Using Autopsy Series To Estimate the Disease Reservoir for Ductal Carcinoma in Situ of the Breast: How Much More Breast Cancer Can We Find?

American women have reason to believe that breast cancer is becoming more and more common. Well-intended messages designed to promote mammography may be partly responsible, but so too may a woman's own personal experience as she becomes more likely to have family or friends who are given the diagnosis. Much of this increase in incidence has been attributed to the escalating use of mammography and an enhanced ability to detect more subtle forms of cancer [1-3]. Increased detection is particularly apparent for ductal carcinoma in situ (DCIS), a relatively early form of cancer that is most often identified by mammography. Little is known about the natural history of mammographically detectable DCIS: Some cases may progress to invasive breast cancer, whereas others may not [4-6]. Such uncertainty has become more problematic because the reported incidence of DCIS has increased more than fourfold since 1980 [7]; this type of cancer now accounts for nearly half of mammographically detected cases of cancer [8, 9]. Our increased ability to detect subtle forms of breast cancer is a two-edged sword. On the one hand, it offers the hope of preventing some cases of advanced breast cancer through early detection and treatment. On the other hand, it fosters increased worry and labels more women as having disease, many of whom may never develop invasive cancer [10, 11]. It also presents clinicians with yet another uncertainty: How should these subtle forms of breast cancer be treated? In one area, however, there is little uncertainty-the ability to detect early forms of breast cancer will continue to improve. To learn how many cases of breast cancer might be found if women were thoroughly examined, we reviewed autopsy series of women not known to have had the disease during life. The prevalence of disease observed at autopsy but undetected during life has been dubbed the disease reservoir by Feinstein and others [12-14]. In this article, we review efforts to define the reservoir for breast cancer and consider the effect of different prevalences on the risk for death from detected DCIS. We also discuss the role of the level of scrutiny and the pathologist's threshold for making the diagnosis. Methods Data Sources We searched the MEDLINE database (1966 to the present) for English-language articles that were indexed under the Medical Subject Headings breast diseases (excluding mastitis, gynecomastia, and lactation disorders) and epidemiology or pathology. After excluding case reports, we reviewed all citations that contained the term autopsy (or autopsies) either as a subheading or in text. To estimate the disease reservoir, we restricted the data to autopsies performed on women not known to have had breast cancer during life. The series fell into two broad categories: hospital-based autopsies [15-18] and forensic (or medicolegal) autopsies [19-21]. The hospital-based autopsy series often included data from women known to have had breast cancer (either cancerous breasts or breasts contralateral to those with cancer). Such series were included in our review only if the investigators presented disaggregated data that unambiguously excluded these patients. The forensic autopsy series were based on consecutive cases that were examined in the coroner's office; in these series, women known to have had breast cancer were seen infrequently. The investigators either specifically excluded such women or highlighted them (so that we could easily remove them from the numerator and denominator of the prevalence estimates). Thus, we are confident that the observed prevalences reported here apply to women who are not known to have breast cancer-that is, women who could be eligible for breast cancer screening. Data Extraction and Analysis To construct Table 1, we sought to determine the level of scrutiny and the findings in each autopsy series. To establish the scrutiny given to the pathologic specimens, we reviewed the method by which tissue samples were obtained for microscopic inspection and determined the average number of slides examined for each breast. We then catalogued the pathologic finding of either occult invasive breast cancer or DCIS. Because lobular carcinoma in situ has uncertain biological importance, we did not include cases of this type of cancer. Our calculation of observed prevalence used the number of women who were given a diagnosis as the numerator (we did not use the number of lesions because multifocal and bilateral lesions were regularly reported) and the number of women examined (as opposed to the number of breasts) as the denominator. To consider the effect of lower diagnostic thresholds, we also extracted the observed prevalence of potential precursor lesions (various categories of atypia or epithelial proliferation). Table 1. Autopsy Series of Women Not Known To Have Had Breast Cancer during Life* To improve comparability across the autopsy