The cause of ovarian cancer is unknown. The patient characteristics found to be associated with an increased risk for epithelial ovarian cancer include white race, late age at menopause, family history of cancer of the ovary, breast, or bowel, and prolonged intervals of ovulation uninterrupted by pregnancy. There is an increased prevalence of ovarian cancer in nulliparous women and those who have been infertile.

The incidence of ovarian cancer varies in different geographic locations. Western countries, including the United States, have rates that are 3 to 7 times greater than those in Japan. Second-generation Japanese immigrants to the United States have an incidence of ovarian cancer similar to that of American women. White Americans experience ovarian cancer about 1.5 times more frequently than do black Americans.

About 10% of epithelial ovarian cancers occur in women with a hereditary predisposition. In women with hereditary cancers, two or more first-degree relatives on either the paternal or maternal side typically have had breast or ovarian cancer. The pattern of inheritance is autosomal dominant. Breast cancers generally occur in young premenopausal women, whereas ovarian cancers have a median age of about 50 years. The breast-ovarian cancer syndrome is due to germline mutations of BRCA1, which is located on chromosome 17, and BRCA2, which is located on chromosome 13. The Lynch II syndrome, nonpolyposis colorectal cancer syndrome, is associated with mutations in the mismatch repair genes. Adenocarcinomas of the ovary, breast, colon, stomach, pancreas, and endometrium are seen in the families of these individuals.

The use of oral contraceptives has been found to protect against ovarian cancer, possibly because of suppression of ovulation. It has been postulated that incessant ovulation may predispose to malignant transformation in the ovary.

Patients with a known germline mutation (e.g., BRCA1 and BRCA2 mutations) may be offered prophylactic salpingo-oophorectomy once childbearing has been completed, and this operation is highly protective for ovarian and fallopian tube carcinomas. Indeed, the risk for subsequent breast cancer is also significantly reduced in these women. There is still a small risk for peritoneal carcinoma after prophylactic salpingo-oophorectomy.

Some case-control studies have suggested that the use of postmenopausal estrogen replacement therapy may increase the risk for ovarian cancer, but these data are controversial.

It has also been postulated that a causative agent could enter the peritoneal cavity through the lower genital tract. For example, the perineal use of asbestos-contaminated talc has been linked to the development of epithelial ovarian cancer. This possibility remains controversial, although tubal ligation and hysterectomy are both associated with a decreased risk for the disease.

Population screening for ovarian cancer is not feasible because ultrasonography and available tumor markers, for example, CA 125, lack specificity and sensitivity for early-stage disease. CA 125 is more useful in postmenopausal women because false-positive measurements occur commonly in premenopausal women in association with endometriosis, pelvic inflammatory disease, or uterine fibroids. Patients with a strong family history of epithelial ovarian cancer may benefit from surveillance with serial transvaginal ultrasonography and serum CA 125 titers.

The diagnosis of ovarian cancer requires a laparotomy or laparoscopy. Routine preoperative hematologic and biochemical studies should be obtained, as should a chest radiograph. A pelvic and abdominal computed tomography scan will exclude liver metastases, but it is not mandatory.

A Papanicolaou smear should be obtained to evaluate the cervix, but this test is of limited value in detecting ovarian cancer. Endometrial biopsy and endocervical curettage are necessary in patients with abnormal vaginal bleeding because concurrent primary tumors occasionally occur in the ovary and endometrium. In the presence of a pelvic mass, it is preferable not to perform abdominal paracentesis for cytologic evaluation of ascitic fluid, unless neoadjuvant chemotherapy is planned, because seeding of the abdominal wall may occur.

An abdominal radiograph may be useful in a younger patient to locate calcifications associated with a benign cystic teratoma (dermoid cyst), which is the most common neoplasm in patients younger than 25 years of age. In patients with occult blood in the stool or significant intestinal symptoms, a barium enema or lower gastrointestinal endoscopy should be obtained to rule out a primary colonic cancer with ovarian metastasis.

Similarly, an upper gastrointestinal endoscopy is important if there are significant gastric symptoms. Breast cancer may also metastasize to the ovaries, so bilateral mammograms should be obtained if there are any suspicious breast masses.

Pelvic ultrasonography, particularly transvaginal ultrasonography with or without color Doppler studies, may be useful for smaller (<8 cm) masses in premenopausal women. Masses that are predominantly solid or multilocular have a high probability of being neoplastic, whereas unilocular cystic masses are generally functional cysts. In postmenopausal women, ultrasonography may also be useful because small, unilocular cysts (<5 cm) that are stable are generally benign.

Several tumor markers have been investigated, but none has been consistently reliable. The tumor-associated antigen CA 125 is elevated in only about 50% of women with stage I ovarian cancer. When this assay is elevated, it is useful for monitoring the clinical course of the disease.

