The latest evidence implies that the human papilloma virus (HPV) may be responsible for carcinogenesis in the oral cavity [12, 13]; however, its role is debatable. The interaction of the HPV’s E6 and E7 oncoproteins with cell cycle proteins disturbs the cell cycle mechanism and subsequent alteration in the expression of proteins such as p53, p63, and Ki-67 [14]. In our case, the immunohistochemical examination of these cell cycle-related proteins demonstrated overexpression in the basal cell layer, which might be implicated in HPV infection and carcinogenesis. p16 has been regarded as one of the useful markers for HPV-associated carcinogenesis as well as other cell cycle proteins. Particularly in oropharyngeal SCCs, overexpression of p16 notably demonstrates a strong correlation with HPV infection, although it has failed to reveal such strong correlation with oral SCCs [15]. In our case, negative expression of p16 was observed, suggesting negative for HPV infection.

The relationship between the oral microbiome and oral SCC has increasingly been reported since the 1998 study by Nagy et al. [16], which found significantly higher levels of Porphyromonas species and Fusobacterium species on oral SCC, compared with the adjacent healthy mucosa. Recently, Gallimidi et al. [17] indicated that the periodontal pathogens Porphyromonas gingivalis and Fusobacterium nucleatum stimulated tumorigenesis via direct interaction with oral epithelial cells through toll-like receptors.

Evidence that persistent chronic inflammation may be a causative factor for carcinogenesis has accumulated from preclinical and clinical studies since Virchow proposed a close relationship between chronic inflammation and tumorigenesis [18]. It has been shown that chronic infection and related inflammation contributed to almost 20% of all malignancies worldwide. Various mechanisms for carcinogenesis related to chronic inflammation have been suggested. Inflammatory cells excrete a number of cytokines and growth factors that promote the survival of neoplastic cells and prevent their apoptosis [19]. Reactive oxygen and nitrogen species induced by chronic inflammation could cause damage to cellular deoxyribonucleic acid (DNA), contributing to malignant cell transformation [20]. Furthermore, a recent study suggested that inflammation could initiate cancer-specific epigenetic changes, including DNA methylation alterations in epithelial cells [21].