Aggressive PTH-secreting lung carcinoma with a BRD3: NUTM1 fusion presenting with refractory hypercalcemia

Introduction: Nuclear protein in testis (NUT) midline carcinomas (NMCs) are rare and aggressive cancers. These carcinomas are defined by gene re-arrangement leading to fusion of the NUT gene on chromosome 15 with other genes. These are named as such as they are solid tumors most frequently occurring in the midline including lung, central nervous system, kidneys, head and neck. They are underdiagnosed and under-reported, with most available literature on them in the form of case reports and case series. There are currently no targeted treatments available, and as a result they are associated with poor outcomes. We report an unusual case of this cancer type: a BRD3::NUTM1 fusion lung cancer presenting with refractory hypercalcemia secondary to parathyroid hormone-related protein (PTHrP) secretion. Both the fusion partner, and the presentation of this case of NMC carry particular rarity. Case Report: A 51-year-old female patient presented to her local Emergency Department with palpitations and was found to have a severely elevated calcium at 4.8 mmol/L (normal range 2.20–2.60 mmol/L). She was admitted and treated aggressively with intravenous fluids, zoledronic acid and denosumab. Her parathyroid hormone (PTH) was suppressed, but her PTHrP was too high to be measured. Further investigation in the form of a computed tomography (CT) chest, abdomen, and pelvis identified a large pulmonary mass and multiple bony metastases. The patient’s calcium level proved resistant to medical treatment, and her consciousness level reduced, leading to admission to Intensive Care for hemofiltration. An endobronchial biopsy and tumor molecular diagnostics identified the presence of a rare BRD3::NUTM1 fusion. Despite correction of her calcium, the patient did not regain full consciousness, and the difficult decision was made to stop active treatment. Conclusion: This case describes a rare fusion pulmonary NMC presenting with hypercalcaemia and PTHrP secretion. It adds to the literature surrounding this aggressive cancer type, and highlights the need for early tissue diagnosis and immunohistochemistry in atypical and aggressive lung cancers.