Ovarian Cancer
Jill H. Tseng
Edward J. Tanner III
Ovarian cancer is the 10th most common cancer and the fifth leading cause of cancer-related death in American women. Ovarian cancer is the second most common gynecologic cancer following cancer of the uterine corpus and has the highest mortality of all female reproductive system malignancies.
EPIDEMIOLOGY OF OVARIAN CANCER
For women in the United States, the lifetime risk of developing ovarian cancer is estimated to be 1 in 72 (1.4%). This likelihood increases with age, with a median age at diagnosis of 63 years.
The risk of malignancy in a solid adnexal mass is 7% in a premenopausal woman and increases to 30% in a postmenopausal woman. Each year, an estimated 22,240 women will be diagnosed with ovarian cancer and 14,030 will die from their disease.
Ovarian neoplasms, of which 80% are benign, are divided into three major groups: epithelial, germ cell, and sex cord-stromal tumors (Table 48-1). The ovary can also be a site of metastatic cancer from other sites, particularly from the breast or the gastrointestinal tract (e.g., Krukenberg tumors).
EPITHELIAL OVARIAN TUMORS
Tumors derived from the coelomic epithelium are the most common ovarian neoplasms, accounting for 65% of ovarian neoplasms and 90% of ovarian cancers.
Histologic types include serous, mucinous, endometrioid, clear cell, and transitional (Brenner).
Risk Factors
Age older than 40 years, white race, nulliparity, infertility, history of endometrial or breast cancer, and family history of ovarian cancer have been consistently found to increase the risk of invasive epithelial cancer. Increased parity, use of oral contraceptive pills (OCPs), history of breast-feeding, tubal ligation, and hysterectomy have been associated with a decreased risk of ovarian cancer.
Patients with a family history of ovarian, breast, endometrial, or colon cancer are at increased risk of developing ovarian carcinoma.
Hereditary familial ovarian cancer accounts for approximately 10% of all newly diagnosed cases. Women with one first-degree relative with ovarian cancer have a 5% lifetime risk of developing the disease and those with two first-degree relatives with ovarian cancer have a 7% risk.
There are three distinct autosomal dominant syndromes that have been termed familial ovarian cancer: site-specific ovarian cancer, breast-ovarian cancer (BRCA1 and BRCA2), and hereditary nonpolyposis colorectal cancer (HNPCC or Lynch syndrome II).
TABLE 48-1 Classification of Ovarian Neoplasms
Epithelial Tumors
Serous (histology resembles the lining of the fallopian tube)
Mucinous (histology resembles endocervical epithelium)
Endometrioid (histology resembles endometrial lining)
Clear cell (histology resembles vaginal mucosa)
Transitional cell (Brenner; histology resembles bladder)
Germ Cell Tumors
Dysgerminoma
Endodermal sinus tumor
Embryonal carcinoma
Polyembryoma
Choriocarcinoma
Teratoma:
Immature
Mature
Sex Cord-Stromal Tumors
Granulosa-stromal cell
Granulosa cell
Thecoma-fibromas
Sertoli-Leydig cell
Sex cord tumor
Sex cord tumor with annular tubules
Gynandroblastoma
Unclassified and Metastatic
HNPCC, also known as Lynch syndrome II, is an autosomal dominant cancer susceptibility syndrome that describes a familial predisposition to multiple cancers (primarily colon and also endometrial, ovarian, and genitourinary tract).
Women with HNPCC have a 40% to 60% lifetime risk for endometrial cancer and a 12% lifetime risk for ovarian cancer. Mutations in three DNA mismatch repair genes, MLH1, MSH2, and MSH6, account for over 95% of mutations found with Lynch syndrome.
BRCA: Two breast and ovarian cancer susceptibility genes (BRCA1, located on chromosome 17q, and BRCA2, located on chromosome 13q) have been identified. These genes, which are involved in DNA repair, have been linked to familial breast cancer, breast-ovary, and site-specific ovarian cancer syndromes.
Women with BRCA gene mutations have a lifetime breast cancer risk of 82%. The lifetime ovarian cancer risks of BRCA1 and BRCA2 carriers are 25% to 60% and 15% to 25%, respectively. These women also develop the disease at an earlier age than women without mutations. Genetic screening tests are available.
