Immature squamous metaplastic epithelium of Weber's glandular duct: a significant origin of HPV-independent oropharyngeal squamous cell carcinoma in the base of the tongue.

PURPOSE: This study investigated the anatomical and pathological mechanisms of immature squamous metaplastic epithelium in Weber's glandular ducts at the tongue base in human papillomavirus (HPV)-independent oropharyngeal squamous cell carcinoma (OPSCC). METHODS: An analysis of 80 tongue base carcinoma cases clarified the anatomical connection to Weber's glands. Histological and immunohistochemical studies of these glandular ducts identified areas susceptible to cancer. A mouse model using 4-nitroquinoline-N-oxide was employed to simulate carcinogenic development. RESULTS: 42.5% of cases were linked to Weber's glands, with 20 directly connected to glandular ducts. Only one case was p16-positive, indicating that carcinogenesis in Weber's glandular ducts is largely non-HPV-mediated. The transformation zone with immature squamous metaplastic epithelium and CK17/p63+ reserve cells at Weber's glandular ducts were found, akin to cervical cancer susceptibility. CK17 studies indicated that the immature epithelium had "compromised barrier function" and "hyperproliferative activity", accelerating mutation and carcinogenesis. An atypical opening of the Weber's gland exposed the ductal epithelium to oncogenic factors, increasing carcinogenic risk. A mouse model confirmed the progression from metaplasia to carcinoma and the oncogenic potential of Weber's glandular ducts. CONCLUSIONS: Weber's glandular ducts are an important origin of HPV-independent OPSCC. The first animal model replicating this process offers an essential platform for studying HPV-independent OPSCC.