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2002 Selected Articles

The Scientific Basis for the Accurate Detection of Early Stage Epithelial Ovarian Carcinoma, Part 1

David A. Fishman, MD; Leeber Cohen, MD; Kenny Bozorgi, MD; Diljeet Singh, MD; Anna O’Donnell, RN; MaryAnn Donnelly, RN; Jennifer O’Rourke, RN, MS; Kate Pfeifer, MS, CGC; Thanh Lu; Nita Maihle PhD; Andre Baron PhD; M. Sharon Stack PhD; John Lurain MD; Peter E. Schwartz MD

In the United States, ovarian carcinoma is the leading cause of death from gynecologic malignancies and is the fifth most common female cancer. The incidence of ovarian cancer has been steadily increasing over the past 10 years (overall lifetime risk 1.8%), with the mean age of occurrence at 60 years.¹ This year, approximately 23,300 women will be newly diagnosed with ovarian cancer and 13,900 will die from this disease.¹ Despite significant improvement in surgical technology, critical care, and new chemotherapeutic regimens, the overall 5-year survival for women with stage III/IV epithelial ovarian carcinoma has remained constant (12%) over the past 30 years. However, those women fortunate enough to be diagnosed with disease confined to the ovary (stage IA-IB) often require less morbid surgical intervention, may not require adjuvant chemotherapy, and most importantly, have an overall 5-year survival approximating 90%.² Therefore, short of an effective ovarian cancer-specific therapy, the early detection of early stage epithelial ovarian cancer is essential in decreasing the morbidity and mortality associated with the disease. In part 1, the authors review the scientific basis for the detection of early stage disease, including identification and management of women at increased risk and the use of ultrasound for early detection. In part 2, the future for early detection will be discussed.

The Scientific Basis

An understanding of the biochemical and molecular biology of ovarian carcinogenesis, invasion, and metastasis is critical if we are to identify asymptomatic women at increased risk for ovarian cancer. This knowledge will enable the development of accurate serum/plasma assays for the early detection of asymptomatic ovarian cancer, chemoprevention programs, and ovarian cancer-specific therapies that shift the current paradigm from nonspecific antiproliferative therapy to treatments that prevent invasion and metastatic dissemination.

Identification and Management of Women at Increased Risk

Ovarian cancer most commonly occurs in a sporadic fashion without any antecedent history of disease in the family. Epidemiologic factors associated with ovarian cancer include nulliparity, a personal or family history of colon or breast cancer, an affected first-degree relative with ovarian cancer or a family history of a recognized inherited malignancy syndrome, as well as a history of prolonged use of fertility drugs.^2-5 However, nulliparity and fertility drug use are contested as risk factors because those nulliparous women who used oral contraceptive pills actually have a decreased risk as compared to those with unintended infertility.^6-7 Similarly, the use of infertility medications to achieve fertility does not appear to increase the risk for epithelial ovarian cancer.⁸ Approximately 5% of epithelial ovarian cancers are attributable to the inheritance of highly penetrant mutations in the breast/ovarian cancer susceptibility genes BRCA1 and BRCA2.^3-8

Ovarian cancer is a component of the autosomal dominant hereditary breast-ovarian cancer syndrome, and may be due to a mutation in either the BRCA1 or BRCA2 genes. Two mutations in BRCA1 (185delAG and 5382insC) and one mutation in BRCA2 (6174delT) are common in the Ashkenazi Jewish population. Each mutation is associated with an increased risk of ovarian cancer and it is expected that a significant proportion of Jewish women with ovarian cancer will carry one of these mutations.⁵

Individuals with a family history suggestive of an inherited malignancy syndrome should be considered for genetic counseling and testing. Additionally, the following individuals should be offered formal genetic evaluation and testing as deemed appropriate: women with a diagnosis of breast or epithelial ovarian cancer before age 50; women with a significant family history of breast cancer, (especially premenopausal), or ovarian cancer in one or more affected first-degree relatives; women with a blood relative with a known BRCA1 or BRCA2 mutation; and Ashkenazi women who have ovarian or premenopausal breast cancer or a family history of one or both diseases. Since Narod et al, as well as other authors, reported that approximately 40% of the Jewish women with epithelial ovarian cancer have been found to have a BRCA1 or BRCA2 mutation, it is now the authors’ clinical practice to offer genetic testing to all Jewish women with ovarian cancer.⁵ The benefits of genetic testing for the BRCA mutations include identification of those individuals at increased risk for the development of breast or ovarian cancer, individualizing surveillance measures that may enhance the early detection of cancer, offering prophylactic surgery (mastectomy and/or bilateral salpingo-oophorectomy [BSO]) as well as knowledge of the potential for passing the mutation to future generations. Genetic testing for mutations in these genes also has potential risks such as adverse psychological effects, disruption of family dynamics, and insurance or employer discrimination.

