Covariates of high-risk human papillomavirus (HPV) infections are distinct for incident CIN1, CIN2 and CIN3 as disclosed by competing-risks regression models

Background: In addition to the oncogenic human papillomavirus (HPV), several cofactors are needed in cervical carcinogenesis, but whether the HPV covariates associated with incident i) CIN1 are different from those of incident ii) CIN2 and iii) CIN3 needs further assessment. Objectives: To gain further insights into the true biological differences between CIN1, CIN2 and CIN3, we assessed HPV covariates associated with incident CIN1, CIN2, and CIN3. Study Design and Methods: HPV covariates associated with progression to CIN1, CIN2 and CIN3 were analysed in the combined cohort of the NIS (n = 3,187) and LAMS study (n = 12,114), using competing-risks regression models (in panel data) for baseline HR-HPV-positive women (n = 1,105), who represent a sub-cohort of all 1,865 women prospectively followed-up in these two studies. Results: Altogether, 90 (4.8%), 39 (2.1%) and 14 (1.4%) cases progressed to CIN1, CIN2, and CIN3, respectively. Among these baseline HR-HPV-positive women, the risk profiles of incident GIN I, CIN2 and CIN3 were unique in that completely different HPV covariates were associated with progression to CIN1, CIN2 and CIN3, irrespective which categories (non-progression, CIN1, CIN2, CIN3 or all) were used as competing-risks events in univariate and multivariate models. Conclusions: These data confirm our previous analysis based on multinomial regression models implicating that distinct covariates of HR-HPV are associated with progression to CIN1, CIN2 and CIN3. This emphasises true biological differences between the three grades of GIN, which revisits the concept of combining CIN2 with CIN3 or with CIN1 in histological classification or used as a common end-point, e.g., in HPV vaccine trials.

CIN; HPV; Covariates; Progression; Competing-risks regression; Univariate; Multivariate; Prospective follow-up; NIS Cohort; LAMS Study

[1] Syrjänen K.J.: “Biology of human papillomavirus (HPV) infections and their role in squamous cell carcinogenesis”. Med. Biol., 1987, 65, 21.[2] Syrjänen K., Syrjänen S. (eds.): “Papillomavirus Infections in Human Pathology”. New York, J. Wiley & Sons, 2000, 1.[3] Syrjänen S., Syrjänen K.: “The history of papillomavirus research”. Cent. Eur. J. Public Health, 2008, 16 (suppl.), S7.[4] zur Hausen H.: “Papillomaviruses in the causation of human cancers- a brief historical account”. Virology, 2009, 384, 260.[5] Castellsague X., Muñoz N.: “Cofactors in human papillomavirus carcinogenesis-role of parity, oral contraceptives, and tobacco smoking”. J. Natl. Cancer Inst. Monogr., 2003, 20.[6] Kataja V., Syrjänen S., Yliskoski M., Hippeläinen M., Väyrynen M., Saarikoski S. et al.: “Risk factors associated with cervical human papillomavirus infections: a case-control study”. Am. J. Epidemiol., 1993, 138, 735.[7] Wang S.S., Zuna R.E., Wentzensen N., Dunn S.T., Sherman M.E., Gold M.A. et al.: “Human papillomavirus cofactors by disease progression and human papillomavirus types in the study to understand cervical cancer early endpoints and determinants”. Cancer Epidemiol. Biomarkers Prev., 2009, 18, 113.

[8] Muñoz N., Bosch F.X., de Sanjose S., Herrero R., Castellsague X., Shah K.V. et al.: “Epidemiologic classification of human papillomavirus types associated with cervical cancer”. N. Engl. J. Med., 2003, 348, 518.[9] Campo S. (ed). Papillomavirus Research: From Natural History to Vaccines and Beyond. Caister Academic Press, Norwich, UK, 2006, 1.[10] Syrjänen K., Väyrynen M., Castren O., Yliskoski M., Mäntyjärvi R., Pyrhönen S., Saarikoski S.: “Sexual behaviour of women with human papillomavirus (HPV) lesions of the uterine cervix”. Br. J. Vener. Dis., 1984, 60, 243.[11] Reeves W.C., Rawls W.E., Brinton L.A.: “Epidemiology of genital papillomaviruses and cervical cancer”. Rev. Infect. Dis., 1989, 11, 426. [12] Rieck G., Fiander A.: “The effect of lifestyle factors on gynaecological cancer”. Best. Pract. Res. Clin. Obstet. Gynaecol., 2006, 20, 227.[13] Almonte M., Albero G., Molano M., Carcamo C., Garcia P.J., Perez G.: “Risk factors for human papillomavirus exposure and co-factors for cervical cancer in Latin America and the Caribbean”. Vaccine, 2008, 26 (suppl, 11), L16.[14] Naud P., Matos J., Hammes L., Stuckzynski J., Brouwers K., Magno V. et al.: “Factors predicting intermediate endpoints of cervical cancer and exposure to human papillomavirus (HPV) infections in young women screened as potential targets for prophylactic HPV vaccination in south of Brazil”. Eur. J. Obstet. Gynecol. Reprod. Biol., 2006, 124, 110. [15] Syrjänen K., Shabalova I., Petrovichev N., Kozachenko V., Zakharova T., Pajanidi J. et al.: “Oral contraceptives are not anindependent risk factor for cervical intraepithelial neoplasia or high- risk human papillomavirus infections”. Anticancer Res., 2006, 26, 4729.[16] Syrjänen K., Shabalova I., Petrovichev N., Kozachenko V., Zakharova T., Pajanidi J. et al.: “Age at menarche is not an independent risk factor for high-risk human papillomavirus infections and cervical intraepithelial neoplasia”. Int. J. STD AIDS, 2008, 19, 16.[17] Syrjänen K., Kulmala S.M., Shabalova I., Petrovichev N., Kozachenko V., Zakharova T. et al.: “Epidemiological, clinical and viral determinants of the increased prevalence of high-risk human papillomavirus (HPV) infections in elderly women”. Eur. J. Gynaecol. Oncol., 2008, 29, 114.[18] Syrjänen K., Shabalova I., Petrovichev N., Kozachenko V., Zakharova T., Pajanidi J. et al.: “Smoking is an independent risk factor for oncogenic human papillomavirus (HPV) infections but not for high- grade CIN”. Eur. J. Epidemiol., 2007, 22, 723.

