The Potential Utility of HPV Genotyping in Screening and Clinical Management

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Detection of specific human papillomavirus (HPV) genotypes, or HPV genotyping, may be useful for differentiating between those women who are carcinogenic HPV-positive at lower and higher risk for cervical precancer and cancer. Considerable evidence already exists that the absolute risk for cervical precancer and cancer varies considerably among specific HPV genotypes, and that detection of HPV-16 and -18 may have clinical usefulness, especially among women who tested positive for carcinogenic HPV and have negative cytology. Detection of persistent carcinogenic HPV is strongly associated with cervical precancer and cancer and strongly predicts its development, and might be used to monitor the outcomes of HPV infections. However, several practical considerations must be addressed before HPV genotyping can be used in screening and clinical management.

Correspondence: Philip E. Castle, PhD, MPH, Division of Cancer Epidemiology and Genetics, National Cancer Institute, 6120 Executive Boulevard, Room 5004, EPS MSC 7234, Bethesda, MD 20892-7234. E-mail: castlep@mail.nih.gov
  • 1.

    IARC Handbooks of Cancer Prevention, Vol. 10: Cervix Cancer Screening. Lyon, France: IARC Press; 2005.

  • 2.

    Jemal A, Siegel R, Ward E. Cancer statistics, 2007. CA Cancer J Clin 2007;57:4366.

  • 3.

    Kitchener HC, Castle PE, Cox JT. Chapter 7: achievements and limitations of cervical cytology screening. Vaccine 2006;24(Suppl 3):S6370.

  • 4.

    Nanda K, McCrory DC, Myers ER. Accuracy of the Papanicolaou test in screening for and follow-up of cervical cytologic abnormalities: a systematic review. Ann Intern Med 2000;132:810819.

    • Search Google Scholar
    • Export Citation
  • 5.

    Cuzick J, Clavel C, Petry KU. Overview of the European and North American studies on HPV testing in primary cervical cancer screening. Int J Cancer 2006;119:10951101.

    • Search Google Scholar
    • Export Citation
  • 6.

    Stoler MH, Schiffman M. Interobserver reproducibility of cervical cytologic and histologic interpretations: realistic estimates from the ASCUS-LSIL Triage Study. JAMA 2001;285:15001505.

    • Search Google Scholar
    • Export Citation
  • 7.

    Kurman RJ, Henson DE, Herbst AL. Interim guidelines for management of abnormal cervical cytology. The 1992 National Cancer Institute Workshop. JAMA 1994;271:18661869.

    • Search Google Scholar
    • Export Citation
  • 8.

    Walboomers JM, Jacobs MV, Manos MM. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol 1999;189:1219.

    • Search Google Scholar
    • Export Citation
  • 9.

    Munoz N, Bosch FX, de Sanjose S. Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med 2003;348:518527.

    • Search Google Scholar
    • Export Citation
  • 10.

    Schiffman MH, Bauer HM, Hoover RN. Epidemiologic evidence showing that human papillomavirus infection causes most cervical intraepithelial neoplasia. J Natl Cancer Inst 1993;85:958964.

    • Search Google Scholar
    • Export Citation
  • 11.

    Wright TC Jr, Schiffman M. Adding a test for human papillomavirus DNA to cervical-cancer screening. N Engl J Med 2003;348:489490.

  • 12.

    Solomon D, Schiffman M, Tarone R. Comparison of three management strategies for patients with atypical squamous cells of undetermined significance: baseline results from a randomized trial. J Natl Cancer Inst 2001;93:293299.

    • Search Google Scholar
    • Export Citation
  • 13.

    Arbyn M, Buntinx F, Van Ranst M. Virologic versus cytologic triage of women with equivocal Pap smears: a meta-analysis of the accuracy to detect high-grade intraepithelial neoplasia. J Natl Cancer Inst 2004;96:280293.

    • Search Google Scholar
    • Export Citation
  • 14.

    Arbyn M, Sasieni P, Meijer CJ. Chapter 9: clinical applications of HPV testing: a summary of meta-analyses. Vaccine 2006;24(Suppl 3):S7889.

  • 15.

    Manos MM, Kinney WK, Hurley LB. Identifying women with cervical neoplasia: using human papillomavirus DNA testing for equivocal Papanicolaou results. JAMA 1999;281:16051610.

