Primary Pulmonary NUT Carcinoma: A Case Illustration of Therapeutic Challenges and Review of Emerging Targeted Therapies

Background Pulmonary NUT carcinoma is a rare but highly aggressive malignancy with poor prognosis. It typically affects younger patients with no smoking history. Given its rapid progression, it is crucial to consider it as a differential diagnosis in a poorly differentiated thoracic mass to ensure timely diagnosis and management. Case Presentation We report a case of primary pulmonary NUT carcinoma diagnosed in a 59‐year‐old male with a never‐smoking history during routine screening for possible occupational asbestos exposure. The preliminary diagnosis of metastatic keratinizing squamous cell carcinoma was later reclassified as NUT carcinoma by immunohistochemistry. Next generation sequencing of ctDNA showed CDKN2A mutation. The therapeutic course was complicated by several hypersensitivity reactions to first line treatments. Due to rapidly deteriorating clinical status, the patient was no longer eligible for a BET inhibitor clinical trial and died approximately 5 months after diagnosis. Conclusion Due to its rarity and poor therapeutic response, there is currently no established standard of treatment for pulmonary NUT carcinoma. Timely and accurate diagnosis remains challenging due to its nonspecific presentation and rarity, resulting in low clinical suspicion, especially in patients outside the typical demographic. Common first‐line treatments include platinum‐based regimens in combination with etoposide or paclitaxel. Several clinical trials of BET and histone deacetylase inhibitors are active, and clinicians are encouraged to enroll patients to maximize survival outcomes.