Pathologists also classify adenocarcinomas according to the degree of histologic differentiation. Those tumors retaining 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 showing 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
Staging 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.
TABLE 2Procedures for surgical staging for apparent early ovarian cancer
The issue of adequate surgical staging becomes particularly acute in just the patient population likely to be operated upon by individuals with no specialized training in gynecologic oncology: patients with adnexal masses that are not obvious cancers on preoperative evaluation. At the time of exploration, 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 and uninvolved ovaries and fallopian tubes.
The elements of surgical staging for apparent early ovarian cancer are listed in Table 2.
Prognostic 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 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 possibly mucinous tumors may 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.
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. The American Society of Clinical Oncology (ASCO) recently reviewed the relevant literature on the subject and reached the same conclusion for cancers in general.
Treatment
Surgery plays a crucial role in all phases of the management of ovarian cancer and, when applied as part of a multidisciplinary approach, affords patients the highest likelihood of a favorable outcome. For most patients with ovarian carcinoma, surgery is not curative due to dissemination of tumor cells throughout the abdominal cavity. Therefore, successful management generally requires additional treatment.
The use of postoperative chemotherapy is standard for all patients with advanced-stage disease and for many patients with early-stage disease. Adjunctive chemotherapy significantly prolongs survival, with most current data supporting the use of platinum- and taxane-based regimens.
Despite a long history of the use of radiation therapy in ovarian carcinoma, due to the relatively high sensitivity of ovarian cancer to radiation in general, opinions on indications for its use differ widely. Presumably, this controversy is due to the limited amount and adequacy of data comparing radiotherapy with modern chemotherapy regimens, as well as concerns regarding potential toxicities. Studies using radiation in both radical and palliative settings have been published, but standardization of the use of radiation varies significantly worldwide.
management of early-stage disease
Clearly, comprehensive surgical staging is necessary to properly identify patients with stages I and II ovarian carcinoma. Beyond surgery, the need for adjuvant treatment with chemotherapy has been recently supported, with the exception of patients with stage I disease and well-differentiated histology.
Surgery
Suspicious adnexal masses should be excised intact and submitted for frozen section. If a malignancy is confirmed and there is no obvious metastatic spread, complete surgical staging should be undertaken. As discussed previously (see section on "Staging and prognosis"), it is of critical importance that surgical staging be performed systematically and completely. Inadequate staging may result in inappropriate postoperative treatment, which can severely compromise the chances for cure.
Data from the American College of Surgeons community hospital-based tumor registry show that almost 75% of the primary surgeries for ovarian cancer performed in this country are done so without the involvement of a gynecologic oncologist. This finding is unfortunate given the fact that, with physical examination, measurement of CA-125 levels, and appropriate imaging tests, the majority of cases of ovarian cancer can be identified preoperatively. Results from other studies suggest that when a gynecologic oncologist is not present at the initial operation, staging is more often inadequate, cytoreduction is more often suboptimal, and long-term survival is poorer.
Conservation of reproductive organs In a woman of reproductive age with cancer limited to one ovary, it may be possible to conserve the uterus and opposite fallopian tube and ovary if she wishes to maintain the option of future fertility. To facilitate such intraoperative decision-making, it is essential that the surgeon's preoperative discussion with the patient and her family address the possibility of malignancy and review the surgical options for both benign and malignant diseases.
Operative laparoscopy Recent advances in the instrumentation for operative laparoscopy have led to an increase in the proportion of adnexal masses being managed with this technique. Physicians should exercise caution in selecting patients with adnexal masses for operative laparoscopic approaches. Unless the surgeon's laparoscopic skills are extraordinary, suspicious masses are best managed by laparotomy. For masses that are approached laparoscopically, the same surgical principles of removal without spill and complete surgical staging apply.
Systemic chemotherapy for early-stage disease
The current management of patients with early-stage disease focuses on comprehensive surgical staging and the identification of high-risk features. Patients with stage IA or IB tumors with well-differentiated histology have excellent 5-year survival rates, and adjuvant chemotherapy is generally not used in such patients. High-risk features include moderately to poorly differentiated tumors, stage IC or II disease, and clear-cell histology.
The reported survival rates of 60% to 80% in patients who have early-stage tumors with high-risk features suggested a potential role for adjuvant therapy. The IICG conducted two randomized trials to evaluate the role of adjuvant therapy in patients with stage I disease. The first trial compared cisplatin, 50 mg/ m² q28d × 6, with observation in 85 patients with stage IA or IB, grade 2–3 disease. The 5-year disease-free survival rate was higher in patients treated with cisplatin than in those who were observed (83% vs 63%), but the 5-year overall survival rate was similar in the two groups (88% vs 82%).
The second trial compared cisplatin (same dose) to phosphorus-32 (P-32) administration in 161 patients with stages IA–IB, grade 2, or stage IC disease. The 5-year disease-free survival rate again favored the platinum arm (85% vs 65%), but the 5-year overall survival rate was unchanged and similar to that reported in the previous trial. P-32 administration was associated with more long-term toxicity.
More recent data have provided support for a survival benefit to the immediate use of adjuvant chemotherapy in patients with early-stage disease. The results of the EORTC–ACTION trial and the ICON1 trial were combined and reported. A 5-year survival rate improvement of 8% was reported for those receiving immediate chemotherapy compared with reserving chemotherapy for those who relapsed (74% vs 82%; 95% CI: 2%–12%).
Improvements in systemic chemotherapy for advanced ovarian cancer with associated improvements in survival are relevant to the design of regimens for early-stage disease. GOG 157 evaluated 3 vs 6 cycles of paclitaxel and carboplatin in patients with stage IA or IB, grade 2–3; stage IC; or stage II disease. The trial completed accrual in 1995, and final results showed no significant benefit to the longer regimen. The GOG replacement trial evaluated 3 cycles of paclitaxel plus carboplatin with or without additional weekly paclitaxel (40 mg/ m²) in patients with early-stage disease. These data are reported in abstract form, but no benefit to extended-schedule paclitaxel was seen.
In the absence of additional data, taxane- and platinum-based systemic chemotherapy should be considered the standard approach for patients who have early-stage disease with the exception of well-staged IA or IB, grade 1 disease. The optimal number of cycles is currently unclear, but 3 cycles were considered the standard arm in the GOG 157 trial, although many clinicians offer 6 cycles of therapy in the absence of prohibitive toxicity.
Past GOG trials have established that patients with stages IA–IB, well-differentiated or moderately differentiated tumors have a 5-year survival rate of 90% to 98%, which does not seem to improve with adjuvant chemotherapy. However, patients with less favorable neoplasms by virtue of higher grade or stage have poorer outcomes (80% 5-year survival rate among treated patients).