Prior to initiation of genetic testing, it is imperative to assess who is appropriate for such testing, provide expert genetic counseling regarding the implications of genetic testing, and obtain consent from the individual. The American Society of Clinical Oncology (ASCO) as well as the ethical, legal, and social issues branch of the Human Genome Project, emphasize the importance of expert counseling for genetic testing. Genetic counseling is the process of translating medical and scientific knowledge into practical, understandable information for the patient. Unfortunately, there are no accepted guidelines on genetic counseling for cancer, and the quality of counseling provided to patients can be quite variable. The optimal clinical management of individuals who test positive for BRCA mutations is evolving. Therefore, ovarian cancer risk assessment and testing are most effective when performed within the context of a multidisciplinary team approach. The American College of Obstetricians and Gynecologists Committee Opinion states "women with a documented familial history of an inherited malignancy syndrome that increases their risk for the development of ovarian cancer who do not wish to retain fertility may be offered a prophylactic BSO after age 35."^3,9 It is the authors’ practice to only offer BSOto those select women who have completed childbearing and have received formal counseling on laparoscopic surgery to remove the fallopian tubes and ovaries. Unfortunately, approximately 1% to 11% of women continue to develop primary peritoneal carcinoma, a distinct pathologic entity from epithelial ovarian carcinoma, after prophylactic BSO.

Women with a BRCA mutation not desirous of prophylactic surgery may be at a significantly increased risk for the development of ovarian cancer (up to 40%), as well as breast cancer (up to 60%), by age 70 years and therefore require more intensive clinical surveillance.^2-9 Oral contraceptives (OC) have been shown to decrease the risk by approximately 11% per year of use with a maximum decrease approaching 70%.⁷ It is believed that OCs decrease the risk secondary to a reduction in the number of ovulatory cycles a woman experiences in her lifetime, yet the degree of protection is significantly greater than the relative reduction in lifetime ovulations, especially since approximately 30% of women continue to ovulate despite OC use. One means for the enhanced protection has been attributed to the progestin effect on the surface epithelium to induce apoptosis.^10-12

Women at significantly increased risk for the development of ovarian cancer require more intensive clinical surveillance and should consider participation in an IRB-approved research program. The National Ovarian Cancer Early Detection Program (NOCEDP), as part of the National Cancer Institute’s Early Detection Research Network (NCI-EDRN), is committed to the development of effective means for the accurate detection of early stage epithelial ovarian cancer.^9,14-16 Only asymptomatic women with normal gynecologic examinations deemed at increased risk for ovarian cancer are eligible to participate in our IRB-approved program. Eligibility includes those women with at least one affected first-degree relative with ovarian cancer; a personal history of breast, ovarian, or colon cancer; one or more affected first- and/or second-degree relatives with breast and/or ovarian cancer; inheritance of a BRCA mutation from an affected family member; or membership within a recognized cancer syndrome such as HNPCC. All women are seen every 6 months for formal genetic counseling, pelvic examination by a board-certified gynecologic oncologist, ultrasound examination by an expert sonologist, and have blood drawn for investigational biomarker analyses.

