Human papillomavirus (HPV) testing in the management of women with abnormal pap smears. Experience of a colposcopy referral clinic

Background and objectives: Several detailed algorithms for the appropriate use of human papillomavirus (HPV) testing in the management of women with abnormal Pap (Papanicolaou) smears have been launched, but their direct country-to-country adoption is difficult. This necessitates their testing in individual settings, which is ongoing in our colposcopy referral clinic.

Methods: A series of 224 consecutive women attending the clinic with the usual referral indications (ASC-US or higher in Pap) were examined by the conventional diagnostic tools (PAP smear, colposcopy, punch biopsy) and subjected to HPV testing and viral typing for both low-risk (L-R) and high-risk (H-R) types by nested PCR-based techniques. Predictors of the high-grade diagnostic categories were analysed using both univariate- and multivariate modelling, and the performance characteristics (sensitivity, specificity, NPV, PPV) of all tests in detecting high-grade CIN were calculated.

Results: In the PAP test, ASC-US smears were most common (37.9%), followed by low-grade squamous intraepithelial lesions (LSIL) (26.3%) and high-grade SIL (HSIL) (4.9%). Colposcopy was performed for 180 women, of whom 48.3% had a normal transformation zone (TZ), 40.6% had ATZ1 (abnormal TZ grade 1), and 5.6% had ATZ2. In biopsy (n = 71), 49.3% had CIN1, 5.6% CIN2, and 16.9% CIN3. The HPV test was positive in 64 (28.8%) women, more often in those aged < 35 years (p = 0.025). High-grade colposcopy (ATZ2) was significantly associated with HSIL in the Pap test (OR 20.5; 95% CI: 4.34-96.47), and with HPV test positivity (OR 6.37; 95% CI: 1.58-25.73). The most significant predictors of CIN3 were HSIL in the PAP, HPV test positivity, and high-grade colposcopy. HSIL and HPV test (for H-R types), but not colposcopy, retained their significance as independent predictors of CIN3 also in adjusted multivariate models: OR 88.27; 95% CI 4.17-1867.04, and OR 19.46; 95% CI 2.01-187.75, for the HSIL and H-R HPV test, respectively. Changing the cut-off level of the Pap test from ASC-US to HSIL increased the specificity of the test up to 96.4%, with the loss in sensitivity from 87.5% to 43.8%. Colposcopy (ATZ2) had 92% specificity, and NPV competing with that of the Pap test. The sensitivity of HPV test exceeds that of the Pap test at HSIL cut-off level, but the specificity of the PAP test is clearly superior.

Conclusions: Accurate predictors of significant cervical pathology (CIN3) are well defined, but the problem is the different performance of the diagnostic tools in clinical practice. A proficient combination of the tests is likely to result in the most satisfactory clinical practice in the management of women with abnormal Pap tests (MAPS).

Pap smear; Colposcopy; Biopsy; HPV typing; PCR; Test performance

[1] IARC Monographs on the evaluation of carcinogenic risks to humans. Papillomaviruses. Lyon. !ARC, 1995, 64, 1.

[2] zur Hausen H.: "Cervical carcinoma and human papillomavuus: on the road to preventing a major human cancer". J. Natl. Cancer Inst., 2001, 93, 252.

[3] zur Hausen H.: "Papillomaviruses and cancer: from basic studies to clinical application". Nature Rev. Cancer, 2002, 2, 342.

[4] Syrjiinen K., Syrjiinen S.: "Papillomavirus Infections in Human Pathology". Chichester, J. Wiley & Sons, 2000, 1.

[5] Aubin F., Pretet J.L., Mougin C. (eds): "Papillomavirus Humams Biologie et Pathologie Tumorale". Editions TEC & DOC, Paris 2003, 1.

[6] Miller A.B., Nazeer S., Fonn S., Brandup-Lukanow A., Rehman R., Cronje H. et al.: "Report on consensus conference on cervical cancer screening and management". Int. J. Cancer, 2000, 86, 440.

[7] Franco E., Syrjiinen K., de-Wolf C., Patnick J., Ferenczy A., McGoogan E. et al.: "New developments in cervical cancer screening and prevention". Geneva, Switzerland, June 17-19 1996. Workshop. Cancer Epidemiol. Biomarkers P rev., 1996, 5, 853

[8] Davey D.D., Zarbo R.J.: "Human pap仆lomavirus testing-are you ready for a new era in cervical cancer screening?". Arch. Pathol. Lab. Med., 2003, 127, 927.

