Nuclear protein in testis (NUT) carcinoma is a rare and highly aggressive malignancy characterized by rearrangement of the NUT midline carcinoma family member 1 (NUTM1) gene, most commonly involving a bromodomain-containing protein 4 (BRD4)–NUTM1 fusion, and is frequently underdiagnosed due to its histologic resemblance to poorly differentiated squamous cell carcinoma. We report a 41-year-old male who presented with cough and respiratory distress requiring airway stabilization and tracheobronchial stenting. Initial biopsy suggested poorly differentiated nonkeratinizing squamous cell carcinoma in the tracheoesophageal groove, and the patient received platinum-based chemotherapy followed by definitive chemoradiation, achieving a partial locoregional metabolic response. However, within 2 months, he developed early skeletal metastases confirmed on positron emission tomography/computed tomography and magnetic resonance imaging. Comprehensive molecular profiling subsequently identified a BRD4–NUTM1 fusion, leading to molecular reclassification as NUT carcinoma. The tumor demonstrated low Programmed Death-Ligand 1 (PD-L1) expression, low tumor mutational burden, and microsatellite stability. The patient was enrolled in a clinical trial evaluating bromodomain and extra-terminal domain inhibitors/BRD4 degraders. This case highlights the aggressive clinical course, diagnostic challenges, and the critical role of molecular profiling in accurately identifying NUT carcinoma and guiding targeted therapeutic strategies.
Mauryakrishna et al. (2026) studied this question.