The incidence of human papilloma virus (HPV) induced oropharyngeal squamous cell carcinoma (OPSCC) increases in the western countries. These OPSCC show distinct molecular characteristics and are characterized by an overexpression of p16, considered a surrogate marker for HPV infection. When compared to patients with p16 negative OPSCC, patients with HPV induced p16 positive OPSCC show a significantly better prognosis, which is reported to be caused by increased radiosensitivity. The objective of the present study was to analyze the impact of p16 expression status on the prognosis of OPSCC treated by either radiotherapy (RT) or primary surgery. Results are based upon a tissue microarray (TMA) of 365 head neck squamous cell carcinomas (HNSCC) including 85 OPSCC with clinico-pathological and follow-up data. p16 positivity correlated significantly with oropharyngeal tumor localization (p < 0.001). Patients with p16 positive OPSCC exhibited a significantly better overall survival than those with p16 negative tumors (p 5 0.007). In a multivariate analysis, survival benefit of patients with p16 positive OPSCC was independent of clinico-pathological parameters such as cT and cN classification and treatment modality. The improved prognosis of p16 positive OPSCC is found after RT as well as after surgery.Although incidence of head and neck squamous cell carcinoma (HNSCC) in general has decreased progressively during the last two decades, 1 an increased incidence of oral and oropharyngeal squamous cell carcinoma (OPSCC) was reported in the United States as well as in Europe. [2][3][4] As already suggested in 1983, these OPSCC are characterized by human papilloma virus (HPV) infection. 5 Viral DNA of high risk HPV 16 can be detected in nuclei of tonsillar cancer cells, 6 and is responsible for the vast majority of HPV positive tumors. 7 These tumors arise mainly in the lingual and palatal tonsils and are characterized as being a type of HNSCC with different distinct epidemiological, molecular, and clinical characteristics. 8 The main risk factor for these HPV positive OPSCC is sexual behavior with a high number of vaginal or oral sex partners. 8,9 HPV-induced OPSCC show distinct molecular characteristics suggesting a different pathway in carcinogenesis compared to HPV negative HNSCC. 10 One particular molecular difference among others concerns p16 expression. p16 functions as a cell-cycle checkpoint regulator, a tumor suppressor gene located on chromosome 9p21.In HPV negative HNSCC p16 is frequently inactivated by deletions, mutations or promoter methylation. 11 In HPV positive OPSCC, overexpressed viral oncoprotein E7 degrades pRb, 12 which otherwise inhibits p16 transcription. 13 The resulting nuclear and cytoplasmic p16 overexpression correlates precisely to HPV positivity and is suggested to be specific for HPV positive OPSCC. 14,15 As p16 overexpression is very rarely seen in HPV negative HNSCC it is considered a surrogate marker for HPV positive OPSCC. Direct diagnosis of HPV in HNSCC is only reliably possible by in s...

Coexpression of p21/Ki-67 is a strong negative prognostic factor in HNSCC and could be of particular relevance in tumors treated by primary radiotherapy.