NUT carcinoma (NC) is a rare, aggressive, and often misdiagnosed tumor with a predilection for midline structures, including the head, neck, and mediastinum.^1,2 It is rapidly lethal, often at an advanced stage at diagnosis, and is minimally responsive to standard treatments of surgical resection, chemotherapy, or radiation therapy.³ The average age at diagnosis is mid-to-late 20s,^1,4,5 though NC has been found in a range of ages from newborn to 82 years.⁵ It occurs equally in males and females,^1,3,5 and there is no known association with smoking, other environmental factors, or infectious causes such as EBV or HPV.^1,5 The average overall survival is approximately 6.5 months.¹ Primary pulmonary NUT carcinoma has a worse prognosis with an average overall survival of less than 3 months.⁴

The thorax is the most common primary site of NC (approximately 50%).^1,2,5 Patients with pulmonary involvement typically present with symptoms of chest pain, cough, dyspnea, back pain, or hemoptysis.1,2,3,4 Imaging shows an irregular mass lesion in the thorax, often with associated pleural effusion or lymph node involvement. Atelectasis or pulmonary necrosis may also be seen.^3,5 At least 50% of patients have distant metastasis at diagnosis, with bone being the most common site.^3,4 Head and neck NC accounts for another 33% of cases.⁵

The NUTM1 gene is located on chromosome 15. The gene’s expression should only occur in the testis and ovary.³ NUT carcinoma is characterized by the fusion of a transcription regulation gene (oncogene).⁵ The most common fusion is BRD4-NUTM1 resulting from chromosomal translocation t(15;19)(q14;p13.1) (75%), followed by BRD3-NUTM1 (15%), NSD3 (5%), and ZNF532 and ZNF592 (5%).⁶ The BRD genes belong to the BET protein family, involved in transcription activation.¹ In this particular case study, the patient was found to have the less frequent NSD3-NUTM1 gene fusion.

The diagnosis of NC is often missed due to its rarity, lack of defining histologic features, nonspecific immunoprofile, and lack of available molecular testing.^1,3 NC can take on different appearances to mimic a variety of malignancies but most often presents as clusters of malignant cells with scant cytoplasm, hyperchromatic nuclei, discrete nucleoli, and necrosis. Approximately one third of NC demonstrate characteristic abrupt foci of keratinization.^1,2,3,5

Immunohistochemical staining can be misleading as NC can be positive for a variety of markers. Most commonly, NC is positive for pancytokeratin, p40, p63, CK5/6, and NUT. Other variably positive stains include EMA, BerEP4, and CEA.^1,2,3,4,5 The Ki-67 proliferation index is high. The NUT immunostain (monoclonal NUT antibody (clone C52B1) is highly specific, with a specificity of 100% and a sensitivity of 87%.^1,3 It is considered diagnostic for NC when more than 50% of tumor cells show strong nuclear-speckled staining.⁷ A negative result from the NUT immunostain does not rule out the possibility of NC. If the stain is negative, FISH or NGS should be conducted to confirm the diagnosis.³