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


OBJECTIVE
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.


CONCLUSIONS
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.
Kreuter
Alexander
A
Department of Dermatology, Ruhr-University Bochum, Bochum, Germany. a.kreuter@derma.de
Jesse
Maciej
M
Potthoff
Anja
A
Brockmeyer
Norbert H
NH
Gambichler
Thilo
T
Stücker
Markus
M
Bechara
Falk G
FG
Pfister
Herbert
H
Wieland
Ulrike
U
D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D023241:Antiretroviral Therapy, Highly Active / Q000379:methods; D001005:Anus Neoplasms / Q000175:diagnosis / Q000473:pathology* / Q000821:virology; D014408:Biomarkers, Tumor / Q000032:analysis*; D001707:Biopsy, Needle; D002278:Carcinoma in Situ / Q000175:diagnosis / Q000473:pathology* / Q000821:virology; D004279:DNA, Viral / Q000032:analysis; D015658:HIV Infections / Q000150:complications / Q000175:diagnosis* / Q000188:drug therapy; D006679:HIV Seropositivity; D018451:Homosexuality, Male; D006801:Humans; D007150:Immunohistochemistry; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D030361:Papillomavirus Infections / Q000150:complications / Q000175:diagnosis; D016133:Polymerase Chain Reaction / Q000379:methods; D011230:Precancerous Conditions / Q000473:pathology; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis / Q000378:metabolism*; D012016:Reference Values; D018570:Risk Assessment; D012680:Sensitivity and Specificity; D019562:Viral Load; D055815:Young Adult
D014408:Biomarkers, Tumor; D004279:DNA, Viral; D018809:Proliferating Cell Nuclear Antigen