HPV-Associated Oropharyngeal Squamous Cell Carcinoma in Arab Populations: Histological Heterogeneity, Regional Evidence, and the Syrian Knowledge Gap

Abstract

Human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) is biologically and clinically distinct from HPV-independent disease. Classically, HPV-associated OPSCC is nonkeratinizing in morphology, less desmoplastic in stroma, and more lymphoid-rich in background; however, it is increasingly recognized as histologically heterogeneous. Keratinizing, maturing, basaloid, papillary, lymphoepithelial, glandular, and other components can be encountered in an HPV-associated tumor, and recent evidence suggests that such micromorphological diversity may be prognostically significant after HPV association has been demonstrated through established assays. In contrast, research from Arab populations has focused largely on HPV prevalence, p16 expression, genotype, and clinical outcome rather than on detailed histology or tumor organization. This critical review synthesizes evidence from Arab countries (focused on Syria) into the contemporary international literature and suggests a regional framework for understanding HPV-associated OPSCC pathology. Studies from Jordan, Lebanon, Egypt, Saudi Arabia, and the United Arab Emirates have demonstrated HPV-related or p16-positive OPSCC, with widely varying estimates due to differing anatomical selection and testing strategies. Syrian studies identify high-risk HPV in head-and-neck squamous carcinomas but have not yet estimated the HPV-attributable fraction or histology of anatomically verified Syrian OPSCC. We speculate that future regional research should shift from dichotomous HPV categorization to quantitative characterization of squamous maturation, tumor architecture, stromal response, tumor-associated lymphocytes, front of invasion morphology, and spatial tumor heterogeneity. Digital pathology and interpretable artificial intelligence offer exciting opportunities to engage with these questions. A principal unresolved regional question is the extent and biological significance of HPV involvement in oropharyngeal SCCs, while an important research challenge is to understand how HPV-associated carcinogenesis is expressed through regional variations in tissue architecture.