Histopathologic Extent of Cervical Intraepithelial Neoplasia 3 Lesions in the Atypical Squamous Cells of Undetermined Significance Low-grade Squamous Intraepithelial Lesion Triage Study: Implications for Subject Safety and Lead-time Bias 1 Mark E. Sherman, 2 Sophia S. Wang, Robert Tarone, Laurie Rich, and Mark Schiffman The National Cancer Institute, Division of Cancer Epidemiology and Genetics, Bethesda, Maryland 20892 [M. E. S., S. S. W., R. T., M. S.], and Information Management Services, Silver Spring, Maryland [L. R.] Abstract Cervical intraepithelial neoplasia 3 (CIN3) is the precursor of most squamous carcinomas and serves as a surrogate end point. However, small CIN3 lesions are rarely associated with concurrent invasion. We hypothesized that aggressive follow-up for cytology of atypical squamous cells of undetermined significance (ASCUS) or low-grade squamous intraepithelial lesion (LSIL) leads predominantly to detection of smaller CIN3 lesions than those usually associated with cancer. We assessed this hypothesis in a masked histopathologic review of 330 CIN3 lesions in the ASCUS LSILTriage Study, focusing on ASCUS referrals. ASCUS referrals underwent randomized management [colposcopy for repeat cytology of high-grade squamous intraepithelial lesion (HSIL), colposcopy for oncogenic human papillomavirus (HPV) detection or repeat HSIL, or immediate colposcopy]; then all were followed with repeat cytology for 2 years, followed by colposcopy and aggressive treatment. We assessed all CIN3 lesions qualitatively and measured 39 of them. CIN3 lesions were overwhelmingly small. Compared with enrollment, lesions found at follow-up or exit involved fewer tissue fragments (P < 0.01) and showed less diffuse gland involvement (P  0.03). CIN3 lesions found postenrollment after HPV testing involved the fewest tissue fragments [versus immediate colposcopy (P  0.04) or repeat cytology of HSIL (P  0.02)], and none showed diffuse gland involvement. The median distal-proximal length was 6.5 mm (median replacement of total epithelium  5%) in the 39 measured cases. We conclude that CIN3 lesions underlying ASCUS or LSIL generally lack features associated with invasion, particularly if managed using HPV testing, suggesting that aggressive management leads to early detection of CIN3 but probably prevents relatively few cancers in screened populations. Introduction The goal of cervical cancer prevention programs is to detect and treat all committed cancer precursors before invasion develops. Although it cannot be determined whether any individual pre- cursor lesion will progress to cancer, data indicate that higher grades of CIN 3 are more likely to persist and progress than lower grade lesions (1– 4). Specifically, most CIN1 lesions, and a smaller, but substantial proportion of CIN2 lesions, regress spontaneously, and the HPV infections that cause these lesions become undetectable using currently available methods. In con- trast, untreated CIN3 lesions pose a substantially greater cu- mulative cancer risk over time, which makes CIN3 an attractive surrogate end point for cancer in cervical screening studies. The true natural history of CIN3 is unknown because it would be unethical to follow women prospectively with un- treated CIN3 for prolonged periods. However, the fact that CIN3 lesions are detected 10 years earlier than microinvasive carcinoma (5) implies that most CIN3 lesions persist for lengthy periods before becoming invasive. In a study that examined outcomes after incomplete treatment of cervical car- cinoma in situ, 22% of 131 women developed invasion, and 69% had persistent cervical carcinoma in situ during follow-up of 5–19 years (6). More recently, Nobbenhuis et al. (7) care- fully followed a group of women until they had developed extensive colposcopic evidence of CIN3 without any patients developing carcinoma, consistent with the hypothesis that in- vasion usually occurs after years of persistence and intraepi- thelial expansion of CIN3. Similarly, pathologic studies have suggested that CIN3 lesions are heterogeneous with respect to immediate invasive potential (8 –11). In one study, CIN3 lesions associated with invasion were seven times larger than CIN3 lesions without coexisting invasion (8). Cytoplasmic maturation and necrosis in CIN3 lesions were also associated with invasion (8). Characterizing the size and appearance of CIN3 lesions detected by different screening modalities can provide insights into the performance of these methods that would be missed by Received 8/8/02; revised 12/10/02; accepted 1/1/03. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 1 Supportedy by The National Cancer Institute and NIH Department of Health and Human Services contracts CN-55153, CN-55154, CN-55155, CN-55156, CN- 55157, CN-55158, CN-55159, and CN-55105. 2 To whom requests for reprints should be addressed, at National Cancer Institute, Division of Cancer Epidemiology and Genetics, 6120 Executive Boulevard, Room 7080, Rockville, MD 20892-7374. Phone: (301) 594-7661; Fax: (301) 402- 0916; E-mail: shermanm@mail.nih.gov. 3 The abbreviations used are: CIN, cervical intraepithelial neoplasia; HPV, human papillomavirus; ASCUS, atypical squamous cells of undetermined significance; ALTS, atypical squamous cells of undetermined significance low-grade squa- mous intraepithelial lesion triage study; LSIL, low-grade squamous intraepithelial lesion; LEEP, loop electrosurgical excision procedure; HSIL, high-grade squa- mous intraepithelial lesion; TDS, total dimension score; CI, confidence interval. 372 Vol. 12, 372–379, April 2003 Cancer Epidemiology, Biomarkers & Prevention Research. on December 13, 2021. © 2003 American Association for Cancer cebp.aacrjournals.org Downloaded from