Human Papillomavirus Infection and Time to Progression and Regression of Cervical Intraepithelial Neoplasia
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Human Papillomavirus Infection and Time to Progression and Regression of Cervical Intraepithelial Neoplasia Nicolas F. Schlecht, Robert W. Platt, Eliane Duarte-Franco, Maria C. Costa, Joa˜o P. Sobrinho, Jose´ C. M. Prado, Alex Ferenczy, Thomas E. Rohan, Luisa L. Villa, Eduardo L. Franco cervical cancer (1). This sequence forms the premise on which Background: Little is known about the duration of precan- cytologic screening for cervical cancer is based and corresponds cerous cervical lesions in relation to human papillomavirus to an underlying multistep carcinogenic process in the develop- (HPV) infection. We estimated rates of progression and re- ment of cervical intraepithelial neoplasia (CIN) (2). Low-grade Downloaded from https://academic.oup.com/jnci/article/95/17/1336/2520427 by guest on 29 September 2021 gression and sojourn times of cervical squamous intraepi- squamous intraepithelial lesions (LSILs) may progress to high- thelial lesions (SILs) according to HPV status. Methods: We grade SILs (HSILs) and invasive cervical cancer or may regress used data from a longitudinal study of HPV infection and to a normal state (3). However, few studies of cervical neoplasia cervical neoplasia in Sa˜o Paulo, Brazil. Cervical specimens have evaluated lesion recurrence (4,5) or disease progression (3) were taken from 2404 women for Pap cytology and polymer- over time. Likewise, lesion progression or regression has not ase chain reaction–based HPV testing every 4–6 months over been evaluated in relation to the presence of human papilloma- a period of 8 years. We used actuarial and non-actuarial viruses (HPV), the main etiologic agents in the initiation of analyses to measure time to and rates of lesion progression cervical neoplasia (6). The use of a biomarker that can predict and regression according to status and type of HPV infec- the rate of progression or regression and the duration of the tion. Results: During follow-up, 118 low-grade SIL (LSIL), preinvasive stages of cervical cancer could represent an attrac- 24 high-grade SIL (HSIL), and 173 atypical squamous cells tive means for targeting screening or chemoprevention. of undetermined significance (ASCUS) events were detected. Beginning in 1993, we initiated a cohort study involving Mean time to progression from ASCUS to LSIL or worse repeated measurements of HPV infection and cervical cytology and from LSIL to HSIL or worse was shorter in women with in women attending a comprehensive maternal and child health oncogenic HPV types than in women with no HPV infection program that serves low-income families living in neighbor- (mean times for ASCUS progression were 67.0 and 88.0 hoods located in the northern sector of the city of Sa˜o Paulo, months, respectively, in women with oncogenic HPV and no Brazil (7). In this population, early precursor lesions are gener- HPV, difference = 21.0 months, 95% confidence interval [CI] ally not treated, which enabled us to evaluate prospectively the = 11.3 to 30.7 months; mean times for LSIL progression occurrence of SIL events at regular intervals over time. In par- were 73.3 and 83.5 months, respectively, difference = 10.2 ticular, we sought to measure the frequency and rates of pro- gression and regression, as well as the durations (i.e., sojourn months, 95% CI = –0.15 to 20.6 months). Half of the LSILs time) of early cervical precursor lesions according to their HPV regressed to normal or ASCUS within 6 months. Mean times status. for regression from ASCUS to normal, from LSIL to ASCUS or normal, and from HSIL/cervical intraepithelial neoplasia SUBJECTS AND METHODS 2 to ASCUS or normal were longer for women with onco- genic HPV types (16.8 months, 95% CI = 7.5 to 26.2 months; Subject Recruitment 13.8 months, 95% CI = 8.8 to 18.7 months; and 17.1 months, Two study nurses approached 4990 women from daily lists of 95% CI = 4.1 to 30.1 months, respectively) than for women outpatients in the family medicine, gynecology, and family plan- with non-oncogenic HPV types (7.7 months, 95% CI = 5.2 to ning clinics at the Vila Nova Cachoeirinha municipal hospital in 10.2 months; 7.8 months, 95% CI = 5.3 to 10.2 months; 8.9 Sa˜o Paulo, Brazil, for an interview. Women who were poten- months, 95% CI = 3.3 to 14.6 months) or for women with no HPV infection (7.6 months, 95% CI = 6.9 to 8.4 months; 7.6 months, 95% CI = 6.4 to 8.7 months; and 7.0 months, 95% Affiliations of authors: N. F. Schlecht, E. L. Franco (Departments of On- CI = 5.0 to 8.9 months, respectively). Conclusion: Precursor cology and Epidemiology and Biostatistics), R. W. Platt (Departments of Epi- lesions of the cervix persist longer and progress more demiology and Biostatistics and Pediatrics), E. Duarte-Franco (Department of quickly in women with oncogenic HPV infections than in Oncology), McGill