Ovarian Cancer 

Malignant lesions of the ovaries include primary lesions arising from normal structures within the ovary and secondary lesions from cancers arising elsewhere in the body. Primary lesions include epithelial ovarian carcinoma (70% of all ovarian malignancies), germ-cell tumors, sex-cord stromal tumors, and other more rare types. Metastases to the ovaries are relatively frequent, with the most common being from the endometrium, breast, colon, stomach, and cervix. Although many histologic types of ovarian tumors have been described, more than 90% of ovarian malignancies are epithelial tumors. (See Pathophysiology.)

The precise cause of ovarian cancer is unknown, but several risk and contributing factors (including both reproductive and genetic factors) have been identified. (See Etiology.)

Ovarian cancer is the most common cause of cancer death from gynecologic tumors in the United States. Around the world, more than 200,000 women are estimated to develop ovarian cancer every year and about 100,000 die from the disease. The lifetime risk of a woman developing epithelial ovarian cancer is 1 in 70. (See Epidemiology.)

Early disease causes minimal, nonspecific, or no symptoms. Therefore, most cases are diagnosed in an advanced stage. The prognosis of ovarian cancer is closely related to the stage at diagnosis; thus, overall, prognosis for these patients remains poor. (See Clinical Presentation and Prognosis.)

Standard treatment involves aggressive debulking surgery followed by chemotherapy. (See Treatment Strategies and Management.)

Most theories of the pathophysiology of ovarian cancer include the concept that it begins with the dedifferentiation of the cells overlying the ovary. During ovulation, these cells can be incorporated into the ovary, where they then proliferate. Ovarian cancer typically spreads to the peritoneal surfaces and omentum.

Ovarian carcinoma can spread by local extension, lymphatic invasion, intraperitoneal implantation, hematogenous dissemination, and transdiaphragmatic passage. Intraperitoneal dissemination is the most common and recognized characteristic of ovarian cancer. Malignant cells can implant anywhere in the peritoneal cavity but are more likely to implant in sites of stasis along the peritoneal fluid circulation. As discussed later, these mechanisms of dissemination represent the rationale to conduct surgical staging, debulking surgery, and intraperitoneal administration of chemotherapy. In contrast, hematogenous spread is clinically unusual early on in the disease process, although it is not infrequent in patients with advanced disease.

Epithelial ovarian cancer

Epithelial tumors represent the most common histology (90%) of ovarian tumors. Other histologies include the following:

• Sex-cord stromal tumors
• Germ cell tumors
• Primary peritoneal carcinoma
• Metastatic tumors of the ovary

Epithelial ovarian cancer is thought to arise from epithelium covering the ovaries, which is derived from the coelomic epithelium in fetal development. This coelomic epithelium is also involved in formation of the Müllerian ducts, from which the Fallopian tubes, uterus, cervix, and upper vagina develop.

Five main histologic subtypes, which are similar to carcinoma, arise in the epithelial lining of the cervix, uterus, and fallopian tube, as follows:

• Serous (from fallopian tube)
• Endometrioid (endometrium)
• Mucinous (cervix)
• Clear cell (mesonephros)
• Brenner

Some variation is observed in the patterns of spread and disease distribution within the various histologic subtypes.

Epithelial tumors are found as partially cystic lesions with solid components. The surface may be smooth or covered in papillary projections (see the image below), and the cysts contain fluid ranging from straw-colored to opaque brown or hemorrhagic.

Epithelial ovarian cancer most often spreads initially within the peritoneal cavity (see the images below). Metastatic disease often is found on the peritoneal surfaces, particularly on the undersurface of the diaphragms, the paracolic gutters, the bladder, and the cul-de-sac. Other common sites are the surface of the liver, the mesentery and serosa of the large and small bowel, in the omentum, the uterus, and para-aortic and pelvic lymph nodes.

Outside the peritoneal cavity, epithelial ovarian cancer may spread to the pleural cavity, lungs, and groin lymph nodes. Presence of pleural effusion does not necessarily indicate disease in the chest, and malignancy can be diagnosed only cytologically. Mucinous tumors tend to form large dominant masses, while papillary serous tumors have a more diffuse distribution and are more commonly bilateral. Endometrioid and clear-cell variants more commonly exhibit local invasion, retroperitoneal disease, and hepatic metastases.

The precise cause of ovarian cancer is unknown, but several risk and contributing factors have been identified.

Reproductive factors

Parity is an important risk factor. The risk of epithelial ovarian cancer is increased in women who have not had children and possibly those with early menarche or late menopause. Women who have been pregnant have a 50% decreased risk for developing ovarian cancer compared with nulliparous women. Multiple pregnancies offer an increasingly protective effect. Oral contraceptive use decreases the risk of ovarian cancer.

