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Affiliations of authors: C. W. Critchlow (Department of Epidemiology, School of Public Health and Community of Medicine), N. B. Kiviat (Departments of Pathology and Medicine, School of Medicine), University of Washington, Seattle.
Correspondence to: Nancy B. Kiviat, M.D., HPV Research Group,6 Nickerson, Suite 310, Seattle, WA 98109 (e-mail: nbk{at}u.washington.edu).
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 high-grade 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 classification would be of little use if moderate dysplasias continue to be treated as are severe dysplasias.
The characterization of HPV infection in HIV-positive and HIV-negative women participating in the Women's Interagency HIV Study (WIHS), presented in this issue by Palefsky et al. (4), examines an issue of increasing concern. It has been well documented that immunosuppression, including that produced by HIV infection, is associated with increased risk of both HPV detection and HPV-associated intraepithelial and invasive squamous cell neoplasia. The findings by Palefsky et al. (4) provide additional information that may be of use in assessing the risk of subsequent cervical neoplasia among HIV-seropositive women. This study is the most comprehensive investigation to date examining the prevalence of, and risk factors for, cervicovaginal HPV infection among a representative sample of HIV-seropositive and high-risk HIV-seronegative women. HPV risk factors identified in previous studies, such as younger age, fewer prior pregnancies, and a history of genital warts, were also associated with infection in this study.
A major contribution of this study is the demonstration that HIV-seropositive women—either with low CD4 counts or high plasma HIV RNA load, regardless of CD4 count—are at markedly increased risk of HPV infection, particularly with high-risk oncogenic types. While the effect of highly active antiretroviral therapy (HAART) could not be evaluated in the WIHS investigation, a recent study by Heard et al. (7) demonstrated, interestingly, that HAART may result in a decreased risk of dysplasia despite little change in the prevalence of HPV detection. Palefsky et al. additionally suggest that the higher prevalence of HPV among HIV-positive women is due primarily to reactivation of latent infection, rather than recent acquisition of new infection. Sun et al. (8), who also did not find an association between HPV detection and recent sexual activity, reported a high rate of persistent HPV infection with high-risk HPV types among HIV-positive women. Even though HIV-positive women are much more likely to be HPV positive as well as to have dysplasia present, there is no indication that cytology differs in sensitivity for the detection of high-grade lesions among HIV-positive as compared with HIV-negative women (9). These findings taken together suggest that measures of immune function (both CD4 count and HIV RNA load) and perhaps HPV type, particularly if persistently detected, would be valuable in identifying a subset of HIV-positive women as at high risk for cervical neoplasia and in need of frequent, repeated cytologic screening.
REFERENCES
1 Giles JA, Deery A, Crow J, Walker P. The accuracy of repeat cytology in women with mildly dyskaryotic smears. Br J Obstet Gynaecol 1989;96:1067-70.[Medline]
2 Giles JA, Hudson E, Crow J, Williams D, Walker P. Colposcopic assessment of the accuracy of cervical cytology screening. Br Med J (Clin Res Ed) 1988;296:1099-102.[Medline]
3
Holowaty P, Miller AB, Rohan T, To T. Natural history of
dysplasia of the uterine cervix. J Natl Cancer Inst 1999;91:252-8.
4
Palefsky JM, Minkoff H, Kalish LA, Levine A, Sacks HS, Garcia
P, et al. Cervicovaginal human papillomavirus infection in human immunodeficiency virus-1
(HIV)-positive and high-risk HIV-negative women. J Natl Cancer Inst 1999;91:226-36.
5 Kiviat NB, Critchlow CW, Kurman RJ. Reassessment of the morphological continuum of cervical intraepithelial lesions: does it reflect different stages in the progression to cervical carcinoma? IARC Sci Publ 1992. p 59-66.
6 National Cancer Institute Workshop. The 1988 Bethesda System for reporting cervical/vaginal cytological diagnoses. JAMA 1989;262:931-4.[Medline]
7 Heard I, Schmitz V, Costagliola D, Orth G, Kazatchkine MD. Early regression of cervical lesions in HIV-seropositive women receiving highly active antiretroviral therapy. AIDS 1998;12:1459-64.[Medline]
8
Sun XW, Kuhn L, Ellerbrock TV, Chiasson MA, Bush TJ,
Wright TC Jr. Human papillomavirus infection in women infected with the human
immunodeficiency virus. N Engl J Med 1997;337:1343-9.
9 Maiman M, Fruchter RG, Sedlis A, Feldman J, Chen P, Burk RD, et al. Prevalence, risk factors, and accuracy of cytologic screening for cervical intraepithelial neoplasia in women with the human immunodeficiency virus. Gynecol Oncol 1998;68:233-9.[Medline]
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