Hence, using an unbiased cohort of consecutively and homogeneously treated (surgery) HNSCC patients, we conducted a comprehensive study to investigate the prognostic significance of multiple genetic and biochemical alterations in key players of the PI3K/AKT/mTOR pathway (i.e. PIK3CA and AKT1 mutations and immunohistochemical expression of EGFR, PDK1, p-AKT, PTEN and p-S6). This evidence concerns the gene RPS6 and head and neck squamous cell carcinoma.