Can viral load, semi-quantitatively evaluated, of human papillomavirus predict cytological or histological outcome in women with atypical squamous or glandular cells of undetermined significance cytology?

Objective: 1) To assess the regression to normal cytology in women with cervical smears diagnosed as atypical squamous or glandular cells of undetermined significance (ASCUS/AGUS) and absence or clearance of human papillomavirus (HPV) infection; 2) To evaluate the association between viral load, semi-quantitatively evaluated, and cytological or histological outcome.

Material and methods: In this cohort study HPV test and biopsy was taken in 148 women with ASCUS/AGUS cytology. After 12-18 months a HPV test and cervical smear were repeated in 121 women.

Results: Absence or clearance of HPV showed significantly more regression to normal cytology than persistent or newly acquired infected women, odds ratio 27 (95% confidence interval; 7-103). The viral load of the HPV test at enrollment was not correlated with the follow-up cytological outcome (Spearman correlation coefficient 0.2, p = 0.2). A marked association between viral load and histological outcome at enrollment was shown (Spearman correlation coefficient 0.43, p < 0.0001).

Conclusion: Absence or clearance of HPV can predict regression to normal cytology. Viral load at enrollment cannot predict cytological regression. There was a marked association between viral load and the underlying CIN at enrollment. However, there was large overlapping of viral loads among the grades of CIN. Therefore, viral load is not a useful parameter to predict high-grade lesions in women with ASCUS/AGUS cytology.

Atypical squamous cells of undetermined significance; Atypical glandular cells of undetermined significance; Human papillomavirus; Viral load; Cervical intraepithelial neoplasia

[1] Manos M.M., Kinney W.K., Hurley L.B., Sherman M.E., ShiehNgai J., Kurman R.J. et al.: "Identifying women with cervical neoplasia: using human papillomavirus DNA testing for equivocal Papanicolaou results". JAMA, 1999, 281, 1605.

[2] 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, 293.

[3] Cox J.T., Lorincz A.T., Schiffman M.H., Sherman M.E., Cullen A., Kurman R.J.: "Human papillomavirus testing by hybrid capture appears to be useful in triaging women with a cytologic diagnosis of atypical squamous cells of undetermined significance". Am. J. Obstet. Gynecol., 1995, 172, 946.

[4] Lachman M.F., Cavallo-Calvanese C.: "Qualification of atypical squamous cells of undetermined significance in an independent laboratory: is it useful or significant7". Am. J. Obstet. Gynecol., 1998, 179, 421.

[5] Williams M.L., Rimm D.L., Pedigo M.A., Frable W.J.: "Atypical squamous cells of undetermined significance: correlative histologic and follow-up studies from an academic medical center" Diagn. Cytopathol., 1997, 16, 1.

[6] Shlay J.C., Dunn T., Byers T., Baron A.E., Douglas J.M. Jr.: "Prediction of cervical intraepithelial neoplasia grade 2-3 using risk assessment and human papillomavirus testing in women with atypia on papanicolaou smears". Obstet. Gynecol., 2000, 96, 410.

[7] Wensveen C.W.M., Kagie M.J., Veldhuizen R.W., de Groot C.J.M., Denny L., Zwinderman C. et al.: "Detection of cervical intraepithelial neoplasia in women with atypical squamous or glandular cells of undetermined significance: A prospective study". Acta Obstet. Gynecol. Scand., 2003, 82, 883.

[8] Ferenczy A., Franco E.: "Persistent human papillomavirus infection and cervical neoplasia". Lancet Oneal., 2002, 3, 11.

[9] Nobbenhuis M.A., Walboomers J.M., Helmerhorst T.J., Rozendaal L., Remmink A.J., Risse E.K. et al.: "Relation of human papillomavirus status to cervical lesions and consequences for cervicalcancer screening: a prospective study". Lancet. 1999, 354, 20.

[10] Cuzick J., Szarewski A., Terry G., Ho L., Hanby A., Maddox P. et al.: "Human papillomavirus testing in primary cervical screening" Lancet, 1995, 345, 1533.

[11] Kulasingam S.L., Hughes J.P., Kiviat N.B., Mao C., Weiss N.S., Kuypers J.M. et al.: "􀄨valuation 􀄩f human papillomavirus.testing in primary screening for cervical abnormalities: comparison of sensitivity, specificity, and frequency of referral". JAMA, 2002, 288, 1749.

[12] Hatch K.D., Schneider A., Abdel-Nour M.W.: "An evaluation of human papillomavirus testing for intermediate- and high-risk types as triage before colposcopy". Am. J. Obstet. Gynecol., 1995, 172, 1150.

[13] 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 Significance/Low-Grade Squamous Intraepithelial Lesion Triage Study (ALTS)". J. Natl. Cancer Inst., 2002, 94, 102.

[14] Ferris D.G., Wright T.C. Jr., Litaker M.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.

[15] Ferenczy A., Franco E., Arseneau J., W right T.C., Richart R.M "Diagnostic performance of Hybrid Capture human papillomavirus deoxyribonucleic acid assay combined with liquid-based cytologic study". Am. J. Obstet. Gynecol., 1996, 175, 651.

[16] Hanselaar A.G.: "KOPAC-B in beeld [CD-ROM]". N1Jmegen, University Medical Center 1997.

[17] Yooijs G.P.: "De advisering bij afwijkende bevindingen van cytologisch onderzoek van de cervix uteri". Ned. Tijdschr. Geneeskd., 1987, 131, 1662.

[18] 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.

[19] Chenoy R., Billingham L., Irani S., Rollason T.P., Luesley D.M., Jordan J.A.: "The effect of directed biopsy on the atypical cervical transformation zone: assessed by digital imaging colposcopy". Br. J. Obstet. Gynaecol., 1996, 103, 457.

[20] Ho G.Y., Bierman R., Beardsley L., Chang C.J., Burk R.D "Natural history of cervicovaginal papillomavirus infection in young women". N. Engl. J. Med., 1998, 338, 423.

[21] Bory J.P., Cucherousset J., Lorenzato M., Gabriel R., Quereux C., Birembaut P. et al.: "Recurrent human papillomavirus infection detected with the Hybrid Capture II assay selects women with normal cervical smears at risk for developing high grade cervical lesions: a longitudinal study of 3,091 women". Int. J. Cancer. 2002, 102, 519.

[22] Franco E.L., Villa L.L., Sobrinho J.P., Prado J.M., Rousseau M.C., Desy M. et al.: "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.

[23] Cuzick J., Terry G., Ho L., Hollingworth T., Anderson M.: "Typespecific human papillomavirus DNA in abnormal smears as a predictor of high-grade cervical intraepithelial neoplasia". Br. J Cancer. 1994, 69, 167.

[24] van Duin M., Snijders P.J., Schrijnemakers H.F., Yoorhorst F.J., Rozendaal L., Nobbenhuis M.A. et al.: "Human papillomavirus 16 load in normal and abnormal cervical scrapes: an indicator of CIN II/III and viral clearance". Int. J. Cancer. 2002, 98, 590.