Abstract
PURPOSE: NUT carcinoma (NC) is a rare, aggressive neoplasm with limited therapeutic options. This study aimed to delineate the clinicopathologic and molecular characteristics of head and neck NC (HNNC) to refine diagnostic strategies and identify prognostic factors. METHODS AND RESULTS: We conducted a retrospective analysis of 18 HNNC cases from a single institution (2015-2024). Our cohort consisted of 7 males and 11 females, aged 14-72 years (mean: 45 years), with the predominant site of involvement being the sinonasal tract (77.8%), followed by the larynx (16.7%) and the nasopharynx (5.5%). Microscopically, HNNCs typically grew as nests and sheets of poorly differentiated cells with focal or extensive abrupt keratinization. Several cases also displayed distinct morphological variants, including spindle cell components (4/18), basaloid (1/18), ameloblastic-like (1/18), papillary structures (1/18), monomorphic cell clusters (1/18), and concentric pattern around blood vessels (2/18). All cases were moderately to strongly positive for NUT protein (H-score: 80 to 300). PD-L1 was expressed in 43.8% of tumors (7/16). FISH confirmed NUTM1 rearrangement in 15 cases (15/16, 93.8%), and RNA sequencing analysis of 14 cases revealed the following fusion patterns: NUTM1::BRD4 (10/14, 71.4%), NUTM1::BRD3 (3/14, 21.4%), and NUTM1::NSD3 (1/14, 7.1%). Follow-up data were available for 17 patients (range: 2-52 months), among whom 10 patients died of the disease. The median overall survival was 12 months. CONCLUSIONS: This large single-center series confirms that HNNC exhibits marked morphological heterogeneity and poor prognosis. Accurate diagnosis relies on immunohistochemistry, with FISH and RNA sequencing as needed, offering molecular insights to guide prognosis and clinical management.