[9] 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, 283, 81.

[10] Sheri aw-Johnson C., Gallivan S.: "The planning of cervical cancer screening programmes in eastern Europe: is viral testing a suitable alternative to smear testing?". Health Care Manag Sci., 2000, 3, 323.

[11] Schiffman M., Herrero R., Hildesheim A., Sherman M.E., Bratti M., Wacholder S. et al.: "HPV DNA testing in cervical cancer screening: results from women in a high-risk province of Costa Rica". JAMA, 2000, 283, 87.

[12] Lorincz A.T., Richart R.M.: "Human papillomavirus DNA testing as an adjunct to cytology in cervical screening programs". Arch Pathol. Lab. Med., 2003, 127, 959.

[13] Syrjanen K.J.: "Management of abnormal PAP smears (MAPS) Implications of terminology used in cytopathology". J. Lower Genital Tract Dis., 2000, 4, 217.

[14] Strickler H., Shah K. Re: "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, 951.

[15] Rebello G., Hallam N., Smart G., Farquharson D., McCafferty J.: "Human papillomavirus testing and the management of women with mildly abnormal cervical smears: an observational study". BMJ, 2001, 322, 893.

[16] Morris K.A., Kavanagh A.M., Gunn J.M.: "Management of women with minor abnormalities of the cervix detected on screening: a qualitative study". Med. J. Aust., 2001, 174, 126.

[17] Lee N.W., Kim D., Park J.T., Kim A.: "Is the human papillomavirus test in combination with the papanicolaou test useful for management of patients with diagnoses of atypical squamous cells of undetermined significance/low-grade squamous intraepithelial lesions?". Arch. Pathol. Lab. Med., 2001, 125, 1453.

[18] Costa S., Simone P.D., Venturoli S., Cricca M., Zerbini M.L., Musiani M. et al.: "Factors predicting Human papillomavirus (HPV) clearance in cervical intraepithelial neoplasia (CIN) lesions treated by conization". Gynecol. Oncol., 2003, 90, 358.

[19] Wright T.C. Jr., Cox J.T., Massad L.S., Twiggs L.B., Wilkmson E.J.: "2001 Consensus Guidelines for the management of women with cervical cytological abnormalities". JAMA, 2002, 287, 2120.

[20] Wright T.C. Jr., Cox J.T., Massad L.S., Carlson J., Twiggs L.B., Wilkinson E.J.: "2001 consensus guidelines for the management of women with cervical intraepithelial neoplasia". Am. J. Obstet Gynecol., 2003, 189, 295.

[21] Patnick J., Monsonego J., de Wolf C., Verbeek A., Bonte J., Agnantis N. et al.: "ESGO consensus document on cervical cancer screening. European Society of Gynaecological Oncology". Eur. J Gynaecol. Oncol., 2001, 22, 99.

[22] Jin X.W., Nielsen C., Brainard J., Yen-Lieberman B.: "New advances transform the management of women with abnormal pap tests". Cleve Clin. J. Med., 2003, 70, 641.

[23] Herbst A.L., Pickett K.E., Follen M., Noller K.L.:'The management of ASCUS cervical cytologic abnormalities and HPV testing: a cautionary note". Obstet. Gynecol., 2001, 98, 849.

[24] Chirenje Z.: "The management of cervical intra-epithelial neoplasia". Cent. Afr. Med., 2000, 46, 309.

[25] Syrjanen S., Shabalova I.P., Petrovichev N., Kozachenko VP., Zakharova T., Pajanidi A. et al.: "Human papillomavirus testing and conventional PAP smear cytology as optional screening tools of women at different risk for cervical cancer in countries of former Soviet Union". J. Lower Genital Tract. Dis.. 2002, 6, 97.

[26] Lonky N.M., Felix J.C., Naidu Y.M., Wolde-Tsadik G.:'Triage of atypical squamous cells of undetermined significance with hybrid capture II: Colposcopy and histologic human papillomavirus correlation". Obstet. Gynecol., 2003, 101, 481.

[27] Sherman M.E., Schiffman M., Cox J.T.: "Effects of age and human papilloma viral load on colposcopy triage: Data from the randomized atypical squamous cells of undetermined significancel low-grade squamous intraepithelial lesion triage study (ALTS)". J. Natl. Cancer Inst., 2002, 94, 102.

