Early Precancerous Ovarian Cell Changes May Be Common in Women at Increased Risk of Ovarian Cancer

Distinct cellular anomalies have been found with far greater frequencyin the ovaries of women at high risk of ovarian cancer than in the ovariesof women whose organs were removed for non-cancer-related reasons. Thisfinding may provide clues to cellular changes that precede ovarian cancer,according to a study in the December 18th Journal of the National CancerInstitute.

Hernando Salazar, MD (now at the Reading Hospital Medical Center, Reading,PA), Thomas C. Hamilton, PhD (Fox Chase Cancer Center, Philadelphia), andcolleagues explain that, unlike the clearly elucidated sequence of changesthat lead to the development of colon cancer, it has not been possibleto firmly identify cellular changes or other conditions that precede thedevelopment of ovarian cancer. Because no effective early detection methodsexist 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 andstudy a sizable number of ovaries, particularly specimens without evidentdisease, to assess shared cellular changes that might be associated withincreased 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 20women considered to be at high risk of ovarian cancer, based on a strongfamily history of ovarian and/or breast cancer and, in some cases, on aknown genetic predisposition ascertained by linkage studies or DNA sequencing.When it became apparent that these ovaries contained numerous atypicalfeatures compared with the expected appearance of normal ovaries, Salazarand co-workers expanded the study to include examination of ovaries froma control group of women whose ovaries were removed for reasons unrelatedto cancer. Although the study was not blinded, it was possible to comparedifferences in the two groups of ovaries with respect to both the numberand intensity of atypical features.

Two unanticipated microscopic or near-microscopic malignant neoplasmsand other benign and borderline tumors were discovered in the ovaries ofthe high-risk individuals. Among the ovaries from the high-risk women,85% had two or more atypical histologic features and 75% had three or moresuch features. By comparison, only 30% of ovaries from the control grouphad two or more atypical changes, and only 10% had three or more changes.These differences were statistically highly significant. The observed atypicalchanges included those involving the surface epithelial cells (pseudostratification,papillomatosis, deep cortical invaginations with microscopic papillarycystadenomas, and inclusion cysts) and stromal cells (cortical stromalhyperplasia 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-riskovaries compared with the ovaries obtained from the control group suggeststhat a characteristic precancerous phenotype, defined by the type and intensityof the observed cellular changes, does exist. Salazar and colleagues speculatethat limited access to numerous small (stage I) ovarian cancers or cancer-proneovaries by any one pathologist may explain the failure to identify clearlythis phenotype in the past. They note that one of the microscopic malignanttumors in this study was not discovered until extensive microscopic examinationwas performed. This finding suggests that cursory inspection of prophylacticallyremoved ovaries may miss such small tumors that could already have acquiredmalignant capability and require systemic treatment.

In addition to providing evidence of a cancer-prone phenotype, say theresearchers, the findings raise other questions about the process of malignanttransformation of surface ovarian epithelium (eg, the specific gene mutationsinvolved and the importance of the observed stromal changes) that warranta larger-scale investigation.

In an editorial accompanying this report, William J. Hoskins, MD, MemorialSloan-Kettering Cancer Center, New York, notes that of the 26,700 womenexpected to be diagnosed with ovarian cancer in 1996, over 16,000 willbe diagnosed at advanced stages because of the continued lack of effectiveearly detection methods. The identification of premalignant ovarian abnormalitieshas eluded investigators, he says, and while the current findings do notestablish that the epithelial abnormalities observed are premalignant changesthat will develop into invasive ovarian cancer, they add to the evidencethat such abnormalities do exist and make a valuable contribution to ourknowledge about the biology of ovarian tissue in high-risk women.

Perhaps most important, says Hoskins, this study has identified a potentiallyvaluable model for studying the biologic differences within the ovariesof women at increased risk of ovarian cancer and the ovaries of women withoutincreased risk. Understanding the biologic mechanisms underlying ovariancancer, which are likely to be similar in both uninherited (sporadic) andfamilial ovarian cancer, is a prerequisite first step in developing rationalapproaches to the improved diagnosis, treatment, and, most important, preventionof this deadly disease.