Carcinoma of unknown primary (CUP) of the head and neck: state of the art and future perspectives

Despite advances in molecular oncology, head and neck cancer diagnosis still relies on anatomical site and histopathology. In up to 5% of metastatic cases, no identifiable primary tumor is found, defining carcinoma of unknown primary (CUP) and posing significant diagnostic and therapeutic challenges. We conducted a narrative review of the literature focusing on current diagnostic and treatment strategies for head and neck CUP, including imaging, viral biomarkers (HPV, EBV), minimally invasive procedures, and transoral robotic surgery (TORS). While TORS plays a dual role in diagnosis and treatment, a multidisciplinary approach of neck dissection, radiotherapy, and chemotherapy in high-risk patients, remains the cornerstone of management. Personalization is increasingly crucial in this comprehensive context, mainly involving treatment tailoring and radiotherapy planning, where limited evidence on field definition is available. Ongoing trials, such as UK FIND study, highlight the potential of targeted surgery to tailor and possibly reduce radiotherapy fields for better patient outcomes and improved quality of life.