HPV-Associated Adenosquamous Carcinoma of the Oropharynx With a PARD3B::ERBB4 Fusion

Head and neck carcinomas can be diagnostically challenging because of their diverse histologic subtypes. We report a case of a 55-year-old male presenting with right-sided cervical adenopathy, in whom imaging revealed a cystic lesion that was subsequently confirmed to be metastatic from a lesion at the base of the tongue. Histological examination of the lesion at the base of the tongue demonstrated a biphasic tumor proliferation composed of nonkeratinized basaloid cells arranged in cohesive lobules, with focal small ductal structures. Immunohistochemistry highlighted the biphasic morphology, with strong nuclear expression of p40/p63 in the abluminal cells and prominent membranous staining of CEA and CK7 in the luminal cells. Ancillary testing further characterized the lesion, identifying an HPV16 by DNA PCR. RNA sequencing revealed a PARD3B::ERBB4 fusion involving PARD3B exon 13 and ERBB4 exon 17, while targeted next-generation sequencing identified a KRAS exon 2 c.35G>A (p.Gly12Asp) mutation. Microdissection-based analysis confirmed the same KRAS mutation in both the glandular and squamous components, supporting a shared clonal origin. This case highlights the clinicopathologic complexity of HPV-associated adenosquamous carcinoma and expands the molecular spectrum of head and neck tumors through identification of a PARD3B::ERBB4 fusion.