    • Search Google Scholar
    • Export Citation
  • 16.

    Kulasingam SL, Kim JJ, Lawrence WF. Cost-effectiveness analysis based on the atypical squamous cells of undetermined significance/low-grade squamous intraepithelial lesion Triage Study (ALTS). J Natl Cancer Inst 2006;98:92100.

    • Search Google Scholar
    • Export Citation
  • 17.

    Kim JJ, Wright TC, Goldie SJ. Cost-effectiveness of human papillomavirus DNA testing in the United Kingdom, The Netherlands, France, and Italy. J Natl Cancer Inst 2005;97:888895.

    • Search Google Scholar
    • Export Citation
  • 18.

    Cuzick J, Szarewski A, Cubie H. Management of women who test positive for high-risk types of human papillomavirus: the HART study. Lancet 2003;362:18711876.

    • Search Google Scholar
    • Export Citation
  • 19.

    Ronco G, Giorgi-Rossi P, Carozzi F. Human papillomavirus testing and liquid-based cytology in primary screening of women younger than 35 years: results at recruitment for a randomised controlled trial. Lancet Oncol 2006;7:547555.

    • Search Google Scholar
    • Export Citation
  • 20.

    Sherman ME, Lorincz AT, Scott DR. Baseline cytology, human papillomavirus testing, and risk for cervical neoplasia: a 10-year cohort analysis. J Natl Cancer Inst 2003;95:4652.

    • Search Google Scholar
    • Export Citation
  • 21.

    Ronco G, Segnan N, Giorgi-Rossi P. Human papillomavirus testing and liquid-based cytology: results at recruitment from the new technologies for cervical cancer randomized controlled trial. J Natl Cancer Inst 2006;98:765774.

    • Search Google Scholar
    • Export Citation
  • 22.

    Kjaer S, Hogdall E, Frederiksen K. The absolute risk of cervical abnormalities in high-risk human papillomavirus-positive, cytologically normal women over a 10-year period. Cancer Res 2006;66:1063010636.

    • Search Google Scholar
    • Export Citation
  • 23.

    Walker JL, Wang SS, Schiffman M, Solomon D. Predicting absolute risk of CIN3 during post-colposcopic follow-up: results from the ASCUS-LSIL Triage Study (ALTS). Am J Obstet Gynecol 2006;195:341348.

    • Search Google Scholar
    • Export Citation
  • 24.

    Kreimer AR, Guido RS, Solomon D. Human papillomavirus testing following loop electrosurgical excision procedure identifies women at risk for posttreatment cervical intraepithelial neoplasia grade 2 or 3 disease. Cancer Epidemiol Biomarkers Prev 2006;15:908914.

    • Search Google Scholar
    • Export Citation
  • 25.

    Arbyn M, Paraskevaidis E, Martin-Hirsch P. Clinical utility of HPV-DNA detection: triage of minor cervical lesions, follow-up of women treated for high-grade CIN: an update of pooled evidence. Gynecol Oncol 2005;99(3 Suppl):S711.

    • Search Google Scholar
    • Export Citation
  • 26.

    Gok M, Coupe VM, Berkhof J. HPV16 and increased risk of recurrence after treatment for CIN. Gynecol Oncol 2007;104:273275.

  • 27.

    Castle PE, Wheeler CM, Solomon D. Interlaboratory reliability of Hybrid Capture 2. Am J Clin Pathol 2004;122:238245.

  • 28.

    Carozzi FM, Del Mistro A, Confortini M. Reproducibility of HPV DNA testing by Hybrid Capture 2 in a screening setting. Am J Clin Pathol 2005;124:716721.

    • Search Google Scholar
    • Export Citation
  • 29.

    Wright TC Jr, Schiffman M, Solomon D. Interim guidance for the use of human papillomavirus DNA testing as an adjunct to cervical cytology for screening. Obstet Gynecol 2004;103:304309.

    • Search Google Scholar
    • Export Citation
  • 30.

    Smith JS, Lindsay L, Hoots B. Human papillomavirus type distribution in invasive cervical cancer and high-grade cervical lesions: a meta-analysis update. Int J Cancer 2007.

