LAUSR

Nuclear protein in testis (NUT) carcinoma, formerly known as NUT midline carcinoma, is a rare but aggressive cancer. The exact prevalence is unknown, but median prognosis is approximately 6 months in the reported cases. NUT carcinoma arises from chromosomal rearrangements of the NUT gene, resulting in a poorly differentiated squamous cell carcinoma. Twothirds of cases result from t(15;19) translocation, a fusion protein of NUT (15q14) to BRD4 (19p13.1). BRD4 binds to hyper-acetylated histone regions of chromatin, resulting in constitutional activation of transcriptional regulators ultimately inhibiting cell differentiation. The remaining cases, named NUT variant, result from NUT fusion to other partner genes. Diagnosis is made through positive immunohistochemistry to the NUT antibody, by fluorescent in situ hybridisation or nextgeneration sequencing. Typically, NUT carcinoma affects the nasal cavities and sinus, the nasopharynx, thymus, mediastinum and thorax, hence the term ‘midline’. Occasionally, NUT carcinoma has affected rarer sites (e.g. the bladder and pancreas). The median age of diagnosis for documented cases in NUT carcinoma is 22 years but it has been reported in patients up to 81 years. In many published cases, due to the rarity of the disease and non-specific presentation, patients are misdiagnosed and commonly treated for undifferentiated carcinoma and primary sinonasal carcinomas. This case highlights the clinical challenges of diagnosing and treating NUT carcinoma. A 22-year-old non-smoking man presented with a 4-week history of non-productive cough, dyspnoea and nausea but no constitutional symptoms. Apart from asthma, he had no significant medical history. On review by his general practitioner, he was found to have decreased air entry to the right base, warranting a chest computed tomography (CT) scan that demonstrated mediastinal and upper abdominal masses. He was referred to a haematology inpatient service for mediastinoscopy and biopsy, which revealed a poorly differentiated malignancy with patchy TTF-1 and no driver mutation identified (PD-L1, EGFR, ALF, WT and ROS-1 negative). Subsequent testing of the sample with next-generation sequencing demonstrated the presence of BRD4-NUT fusion, diagnostic for NUT carcinoma. Planning positron emission tomography-CT scan showed an extensive disease burden: mediastinal masses, patchy upper abdominal nodal disease, retroclavicular node involvement and several bone lesions, including the pelvis, thoracic spine and right humerus. During this inpatient admission, he developed supraventricular tachycardia and was admitted to the intensive care unit for tachycardia and dyspnoea. Repeat imaging (Fig. 1) demonstrated superior vena caval obstruction, oesophageal obstruction and pneumonia. Prior to the diagnosis of NUT carcinoma, he commenced empiric treatment for non-small-cell lung cancer (NSCLC): cisplatin/pemetrexed/pembrolizumab chemotherapy with a plan for radiotherapy. Encroachment of his mediastinal mass on the superior vena cava and heart warranted the addition of dexamethasone. Bulky disease was so severe that the resulting nausea required nasogastric feeding. He had recurrent febrile episodes treated as culture-negative sepsis. Owing to clinical deterioration, he was treated with palliative radiotherapy to the right lung (20 Gy in five fractions over 1 week) and to the spine for bony pain from lumbar spinal metastases. He was planned to receive a bromodomain and extraterminal motif (BET) inhibitor, but unfortunately deteriorated and died less than 2 months after diagnosis. NUT carcinoma is challenging to diagnose and treat. History, examination and investigation findings for NUT carcinoma mimic much more common conditions, including pneumonia, primary lung cancer and lymphoma. Nearly half of the cases are reported in the USA, disproportionately in Massachusetts, the centre of NUT carcinoma research. Ambiguous pathology, uncertainty about the primary site of the tumour and rapidly progressive disease meant our patient was initially treated for NSCLC. Currently, there is no standard of care for treatment of NUT carcinoma: therapeutic decisions are largely based on clinician discretion. First, the lack of documented clinical cases has prevented the development of a robust consensus opinion. Second, tumours are poorly responsive to conventional therapies. The largest retrospective study of treatment regimens in NUT carcinoma demonstrated the challenges in treatment. While overall survival remains poor in all patients, the best chance of progression-free survival and the hope of cure relies on early resection, ideally total resection, and adjuvant radiotherapy. Since its first description in 1998, there has been little evolution in NUT carcinoma management, largely due to the lack of documented cases. However, given that the