Ovarian Cancer: Early DetectionWHEC Practice Bulletin and Clinical Management Guidelines for healthcare providers. Educational grant provided by Women's Health and Education Center (WHEC).
Although ovarian cancer is the second most common female reproductive cancer, preceded by cancer of the uterus, more women die from ovarian cancer than from cervical and uterine cancers combined. Ovarian cancer remains the most lethal of the gynecologic malignancies. Each year, approximately 16,000 women die of the disease. The poor prognosis of ovarian cancer often is attributed to the fact that it is a "silent" cancer, with symptoms appearing only late in the disease process. However, more attention is being directed toward the study of the early warning symptoms of ovarian cancer (eg, persistent abdominal complaints, urinary frequency, and fatigue) to determine if closer attention to these symptoms can lead to an earlier diagnosis of the disease (1). In this survey of 1,725 women with ovarian cancer, 70% recalled having symptoms for 3 months or longer before the diagnosis, and 35% recalled having symptoms for at least 6 months. About three fourths of these women had abdominal symptoms and half had pain or constitutional symptoms. Currently, it appears that the best way to detect early ovarian cancer is for both the patient and her healthcare provider to have a high suspicion of the diagnosis in the symptomatic woman. A precursor lesion, while thought by many to exist, has so far not been successfully identified.
The purpose of this document is to understand various screening tests available and advances in the early detection of ovarian cancer. The role of the generalist obstetricians -- gynecologists and primary care physicians in early detection of ovarian cancer is also defined in this article. Recommended cancer-screening protocols in women with high-risk is also discussed. Data suggest that currently available screening tests do not appear to be beneficial for screening low-risk, asymptomatic women. An annual gynecologic examination with an annual pelvic examination is recommended for preventive health care. Approximately one in 70 women will develop ovarian cancer in their lifetime. This increases to 4% to 6% if there is a family history in a first-degree relative.
All the evidence suggests that a precursor lesion may exist that could be followed over time. However, unlike the cervix, the ovary is not easily accessible for screening examination, and it is not clear whether a Pap smear of the ovary will ever be clinically relevant. Annual pelvic examination is recommended for all women over age 18. The low incidence of ovarian cancer combined with low sensitivity of physical examination of the pelvic organs severely limits the usefulness of physical examination for early detection of ovarian tumors. A woman with a suspicious or persistent complex adnexal mass requires surgical evaluation. Diagnostic criteria based on physical examination and imaging techniques that should be used to consider referral to or consultation with a gynecologic oncologist are as follows (2):
- Postmenopausal women who have a pelvic mass that is suspicious for a malignant ovarian neoplasm, as suggested by at least one of the following indicators: elevated CA 125 level; ascites; a nodular or fixed pelvic mass; evidence of abdominal or distant metastasis; a family history of one or more first-degree relatives with ovarian or breast cancer.
- Premenopausal women who have a pelvic mass that is suspicious for a malignant ovarian neoplasm, as suggested by at least one of the following indicators: very elevated CA 125 level (eg, >200 U/mL); ascites; evidence of abdominal or distant metastasis; a family history of a one or more first-degree relatives with ovarian or breast cancer.
Role of Ultrasound:
Although pelvic ultrasound appears to have higher sensitivity than CA 125 for preclinical ovarian cancer, the major limitation to the use of pelvic ultrasound as a screening test for ovarian cancer is its relative lack of specificity. Even in the most experienced hands, definitive distinction between early benign and malignant ovarian neoplasms is often not possible on the basis of their ultrasonic appearance alone. Introduction of transvaginal ultrasound has allowed superior imaging of the ovaries as compared with a transabdominal approach. Additionally, in an attempt to better quantify the likelihood of malignancy, morphologic criteria suggestive of malignancy have been utilized to develop ultrasound-scoring systems.