These factors support the idea that risk for ovarian cancer is related to ovulation. Two theories regarding this relationship have been proposed. The incessant ovulation theory suggests that repeated ovarian epithelial trauma caused by follicular rupture and subsequent epithelial repair results in genetic alterations within the surface epithelium. The gonadotropin theory proposes that persistent stimulation of the ovaries by gonadotropins, coupled with local effects of endogenous hormones, increases surface epithelial proliferation and subsequent mitotic activity.

Thus, the probability of ovarian cancer may be related to the number of ovulatory cycles, and conditions that suppress the ovulatory cycle may play a protective role. Ovulation suppression has been shown to decrease cancer incidence. Although treatment with agents that induce ovulation in women with infertility has been suggested to increase the incidence of epithelial ovarian cancer, this is unproven.

Genetic factors

Family history plays an important role in the risk of developing ovarian cancer. The lifetime risk for developing ovarian cancer is 1.6% in the general population. This compares with a 4-5% risk when 1 first-degree family member is affected, rising to 7% when 2 relatives are affected. From 5-10% of cases of ovarian cancer occur in an individual with a family history of the disease. Only a small percentage of these patients have an inherited genetic abnormality, and the risk of this occurrence increases with the strength of the family history. Hereditary epithelial ovarian cancer occurs at a younger age (approximately 10 years younger) than nonhereditary epithelial ovarian cancer, but the prognosis may be somewhat better.

Integrated genomic analyses by the Cancer Genome Atlas Research Network have revealed high-grade serous ovarian cancer is characterized by TP53 mutations in almost all tumors. The findings also include the low prevalence but statistically recurrent somatic mutations in 9 further genes, including NF1, BRCA1, BRCA2, RB1, and CDK12, along with 113 significant focal DNA copy number aberrations and promoter methylation events involving 168 genes. Pathway analyses revealed defective homologous recombination in about half of all tumors, and that NOTCH and FOXM1 signaling are involved in serous ovarian cancer pathophysiology.^[1]

At least 2 syndromes of hereditary ovarian cancer are clearly identified, involving either (1) disorders of the genes associated with breast cancer, BRCA1 and BRCA2, or (2) more rarely, genes within the Lynch II syndrome complex. Breast/ovarian cancer syndrome is associated with early onset of breast or ovarian cancer. Inheritance follows an autosomal dominant transmission. It can be inherited from either parent. Most cases are related to the BRCA1 gene mutation. BRCA1 is a tumor suppressor gene that inhibits cell growth when functioning properly; the inheritance of mutant alleles of BRCA1 leads to a considerable increase in risk for developing ovarian cancer.

Approximately 1 person in 4000 in the general population carries a mutation of BRCA1. Some populations have a much higher rate of BRCA1 and BRCA2 mutations, especially Ashkenazi Jews. In families with 2 first-degree relatives (mother, sister, or daughter) with premenopausal epithelial ovarian cancer, the likelihood of a female relative having an affected BRCA1 or BRCA2 gene is as high as 40%. The probability is much lower when the disease occurs in relatives postmenopausally.

Individuals with a BRCA1 gene mutation have a 50-85% lifetime risk of developing breast cancer and a 15-45% risk of developing epithelial ovarian cancer. Those with a BRCA2 gene mutation have a 50-85% lifetime risk of developing breast cancer and a 10-20% risk of developing epithelial ovarian cancer. Families with BRCA2 mutations are at risk for developing cancer of the prostate, larynx, pancreas, and male breast.

Germline mutations in the BRCA1 and BRCA2 genes are associated with increased risks of breast and ovarian cancers; however, in an investigation of a common genetic variation at the 9p22.2 locus, a decreased risk of ovarian cancer was noted in carriers of a BRCA1 or BRCA2 mutation.^[2]

Families with Lynch II syndrome or hereditary nonpolyposis colorectal cancer are characterized by a high risk for developing colorectal, endometrial, stomach, small bowel, breast, pancreas, and ovarian cancers. This syndrome is caused by mutations in the mismatch repair genes. Mutations have been demonstrated in mismatch repair genes MSH2, MLH1, PMS1, and PMS2.

Women with a history of breast cancer have an increased risk of epithelial ovarian cancer.

Previous hormone therapy

A nationwide prospective cohort study over 10 years that included all Danish women aged 50-79 years concluded that risk for ovarian cancer is increased with hormone therapy, regardless of duration of use, formulation, estrogen dose, regimen, progestin type, and administration route.^[3] Nearly 1 million women without hormone-sensitive cancer or bilateral oophorectomy were followed. In an average of 8 years of follow-up, 3068 ovarian cancers were detected, of which 2681 were epithelial cancers.

