**Author details**

Ralf Hilfrich

Cytoimmun Diagnostics GmbH Pirmasens, Germany

#### **References**


[6] Papanicolaou GN; Traut HF. Diagnosis of uterine cancer by the vaginal smear. New York, Commonwealth Fund, 1943.

As stated by different authors a close follow-up with colposcopy and histological evaluation

112 Human Papillomavirus and Related Diseases – From Bench to Bedside A Diagnostic and Preventive Perspective

On the other hand the low malignant potential of HPV-L1 positive cases indicates transient

Only 13,1% of the L1 positive LSIL, and 34,6% of the L1 positive HSIL progressed to CIN3,

Integrating the promising serological HPV L1 antibody rapid test into this procedure seems to be able to improve this data further, thus preventing overtreatment especially for women

At the end of the day a combination of cytology, colposcopy, HPV DNA determination and HPV L1 detection offers a unique possibility to increase the benfits of cervical cancer screening

[1] Ferlay J, Shin HR, Bray F, Forman D, Mathers C and Parkin DM. GLOBOCAN 2008 v1.2, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 10.Lyon, France: International Agency for Research on Cancer; 2010. Available from: http://

[2] Meisels A, Fortin R : Condylomatous lesions of the cervicx and vagina. I. Cytologic

[3] Meisels A, Fortin R, Roy M : Condylomatous lesions of the cervic. II. Cytologic, col‐

[4] Gissmann L, zur Hausen H : Partial characterization of viral DNA from human geni‐

[5] WHO/ICO information centre on Human Papilloma Virus (HPV) and Cervical Can‐

poscopic and histopathologic study. Acta Cytol 1977, 21 : 379-390

tal warts (Condylomata acuminata). Int J Cancer 1980, 25 : 605-609

typically thresholds justifying ´a watch and wait strategy´ with cytological follow-up.

Only in case of persistence of the L1 positive lesion a colposcopy should be performed.

is advisable and removal of these lesions should be considered.

HPV infection, or true ´low grade lesions´.

programs, by reducing the potentials harms.

Cytoimmun Diagnostics GmbH Pirmasens, Germany

patterns. Acta Cytol 1976, 20 : 505-509

cer, www.who.int/hpvcentre

in their reproductive age.

**Author details**

Ralf Hilfrich

**References**

globocan.iarc.fr.


to moderate cervical intraepithelial lesions. Eur J Obstet Gynecol Reprod Biol 2008 Oct;140(2):258-62. Epub 2008 Jul 14.

[32] Romanczuk H, Howley PM, Disruption of either the E1 and E2 regulatory gene of human papillomavirus type 16 increase viral immortalization capacity. Proc Natl

HPV L1 Detection as a Prognostic Marker for Management of HPV High Risk Positive Abnormal Pap Smears

http://dx.doi.org/10.5772/55902

115

[33] Pett M, Coleman N, Integration of high-risk human papilloma virus a key event in

[34] Goll MG, Bestor TH. Eukaryotic cytosine methyltransferases. Annu Rev Biochem.

[36] Badal V, Chuang LS, Tan EH, Badal S, Villa LL et al., CpG methylation of human papillomavirus type 16 DNA in cervical cancer cell lines and in clinical specimen : Genomic hypomethylation correlates with carcinogenic progression. J Virol 77:

[37] Kalantari M, Calleja-Macias IE, Tewari D, Hagmar B, Lie K, Barrera-Saldana HA, Wi‐ ley DJ, Bernard HU. Conserved methylation patterns of human papillomavirus type 16 DNA in asymptomatic infection and cervical neoplasia. J Virol. 2004 Dec;78(23):

[38] Vinokurova S , von Knebel Doeberitz M, Differential Methylation of the HPV 16 up‐ stream regulatory region during epithelial differentiation and neoplastic transforma‐

[39] Mori S, Ozaki S, Yasugi T, Yoshikawa H, Taketani Y, Kanda T, Inhibitory cis-ele‐ ment-mediated decay of human papillomavirus type 16 L1-transcript in undifferenti‐

[40] Koffa MD, Graham SV, Takagaki Y, Manley JL, Clements JB, The human papilloma‐ virus type 16 negative regulatory RNA element interacts with three proteins that act at different posttranscriptional levels. Proc Natl Acad Sci USA, 2000, 97, 4677-4682.

[41] Zhao X, Rush M, Schwartz S, Identification of an hnRNA A1-dependent splicing si‐ lencer in the human papillomavirus type 16 L1 coding region that prevents prema‐

[42] Gu W, Li M, Zhao WM, Fang NX, Bu S, Frazer IH, Zhao KN, tRNASer(CGA) differ‐ entially regulates expression of wildtype and codon-modified papillomavirus L1

[43] Fang NX, Gu W, Ding J, Saunders NA, Frazer IH, Zhao KN, Calcium enhances kera‐ tinocyte differentiation in vitro to differentially regulate expression of papillomavi‐

[44] Stanley M, Immune responses to human papillomvirus. Vaccine 2006, 24 (Suppl.1):

rus authentic and codon modified L1 genes. Virology 2007, 365, 187-197.

ture expression of the late L1 gene. J Virol 2004, 78, 10888-10905.

[35] Kulis M, Esteller M, DNA methylation and cancer. Adv. Genet 2010, 70 : 27-56.

Acad Sci USA, 89 : 3159-3163.

2005;74:481-514.

6227-6234.

12762-72.

16-22

cervical carcinogenesis?, J Pathol 212: 356-367.

tion. PloS ONE 2011, 6 (9), 24451-24464.

ated cells. Mol Cell Biochem 2006, 288, 47-57

genes. Nucl Acids Res 2004, 32, 4448-4461.


