Thus, it is plausible to speculate that caspase-8 (as well as DR5) in primary HNSCC without LNM (Tu−met) may be predominantly associated with its pro-apoptotic function and thus higher caspase-8 or caspase-8 plus DR5 provides protective advantage against cancer and correlates with better survival.Whereas in HNSCC with LNM (Tu+met) which are resistant to apoptosis, caspase-8 and even DR5 may primarily exert their non-apoptotic function, i.e., activation of PI3K and promotion of migration, and thus higher caspase-8 expression negatively impacts patient survival. This evidence concerns the gene CASP8 and cancer.