Esophageal Squamous Papillomas: Human Papillomavirus Association and Natural History

Introduction: Esophageal squamous papillomas (ESPs) are rare epithelial lesions with an incompletely understood pathogenesis and uncertain malignant potential. Prior studies evaluating the association between ESP and human papillomavirus (HPV) have demonstrated conflicting results, often limited by small cohorts and heterogeneous HPV detection methodologies. Methods: We conducted a retrospective cohort study of histologically confirmed ESPs at Cleveland Clinic between January 2019 and July 2023. Clinical, endoscopic, and histopathologic data were collected. Formalin-fixed, paraffin-embedded tissue underwent RNA in situ hybridization (RNA ISH) targeting E6/E7 mRNA to detect transcriptionally active low- and high-risk HPV subtypes. Results: 184 ESP cases were identified, representing the largest single-center cohort. Lesions were predominantly solitary, small (<5 mm), and located in the mid-esophagus. GERD and dysphagia were the most common indications for endoscopy. No lesion demonstrated dysplasia, epidermoid metaplasia, or invasive carcinoma at index endoscopy. All evaluable lesions were negative for transcriptionally active HPV by RNA ISH (0/177; 95% CI, 0–2.1%). Follow-up endoscopy was available in 70 patients (38%), with a median follow-up of 24 months and surveillance extending to ≥4 years. No dysplasia / malignant transformation was observed during available follow-up. Persistent/residual ESP was identified in 6 patients following non-removal or biopsy-only sampling of the index lesion. Conclusions: The absence of transcriptionally active HPV supports a limited role for HPV in ESP pathogenesis and does not support routine HPV testing in typical, non-dysplastic ESPs. Our findings support the generally benign natural history of ESPs and highlight the need for prospective studies with standardized long-term surveillance to better define their malignant potential