Objective: High-grade squamous intraepithelial lesions (HSIL) are the precursors of invasive cervical carcinomas and are generally associated with the integration of mucosotropic human papillomavirus (HPV) DNA into the host cell genome. Detection of HPV is easy to perform nowadays, even in laboratories with limited technological capacity, and follow-up procedures for patients with HSIL are well established. Study Design: HPV detection was performed in a large group of patients with HSIL, and results were correlated with cytological, histological, and colposcopic findings. Discrepancies were examined and discussed. Results: Conventional Papanicolaou (Pap) screening detected 446 HSIL (0.20%) in 218,906 cervical smears. HPV detection by PCR was positive in 339/358 (94.7%) patients. The strains involved were: HPV 16 in 180 patients (53.1%), HPV 18 in 35 (10.3%), HPV 31/33 in 27 (8%), HPV 6/11 in 10 (2.96%), and an unidentified type in 73 (30%). For the last 97 patients (2006–2007), HPV typing was expanded with the following results: HPV 52 was detected in 9 patients (9.2%), HPV 58 in 6 (6.1%), HPV 51 in 4 (4.1%), HPV 68 in 2 (2.0%), and HPV 39 in 1 (1.0%). The number of nonidentified patients dropped to 9 (9.4%); in addition, 14/97 (14.4%) patients were infected with 2 or more viral types. Finally, 19 (5.3%) patients were HPV negative. Colposcopy revealed minor changes in 59 patients (17.3%), major changes in 264 (77.6%), and normal findings in 17 (5.1%). A biopsy was taken in 331/446 patients, and the diagnosis of HSIL or overt malignancy was histologically confirmed in 281 (84.9%) patients: CIN II in 46, CIN III in 224, and histologically upgraded in 11 (6 microinvasive squamous carcinomas, 1 squamous carcinoma, 2 in situ endocervical adenocarcinomas, and 2 microinvasive endocervical adenocarcinomas). Thirty-five patients (10.6%) were downgraded to CIN I and 15 (4.5%) patients had a negative biopsy. Follow-up in the negative-biopsy patients confirmed the existence of SIL in 11 patients [1 HSIL and 10 low-grade squamous intraepithelial lesions (LSIL)] while 4 were considered false positives (atrophic changes, 2; reactive changes, 2). After treatment, 31/331 (9.36%) patients displayed recurrence (HSIL in 29 and LSIL in 2). The viral strains involved in patients with recurrence were HPV 16 in 16 patients (51.6%); HPV 18 in 4 (12.9%); HPV 16 and 18 in 1 (3.2%); HPV 31 in 1 (3.2%); HPV 52 in 1 (3.2%); HPV 18, 31, and 58 in 1 (3.2%); HPV 68 in 1 (3.2%); HPV 51 and 73 in 1 (3.2%), and an unidentified type in 5 (16.1%). Follow-up in 14/19 HSIL and HPV-negative patients confirmed the existence of cervical pathology. Conclusions: HPV detection improves diagnostic sensitivity and provides an ideal tool for monitoring the response to treatment in HSIL patients. The pathogenic relevance of HPV strain 18 may be greater than previously assumed.

Keywords:
Dysplasia, Cervical intraepithelial neoplasia, High-grade squamous intraepithelial lesion, Bethesda System, Human papillomavirus, Cervical carcinoma
1.
Waggoner SE: Cervical cancer. Lancet 2003;361:2217–2225.
2.
Klinkhamer PJ, Meerding WJ, Rosier PF, Hanselaar AG: Liquid-based cervical cytology. Cancer 2003;99:263–271.
3.
Koss LG: The Papanicolaou test for cervical cancer detection: a triumph and a tragedy. JAMA 1989;261:737–743.
4.
Renshaw AA: Measuring sensitivity in gynecologic cytology: a review. Cancer 2002;96:210–217.
5.
Walboomers JM, Jacobs MV, Manos MM, Bosch FX, Kummer JA, Shah KV, Snijders PJ, Peto J, Meijer CJ, Munoz N: Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol 1999;189:12–19.
6.
Bosch FX, Lorincz A, Munoz N, Meijer CJ, Shah KV: The causal relation between human papillomavirus and cervical cancer. J Clin Pathol 2002;55:244–265.
7.
Vinokurova S, Wentzensen N, Kraus I, Klaes R, Driesch C, Melsheimer P, Kisseljov F, Durst M, Schneider A, von Knebel Doeberitz M: Type-dependent integration frequency of human papillomavirus genomes in cervical lesions. Cancer Res 2008;68:307–313.
8.
Cuzick J, Terry G, Ho L, Hollingworth T, Anderson M: Type-specific human papillomavirus DNA in abnormal smears as a predictor of high-grade cervical intraepithelial neoplasia. Br J Cancer 1994;69:167–171.
9.
