title: Diagnostic accuracy of p16INK4aimmunohistochemistry in oropharyngeal squamous cell carcinomas: A systematic review and meta-analysis.
abstract: The accurate diagnosis of human papillomavirus (HPV) causality in oropharyngeal squamous cell carcinomas (OPSCC) is likely to influence therapeutic decisions in affected patients in the near future. We conducted a systematic review and meta-analysis to determine the diagnostic accuracy of p16INK4aimmunohistochemistry (IHC) to identify HPV-induced OPSCC. We identified all studies that performed p16INK4aIHC (index test) and HPV E6/E7 mRNA detection using an amplification-based method (gold standard to indicate a transforming relevance of HPV) in OPSCC. Testing with one or more comparator tests (HPV DNA PCR, HPV DNA in situ hybridization (ISH) and p16INK4aIHC/HPV DNA PCR combined testing) was an optional criterion for inclusion. Among 1,636 retrieved studies 24 fulfilled the inclusion criteria. The pooled sensitivity of p16INK4aIHC, HPV DNA PCR, HPV DNA ISH and p16INK4aIHC/HPV DNA PCR combined testing was 94% (95%-confidence interval (CI) 91-97%), 98% (CI 94-100%), 85% (CI 76-92%) and 93% (CI 87-97%), respectively. The pooled specificity was 83% (CI 78-88%), 84% (CI 74-92%), 88% (CI 78-96%) and 96% (CI 89-100%), respectively. p16INK4aIHC/HPV DNA PCR combined testing was as sensitive as either p16INK4aIHC or HPV DNA PCR alone but significantly more specific than either separate test. In conclusion, p16INK4aIHC is highly sensitive but moderately specific to diagnose HPV-transformed OPSCC when used as a single test. Combined p16INK4aIHC and HPV DNA PCR testing significantly enhances specificity while maintaining high sensitivity. This diagnostic test combination thus represents an attractive testing strategy for the reliable diagnosis of HPV-induced OPSCC in the clinical setting and may constitute an inclusion criterion for future therapeutic trials.
authors.affiliation: Department of Applied Tumor Biology, Institute of Pathology, University Hospital Heidelberg, and Clinical Cooperation Unit Applied Tumor Biology, German Cancer Research Center (DKFZ), Heidelberg, 69120, Germany.
authors.forename: Elena-Sophie
authors.initials: ES
authors.lastname: Prigge
authors.affiliation: Belgian Cancer Centre and Unit of Cancer Epidemiology, Scientific Institute of Public Health, Brussels, B1050, Belgium.|University of Antwerp, Antwerp, Belgium.
authors.forename: Marc
authors.initials: M
authors.lastname: Arbyn
authors.affiliation: Department of Applied Tumor Biology, Institute of Pathology, University Hospital Heidelberg, and Clinical Cooperation Unit Applied Tumor Biology, German Cancer Research Center (DKFZ), Heidelberg, 69120, Germany.
authors.forename: Magnus
authors.initials: M
authors.lastname: von Knebel Doeberitz
authors.affiliation: Department of Applied Tumor Biology, Institute of Pathology, University Hospital Heidelberg, and Clinical Cooperation Unit Applied Tumor Biology, German Cancer Research Center (DKFZ), Heidelberg, 69120, Germany.
authors.forename: Miriam
authors.initials: M
authors.lastname: Reuschenbach
mesh_terms: D014408:Biomarkers, Tumor / Q000032:analysis*; D002294:Carcinoma, Squamous Cell / Q000737:chemistry / Q000175:diagnosis* / Q000821:virology; D002472:Cell Transformation, Viral; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000032:analysis*; D004279:DNA, Viral / Q000032:analysis; D006801:Humans; D017403:In Situ Hybridization; D009363:Neoplasm Proteins / Q000032:analysis*; D009856:Oncogene Proteins, Viral / Q000235:genetics; D009959:Oropharyngeal Neoplasms / Q000737:chemistry / Q000175:diagnosis* / Q000821:virology; D027383:Papillomaviridae / Q000235:genetics / Q000302:isolation & purification*; D030361:Papillomavirus Infections / Q000175:diagnosis* / Q000378:metabolism; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000032:analysis; D012367:RNA, Viral / Q000032:analysis; D012680:Sensitivity and Specificity
chemical_list: D014408:Biomarkers, Tumor; C000614131:CDKN2A protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004279:DNA, Viral; D009363:Neoplasm Proteins; D009856:Oncogene Proteins, Viral; D012333:RNA, Messenger; D012367:RNA, Viral
keywords: HPV; OPSCC; human papillomavirus; oropharyngeal squamous cell carcinoma; p16