To better understand the ultrasonographic appearance of postmenopausal ovaries, one must first understand what happens anatomically. Folliculogenesis ceases. The tunica albuginea becomes very dense causing the surface of the ovary to become scarred and shrunken. So a lingering question is: will the failure to identify normal ovaries on ultrasound be as reassuring as definitively locating them and seeing them as atrophic? Obviously the percentage of normal postmenopausal ovaries identified on ultrasound depends on the skills of the ultrasonographer. The ultrasound community has long been concerned with adnexal cysts. This is because 85% of ovarian tumors are epithelial, and virtually all of these will have some cystic component at some point in their growth. A more recent analysis of cystic structures in asymptomatic postmenopausal women greater than 50 years of age was reported by Bailey et al (3). Of 7,705 women scanned, unilocular cysts were present in 3.3% (N=256). Of these, 49% resolved in 60 days, 51% persisted. 45 women who were operated on displayed no malignancies; 32 (71%) were cystadenomas. This is the same ratio as the simple cysts operated on in one of the original papers in the mid-1980s. In the series by Bailey et al, 86 women were followed every 3 to 6 months with no development of any malignancies.
It is important to remember that not all cystic adnexal structures are ovarian in origin. Some will be paraovarian, peritoneal inclusion cysts from prior surgery, or even hydrosalpinges. The evidence suggests that the majority of unilocular ovarian cysts <5 cm are benign and remain unchanged or resolve. These lesions can be managed expectantly as long as there is no increase in size, change in morphology, or abnormal levels of CA 125. Transvaginal color flow Doppler to assess the vascularity of the ovarian vessels has been shown to be useful adjunct to ultrasonography, but it has not shown to be useful in screening (4).
It is likely that despite advancing technology, no single biomarker will be identified that has high enough sensitivity or specificity to be used alone for the early diagnosis of ovarian cancer.
CA 125: It is an antigenic determinant of a high-molecular-weight glycoprotein recognized by a monoclonal antibody (OC 125), which is raised against a papillary serous ovarian cancer cell line. CA 125 is expressed by ovarian epithelial tumors in addition to normal and pathologic tissues of Mullerian origin. Because CA 125 levels are elevated in various non-gynecologic malignant conditions as well as in physiologic and benign gynecologic conditions, its specificity for early ovarian cancer detection, especially in premenopausal women is limited. It was originally hoped that CA 125 would be a useful screening tool for ovarian cancer detection. Pre-operative CA 125 levels were found to be elevated to >35 U/mL in up to 85% of women with epithelial ovarian cancer as compared with 1% of healthy controls. In some women, CA 125 levels are elevated up to 60 months before the clinical detection of ovarian cancer. However, only 50% of patients with stage I disease have elevated CA 125 levels. Furthermore, using a reference level of 35 U/mL, requiring a sensitivity of 50% and specificity of 99%, the positive predictive value of CA 125 as a screening test in asymptomatic women would be only 2.4%, well under the minimal acceptable level of 10%. Two distinct screening strategies have emerged, one based on ultrasonography and the other based on measurement of the serum tumor marker CA 125 with ultrasonography as the secondary test (multimodal screening). Overall data from large prospective studies of screening for ovarian cancer in the general population suggest that sequential multimodal screening has superior specificity as compared with strategies based on transvaginal ultrasound alone. However, ultrasonography as a first-line test may offer greater sensitivity for early-stage disease (5).
New tumor markers that may be useful in screening for ovarian carcinoma are: CA 72-4 or TAG 72; M-CSF; OVX1; LPA; Prostasin; Osteopontin; Inhibin; Kallilrein. It is likely that in future, the early detection of ovarian cancer will involve high throughput proteomic profiling, either alone or in combination with markers already in use. Use of multiple markers may increase the sensitivity for early detection of ovarian cancer. However, increased sensitivity is usually associated with decreased specificity.
Proteomics: the rapidly advancing field of proteomics is another approach to biomarker discovery. It is hoped that proteomics methods will lead to the identification of markers that due to modifications after protein synthesis, would be missed by DNA or RNA analysis. The technique of surface-enhanced laser desorption ionization time-of-flight (SELDI-TOF) technology is increasingly being utilized for the global analysis of proteins in complex solutions such as plasma, serum and urine.
