Objective: A vast majority of cervicovaginal intraepithelial lesions are caused by high-risk human papillomaviruses (HPVs). The Pap test has been the sole method used for the screening of cervicovaginal squamous intraepithelial lesions (SIL). Recently, the FDA approved an HPV-DNA assay as a method of primary screening. We report on a series of FDA-approved HPV-DNA test-negative SIL with HPV genotyping, using an alternative method on the corresponding surgical biopsy specimens. Study Design: A retrospective review identified cytology-positive HPV-negative cases over a 15-month period at a tertiary care gynecologic oncology institution. Corresponding biopsies were reviewed and genotyped for high-risk HPVs. Results: Of the 18,200 total cases, 17 patients meeting the study criteria were selected with 27 surgical specimens corresponding to their cytologic diagnoses. Four patients with high-grade lesions were identified, 3 of whom (75%) were positive for HPV. One of these 4 patients (25%) showed high-grade SIL on biopsies from 4 separate sites in the cervix and vagina. Multiviral HPV infections were frequent. Conclusions: We discuss the relevance of cotesting for screening cervical SILs and emphasize that false-negative results are possible with the FDA-approved HPV screening assay, also in patients with high-grade SIL. These cases may be detectable by cytologic examination and this suggests that the Pap test remains an important diagnostic tool.

1.
Gravitt PE: The known unknowns of HPV natural history. J Clin Invest 2011;121:4593-4599.
2.
Doorbar J, Quint W, Banks L, et al: The biology and life cycle of human papillomaviruses. Vaccine 2012;30:F55-F70.
3.
Burk RD, Harariet A, Chen Z: Human papillomavirus genome variants. Virology 2013;445:232-243.
4.
Schiffman M, Herrero R, Desalle R, et al: The carcinogenicity of human papillomavirus types reflects viral evolution. Virology 2005;337:76-84.
5.
Bansal S, Zhao C: Prevalence of high-risk human papillomavirus in women with abnormal and normal vaginal ThinPrep Papanicolaou cytology. J Lower Gen Tract Dis 2011;15:105-109.
6.
Guo M, Gong Y, Wang J, et al: The role of human papillomavirus type 16/18 genotyping in predicting high-grade cervical/vaginal intraepithelial neoplasm in women with mildly abnormal Papanicolaou results. Cancer Cytopathol 2013;121:79-85.
7.
Lees BF, Erickson BK, Huh WK: Cervical cancer screening: evidence behind the guidelines. Am J Obset Gynecol 2016;214:438-443.
8.
Darragh TM, Colgan TJ, Thomas CJ, et al: The lower anogenital squamous terminology standardization project for HPV-associated lesions: background and consensus recommendations from the College of American Pathologists and the American Society for Colposcopy and Cervical Pathology. J Low Gen Tract Dis 2012;16:205-242.
9.
Muñoz N, Bosch FX, de Sanjose S, et al: Epidemiologic classification of human papillomavirus types associated with cervical cancer. NEJM 2003;348:518-527.
10.
Dalstein V, Riethmuller D, Pretet JL, et al: Persistence and load of high-risk HPV are predictors for development of high-grade cervical lesions: a longitudinal French Cohort study. Int J Cancer 2003;106:396-403.
11.
Massad LS, Einstein MH, Huh WK, et al: 2012 updated consensus guidelines for the management of abnormal cervical cancer screening tests and cancer precursors. Obstet Gynecol 2013;121:829-846.
12.
Nayar R, Goulart RA, Tiscornia-Wasserman PG, et al: Primary human papillomavirus screening for cervical cancer in the United States - US Food and Drug Administration approval, clinical trials, and where we are today. Cancer Cytopathol 2014;122:720-729.
13.
Wright TC, Stoler MH, Sharma A, et al: Evaluation of HPV-16 and HPV-18 genotyping for the triage of women with high-risk HPV+ cytology-negative results. Am J Clin Pathol 2011;136:578-586.
14.
Castle PE, Stoler MH, Wright TC, et al: Performance of carcinogenic human papillomavirus (HPV) testing and HPV 16 or HPV 18 genotyping for cervical cancer screening of women aged 25 years and older: a subanalysis of the ATHENA study. Lancet Oncol 2011;12:880-890.
15.
Wright TC, Stoler MH, Behrens CM, et al: The ATHENA human papillomavirus study: design, methods, and baseline results. Am J Obstet Gynecol 2012;206:46.e1-e11.
16.
Monsonego J, Cox JT, Behrens C, et al: Prevalence of high-risk human papilloma virus genotypes and associated risk of cervical precancerous lesions in a large U.S. screening population: data from the ATHENA trial. Gynecol Oncol 2015;137:47-54.
17.
Kitchener HC, Almonte M, Gilham C, et al: ARTISTIC: a randomised trial of human papillomavirus (HPV) testing in primary cervical screening. Health Technol Assess 2009;13:1-150.
18.
