| Summary: | The aim of this study was to investigate the clinical, histopathologic, and immunologic differences of oral squamous cell carcinoma of never-smokers/never-drinkers and smokers/drinkers. Immunohistochemical staining for CD4, CD8, FoxP3, CD1a, and p16 was performed in 131 oral squamous cell carcinomas from smokers/drinkers and never-smokers/never-drinkers. Associations of smoking/drinking status with clinicopathologic data, immunohistochemical antibody expression, and survival were examined. Oral squamous cell carcinoma in never-smokers/never-drinkers was associated with the female gender (<i>p</i> < 0.001). Never-smokers/never-drinkers were older at diagnosis than smokers/drinkers (<i>p</i> < 0.001). Never-smokers/never-drinkers had more tumors in the maxilla, mandible, and tongue (<i>p</i> < 0.001). Pre-existing oral potentially malignant disorders appeared to be more common in never-smokers/never-drinkers (<i>p</i> < 0.001). Perineural invasion was more common in smokers/drinkers (<i>p</i> = 0.039). Never-smoking/never-drinking was associated with better overall survival (<i>p</i> = 0.004) and disease-specific survival (<i>p</i> = 0.029). High CD4+ T cell infiltration was associated with never-smoking/never-drinking (<i>p</i> = 0.008). Never-smokers/never-drinkers also showed increased CD8+ T cell infiltration (<i>p</i> = 0.001) and increased FoxP3+ Treg infiltration (<i>p</i> = 0.023). Furthermore, the total group of tumor-infiltrating lymphocytes was associated with never smoking/never drinking (<i>p</i> = 0.005). To conclude oral squamous cell carcinoma of the never-smokers/never-drinkers appears to be a distinct type of tumor, as it appears to have unique clinical and pathologic features and a more immunogenic microenvironment.
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