2ª PONENCIA
FACTORES DE RIESGO EN GINECOLOGÍA ONCOLÓGICA
Cancer of the ovary: risk factors, screening and prevention1
C. Paul Morrow, MD
Charles Langmade Professor of Gynecology
University of California School of Medicine
Women and Childrens Hospital
1240 N. Mission Road
Los Angeles, CA 90033
1 From: Etiology and Detection of Gynecologic Cancer, in Sypnosis of Gynecologic Oncology, Morrow CP and Curtin JP, 5th Edition, Churchill Livingstone, 1998, pp. 1-15.
1. EPIDEMIOLOGY OF OVARIAN CARCINOMA
A. Epithelial Ovarian Cancer
From the viewpoint of morbidity and mortality, ovarian malignancies are the most important group of neoplasms in the field of gynecologic oncology. In the United States, only 35 percent of all women diagnosed as having ovarian cancer survive 5 years. The number of deaths per year increased by 250 percent from 1930 to 1970, although the mortality rate has been stable over the past 20 years. The U.S. estimates for 1997 anticipate approximately 26,800 new cases and 14,200 deaths due to this malignancy. The number of deaths from ovarian cancer surpasses the combined number of deaths from endometrial cancer (6,000/year) and cervical cancer (4,800/year).
Ovarian cancer is predominantly a disease of peri- and postmenopausal women, with an average age of 54 years at diagnosis. The histologic type of neoplasm and the overall frequency of occurrence vary with age. In children and young women of less than 20 years of age, 60 percent of ovarian neoplasms are of germ cell origin. However, over 80 percent of ovarian tumors that occur in postmenopausal women are epithelial adenocarcinomas. Borderline ovarian tumors occur most often in younger women and are more commonly confined to the ovary than are invasive ovarian tumors (Harlow y cols., 1987).
The worldwide incidence rate varies from 2.5 per 100,000 women in Japan to 15 per 100,000 women in Scandinavian countries (Parazzini y cols., 1991). In the United States, the annual incidence for white women is 13 per 100,000 women, which is one of the highest rates in the world. The rate for black women is 10 per 100, 000 women.
Many epidemiological studies have related reproductive events to the risk of epithelial ovarian cancer (Table 1). Women who are nulliparous, have not used oral contraceptives, or are infertile have a higher rate of ovarian cancer (Bristow and Karlan, 1996). The theory of incessant ovulation (Fathalla, 1972) has been addressed in several case-control studies. The greater the duration of ovulation (i.e., no pregnancies, no ovulation suppression, and late versus early menopause), the greater the risk of developing ovarian cancer (Casagrande y cols., 1979; Beral y cols., 1988). Other risk factors, such as high socioeconomic status and ethnic background, merely reflect the associated low parity and/or high-fat diet in this subset of the general population (Heintz y cols., 1985; Rose y cols., 1986). There is an increased risk of ovarian cancer in women with a prior history of malignancy, particularly breast and colon cancers (Rosen y cols., 1989). Endometrial cancer is also associated with ovarian cancer, usually synchronously.
Table 1 Risk Factors and Ovarian Carcinoma | |
| Risk Factor | Relative Risk |
| Positive Family History | |
| One First Degree Relative | 1.9-3.6 |
| Hereditary | 17-50 |
| Breast Cancer | 1.0-1.6 |
| Nulliparous vs. Parous | 4.0-5.0 |
| Oral Contraceptive Use (> 3-5 years) | 0.5 |
| White vs Black Race | 1.5 |
| High Fat Diet | 1.5-4.0 |
| Talc Use | 3.0 |
| Source: Beral y cols. 1988; Casagrande y cols. 1979; Cramer y cols. 1982a, b; Lynch y cols. 1985; Mori y cols. 1984; Schildkraut y cols. 1988. | |
Familial and Hereditary Ovarian Cancer
Among women with ovarian cancer, approximately 5 to 7 percent will report a family history of ovarian and/or breast cancer. Broadly speaking, there are three categories of patients:(1) those with no significant family history of cancer;(2) those who have a positive family history (i.e., one or more first-degree relatives with ovarian and/or breast cancer) and who therefore may have an increased risk of an ovarian malignancy; and(3) those with a hereditary or genetic predisposition to develop epithelial ovarian cancer. A careful family history and, if possible, review of pertinent pathology allows the clinician to make a preliminary determination as to whether the patient is at increased risk of developing ovarian cancer. Schildkraut and Thompson (1988) estimated that the increase in relative risk for women with a history of ovarian cancer in first-degree relatives was 3.6, and for second-degree relatives was 2.9, compared with women who reported a negative family history.