Wallin KL, Wiklund F, Angstrom T, Bergman F, Stendahl U, Wadell G, Hallmans G, Dillner J: Type-specific persistence of human papillomavirus DNA before the development of invasive cervical cancer. N Engl J Med 1999;341:1633–1638.
10.
Mantovani F, Banks L: The human papillomavirus E6 protein and its contribution to malignant progression. Oncogene 2001;20:7874–7887.
11.
Tringler B, Gup CJ, Singh M, Groshong S, Shroyer AL, Heinz DE, Shroyer KR: Evaluation of p16INK4a and pRb expression in cervical squamous and glandular neoplasia. Hum Pathol 2004;35:689–696.
12.
Food and Drug Administration: http://www.accessdata.fda.gov/cdrh_docs/pdf/p890064s009a.pdf (accessed March 31, 2003).
13.
Kulasingam SL, Hughes JP, Kiviat NB, Mao C, Weiss NS, Kuypers JM, Koutsky LA: Evaluation of human papillomavirus testing in primary screening for cervical abnormalities: comparison of sensitivity, specificity, and frequency of referral. JAMA 2002;288:1749–1757.
14.
An HJ, Cho NH, Lee SY, Kim IH, Lee C, Kim SJ, Mun MS, Kim SH, Jeong JK: Correlation of cervical carcinoma and precancerous lesions with human papillomavirus (HPV) genotypes detected with the HPV DNA chip microarray method. Cancer 2003;97:1672–1680.
15.
Kurman RJ, Solomon D: The Bethesda System for Reporting Cervical/Vaginal Cytologic Diagnoses. N.Y., Springer, 2003.
16.
National Comprehensive Cancer Network: NCCN cervical cancer screening. 2010. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp.
17.
IARC: Cervical Cancer Screening. IARC Handbooks of Cancer Prevention. Lyon, IARC Press, 2005.
18.
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;188:1401–1405.
19.
Centers for Disease Control and Prevention: Sexually transmitted diseases – interactive data 1996–2008. 2011. http://www.cdc.gov/std/hpv/default.htm.
20.
Lerma E, Quintana MJ, Quilez M, Esteva E, Carreras A, Bonfill X, Prat J, Calaf J: Effectiveness of liquid-based cytology and Papanicolaou tests in a low risk population. Acta Cytol 2007;51:399–406.
21.
Saslow D, Runowicz CD, Solomon D, Moscicki AB, Smith RA, Eyre HJ, Cohen C: American Cancer Society guideline for the early detection of cervical neoplasia and cancer. CA Cancer J Clin 2002;52:342–362.
22.
Sargent A, Bailey A, Almonte M, Turner A, Thomson C, Peto J, Desai M, Mather J, Moss S, Roberts C, Kitchener HC: Prevalence of type-specific HPV infection by age and grade of cervical cytology: data from the ARTISTIC trial. Br J Cancer 2008;98:1704–1709.
23.
Munoz N, Bosch FX, de Sanjose S, Herrero R, Castellsague X, Shah KV, Snijders PJ, Meijer CJ: Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med 2003;348:518–527.
24.
Moscicki AB, Schiffman M, Kjaer S, Villa LL: Updating the natural history of HPV and anogenital cancer. Vaccine 2006;24(suppl 3):S3/42–51.
25.
Lee YH, Kim YR, Ji JD, Sohn J, Song GG: Fas promoter-670 polymorphism is associated with development of anti-RNP antibodies in systemic lupus erythematosus. J Rheumatol 2001;28:2008–2011.
26.
Zhang Z, Borecki I, Nguyen L, Ma D, Smith K, Huettner PC, Mutch DG, Herzog TJ, Gibb RK, Powell MA, Grigsby PW, Massad LS, Hernandez E, Judson PL, Swisher EM, Crowder S, Li J, Gerhard DS, Rader JS: CD83 gene polymorphisms increase susceptibility to human invasive cervical cancer. Cancer Res 2007;67:11202–11208.
27.
Lai HC, Sytwu HK, Sun CA, Yu MH, Yu CP, Liu HS, Chang CC, Chu TY: Single nucleotide polymorphism at Fas promoter is associated with cervical carcinogenesis. Int J Cancer 2003;103:221–225.
28.
de Sanjose S, Quint WG, Alemany L, Geraets DT, Klaustermeier JE, Lloveras B, et al: Human papillomavirus genotype attribution in invasive cervical cancer: a retrospective cross-sectional worldwide study. Lancet Oncol 2010;11:1048–1056.
29.
Wentzensen N, Vinokurova S, von Knebel Doeberitz M: Systematic review of genomic integration sites of human papillomavirus genomes in epithelial dysplasia and invasive cancer of the female lower genital tract. Cancer Res 2004;64:3878–3884.
30.
Plummer M, Schiffman M, Castle PE, Maucort-Boulch D, Wheeler CM: A 2-year prospective study of human papillomavirus persistence among women with a cytological diagnosis of atypical squamous cells of undetermined significance or low-grade squamous intraepithelial lesion. J Infect Dis 2007;195:1582–1589.