[19] Simen-Kapeu A., Kataja V., Yliskoski M., Syrjänen K., Dillner J., Koskela P. et al.: “Smoking impairs human papillomavirus (HPV) type 16 and 18 capsids antibody response following natural HPV infection”. Scand. J. Infect. Dis., 2008, 40, 745. [20] Plummer M., Herrero R., Franceschi S., Meijer C.J., Snijder S.P., Bosch F.X. et al.: “Smoking and cervical cancer: pooled analysis of the IARC multi-centric case-control study”. Cancer Causes Control, 2003, 14, 805. [21] Syrjänen K., Naud P., Derchain S., Roteli-Martins C., Longatto-Filho A., Tatti S. et al.: “Drug addiction is not an independent risk factor for oncogenic human papillomavirus infections or high-grade cervical intraepithelial neoplasia: case- control study nested within the Latin American Screening study cohort”. Int. J. STD AIDS, 2008, 19, 251.[22] Richart R.M.: “Cervical intraepithelial neoplasia”. Pathol. Annu., 1973, 8, 301.[23] Solomon D., Davey D., Kurman R., Moriarty A., O’Connor D., Prey M. et al.: “The 2001 Bethesda System: terminology for reporting results of cervical cytology”. JAMA, 2002, 287, 2114.[24] Fox H., Buckley C.H. (eds). “Histopathology Reporting in Cervical Screening”. NHSCSP Publications No 10, Sheffield 1999, 1.[25] Fox H., Wells M. (eds.). Haines & Taylor Obstetrical and Gynaecological Pathology, 5th Ed., Churchill Livinsgtone, Edinburgh 2003, Vol 1, 297.

[26] von Knebel-Döberitz M., Syrjänen K.: “Molecular markers. How to apply in practice”. Gynecol. Oncol., 2006, 103, 18.[27] Branca M., Ciotti M., Giorgi C., Santini D., Di Bonito L., Costa S. et al.: “Predicting high-risk human papillomavirus (HPV) infection, progression of cervical intraepithelial neoplasia (CIN) and prognosis of cervical cancer with a panel of 13 biomarkers tested in multivariate modelling”. Int. J. Gynecol. Pathol., 2008, 27, 265.[28] Belinson S., Smith J.S., Myers E., Olshan A., Belinson J., Pretorius R. et al.: “Descriptive evidence that risk profiles for cervical intraepithelial neoplasia 1, 2, and 3 are unique”. Cancer Epidemiol. Biomarkers Prev., 2008, 17, 2350. [29] Moscicki A.B., Ma Y., Wibbelsman C., Powers A., Darragh T.M., Farhat S. et al.: “Risks for cervical intraepithelial neoplasa 3 among adolescents and young women with abnormal cytology”. Obstet. Gynecol., 2008, 112, 1335.[30] Syrjänen K., Shabalova I., Naud P., Sarian L., Derchain S., Kozachenko V. et al.: “Cofactors of high-risk human papillomavirus (HPV) infections display unique profiles in incident CIN1, CIN2 and CIN3. Analysis of the combined prospective cohort of the NIS* and LAMS studies”. Int. J. STD & AIDS, 2011, 22, 263.[31] Xue X., Gange S.J., Zhong Y., Burk R.D., Minkoff H., Massad L.S. et al.: “Marginal and mixed-effects models in the analysis of human papillomavirus natural history data”. Cancer Epidemiol. Biomarkers Prev., 2010, 19, 159. [32] Fine J.P., Gray R.J.: “A proportional hazards model for the subdistribution of a competing risk”. J. Am. Stat. Assoc., 1999, 94, 496.

