Expanding the Histologic Spectrum of Human Papillomavirus (HPV)-Associated Oropharyngeal Carcinoma: A Retrospective Study of 379 Cases Focusing on Classification, Histologic Features, and their Prognostic Significance

The WHO classification includes squamous cell carcinoma (SCC) and neuroendocrine carcinoma as two histotypes of HPV-associated oropharyngeal carcinoma (HPV + OPC). Among SCC, the recognized subtypes include non-keratinizing, keratinizing, papillary, adenosquamous, ciliated adenosquamous, lymphoepithelial, spindle cell, and basaloid subtypes.

This retrospective study included 379 consecutive cases of HPV+ OPC resected between 2017 and 2024.

The morphologies included SCC (83.4%), adenosquamous carcinoma (n=11, 2.9%, including 6 with cilia), combined neuroendocrine carcinoma and SCC (n=3, 0.8%), adenocarcinoma (n=1, 0.3%), and undifferentiated carcinoma (n=1, 0.3%). Among SCC subtypes, the most common was non-keratinizing (n=316), followed by papillary (n=22), lymphoepithelial (n=9), basaloid (matrix-producing, n=9), keratinizing (n=6), and spindle cell (sarcomatoid, n=1). Tumors could display various histologic features, such as papillary architecture (29.2%), lymphoepithelial regions (10.3%), and basaloid (matrix-producing) areas (7.1%). On univariate survival analysis, adverse histologic features included any percentage of glandular differentiation, a basaloid component, extranodal extension (ENE), and low stromal tumor infiltrating lymphocytes (sTIL). Basaloid areas and extranodal extension were independent adverse prognostic factors identified on multivariate survival analysis.

Herein, we report two histotypes of HPV+ OPC not yet recognized by the WHO classification, being adenocarcinoma and undifferentiated carcinoma. Additionally, multiple adverse histologic features were identified, including basaloid components and ENE as independent prognostic factors. Therefore, recognizing and reporting such features in the pathology report of HPV+ OPC, even when present in minor proportions, is important for risk stratification and clinical management.

Not applicable.