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Undifferentiated carcinomas of the upper aerodigestive tract (UCUAT) occur most frequently within the nasopharynx and are most often associated with infection by Epstein-Barr virus (EBV) (WHO undifferentiated nonkeratinizing squamous cell carcinoma). An unusual group of aggressive carcinomas are characterized by translocations that involve Nuclear Protein in Testis (NUT), a novel gene on chromosome 15. In about two-thirds of cases, NUT is fused to BRD4 on chromosome 19. These tumors, here termed NUT midline carcinomas (NMCs), are undifferentiated, may have focal squamous differentiation, and are reported to occur in children and young adults. This study investigates the prevalence of NUT rearrangement and the diagnostic significance of NUT expression in a series of upper aerodigestive tract undifferentiated carcinomas. The histologic features of these tumors are described in detail.All UCUAT not associated with EBV infection seen at the University of Virginia (UVA) over a 16-year period were reviewed. Clinical and histologic features were noted. Additional material was submitted for fluorescent in situ hybridization (FISH) using split-apart probes to the NUT and BRD4 genes. Immunohistochemistry (IHC) was performed on all cases using a polyclonal antibody to NUT, and on select cases with antibody to p63.Thirty-one UCUAT were identified. Twenty-five tumors had originally been diagnosed as sinonasal undifferentiated carcinomas. Five of 28 cases (2 males, 3 females; average age 47; range 31 to 78) with interpretable results showed rearrangements of the NUT and BRD4 genes by FISH. Three of these 5 cases showed diffuse (>90%) nuclear staining for NUT by IHC; 22 of 23 other tumors showed at most focal (<50%) nuclear staining. Undifferentiated carcinomas with NUT gene rearrangement had focal abrupt squamous differentiation in 2 cases, and intense and diffuse immunoreactivity with antibody to p63 in 4 cases.Approximately, 20% of UCUAT not associated with EBV infection were found to have rearrangements of NUT by FISH. Although previous reports suggest that NMCs afflict only children and young adults, 4 of 5 of the patients described are mature adults older than any heretofore reported, suggesting that previous reports may have been biased in their case selections. Furthermore, because these tumors are indistinguishable from other poorly differentiated carcinomas, IHC using NUT antibody may be a useful method for the identification of these tumors. Despite the lack of overt squamous differentiation in most cases, their p63 immunoreactivity suggests that NMCs may generally be of squamous lineage.