Distinct cellular anomalies have been found with far greater frequency in the ovaries of women at high risk of ovarian cancer than in the ovaries of women whose organs were removed for non-cancer-related reasons. This finding may provide clues to cellular changes that precede ovarian cancer, according to a study in the December 18th Journal of the National Cancer Institute.
Hernando Salazar, MD (now at the Reading Hospital Medical Center, Reading, PA), Thomas C. Hamilton, PhD (Fox Chase Cancer Center, Philadelphia), and colleagues explain that, unlike the clearly elucidated sequence of changes that lead to the development of colon cancer, it has not been possible to firmly identify cellular changes or other conditions that precede the development of ovarian cancer. Because no effective early detection methods exist and early-stage ovarian cancers are often asymptomatic, say the researchers, most ovarian cancers are already in an advanced stage when they are diagnosed. Moreover, it is rare that any single pathologist is able to access and study a sizable number of ovaries, particularly specimens without evident disease, to assess shared cellular changes that might be associated with increased cancer risk, ie, a cancer-prone phenotype.
Atypical Histologic Features Found
In this study, however, the research team was able to compare the cellular (histologic) features of ovaries removed as a preventive measure from 20 women considered to be at high risk of ovarian cancer, based on a strong family history of ovarian and/or breast cancer and, in some cases, on a known genetic predisposition ascertained by linkage studies or DNA sequencing. When it became apparent that these ovaries contained numerous atypical features compared with the expected appearance of normal ovaries, Salazar and co-workers expanded the study to include examination of ovaries from a control group of women whose ovaries were removed for reasons unrelated to cancer. Although the study was not blinded, it was possible to compare differences in the two groups of ovaries with respect to both the number and intensity of atypical features.
Two unanticipated microscopic or near-microscopic malignant neoplasms and other benign and borderline tumors were discovered in the ovaries of the high-risk individuals. Among the ovaries from the high-risk women, 85% had two or more atypical histologic features and 75% had three or more such features. By comparison, only 30% of ovaries from the control group had two or more atypical changes, and only 10% had three or more changes. These differences were statistically highly significant. The observed atypical changes included those involving the surface epithelial cells (pseudostratification, papillomatosis, deep cortical invaginations with microscopic papillary cystadenomas, and inclusion cysts) and stromal cells (cortical stromal hyperplasia and hyperthecosis), as well as increased follicular activity, corpus luteum hyperplasia, and hilar cell hyperplasia.
Existence of Precancerous Phenotype Suggested
The authors believe that the frequency of these changes in the high-risk ovaries compared with the ovaries obtained from the control group suggests that a characteristic precancerous phenotype, defined by the type and intensity of the observed cellular changes, does exist. Salazar and colleagues speculate that limited access to numerous small (stage I) ovarian cancers or cancer-prone ovaries by any one pathologist may explain the failure to identify clearly this phenotype in the past. They note that one of the microscopic malignant tumors in this study was not discovered until extensive microscopic examination was performed. This finding suggests that cursory inspection of prophylactically removed ovaries may miss such small tumors that could already have acquired malignant capability and require systemic treatment.
In addition to providing evidence of a cancer-prone phenotype, say the researchers, the findings raise other questions about the process of malignant transformation of surface ovarian epithelium (eg, the specific gene mutations involved and the importance of the observed stromal changes) that warrant a larger-scale investigation.
In an editorial accompanying this report, William J. Hoskins, MD, Memorial Sloan-Kettering Cancer Center, New York, notes that of the 26,700 women expected to be diagnosed with ovarian cancer in 1996, over 16,000 will be diagnosed at advanced stages because of the continued lack of effective early detection methods. The identification of premalignant ovarian abnormalities has eluded investigators, he says, and while the current findings do not establish that the epithelial abnormalities observed are premalignant changes that will develop into invasive ovarian cancer, they add to the evidence that such abnormalities do exist and make a valuable contribution to our knowledge about the biology of ovarian tissue in high-risk women.
Perhaps most important, says Hoskins, this study has identified a potentially valuable model for studying the biologic differences within the ovaries of women at increased risk of ovarian cancer and the ovaries of women without increased risk. Understanding the biologic mechanisms underlying ovarian cancer, which are likely to be similar in both uninherited (sporadic) and familial ovarian cancer, is a prerequisite first step in developing rational approaches to the improved diagnosis, treatment, and, most important, prevention of this deadly disease.