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. 2000 Nov 22;83(11):1462–1467. doi: 10.1054/bjoc.2000.1491

Prediction of high-grade cervical intraepithelial neoplasia in cytologically normal women by human papillomavirusesting

F Carozzi 1, G Ronco 2, M Confortini 1, D Noferini 1, C Maddau 1, S Ciatto 3, N Segnan 2
PMCID: PMC2363415  PMID: 11076654

Abstract

Human papillomavirus (HPV) testing has been suggested for primary screening of cervical cancer. Prediction of future high-grade cervical lesions is crucial for effectiveness and cost. We performed a case control study in a retrospective cohort of women with at least two cervical smears, all but the last one being negative, from the organized cervical screening programme in Florence, Italy. We searched for high-risk HPV in all previous, archival, smears from cases (new histologically confirmed cervical intraepithelial neoplasia (CIN) grade II or worse) and in one previous smear from each control (last smear cytologically normal, matched by age and interval (latency) from last smear). We applied polymerase chain reaction (PCR), and the b-globin gene was used as a DNA preservation marker. High-risk HPV was identified in 71/92 (77.17%) previous smears from 79 cases and 17/332 controls (5.12%). The odds ratio (OR) was 63.76 (95% CI 30.57–132.96). Among cases the proportion of HPV-positive smears declined slightly with increasing latency. Among cases, HPV was found in 81.24% (95% CI 69.93–88.96%) of smears with latency < 4 years and in 67.80% (95% CI 47.72–82.93%) of those taken at longer intervals, up to 6 years. These findings suggest that testing for high-risk HPV allows predicting 80% of CINII/III 3 years before the cytological diagnosis and two thirds 6 years before. They also suggest that testing women negative for high-risk HPV at longer interval and strictly following-up women who are HPV positive could be an effective strategy for cervical cancer screening. © 2000 Cancer Research Campaign http://www.bjcancer.com

