Unknown primary of the head and neck: a new entry in the TNM staging system with old dilemmas for everyday practice.

Purpose Of Review: To summarize the most recent nuances in diagnosis, management, and prognostic stratification of carcinoma of unknown primary of the head and neck (CUPHN), in light of its recent re-assessment in the eighth edition of the TNM Classification Manual.

Recent Findings: At least in Western Countries, most CUPHN are expected to be Human Papilloma Virus (HPV)-positive with an oropharyngeal origin. Their appropriate diagnosis starts with fine needle aspiration cytology and/or core biopsy of pathologic lymph node(s) with staining for p16 by immunohistochemistry and subsequent HPV detection by PCR. If these exams are negative (especially in Eastern Countries), in-situ hybridization for Epstein-Barr virus detection should be added. Thorough clinical examination should encompass white light videoendoscopy with the adjunction of bioendoscopic techniques (such as narrow band imaging). Radiologic workup (by CT, MR and/or PET) should be limited to cases that are persistently negative after comprehensive endoscopic evaluation. Invasive diagnostic procedures, such as unilateral or bilateral palatine tonsillectomy and base of tongue mucosectomy, may play a staging as well as a therapeutic role in CUPHN management.

Summary: Every effort should be made to identify and remove the primary site of a CUPHN: in doing so, possible subsequent de-intensification protocols by irradiation of the neck alone (with or without previous neck dissection according to the cN category, patient's risk profile, and general status) can be taken into consideration on a case-by-case basis.