The clinical outcome of esophageal small-cell carcinoma patients is significantly worse than that of p16-positive high-grade squamous cell carcinoma patients despite the common p16/Rb1 signaling activation status; however, this has to be further confirmed in a study with a higher number of the relevant neoplasms. The gene discussed is RB1; the disease is esophageal small cell neuroendocrine carcinoma.