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
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.