The Utility/Futility of Ultrasound for Early Detection

Ultrasound has proven utility in detecting ovarian cancer in asymptomatic women with advanced stage disease. However, its value for the detection of early stage disease has yet to be determined. Multiple studies have reported the utility and limitations of ultrasound for identifying Stage I epithelial ovarian carcinoma in asymptomatic women. As expected, due to the low annual prevalence of ovarian cancer within the general population, a large number of women must be screened to identify a single ovarian cancer. Van Nagell et al reported they performed 57,214 scans on a general population consisting of postmenopausal women and women over age 25 with a family history of ovarian cancer.¹⁷ They identified 11 epithelial ovarian carcinomas, three granulosa cell tumors, and three borderline ovarian tumors. A total of 11 Stage I tumors were identified, five of which were epithelial ovarian carcinoma (EOC), three granulosa cell tumors, and three borderline tumors. Of the Stage I tumors, three were abnormally enlarged as appreciated on clinical examination (two borderline, one EOC), yet only 1 of 15 malignancies (excluding borderline tumors and palpable tumors) developed in women under the age of 50 years. If one excludes granulosa cell and borderline tumors that are usually clinically detected and confined to the ovary (Stage I) due to unknown inherent biological properties, the sensitivity for EOC is approximately 31%. It is also recognized that a negative ultrasound examination, while clinically reassuring, is imperfect as women continued to develop advanced stage ovarian cancer within 6 to 12 months of a normal scan. Therefore, a major limitation of transvaginal architectural screening is that ovarian cancers can arise from normal sized, structurally normal appearing ovaries despite advanced diagnostic imaging technology.

Recent technological advances, such as 3D volume acquisition and 3D power Doppler, may have clinical utility in the early identification of abnormal vascularity and ovarian architecture.^14,15,18-20 3D volume acquisition allows for careful evaluation of the internal surfaces of cyst walls for intracystic papillations otherwise not appreciated by 2D technology. While the addition of 3D power Doppler provides a new tool for measuring the quality of ovarian vascularity, its clinical value for the early detection of ovarian carcinoma has yet to be determined. In our diagnostic paradigm, gray-scale ultrasound is used as a primary evaluation; however, many masses are not sufficiently characteristic in echo-pattern to predict histology with certainty, which is similar to other reports.^14,15 Our practice is to describe a mass as cystic, multiloculated, complex, or solid. If the echo-features are highly suggestive of a functional cyst, hemorrhagic cyst, endometrioma, cystic teratoma, cystadenoma, or hydrosalpinx, it is noted on the report. Previous experience in the authors’ program suggests that endometriomas and cystic teratomas can often be correctly identified by their characteristic echo-patterns.^14,15 The authors observed that 80% of endometriomas and 70% of cystic teratomas were correctly identified by ultrasound. However, only 28% of cystadenomas and adenofibromas were sufficiently characteristic in echo-pattern for a correct histologic ultrasound prediction. Many cystadenomas and cystadenofibromas referred to the program were architecturally unusual in that they presented with a highly complex echo pattern. It is also important to note that there can be overlap between the echo-features of certain benign histologies and frank malignancies. For example, we have found that the gray-scale patterns of granulosa cell tumors can resemble those of endometriomas, yet adenofibromas, cystic teratomas, LMP tumors, and papillary serous ovarian carcinoma can contain areas of dense echogenicity with posterior shadowing.

The addition of Doppler examination is helpful in this regard due to the absence of vascular flow within the central regions of endometriotic cysts and the echogenic portions of most cystic teratomas. It is not unexpected that 2D TVS identified 100% of the malignant adnexal masses because they were enlarged and complex in echo-architecture. The published literature has found that 2D TVS is 85% to 100% sensitive for identifying adnexal masses as malignant.^14,15,18-20 Although 3D TVS with rendering improves visualization of the internal capsule wall and intracystic papillations, it is the addition of PD3D that the authors found most helpful. The 3D TVS did not change the morphologic score (viz, cystic, multiloculated, complex, or solid) compared to the 2D TVS; however, the rendering of the internal aspect of cystic masses can yield high detail of internal excrescences previously identified on 2D TVS (Figures). It is more useful, however, in ruling out excrescences rather than in their identification. In the authors’ experience, three-dimensional power Doppler imaging better defines the morphologic and vascular characteristics of ovarian lesions resulting in a significant improvement in specificity (54% to 75%) for ovarian cancer detection.¹⁵ This improved diagnostic accuracy may promote improved patient care by separating complex benign masses from ovarian cancer, therefore facilitating appropriate physician referral.

