Human Papillomavirus Status Before and After Neoadjuvant Chemotherapy and Its Association With Treatment Sensitivity in Esophageal Squamous Cell Carcinoma

Background Our previous study confirmed that p16 is considered a reliable surrogate marker for Human papillomavirus (HPV) infection in esophageal squamous cell carcinoma (ESCC). Since neoadjuvant chemotherapy (NAC) followed by esophagectomy is the standard treatment, p16 expression may be affected by NAC, making pre-treatment biopsy more appropriate for assessment. HPV-driven cancers are generally more sensitive to chemotherapy and have a better prognosis. However, in ESCC, the association between HPV status and response to NAC remains unclear. This study aimed to evaluate the HPV status before and after NAC and explore the relationship between HPV status and treatment response to NAC. Methods A total of 206 patients with ESCC underwent esophagectomy with NAC from 2007 to 2022 were included. Preoperative biopsy specimens were collected and examined for p16 expression by immunohistochemistry, with a labeling index ≥10% defined as positive. HPV DNA was further detected by polymerase chain reaction in biopsy samples with p16- positive expression. In addition, surgically resected specimens were collected from patients with p16-positive in biopsy for subsequent evaluation of both p16 expression and HPV DNA status. Results Among biopsy samples, p16 positivity was found in 20.4% (42/206), and HPV DNA was detected in 1 of 42 p16-positive cases (2.4%). Surgical specimens were available for 39 of these patients, and 59.0% (23/39) remained p16-positive. Only one surgical specimen tested strong positive for HPV DNA, corresponding to the same patient who was HPV-positive in the biopsy. This patient was a 41-year-old female with clinical stage II, moderately differentiated ESCC, and showed a Grade 1a response to NAC. Due to insufficient HPV-positive cases, the sensitivity of HPV status to NAC could not be evaluated. Conclusion The extremely low HPV positivity rate observed in this study may reflect random infection with a minimal viral presence. HPV DNA with a high viral load may not be significantly affected by NAC, whereas HPV DNA with a low viral load could potentially be influenced by NAC and become undetectable. Further validation through larger-scale studies comparing HPV status between biopsy and surgically resected specimens are needed to clarify this issue.