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 (NIH) 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, because of its high false-positive rate, leads to an unacceptable amount of invasive interventions in women without significant disease.
In September 2009, the Food and Drug Administration (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 in women with 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).
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, because 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 before surgery. This assessment should include a complete history and physical examination and serum CA-125 level determination. In women younger than 30, determinations of β-human chorionic gonadotropin and α-fetoprotein levels are useful, because germ cell tumors are more common in this age-group.
Sidebar: The NIH Prostate, Lung, Colorectal, and Ovarian (PLCO) cancer screening trial was reported in an oral presentation at the 2011 American Society of Clinical Oncology (ASCO) Annual Meeting. The study screened 78,216 patients with ovarian cancer by obtaining CA-125 levels annually for 6 years and transvaginal ultrasonograms annually for 4 years. The study had 88% power to detect a 35% reduction in mortality. With regard to incidence, there were 212 cases in the intervention arm vs 176 cases in usual-care arm (rate ratio = 1.21; 95% confidence interval [CI], 0.99–1.48). With regard to mortality, there were 118 deaths in the intervention arm vs 100 deaths in usual-care arm (rate ratio = 1.18; 95% CI, 0.91–1.54). Screening with this strategy (limiting screening to 6 years and using a CA-125 cutoff rather than trend) did not reduce mortality and 166 of 3285 patients who required surgery for a false-positive examination had at least one serious adverse event, illustrating harm from false-positive screens (Buys SS et al: J Clin Oncol 29(s):abstract 5001, 2011).
Abdominal CT and MRI
CT or 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
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.
Pathology
The ovaries are notable for their ability to give rise to a large variety of neoplasms with distinct embryologic origins and differing histologic appearances.
Epithelial Adenocarcinoma
Approximately 90% of all ovarian malignancies are of epithelial origin, arising from the cells on the surface of the ovaries. These cells give rise to a variety of adenocarcinomas, including serous, mucinous, endometrioid, and clear-cell types. These tumors have benign counterparts of similar histologic appearance and can also exist as "borderline" cancers, also known as "tumors of low malignant potential." There is some prognostic significance to the cell type of the tumor, with clear-cell and mucinous varieties tending to be especially virulent.
Pathologists also classify adenocarcinomas according to the degree of histologic differentiation. Those tumors that retain clear-cut glandular features are considered grade 1, or well differentiated, whereas those that are largely composed of solid sheets of tumor are considered grade 3, or poorly differentiated. Tumors that show both glandular and solid areas are assigned to grade 2. The histologic grade seems to correlate roughly with biologic aggressiveness.
Stromal and Germ Cell Tumors
Malignancies can also arise from the ovarian stroma or the primordial germ cells contained within the ovaries. Stromal tumors are often hormone-producing and include such types as the granulosa tumor, Sertoli-Leydig tumor, and several variants. Germ cell tumors, which tend to be highly aggressive, include the dysgerminoma, endodermal sinus tumor, malignant teratoma, embryonal carcinoma, and rare primary choriocarcinoma of the ovaries. Malignant germ cell tumors occur primarily in younger patients, with an average age at diagnosis of about 19 years.
Staging and Prognosis
FIGO staging system for ovarian cancerStaging System
The staging system for ovarian cancer shown in Table 1, developed by the International Federation of Gynecology and Obstetrics (FIGO), is used uniformly in all developed countries. It is based on the results of a properly performed exploratory laparotomy, a fact that bears emphasis, since inadequate surgical staging has been and continues to be a significant problem.
Surgical staging
The surgical staging of ovarian cancer is based on an understanding of the patterns of disease spread and must be conducted in a systematic and thorough manner. It should include a complete evaluation of all visceral and parietal surfaces within the peritoneal cavity, omentectomy, and biopsy of aortic and pelvic lymph nodes. It generally includes removal of the internal reproductive organs as well, although exceptions to this rule can be made for younger women with limited disease who may wish to retain fertility.
At the time of exploration for an adnexal mass, if the mass is shown to be malignant on frozen section and there is no obvious metastatic disease, a complete staging operation is essential to search for occult metastatic spread, which may be present in 20% to 30% of such cases. Also, if the tumor is documented to be stage IA by thorough staging and the patient wishes to preserve the potential for future fertility, it may be appropriate to conserve the uterus, uninvolved ovary, and fallopian tubes. It is important that an individual with specialized training in gynecologic oncology be available to assist in the event the mass is malignant. Less optimal, but sometimes necessary, is for the operating surgeon to remove only the involved ovary and refer the patient to a surgeon with specialized training in gynecologic oncology to reoperate on the patient.
The elements of surgical staging for apparent early ovarian cancer are listed in Table 2.
Procedures for surgical staging for apparent early ovarian cancerPrognostic Factors
The prognosis of epithelial ovarian cancer depends on a number of factors.
Disease stage
Of primary importance is the disease stage, which, when properly determined, is of strong prognostic significance. The distribution of ovarian cancer cases by stage is as follows: stage I, 26%; stage II, 15%; stage III, 42%; stage IV, 17%. For patients with advanced ovarian cancer, the amount of residual tumor at the conclusion of the initial operation is of major importance. Patients with stage III disease who have minimal or no residual tumor may have a 30% to 50% chance of 5-year survival, whereas those patients with stage III disease left with bulky tumor masses have a 5-year survival rate of only about 10%.
Histologic grade and type
Most studies have found the histologic grade of the tumor to have prognostic significance; the histologic cell type of the tumor is of less importance, although patients with clear-cell and mucinous tumors have a worse prognosis.
Molecular markers
In recent years, a great deal of effort has been devoted to the identification of molecular markers of prognosis in ovarian cancer. Studies of HER2, p53, ras, and other oncogenes and tumor-suppressor genes have had varying results relative to prognostic significance. Currently, the assessment of molecular markers is ongoing in numerous studies, in the hope of identifying clinically relevant targets that are susceptible to available agents. The continued progress in developing high-throughput techniques for determining gene and protein expression increases the likelihood that good candidates will be found. The Cancer Genome Atlas Project is currently evaluating gene expression patterns to see whether these corrlate with overall survival and would predict response to targeted therapies. To date, ovarian cancer appears to be more one of DNA instability ("BRCA-ness") rather than having frequent and easily identifiable driver mutations that are targetable with currently available novel agents.
Predictors of chemosensitivity
Despite a continued effort to assess in vitro methods to predict the sensitivity or resistance of ovarian cancers to various chemotherapeutic drugs, the clinical usefulness of such an approach remains under investigation. ASCO recently reviewed the relevant literature on the subject and reached the same conclusion for cancers in general.
