Prevalence and distribution of human papillomavirus type 16 in esophageal squamous cell carcinoma and its association with p16INK4A expression: A large-scale study in Japan

The infection rate of human papillomavirus (HPV) in esophageal squamous cell carcinoma (ESCC) varies widely (0 %-88.9 %), and the diagnostic utility of p16INK4A as a surrogate marker remains controversial. Moreover, the distribution of HPV infection in ESCC has not been previously investigated. Patients with ESCC who underwent esophagectomy without neoadjuvant therapy between 2007 and 2022 were included in this study. Three formalin-fixed, paraffin-embedded blocks (oral side, tumor, and esophagogastric junction (EGJ)) were collected. p16INK4A expression was assessed by immunohistochemistry (positivity defined as a labeling index of ≥10 %), whereas HPV type 16 DNA was detected by polymerase chain reaction. The distribution of HPV distribution was also assessed. In total, 158 patients were analyzed. p16INK4A was detected in 19.0 % (30/158) and HPV DNA in 3.8 % (6/158) of tumor samples. The sensitivity and positive predictive value of p16INK4A immunohistochemistry for detecting HPV DNA were 100 % and 20.0 %, respectively. HPV DNA was also detected in 3.6 % (5/137) of the oral side and 2.7 % (4/146) of EGJ samples. Infectious mapping revealed a random distribution pattern across the three anatomical regions. This large-scale study demonstrated a low prevalence of HPV infection in ESCC and indicated that p16INK4A immunohistochemistry may aid in reducing the risk of missing patients with HPV-positive tumors. Notably, the random-like distribution of HPV DNA across the three anatomical sites suggests partial viral clearance by the host immune response. These findings underscore the potential for false-negative results in biopsy specimens obtained from non-infected regions in otherwise HPV-positive patients.