[33] Putter H., Fiocco M., Geskus R.B.: “Tutorial in biostatistics: competing risks and multi-state models”. Stat. Med., 2007, 26, 2389. [34] Syrjänen K., Shabalova I., Naud P., Kozachenko V., Derchain S., Zakharchenko S. et al.: “Persistent high-risk human papillomavirus (HPV) infections and other endpoint markers of progressive cervical disease among women prospectively followed-up in the NIS and LAMS cohorts”. Int. J. Gynecol. Cancer, 2009, 19, 934. [35] Syrjänen S., Shabalova I.P., Petrovichev N., Kozachenko V.P., 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 SovietUnion”. J. Lower Genital Tract. Dis., 2002, 6, 97.

[36] Syrjänen K., Naud P., Derchain S.M., Roteli-Martins C., Longatto-Filho A., Tatti S. et al.: “Comparing Pap smear cytology, aided visual inspection, screening colposcopy, cervicography and HPV testing as optional screening tools in Latin America. Study design and baseline data of the LAMS Study”. Anticancer Res., 2005, 25, 3469.

[37] Longatto-Filho A., Maeda M.Y.S., Eržen M., Branca M., Roteli-Martins C., Naud P. et al.: “Conventional Pap smear and liquid-based cytology as screening tools in low -resource settings of Latin America. Experience of the Latin American Screening Study”. Acta Cytol., 2005, 49, 500.

[38] Sarian L., Derchain S.M., Naud P., Roteli-Martins C., Longatto-Filho A., Tatti S et al.: “Evaluation of visual inspection with acetic acid (VIA), Lugol’s iodine (VILI) cervical cytology and HPV testing as cervical screening tools in Latin America. This report refers to partial results from the LAMS (Latin American Screening) study”. J. Med. Screen, 2005, 12, 142.

[39] Longatto-Filho A., Eržen M., Branca M., Roteli Martins C., Naud P., Derchain S. et al.: “Human papillomavirus (HPV) testing as an optional screening tool in low-resource settings of Latin America. Experience from the LAMS Study”. Int. J. Gynecol. Cancer, 2006, 16, 955. [40] Syrjänen S., Shabalova I.P., Petrovichev N., Kozachenko V.P., Zakharova T., Pajanidi A. et al.: “Sexual habits and Human papillomavirus (HPV) infections among women in three new independent states of the former Soviet Union”. Sex. Transm. Dis., 2003, 30, 680.[41] Koshiol J., Lindsay L., Pimenta J.M., Poole C., Jenkins D., Smith J.S.: “Persistent human papillomavirus infection and cervical neoplasia: a systematic review and meta-analysis”. Am. J. Epidemiol., 2008, 168, 123.[42] Kataja V., Syrjänen K., Syrjänen S., Mäntyjärvi R., Yliskoski M., Saarikoski S. et al.: “Prospective follow-up of genital HPV infections: Survival analysis of the HPV typing data”. Eur. J. Epidemiol., 1990, 6, 9.[43] Kataja V., Syrjänen K., Syrjänen S., Mäntyjärvi R., Yliskoski M., Saarikoski S., Salonen J.T.: “Prognostic factors in cervical human papillomavirus (HPV) infections”. Sex. Transm. Dis., 1992, 19, 154.[44] Hildesheim A., Herrero R., Castle P.E., Wacholder S., Bratti M.C., Sherman M.E. et al.: “HPV cofactors related to the deelopment of cervical cancer: results from a population-based study in Costa Rica”. Br. J. Cancer, 2001, 84, 1219.[45] Östor A.G.: “Natural history of cervical intraepithelial neoplasia - a critical review”. Int. J. Gynecol. Pathol., 1993, 12, 186.[46] Syrjänen K., Kataja V., Yliskoski M., Chang F., Syrjänen S., Saarikoski S.: “Natural history of cervical HPV lesions does not substantiate the biologic relevance of the Bethesda system”. Obstet. Gynecol., 1992, 79, 675.[47] Louvanto K., Rintala M.A., Syrjänen K.J., Grénman S.E., Syrjänen S.M.: “Genotype-specific prevalence and persistence of genital high- and low-risk human papillomavirus (HPV) infections in women followed up for 6 years in the Finnish Family HPV Study”. J. Infect. Dis., 2010, 202, 436.[48] Louvanto K., Rintala M.A., Syrjänen K.J., Grénman S.E., Syrjänen S.M.: “Incident cervical infections with high- and low-risk human papillomavirus (HPV) infections among mothers in the prospective Finnish Family HPV Study”. BMC Infect. Dis., 2011, 11, 179.[49] Louvanto K., Syrjänen K.J., Grénman S.E., Rintala M.A., Syrjänen S.M.: “Genotype specific clearance of genital human papillomavirus (HPV) infections among mothers in the Finnish Family HPV Study”. J. Clin. Microbiol., 2010, 48, 2665.