[28] Little J.: "Human pap仆lomavirus testing. Effectiveness of testmg for high risk HPV for triage of low grade abnormal smears is being assessed in TOMBOL A trial". Br. Med. J, 2001, 323, 109.

[29] Smith J.H.: "Bethesda 2001". Cytopathology, 2002, 13, 4.

[30] Stafl A., Wilbanks G.D.: "An international terminology of colposcopy: report of the Nomenclature Committee of the International Federation of Cervical Pathology and Colposcopy". Obstet. Gynecol., 1991, 77, 313.

[31] Costa S., De Nuzzo M., Bonavita B., Infante F.E., Marinelli M., Rambelli V., Rubino A.: "Cervical loop excision: Colposcopy limits in pre-surgical assessment of CIN Lesions". Tumori, 2001, 87, 13.

[32] Bauer H.M., Greer C.E., Manos M.: "Determination of genital human papillomavirus infection using consensus PCR". In: C.S. Herrington and J.O.D. McGee (eds.), "Diagnostic Molecular Pathology: A Practical Approach". Oxford, Oxford University Press, 1992, 132.

[33] 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, 72, 1039.

[34] Franco E.L., Villa L.L., Sobrinho J.P., Prado J.M., Rousseau M.C., Desy M.: "Epidemiology of acquisition and clearance of cervical human papillomavirus infection in women from a high-risk area for cervical cancer". J. Infect. Dis., 1999, 180, 1415.

[35] Nobbenhuis M.A., Helmerhorst T.J., van den Brule A.J., Rozendaal L., Voorhorst F.J., Bezemer P.O. et al.: "Cytological regression and clearance of high-risk human papillomavirus in women with an abnormal cervical smear". Lancet, 2001, 358, 1782.

[36] Schiffman M., Wheeler C.M., Castle P.E.: "Human papillomavirus DNA remains detectable longer than related cervical cytologic abnormalities". J. Infect. Dis., 2002, 186, 1169.

[37] Syrjanen S., Shabalova I.P., Petrovichev N., Kozachenko VP., Zakharova T., Pajanidi A. et al.: "Clearance of high-risk Hul'lan Papillomavirus (HPV) DNA and PAP smear abnormalities in a cohort of women subjected to HPV screening in the New Independent States (NIS) of the former Soviet Union". Eur. J. Cancer, 2003, Submitted.

[38] Cuzick J., Sasieni P., Davies P., Adams J., Normand C., Frater A. et al.: "A systematic review of the role of human papillomavirus testing within a cervical screening programme". Health Technol Assess., 1999, 3, 1.

[39] van den Akker-van Marie M.E., van Ballegooijen M., van Oortmarssen G.J., Boer R., Habbema J.D.: "Cost-effectiveness of cervical cancer screening: comparison of screening policies". J. Natl Cancer Inst., 2002, 94, 193.

[40] Bosze P., Luesley D.M. (eds). "EAGC Course Book on Colposcopy". Budapest, Primed-X Press, 2003, 1.

[41] Branca M., Rossi E., Alderisio M., Migliore G., Morosini P.L., Vecchione A. et al.: "Performance of cytology and colposcopy in diagnosis of cervical intraepithelial neoplasia (CIN) in HIV-positive and HIV-negative women". Cytopathology, 2001, 12, 84.

[42] Ferris D.G., Wright T.C., Litaker S., Richart R.M., Lorincz A.T., Sun X.W. et al.: "Triage of women with ASCUS and LSIL on Pap smear reports: Management by repeat Pap smear, HPV DNA testing, or colposcopy?". J. Fam. Pract., 1998, 46, 125.

[43] Peyton C.L., Schiffman M., Lorincz AT., Hunt W.C., Mielzynska I., Bratti C. et al.: "Comparison of PCR- and hybrid capture-based human papillomavirus detection systems using multiple cervical specimen collection strategies". J. Clin. Microbial., 1998, 36, 3248.

[44] Venturoli S., Cricca M., Bonvicini F., Giosa F., Pulvirenti F.R., Galli C. et al.: "Human papillomavirus DNA testing by PCRELISA and hybrid capture II from a single cytological specimen concordance and correlation with cytological results". J. Clin. Viral., 2002, 25, 177.