Notable advances in chemotherapy and surgery over the past several decades have begun to translate into improved survival. According to American Cancer Society data, the overall 5-year survival rate from ovarian cancer has increased significantly, from 37% in the mid-1970s to 46% in the mid-2000s ( P < .05). Recent data from the National Cancer Institute show a similar increase in stage-specific survival. It is expected that data from the current decade, reflecting continued improvements in chemotherapy and surgery, will continue this trend.
This chapter will focus on epithelial cancers of the ovaries, which account for about 90% of ovarian malignancies.
Epidemiology
Age Ovarian cancer is primarily a disease of postmenopausal women, with the large majority of cases occurring in women between 50 and 75 years old. The incidence of ovarian cancer increases with age and peaks at a rate of 61.5 per 100,000 women in the 75–79-year-old age group.
Race The incidence of ovarian cancer appears to vary by race, although the effects of race are difficult to separate from those of environment related to culture, geography, and socioeconomic status. In the United States, the age-adjusted rate of ovarian cancer for Caucasians is estimated to be 17.9 per 100,000 population, which is significantly higher than 11.9 per 100,000 for the African-American population.
Geography There are distinct geographic variations in the incidence of ovarian cancer, with the highest rates found in industrialized countries and the lowest rates seen in underdeveloped nations. Japan, with an incidence of only about 3.0 per 100,000 population, is a notable exception to this observation. It has been postulated that geographic variations in the incidence of ovarian cancer are related, in part, to differences in family size.
Some of the highest rates are seen in women of Eastern European Jewish ancestry, who have an estimated incidence of 17.2 per 100,000 population, a probable result of the relatively high frequency of BRCA1 and BRCA2 mutations in this population.
Etiology and risk factors
The cause of epithelial ovarian cancer remains unknown. Although it now appears certain that, at the cellular level, ovarian cancer results from the accumulation of multiple discrete genetic defects, the mechanism(s) by which these defects develop have yet to be determined. Epidemiologic studies have identified a number of factors that may increase or decrease the risk of the disease. In addition, a small proportion of ovarian cancers in the United States, approximately 5% to 10%, result from inherited defects in the BRCA1 gene or other genes, including BRCA2 and the hereditary nonpolyposis colorectal cancer (HNPCC) genes.
Diet It has been suggested that numerous dietary factors increase the risk of ovarian cancer, although the magnitude of the reported increase is relatively modest.
A low-fat diet may reduce the incidence of ovarian cancer among postmenopausal women.
Populations with a high dietary intake of lactose who lack the enzyme galactose-1-phosphate uridyltransferase have been reported to be at increased risk.
Conflicting reports have been published regarding the role of coffee consumption and the risk of ovarian cancer.
Environmental factors Various environmental risk factors also have been suggested.
Exposure to talc (hydrous magnesium trisilicate) used as dusting powder on diaphragms and sanitary napkins has been reported in some studies to increase the risk of ovarian cancer, although other studies have failed to find an association.
No association between exposure to ionizing radiation and the risk of ovarian cancer has been documented.
Several studies have examined the effect of viral agents, including mumps, rubella, and influenza viruses, on the risk of ovarian cancer. No clear relationship has been demonstrated.
Physical activity may decrease the risk of ovarian cancer.
Hormonal and reproductive factors In contrast to the conflicting data on dietary and environmental factors, some clear associations have been drawn between certain hormonal and reproductive factors and the risk of developing ovarian cancer.
Several analyses have documented that women with a history of low parity or involuntary infertility are at increased risk of ovarian cancer.
Tubal ligation significantly decreases the risk of ovarian cancer, as demonstrated by several epidemiologic studies.
Evidence suggests that treatment with ovulation-inducing drugs, particularly for prolonged periods, may be a risk factor, although it is difficult to separate the increased risk related to the infertility itself from the risk carried by use of ovulation-inducing agents.
Breastfeeding for long durations may decrease ovarian cancer risk.
Although the data are not consistent, some studies have shown an association between the use of postmenopausal hormone replacement and the development of ovarian cancer. Data from the Women's Health Initiative randomized trial of estrogen plus progestin showed a slight increase in the risk of ovarian cancer in users of hormone replacement therapy, although it was not statistically significant.
Several large case-controlled studies have documented a marked protective effect of oral contraceptives against ovarian cancer. Women who have used oral contraceptives for at least several years have approximately half the risk of ovarian cancer as do nonusers, and the protective effect of oral contraceptives appears to persist for years after their discontinuation. It is estimated that the routine use of oral contraceptives may prevent nearly 2,000 cases of ovarian cancer yearly in the United States. Evidence suggests that the protective effect of oral contraceptives also applies to women carrying BRCA mutations.