Environmental factors may play a role in ovarian cancer. A recent meta-analysis does not support a causal relationship between talc exposure and ovarian cancer.
Reproductive factors play an important role in ovarian cancer risk. Increasing parity is associated with a decreased relative risk of developing ovarian cancer, whereas nulliparity is associated with an increased risk.
The use of OCPs also has been associated with a decreased relative risk.
Women with a history of breast-feeding have a lower risk of ovarian cancer than nulliparous women and parous women who have not breast-fed.
Women with infertility have an elevated risk of ovarian cancer, independent of nulliparity.
Although fertility drugs have been implicated in the development of ovarian cancer, their association has not been clearly separated from the risk that nulliparity and infertility confer.
Tubal ligation and hysterectomy with ovarian preservation both appear to lower the risk of ovarian cancer, although the mechanisms remain unclear.
Screening and Prevention
Early ovarian cancer is often asymptomatic. No available screening test has sufficient positive predictive value for early-stage ovarian cancer.
Routine yearly pelvic examination is currently recommended for the general population as a screening tool, but it has poor sensitivity for detecting early disease.
Cancer antigen 125 (CA-125) is a biomarker for ovarian cancer. A level >35 U/mL in postmenopausal women is usually considered abnormal. Approximately 50% of ovarian cancer cases confined to the ovary, and >85% of advanced ovarian cancer cases have elevated CA-125 levels. However, this biomarker alone is neither sufficiently sensitive nor specific enough to be diagnostic for ovarian cancer.
CA-125 levels may be elevated in several benign conditions (including pelvic inflammatory disease, endometriosis, fibroids, pregnancy, hemorrhagic ovarian cysts, liver disease, and any other lesion that causes peritoneal irritation) as well as in other malignant conditions (including breast, lung, pancreatic, gastric, and colon cancer). In addition, CA-125 is normal in approximately half of women with stage I ovarian cancer. The most important use is following serial CA-125 levels to monitor response to treatment and to detecting recurrence in women with known ovarian cancer.
Human epididymis protein 4 (HE4) has similar sensitivity to CA-125 when ovarian cancer patients are compared to healthy controls; however, it has greater sensitivity when compared to those with benign gynecologic disease. Although not yet used for screening, HE4 is currently approved in the United States for monitoring disease progression or recurrence.
Other biomarkers: CA 19-9, CA 15-3, CA 72-4, carcinoembryonic antigen, lysophosphatidic acid, sFas, mesothelin, haptoglobin-alpha, bikunin, HE4, and OVX1 are and have been investigated with combined biomarker tests commercially available for use in high-risk patients.
Transvaginal ultrasonography has been evaluated as a potential screening tool. Characteristics suggestive of malignancy include complex ovarian cysts with solid components, the presence of septations, papillary projections into the cyst, thick cyst walls, surface excrescences, ascites, and neovascularization. When used to screen the general population, transvaginal ultrasonography has a poor positive predictive value. However, when limited to postmenopausal women with pelvic masses, a sensitivity of 84% and specificity of 78% has been reported.
Multimodal screening using CA-125 measurement with transvaginal ultrasonography yields a higher specificity and positive predictive value than either modality alone. In postmenopausal women, the combination of transvaginal ultrasound
and a CA-125 >65 U/mL increased sensitivity to 92% and specificity to 96%. However, the role of multimodal screening remains unclear.
A large prospective screening study, the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, found that concurrent multimodal screening did not reduce ovarian cancer mortality. Another ongoing large randomized trial, the United Kingdom Collaborative Trial of Ovarian Cancer Screening, demonstrated sequential multimodal screening (abnormal CA-125 followed by transvaginal ultrasound) to have a much greater sensitivity for primary ovarian and tubal cancers compared to transvaginal ultrasound alone in the initial years of screening. Final results are not expected until 2015. For this reason, additional studies are needed to determine the appropriateness of multimodal screening for ovarian cancer at this time.
Current recommendations for screening: According to the U.S. Preventive Services Task Force, no existing evidence suggests that any screening test, including CA-125, ultrasound, or pelvic examination, reduces mortality from ovarian cancer; therefore, routine screening is not recommended. The American College of Obstetricians and Gynecologists (ACOG) agrees that routine screening tests are not beneficial for low-risk, asymptomatic women. ACOG advises the obstetriciangynecologist to remain vigilant for the early signs and symptoms of ovarian cancer. The American Cancer Society does not recommend routine screening but states that women at high risk of ovarian cancer should be offered the combination of a pelvic exam, transvaginal ultrasound, and CA-125.
