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1 Lab Clin Pract HPV DNA human papillomavirus HPV HPV HPV HPV HPV DNA HPV DNA 1)2) HPV DNA 9 2 HPV 3) HPV DNA HPV HPV % HPV DNA 30 HPV HPV HPV DNA 1 HPV HPV HPV 1 HPV 6, 11 HPV 16 HPV 4) 6) 1 HPV E6 4) 5) 7) CIN 3 HPV 17 CIN 1 CIN 2 A2, A4 HPV 69

2 Lab Clin Pract HPV 1 6) 49 HPV 45, HPV 73 5)6) HPV Squamo columnar junction: SC junction 2 SC junction Transformation zone G1 G0 HPV E7 E7 prb E2F prb 8) HPV DNA 2 HPV DNA E1 E2 E1 HPV DNA E2 HPV DNA 9) E1 E2 E4 10) E4 L1 L2 HPV DNA E4 HPV 2 HPV 70

3 HPV DNA 2 HPV HPV E6 hscrib 11) hdlg 12 PDZ CIN HPV E6 p53 13) p53 DNA E7 p53 p53 HPV HPV E6 E7 DNA 14)15) HPV 16 E6 E7 HPV 16 E6 E7 16) HPV DNA DNA HPV DNA E6 E7 HPV DNA E2 E7 17)18) 3 HPV HPV HPV HIV HPV 19) HPV 71

4 Lab Clin Pract HPV HPV DNA 20) HPV DNA LCR E7PCR 21) DNA chip 22 DNA LCR E7 HPV HPV HPV DNA chip HPV HPV HPV 4 1 Dyskeratosis G N / C smudged nucleation parakeratosis 2 Parakeratosis / hyperkeratosis G parakeratosis hyperkeratosis 3 koilocytosis 4 koilocytosis halo 5 Cytoplasmic vacuolation or inclusion body 6 Smudged nucleation 7 Bizarre nucleation 23 8 Multinuclation 2 72

5 HPV DNA 4 9 Giant cell 150 mm 10 Immature metaplasia parabasal cells Immature glandular cells 11 Cannon ball 1 HPV 1 Odd Koilocytosis 95 % Odd 15 Koilocytosis 71 % Odd 3.5 HPV HPV 16 % 35/ 218 Smudged nucleation SN 94 % Odd 5.4 Bizarre nucleation BN 88 % Odd 4.7 Giant cell 80 % Odd 3.3 Dyskeratosis 73 % Odd 2.8 Parakeratosis 61 % Odd 2.2 Cannon ball appearance 57 % Odd 1.8 Immature metaplasia / parabasal cells 62 % Odd 1.7 Multinucleation HPV 65 % HPV HPV HPV 70 % HPV HPV HPV HPV smudged nucleation 19 % HPV 9.6 % Fisher s test p=0.08 HPV 73

6 Lab Clin Pract HPV 1 HPV Odd 95 % CI 1. Koilocytosis 33 % 1 71 % 3.5* % 15* Smudged nucleation SN 39 % 1 94 % 5.4* Bizarre nucleation BN 40 % 1 88 % 4.7* Giant cell 36 % 1 80 % 3.3* Dyskeratosis 31 % 1 73 % 2.8* Parakeratosis / hyperkeratosis 31 % 1 61 % 2.2* Cannon ball Cannon ball appearance 38 % 1 57 % 1.8* Immature metaplasia 31 % 1 62 % 1.7* Multinucleation 38 % 1 65 % : 2:*: p 0.05 HPV 12 % 3a HPV 46 % 58 % 3a HPV p HPV DNA hybrid capture 24 HPV DNA HPV 5 HPV HPV 6 HPV HPV HPV HPV % 30 HPV DNA 74

7 HPV DNA 5 HPV N= HPV 1089 HPV DNA a 3a CIN 1 CIN 2 4 CIN

8 Lab Clin Pract CIN 1 CIN % 59 % 99 % 99 % 2 CIN 1 CIN % 74 % 98 % 96 % 3 2 CIN 2 3a CIN 3 3 HPV DNA LCR E7 PCR HPV CIN 1 CIN % 100 % 81 % 85 % Hybrid capture HPV CIN 1 CIN % 90 % 88 % 89 % CIN a CIN 3 2 CIN 1 47 % CIN 2 59 % CIN 1 66 % CIN 2 74 % 41 % 26 % CIN 2 CIN 3 CIN HPV DNA 3 LCR E7 PCR CIN % hybrid capture 23)24) 90 % CIN 1 98 % HPV % HPV HPV 30 HPV DNA 4 HPV DNA 30 HPV HPV HPV 3 HPV 76

9 HPV DNA ) HPV HPV CIN HPV Bethesda System HPV 26 Bethesda System 2001 ASC US ASC H Bethesda System 2001 ASC US koilocytosis ASC H Immature metaplasia Parabasal cell 7 HPV Cannon ball parakeratosis dyskeratosis HPV immature metaplasia parabasal cell 7 77