University, Montreal, Quebec, Canada; M. C. Costa, J. P. Sobrinho, J. C. M. Prado, L. L. Villa, Ludwig Institute for Cancer Research, women with non-oncogenic infections or without HPV. Test- Sa˜o Paulo, Brazil; A. Ferenczy, Department of Pathology, McGill University; ing cervical lesions for oncogenic HPVs may help identify T. E. Rohan, Department of Epidemiology and Population Health, Albert Ein- those that are likely to progress rapidly. [J Natl Cancer Inst stein College of Medicine, New York, NY. 2003;95:1336–43] Correspondence to: Eduardo L. Franco, PhD, Department of Oncology, McGill University, 546 Pine Ave. West, Montreal, Quebec, Canada H2W 1S6 (e-mail: [email protected]). The natural history of cervical cancer involves reversible See “Notes” following “References.” changes in the cervical tissue from a normal state, in which no DOI: 10.1093/jnci/djg037 neoplastic changes are detected in the squamous epithelium, to Journal of the National Cancer Institute, Vol. 95, No. 17, © Oxford University varying states of cellular abnormalities that ultimately lead to Press 2003, all rights reserved. 1336 ARTICLES Journal of the National Cancer Institute, Vol. 95, No. 17, September 3, 2003 tially eligible were presented with a detailed overview of the HPV DNA Detection study and invited to participate. Recruitment began in November 1993 and continued until March 1997. Cervical specimens were tested for the presence of HPV Women were eligible to participate if they 1) were between DNA by using the MY09/11 polymerase chain reaction (PCR) 18 and 60 years of age; 2) were permanent residents of Sa˜o protocol (9,10). The amplified products were typed by hybrid- Paulo (city), Brazil; 3) were not currently pregnant and had no ization with individual oligonucleotide probes specific for 27 intention of becoming pregnant during the next 12 months; 4) genital HPV types (10). Amplified products that hybridized with had an intact uterus and no current referral for hysterectomy; 5) the generic probe but with none of the type-specific probes were reported no use of vaginal medication in the previous 2 days; and further tested by restriction fragment length polymorphism 6) had not received treatment for cervical disease in the previous analysis (11) to extend the range of identifiable HPV types. To 6 months. In addition to these criteria, women were considered verify the specificity of the hybridizations, we included more eligible only if they expressed willingness to comply with all than 30 type-specific positive controls in each HPV test run. To scheduled return visits, at least for the initial 2 years. check the integrity of the host DNA extracted from the speci- Subjects entered the study only after giving signed informed mens, assays also included an additional set of primers to am-  consent. The study protocol was approved by institutional ethi- plify the -globin gene (9). HPV types were separated into two Downloaded from https://academic.oup.com/jnci/article/95/17/1336/2520427 by guest on 29 September 2021 cal and research review boards of the participating institutions in groups by level of oncogenicity. Oncogenic types included Canada (McGill University) and Brazil (Ludwig Institute for HPV16, -18, -31, -33, -35, -39, -45, -51, -52, -56, -58, -59, and Cancer Research). A detailed description of the design and -68; non-oncogenic types included 6/11, -26, -32, -34, -40, -42, methods of the study has been published previously (7). All -44, -53, -54, -55, -57, -62, -64, -66, -67, -69, -70, -71, -72, -73, participants were seen every 4 months in the first year (at 0, 4, -81, -82, -83, -84, CP6108, and other unknown types. All HPV 8, and 12 months) and every 6 months thereafter. Delays in assays were done on coded specimens, with no identification returning for a given follow-up appointment were allowed; the that could link specimens from the same woman. Appropriate visit numbering sequence was maintained, even when subjects precautions were taken to reduce the possibility of specimen returned for their follow-up visit after the scheduled date, with contamination. the information and specimens collected being assigned to the Statistical Analyses originally scheduled follow-up visit. As a result, the same num- ber of scheduled visits was retained, precluding missing interval For the analyses reported here, follow-up began in November visits. However, all time-to-event analyses were based on the 1993 and continued through mid-April 2002. Subjects with actual time of the visits. Cervical specimens were taken for atypical squamous cells of undetermined significance (ASCUS), conventional Pap smear and HPV testing at every visit. The LSIL, or HSIL on cytology were included in each risk set at the study nurses also performed a detailed interview at enrollment to time of their first detected result. Depending on the index lesion collect information on sociodemographic factors, reproductive of interest, prevalent cases of equivalent grade of abnormality at health, sexual activity, and smoking status.