Prophylactic bilateral salpingo-oophorectomy: Women older than age 45 years who are undergoing any pelvic surgery may consider prophylactic removal of the ovaries and fallopian tubes. A bilateral salpingo-oophorectomy will essentially eliminate the risk for developing ovarian cancer, although a small risk of developing primary peritoneal cancer still remains. The sequelae of surgical menopause must be weighed against the potential benefit of averting ovarian malignancy.
For this reason, there is no commonly agreed upon age at which bilateral salpingooophorectomy is recommended for normal-risk women, although studies have shown that prophylactic oophorectomy prior to age 45 years may decrease life span and risk of all-cause mortality.
Women at high risk of ovarian cancer (e.g., Lynch syndrome, BRCA mutations) should consider prophylactic bilateral salpingo-oophorectomy when childbearing is complete.
OCP prophylaxis is the only documented method of chemoprevention for ovarian cancer, and the effect is substantial. The overall estimate of protection with OCPs is approximately 40%. Increased duration of use appears to be associated with further decreased risk, and the protective effect persists for 10 or more years after discontinuation. The use of OCPs in BRCA mutation carriers also confers a decreased risk of ovarian cancer without increasing the risk of breast cancer.
Presentation and Diagnosis
Presentation: Only 19% of ovarian cancer cases are diagnosed while the cancer is localized (stage I), and approximately 68% of patients with epithelial ovarian cancer have advanced disease (stage III or greater) at time of diagnosis. Although some women with early disease experience symptoms, the majority are asymptomatic.
When symptoms develop, they are nonspecific and can include abdominal bloating, early satiety, weight loss, constipation, anorexia, urinary frequency, dyspareunia, fatigue, and irregular menstrual bleeding.
TABLE 48-2 Risks of Specific Types of Cancers Associated with Autosomal Dominant Genetic Risk Syndromes
Genetic Syndrome
BRCA1
BRCA2
HNPCC
Type of Cancer
Ovarian cancer
25%-60%
15%-25%
12%
Breast cancer
82%
82%
Not associated
Endometrial cancer
Not associated
Not associated
40%-60%
Colon cancer
Possibly increased risk
Not associated
70%-80%
Stomach cancer
Not associated
Possibly increased risk
20%
HNPCC, hereditary nonpolyposis colorectal cancer.
On physical examination, a pelvic mass is an important sign of disease. In more advanced stages, abdominal distention may develop, and chest examination may reveal evidence of pleural effusion.
Workup: Evaluation of a pelvic mass varies depending on the patient’s age, significant medical and family history, and the sonographic characteristics of the mass. Women with pelvic masses that are suspicious for malignancy should be referred to a gynecologic oncologist (Table 48-2). In premenopausal women, an adnexal mass <8 to 10 cm in diameter with no other concerning features is typically monitored with serial sonograms. If the decision is made to proceed with surgical evaluation, the preoperative evaluation should include a full history and physical examination, including a pelvic examination and a Pap smear.
Additional tests should be performed on the basis of a patient’s risk factors and underlying medical status. Consideration should be given to performing a computed tomography (CT) scan of the chest, abdomen, and pelvis to evaluate for metastatic disease. If surgery is necessary, a surgeon capable of performing an adequate staging procedure should be available, preferably a gynecologic oncologist, to optimize outcomes in cases of malignancy.
Staging and Prognosis
Epithelial ovarian tumors are classified by cell type and behavior as benign, atypically proliferating, or malignant. Atypically proliferating tumors are also referred to as tumors of low malignant potential (LMPs) or “borderline” tumors.
Ovarian cancer is surgically staged (Table 48-3). The importance of complete surgical staging in treatment planning and prognosis cannot be overemphasized. The standard surgical approach involves a vertical midline incision to allow for adequate exposure, although more recent advances in laparoscopic surgery have made minimally invasive options available (Table 48-4).
