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Head and neck squamous cell carcinomas (HNSCC) frequently recur, and patients often develop second primary tumors. Their distinction is clinically challenging. TP53 mutational heterogeneity may indicate novel molecular events rather than resistant clones' expansion or persistent disease. Surveillance and therapeutic strategies should be adjusted, especially in the case of a second primary arising in an already irradiated field., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025. Published by Elsevier B.V.)