Whole-Exome Profiling of Epstein-Barr Virus-Positive Neuroendocrine Carcinoma of the Nasopharynx.

Epstein-Barr virus (EBV)-positive neuroendocrine carcinoma (NEC) of the nasopharynx is a rare malignancy with poor prognosis and lacks squamous markers, rendering it biologically distinct from nasopharyngeal carcinoma (NPC) of squamous epithelial origin. However, its molecular features remain largely undefined, and the entity has not been formally recognized as a nasopharyngeal carcinoma subtype, substantially limiting advances in its diagnosis and treatment. In this study, we performed whole-exome sequencing on seven EBV-positive nasopharyngeal NECs. These tumors exhibited a high tumor mutational burden and recurrent mutations in TP53, APC, and PROK2, with enrichment of alterations in the TP53/WNT, NOTCH, and RTK/RAS/PI3K pathways-mimicking the genomic landscape of NECs at other anatomical sites but clearly diverging from that of NPC. In addition, we identified potentially actionable alterations involving TP53 and KMT2A, suggesting avenues for targeted therapeutic exploration. Collectively, our findings provide molecular evidence supporting EBV-positive NEC of the nasopharynx as a distinct clinicopathologic entity, and offer valuable insights into its oncogenesis and potential therapeutic vulnerabilities.