Abstract Introduction Nuclear protein in testis (NUT) carcinoma is a rare, aggressive cancer with a median age of onset of 30 years and overall survival of 6.7 months. It mostly originates from midline structures (thorax, head, and neck). Thoracic NUT carcinoma accounts for about 50% of all cases with fewer than 100 cases reported worldwide. Diagnosis is frequently delayed or missed and there is no established standard therapy, but treatment options include chemotherapy, immunotherapy, and radiotherapy. Our case highlights a diagnostically challenging presentation of thoracic NUT carcinoma in an elderly patient initially misdiagnosed as small cell lung cancer (SCLC). Case Presentation A 76-year-old man with history of chronic obstructive pulmonary disease and tobacco use presented with dyspnea, cough, and blood-tinged sputum who was initially treated for pneumonia without improvement. Imaging showed pleural effusion, mass-like consolidation, and nodal involvement. Biopsy showed poorly differentiated carcinoma with focal neuroendocrine features that was initially presumed SCLC, but next-generation sequencing (NGS) later showed NSD3-NUTM1 fusion confirming NUT carcinoma. Patient was started on chemoradiation with weekly carboplatin/paclitaxel, then was switched to full-dose chemotherapy and pembrolizumab due to disease progression. Course was complicated by deep venous thrombosis, pulmonary embolism, worsening pleural effusion, and metastasis including adrenal involvement and lumbar vertebral fracture. He was considered for bromodomain and extraterminal domain (BET) inhibitor trial, but he declined rapidly and was transitioned to hospice. He passed away 6 months after initial presentation. Discussion NUT carcinoma is a rare epithelial malignancy defined by NUTM1 gene fusions, mostly BRD4-NUTM. Our case showed NSD3-NUTM1, which is a rarer variant (∼6%). The advanced age of the patient and initial misdiagnosis as SCLC due to overlapping histology underscores its rarity and the limited clinical familiarity surrounding the disease which makes it underreported or misdiagnosed. Tumor morphology is often nonspecific, and NUT immunohistochemistry is critical for diagnosis, supported by fluorescence in situ hybridization or NGS. Conventional therapies like chemotherapy and radiotherapy show limited, short-term benefit. Ifosfamide regimens have shown higher response rates but are poorly tolerated in older patients. BET and histone deacetylase inhibitors are promising but remain investigational with few trials actively recruiting. Immunotherapy has limited efficacy due to low PD-L1, though rare durable responses have been observed, especially with combination approaches. Ultimately, this case reinforces the critical role of early molecular diagnosis, not only to prevent misclassification but to guide appropriate therapy and clinical trial referral in this otherwise devastating disease. This abstract is funded by: None
Mahmoud et al. (Fri,) studied this question.