title: P16(INK4A) immunostaining is a strong indicator for high-risk-HPV-associated oropharyngeal carcinomas and dysplasias, but is unreliable to predict low-risk-HPV-infection in head and neck papillomas and laryngeal dysplasias.
abstract: Human papillomavirus (HPV) is a risk factor for the development of benign and malignant mucosal head and neck lesions. P16(INK4A) is often used as a surrogate marker for HPV-infection, although there is still controversy with respect its reliability. Our aim was to determine if p16(INK4A) overexpression can accurately predict both high-risk and low-risk-HPV-presence in (pre)malignant and benign head and neck lesions. P16(INK4A) immunohistochemistry was performed on paraffin-embedded tissue sections of 162 oropharyngeal squamous cell carcinomas (OPSCC), 14 tonsillar and 23 laryngeal dysplasias, and 20 tonsillar and 27 laryngeal papillomas. PCR, enzyme-immunoassay and FISH analysis were used to assess HPV-presence and type. Of the 162 OPSCC and 14 tonsillar dysplasias, 51 (31%) and 10 (71%) were HPV16-positive, respectively. All tonsillar papillomas were HPV-negative and four laryngeal dysplasias and 26 laryngeal papillomas were positive for HPV6 or -11. P16(INK4A) immunohistochemistry revealed a strong nuclear and cytoplasmic staining in 50 out of 51 HPV16-positive and 5 out of 111 HPV-negative OPSCC (p < 0.0001) and in all HPV16-positive tonsillar dysplasias, whereas highly variable staining patterns were detected in the papillomas and laryngeal dysplasias, irrespective of the HPV-status. In addition, the latter lesions generally showed a higher nuclear than cytoplasmic p16(INK4A) immunostaining intensity. In conclusion, our data show that strong nuclear and cytoplasmic p16(INK4A) overexpression is a reliable surrogate indicator for HPV16 in OPSCC and (adjacent) dysplasias. For HPV6 or -11-positive and HPV-negative benign and premalignant lesions of the tonsil and larynx, however, p16(INK4A) immunostaining is highly variable and cannot be recommended to predict HPV-presence.
authors.affiliation: Department of Otorhinolaryngology, Head and Neck Surgery, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Centre, The Netherlands.
authors.forename: Jeroen J
authors.initials: JJ
authors.lastname: Mooren
authors.forename: Sibel E
authors.initials: SE
authors.lastname: Gültekin
authors.forename: Jos M J A A
authors.initials: JM
authors.lastname: Straetmans
authors.forename: Annick
authors.initials: A
authors.lastname: Haesevoets
authors.forename: Carine J
authors.initials: CJ
authors.lastname: Peutz-Kootstra
authors.forename: Christian U
authors.initials: CU
authors.lastname: Huebbers
authors.forename: Hans P
authors.initials: HP
authors.lastname: Dienes
authors.forename: Ulrike
authors.initials: U
authors.lastname: Wieland
authors.forename: Frans C S
authors.initials: FC
authors.lastname: Ramaekers
authors.forename: Bernd
authors.initials: B
authors.lastname: Kremer
authors.forename: Ernst-Jan M
authors.initials: EJ
authors.lastname: Speel
authors.forename: Jens P
authors.initials: JP
authors.lastname: Klussmann
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000821:virology*; D002648:Child; D002675:Child, Preschool; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism*; D005260:Female; D006258:Head and Neck Neoplasms / Q000378:metabolism / Q000821:virology*; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D007223:Infant; D007822:Laryngeal Neoplasms / Q000378:metabolism / Q000821:virology; D008297:Male; D008875:Middle Aged; D009959:Oropharyngeal Neoplasms / Q000378:metabolism / Q000821:virology*; D010212:Papilloma / Q000378:metabolism / Q000821:virology*; D030361:Papillomavirus Infections / Q000150:complications / Q000175:diagnosis*; D011230:Precancerous Conditions / Q000175:diagnosis* / Q000378:metabolism / Q000821:virology; D012307:Risk Factors; D000077195:Squamous Cell Carcinoma of Head and Neck; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D019941:Cyclin-Dependent Kinase Inhibitor p16
keywords: FISH; PCR; human papillomavirus; immunohistochemistry