Genetic Risk for Epithelial Ovarian Cancer:
The risk of ovarian cancer is higher than that of the general population in women with certain family histories. Most epithelial ovarian cancer is sporadic, with familial or hereditary patterns accounting for 5% to 10% of all malignancies. Genetic testing is appropriate only when pre- and post-test counseling is available, the test can be interpreted, and the results will help in medical and surgical management. Ideally, testing should take place in the setting of a multi-disciplinary team with expertise in the interpretation of verified family cancer pedigrees and in the medical, emotional, financial and legal ramifications of genetic testing. One of the most important roles of a genetic counselor is constructing as accurate a pedigree as possible.
BRCA 1 and BRCA 2: Most hereditary ovarian cancer is associated with mutations in the BRCA 1 gene that is located on chromosome 17. A small proportion of inherited disease has been traced to another gene, BRCA 2, located on chromosome 13. Discovered through linkage analysis, these two genes are associated with the genetic predisposition to both ovarian and breast cancer. The mutations are passed via autosomal dominance, and thus, a full pedigree analysis, i.e., both maternal and paternal sides of the family must be carefully evaluated. Based on analysis of women who have a mutation in the BRCA 1 gene and are from high-risk families, the lifetime risk of ovarian cancer may be as high as 28% to 44%, and the risk has been calculated to be as high as 27% for those women with a BRCA 2 mutation (6). Hereditary ovarian cancers generally occur in women about 10 years younger than those with non-hereditary tumors. As the median age of epithelial ovarian cancer is in mid- to late 50s, a woman with a first- or second-degree relative who had premenopausal ovarian cancer may have a higher probability of carrying an affected gene. Breast and ovarian cancer may exist in a family in which there is a combination of epithelial ovarian and breast cancer, affecting a mixture of first- and second-degree relatives. Women with this syndrome tend to have their breast cancers at a very young age, and the breast cancers may be bilateral. If two first-degree relatives are affected, this pedigree is consistent with an autosomal dominant mode of inheritance.
There is a higher carrier rate of BRCA 1 and BRCA 2 mutations in women of Ashkenazi Jewish descent and in Islandic women. The total carrier rate of at least one of these mutations for a patient of Ashkenazi Jewish descent is 1 in 40 or 2.5%, and thus there is a substantial risk in this population. The increase risk is a result of the "founder effect", ie, a higher rate of mutations that have occurred within a defined geographic area. Lynch II syndrome (Hereditary Non-polyposis Colorectal Cancer Syndrome, HNPCC Syndrome), which includes multiple adenocarcinomas, involves a combination of familial colon cancer and a higher rate of ovarian, uterine and breast cancers. A full pedigree analysis of such families should be performed by a geneticist to more accurately determine the risk.
Other Risk Factors:
Findings on the following potential risk factors for ovarian cancer may help address the patient's concern.
Dietary Factors/ Obesity: In a recent study, obesity was associated with an increased risk of ovarian cancer (7). Women who eat a diet high in saturated fat and low in vegetable fiber also may face an increased risk. The reason postulated by the investigators: when compared with matched controls, women with ovarian cancer were more likely to have high levels of galactose, a component sugar of the disaccharide lactose and a known oocyte toxin. This observation, however, has been inconsistent; it is good to advise patients to maintain a normal body mass index.
Talc Exposure: When talc is placed on the perineum, it may enter the vagina and ascend to the upper genital tract. Because, talc is structurally similar to asbestos, it may theoretically increase the ovarian cancer risk. The practice of applying genuine talc to the perineum should be discouraged. Cornstarch-based dusting powders are widely available.
