaves the ovary during the ovulatory cycle, there is an increased risk of wounding to the epithelial layer of the ovary. The more ovulatory cycles that occur, the greater the chance for a mutation to occur in the epithelial cells. Under this causative theory, early menstruation, late menopause, and nulliparity would increase a women’s risk of ovarian cancer, while late menstruation, early menopause, pregnancy and breast-feeding, and use of oral contraceptive medication would be protective.
Pituitary gonadotropin hormones are also thought to affect the risk of ovarian cancer. This theory submits that during ovulation there is a surge of hormones produced by the pituitary gland, which in turn increase the stimulation of estrogen.3 This increase in estrogen can affect the epithelial cells of the ovary, causing them to develop into inclusion cysts that may transform into cancerous tumors.3
Decreasing of Risk of Ovarian Cancer
Protective Factors
Several factors are seen to protect a woman against ovarian cancer. The risk of ovarian cancer is decreased at a rate of 12% for every pregnancy. Also, if the last birth is between the ages of 30 and 35 years, a woman’s risk of ovarian cancer can be reduced by as much as 58% compared with a woman who has never been pregnant.3
Women who have breast-fed their babies for 18 months or more have a reduced risk of ovarian cancer due to the suppression of ovulation, resulting in a decrease in the gonadotropin levels.
Tubal ligations may alter growth factors and hormonal levels, thereby decreasing the risk of epithelial ovarian cancers, as well as preventing carcinogens and inflammatory factors from reaching the ovary from the uterus. Likewise, a hysterectomy decreases the risk of ovarian cancer, with the added benefit of making it easier to examine the ovaries during the pelvic examination.
Progesterone plays a role in the risk of ovarian cancer. When a woman experiences a higher level of progesterone, either through pregnancy or the use of oral contraceptive pills, it is thought to cause a change in the cell cycle and induce apoptosis of the cells of the epithelium of the ovary. The protection offered by the increase in progesterone is thought to last long after the progesterone levels return to normal.3
Available Screening Tests for Ovarian Cancer
A number of screening tests have been evaluated, and the 2 that have remained and are consistently referenced in the literature are the CA125 blood test and the use of transvaginal ultrasound (TVU).
CA125 tests for a protein produced by the cancerous epithelial cells of the ovaries. Approximately 90% of women with epithelial ovarian cancer have an elevation of this marker. Unfortunately, in the majority of these women the cancer is at an advanced stage when diagnosed. Studies have also shown that CA125 is not a reliable marker for ovarian cancer, as it can be elevated in 2% to 3% of the postmenopausal population who do not have ovarian cancer. Many factors can cause a rise in CA125, including inflammation of the peritoneum, pelvic infection, or another cancer.4
TVU has proven to be the most promising imaging test to screen for ovarian cancer. There is some indication that the combination of the CA125 blood test and the TVU may have increased sensitivity.4
Organizational Recommended Screening Guidelines for Ovarian Cancer
A number of guidelines for ovarian cancer screening have been published. There is agreement among these bodies that there is insufficient evidence to indicate that routine screening of the general public will result in fewer deaths from ovarian cancer. There are, however, indications for scheduled screening for those at an increased risk of developing ovarian cancer. Table 2 provides a summary of the most recent guidelines.5-11
National Comprehensive Cancer Network (NCCN) Recommendations
The NCCN defines women at high risk for developing ovarian cancer as those who have a family history of ovarian cancer, a BRCA mutation, or a personal history of breast cancer. It recommends that these women begin screening between the ages of 30 and 35 or 5 to 10 years before the age when a family member was diagnosed with ovarian cancer. Screening should be done every 6 months utilizing a combination of CA125 and TVU. The NCCN also recommends that high-risk women consider a prophylactic salpingo-oophorectomy at the completion of childbearing.5
National Cancer Institute Recommendations
The National Cancer Institute has made the following statement of benefit: There is inadequate evidence to determine whether routine screening for ovarian cancer with the serum marker CA125, TVU, or pelvic examinations would result in a decrease in mortality from ovarian cancer.6
US Department of Health & Human Services Recommendations
The US Department of Health & Human Services guidelines are evidence-based, using the American College of Radiology and the Scottish Intercollegiate Guidelines Network guidelines.7
The US Department of Health & Human Services is in agreement with the NCCN that there is insufficient evidence to recommend routine screening for ovarian cancer for the general population and that a prophylactic oophorectomy should be considered when childbearing is no longer desired. For women at high risk for developing ovarian cancer, preventive counseling should be started in their early 20s by a gynecologic oncologist or geneticist. The benefits of oral contraceptive use and genetic testing should be addressed and considered.