[32] Romanczuk H, Howley PM, Disruption of either the E1 and E2 regulatory gene of human papillomavirus type 16 increase viral immortalization capacity. Proc Natl Acad Sci USA, 89 : 3159-3163.

to moderate cervical intraepithelial lesions. Eur J Obstet Gynecol Reprod Biol 2008

[21] Scheidemantel T, Simmerman K, Ji X, Dolar S, Brainard J, Tubbs R, Hilfrich R, Yang B. 2008. Expression pattern of HPV L1 capsid protein in PAP tests: a potential bio‐ marker in risk assessment for high grade SIL lesion. Abstract Ann. M. Am. Soc. of

114 Human Papillomavirus and Related Diseases – From Bench to Bedside A Diagnostic and Preventive Perspective

[22] Hilfrich R, Weiss A, Griesser H, Use of the ThinPrep® Imager for evaluation of slides stained immunocytochemically with Cytoactiv®. Presentation ICC2010, Edinburgh.

[23] Griesser H, Sander H, Walczak C, Hilfrich R. HPV vaccine protein L1 predicts dis‐ ease outcome of high-risk HPV+ early dysplastic lesions. Am J Clin Pathol 2009 Dec;

[24] Stemberger-Papic S, Vrdoljak-Mozetic D, Ostojic DV, Rubesa-Mihaljevic R, Manestar M, Evaluation of the HPV L1 capsid protein in prognosis of mild and moderate dys‐

[25] Lee SJ, Lee AW, Kim TJ et al. Correlation between immunocytochemistry of human papilloma virus L1 capsid protein and behavior of low-grade cervical cytology in Ko‐ rean women. Journal of Obstetrics and Gynaecology Research 2011 Sep;37(9):1222-8.

[26] Mehlhorn G, Obermann E, Negri G, Bubendorf L, Mian Chr, Koch M, Sander H, Simm B, Lütge M, Banrevi Zs, Weiss A, Gieri C, Hilfrich R, Beckmann M, Griesser H, HPV L1 detection discriminates cervical precancer from transient HPV infection – a prospective international multicenter study. Nature – Modern Pathology in press. [27] Negri G, Bellisano G, Zannoni GF et al. p16 and HPV immunohistochemistry is help‐ ful for estimating the behaviour of low grade dysplastic lesions of the cervix uteri.

[28] Hilfrich R, Hariri J. Prognostic relevance of HPV L1 capsid protein detection within mild to moderate dysplastic lesions of the cervix uteri in combination with a second

[29] Choi YS, Kang WD, Kim SM et al. Human Papillomavirus L1 Capsid Protein and Human Papillomavirus Type 16 as Prognostic Markers in Cervical Intraepithelial Ne‐

[30] Ungureanu C, Socolov D, Anton G, Mihailovici MS, Teleman S, Immunocytochemi‐ cal expression of p16ink4a and HPV L1 capsid proteins as predictive markers of the

[31] Vinokurova S, Wentzensen N, Kraus I et al., Type-dependent integration frequency of human papillomavirus genomes in cervical lesions. Cancer Res 2008; 68: 307-313.

cervical lesions progression risk. Rom J Morphol Embryol. 2010;51(3):497-503.

plasia of the cervix uteri. Coll Antropol 2010, 34, 2 : 419-423.

biomarker p16. Anal Quant Cytol Histl 2008 Apr;30(2):78-82.

oplasia 1. Int J of Gynecological Cancer 2010 Feb;20(2):288-93.

Am J Surg Pathol 2008 Nov;32(11):1715-20.

Oct;140(2):258-62. Epub 2008 Jul 14.

Cytopathology

132(6):840-5.


[45] Scott M, Nakagawa M, Moscicki AB, Cell-mediated immune response to human pap‐ illomavirus infection. Clin Diagn Lab Immunol 2001, 8 : 209-220.

**Chapter 5**

**Ancillary Techniques in the Histopathologic**

**Intraepithelial Lesions of the Uterine Cervix**

introduction of vaccination against human papilloma virus (HPV) [2-4].

Squamous cell carcinoma, adenocarcinoma and adenosquamous carcinoma comprise the most common cancers of the uterine cervix. Cervical cancer is one of the common cancers in women, especially in certain parts of the world, as Sub-Saharan Africa, Central America, South Central Asia and Melanesia [1]. In several countries the incidence of cervical cancer was reduced after the introduction of effective screening methods and prevention programs, initially based on the Papanicolaou smear (Pap test), and it is expected to diminish much further with the

In recent years papilloma virus has been linked to these cancers through a significant amount of scientific data, derived from epidemiologic, clinical, experimental and molecular studies [5-10]. A. large number of scientific reports during the last three decades led to an explosion of information regarding the role of HPV in lower genital tract carcinogenesis, thus paving the way for the introduction of effective vaccines against the virus, expected to diminish the incidence of both HPV-related carcinomas and precursor lesions in forthcoming years [2,3,5]. This has affected in several ways the histopathologic diagnostic approach to cervical carcino‐ mas and their precursor lesions, including the classification and terminology of the latter. Although several important questions remain, we are now able to examine HPV-related morphologic alterations from a different perspective that encompasses parts -although limited- of this new information, in an effort to achieve more efficient and precise recognition

In the field of cervical squamous precursor lesions the basic concept underlying the Cervical Intraepithelial Neoplasia (CIN) terminology, which refers to a single disease spectrum, has

and reproduction in any medium, provided the original work is properly cited.

© 2013 Kostopoulou and Koukoulis; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

**Diagnosis of Squamous and Glandular**

Evanthia Kostopoulou and George Koukoulis

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/55897

**1. Introduction**

of precancerous lesions.

