Ovarian cancer is often fatal because it is usually advanced when diagnosed. Symptoms are usually absent in early stages and nonspecific in advanced stages. Evaluation usually includes ultrasonography, CT or MRI, and measurement of tumor markers (eg, cancer antigen 125). Diagnosis is by histologic analysis. Staging is surgical. Treatment requires hysterectomy, bilateral salpingo-oophorectomy, excision of as much involved tissue as possible, and, unless cancer is localized, chemotherapy.

In the US, ovarian cancer is the 2nd most common gynecologic cancer (affecting about 1/70) and the deadliest (1% of all women die of it); it is the 5th leading cause of cancer-related deaths in women, causing an estimated 15,000 deaths in 2008. Incidence is higher in developed countries.

Etiology

Ovarian cancer affects mainly perimenopausal and postmenopausal women. Nulliparity, delayed childbearing, early menarche, and delayed menopause increase risk. Oral contraceptive use decreases risk.

A personal or family history of endometrial, breast, or colon cancer increases risk. Probably 5 to 10% of ovarian cancer cases are related to mutations in the autosomal dominant BRCA gene, which is associated with a 50 to 85% lifetime risk of developing breast cancer. Women with BRCA1 mutations have a 20 to 40% lifetime risk of developing ovarian cancer; risk among women with BRCA2 mutations is increased less.

XY gonadal dysgenesis predisposes to ovarian germ cell cancer.

Pathology

Ovarian cancers are histologically diverse (see Table 1: Gynecologic Tumors: Types of Ovarian Cancers). At least 80% originate in the epithelium; 75% of these cancers are serous cystadenocarcinoma. The remaining 20% of ovarian cancers originate in primary ovarian germ cells or in sex cord and stromal cells or are metastases to the ovary (most commonly, from the breast or GI tract). Germ cell cancers usually occur in women < 30.

Table 1
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Types of Ovarian Cancers Origin Types Epithelium Brenner tumor Clear cell carcinomas Endometrioid carcinomas Mucinous carcinomas Serous cystadenocarcinomas (most common overall) Transitional cell carcinomas Unclassified carcinomas Primary germ cells Choriocarcinomas Dysgerminomas Embryonal carcinomas Endodermal sinus tumors Immature teratomas Polyembryoma Sex cord and stromal cells Granulosa-theca cell tumors Sertoli-Leydig cell tumors Metastases Breast cancer Cancer of the GI tract

Ovarian cancer spreads by direct extension, exfoliation of cells into the peritoneal cavity (peritoneal seeding), lymphatic dissemination to the pelvis and around the aorta, or, less often, hematogenously to the liver or lungs.

Symptoms and Signs

Early cancer is usually asymptomatic; an adnexal mass, often solid, irregular, and fixed, may be discovered incidentally. Pelvic and rectovaginal examinations typically detect diffuse nodularity. A few women present with severe abdominal pain secondary to torsion of the ovarian mass (see Benign Gynecologic Lesions: Adnexal Torsion). Most women with advanced cancer present with nonspecific symptoms (eg, dyspepsia, bloating, early satiety, gas pains, backache). Later, pelvic pain, anemia, cachexia, and abdominal swelling due to ovarian enlargement or ascites usually occur.

Germ cell or stromal tumors may have functional effects (eg, hyperthyroidism, feminization, virilization).

Diagnosis

• Ultrasonography (for suspected early cancers) or CT or MRI (for suspected advanced cancers)
• Tumor markers
• Surgical staging

Ovarian cancer is suspected in women with the following:

• Unexplained adnexal masses
• Unexplained abdominal bloating
• Changes in bowel habits
• Unintended weight loss
• Unexplained abdominal pain

An ovarian mass is more likely to be cancer in older women. Benign functional cysts (see Benign Gynecologic Lesions: Benign Ovarian Masses) can simulate functional germ cell or stromal tumors in young women.

A pelvic mass plus ascites usually indicates ovarian cancer but sometimes indicates Meigs' syndrome (a benign fibroma with ascites and right hydrothorax).

Imaging

If early cancer is suspected, ultrasonography is done first; the following findings suggest cancer:

• A solid component
• Surface excrescences
• Size > 6 cm
• Irregular shape
• Low vascular resistance detected by transvaginal Doppler flow studies

If advanced cancer is suspected (eg, based on ascites, abdominal distention, or nodularity or fixation detected during physical examination), CT or MRI is usually done before surgery to determine extent of the cancer.

Tumor markers

Tumor markers, including the β subunit of human chorionic gonadotropin (β-hCG), LDH, α-fetoprotein, inhibin, and cancer antigen (CA) 125, are typically measured in young patients, who are at higher risk of nonepithelial tumors (eg, germ cell tumors, stromal tumors). In perimenopausal and postmenopausal patients, only CA 125 is measured because most ovarian cancers in this age group are epithelial tumors. CA 125 is elevated in 80% of advanced epithelial ovarian cancers but may be mildly elevated in endometriosis, pelvic inflammatory disease, pregnancy, fibroids, peritoneal inflammation, or nonovarian peritoneal cancer. A mixed solid and cystic pelvic mass in postmenopausal women, especially if CA 125 is elevated, suggests ovarian cancer.

