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Journal of the American Academy of Dermatology
Volume 63, n° 3
pages 490-498 (septembre 2010)
Doi : 10.1016/j.jaad.2009.08.043
Dermatopathology

Expression of proliferative biomarkers in anal intraepithelial neoplasia of HIV-positive men
 

Alexander Kreuter, MD a, , Maciej Jesse, MD a, Anja Potthoff, MD a, Norbert H. Brockmeyer, MD a, Thilo Gambichler, MD a, Markus Stücker, MD a, Falk G. Bechara, MD a, Herbert Pfister, PhD b, Ulrike Wieland, MD b
a Department of Dermatology, Ruhr-University Bochum, Bochum, Germany 
b Institute of Virology, National Reference Center for Papillomaviruses and Polyomaviruses, University of Cologne, Cologne, Germany 

Reprint requests: Alexander Kreuter, MD, Department of Dermatology and Allergology, Ruhr-University Bochum, Gudrunstrasse 56, D-44791 Bochum, Germany.
Abstract
Background

Anal intraepithelial neoplasia (AIN), a human papillomavirus (HPV)–associated precursor lesion of anal carcinoma, is highly prevalent among HIV-infected individuals, especially in men having sex with men (MSM). Early diagnosis and treatment of AIN might prevent development of anal cancer.

Objectives

We aimed to evaluate the expression of 8 promising proliferative biomarkers in anal dysplasia and to compare the efficacy of these markers in diagnosing high-grade AIN.

Methods

Immunohistochemical analysis of minichromosome maintenance proteins (MCM3, MCM4, MCM6, and MCM7), p21, Ki-67, p16, and proliferating cell nuclear antigen (PCNA) was performed in a total of 49 specimens of normal anal mucosa and high- and low-grade anal dysplasia. HPV typing for 36 high- and low-risk HPVs was performed, and high-risk HPV-DNA loads were determined by real-time polymerase chain reaction (PCR) for HPV-types 16, 18, 31, and 33.

Results

A total of 392 immunohistochemical slides were analyzed in this study. In the progression from normal epithelium to high-grade dysplasia, we found significant differences in the expression of all biomarkers. A cutoff of 25% or 50% lesional immunopositivity for the 4 MCMs, Ki-67, and p16 resulted in 100% sensitivity and 100% specificity to diagnose high-grade AIN. Sensitivity and specificity of PCNA and p21 for a high-grade AIN diagnosis were lower. HPV-DNA was detectable in 100% of high-grade AIN and 87.5% of low-grade AIN lesions. All MCMs, p16, Ki-67, and PCNA, but not p21 correlated with cumulative lesional high-grade HPV-DNA loads.

Limitations

The relatively small number of samples is a limitation, especially for adequate subgroup analyses.

Conclusions

MCMs, Ki67, and p16 are reliable immunohistochemical adjuncts for diagnosing high-grade AIN.

The full text of this article is available in PDF format.

Key words : anal intraepithelial neoplasia, human papillomavirus, men who have sex with men, mini-chromosome maintenance protein, p16, proliferative biomarkers

Abbreviations used : AIN, CDK, CIN, HAART, HIV, HPV, MCM, MSM, PCNA



 Supported by The Federal Ministry of Education and Research (Grant No. 01 KI 0771, TP7), the German Network of Competence HIV/AIDS (Grant No. 01 KI 0501), and FoRUM (Forschungsförderung Ruhr Universität Bochum Medizinische Fakultät, project F615-2008).
 Conflicts of interest: None declared.



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