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NUT midline carcinoma in a young woman.

Case Report A 22-year-old Latvian woman presented to the accident and emergency department with a 3-week history of nonproductive cough and right-sided pleuritic chest pain. Her medical, surgical, and family histories were unremarkable. Socially, she smoked approximately 20 cigarettes per day and drank alcohol infrequently. Examination of her chest was significant for right basal crepitations, reduced breath sound on auscultation, and stoney dullness on percussion, clinically consistent with a right-sided pleural effusion. Laboratory investigations were significant for elevated WBC of 14.5 10mm/L (normal range [NR], 4.0 to 11.0 10mm/L) consisting predominantly of neutrophils (11.3 10mm/L; NR, 2.0 to 7.5 10mm/L), raised C-reactive protein (155 mg/L; NR, 0 to 5 mg/L), and lactate dehydrogenase (LDH; 762 u/L; NR, 100 to 350 u/L). Chest radiograph demonstrated a right-sided pleural effusion and widening of the mediastinum, suggestive of a hilar mass (Fig 1). Computed tomography (CT) of the thorax confirmed a large 13 11 cm right anterior upper mediastinal mass with extension into the right lower lobe and a pleural effusion (Figs 2A, cross-sectional CT of thorax at diagnosis; 2B, coronal view of right anterior medistinal mass at diagnosis). The differential diagnosis was extensive, but because the clinical picture was suggestive of lymphoma, a positron emission tomography/CT scan was performed. There were multiple focal abnormal areas of fluorodeoxyglucose accumulation in the visualized axial and appendicular skeleton, suggestive of bone marrow involvement. Pleurocentesis confirmed an exudate but demonstrated nonmalignant cytology. Endoscopic ultrasound–guided core biopsy of the mediastinal mass revealed a neoplastic process consisting of small to moderately sized neoplastic cells with focal areas of necrosis. Immunohistochemistry staining ruled out lymphoma. The tumor demonstrated a high proliferative index with focal cytokeratin staining of uncertain significance. The differential diagnosis now included Ewing’s sarcoma, synovial sarcoma, or another rare variant of poorly differentiated carcinoma. Because more tissue was required, bone marrow samples were obtained. Hematoxylin and eosin (HE) staining showed hypercellular marrow with approximately 50% replacement by malignant cells of intermediate size with high nuclear to cytoplasmic ratio (Fig 3A, low-power HE staining of bone marrow biopsy demonstrating replacement of marrow space by tumor cells on left). A majority of the cells were dyshesive, with some focal cohesive growth pattern and no clear pattern of differentiation (Fig 3B, high-power HE staining of bone marrow biopsy demonstrating medium to large tumor cells with dyshesive growth pattern). Immunohistochemistry showed focal positivity for pan-cytokeratin AE1/AE3, CK7, and CK19; diffuse expression of EMA and CD99; and scanty vimentin positivity, with no evidence of melanocytic, germ cell, or mesothelial differentiation (Fig 3C, immunohistochemical staining for AE1/3). Molecular testing for the transcripts associated with synovial sarcoma was negative. Given the patient’s age and presence of disseminated disease in the context of a mediastinal mass, a diagnosis of NUT carcinoma was considered. Sections sent for immunohistochemical staining at the Brigham and Women’s Hospital (Boston, MA) were positive for expression of nuclear protein in testis (NUT), confirming this diagnosis (Fig 3D). At confirmation of diagnosis, the patient had worsening chest pain and elevated LDH of 13,525 U/L. Intensive chemotherapy (doxorubicin 60 mg/m day 1 and ifosfamide 1,750 mg/m continuous infusion days 1 to 3, every 3 weeks) was urgently administered. Within 10 days of chemotherapy administration, the patient had clinically improved, and LDH had fallen to 2,000 U/L. She was discharged from the hospital and received two additional treatment cycles without complications. Despite this initial improvement, she was readmitted to the hospital before her fourth treatment cycle with worsening chest pain and dyspnea. CT scan confirmed marked disease progression, with compromise of the superior vena cava and obliteration of the right main bronchus (Figs 4A, crosssectional CT of thorax at 3 months postdiagnosis; 4B, coronal view of CT of thorax at 3 months postdiagnosis). She deteriorated rapidly over 3 days and died.