We demonstrated that CNA-quiet OCSCC lacking or having few CNAs, should be considered as a separate subclass of HPV-negative HNSCC since they have a different mutational profile (enriched for CASP8 and HRAS mutations with generally wtTP53), other histological characteristics (predominantly cohesive growth pattern and well-differentiated tumors), a less immunosuppressed TIME, and distinct clinical appearance with older patients, more women, more never smokers and alcohol users, and improved overall survival compared to CNA-other OCSCC. This evidence concerns the gene CASP8 and head and neck squamous cell carcinoma.