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Selected References

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  1. Brookmeyer R., Liang K. Y., Linet M. Matched case-control designs and overmatched analyses. Am J Epidemiol. 1986 Oct;124(4):693–701. doi: 10.1093/oxfordjournals.aje.a114443. [DOI] [PubMed] [Google Scholar]
  2. Burk R. D., Kelly P., Feldman J., Bromberg J., Vermund S. H., DeHovitz J. A., Landesman S. H. Declining prevalence of cervicovaginal human papillomavirus infection with age is independent of other risk factors. Sex Transm Dis. 1996 Jul-Aug;23(4):333–341. doi: 10.1097/00007435-199607000-00013. [DOI] [PubMed] [Google Scholar]
  3. Clavel C., Masure M., Bory J. P., Putaud I., Mangeonjean C., Lorenzato M., Gabriel R., Quereux C., Birembaut P. Hybrid Capture II-based human papillomavirus detection, a sensitive test to detect in routine high-grade cervical lesions: a preliminary study on 1518 women. Br J Cancer. 1999 Jul;80(9):1306–1311. doi: 10.1038/sj.bjc.6690523. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Confortini M., Biggeri A., Cariaggi M. P., Carozzi F. M., Minuti P. A., Russo A., Palli D. Intralaboratory reproducibility in cervical cytology. Results of the application of a 100-slide set. Acta Cytol. 1993 Jan-Feb;37(1):49–54. [PubMed] [Google Scholar]
  5. Cuzick J., Beverley E., Ho L., Terry G., Sapper H., Mielzynska I., Lorincz A., Chan W. K., Krausz T., Soutter P. HPV testing in primary screening of older women. Br J Cancer. 1999 Oct;81(3):554–558. doi: 10.1038/sj.bjc.6690730. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Cuzick J. Human papillomavirus testing for primary cervical cancer screening. JAMA. 2000 Jan 5;283(1):108–109. doi: 10.1001/jama.283.1.108. [DOI] [PubMed] [Google Scholar]
  7. Cuzick J., Szarewski A., Terry G., Ho L., Hanby A., Maddox P., Anderson M., Kocjan G., Steele S. T., Guillebaud J. Human papillomavirus testing in primary cervical screening. Lancet. 1995 Jun 17;345(8964):1533–1536. doi: 10.1016/s0140-6736(95)91086-7. [DOI] [PubMed] [Google Scholar]
  8. Fujinaga Y., Shimada M., Okazawa K., Fukushima M., Kato I., Fujinaga K. Simultaneous detection and typing of genital human papillomavirus DNA using the polymerase chain reaction. J Gen Virol. 1991 May;72(Pt 5):1039–1044. doi: 10.1099/0022-1317-72-5-1039. [DOI] [PubMed] [Google Scholar]
  9. Gustafsson L., Adami H. O. Natural history of cervical neoplasia: consistent results obtained by an identification technique. Br J Cancer. 1989 Jul;60(1):132–141. doi: 10.1038/bjc.1989.236. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Gustafsson L., Adami H. O. Optimization of cervical cancer screening. Cancer Causes Control. 1992 Mar;3(2):125–136. doi: 10.1007/BF00051652. [DOI] [PubMed] [Google Scholar]
  11. Ho G. Y., Burk R. D., Klein S., Kadish A. S., Chang C. J., Palan P., Basu J., Tachezy R., Lewis R., Romney S. Persistent genital human papillomavirus infection as a risk factor for persistent cervical dysplasia. J Natl Cancer Inst. 1995 Sep 20;87(18):1365–1371. doi: 10.1093/jnci/87.18.1365. [DOI] [PubMed] [Google Scholar]
  12. Kjellberg L., Wiklund F., Sjöberg I., Wadell G., Angström T., Dillner J., Mählck C. G. A population-based study of human papillomavirus deoxyribonucleic acid testing for predicting cervical intraepithelial neoplasia. Am J Obstet Gynecol. 1998 Dec;179(6 Pt 1):1497–1502. doi: 10.1016/s0002-9378(98)70015-8. [DOI] [PubMed] [Google Scholar]
  13. Liaw K. L., Glass A. G., Manos M. M., Greer C. E., Scott D. R., Sherman M., Burk R. D., Kurman R. J., Wacholder S., Rush B. B. Detection of human papillomavirus DNA in cytologically normal women and subsequent cervical squamous intraepithelial lesions. J Natl Cancer Inst. 1999 Jun 2;91(11):954–960. doi: 10.1093/jnci/91.11.954. [DOI] [PubMed] [Google Scholar]
  14. Melkert P. W., Hopman E., van den Brule A. J., Risse E. K., van Diest P. J., Bleker O. P., Helmerhorst T., Schipper M. E., Meijer C. J., Walboomers J. M. Prevalence of HPV in cytomorphologically normal cervical smears, as determined by the polymerase chain reaction, is age-dependent. Int J Cancer. 1993 Apr 1;53(6):919–923. doi: 10.1002/ijc.2910530609. [DOI] [PubMed] [Google Scholar]
  15. Morrison E. A., Ho G. Y., Vermund S. H., Goldberg G. L., Kadish A. S., Kelley K. F., Burk R. D. Human papillomavirus infection and other risk factors for cervical neoplasia: a case-control study. Int J Cancer. 1991 Aug 19;49(1):6–13. doi: 10.1002/ijc.2910490103. [DOI] [PubMed] [Google Scholar]
  16. Nobbenhuis M. A., Walboomers J. M., Helmerhorst T. J., Rozendaal L., Remmink A. J., Risse E. K., van der Linden H. C., Voorhorst F. J., Kenemans P., Meijer C. J. Relation of human papillomavirus status to cervical lesions and consequences for cervical-cancer screening: a prospective study. Lancet. 1999 Jul 3;354(9172):20–25. doi: 10.1016/S0140-6736(98)12490-X. [DOI] [PubMed] [Google Scholar]
