title: A prospective study showing long-term infection with human papillomavirus 16 before the development of cervical carcinoma in situ.
abstract: Human papillomavirus 16 (HPV16) is a predominant cause of cervical neoplasia. However, no population-based study with long-term follow-up has clarified the temporal relationship between HPV16 infection and occurrence of carcinoma in situ, or the importance of recurrent or persistent infection. This nested case-control study was carried out in a population-based cohort of women participating in cytological screening whose initial smear, taken in 1969-1995, was normal. During up to 26 years of follow-up, carcinoma in situ was diagnosed in 484 eligible women. Archival smears from these women were compared with smears from 619 individually matched controls. After DNA extraction, a highly sensitive PCR system was used to detect HPV16. Among case women, the prevalence of HPV16 positivity was 56% at the time of diagnosis. The relative risk of cervical carcinoma in situ increased from 3.6 (95% confidence interval, 1.2-11.0) 13 years before diagnosis to 11.1 (95% confidence interval, 5.5-22.2) 1 year before diagnosis. Having a positive smear at entry to the cohort increased risk >5-fold, whereas having persistent infection with HPV in two subsequent smears increased risk 30-fold. We estimated that among HPV16-positive women, the median incubation period from infection to carcinoma in situ was 7-12 years. We conclude that evidence of persistent and/or recurrent infection is associated with a drastically higher risk of cervical carcinoma in situ than occasional infection with HPV16.
authors.affiliation: Department of Medical Epidemiology, Karolinska Institutet, Stockholm, Sweden. Nathalie.Ylitalo@mep.ki.se
authors.forename: N
authors.initials: N
authors.lastname: Ylitalo
authors.forename: A
authors.initials: A
authors.lastname: Josefsson
authors.forename: M
authors.initials: M
authors.lastname: Melbye
authors.forename: P
authors.initials: P
authors.lastname: Sörensen
authors.forename: M
authors.initials: M
authors.lastname: Frisch
authors.forename: P K
authors.initials: PK
authors.lastname: Andersen
authors.forename: P
authors.initials: P
authors.lastname: Sparén
authors.forename: M
authors.initials: M
authors.lastname: Gustafsson
authors.forename: P
authors.initials: P
authors.lastname: Magnusson
authors.forename: J
authors.initials: J
authors.lastname: Pontén
authors.forename: U
authors.initials: U
authors.lastname: Gyllensten
authors.forename: H O
authors.initials: HO
authors.lastname: Adami
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002278:Carcinoma in Situ / Q000453:epidemiology / Q000821:virology*; D002294:Carcinoma, Squamous Cell / Q000453:epidemiology / Q000821:virology*; D016022:Case-Control Studies; D015331:Cohort Studies; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008403:Mass Screening; D008875:Middle Aged; D027383:Papillomaviridae; D030361:Papillomavirus Infections / Q000150:complications* / Q000453:epidemiology / Q000821:virology; D015995:Prevalence; D011446:Prospective Studies; D012307:Risk Factors; D013548:Sweden / Q000453:epidemiology; D013997:Time Factors; D014412:Tumor Virus Infections / Q000150:complications* / Q000453:epidemiology / Q000821:virology; D002583:Uterine Cervical Neoplasms / Q000453:epidemiology / Q000821:virology*; D014626:Vaginal Smears