Ovarian Cancer

Chapter 39 Ovarian Cancer

Ovarian cancer is the fifth most common cancer among females in the United States, accounting for one fourth of all gynecologic cancers. It is the leading cause of death from gynecologic cancer because it is difficult to detect before it disseminates. In 2007, 22,430 new cases and more than 15,280 deaths are expected from this disease. Most women with ovarian cancer are in the fifth or sixth decade of life.

Etiology and Epidemiology

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.

Screening for Ovarian Cancer

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.

Clinical Features

SYMPTOMS

Unfortunately, many patients in whom ovarian cancer develops have only nonspecific symptoms before dissemination takes place. In early-stage disease, vague abdominal pain or bloating is common, although symptoms of a mass compressing the bladder or rectum, such as urinary frequency or constipation, may bring the patient to a physician. Sometimes the patient complains of dyspareunia. Premenopausal women may experience menstrual irregularity. Only rarely does a patient present with acute symptoms, such as pain secondary to torsion, rupture, or intracystic hemorrhage.

In advanced-stage disease, patients most often present with abdominal pain or swelling. The latter may be from the tumor itself or from associated ascites. On careful questioning, there has usually been a history of vague abdominal symptoms, such as bloating, constipation, nausea, dyspepsia, anorexia, or early satiety. Premenopausal patients may complain of irregular menses or heavy vaginal bleeding. Postmenopausal bleeding is occasionally a symptom of ovarian neoplasms, particularly functional stromal tumors.

SIGNS

The disease is frequently misdiagnosed for several months because patients with nonspecific abdominal symptoms do not receive a vaginal and rectal examination. A solid, irregular, fixed pelvic mass is suggestive of ovarian cancer, and if combined with an upper abdominal mass, ascites, or both, the diagnosis is almost certain.

Preoperative Evaluation

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.

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.

Differential Diagnosis

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.

Mode of Spread

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.

Staging

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

Stage I	Growth limited to the ovaries
Stage Ia	Growth limited to one ovary; no ascites. No tumor on the external surface; capsule intact
Stage Ib	Growth limited to both ovaries; no ascites. No tumor on the external surfaces; capsules intact
Stage Ic	Tumor either stage Ia or Ib but with tumor on the surface of one or both ovaries or with capsule ruptured or with ascites present containing malignant cells or with positive peritoneal washings
Stage II	Growth involving one or both ovaries with pelvic extension
Stage IIa	Extension or metastases, or both, to the uterus or tubes, or both
Stage IIb	Extension to other pelvic tissues
Stage IIc	Tumor either stage IIa or IIb but with tumor on the surface of one or both ovaries or with capsule or capsules ruptured or with ascites present containing malignant cells or with positive peritoneal washings
Stage III	Tumor involving one or both ovaries with peritoneal implants outside the pelvis or positive retroperitoneal or inguinal nodes, or both. Superficial liver metastasis equals stage III. Tumor is limited to the true pelvis, but with histologically proven malignant extension to small bowel or omentum
Stage IIIa	Tumor grossly limited to the true pelvis with negative nodes but with histologically confirmed microscopic seeding of abdominal peritoneal surfaces
Stage IIIb	Tumor of one or both ovaries with histologically confirmed implants of abdominal peritoneal surfaces, none exceeding 2 cm in diameter. Nodes negative for disease
Stage IIIc	Abdominal implants >2 cm in diameter or positive retroperitoneal or inguinal nodes, or both
Stage IV	Growth involving one or both ovaries with distant metastasis. If pleural effusion is present, there must be positive cytologic test results to allot a case to stage IV. Parenchymal liver metastasis equals stage IV.