31.
Bulkmans NW, Berkhof J, Rozendaal L, van Kemenade FJ, Boeke AJ, Bulk S, Voorhorst FJ, Verheijen RH, van Groningen K, Boon ME, Ruitinga W, van Ballegooijen M, Snijders PJ, Meijer CJ: Human papillomavirus DNA testing for the detection of cervical intraepithelial neoplasia grade 3 and cancer: 5-year follow-up of a randomised controlled implementation trial. Lancet 2007;370:1764–1772.
32.
Mayrand MH, Duarte-Franco E, Rodrigues I, Walter SD, Hanley J, Ferenczy A, Ratnam S, Coutlee F, Franco EL: Human papillomavirus DNA versus Papanicolaou screening tests for cervical cancer. N Engl J Med 2007;357:1579–1588.
33.
Naucler P, Ryd W, Törnberg S, Strand A, Wadell G, Elfgren K, Rådberg T, Strander B, Johansson B, Forslund O, Hansson BG, Rylander E, Dillner J: Human papillomavirus and Papanicolaou tests to screen for cervical cancer. N Engl J Med 2007;357:1589–1597.
34.
Ibrahim SN, Krigman HR, Coogan AC, Wax TD, Dodd LG, Bentley RC, Robboy SJ, Johnston WW: Prospective correlation of cervicovaginal cytologic and histologic specimen. Am J Clin Pathol 1996;106:319–324.
35.
Tritz DM, Weeks JA, Spires SE, Sattich M, Banks H, Cibull ML, Davey DD: Etiologies for non-correlating cervical cytologies and biopsies. Am J Clin Pathol 1995:103:594–597.
36.
Bewtra C, Pathan M, Hashish H: Abnormal pap smear with negative follow-up biopsies: improving cytohistological correlation. Diagn Cytopathol 2003;29:200–202.
37.
Anschau F, Guimaraes MA: Discordance between cytology and biopsy histology of the cervix: what to consider and what to do. Acta Cytol 2011;55:158–162.
38.
Ortiz M, Torres M, Muñoz L, Fernández-García E, Canals J, Cabornero AI, Aguilar E, Ballesteros J, Del Amo J, García-Sáiz A: Oncogenic human papillomavirus (HPV) type distribution and HPV type 16E6 variants in two Spanish population groups with different levels of HPV infection risk. J Clin Microbiol 2006;44:1428–1434.
39.
del Amo J, González C, Losana J, Clavo P, Muñoz L, Ballesteros J, García-Saiz A, Belza MJ, Ortiz M, Menéndez B, del Romero J, Bolumar F: Influence of age and geographical origin in the prevalence of high risk human papillomavirus in migrant female sex workers in Spain. Sex Transm Infect 2005;81:79–84.
40.
Garcia-García JA, Pérez-Vallés A, Martorell M, Gómez B, Gómez-Cabrero D, Soler F, Calabuig C: Distribution of human papillomavirus types women from Valencia, Spain, with abnormal cytology. Acta Cytol 2010;54:159–164.
41.
Smith JS, Lindsay L, Hoots B, Keys J, Franceschi S, Winer R, Clifford GM: Human papillomavirus type distribution in invasive cervical cancer and high-grade cervical lesions: a meta-analysis update. Int J Cancer 2007;121:621–632.
42.
Wheeler CM, Hunt WC, Joste NE, Key CR, Quint WG, Castle PE: Human papillomavirus genotype distributions: implications for vaccination and cancer screening in the United States. J Natl Cancer Inst 2009;101:475–487.
43.
Castellsagué X, Drudis T, Cañadas MP, Goncé A, Ros R, Pérez JM, Quintana MJ, Muñoz J, Albero G, de Sanjosé S, Bosch FX: Human papillomavirus (HPV) infection in pregnant women and mother-to-child transmission of genital HPV genotypes: a prospective study in Spain. BMC Infect Dis 2009;9:74.
44.
Insinga RP, Liaw KL, Johnson LG, Madeleine MM: A systematic review of the prevalence and attribution of human papillomavirus types among cervical, vaginal, and vulvar precancers and cancers in the United States. Cancer Epidemiol Biomarkers Prev 2008; 17:1611–1622.
45.
Prétet JL, Jacquard AC, Saunier M, Clavel C, Dachez R, Gondry J, Pradat P, Soubeyrand B, Leocmach Y, Mougin C, Riethmuller D: Human papillomavirus genotype distribution in low-grade squamous intraepithelial lesions in France and comparison with CIN2/3 and invasive cervical cancer: the EDiTH III study. Gynecol Oncol 2008;110:179–184.
46.
Safaeian M, Schiffman M, Gage J, Solomon D, Wheeler CM, Castle PE: Detection of precancerous cervical lesions is differential by human papillomavirus type. Cancer Res 2009;69:3262–3266.
© 2011 S. Karger AG, Basel
2011
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.