Ovarian Cancer

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Ovarian cancer is the second most commonly diagnosed gynecologic malignancy, the deadliest gynecologic malignancy, and the fourth leading cause of cancer-related deaths in women in the USA. About 1 in 70 women eventually develops ovarian cancer, and 1 in 100 women dies of it. Ovarian cancer affects predominantly perimenopausal and postmenopausal women.

Etiology and Pathology
Incidence is higher in industrialized countries in which dietary fat intake is high. A history of nulliparity, infertility, late childbearing, and delayed menopause increases risk. Use of oral contraceptives significantly decreases risk.
A personal or family history of endometrial, breast, or colon cancer increases risk. Probably < 5% of ovarian cancer cases are related to an inherited autosomal dominant gene, the BRCA gene. Females with XY gonadal dysgenesis are predisposed to ovarian malignant germ cell tumors.

Ovarian tumors are the most histologically diverse group of tumors. At least 80% of malignant ovarian tumors arise from the coelomic epithelium. The most common type is serious cystadenocarcinoma, which accounts for 75% of cases of epithelial ovarian cancer. Others include mucinous, endometroid, transitional cell, Brenner, clear cell, and unclassified carcinomas. The remaining 20% of malignant ovarian tumors are germ cell and sex cord-stromal cell tumors, which are nonepithelial in origin, and metastatic carcinomas to the ovary (most commonly, breast and GI carcinomas). Germ cell tumors, which arise from the primary germ cells of the ovary, occur in young women and are uncommon in women > 30 yr. Malignant germ cell tumors include dysgerminomas, immature teratomas, endodermal sinus tumors, embryonal carcinomas, choriocarcinoma, and polyembryomas. Stromal malignancies include granulosa-theca cell tumors and Sertoli-Leydig cell tumors.

Ovarian cancer spreads by direct extension, by intraperitoneal implantation via exfoliation of cells into the peritoneal cavity, by lymphatic dissemination in the pelvis and para-aortic region, and, less commonly, hematogenously to the liver or lungs.

Symptoms, Signs, and Diagnosis
Most women (75%) present with advanced-stage disease, and most have vague, nonspecific symptoms, such as dyspepsia, bloating, early-satiety anorexia, gas pains, and backache. The most common early finding is an adnexal mass, which is often solid, irregular, and fixed. A patient may be asymptomatic until an abdominal mass is discovered during routine pelvic examination or until the disease is advanced. Occasionally, a patient presents with severe abdominal pain secondary to torsion of the ovarian mass. Late in the course, pelvic pain, anemia, cachexia, and abdominal swelling due to ovarian enlargement or accumulation of ascitic fluid usually occur. Nodular implants noted on the rectovaginal examination suggest extensive pelvic malignant disease.

Functional effects of germ cell or stromal tumors include hyperthyroidism, feminization, and virilization. However, benign functional cysts are common in young women; vaginal sonography or reexamination after 6 wk helps differentiate cysts from tumors. Surgery is indicated when a mass is persistent or suspicious; tumor markers for germ cell malignancies, including the β subunit of human chorionic gonadotropin (β-hCG), LDH, α-fetoprotein, and cancer antigen 125 (CA 125), should be measured.

The probability that an enlarged ovary represents ovarian cancer is directly proportional to the patient’s age. The ovaries of postmenopausal women are small and are usually not palpable but may contain benign cysts, detected by vaginal sonography. A complex pelvic mass in a postmenopausal woman, especially with elevated CA 125, suggests ovarian cancer. CA 125 is a cell surface glycoprotein detectable in 80% of cases of epithelial ovarian cancer. However, it is not specific to patients with ovarian cancer and, among premenopausal patients, can be mildly elevated in several benign disorders, including endometriosis, pelvic inflammatory disease, pregnancy, and leiomyomata uteri. Other malignancies and inflammatory conditions of the peritoneum can also elevate CA 125. A pelvic mass and ascites usually indicate a malignant ovarian tumor; however, a benign fibroma with ascites and right hydrothorax occurs in Meigs’ syndrome.