    • Search Google Scholar
    • Export Citation
  • 31.

    Khan MJ, Castle PE, Lorincz AT. The elevated 10-year risk of cervical precancer and cancer in women with human papillomavirus (HPV) type 16 or 18 and the possible utility of type-specific HPV testing in clinical practice. J Natl Cancer Inst 2005;97:10721079.

    • Search Google Scholar
    • Export Citation
  • 32.

    Sherman ME, Wang SS, Carreon J, Devesa SS. Mortality trends for cervical squamous and adenocarcinoma in the United States. Relation to incidence and survival. Cancer 2005;103:12581264.

    • Search Google Scholar
    • Export Citation
  • 33.

    Bray F, Carstensen B, Moller H. Incidence trends of adenocarcinoma of the cervix in 13 European countries. Cancer Epidemiol Biomarkers Prev 2005;14:21912199.

    • Search Google Scholar
    • Export Citation
  • 34.

    Berkhof J, Bulkmans NW, Bleeker MC. Human papillomavirus type-specific 18-month risk of high-grade cervical intraepithelial neoplasia in women with a normal or borderline/mildly dyskaryotic smear. Cancer Epidemiol Biomarkers Prev 2006;15:12681273.

    • Search Google Scholar
    • Export Citation
  • 35.

    Bulk S, Berkhof J, Bulkmans NW. Preferential risk of HPV16 for squamous cell carcinoma and of HPV18 for adenocarcinoma of the cervix compared to women with normal cytology in The Netherlands. Br J Cancer 2006;94:171175.

    • Search Google Scholar
    • Export Citation
  • 36.

    Bulkmans NW, Bleeker MC, Berkhof J. Prevalence of types 16 and 33 is increased in high-risk human papillomavirus positive women with cervical intraepithelial neoplasia grade 2 or worse. Int J Cancer 2005;117:177181.

    • Search Google Scholar
    • Export Citation
  • 37.

    Naucler P, Ryd W, Tornberg S. HPV type-specific risks of high-grade CIN during 4 years of follow-up: a population-based prospective study. Br J Cancer 2007;97:129132.

    • Search Google Scholar
    • Export Citation
  • 38.

    Mitchell H, Medley G, Gordon I, Giles G. Cervical cytology reported as negative and risk of adenocarcinoma of the cervix: no strong evidence of benefit. Br J Cancer 1995;71:894897.

    • Search Google Scholar
    • Export Citation
  • 39.

    Lorincz AT, Reid R, Jenson AB. Human papillomavirus infection of the cervix: relative risk associations of 15 common anogenital types. Obstet Gynecol 1992;79:328337.

    • Search Google Scholar
    • Export Citation
  • 40.

    Bulk S, Berkhof J, Rozendaal L. The contribution of HPV18 to cervical cancer is underestimated using high-grade CIN as a measure of screening efficiency. Br J Cancer 2007;96:12341236.

    • Search Google Scholar
    • Export Citation
  • 41.

    Kovacic MB, Castle PE, Herrero R. Relationships of human papillomavirus type, qualitative viral load, and age with cytologic abnormality. Cancer Res 2006;66:1011210119.

    • Search Google Scholar
    • Export Citation
  • 42.

    Schiffman M, Herrero R, Desalle R. The carcinogenicity of human papillomavirus types reflects viral evolution. Virology 2005;20;337:7684.

  • 43.

    Schlecht NF, Kulaga S, Robitaille J. Persistent human papillomavirus infection as a predictor of cervical intraepithelial neoplasia. JAMA 2001;286:31063114.

    • Search Google Scholar
    • Export Citation
  • 44.

    Kjaer SK, van den Brule AJ, Paull G. Type specific persistence of high risk human papillomavirus (HPV) as indicator of high grade cervical squamous intraepithelial lesions in young women: population based prospective follow up study. BMJ 2002;325:572.

    • Search Google Scholar
    • Export Citation
  • 45.

    Schiffman M, Herrero R, Desalle R. The carcinogenicity of human papillomavirus types reflects viral evolution. Virology 2005;337:7684.

  • 46.

    Castle PE, Schiffman M, Herrero R. A prospective study of age trends in cervical human papillomavirus acquisition and persistence in Guanacaste, Costa Rica. J Infect Dis 2005;191:18081816.

