HPV-Associated Non-Salivary Adenocarcinoma of the Oropharynx

Human papillomavirus (HPV)-associated non-salivary adenocarcinoma of the oropharynx is exceptionally rare and poorly defined. We report a multi-institutional series of 12 cases from 6 tertiary centers. Histologic, immunohistochemical, HPV testing, molecular, and follow-up data were reviewed. Among 11 patients with available sex data, all were men; the median age was 62 years (range: 46 to 70 y). The cohort comprised 9 primary oropharyngeal adenocarcinomas and 3 metastatic adenocarcinomas, including a right neck metastasis of presumed oropharyngeal origin and 2 distant metastases in patients with previously documented HPV-associated oropharyngeal squamous cell carcinoma. Primary sites included the palatine tonsil or tonsil-palate region (n=7), base of tongue (n=1), and oropharynx, not otherwise specified (n=1). Among cases with available T-category, 5 of 6 were T3/T4. All tumors showed high-grade adenocarcinoma morphology without a recognizable squamous component, with infiltrative glandular, ductal, or cribriform architecture. Diffuse p16 expression was present in all cases, and high-risk HPV was confirmed by polymerase chain reaction or in situ hybridization. p40 was negative in the tumor cell population in cases 1 to 6, 8, 9, 11, and 12, whereas case 7 showed p40 and CK5/6 expression confined to abluminal cells. Molecular profiling in 2 cases identified alterations or variants involving PIK3CA and PIK3R1. Follow-up in 6 patients with primary tumors showed distant metastases in 3 and disease-specific death in 1. HPV-associated nonsalivary adenocarcinoma of the oropharynx is a diagnostically challenging tumor that expands the morphologic spectrum of HPV-related oropharyngeal carcinoma. Recognition requires exclusion of salivary-type and metastatic adenocarcinoma and confirmation of HPV association.