Hereditary cancer syndromes There has been a fascinating evolution in our understanding of the role of hereditary factors in the development of ovarian cancer. It has been recognized for many years that women with a family history of cancer, particularly cancer of the ovaries or breasts, are themselves at increased risk of ovarian cancer. In the 1980s, Lynch and colleagues refined these observations by delineating several apparently distinct syndromes of hereditary cancer involving the ovaries, including breast-ovarian cancer syndrome, site-specific ovarian cancer syndrome, and Lynch II syndrome (HNPCC).
Epidemiologically, these syndromes appear to be inherited as an autosomal-dominant trait with variable penetrance. During the past decade, the specific genes responsible for HNPCC (MSH1 and MLH2) and for most cases of hereditary ovarian cancer have been identified, allowing fundamental observations to be made regarding their molecular pathophysiology.
The BRCA1 gene is classified as a tumor suppressor, since mutations in this gene increase the risk of breast and ovarian cancers. Definitive identification of the function of the protein translated from this gene remains to be elucidated, although evidence suggests that it plays a role in the repair of oxidative damage to DNA. Part of the protein appears to contain a DNA-binding domain, suggesting that it also functions as a transcriptional regulator.
The frequency of BRCA1 mutations in the general population is estimated at approximately 1 in 800, and in Jewish women of Eastern European descent, 1 in 100.
Women carrying a germline mutation of BRCA1 have a significantly elevated risk of both breast and ovarian cancers compared with the general population. The average population risk of developing breast cancer is about 12.5% (one in eight) and of developing ovarian cancer, 1.5%. However, in the presence of a germline BRCA1 mutation and a strong family history of cancer, these risks rise to about 90% and 40% for breast and ovarian cancers, respectively.
It is important to recognize that these risk estimates are derived from families identified with multiple cases of breast and/or ovarian cancer. The risk for women with BRCA1 mutations from families with less impressive family histories is probably lower for ovarian cancer, perhaps in the range of 15% to 20%.
Although the presence of germline mutations in BRCA1 is not limited to women with a strong family history of breast cancer, data from several laboratories suggest that BRCA1 mutations usually are not a feature of sporadic ovarian cancer. Mutations in this gene appear to play a role in the development of approximately 50% of familial breast cancer cases and may account for the majority of hereditary ovarian cancers. Evidence from multiple studies suggests that BRCA1-related ovarian cancers may have a less aggressive clinical course than do sporadic ovarian cancers.
Hereditary ovarian cancers not related to BRCA1 are most often related to mutations in the BRCA2 gene.
For patients having a BRCA1 or BRCA2 mutation, laparoscopic prophylactic risk-reducing salpingo-oophorectomy after childbearing can reduce the risk of both breast and ovarian carcinomas.
Signs and symptoms
Early-stage disease In the early stages, ovarian cancer may be an insidious disease, but nonspecific symptoms that may be clues to the diagnosis are present more often than previously thought. A case-controlled series by Goff et al proposed that a symptom index could be devised which might suggest a diagnosis of ovarian cancer. It was based on the presence of any of the following symptoms more than 12 times in a given month, but with overall duration less than 1 year. When these criteria were met, the specificity for a diagnosis of ovarian cancers was 90% for women > 50 years of age.The symptoms were pelvic/abdominal pain, urinary frequency, increased abdominal size, and difficulty eating (feeling full). This illustrates the diffuse nature of ovarian cancer symptoms, and taken alone will not yield early diagnosis in most patients. Thus, more than 70% of patients with ovarian cancer will present with disease beyond the confines of the ovaries at initial diagnosis.
The impact of screening patients with serum CA-125 levels and transvaginal ultrasonography on mortality is being addressed in the PLCO Trial. In this study, 39,115 women were randomized to undergo screening. To date, screening has identified both early- and late-stage cancers, and the predictive value is low (3.7% for abnormal CA-125 levels, 1.0% for abnormal transvaginal ultrasonography, and 23.5% for both). Follow-up is ongoing to determine whether there is an effect on mortality.
