The Effectiveness of Tonsillectomy in the Diagnostic Workup of Squamous Cell Carcinoma Unknown Primary in the Head and Neck Based on p16 Immunohistochemistry

<i>Background and Objectives</i>: Despite the distinct entity of both p16-positive and p16-negative squamous cell carcinoma unknown primary in the head and neck (HNSCCUP), the diagnostic workup did not differ. The aim of the study was to determine the effectiveness of palatine tonsillectomy in the identification of primary tumours in two groups of p16-positive and p16-negative HNSCCUP. <i>Materials and Methods</i>: Patients with HNSCCUP managed in two tertiary care referral centres from 1 January 2014 to 31 December 2020 were analysed retrospectively. <i>Results</i>: Sixty-six patients with HNSCCUP diagnosis were included consecutively. HPV status of metastatic cervical lymph nodes using immunohistochemistry with p16 protein was available for all patients. The proportion of both p16-positive and p16-negative groups was not significantly different (<i>p</i> = 0.242). Of the 39 patients who underwent palatine tonsillectomy, tonsillar cancers were revealed histologically in 6 (15.4%) patients, and all these patients were p16-positive. No primary tonsillar tumour was found in the p16-negative group (0 of 17). The primary tumour identification rate in p16-positive HNSCCUP patients using palatine tonsillectomy was 27% (6 of 22). <i>Conclusions</i>: The diagnostic workup of HNSCCUP should be guided according to HPV/p16 status. Palatine tonsillectomy is a useful procedure in identifying primary cancer in p16-positive SCCUP patients, however, its effectiveness in p16-negative patients is debatable.