Journal of the National Cancer Institute Advance Access published online on November 9, 2009
JNCI Journal of the National Cancer Institute, doi:10.1093/jnci/djp367
© The Author 2009. Published by Oxford University Press. All rights reserved.
ARTICLE |
Age-Specific Evaluation of Primary Human Papillomavirus Screening vs Conventional Cytology in a Randomized Setting
Affiliations of authors: Mass Screening Registry, Finnish Cancer Registry, Helsinki, Finland (ML, LK-T, NM, AA); Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Espoo, Finland (PN); Tampere School of Public Health, University of Tampere, Tampere, Finland (NM); Department of Pathology, HUSLAB, Helsinki University Central Hospital, Helsinki, Finland (JT, PL)
Correspondence to: Maarit Leinonen, MD, Mass Screening Registry, Finnish Cancer Registry, Pieni Roobertinkatu 9, FI-00130 Helsinki, Finland (e-mail: maarit.leinonen{at}cancer.fi).
Background: Human papillomavirus (HPV) DNA testing has shown higher sensitivity than cytology for detecting cervical lesions, but it is uncertain whether the higher sensitivity is dependent on the age of the woman being screened. We compared the age-specific performance of primary HPV DNA screening with that of conventional cytology screening in the setting of an organized population-based cervical cancer screening program in Finland.
Methods: From January 1, 2003, to December 31, 2005, randomized invitations were sent to women aged 25–65 years for routine cervical cancer screening by primary high-risk HPV DNA testing (n = 54 207) with a Hybrid Capture 2 assay followed by cytology triage for women who were HPV DNA positive or by conventional cytology screening (n = 54 218). In both screening arms, cytology results of low-grade squamous intraepithelial lesion or worse triggered a referral for colposcopy. Relative rates (RRs) of detection to assess test sensitivity, specificity, and positive predictive values (PPVs) with 95% confidence intervals (CIs) were calculated for the histological endpoints of cervical intraepithelial neoplasia (CIN) grade 1 or higher (CIN 1+), CIN grade 2 or higher (CIN 2+), and CIN grade 3 or higher (CIN 3+). All statistical tests were two-sided.
Results: The overall frequency of colposcopy referrals was 1.2% in both screening arms. Women younger than 35 years were referred more often in the HPV DNA screening vs the conventional screening arm (RR = 1.27, 95% CI = 1.01 to 1.60). The prevalence of histologically confirmed CIN or cancer was 0.59% in the HPV DNA screening arm vs 0.43% in the conventional screening arm. The relative rates of detection for CIN 1, CIN 2, and CIN 3+ for HPV DNA screening with cytology triage vs conventional screening were 1.44 (95% CI = 0.99 to 2.10), 1.39 (95% CI = 1.03 to 1.88), and 1.22 (95% CI = 0.78 to 1.92), respectively. The specificity of the HPV DNA test with cytology triage was equal to that of conventional screening for all age groups (99.2% vs 99.1% for CIN 2+, P = .13). Among women aged 35 years or older, the HPV DNA test with cytology triage tended to have higher specificity than conventional screening. The PPVs for HPV DNA screening with cytology triage were consistently higher than those for conventional screening. In both screening arms, the test specificities increased with increasing age of the women being screening, whereas the highest PPVs were observed among the youngest women being screened. Overall, 7.2% of women in the HPV DNA screening arm vs 6.6% of women in the conventional screening arm were recommended for intensified follow-up, and the percentages were highest among 25- to 29-year-olds (21.9% vs 10.0%, respectively).
Conclusions: Primary HPV DNA screening with cytology triage is more sensitive than conventional screening. Among women aged 35 years or older, primary HPV DNA screening with cytology triage is also more specific than conventional screening and decreases colposcopy referrals and follow-up tests.
| CONTEXT AND CAVEATS Prior knowledge Human papillomavirus (HPV) DNA testing is more sensitive than cytology for detecting cervical lesions, but it is uncertain whether the higher sensitivity depends on the age of the woman being screened. Study design A randomized study comparing the age-specific performance of primary HPV DNA screening with that of conventional cytological screening that was incorporated into the routine screening practice of Finland. Contribution Overall, primary HPV DNA screening with cytology triage was more sensitive than conventional screening for detecting cervical lesions. Among women younger than 35 years, those who got HPV DNA screening were referred for colposcopy more often than those who got conventional screening. Among women aged 35 years or older, HPV DNA testing with cytology triage was more sensitive and more specific than conventional screening, had a higher precision rate, and was associated with fewer colposcopy referrals and follow-up tests. Implications These results support the use of HPV DNA testing with cytology triage in primary cervical screening for women aged 35 years or older. Limitations Use of the conventional screening arm as the reference group may have affected the relative detection rates. Colposcopies were not done on the women who were HPV DNA positive but cytology triage negative nor on women who were negative for any test, resulting in verification bias. Laboratory personnel were aware of the screening test results. A considerable number of women in the HPV DNA screening arm were not screened according to the study protocol, which may have attenuated the performance of HPV DNA screening. From the Editors
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Manuscript received February 10, 2009; revised August 28, 2009; accepted September 21, 2009.