10 Lab Clin Pract bizarre nucleation, smudged nucleation N / C CIN 1 CIN 2 CIN 3 CIN grade CIN 1 CIN 3 HPV HPV HPV HPV 1 Ishi K, Suzuki F, Yamasaki S, et al. Prevalence of human papillomavirus infection and correlation with cervical lesions in Japanese women. J Obstet Gynaecol Res 2004 Oct; 30 5 : Sasagawa T, Tani M, Yasuda H, et al. Sexual behaviour and high risk human papillomavirus infections in Japanese women. Sex Transm Infect 2005 Jun; 81 3 : Moscicki AB, Shiboski S, Hills NK, et al. Regression of low grade squamous intra epithelial lesions in young women. Lancet 2004 Nov 6 12; : Chan SY, Delius H, Halpern AL, et al. Analysis of genomic sequences of 95 papillomavirus types: uniting typing, phylogeny, and taxonomy. J Virol 1995 May; 69 5 : Sasagawa T, Basha W, Yamazaki H, et al. High risk and multiple human papillomavirus infections associated with cervical abnormalities in Japanese women. Cancer Epidemiol Biomarkers Prev 2001 Jan; 10 1 : Matsukura T, Sugase M. relationship between 80 humanpapillomavirus genotypes and different grades of cervical intraepithelial neoplasia: association and causality. Virology 2001; 283: Munoz N, Bosch FX, de Sanjose S, et al. International Agency for Research on Cancer Multicenter Cervical Cancer Study Group. Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med 2003 Feb 6; : Munger K, Basile JR, Duensing S, et al. Biological activities and molecular targets of the human papillomavirus E7 oncoprotein. Oncogene 2001 Nov 26; : Review. 9 Van Tine BA, Dao LD, Wu SY, et al. Human papillomavirus HPV origin binding protein associates with mitotic spindles to enable viral DNA partitioning. Proc Natl Acad Sci USA 2004 Mar 23; : Epub 2004 Mar Raj K, Berguerand S, Southern S, et al. E1 empty set E4 protein of human papillomavirus type 16 associates with mitochondria. J Virol 2004 Jul; : Nakagawa S, Huibregtse JM. Human scribble Vartul is targeted for ubiquitin mediated degradation by the high risk papillomavirus E6 proteins and the E6AP ubiquitin protein ligase. Mol Cell Biol 2000 Nov; : Kiyono T, Hiraiwa A, Fujita M, et al. Binding of high risk human papillomavirus E6 oncoproteins to the human homologue of the Drosophila discs large tumor suppressor protein. Proc Natl Acad Sci U S A 1997 Oct 14; : Scheffner M, Werness BA, Huibregtse JM, et al. The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53. Cell 1990 Dec 21; 63 6 : Sasagawa T, Inoue M, Inoue H, et al. Induction of uterine cervical neoplasias in mice by human papillomavirus type 16 E6/E7 genes. Cancer Res 1992 Aug 15; : Sasagawa T, Kondoh G, Inoue M, et al. Cervical/vaginal dysplasias of transgenic mice 78

11 HPV DNA harbouring human papillomavirus type 16 E6 E7 genes. J Gen Virol 1994 Nov; 75 Pt 11 : Song S, Liem A, Miller JA, et al. Human papillomavirus types 16 E6 and E7 contribute differently to carcinogenesis. Virology 2000 Feb 15; : Gammoh N, Grm HS, Massimi P, Banks L. Regulation of human papillomavirus type 16 E7 activity through direct protein interaction with the E2 transcriptional activatoion. J Virol 2006 Feb; 80 4 : Duensing S, Munger K. Human papillomavirus type 16 E7 oncoprotein can induce abnormal centrosome duplication through a mechanism independent of inactivation of retinoblastoma protein family members. J Virol 2003 Nov; : Azar KK, Tani M, Yasuda H, et al. Increased secretion patterns of interleukin 10 and tumor necrosis factor alpha in cervical squamous intraepithelial lesions. Hum Pathol 2004 Nov; : HPV. 2002; 87: Sasagawa T, Minemoto Y, Basha W, et al. A new PCR based assay amplifies the E6 E7 genes of most mucosal human papillomaviruses HPV. Virus Res 2000 Apr; 67 2 : An HJ, Cho NH, Lee SY, et al. Correlation of cervical carcinoma and precancerous lesions with human papillomavirus HPV genotypes detected with the HPV DNA chip microarray method. Cancer 2003 Apr 1; 97 7 : , ; 36: Yamazaki H, Sasagawa T, Basha W, et al. Hybrid capture II and LCR E7 PCR assays for HPV typing in cervical cytologic samples. Int J Cancer 2001 Oct 15; 94 2 : Wright TC Jr, Cox JT, Massad LS, Twiggs LB, Wilkinson EJ. ASCCP Sponsored Consensus Conference Consensus Guidelines for the management of women with cervical cytological abnormalities. JAMA 2002 Apr 24; : Solomon D, Nayar R. The Bethesda System for reporting cervical cytology, second edition, Springer

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