Early ovarian cancer also may be detected as a pelvic mass noted fortuitously at the time of a routine pelvic examination. Imaging with sonography, CT, or MRI will confirm the presence of a mass. The size, internal architecture, and blood flow of the mass can be used to make an educated guess as to whether it is benign or malignant, but imaging findings are not diagnostic in this regard. Approximately 50% of patients with early ovarian cancers have an elevated serum CA-125 level.
b Patients may complain of abdominal bloating or swelling if ascites is present, and large pelvic masses may produce bladder or rectal symptoms. Occasional patients may have respiratory distress as a result of a large pleural effusion, which is more common on the right side. Infrequently, there may be a history of abnormal vaginal bleeding.
Most patients with advanced disease have ascites detectable by physical examination or imaging. Complex pelvic masses and an omental tumor cake may be present, and nodules can frequently be palpated in the pelvic cul-de-sac on rectovaginal examination. It should be noted that some patients with advanced ovarian cancer have essentially normal-sized ovaries. Approximately 80% of patients with advanced ovarian cancer will have an elevated serum CA-125 level.
Screening and diagnosis
Screening Unfortunately, no effective strategy exists for screening of the general population for ovarian cancer. Imaging techniques, including abdominal and transvaginal sonography, have been studied extensively, as has the serum marker CA-125. None of these techniques, alone or in combination, is specific enough to serve as an appropriate screening test, even in populations targeted by age.
Both the National Institutes of Health Consensus Conference (see full page of NIH guidelines) and the American College of Obstetricians and Gynecologists have issued statements advising against routine screening for ovarian cancer, which, due to its high false-positive rate, leads to an unacceptable amount of invasive interventions in women without significant disease.
In September 2009, the FDA approved a test called OVA1 as an adjunct to other clinical and radiographic tests to help detect ovarian cancer. OVA1 uses a blood sample to test for levels of five proteins that change due to ovarian cancer. The test combines the five separate results into a single numerical score between 0 and 10 to indicate the likelihood that a pelvic mass known to require surgery is benign or malignant. Approval of OVA1 was based on the FDA's review of a study of 516 patients that compared OVA1 results with biopsy results. A total of 269 of these patients were evaluated by non-gynecologic oncologists. Results of the study also indicated that OVA1 may help identify patients who might benefit from referral to a gynecologic oncologist. The study was presented earlier in 2009 at a meeting of the Society of Gynecologic Oncologists (Ueland F et al: Gynecol Oncol 116[suppl 1]:S23, 2010).
The NIH PLCO Screening Trial accrued its full complement of 152,000 patients in 2001. For the ovarian cancer segment of the trial, half of the women are being screened via physical examination, CA-125 level, and vaginal ultrasonography, and the other half, via standard medical care. Since patients will be followed for 13 years or more, final results are not yet available. It is not expected that these screening modalities will have a significant impact on the general population.
Recent studies using serum proteomics to screen for early ovarian cancer have yielded disappointing results. Work in this area is ongoing and may result in a clinically useful assay.
Management of women from families with hereditary ovarian cancer is controversial. Evidence suggests that surveillance of such women with serum markers and sonography is of limited benefit in early detection of ovarian cancer. Most experts recommend prophylactic laparoscopic excision of the ovaries and fallopian tubes after age 35 if the woman has completed childbearing, as several studies have shown that it will dramatically reduce the risk of ovarian cancer. Evidence also suggests that prophylactic oophorectomy substantially lowers the risk of breast cancer in women from high-risk families.
Patients with suspected ovarian cancer should undergo a thorough evaluation prior to surgery. This assessment should include a complete history and physical examination and serum CA-125 level determination. In women younger than age 30, determinations of β-human chorionic gonadotropin (-hCG) and α -fetoprotein (AFP) levels are useful, as germ-cell tumors are more common in this age group.
Abdominal CT and MRI In apparent early-stage cases, abdominal scanning by CT or MRI adds little to the diagnostic evaluation, and, thus, these studies are not routinely necessary. CT and MRI may be useful in providing a preoperative assessment of disease extent in probable advanced-stage cases.
Exploratory laparotomy The diagnosis of ovarian cancer is generally made by histopathologic study following exploratory laparotomy. The stage of the disease can only be determined by surgery, as discussed later.
Preoperative endometrial sampling Women with abnormal vaginal bleeding should undergo preoperative endometrial sampling.
Preoperative cytologic or histologic evaluation of effusions or tumor masses is neither necessary nor desirable. Often, patients with ascites and large pelvic masses, for whom exploration is necessary, are subjected to paracentesis or needle biopsy. These procedures only delay definitive management and may lead to seeding of tumor cells along needle tracks.