When a hereditary syndrome is suggested by the family history, referral to a clinical genetics service is recommended. Ovarian cancer risk is increased in three syndromes: ovarian-specific cancer syndrome, breast/ovarian cancer syndrome, and hereditary non-polyposis colorectal cancer or Lynch 11 syndrome. These can be presumptively identified by pedigree analysis or by testing for the responsible gene (Lynch y cols., 1991, 1996; Claus y cols., 1996). Among all women with ovarian cancer, approximately 2 to 5 percent develop their cancer as a result of a genetic susceptibility (Whittemore y cols., 1997). Previously, these women were identified when there was evidence of two or more first-degree female relatives with ovarian cancer plus or minus breast cancer. The most common form of hereditary ovarian cancer is a component of the breast/ovarian cancer syndrome; mutations of a gene designated BRCA-1, located on the long arm of chromosome 17, are thought to account for the majority of hereditary ovarian cancers (Miki y cols., 1994). Another gene, BRCA-2, which is located on the long arm of chromosome 13, has also been linked to hereditary ovarian cancer. Both the BRCA-I and BRCA-2 genes have been cloned, and it is now possible to test an individual for germ-line mutations of either of these genes. Among women with BRCA-I mutations, the estimated lifetime risk of developing ovarian cancer ranges from 10 to 70 percent (Claus y cols., 1996). Given the far-reaching implications of testing positive for a gene mutation associated with a hereditary predisposition to cancer, the testing should be carried out in a setting that can provide comprehensive counseling, as well as long-term follow-up of the patient and her extended family.
B. Non-epithelial Ovarian Cancer
Because of the relative rarity of non-epithelial ovarian neoplasms, epidemiological data regarding their incidence and risk factors are not as extensive as those available from studies of epithelial ovarian cancers. Familial occurrences have been reported for dysgerminoma, Sertoli-Leydig cell tumors (sometimes associated with thyroid nodules), and benign cystic teratomas.
Certain genetic syndromes are known to be commonly associated with ovarian neoplasms. Women who have an XY karyotype or a Y fragment (i.e., gonadal dysgenesis) are predisposed to develop gonadoblastomas, which often give rise to dysgerminomas and occasionally other germ cell malignancies. Case-control studies of patients with ovarian germ cell tumors have suggested that in utero exposure to high levels of estrogen (exogenous or endogenous) may be a risk factor for development of these rare tumors (Walker y cols., 1988). Patients who have a history of surgical resection of a benign cystic teratoma are reported to be at increased risk of developing a malignant germ cell tumor of the ovary (Anteby y cols., 1994). The Peutz-Jeghers syndrome of buccal pigmentation and intestinal polyposis is associated with a 5 percent incidence of gonadal stromal tumors. Women with Gorlin''s syndrome (multiple nevoid basal carcinomas) may develop ovarian fibromas.
2. SCREENING FOR OVARIAN CANCER
Screening for ovarian cancer, the most deadly of all gynecologic cancers, is an unrealized goal. Despite therapeutic advances in the treatment of advanced ovarian cancer, it is unlikely that these methods will provide a means of regularly eradicating disease that has spread beyond the ovary at diagnosis. A more reasonable prospect for improving the prognosis of ovarian cancer is early diagnosis. Routine pelvic examination is ill suited to mass screening for ovarian cancer. MacFarlane y cols. (1955) discovered six ovarian carcinomas during 18,753 pelvic examinations of 1,319 women ages 30 to 90 years in a 15-year study. Five of the six died of ovarian cancer.
Atypical or malignant cells found in a Pap smear when the lower genital tract is normal should lead to prompt evaluation of the tubes and ovaries. Culdocentesis, which provides convenient access to the peritoneal cavity, has been used to obtain fluid for cytologic studies in hopes of detecting early asymptornatic ovarian cancer. Although initial reports of this technique were encouraging, the overall results have been disappointing in terms of unsatisfactory specimens and the yield of asymptomatic, early ovarian cancer. The most significant drawback is patient discomfort, which limits the usefulness of this technique in terms of compliance.