US Preventive Services Task Force Recommendations
The US Preventive Services Task Force recommendations found that while screening for ovarian cancer using TVU and CA125 would be beneficial for women determined to be at high risk for ovarian cancer, the risks outweigh the benefits for those who have no signs or symptoms.8
Memorial Sloan-Kettering Cancer Center Recommendations
Memorial Sloan-Kettering Cancer Center has posted detailed recommendations for ovarian cancer screening. It divided high-risk women into 2 groups: (1) those with a 3 to 6 times increased risk, and (2) those with a known genetic mutation, and provided recommendations for each group.9
American College of Obstetricians and Gynecologists (ACOG) Recommendations
ACOG does not recommend routine screening for ovarian cancer in women who are at low risk of developing ovarian cancer.10 However, in women who are at high risk for developing ovarian cancer, screening is recommended utilizing CA125 and TVU.10 Women at high risk are defined as those who are of Ashkenazi Jewish descent, have a BRCA1 or BRCA2 mutation, or have a family history suggestive of a hereditary cancer syndrome.11 Screening should begin between the ages of 30 and 35 years and take place every 6 months. If the woman has a relative with ovarian cancer, screening should begin 5 to 10 years before the age of diagnosis of that family member.11
New Research Recommendations
Two screening trials show benefits in terms of diagnosing ovarian cancer at an earlier stage. However, survival benefits of an earlier diagnosis are yet to be seen.
PLCO Screening Recommendations
A large screening trial called the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial took place across the United States between November 1993 and July 2001. It randomized 78,216 women, aged 55 to 74 years, to undergo usual care or annual screening. The screening arm included TVU at the time of the initial examination, followed by annual TVU for a length determined by the study. The screening arm also specified yearly CA125 drawn for 4 years. The usual care group underwent a routine pelvic examination with palpation of the ovaries. Buys and colleagues recently published the long-term results of the trial.12 In the intervention group, 212 ovarian cancers were diagnosed, with 118 deaths as a result of ovarian cancer. In the usual care group, 176 ovarian cancers were diagnosed, with 100 deaths. There was no statistically significant difference in overall survival between the groups. There was very little difference in the stage of ovarian cancer being diagnosed between the groups. In the screening arm, 69% of the cancers were diagnosed at a late stage versus 78% in the usual care group.12 The authors concluded that screening did not impact survival.
University of Kentucky Ovarian Cancer Screening Trial
The University of Kentucky Ovarian Cancer Screening Trial resulted in an algorithm used to determine the screening and frequency of tests based on outcome after 37,293 women were screened between January 1987 and June 2011.13
Using the algorithm, 47 invasive epithelial ovarian cancers and 15 borderline tumors (also referred to as tumors of low malignant potential) were detected.
Of the 47 patients diagnosed with invasive cancer, 70% had early-stage disease (stage I or II), and 30% had advanced-stage (stage III). In contrast, of the 2560 unscreened women who were diagnosed and entered into the Kentucky Tumor Registry during this time, 27% had stage I/II disease, and 46% had stage III disease. The screening group also had advanced-stage cancer diagnosed at stage IIIA and IIIB more consistently than the control group, which tended to have a higher incidence of stage IIIC ovarian cancer.13 The authors concluded that using an algorithm to determine screening can result in ovarian cancers being detected at an earlier stage, which will hopefully lead to an overall survival benefit.
Conclusion
The ability to effectively screen for ovarian cancer remains elusive. The sensitivity and specificity of our current screening methods, either CA125 or TVU, remain too low to achieve meaningful benefit for early diagnosis or reduction in mortality. Recent research studies utilizing CA125 and TVU together as a multimodal screening program, taking into account other risk factors such as age, parity, and family history, may lead to an algorithm that will result in more cancers being detected at an early stage. It has yet to be determined if detecting ovarian cancer at an earlier stage will lead to a statistically significant increase in overall survival.
References
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