In our present study, we aimed to clarify (i) the status of p16 and its relation with HPV infection, (ii) the clinicopathological characteristics of p16-positive tumors in comparison with p16-negative tumors, and (iii) the clinical outcome of the corresponding patients in highly malignant neoplasms of the esophagus including poorly differentiated and basaloid squamous cell carcinomas, as well as esophageal small-cell carcinomas. Here, CDKN2A is linked to esophageal small cell neuroendocrine carcinoma.