Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer, with metastasis rates between 1.2% and 5%, according to researchers of a recent study published online in the International Journal of Molecular Sciences. The study examined the roles of ribosomal protein S6 (p-S6) and p21 in head and neck cSCC (cSCCHN). Immunohistochemistry on 116 patient samples revealed that p-S6 expression inversely correlated with tumor thickness, size, desmoplastic growth, stage, perineural invasion, and tumor buds. Negative p-S6 expression significantly predicted increased nodal metastasis risk (HR, 2.63; P<0.001). Of note, p21 expression, though inversely related to certain tumor characteristics, did not predict nodal metastasis risk. Thus, p-S6-negative expression serves as an independent predictor of nodal metastasis, suggesting its utility in risk stratification and management of cSCCHN.