Gianluca Tenore, Ahmed Mohsen, Gian Marco Podda, Lucia Borghetti, Federica Rocchetti, Laura Sansotta, Andrea Battisti, Valentino Valentini, Antonella Polimeni, Umberto Romeo
Background: Oral squamous cell carcinoma (OSCC) is a multifactorial malignancy traditionally associated with tobacco exposure, alcohol consumption, and human papillomavirus (HPV) infection. It may also arise through the malignant transformation of oral potentially malignant disorders (OPMDs). However, a substantial proportion of tumors arise without clinically detectable precursor lesions, suggesting heterogeneous carcinogenic pathways. This study aimed to compare the clinicopathological characteristics of OPMDs-associated and apparently de novo OSCC. Methods: A retrospective analysis was conducted on patients with histologically confirmed OSCC referred to the department between 2015 and 2025. Baseline patient characteristics, clinical, and histopathological diagnostic management data were collected from medical records, and patients were classified as the OSCC with OPMD group or the de novo OSCC group based on the presence or absence of a history of OPMDs. Results: Seventy-seven patients were included (mean age: 70.4 years; 53.2% males, 46.75% females). OPMDs were documented in 37.66% of cases, while 62.34% of tumors developed without documented precursor lesions. No significant difference was observed in histological grade distribution between the two groups (p = 0.206), although G1 tumors were more frequent in the OSCC with OPMD group (25.93%) than in the de novo OSCC group (9.30%). The de novo OSCC group showed a significantly higher prevalence of denture-related lesions. No significant differences were observed between the two considered groups in age, sex, tobacco or alcohol exposure, HPV status, systemic diseases, or oncological history. Patients with OPMDs underwent significantly more biopsies in total and biopsies per year. Conclusions: OSCC may develop through distinct pathogenic pathways, emphasizing the need for broader clinical vigilance beyond OPMD surveillance to improve early diagnosis.