The utility of traditional markers for the documentation of neuroendocrine differentiation, i.e., synaptophysin, chromogranin, and CD56, is limited due to several drawbacks: the imperfect sensitivity of only 50–80% (individual or combined) for high-grade NECs; cross-reactivity and, consequently, expression in other, non-neuroendocrine tumors of the head and neck; and the difficulty of interpreting the weak/focal reactivity of granular cytoplasmic staining. This evidence concerns the gene SYP and neuroendocrine neoplasm.