    • Search Google Scholar
    • Export Citation
  • 47.

    Shew ML, Fortenberry JD, Tu W. Association of condom use, sexual behaviors, and sexually transmitted infections with the duration of genital human papillomavirus infection among adolescent women. Arch Pediatr Adolesc Med 2006;160:151156.

    • Search Google Scholar
    • Export Citation
  • 48.

    Wheeler CM, Hunt WC, Schiffman M, Castle PE. Human papillomavirus genotypes and the cumulative 2-year risk of cervical precancer. J Infect Dis 2006;194:12911299.

    • Search Google Scholar
    • Export Citation
  • 49.

    Trottier H, Franco EL. The epidemiology of genital human papillomavirus infection. Vaccine 2006;24(Suppl 1):S115.

  • 50.

    Castle PE, Schiffman M, Herrero R. A prospective study of age trends in cervical human papillomavirus acquisition and persistence in Guanacaste, Costa Rica. J Infect Dis 2005;191:18081816.

    • Search Google Scholar
    • Export Citation
  • 51.

    Plummer M, Schiffman M, Castle PE. A 2-year prospective study of human papillomavirus persistence among women with atypical squamous cells of undetermined significance or low-grade squamous intraepithelial lesion. J Infect Dis 2007;195:15821589.

    • Search Google Scholar
    • Export Citation
  • 52.

    Richardson H, Kelsall G, Tellier P. The natural history of type-specific human papillomavirus infections in female university students. Cancer Epidemiol Biomarkers Prev 2003;12:485490.

    • Search Google Scholar
    • Export Citation
  • 53.

    Kulasingam SL, Hughes JP, Kiviat NB. Evaluation of human papillomavirus testing in primary screening for cervical abnormalities: comparison of sensitivity, specificity, and frequency of referral. JAMA 2002;288:17491757.

    • Search Google Scholar
    • Export Citation
  • 54.

    Ho GY, Bierman R, Beardsley L. Natural history of cervicovaginal papillomavirus infection in young women. N Engl J Med 1998;338:423428.

  • 55.

    Wallin KL, Wiklund F, Angstrom T. Type-specific persistence of human papillomavirus DNA before the development of invasive cervical cancer. N Engl J Med 1999;341:16331638.

    • Search Google Scholar
    • Export Citation
  • 56.

    Castle PE, Sideri M, Jeronimo J. Risk assessment to guide the prevention of cervical cancer. Am J Obstet Gynecol 2007;197:356.e16.

  • 57.

    Guido R, Schiffman M, Solomon D, Burke L. Postcolposcopy management strategies for women referred with low-grade squamous intraepithelial lesions or human papillomavirus DNA-positive atypical squamous cells of undetermined significance: a two-year prospective study. Am J Obstet Gynecol 2003;188:14011405.

    • Search Google Scholar
    • Export Citation
  • 58.

    Gage JC, Hanson VW, Abbey K. Number of cervical biopsies and sensitivity of colposcopy. Obstet Gynecol 2006;108:264272.

  • 59.

    Jeronimo J, Schiffman M. Colposcopy at a crossroads. Am J Obstet Gynecol 2006;195:349353.

  • 60.

    Schiffman M, Adrianza ME. ASCUS-LSIL Triage Study. Design, methods and characteristics of trial participants. Acta Cytol 2000;44:726742.

  • 61.

    Castle PE, Solomon D, Schiffman M, Wheeler CM. Human papillomavirus type 16 infections and 2-year absolute risk of cervical precancer in women with equivocal or mild cytologic abnormalities. J Natl Cancer Inst 2005;20;97:1066–1071.

    • Search Google Scholar
    • Export Citation
  • 62.

    FUTURE II Study Group. Quadrivalent vaccine against human papillomavirus to prevent high-grade cervical lesions. N Engl J Med 2007;356:19151927.

    • Search Google Scholar
    • Export Citation
  • 63.

    Garland SM, Hernandez-Avila M, Wheeler CM. Quadrivalent vaccine against human papillomavirus to prevent anogenital diseases. N Engl J Med 2007;356:19281943.

    • Search Google Scholar
    • Export Citation
  • 64.

