Distinct Molecular Landscape and Clinical Subtype of HPV-Positive Esophageal Squamous Cell Carcinoma

Background: This study aimed to investigate the prevalence of human papillomavirus (HPV) infection in Chinese patients with esophageal squamous cell carcinoma (ESCC) and its association with driver gene mutations (EGFR, KRAS, PIK3CA, PTEN), clinicopathological features, and prognosis. Methods: A retrospective cohort of 120 Chinese ESCC patients was analyzed. HPV infection status and typing were determined by polymerase chain reaction (PCR)-based reverse hybridization in tumor tissues; EGFR, KRAS, PIK3CA, and PTEN mutations were assessed by Sanger sequencing. Associations with clinicopathological variables and survival were evaluated. Results: The HPV infection rate was 44.2%, with 37.5% single-type and 6.7% mixed infections, predominantly high-risk types. No EGFR or KRAS mutations were detected, whereas PTEN and PIK3CA mutations were found in 16.7% and 6.7% of patients, respectively, and were mutually exclusive. HPV-negative tumors more frequently showed lymphovascular invasion (p = 0.03) and PTEN mutations (p = 0.017). HPV positivity was associated with better recurrence-free survival and overall survival. Conclusions: HPV infection is prevalent in Chinese ESCC and may delineate a distinct molecular profile; HPV-negative ESCC was more frequently associated with aggressive clinicopathological features, including lymphovascular invasion and PTEN mutations. These findings support subtype-stratified prevention and treatment strategies for ESCC.