  17. Palli D., Carli S., Cecchini S., Venturini A., Piazzesi G., Buiatti E. A centralised cytology screening programme for cervical cancer in Florence. J Epidemiol Community Health. 1990 Mar;44(1):47–51. doi: 10.1136/jech.44.1.47. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Palli D., Confortini M., Biggeri A., Russo A., Cariaggi P., Carozzi F., Minuti P. A. A quality control system involving peer review of abnormal cervical smears. Cytopathology. 1993;4(1):17–25. doi: 10.1111/j.1365-2303.1993.tb00069.x. [DOI] [PubMed] [Google Scholar]
  19. Reid R., Greenberg M. D., Lorincz A., Jenson A. B., Laverty C. R., Husain M., Daoud Y., Zado B., White T., Cantor D. Should cervical cytologic testing be augmented by cervicography or human papillomavirus deoxyribonucleic acid detection? Am J Obstet Gynecol. 1991 Jun;164(6 Pt 1):1461–1471. doi: 10.1016/0002-9378(91)91425-v. [DOI] [PubMed] [Google Scholar]
  20. Remmink A. J., Walboomers J. M., Helmerhorst T. J., Voorhorst F. J., Rozendaal L., Risse E. K., Meijer C. J., Kenemans P. The presence of persistent high-risk HPV genotypes in dysplastic cervical lesions is associated with progressive disease: natural history up to 36 months. Int J Cancer. 1995 May 4;61(3):306–311. doi: 10.1002/ijc.2910610305. [DOI] [PubMed] [Google Scholar]
  21. Richart R. M. Screening. The next century. Cancer. 1995 Nov 15;76(10 Suppl):1919–1927. doi: 10.1002/1097-0142(19951115)76:10+<1919::aid-cncr2820761308>3.0.co;2-9. [DOI] [PubMed] [Google Scholar]
  22. Ronco G., Biggeri A. Estimating sensitivity and specificity when repeated tests are performed on the same subject. J Epidemiol Biostat. 1999;4(4):329–336. [PubMed] [Google Scholar]
  23. Rozendaal L., Walboomers J. M., van der Linden J. C., Voorhorst F. J., Kenemans P., Helmerhorst T. J., van Ballegooijen M., Meijer C. J. PCR-based high-risk HPV test in cervical cancer screening gives objective risk assessment of women with cytomorphologically normal cervical smears. Int J Cancer. 1996 Dec 11;68(6):766–769. doi: 10.1002/(SICI)1097-0215(19961211)68:6<766::AID-IJC13>3.0.CO;2-Z. [DOI] [PubMed] [Google Scholar]
  24. Schiffman M. H. Recent progress in defining the epidemiology of human papillomavirus infection and cervical neoplasia. J Natl Cancer Inst. 1992 Mar 18;84(6):394–398. doi: 10.1093/jnci/84.6.394. [DOI] [PubMed] [Google Scholar]
  25. Schiffman M., Herrero R., Hildesheim A., Sherman M. E., Bratti M., Wacholder S., Alfaro M., Hutchinson M., Morales J., Greenberg M. D. HPV DNA testing in cervical cancer screening: results from women in a high-risk province of Costa Rica. JAMA. 2000 Jan 5;283(1):87–93. doi: 10.1001/jama.283.1.87. [DOI] [PubMed] [Google Scholar]
  26. Solomon D. Screening for cervical cancer: prospects for the future. J Natl Cancer Inst. 1993 Jul 7;85(13):1018–1019. doi: 10.1093/jnci/85.13.1018. [DOI] [PubMed] [Google Scholar]
  27. Svare E. I., Kjaer S. K., Smits H. L., Poll P., Tjong-A-Hung S. P., ter Schegget J. Risk factors for HPV detection in archival Pap smears. A population-based study from Greenland and Denmark. Eur J Cancer. 1998 Jul;34(8):1230–1234. doi: 10.1016/s0959-8049(98)00131-2. [DOI] [PubMed] [Google Scholar]
  28. Wallin K. L., Wiklund F., Angström T., Bergman F., Stendahl U., Wadell G., Hallmans G., Dillner J. Type-specific persistence of human papillomavirus DNA before the development of invasive cervical cancer. N Engl J Med. 1999 Nov 25;341(22):1633–1638. doi: 10.1056/NEJM199911253412201. [DOI] [PubMed] [Google Scholar]
  29. Wright T. C., Jr, Denny L., Kuhn L., Pollack A., Lorincz A. HPV DNA testing of self-collected vaginal samples compared with cytologic screening to detect cervical cancer. JAMA. 2000 Jan 5;283(1):81–86. doi: 10.1001/jama.283.1.81. [DOI] [PubMed] [Google Scholar]
  30. Zeger S. L., Liang K. Y. Longitudinal data analysis for discrete and continuous outcomes. Biometrics. 1986 Mar;42(1):121–130. [PubMed] [Google Scholar]
  31. de Roda Husman A. M., Snijders P. J., Stel H. V., van den Brule A. J., Meijer C. J., Walboomers J. M. Processing of long-stored archival cervical smears for human papillomavirus detection by the polymerase chain reaction. Br J Cancer. 1995 Aug;72(2):412–417. doi: 10.1038/bjc.1995.347. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. van Ballegooijen M., van den Akker-van Marle M. E., Warmerdam P. G., Meijer C. J., Walboomers J. M., Habbema J. D. Present evidence on the value of HPV testing for cervical cancer screening: a model-based exploration of the (cost-)effectiveness. Br J Cancer. 1997;76(5):651–657. doi: 10.1038/bjc.1997.440. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. van Oortmarssen G. J., Habbema J. D. Epidemiological evidence for age-dependent regression of pre-invasive cervical cancer. Br J Cancer. 1991 Sep;64(3):559–565. doi: 10.1038/bjc.1991.350. [DOI] [PMC free article] [PubMed] [Google Scholar]

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