CA 125 and pelvic ultrasonography are ineffective for screening asymptomatic women in the general population.

Treatment
Surgical staging:
A benign adnexal mass may be managed by cystectomy, oophorectomy, or hysterectomy with bilateral salpingo-oophorectomy, depending on the patient’s age and desire for pregnancy. If a malignancy is suspected or confirmed, comprehensive surgical staging is indicated. A large proportion of patients with apparently early-stage disease have extraovarian spread. Accurate surgical staging improves prognostic accuracy and determines appropriate postoperative therapy. Staging is based on surgical findings (see Table 241-2).

When a malignancy is suspected, an abdominal incision, usually midline, allowing adequate access to the upper abdomen is required. When the cancer appears confined to the pelvis, the tumor should be removed intact or unruptured. All peritoneal surfaces, hemidiaphragms, and abdominal and pelvic viscera should be inspected and palpated. Washings from the pelvis, abdominal gutters, and diaphragmatic recesses should be obtained, and multiple biopsies of the pelvis and abdominal peritoneum performed. An omentectomy should be performed, and pelvic and para-aortic lymph nodes sampled.

Hysterectomy and bilateral salpingo-oophorectomy are usually indicated. One exception is a young patient with a low-grade unilateral epithelial lesion or a nonepithelial malignancy. Reproductive capability can be preserved by excising only the affected ovary; the remainder of the surgical staging procedures should be completed.

For patients with advanced-stage epithelial ovarian cancer, cytoreductive (tumor-debulking) surgery is advised to improve the efficacy of adjunctive therapies. The goal is to reduce the tumor burden so that the maximum diameter of the remaining implants is < 1 cm. Cytoreductive surgery usually includes total hysterectomy, bilateral salpingo-oophorectomy, omentectomy, and excision of the tumor from any other sites. Rectosigmoid resection (usually with primary reanastomosis), radical peritoneal stripping, resection of diaphragmatic peritoneum, or splenectomy may be required. Prognosis for patients with advanced disease is directly related to the success of cytoreductive surgery.

Postoperative therapy:
Patients with stage IA or B, grade 1 epithelial adenocarcinoma require no additional therapy. Their 5-yr survival rate is not improved by adjuvant therapy. Patients with stage IA or B, grade 2 and 3 tumors and patients with stage II disease require three to six courses of adjuvant chemotherapy. Paclitaxel is combined with cisplatin or carboplatin. The 5-yr survival rate is 70 to 100% for patients with stage I disease, depending on tumor grade, and 50 to 70% for patients with stage II disease.

Patients with stage III or IV disease require six courses of paclitaxel and platinum-based chemotherapy. The median survival for patients with microscopic residual disease at the beginning of chemotherapy is 30 to 40 mo vs. 12 to 20 mo for patients with suboptimal cytoreductive surgery. Intraperitoneal chemotherapy or high-dose chemotherapy with bone marrow transplantation is being evaluated in clinical trials. Radiation therapy is infrequently used.

Advanced-stage ovarian cancer usually recurs. Response to chemotherapy can be assessed by measuring CA 125. After completion of chemotherapy, a second-look laparotomy may be needed because about 2/3 of patients with stage III or IV disease have pathologically proven residual disease even after a complete clinical response to chemotherapy. The 5-yr survival rate is 5 to 40%.

Patients with recurrent or progressive ovarian cancer may be given cisplatin if they have previously responded to this drug. Other useful drugs include topotecan, hexamethylmelamine, ifosfamide, doxorubicin, and etoposide.

Most patients with advanced-stage germ cell malignancies or high-risk early-stage disease can be cured with combination chemotherapy. Bleomycin, etoposide, and cisplatin are most commonly used.

RELATED STORIES:
Gestational Trophoblastic Disease   Uterine Cancer   Cervix Cancer   Cervical Cancer   Carcinoma of the Fallopian Tube   Endometrial Cancer   Vulvar Cancer   Gestational Trophoblastic Neoplasia   Fallopian Tube Cancer   Cancer of the Vulva   Ovarian Cancer   Ovarian Germ Cell Tumors   Vaginal Cancer

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