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The sea of uncertainty surrounding ductal carcinoma in situ--the price of screening mammography.

Wouldn’t it be easier if we lived in a binary world? Everything would be either black or white, yes or no, 1 or 0. And biopsy results would be either normal or cancer. Unfortunately, in the world of cancer, our efforts to detect the disease early have made this a fantasy. We are increasingly faced with the reality of a big gray zone — a broad spectrum of pathologic fi ndings between normal tissue and invasive cancer. And our nosology refl ects the associated ambiguity — dysplasia, intraepithelial neoplasia, hyperplasia with atypia, and even abnormalities of “unknown signifi cance.” The unifying theme for these fi ndings is that they may progress to invasive cancer. Or they may not. Despite the presence of the word “carcinoma,” ductal carcinoma in situ (DCIS) is the poster child for this problem (a senior pathologist involved in developing classifi cation systems confi ded to one of us that he regretted the use of the term carcinoma in DCIS). No one believes that DCIS always progresses to invasive cancer, and no one believes it never does. Although no one is sure what the probability of progression is, studies of DCIS that were missed at biopsy ( 1 , 2 ) and the autopsy reservoir ( 3 ) suggest that the lifetime risk of progression must be considerably less than 50%. There is an added complexity: DCIS is associated with not just one risk but two. In addition to the specifi c risk that the lesion might progress to invasive cancer, DCIS confers a general risk. It is a marker for an increased chance of developing invasive cancer elsewhere in the ipsi- or contralateral breast. Again, although no one is sure what this probability is, a recent prospective study of a cohort of patients with DCIS who were treated largely by excision alone suggested that the 5-year risk of subsequent invasive breast cancer elsewhere is less than 10% ( 4 ). In short, there is a sea of uncertainty surrounding DCIS. Some lesions will progress to cancer, others will not. Some women with DCIS will develop cancer elsewhere in their breasts, whereas others will not. And we’re not sure what the chances are. It isn’t surprising that among women with DCIS the uncertainty of being in this gray zone leads to anxiety. In this issue of the Journal, Partridge et al. ( 5 ) report that many women with DCIS are anxious — even months after the diagnosis. The authors also report that anxiety is associated with exaggerated risk perceptions — many women with DCIS estimate their risk of developing invasive cancer 5 years following treatment to be greater than 50%. Although it’s tempting to hope that better educating women (and their doctors) about the actual risks of DCIS would reduce anxiety, it’s entirely possible that our measures of risk perception and anxiety are simply markers for the same underlying construct — how women feel about being in the gray zone. They are told that they don’t have cancer, but they are not normal; instead, they are at higher risk for developing cancer. Because DCIS is an asymptomatic and nearly always nonpalpable lesion, the majority of women exposed to this sea of uncertainty got there the same way — via screening mammography. Thus, the associated anxiety must be considered to be a harm of mammographic screening. But anxiety is certainly not the only harm. The fundamental paradox of early cancer detection is that, while some may be helped, others get a diagnosis they’d be better off without. The central harm of screening is overdiagnosis — the detection of abnormalities that meet the pathologic defi nition of cancer but will never progress to cause symptoms. Although this concept may seem implausible to clinicians, basic scientists have begun to uncover biologic mechanisms that halt the progression of cancer ( 6 – 8 ). Overdiagnosis has now been associated with early detection