The greatest hope for early diagnosis of ovarian cancer lies in the development of sufficiently sensitive and reliable tests that are suitable to repetitive screening of the population at risk. The evolution of diagnostic pelvic ultrasonography, as well as the development of sensitive laboratory tests for serum antigens associated with ovarian cancers, have shown mixed results for early detection of ovarian neoplasms.
The first clinically useful serum tumor marker for epithelial ovarian cancer was reported by Bast et al (1983). With a monoclonal antibody, the CA-1 25 ovarian cancer-associated antigen is detectable in more than 80 percent of nonmucinous ovarian carcinomas. One limitation of serum CA-125 as a screening too] is that often the patients with early disease confined to the ovary have a normal (< 35 U/ml) level of CA-125. Another limitation is that many benign gynecologic conditions of reproductive-age women may cause an elevated serum CA-125 level. Zurawski y cols. (1990) reported the preliminary results from a trial of serial serum samples tested for CA-1 25. Limiting the definition of a positive test to those patients with an initial elevated level, followed by a subsequent doubling of the initial level, they report that the specificity was 99.9 percent. The one patient in the initial population of 1,000 screened had a stage III ovarian cancer at surgery. As previously discussed, a screening test must be sensitive enough to detect cancers confined to the ovary if overall survival is to be improved. Jacobs and colleagues (1993) suggest that serum CA-125 can be used to screen the general population, and, for those women who are found to have an elevated level, sonography can be used for follow-up.
Screening of women for ovarian cancer by transabdominal and/or transvaginal sonography has focused primarily on identification of abnormal morphology or, in some studies, on volumetric measurement of the postmenopausal ovaries (Campbell y cols., 1989; van Nagell y cols., 1993). The encouraging results of the initial reports of ultrasonic screening for ovarian cancer have been updated and reviewed by Karlan (1995). While it is true that most cases of ovarian cancer diagnosed by ultrasound screening are confined to the ovary, many of the stage I cases are either low-malignant-potential (LMP) tumors or stromal cell cancers that are known to be predominantly stage I at diagnosis. When the cases of invasive epithelial cancers are considered alone, nearly one half of those discovered in screening studies have advanced-stage disease. Thus ultrasound screening requires further investigation, particularly in regard to interval between screenings and the use of serum tumor markers.
The NIH Consensus Development Conference on Ovarian Cancer (1995) recommended that women who are at high risk for ovarian cancer should be screened by annual rectovaginal examinations, serum CA-125 measurement, and transvaginal ultrasound (Table 2). The best age to begin screening is uncertain; age 25 to 30 may be appropriate unless the pedigree analysis demonstrates very-early-onset ovarian cancer. If the patient is at risk because of Lynch 11 syndrome, enclometrial biopsy should be performed on an annual basis in addition to ovarian cancer screening. Mammography and colonoscopy may be indicated depending upon the risk analysis provided by the genetics consult.
Table 2 Recommendations for Ovarian Cancer Screening | ||
| Number of First | ||
| Degree Relatives | Lifetime Risk | Recommendations |
| Affected | of Ovarian Cancer | for Screening |
| None | 1.4% | Annual gyn exam |
| One | 3-5% | Participation in clinical trials Counseling by a Gyn Oncologist |
| Two or more, or positive test (BRCA1 or 2) | 10-70% | Counseling by a Gyn Oncologist Genetic counseling, annual gyn exam, CA 125, and transvaginal UTZ from age 25-30 years |
| Source: NIH Consensus Conference, 1995. | ||
Because women at increased risk for ovarian carcinoma also may be at increased risk for breast and colon cancer, periodic mammography, breast self-examination, testing of the stool for occult blood, and colonoscopy are recommended.
3. PREVENTION OF OVARIAN CARCINOMA
A. Hormones
For each year of oral contraceptive use and each pregnancy the risk for sporadic ovarian carcinoma is reduced approximately 10%. Thus the possibility exists that population-wide-long term use of hormones will lower the overall incidence of ovarian carcinoma. There are limited data as to whether oral contraceptives and/or pregnancy provide the same protection against ovarian cancer to women with a hereditary ovarian cancer syndrome as that demonstrated in the general population.