series, we addressed two issues. First, the age distribution varied. The Virginia series included only women older than 70 years of age [15], whereas the three forensic autopsy series [19-21] often included many young women (in one series, one quarter of the patients were younger than 25 years of age). Therefore, when possible, we also attempted to calculate prevalences for women likely to be screened (target range, 40 to 70 years of age); the precise age range was defined by the data reported. Second, information on race or ethnicity was generally poorly reported, but the series seemed to predominantly involve white women. Only women of European descent were included in the Australian series [19]; a similar racial or ethnic make-up is probably the case for four other series: two from Northern California [16, 18] and two from Denmark [17, 21]. Because stratification was possible, we restricted the analysis to the Anglo women in the New Mexico series [20], a restriction that was not possible in the Virginia series (half of whom were black) [15]. Given the available data, readers should view the observed prevalences reported here as most accurately reflecting the breast cancer reservoir in white women. To gauge the effect of different prevalences on the risk for death from detected DCIS, we used a method described elsewhere [22]. Estimating the probability that a detected abnormality will naturally progress to death is not possible unless one can follow a cohort through time. The probability is mathematically constrained, however, by the prevalence of the detected abnormality. Calculation of the upper limit of this probability is simple when disease-specific mortality is stable (as is the case for breast cancer [23]). For example, if 12% of women 40 to 50 years of age were found to have DCIS (and given the fact that 3% of unscreened women ultimately die of breast cancer [24]), then the upper-limit probability of death from DCIS is 25% (0.03/0.12). The actual probability is, of course, much lower. First, some cases of invasive breast cancer causing death may not arise from DCIS. Second, some 40- to 50-year-old women will have undetected invasive breast cancer, which undoubtedly is more likely to cause death. Third, some women who will die of breast cancer will have normal breasts at 50 years of age. Finally, many women with DCIS have multifocal disease, making the chance that any single detected lesion will progress to death much less likely. Data Synthesis Table 1 summarizes the seven autopsy series. The median observed prevalence of invasive breast cancer among women not known to have breast cancer was 1.3% (range, 0% to 1.8%). The median prevalence of DCIS was 8.9%, but the rates varied widely: One series found no cases, whereas three found DCIS in more than 10% of the women undergoing autopsy. Observed prevalences were higher among women most likely to be screened-those 40 to 70 years of age. Review of Table 1 prompts two additional observations. First, the level of scrutiny seems related to the observed prevalences. The series that found no cases of DCIS examined nine slides per breast, whereas the two series with the highest prevalence (both of which were performed by the same investigators) were the most assiduous: The investigators examined 95 and 275 specimens per breast after being guided by radiographs of each 5-mm section. Second, a considerable reservoir of potential precursor lesions (such as atypia) was seen in women who had neither invasive breast cancer nor DCIS. Thus, if the pathologists' tendency to diagnose DCIS increased (that is, if the diagnostic threshold was lower), the prevalence of DCIS could become much higher. Table 2 relates the effect of changing disease prevalences on the highest possible risk for dying of detected DCIS. Assuming a constant rate of death from breast cancer, an increase in the detection of DCIS decreases the likelihood that detected DCIS in any one women will be fatal. If, for example, the prevalence of DCIS in 40- to 50-year-old women is 9% (the median prevalence reported here), then the highest possible probability of death from detected DCIS is 33%. If the prevalence of DCIS is 40% (the highest reported prevalence [21]), however, then the highest possible probability of death from detected DCIS decreases to 7.5%. It is important to emphasize that these estimates represent the worst-case scenario. The true risk could be this high only if all deaths from breast cancer were ultimately the result of DCIS present in 40- to 50-year-old women. Table 2. Effect of Various Prevalences on the Upper Limit of the Risk for Death from Ductal Carcinoma in Situ in Women 40 to 50 Years of Age* Discussion In 1992, an estimated 24 000 women in the United States were given a diagnosis of DCIS and 10 000 underwent mastectomy for the disease [7]. The autopsy series reviewed here, however, suggest that the disease reservoir for DCIS is substantial and that many more cases could be detected. In 1992, approximately 40 million U.S. women were at an age at wh