Infertility Drugs: one of the most difficult issues to study is the relationship between infertility drugs and ovarian cancer, although we know that unexplained infertility is an independent risk factor for ovarian cancer. A number of studies, including a large collaborative analysis of 12 case-control studies, have reported an association between infertility drugs and invasive epithelial ovarian cancer (8). In addition, many of the theoretical models of epithelial ovarian cancer pathogenesis implicate both incessant ovulation and high gonadotropin levels as important steps in malignant transformation of ovarian epithelium. It seems prudent, in the absence of convincing data, to use fertility medication only when absolutely indicated, at the lowest effective dose, and for the shortest duration possible without compromising treatment success. However, prior exposure to these agents should not be considered an indication for increased surveillance or prophylactic surgery.
Estrogen Replacement Therapy: although some studies suggest a protective effect of combination hormone replacement regimens that include both estrogen and progesterone, this observation has not been confirmed. Thus, long-term estrogen users should consider an increased risk of developing ovarian cancer when deciding whether to initiate or continue estrogen replacement therapy.
Management of Women at High-risk for Ovarian Cancer:
The management of a woman with a strong family history of epithelial ovarian cancer must be individualized and depends on her age, her reproductive plans, and the extent of risk. In all of these syndromes, women at risk benefit from a thorough pedigree analysis. The value of testing for BRCA 1 and BRCA 2 has been clearly established, and some guidelines for testing now exist. The importance of genetic counseling cannot be overemphasized, as the decision is complex. Although recommended by the National Institutes of Health (NIH) Consensus Conference on Ovarian Cancer, the value of screening with transvaginal ultrasonography, CA 125 levels, or other procedures has not been clearly established in women at high risk. This approach can detect tumors about 10 times more often than in the general population, and thus they recommend screening for high-risk women (9). Data derived from a multi-institutional consortium of genetic screening centers indicate that the use of the oral contraceptive pill is associated with a lower risk of development of ovarian cancer in women who have a mutation of either BRCA 1 (but not BRCA 2) mutations, but the protective effect is not nearly as strong as oophorectomy.
Current recommendations for management of women with high-risk for ovarian cancers are summarized below (10):
- Women who appear to be at high-risk for ovarian and or breast cancer should undergo genetic counseling and, if the risk appears to be substantial, may be offered genetic testing for BRCA 1 and BRCA 2.
- Women who wish to preserve their reproductive capacity can undergo periodic screening by transvaginal ultrasonography every 6 months, although the efficacy of this approach is not clearly established.
- Oral contraceptives should be recommended to young women before a planned family.
- Women who do not wish to maintain their fertility or who have completed their family should be recommended to undergo prophylactic bilateral salpingo-oophorectomy. The risk should be clearly documented, and preferably established by BRCA 1 and BRCA 2 testing, preoperatively. These women should be counseled that this operation does not offer absolute protection, because peritoneal carcinomas may occasionally occur. The concurrent performance of a prophylactic hysterectomy is acceptable, and the option should be discussed with these patients.
- In women who have a strong family history of breast or ovarian cancer, annual mammographic screening should be performed commencing at age 30 years.
- Women with a documented HNPCC syndrome should be treated as above, but in addition, they should undergo periodic screening mammography, colonoscopy, and endometrial biopsy.
Pros and Cons of Risk-Reducing Salpingo-Oophorectomy:
Surgical menopause after prophylactic bilateral salpingo-oophorectomy (BSO) is associated with several detrimental sequelae, including vasomotor symptoms, vaginal atrophy, decreased libido, an accelerated onset and incidence of osteoporosis and cardiovascular disease. Peritoneal serous carcinoma, indistinguishable histologically or macroscopically from ovarian cancer, has been described in rare instances after prophylactic BSO, but the origin of these cancers is unclear (11). It is possible that some serous cancers that occur after prophylactic BSO may arise from benign peritoneal glandular inclusions (endosalpingiosis) rather from the peritoneum. The adnexa are relatively easy to remove completely. Attention should be paid to transaction the ovarian blood vessels at least 2 cm proximal from the ovary so that ovarian remnants are not left behind. If there are adhesions between the adnexa and adjacent structures, careful dissection should be performed to ensure complete removal of the ovaries and fallopian tubes.
