title: p16 is superior to ProEx C in identifying high-grade squamous intraepithelial lesions (HSIL) of the anal canal.
abstract: Although the incidence of human papillomavirus (HPV)-associated anal neoplasia is increasing, interobserver and intraobserver reproducibility in the grading of biopsy specimens from this area remains unacceptably low. Attempts to produce a more reproducible grading scheme have led to the use of biomarkers for the detection of high-risk HPV (HR-HPV). We evaluated the performance of standard morphology and biomarkers p16, ProEx C, and Ki-67 in a set of 75 lesions [17 nondysplastic lesions, 23 low-grade squamous intraepithelial lesions (LSIL)/condyloma, 20 high-grade squamous intraepithelial lesions (HSIL), 15 invasive squamous cell carcinomas] from the anal and perianal region in 65 patients and correlated these findings with HPV subtype on the basis of a type-specific multiplex real-time polymerase chain reaction assay designed to detect HR-HPV. A subset of cases with amplifiable HPV DNA was also sequenced. HSIL was typically flat (15/20), and only a minority (4/20) had koilocytes. In contrast, only 1 LSIL was flat (1/23), and the remainder were exophytic. The majority of LSIL had areas of koilocytic change (20/23). HR-HPV DNA was detected in the majority (89%) of invasive carcinomas and HSIL biopsies, 86% and 97% of which were accurately labeled by strong and diffuse block-positive p16 and ProEx C, respectively. LSIL cases, however, only infrequently harbored HR-HPV (13%); most harbored low-risk HPV (LR-HPV) types 6 and 11. Within the LSIL group, p16 outperformed ProEx C, resulting in fewer false-positive cases (5% vs. 75%). Ki-67 was also increased in HR-HPV-positive lesions, although biopsies with increased inflammation and reactive changes also showed higher Ki-67 indices. These data suggest that strong and diffuse block-positive nuclear and cytoplasmic labeling with p16 is a highly specific biomarker for the presence of HR-HPV in anal biopsies and that this finding correlates with high-grade lesions.
authors.affiliation: Department of Pathology, Division of Infectious Diseases and Geographic Medicine, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Rajeev
authors.initials: R
authors.lastname: Bala
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Pinsky
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Beck
authors.forename: Christina S
authors.initials: CS
authors.lastname: Kong
authors.forename: Mark L
authors.initials: ML
authors.lastname: Welton
authors.forename: Teri A
authors.initials: TA
authors.lastname: Longacre
mesh_terms: D000328:Adult; D000951:Antigens, Neoplasm / Q000032:analysis / Q000096:biosynthesis; D001005:Anus Neoplasms / Q000175:diagnosis* / Q000378:metabolism / Q000821:virology; D014408:Biomarkers, Tumor / Q000032:analysis*; D002278:Carcinoma in Situ / Q000175:diagnosis* / Q000378:metabolism / Q000821:virology; D002294:Carcinoma, Squamous Cell / Q000175:diagnosis* / Q000378:metabolism / Q000821:virology; D018797:Cell Cycle Proteins / Q000032:analysis / Q000096:biosynthesis; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000032:analysis; D004250:DNA Topoisomerases, Type II / Q000032:analysis / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000032:analysis / Q000096:biosynthesis; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000032:analysis; D008297:Male; D008875:Middle Aged; D064111:Minichromosome Maintenance Complex Component 2; D009687:Nuclear Proteins / Q000032:analysis / Q000096:biosynthesis; D030361:Papillomavirus Infections / Q000150:complications; D012680:Sensitivity and Specificity
chemical_list: D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004268:DNA-Binding Proteins; D019394:Ki-67 Antigen; D009687:Nuclear Proteins; C084859:MCM2 protein, human; D064111:Minichromosome Maintenance Complex Component 2; D004250:DNA Topoisomerases, Type II
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