Association of HPV in the Genesis of Head and Neck Squamous Cell Carcinoma: A Case–Control Study in a Bulgarian Cohort

<b>Background/Objectives:</b> Head and neck squamous cell carcinoma (NHSCC) is a significant global health burden, with human papillomavirus (HPV) recognized as a major etiological factor in a growing proportion of cases. The interaction between HPV status, tumor characteristics, and other risk factors remains an important focus for both prevention and clinical management. This study aimed to investigate the association between HPV and OPSCC in a Bulgarian cohort, with emphasis on the influence of behavioral and clinical factors, as well as basic tumor features. <b>Methods:</b> Eighty-nine participants were enrolled, including 50 patients with histologically confirmed NHSCC and 39 healthy controls. Clinical examinations and histopathological verification were conducted for all cases. Brush smear and oral rinse samples were collected for HPV testing, in line with molecular detection protocols, specifically PCR-based assays for viral DNA. Demographic data, behavioral risk factors, and information on concomitant diseases were obtained and analyzed in relation to HPV status. <b>Results:</b> Differences were identified between HPV-positive and HPV-negative NHSCC cases in relation to tumor characteristics, including clinical presentation and histological differentiation. Additional analyses demonstrated associations between certain behavioral factors, comorbidities, and the risk of NHSCC. <b>Conclusions:</b> This study provides data on HPV prevalence, related tumor features, and associated risk factors in OPSCC within a Bulgarian population. These findings highlight descriptive trends related to HPV status but indicate no robust statistical associations in this cohort.