We propose that immunohistochemical staining of the AMAP1 protein on its own, or together with staining of the EGFR protein, provides a simple and reliable diagnosis that predicts the recurrence and survival of HNSCC patients under the current therapeutics. Our identification of these predictive biomarkers, together with our previous findings on the coherent signaling pathway that these biomarkers ultimately generate, namely the EGFR-GEP100-Arf6-AMAP1-cortactin pathway, should be powerful information for the further development of HNSCC therapeutics. Here, ARF6 is linked to head and neck squamous cell carcinoma.