Pros of prophylactic BSO: decreases ovarian and fallopian tube cancer incidence and mortality; can often be delayed to allow completion of childbearing; laparoscopic approach possible in most cases; impact on body image generally acceptable; estrogen replacement can prevent consequences of surgical menopause; and decrease breast cancer risk. Cons for prophylactic BSO: cost; potential morbidity and mortality; small but residual potential for subsequent primary peritoneal carcinoma; and surgical menopause in premenopausal patients who elect not to take hormone replacement.
Malignant cells have been found in pelvic peritoneal washings from women undergoing prophylactic BSO, and in some of these cases a primary cancer in the ovary or fallopian tube cannot be identified. In view of these data, it seems reasonable to recommend that cytologic washings of the pelvis be obtained when performing prophylactic BSO. The pathologist should be informed of the indication for prophylactic BSO and multiple sections of the ovaries and fallopian tubes should be examined to exclude the presence of occult carcinoma. There is some evidence to suggest that the tubal fimbria may be the most common site of cancer development in BRCA mutation carries (12).
Currently, there are no techniques that have proved to be effective in the routine screening of asymptomatic low-risk women for ovarian cancer. Although newer tumor markers and proteomics are undergoing investigation and appear promising for screening, it is unclear whether they will help identify high-risk women or facilitate the early diagnosis of more women with ovarian cancer. Given the false-positive results for both CA 125 and transvaginal ultrasonography, particularly in premenopausal women, these tests are not cost-effective and should not be used routinely to screen for ovarian cancer. Effective primary prevention strategies such as chemoprophylaxis and prophylactic surgery, when appropriately applied, may spare many women the devastating consequences of this dreaded disease.
- World Health Organization
National Cancer Control Programs (pdf)
- U. S. National Institutes of Health (NIH)
- Centers of Disease Control and Prevention (CDC)
Ovarian Cancer Awareness
- Goff BA, Mandel LS, Melancon CH, et al. Frequency of symptoms of ovarian cancer in women presenting to primary care clinics. JAMA. 2004;291:2705-2712.
- Committee Opinion ACOG. The Role of Generalist Obstetrician -- Gynecologist in Early Detection of Ovarian Cancer. Number 280, December 2002.
- Bailey CL, Ueland FR, Land GL et al. The malignant potential of small cystic ovarian tumors in women over 50 years of age. Gynecol Oncol. 1998;69:3-7.
- Kurjak A, Kupesic S, Sparac V et al. The detection of stage I ovarian cancer by three-dimensional sonography and power Doppler. Gynecol Oncol. 2003;90:258-264.
- Garner EI. Advances in the early detection of ovarian carcinoma. J Reprod Med. 2005;447-453.
- Frank TS, Manley SA, Olopade OI et al. Sequence analysis of BRCA 1 and BRCA 2: correlation of mutations with family history and ovarian cancer risk. J Clin Oncol. 1998;16:2417-2425.
- Engeland A, Tretli S, Bjorge T. Height, body mass index, and ovarian cancer; a follow-up of 1.1 million Norwegian women. J Natl Cancer Inst. 2003;95:1244-1248.
- Rossing MA, Daling JR, Weiss NS et al. Ovarian tumors in a cohort of infertile women. N Engl J Med. 1994;331:771-776.
- NIH Consensus Development Panel on Ovarian Cancer. Ovarian cancer: screening, treatment and follow-up. JAMA. 1995;273:491-497.
- Berek JS: Epithelial Ovarian Cancer. In Practical Gynecologic Oncology. Edited by JS Berek, NF Hacker. 4th edition. Publishers: Lippincott Williams and Wilkins. 2005; pp 449-450.
- Finch A, Beiner M, Lubinski J et al. Salpingo-oophorectomy and the risk of ovarian, fallopian tube, and peritoneal cancers in women with a BRCA1 or BRCA2 mutation. Hereditary Ovarian Cancer Clinical Study Group. JAMA. 2006;296:185-192
- Karlan BY, Berchuck A, Mutch D. The role of genetic testing for cancer susceptibility in gynecologic practice. Obstet Gynecol. 2007;110:155-167.
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