Ovarian cancer can spread by direct extension, by exfoliation of cells into the peritoneal cavity (transcoelomic spread), via the bloodstream, or via the lymphatic system. The most common pathway of spread is transcoelomic. Cells from the tumor are shed into the peritoneal cavity and circulate following the clockwise path of the
peritoneal fluid. All peritoneal surfaces are at risk. Lymphatic spread to the pelvic and para-aortic lymph nodes can occur. Hematogenous spread to the liver or lungs can occur in advanced disease.
TABLE 48-3 Pelvic Gynecologic Oncology Referral Mass Evaluation: Criteria for Gynecologic Oncology Referral | ||||||||||||
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Prognostic Factors
The most important prognostic factors are stage, grade, histology of the tumor, the amount of residual disease remaining after initial debulking surgery, and the age of the patient.
The 5-year survival rate of patients with epithelial ovarian cancer correlates directly with tumor stage (Table 48-5).
Within each histologic subtype, tumors may be described as benign, of LMP, or malignant.
The serous subtype is the most common, accounting for over 50% of all malignant ovarian tumors. Approximately one third are malignant, one half are benign, and one sixth are LMP. Serous carcinoma of the ovary closely resembles fallopian tube and peritoneal cancer in histology as well as in clinical behavior, and thus, they are often referred to as one entity. The mean age of patients at diagnosis is 57 years. Psammoma bodies are present in 25% of serous tumors.
Mucinous tumors are lined by cells that resemble endocervical glands or intestinal epithelium. Primary ovarian mucinous tumors account for 3% to 4% of epithelial tumors. Sixty percent of mucinous tumors are stage I, and most are unilateral. They are typically large, often filling the abdominal cavity, cystic, and multiloculated. The mean age of patients diagnosed with malignant mucinous tumors is 54 years. CA-125 levels may not be markedly elevated.
Pseudomyxoma peritonei is a condition associated with mucinous neoplasms, usually of gastrointestinal origin, and is characterized by gelatinous mucus or ascites in the abdomen.
Primary ovarian mucinous tumors may be difficult to differentiate from metastatic neoplasms of the gastrointestinal tract (colon, appendix, pancreas). Prior studies have shown that in general, primary ovarian mucinous tumors are unilateral and measure $10 cm, whereas metastatic tumors are bilateral and measure <10 cm in diameter. Using these criteria, approximately 84% of all mucinous tumors are correctly classified, including 100% of primary ovarian tumors.
TABLE 48-4 International Federation of Gynecology and Obstetrics Staging System for Carcinoma of the Ovary (1988)
Stage
Tumor Characteristics
I
Growth limited to the ovaries
IA
Growth limited to one ovary; no ascites; no tumor on the external surface; capsule intact
IB
Growth limited to both ovaries; no ascites; no tumor on the external surfaces; capsule intact
IC
Tumor either stage IA or IB but with tumor on surface of one or both ovaries; or with capsule ruptured; or with ascites present containing malignant cells; or with positive peritoneal washings
II
Growth involving one or both ovaries with pelvic extension
IIA
Extension or metastases to the uterus or tubes
IIB
Extension to other pelvic tissues
IIC
Tumor either stage IIA or IIB but with tumor on surface of one or both ovaries; or with capsule ruptured; or with ascites present containing malignant cells; or with positive peritoneal washings
III
Tumor involving one or both ovaries with peritoneal implants outside the pelvis and/or positive retroperitoneal or inguinal nodes. Superficial liver metastasis equals stage III. Tumor is limited to the true pelvis but with histologically proven malignant extension to small bowel or omentum.
IIIA
Tumor grossly limited to the true pelvis with negative nodes but with histologically confirmed microscopic seeding of abdominal peritoneal surfaces
IIIB
Tumor of one or both ovaries with histologically confirmed implants of abdominal peritoneal surfaces, none exceeding 2 cm in diameter; nodes are negative
IIIC
Abdominal implants >2 cm in diameter or positive retroperitoneal or inguinal nodes
IV
Growth involving one or both ovaries, with distant metastases. If pleural effusion is present, cytologic findings must be positive to allot a case to stage IV. Parenchymal liver metastasis equals stage IV.
From Current FIGO staging for cancer of the vagina, fallopian tube, ovary, and gestational trophoblastic neoplasia. FIGO Committee on Gynecologic Oncology. Int J Gynecol Obstet 2009;105:3-4.
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