    Paavonen J, Jenkins D, Bosch FX. Efficacy of a prophylactic adjuvanted bivalent L1 virus-like-particle vaccine against infection with human papillomavirus types 16 and 18 in young women: an interim analysis of a phase III double-blind, randomised controlled trial. Lancet 2007;369:21612170.

    • Search Google Scholar
    • Export Citation
  • 65.

    ASCUS-LSIL Triage Study (ALTS) Group. A randomized trial on the management of low-grade squamous intraepithelial lesion cytology interpretations. Am J Obstet Gynecol 2003;188:13931400.

    • Search Google Scholar
    • Export Citation
  • 66.

    ASCUS-LSIL Triage Study (ALTS) Group. Results of a randomized trial on the management of cytology interpretations of atypical squamous cells of undetermined significance. Am J Obstet Gynecol 2003;188:13831392.

    • Search Google Scholar
    • Export Citation
  • 67.

    Kyrgiou M, Koliopoulos G, Martin-Hirsch P. Obstetric outcomes after conservative treatment for intraepithelial or early invasive cervical lesions: systematic review and meta-analysis. Lancet 2006;367:489498.

    • Search Google Scholar
    • Export Citation
  • 68.

    Kreimer AR, Katki H, Schiffman M. Viral determinants of HPV persistence following LEEP treatment for cervical intraepithelial neoplasia grade 2 or 3. Cancer Epidemiol Biomarkers Prev 2007;16:1116.

    • Search Google Scholar
    • Export Citation
  • 69.

    Xi LF, Kiviat NB, Wheeler CM. Risk of cervical intraepithelial neoplasia grade 2 or 3 after loop electrosurgical excision procedure associated with human papillomavirus type 16 variants. J Infect Dis 2007;195:13401344.

    • Search Google Scholar
    • Export Citation
  • 70.

    Bae JH, Kim CJ, Park TC. Persistence of human papillomavirus as a predictor for treatment failure after loop electrosurgical excision procedure. Int J Gynecol Cancer 2007;17:12711277.

    • Search Google Scholar
    • Export Citation
  • 71.

    Jain N, Irwin K, Carlin L. Use of DNA tests for human Papillomavirus infection by US clinicians, 2004. J Infect Dis 2007;196:7681.

  • 72.

    Moriarty AT. A rock and a hard place: HPV testing and financial gain. Diagn Cytopathol 2007;35:463464.

  • 73.

    Sirovich BE, Welch HG. Cervical cancer screening among women without a cervix. JAMA 2004;291:29902993.

  • 74.

    Solomon D, Breen N, McNeel T. Cervical cancer screening rates in the United States and the potential impact of implementation of screening guidelines. CA Cancer J Clin 2007;57:105111.

    • Search Google Scholar
    • Export Citation
  • 75.

    Castle P. Cervical cancer screening among women without a cervix. JAMA 2004;292:15501551.

  • 76.

    Castle PE, Schiffman M, Glass AG. Human papillomavirus prevalence in women who have and have not undergone hysterectomies. J Infect Dis 2006;194:17021705.

    • Search Google Scholar
    • Export Citation
  • 77.

    Castle PE, Schiffman M, Bratti MC. A population-based study of vaginal human papillomavirus infection in hysterectomized women. J Infect Dis 2004;190:458467.

    • Search Google Scholar
    • Export Citation
  • 78.

    Castle PE, Stoler MH, Solomon D, Schiffman M. The relationship of community biopsy-diagnosed cervical intraepithelial neoplasia grade 2 to the quality control pathology-reviewed diagnoses: an ALTS report. Am J Clin Pathol 2007;127:805815.

    • Search Google Scholar
    • Export Citation
  • 79.

    Stoler MH, Castle PE, Solomon D, Schiffman M. The expanded use of HPV testing in gynecologic practice per ASCCP-guided management requires the use of well-validated assays. Am J Clin Pathol 2007;127:13.

    • Search Google Scholar
    • Export Citation
  • 80.

    Bratti MC, Rodriguez AC, Schiffman M. Description of a seven-year prospective study of human papillomavirus infection and cervical neoplasia among 10000 women in Guanacaste, Costa Rica. Rev Panam Salud Publica 2004;15:7589.

    • Search Google Scholar
    • Export Citation
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