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The aim of the present study was to report a rare case of head and neck adenocarcinoma with an unknown primary site in a 59-year-old man. After disease progression followed by multiple cycles of chemotherapy and radiotherapy, genetic screening using next-generation sequencing identified vascular endothelial growth factor A amplification and the TP53 R209Kfs mutation. Treatment with the multi-targeted protein kinase inhibitor sorafenib controlled the patient’s symptoms and improved his quality of life.