title: p16(INK4a) /Ki-67 co-expression specifically identifies transformed cells in the head and neck region.
abstract: p16(INK4a) immunohistochemical overexpression is an overall reliable surrogate marker of human papillomavirus (HPV)-associated head and neck squamous cell carcinomas (HNSCC). However, cases of ambiguous p16(INK4a) overexpression are regularly detected in the head and neck: p16(INK4a) expression can be observed in non-malignant tissue, such as tonsillar crypt epithelium and a proportion of branchial cleft cysts. Additionally, diverse patterns of p16(INK4) expression can complicate interpretation of "p16(INK4a) -positivity". These aspects impede the unrestricted application of p16(INK4a) as a diagnostic marker in the head and neck. We hypothesized that combined detection of p16(INK4a) and the proliferation marker Ki-67 could support clarification of ambiguous p16(INK4a) expression in the head and neck by specifically indicating p16(INK4a) -expressing cells with proliferative activity. p16(INK4a) /Ki-67 co-expression in a combined staining procedure was correlated to distinct p16(INK4a) expression patterns and HPV status (HPV DNA followed by E6*I oncogene mRNA detection) in 147 HNSCC and 50 non-malignant head and neck samples. p16(INK4a) /Ki-67 co-expression only occurred in transformed cells of the head and neck. Co-expression was never detected in non-transformed cells. Combined p16(INK4a) /Ki-67 expression was stringently associated with a diffuse p16(INK4a) expression pattern. All HPV oncogene-expressing HNSCC showed p16(INK4a) /Ki-67 co-expression. We demonstrate that p16(INK4a) /Ki-67 co-expression occurs exclusively in transformed cells of the head and neck. Our findings indicate a substantial impact of combined p16(INK4a) /Ki-67 expression in the assessment of ambiguous p16(INK4a) expression in the head and neck by specifically identifying p16(INK4a) -expressing cells with proliferative activity. This property will be of considerable significance for head and neck histo- and cytopathology.
authors.affiliation: Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, and Clinical Cooperation Unit Applied Tumor Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Elena-Sophie
authors.initials: ES
authors.lastname: Prigge
authors.forename: Csaba
authors.initials: C
authors.lastname: Toth
authors.forename: Gerhard
authors.initials: G
authors.lastname: Dyckhoff
authors.forename: Steffen
authors.initials: S
authors.lastname: Wagner
authors.forename: Franziska
authors.initials: F
authors.lastname: Müller
authors.forename: Claus
authors.initials: C
authors.lastname: Wittekindt
authors.forename: Kolja
authors.initials: K
authors.lastname: Freier
authors.forename: Peter
authors.initials: P
authors.lastname: Plinkert
authors.forename: Jürgen
authors.initials: J
authors.lastname: Hoffmann
authors.forename: Svetlana
authors.initials: S
authors.lastname: Vinokurova
authors.forename: Jens Peter
authors.initials: JP
authors.lastname: Klussmann
authors.forename: Magnus
authors.initials: M
authors.lastname: von Knebel Doeberitz
authors.forename: Miriam
authors.initials: M
authors.lastname: Reuschenbach
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics; D002294:Carcinoma, Squamous Cell / Q000175:diagnosis / Q000235:genetics / Q000821:virology; D002461:Cell Line, Transformed; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics* / Q000378:metabolism; D004279:DNA, Viral / Q000235:genetics; D015870:Gene Expression; D006258:Head and Neck Neoplasms / Q000175:diagnosis / Q000235:genetics / Q000821:virology; D006801:Humans; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000235:genetics* / Q000378:metabolism; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000378:metabolism; D027383:Papillomaviridae / Q000235:genetics; D030361:Papillomavirus Infections / Q000150:complications; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D000077195:Squamous Cell Carcinoma of Head and Neck
chemical_list: D014408:Biomarkers, Tumor; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004279:DNA, Viral; C068651:E6 protein, Human papillomavirus type 16; D019394:Ki-67 Antigen; D009856:Oncogene Proteins, Viral; D012097:Repressor Proteins
keywords: E6*I RNA; HPV; Ki-67; head and neck squamous cell carcinoma; p16