Current users of hormones had incidence rate ratios for all ovarian cancers of 1.38 (95% confidence interval [CI], 11.26-1.51) compared with women who never took hormone therapy. Risk declined as years since last hormone use increased. Incidence rates in current and never users of hormones were 0.52 and 0.40 per 1000 years, respectively. This translates to approximately 1 extra ovarian cancer for approximately 8300 women taking hormone therapy each year.

Other factors

Lactose consumption and the use of talcum powder on the vulva and perineum may be associated with increased risk of epithelial ovarian cancer.

In the United States, the incidence of ovarian cancer is 33 cases per 100,000 women aged 50 years or older. The average patient age at diagnosis is 57 years. The estimated lifetime risk is 1 case in 70 women, which is a 1.4% lifetime incidence.

The American Cancer Society estimated that there would be 21,880 new cases of ovarian cancer in 2010 and 13,850 deaths from the disease.^[4] The 2010 estimates are 21,880 cases and 13,850 deaths. Epithelial ovarian cancer is the eighth most common cancer in women, and uterine (corpus and endometrial) is fourth. The ovaries are the ninth most common site of cancer in women, accounting for approximately 3% of all new cases, but ovarian cancer causes 5% of cancer deaths—more than any other cancer of the female reproductive system. However, during 2001–2005, the incidence of ovarian cancer declined at a rate of 2.4% annually, and the death rate from ovarian cancer has been stable since 1998.^[4]

Ovarian cancer is more common among American women in the white population than it is among those in the black population. Epithelial ovarian cancer can occur in females as young as 15 years, but the mean age is 56 years. In the United States, incidence of ovarian carcinoma is approximately 15 cases per 100,000 women per year for women aged 50-54 years, rising to 35 cases per 100,000 women for women aged 70-74 years.

International statistics

Internationally, the incidence is 3.1 cases per 100,000 women in Japan and 21 cases per 100,000 women in Sweden. Around the world, more than 200,000 women are estimated to develop ovarian cancer every year and about 100,000 die from the disease. Epithelial ovarian cancer occurs most commonly in white women in the industrialized countries of northern and western Europe and North America and least commonly in India and Asia. Asian women have low risk unless they relocate to North America or Europe. Scandinavian and Norwegian women have the highest risk.

Although the 5-year survival rate for ovarian cancer has improved significantly in the past 30 years, the prognosis for ovarian cancer remains poor overall, with a 46% 5-year survival rate. The prognosis of ovarian cancer is closely related to the stage at diagnosis,^{[5, 6]} as determined according to the staging system developed by the International Federation of Gynecology and Obstetrics (FIGO). (See Staging.) Approximately 20%, 5%, 58%, and 17% of women present with stage I, II, III, and IV, respectively.

The 5-year survival rates (rounded to the nearest whole number) for epithelial ovarian carcinoma by FIGO stage are as follows:

• Stage IA - 87%
• Stage IB - 71%
• Stage IC - 79%
• Stage IIA - 67%
• Stage IIB - 55%
• Stage IIC - 57%
• Stage IIIA - 41%
• Stage IIIB - 25%
• Stage IIIC - 23%
• Stage IV - 11%
• Overall survival rate – 46%

Bakhru et al found poorer survival among patients with ovarian cancer and diabetes. Although the underlying reason for this association is unknown, further studies are needed.^[7]

Among women with high-grade serous ovarian cancer, BRCA2 mutation but not BRCA1 deficiency was associated with improved survival, improved chemotherapy response, and genome instability compared with BRCA wild-type.^[8]

Overall survival rate at 5 years according to FIGO is shown below. Others have reported better survival rates with 5-year, 10-year, 15-year, and 20-year survival for patients with serous LMP as 97%, 95%, 92%, and 89%, respectively.

Five-year-survival rate for LMP tumors by FIGO stage (survival percentages rounded to nearest whole number) are as follows:

• Stage IA - 93%
• Stage IB - 90%
• Stage IC - 91%
• Stage IIA - 88%
• Stage IIB - 86%
• Stage IIC - 100%
• Stage IIIA - 29%
• Stage IIIB - 75%
• Stage IIIC - 62%
• Stage IV - 30%
• Overall survival rate - 86%

For excellent patient education resources, visit eMedicine’s Cancer and Tumors Center and Women's Health Center. Also, see eMedicine’s patient education articles Ovarian Cancer and Ovarian Cysts.