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.

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.

Mooren JJ ，Gültekin SE ，Straetmans JM ，Haesevoets A ，Peutz-Kootstra CJ ，Huebbers CU ，Dienes HP ，Wieland U ，Ramaekers FC ，Kremer B ，Speel EJ ，Klussmann JP ... -  《-》

A comprehensive evaluation of human papillomavirus positive status and p16INK4a overexpression as a prognostic biomarker in head and neck squamous cell carcinoma.

Deng Z ，Hasegawa M ，Aoki K ，Matayoshi S ，Kiyuna A ，Yamashita Y ，Uehara T ，Agena S ，Maeda H ，Xie M ，Suzuki M ... -  《-》

Prognostic significance of cell cycle-associated proteins p16, pRB, cyclin D1 and p53 in resected oropharyngeal carcinoma.

Plath M ，Broglie MA ，Förbs D ，Stoeckli SJ ，Jochum W ... -  《Journal of Otolaryngology-Head & Neck Surgery》

Frequency and prognostic significance of p16(INK4A) protein overexpression and transcriptionally active human papillomavirus infection in laryngeal squamous cell carcinoma.

Young RJ ，Urban D ，Angel C ，Corry J ，Lyons B ，Vallance N ，Kleid S ，Iseli TA ，Solomon B ，Rischin D ... -  《-》

HPV DNA, E6*I-mRNA expression and p16INK4A immunohistochemistry in head and neck cancer - how valid is p16INK4A as surrogate marker?

It has been proposed that p16(INK4A) qualifies as a surrogate marker for viral oncogene activity in head and neck cancer (HNSCC). By analyzing 78 HNSCC we sought to validate the accuracy of p16(INK4A) as a reliable marker of active HPV infections in HNSCC. To this end we determined HPV DNA (HPVD) and E6*I mRNA (HPVR) expression status and correlated these results with p16(INK4A) staining. In tonsillar SCC 12/20 were HPVD+ and 12/12 of these showed active HPV infections whereas in non-tonsillar SCC 10/58 were HPVD+ and 5/10 showed active HPV infections. Thus, we prove about 8% of non-tonsillar SCC to be also correlated with HPV-associated carcinogenesis. Strikingly, 3/14 (21.4%) of tonsillar and non-tonsillar HPVD+/HPVR+ cases did not show p16(INK4A) overexpression and these cases would have been missed when applying initial p16(INK4A) staining only. However, in 13 cases negative for HPV, DNA p16(INK4A) was overexpressed. In conclusion, our data confirm tonsillar SCC to be predominantly but not only associated with active HPV infections. Furthermore, our data show that p16(INK4A) overexpression is not evident in a subgroup of HNSCC with active HPV infection. Definitive HPV data should therefore be utilized in diagnostics and treatment modalities of HPV positive and HPV negative HNSCC patients, resulting in a paradigm shift regarding these obviously different tumor entities.

Hoffmann M ，Tribius S ，Quabius ES ，Henry H ，Pfannenschmidt S ，Burkhardt C ，Görögh T ，Halec G ，Hoffmann AS ，Kahn T ，Röcken C ，Haag J ，Waterboer T ，Schmitt M ... -  《-》