B. Prophylactic Oophorectomy
1. Genetic Indications
Lynch y cols. (1985, 1991, 1996) have described three cancer family syndromes: 1) site-specific ovarian cancer; 2) ovarian cancer associated with endometrial and colon cancer (Lynch family syndrome 11); and 3) ovarian-breast syndrome. Each appears to follow the law of simple Mendelian inheritance (autosomal dominant) and, therefore, a patient at risk would have a 50% chance of developing ovarian cancer if the penetrance were 100%. The daughter of a male carrier would also have a 50% risk of ovarian cancer. Lynch is careful to distinguish between hereditary cancer family syndromes and «familial» ovarian cancer, in which the patient at risk has either a first- or second-degree relative with a history of ovarian cancer but it is not documented that a transgenerational autosomal dominant gene exists. The woman with a family history of ovarian cancer has a 2-3 fold increased risk of developing ovarian cancer (Table 2).
Elective oophorectomy has been recommended for those patients who are at increased risk of developing ovarian cancer as a result of a genetic predisposition. In most cases, this will first require a genetics consult and possibly genetic testing to confirm the presence of a genetic marker. Testing positive for the BRCA-1 gene is strong evidence that the patient is at increased risk of developing ovarian cancer (Berchuck y cols., 1996). However, if the patient has a family pedigree strongly suggestive of an autosomal dominant inheritance pattern and tests are negative for the known gene alterations associated with hereditary ovarian cancer, the patient may still be at significant risk and ultrasonic screening or prophylactic oophorectomy should be considered.
Management of the patient from a known or suspected ovarian cancer family should include, after age 25-30, semiannual gynecologic and transvaginal ultrasound examinations, oral contraceptives during times when pregnancy is not being undertaken, and early laparoscopic or surgical evaluation of pelvic symptoms or adnexal enlargement. When the patient with hereditary breast/ovarian or ovarian cancer syndrome has completed planned reproduction and she is age 35 years or older, a prophylactic bilateral salpingo-oophorectomy should be offered to her. If the patient is thought to have Lynch 11 syndrome, a prophylactic hysterectomy and bilateral salpingooophorectomy should be recommended since endometrial cancer is the most common form of non-colonic cancer in these women. A laparoscopic procedure is the preferred method of prophylactic surgery. The patients should be informed that the prophylactic removal of the ovaries is not 100% effective in preventing «ovarian» cancer. The reported incidence of primary peritoneal papillary adenocarcinoma, which mimics ovarian carcinoma, ranges from 2-10% following a prophylactic oophorectomy (Piver y cols., 1993; Tobachman y cols., 1982).
Thorough histologic examination of the ovaries is essential. Salazar y cols. (1996) studied the ovaries removed prophylactically from 20 women with a genetic predisposition to ovarian carcinoma and found a high rate of histologic abnormalities (surface papillations, deep invaginations of surface epithelium, and microscopic cystadenomas, inter alia) compared to a control group. The ovaries in 80% of the study group had two or more abnormalities and 75% had three or more abnormalities compared to 30% and 10% for the control group. Two of the 20 patient study group had subclinical carcinomas.
2. Oophorectomy incidental to surgery
In addition to the familial epithelial ovarian carcinoma, there are other indications for oophorectomy to prevent malignancy (Table 3). These include XY gonadal dysgenesis, because of the risk for germ cell malignancy, and incidental oophorectomy in women near or beyond menopause who are undergoing pelvic surgery, usually hysterectomy. The latter could reduce the overall incidence of ovarian carcinoma by 5 percent, since that is approximately the portion of women who develop ovarian carcinoma after having undergone hysterectomy without oophorectomy. Of course the majority of these women underwent vaginal hysterectomy. Perhaps laparoscopic surgery will allow more high-risk women to have prophylactic oophorectomy at the time of hysterectomy.
Table 3 Prophylactic Oophorectomy |
| 1. As primary indication for surgery |
| XY gonadal dysgenesis |
| Familial/hereditary ovarian carcinoma |
| 2. Incidental to hysterectomy or other surgery |
| Prior benign or malignant epithelial ovarian neoplasm |
| Ovarian failure |
| Age beyond 50 years |
| Colorectal cancer |
| Cancer phobia |
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