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Old and new issues in cervical cancer control.

Clearly, one of the public health successes of the last 50 years has been the development of an effective approach to cervical cancer control. Dramatic decreases in the incidence of invasive cervical cancer (ICC) have occurred following the establishment of routine cytologic screening and treatment of those lesions (severe dysplasia or carcinoma in situ [CIS]) thought to be immediate precursors of ICC. Although it is widely agreed that the aim of cervical cytologic screening should be the identification of all women with these high-grade lesions, there is little agreement as to how best to achieve this. Until recently, in many countries such as Canada, physicians primarily relied on cytology alone to identify women with severe dysplasia/CIS, with referral for colposcopy largely reserved for confirmation of the cytologic diagnosis. However, in the United States, the majority of women with a cytologic diagnosis of mild dysplasia, moderate dysplasia, and repeated squamous atypia (or atypical squamous cells of uncertain significance [ASCUS]) have also been referred for colposcopy and biopsy. The rationale for this approach has been the belief that ASCUS and cervical intraepithelial neoplasia (CIN) grades 1, 2, and 3/CIS represent successive, progressive stages in the pathogenesis of cervical cancer. Furthermore, referral of women with ASCUS or CIN-1 has also been based on the fear that cytologic screening might miss more serious lesions, especially small CIN-3 lesions located high in the endocervical canal. At first glance, referral of women with mild dysplasia for colposcopic examination and timely detection of occult highgrade lesions appears quite reasonable, although such an approach places a severe burden on the health care system. Studies (1,2) have clearly demonstrated the detection of small, occult CIN-3 lesions by colposcopic examination in up to 33% of women with a cytologic diagnosis of mild dysplasia. With increasing numbers of women affected by human immunodeficiency virus (HIV) infection and the potential role of human papillomavirus (HPV) testing in cervical cancer screening, the ongoing debate as to how to best identify women with CIN-3/ CIS and how to follow women with mild dysplasia has become increasingly complex. The two studies reported in this issue of the Journal by Holowaty et al. (3) and Palefsky et al. (4) offer important insights into these issues. The landmark report by Holowaty et al. (3) provides strong support for the appropriateness of following women with a cytologic diagnosis of mild dysplasia without immediate referral to colposcopy and biopsy. Although previous natural history studies have reported low rates of progression of CIN-1 to invasive disease, these studies tended to be small, have shorter periods of follow-up, or have varying study entry criteria. The present study is unique in that cytology information was captured from a large proportion of women in a defined geographic area, all smears were read by one laboratory in a consistent manner, treatment data were available on most women during the study interval (confirming the conservativeness with which women were managed), and information regarding the subsequent development of ICC was based on data obtained from a population-based cancer registry. This study leaves little doubt that the overwhelming majority of mild dysplasias (88% and 62% to one normal and to two normal smears, respectively, within 10 years) and moderate dysplasias (83% and 54%, respectively, within 10 years) spontaneously regress to normal. Furthermore, this study should put to rest the widespread fear that women with mild dysplasia need immediate referral to colposcopy for the detection and treatment of cytologically undetected high-grade lesions, rather than simply undergoing repeated routine cytologic screening. That is not to suggest that some high-grade lesions are not missed by a single cytologic smear, especially among those with mildly dysplastic smears (1). However, since it is likely that many occult CIN-3 lesions were, in fact, present at the time of initial diagnosis of mild dysplasia (especially among women <30 years of age), the low rate of progression to severe dysplasia or worse, 10 years later, without treatment, suggests that a certain number of occult high-grade lesions spontaneously regress. Definitive evidence in support of this must await the results of future studies specifically designed to address this question. Furthermore, at present, all detected high-grade lesions need definitive treatment. We have previously proposed that some cytologically occult, colposcopically detected CIN 2–3 lesions may represent transient expression of high-risk HPV types in metaplastic epithelium (5). It is possible that as HPV DNA testing and more sensitive methods of Pap smear preparation (e.g., monolayer preparation) become increasingly prevalent, many more of these occult high-grade lesions will be detected. This makes it important to gain insights into the biology of such lesions, particularly regarding factors associated with progression risk. Last, this study reopens the debate concerning retention of moderate dysplasia as a separate diagnostic entity, rather than combining it with severe dysplasia as is currently done by the Bethesda classification system (6). Although the risk of progression of moderate dysplasia to CIS or worse was intermediate between that of mild and severe dysplasia, cytopathologists are well aware of the low reproducibility of this diagnosis. On the basis of the data presented in this study, it is not possible to determine whether the moderate dysplasia group represents a mixture of difficult to classify mild and severe dysplasias or a separate biologic entity. Furthermore, retaining a separate clas-