Ovarian malignancies must be differentiated from benign neoplasms and functional cysts of the ovaries. In addition, a variety of gynecologic conditions can simulate a neoplastic process, including tubo-ovarian abscess, endometriosis, and a pedunculated uterine leiomyoma. Nongynecologic causes of pelvic tumor must also be excluded, such as an inflammatory or neoplastic disease of the colon, or a pelvic kidney.

Ovarian cancer typically spreads by exfoliating cells that disseminate and implant throughout the peritoneal cavity. The distribution of intraperitoneal metastases tends to follow the circulatory path of peritoneal fluid, so metastases are commonly seen on the posterior cul-de-sac, paracolic gutters, right hemidiaphragm, liver capsule, and omentum. Implants are also common on the bowel serosa and its mesenteries. In general, they grow around the intestines, encasing them with tumor, without invading the bowel lumen. Widespread bowel metastases can lead to a functional obstruction known as carcinomatous ileus.

Lymphatic dissemination to the pelvic and para-aortic nodes is common, particularly with advanced disease. Extensive blockage of the diaphragmatic lymphatics is at least partially responsible for the development of ascites. Hematogenous metastases are not common, and parenchymal metastases to the liver and lungs are seen in only about 2% of patients at initial presentation.

Death from ovarian cancer usually results from progressive encasement of abdominal organs, leading to anorexia, vomiting, and inanition. The bowel obstruction caused by tumor growth is often incomplete and intermittent and may last for several months before the patient’s demise.

The standard staging system for ovarian cancer is presented in Table 39-1. Ovarian cancer is surgically staged according to the International Federation of Gynecology and Obstetrics (FIGO) staging system.

TABLE 39-1 INTERNATIONAL FEDERATION OF GYNECOLOGY AND OBSTETRICS (FIGO) STAGING FOR PRIMARY CARCINOMA OF THE OVARY

Even though all microscopic disease may appear to be confined to the ovaries at the time of laparotomy, microscopic spread may have already occurred; thus, patients must undergo a thorough surgical staging. Procedures necessary to stage ovarian cancer are shown in Box 39-1.

The histologic classification of ovarian neoplasms is listed in Table 39-2. These lesions fall into four categories according to their tissue of origin. Most ovarian neoplasms (80% to 85%) are derived from coelomic epithelium and are called epithelial carcinomas. Less common tumors are derived from primitive germ cells, specialized gonadal stroma, or nonspecific mesenchyme. In addition, the ovary can be the site of metastatic carcinomas, most often from the gastrointestinal tract or the breast.

TABLE 39-2 HISTOGENETIC CLASSIFICATION OF PRIMARY OVARIAN NEOPLASMS

∗ Combined germ cell and specialized gonadal-stromal elements.

Data from Hart WR, Morrow CP: The ovaries. In Romney SL, Gray MJ, Little AO, et al (eds): Gynecology and Obstetrics: The Health Care of Women, 2nd ed. New York, McGraw-Hill, 1981.

Germ cell tumors of the ovary account for only about 2% to 3% of all ovarian malignancies. They occur predominantly in young patients and frequently produce either human chorionic gonadotropin (hCG) or alpha-fetoprotein (AFP), which serve as tumor markers. The most common germ cell tumors are the dysgerminoma and immature teratoma. Endodermal sinus tumors, embryonal tumors, and nongestational choriocarcinomas are less common. Mixed germ cell tumors are not uncommon.

A group of relatively uncommon tumors is derived from the specialized ovarian stroma. As such, they are often endocrinologically functional, many of them being capable of synthesizing gonadal or adrenal steroid hormones. Because the ovarian stroma has sexual bipotentiality, hormones that are secreted can be either female or male. Estrogen and progesterone are typically associated with granulosa-theca cell tumors, whereas testosterone and other androgens may be secreted by many Sertoli-Leydig cell tumors. Rarely, lipid cell tumors, which are usually virilizing, produce adrenal corticoids and a clinical cushingoid syndrome.

About 4% to 8% of ovarian malignancies are metastatic, most commonly from either the gastrointestinal tract or the breast. The Krukenberg tumor is a specific type of metastatic tumor in which signet-ring cells are seen in the ovarian stroma histologically. Most Krukenberg tumors are bilateral and metastatic from the stomach. Rarely, it has not been possible to locate a primary focus, and removal of the ovarian disease has produced apparent cures.

Primary carcinoma of the fallopian tube accounts for only 0.1% to 0.5% of gynecologic cancers and is diagnostically confused with ovarian carcinoma. The incidence of fallopian tube carcinoma may be higher than previously suspected because some are misclassified as primary ovarian carcinomas. Most are adenocarcinomas, but sarcomas and mixed tumors can occur. There is no official staging system for fallopian tube carcinoma, but in general they are staged like ovarian cancer because the mode of dissemination is similar. Bilateral carcinomas are seen in 10% to 20% of patients.