Nuclear Protein in Testis Midline Carcinoma

Abstract

Introduction Nuclear protein in testis (NUT) midline carcinoma is a recently reported and as yet under-recognized malignancy with a dismal prognosis. Unlike other cancers, this is a genetically defined malignancy, and should be considered in the differential diagnosis of a patient with a poorly differentiated and rapidly growing tumor. Case A 38-year-old female presented with 1 month duration of cough, weight-loss, shortness of breath and chest discomfort. She has a 10 pack-year smoking history and is without other significant comorbidities. Initial computed tomography (CT) showed a 6 cm x 6 cm left hilar mass, which rapidly enlarged within 2 months, largely occupying the left hemithorax and causing extensive post-obstructive left lung atelectasis. Mediastinal lymph node biopsy showed poorly differentiated carcinoma with extensive necrosis. Cytogenetic studies showed translocation involving the NUT gene on chromosome 15 with bromodomain-containing protein 4 (BDR4) on chromosome 19, suggestive of NUT midline carcinoma (NMC). Patient continued to deteriorate despite receiving multiple courses of chemotherapy and radiation. Eventually she elected to be under hospice care, and died within 6 months after initial presentation. Discussion NMC is a poorly differentiated, aggressive, and rare subtype of squamous cell carcinoma that affects all age groups. NMC more commonly arises from midline structure within the neck and thorax, but can affect any organ. The cytogenetic distortion mostly arises from reciprocal translocation of the NUT gene in chromosome 15 with the BRD4 gene on chromosome 19. The BDR-NUT fusion oncogene blocks normal cellular differentiation, resulting in a perpetual state of cellular proliferation. Presenting symptoms are dictated by location of tumor but are nonspecific. Rapid progression and fatal outcome are common. Histopathologic finding reveals a poorly differentiated carcinoma with focal squamous differentiation; but this is not pathognomonic and is often confused with other forms of squamous cell carcinoma, potentially delaying diagnosis. Definitive diagnosis can be achieved by karyotypic analysis that shows t(15:19) or using immunohistochemical staining to identify the BRD-NUT fusion protein, which has 100% specificity and 87% sensitivity. However, diagnosis and estimate of true prevalence are hindered by a lack of awareness and limited availability of diagnostic assays. Unfortunately, current multi-modal treatment yields unsatisfactory response, and death from tumor progression often occurs in months. Targeted therapy, such as with bromodomain and extra terminal inhibitor (BETi) and histone deactylase inhibitor (HDACi), induce squamous differentiation of NMC cells, and are promising therapeutic strategies. Clinical trials of both agents are currently ongoing.