Biopsy

A biopsy is not routinely recommended unless a patient is not a surgical candidate. In those rare cases, samples are obtained by needle biopsy for masses or by needle aspiration for ascitic fluid.

For masses that appear benign on ultrasonography, histologic analysis is not required, and ultrasonography is repeated after 6 wk. Such benign-appearing masses include benign cystic teratomas (dermoid cysts), follicular cysts, and endometriomas.

Staging

Suspected or confirmed ovarian cancer is staged surgically (see Table 2: Gynecologic Tumors: Surgical Staging of Ovarian Carcinoma*).

Table 2
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Surgical Staging of Ovarian Carcinoma* Stage Description I Tumor limited to the ovaries IA Tumor limited to one ovary; no tumor on the external surface and capsule intact IB Tumor limited to both ovaries; no tumor on the external surface and capsules intact IC Stage IA or IB but with tumor on the surface of one or both ovaries, with capsule ruptured, or with ascites or malignant cells in peritoneal washings† II Tumor involving one or both ovaries with pelvic extension or metastases IIA Extension and/or metastases to the uterus, fallopian tubes, or both IIB Extension to other pelvic tissues IIC Stage IIA or IIB but with tumor on the surface of one or both ovaries, with capsule ruptured, or with ascites or malignant cells in peritoneal washings† III Histologically confirmed peritoneal metastases outside the pelvis, superficial liver metastases, positive retroperitoneal or inguinal lymph nodes, or tumor limited to the true pelvis but with histologically verified malignant extension to the small intestine or omentum IIIA Gross tumor limited to the true pelvis with negative lymph nodes but with histologically confirmed microscopic tumor outside pelvis IIIB Histologically confirmed abdominal peritoneal metastases that extend beyond the pelvis and are < 2 cm in diameter and negative lymph nodes IIIC Abdominal peritoneal metastases that extend beyond the pelvis and are > 2 cm in diameter, positive retroperitoneal or inguinal lymph nodes, or both IV Distant metastases, including parenchymal liver metastases; if pleural effusion is present, positive cytologic test results required to signify stage IV *Based on staging established by the International Federation of Gynecology and Obstetrics (FIGO) and American Joint Committee on Cancer (AJCC), 1999, 2002. † For stages IC and IIC, knowing whether capsule rupture was spontaneous or caused by the surgeon and whether the source of malignant cells was ascites or peritoneal washings helps determine prognosis. Surgical Staging of Ovarian Carcinoma* Stage Description I Tumor limited to the ovaries IA Tumor limited to one ovary; no tumor on the external surface and capsule intact IB Tumor limited to both ovaries; no tumor on the external surface and capsules intact IC Stage IA or IB but with tumor on the surface of one or both ovaries, with capsule ruptured, or with ascites or malignant cells in peritoneal washings† II Tumor involving one or both ovaries with pelvic extension or metastases IIA Extension and/or metastases to the uterus, fallopian tubes, or both IIB Extension to other pelvic tissues IIC Stage IIA or IIB but with tumor on the surface of one or both ovaries, with capsule ruptured, or with ascites or malignant cells in peritoneal washings† III Histologically confirmed peritoneal metastases outside the pelvis, superficial liver metastases, positive retroperitoneal or inguinal lymph nodes, or tumor limited to the true pelvis but with histologically verified malignant extension to the small intestine or omentum IIIA Gross tumor limited to the true pelvis with negative lymph nodes but with histologically confirmed microscopic tumor outside pelvis IIIB Histologically confirmed abdominal peritoneal metastases that extend beyond the pelvis and are < 2 cm in diameter and negative lymph nodes IIIC Abdominal peritoneal metastases that extend beyond the pelvis and are > 2 cm in diameter, positive retroperitoneal or inguinal lymph nodes, or both IV Distant metastases, including parenchymal liver metastases; if pleural effusion is present, positive cytologic test results required to signify stage IV *Based on staging established by the International Federation of Gynecology and Obstetrics (FIGO) and American Joint Committee on Cancer (AJCC), 1999, 2002. † For stages IC and IIC, knowing whether capsule rupture was spontaneous or caused by the surgeon and whether the source of malignant cells was ascites or peritoneal washings helps determine prognosis.

If early-stage cancer is suspected, staging may be done by laparoscopy. Otherwise, an abdominal midline incision that allows adequate access to the upper abdomen is required. All peritoneal surfaces, hemidiaphragms, and abdominal and pelvic viscera are inspected and palpated. Washings from the pelvis, abdominal gutters, and diaphragmatic recesses are obtained, and multiple biopsies of the peritoneum in the central and lateral pelvis and in the abdomen are done. For early-stage cancer, the infracolic omentum is removed, and pelvic and para-aortic lymph nodes are sampled.