Vesco KK, Whitlock EP, Eder M, et al: Screening for Cervical Cancer: A Systematic Evidence Review for the U.S. Preventive Services Task Force. Rockville, Agency for Healthcare Research and Quality, 2011, report No: 11-05156-EF-1.
19.
Choi JW, Kim Y, Lee JH, et al: The clinical performance of primary HPV Screening, primary HPV screening plus cytology cotesting, and cytology alone at a tertiary care hospital. Cancer Cytopathol 2016;124:144-152.
20.
Katki HA, Kinney WK, Fetterman B, et al: Cervical cancer risk for women undergoing concurrent testing for human papillomavirus and cervical cytology: a population-based study in routine clinical practice. Lancet Oncol 2011;12:663-672.
21.
Porras C, Wentzensen N, Rodriquez AC, et al: Switch from cytology-based to human papillomavirus test-based cervical screening: implications for colposcopy. Int J Cancer 2012;130:1879-1887.
22.
Gage JC, Schiffman M, Katki HA, et al: Reassurance against future risk of precancer and cancer conferred by a negative human papillomavirus test. J Natl Cancer Inst 2014;18:106.
23.
Hopenhayn C, Christian A, Christian WJ, et al: Prevalence of human papillomavirus types in invasive cervical cancers from seven US cancer registries prior to vaccine introduction. J Low Genit Tract Dis 2014;18:182-189.
24.
Morrison C, Catania F, Wakely P, et al: Highly differentiated keratinizing squamous cell cancer of the cervix: a rare, locally aggressive tumor not associated with human papillomavirus or squamous intraepithelial lesions. Am J Surg Pathol 2001;25:1310-1315.
25.
Casey S, Harley I, Jamison J, et al: A rare case of HPV-negative cervical squamous cell carcinoma. Int J Gynecol Pathol 2015;34:208-212.
26.
von Karsa L, Arbyn M, De Vuyst H, et al: European guidelines for quality assurance in cervical cancer screening. Summary of the supplements on HPV screening and vaccination. Papillomavirus Res 2015;1:22-31.
27.
Rao J, Levin M, Zhao C: Premature conclusions on HPV-only testing. Lancet Oncol 2011;12:992-993.
28.
Austin RM, Zhao C: Is 58% sensitivity for detection of cervical intraepithelial neoplasia 3 and invasive cervical cancer optimal for cervical screening? Cyto J 2014;11:14.
29.
Blatt J, Kennedy R, Luff RD, et al: Comparison of cervical cancer screening results among 256,648 women in multiple clinical practices. Cancer Cytopathol 2015;123:282-288.
30.
Erali M, Pattison DC, Wittwer CT: Human papillomavirus genotyping using and automated film-based chip array. J Mol Diag 2009;11:439-445.
31.
Petry KU, Cox JT, Johnson K, et al: Evaluating HPV-negative CIN2+ in the ATHENA Trial. Int J Cancer 2016;138:2932-2939.
32.
Package insert: Cobas® HPV test. Branchburg, Roche Molecular Systems Inc, 2011.
33.
Castle PE, Eaton B, Reid J, et al: Comparison of human papillomavirus detection by Aptima HPV and Cobas HPV tests in a population of women referred for colposcopy following detection of atypical squamous cells of undetermined significance by Pap cytology. J Clin Microbiol 2015;53:1277-1281.
34.
Söderlund-Strand A, Uhnoo I, Dillner J: Change in Population prevalences of human papillomavirus after initiation of vaccination: the High-Throughput HPV Monitoring Study. Cancer Epidemiol Biomarkers Prev 2014;23:2757-2764.
35.
Brisson M, Laprise JF, Chesson HW, et al: Health and economic impact of switching from a 4-valent to a 9-valent HPV vaccination program in the United States. J Natl Cancer Inst 2016;108:djv282.
36.
Angioli R, Lopez S, Aloisi A, et al: Ten years of HPV vaccines: state of the art and controversies. Crit Rev Oncol Hematol 2016;102:65-72.
37.
El-Zein M, Richardson L, Franco EL: Cervical cancer screening of HPV vaccinated populations: cytology, molecular testing, both or none. J Clin Virol 2016;76:S62-S68.
38.
Khan MJ, Massad LS, Kimmey W, et al: A common clinical dilemma: management of abnormal vaginal cytology and human papillomavirus test results. Gynecol Oncol 2016;141:364-370.
39.
Package insert: INFINITI HPV-HR QUAD®. Vista, AutoGenomics, Inc, 2012.
40.
Lyons YA, Kamat AA, Zhou H, et al: Non-16/18 high-risk HPV infection predicts disease persistence and progression in women with an initial interpretation of LSIL. Cancer Cytopathol 2015;123:435-442.
41.
Hui Y, Manna P, Ou JJ, et al: High-Risk human papilloma virus (HPV) infection involving multiple anatomic sites of the female lower genital tract - a multiplex real-time polymerase chain reaction-based study. Hum Pathol 2015;46:1376-1381.
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.