FIGURES. 3D Doppler

The authors continue to evaluate the utility of new ultrasound technologies in evaluating asymptomatic women deemed at significantly increased risk for the development of ovarian carcinoma. Premenopausal scans are routinely performed transvaginally and postmenopausal scans either transvaginally or transabdominally. Doppler and 3D studies are performed only if an adnexal mass is identified. Masses are graded as cystic, multiloculated, complex, or solid. An overall impression of malignancy risk is assigned to adnexal masses based on morphologic appearance and the presence or absence of central vascularity. Simple cysts and premenopausal hemorrhagic-like cysts are rescanned at 6- to 8-week intervals. Since several recent publications have confirmed a less than 1% malignancy rate in simple menopausal cystic masses measuring less than 5 cm, it is the authors’ practice to conservatively follow these lesions unless architectural changes are demonstrated.^14,15,18-20

Since 1996, within the NOCEDP, approximately 4,000 women have been evaluated by 11,500 scans. The average age of the women was 46 years. Visualization of both ovaries was noted in 98% of premenopausal and in 94% of postmenopausal women. Twelve women had a prior unilateral salpingo-oophorectomy. Recall rates at less than the routine 6-month interval were 0.4% in premenopausal and 0.3% in postmenopausal women. Approximately 96 women with persistent adnexal masses were identified. Fourteen women with simple cysts greater than 5 cm were treated with percutaneous drainage with benign cytology. Thirty women received operative intervention with benign ovarian pathologies that were scored at low risk for malignancy on ultrasound interpretation. Thirty-six menopausal women with stable simple cysts, hydrosalpinges, or fluid-filled adhesive disease have been followed expectantly. A total of 45 invasive surgical procedures were performed for 36 benign ovarian tumors and 9 gynecologic malignancies. All cancers were detected in asymptomatic women who had a normal ultrasound and physical examination 12 and 6 months prior to diagnosis. The detected malignancies were fallopian tube carcinoma (2) stage IIIC, grade 3, primary peritoneal carcinoma (3) stage IIIA, epithelial ovarian carcinoma (2) stage IIIA and IIIB grade 3, and uterine carcinoma (2) stage IA grade 1. Twenty-seven primary and 7 recurrent breast cancers were also detected. Approximately 100 women with a genetic predisposition (BRCA positive) for ovarian cancer have had prophylactic BSO with 32% demonstrating atypical hyperplasia, one unexpected stage IIIA primary peritoneal carcinoma, and one suspected stage 1A mucinous borderline tumor.

The authors’ ongoing study demonstrates the limited value of diagnostic ultrasound as an independent primary screening tool for the detection of early stage ovarian cancer in asymptomatic high-risk women. It is anticipated that the combination of biologically relevant biomarkers, use of novel technologies such as proteomics (SELDI-TOF, AI), and use of high-resolution ultrasound will allow for the accurate detection of early stage epithelial ovarian carcinoma.

David A. Fishman, MD, director and principal investigator; director, gynecologic oncology research, Robert H. Lurie Cancer Center; board-certified gynecologic oncologist; professor of obstetrics and gynecology; Leeber Cohen, MD, chief gynecologic ultrasonologist; board-certified obstetrician-gynecologist; associate professor of obstetrics and gynecology; Kenny Bozorgi, MD, assistant professor of obstetrics and gynecology; Diljeet Singh, MD, MPH, assistant professor of obstetrics and gynecology; Anna O’Donnell, RN, coordinator of clinical research trials; MaryAnn Donnelly, RN, coordinator of clinical research programs; Jennifer O’Rourke, RN, MS, coordinator of communication and educational programs; Kate Pfeifer, MS, CGC, genetic counselor; instructor; M. Sharon Stack PhD, associate professor, Department of Cellular and Molecular Biology; John Lurain MD, section head, gynecologic oncology; board-certified gynecologic oncologist; professor of obstetrics and gynecology; Thanh Lu, grant administrator, data coordinator, all at Northwestern University Medical School, Chicago, Ill; Nita Maihle PhD, professor of biochem/molecular biology; Andre Baron PhD, member of the Mayo Clinic Cancer Center, both at the Mayo Clinic, Rochester, Minn.; and Peter E. Schwartz, MD, professor of obstetrics and gynecology, vice chairman, Department of Obstetrics and Gynecology, chief, section of gynecologic oncology, Yale University, New Haven, Conn.

Supported by NIH/NCI Early Detection Research Network Grant NCI UO1CA85133, NCI P50 CA83639, Friends of Prentice, Northwestern Memorial Foundation, Stenn Fund for Ovarian Cancer Research, Joanne Silverman Cancer Foundation, Kaleidoscope of Life Foundation, Illinois Department of Public Health, and the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.

REFERENCES

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