High malignant potential of betel quid-associated oral verrucous hyperplasia

Objectives. Oral verrucous hyperplasia (OVH) is commonly observed in the oral cavity of betel quid chewers that histologically display epithelial hyperplasia with or without dysplasia. Because of the high frequency of synchronous OVH adjacent to oral carcinomas, OVH is considered a potential malignant disorder, and studies of prognostic factors and genetic alterations are required. Materials and Methods. We conducted a follow-up study of 269 OVH patients at Chi-Mei Medical Center. A Kaplan-Meier analysis and Cox's proportional-hazards regression model were used to calculate the survival rate and prognostic factors of disease recurrence and transformation. Copy number variations (CNVs) were analyzed using a single-nucleotide polymorphism (SNP) array. Results. The 5-year disease-free and cancer-free survival rates of patients with OVH were 52% and 77%, respectively. Heavy betel quid (BQ) chewing (>20 nuts/day), the severity of oral submucosal fibrosis (OSF), and non-buccal and non-tongue lesions were high risk factors for malignant transformation, while dysplasia did not affect outcomes. A genetic analysis showed that OVH already possessed many CNVs present in oral squamous cell carcinoma (OSCC), and a bioinformatics analysis of CNV-associated genes revealed that the upregulation of CTTN, FOLR3, ORAOV1, PPFIA1, and RNF121 could help identify high-risk OVH patients. Conclusions. BQ-associated OVH has a high malignant potential, and more attention must be paid to OVH patients who have a heavy BQ chewing habit and advanced OSF, and whose tumor is located at non-buccal and non-tongue regions. The five CNV-associated genes can be used for early diagnosis and for predicting the prognosis. Peripheral blood, VH and oral cancer tissues were obtained from two distinct Taiwanese oral cancer patients. The copy number variations in the three different stage of lesion were identified. Comparing CNVs in serial pre-cancer (VH) and cancer samples could shed the light on tumor formation and progression.