Cancers are also graded histologically from 1 (least aggressive) to 3 (most aggressive).

Screening

Screening asymptomatic women using ultrasonography and serum CA 125 measurements can detect some cases of ovarian cancer but has not been shown to improve outcome, even for high-risk subgroups (including women with BRCA mutations). However, women should be screened for abnormalities of the BRCA gene if their family history includes any of the following:

• Diagnosis of ovarian cancer in a 1st-degree relative before age 40
• Diagnosis of breast and ovarian cancer in only one 1st-degree relative if one of the cancers was diagnosed before age 50
• Two cases of ovarian cancer among 1st- and 2nd-degree relatives of the same lineage
• Two cases of breast cancer and one case of ovarian cancer among 1st- or 2nd-degree relatives of the same lineage
• One case of breast and one case of ovarian cancer among 1st- or 2nd-degree relatives of the same lineage if breast cancer was diagnosed before age 40 or if ovarian cancer was diagnosed before age 50
• Two cases of breast cancer among 1st- or 2nd-degree relatives of the same lineage if both cases were diagnosed before age 50
• Two cases of breast cancer among 1st- or 2nd-degree relatives of the same lineage if one was diagnosed before age 40

Also, if Ashkenazi Jewish women have one family member with breast cancer diagnosed before age 50 or with ovarian cancer, screening should be considered.

Prognosis

The 5-yr survival rates with treatment are

• Stage I: 70 to 100%
• Stage II: 50 to 70%
• Stage III: 20 to 50%
• Stage IV: 10 to 20%

Prognosis is worse when tumor grade is higher or when surgery cannot remove all visibly involved tissue; then, prognosis is best when the involved tissue can be reduced to < 1 cm in diameter. With stages III and IV, recurrence rate is about 70%.

Treatment

• Usually hysterectomy and bilateral salpingo-oophorectomy
• Usually postoperative chemotherapy, often with carboplatin and paclitaxel

Hysterectomy and bilateral salpingo-oophorectomy are usually indicated except for stage I nonepithelial or low-grade unilateral epithelial cancers in young patients; fertility can be preserved by not removing the unaffected ovary and uterus. All visibly involved tissue is surgically removed if possible. If it cannot be removed completely, removing as much as possible (cytoreductive surgery) improves the efficacy of other therapies. Cytoreductive surgery usually includes supracolic omentectomy, sometimes with rectosigmoid resection (usually with primary reanastomosis), radical peritoneal stripping, resection of diaphragmatic peritoneum, or splenectomy.

Postoperative treatment depends on the stage and grade (see Table 3: Gynecologic Tumors: Postoperative Treatment of Ovarian Cancer by Stage and Type).

Table 3
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Postoperative Treatment of Ovarian Cancer by Stage and Type Stage and Type Treatment Stage IA or B/grade 1 epithelial adenocarcinoma No postoperative therapy Stage IA or B/grade 2 or 3 cancers Stage II cancers 6 courses of chemotherapy (typically, paclitaxel and carboplatin) Stage III cancer Stage IV cancer 6 courses of chemotherapy* as for stage IA or B/grade 2 or 3 Infrequently, radiation therapy Consideration of intraperitoneal cisplatin and paclitaxel Germ cell tumors Stage II or III stromal tumors Most often, combination chemotherapy, usually bleomycin, cisplatin, and etoposide * Intraperitoneal chemotherapy with cisplatin plus paclitaxel results in longer survival than IV chemotherapy but may have a higher complication rate. Intraperitoneal chemotherapy has not yet become standard treatment for stage III or IV ovarian cancer.

Even if chemotherapy results in a complete clinical response (ie, normal physical examination, normal serum CA 125, and negative CT scan of the abdomen and pelvis), about 50% of patients with stage III or IV cancer have residual tumor. Of patients with persistent elevation of CA 125, 90 to 95% have residual tumor. Recurrence rate in patients with a clinical complete response after initial chemotherapy (6 courses of carboplatin and paclitaxel) is 60 to 70%.

If cancer recurs or progresses after effective chemotherapy, chemotherapy is restarted. Other useful drugs may include topotecan, liposomal doxorubicin, docetaxel, vinorelbine, gemcitabine, hexamethylmelamine, and oral etoposide. Targeted therapy with biologic agents is under study.

Prevention

For patients with BRCA1 or BRCA2 gene mutations, risk of ovarian and, to a lesser degree, breast cancer is reduced if prophylactic bilateral salpingo-oophorectomy is done after childbearing is completed. These patients should be referred to a gynecologic oncologist for evaluation. Other resources include the National Cancer Institute Cancer Information Service (1-800-4-CANCER) and the Women's Cancer Network (www.wcn.org).

Last full review/revision November 2008 by David M. Gershenson, MD; Pedro T. Ramirez, MD