A Novel HPV-associated Mixed Neuroendocrine-Nonneuroendocrine Neoplasm of the Rectum.

High-risk human papillomavirus (HPV) is an established oncogenic driver, most commonly associated with oropharyngeal and anogenital squamous cell carcinomas. Although HPV has recently been implicated in a small subset of adenocarcinomas and small-cell neuroendocrine carcinomas of the anorectum, its involvement in both components of a gastrointestinal mixed neuroendocrine-nonneuroendocrine neoplasm (MiNEN) has not been previously described. We herein report a novel tumor, an HPV-associated MiNEN of the rectum in a 60-year-old woman. The patient presented for colonoscopy screening, during which a distal rectal polyp was identified and excised. Histologic examination of the resected tumor demonstrated two intimately admixed components, an adenocarcinoma and a small-cell neuroendocrine carcinoma. Both components showed strong and diffuse p16 immunoreactivity, and high-risk HPV RNA in situ hybridization demonstrated transcriptionally active HPV in both tumor populations, confirming HPV as a likely shared oncogenic driver. To our knowledge, this represents the first well-documented HPV-associated MiNEN in the gastrointestinal tract.