NUT carcinoma, an under-recognized malignancy: a clinicopathologic and molecular series of 6 cases showing a subset of patients with better prognosis and a rare ZNF532::NUTM1 fusion.

NUT carcinoma (NC) is a rare malignancy with aggressive clinical behavior, defined by rearrangements involving the NUTM1 gene locus. This entity is often under-recognized and its diagnosis may be challenging. In this study, we describe a subset of patients that, despite the molecularly proven diagnosis of NC, show improved outcomes. In addition, we describe one case with the novel ZNF532::NUTM1 fusion. All cases of NC diagnosed from 2013 to 2022 in our department were retrieved. FISH using dual color bring-together probes and next-generation sequencing assay were performed to characterize the fusions involving NUTM1. Among 6 patients identified, 5 were men with a median age of 35.6 years. Four patients had primary tumors in the head and neck region (2 ethmoid sinus, 1 parotid gland, and 1 lacrimal gland); 1 in the mediastinum, and another presented with a femoral bone tumor. In all cases, the initial diagnoses were not NC. The cases showed different morphological patterns, including monomorphic, rhabdoid, and pleomorphic appearances. One case showed a pseudopapillary pattern. By immunohistochemistry, all tumors showed squamous differentiation and ≥50% of neoplastic cells with nuclear positivity for NUT antibody. One case expressed WT1 (C-terminus) and other showed chromogranin positivity. Genetic study revealed a BRD4::NUTM1 fusion in all head and neck cases, BRD3::NUTM1 in mediastinum case, and ZNF532::NUTM1 fusion in the femur bone case. They were treated with surgical resection plus chemotherapy and radiotherapy. The median overall survival was 23.11 months (1.6-83.3 months) and the median disease-free survival was 14.86 months (0-54.4 months). The patients with longer overall survival were one with a lacrimal gland primary (83.3 months) and other with a parotid lesion (31.9 months). Both patients were primarily treated with complete surgical resection. Anatomic location may be directly related to the overall survival in NC cases. Resectability of the lesion is also an important factor related to survival. Pathologists should include NC in the differential diagnosis of any poorly differentiated and undifferentiated monomorphic malignancy, regardless of its anatomic location.

A case of NUT midline carcinoma with no HPV infection, slight EWSR1 rearrangement and strong expression of EGFR.

NUT midline carcinoma (NMC) is a rare neoplasm with a poor prognosis and involving mostly young patients. Here we describe a classic NMC with a BRD4-NUT fusion gene in a middle-aged woman. We also analyzed some biological features that could potentially influence its clinical behavior such as HPV infection, EWSR1 rearrangement, and the status of the EGFR gene.

NUT midline carcinoma.

NUT midline carcinoma (NMC) is a rare, aggressive human cancer, genetically defined by rearrangements of the gene NUT (HUGO symbol: C15orf55). In the majority (∼75%) of NMCs, most of the coding sequence of NUT on chromosome 15q14 is fused with BRD4 creating chimeric genes that encode BRD-NUT fusion proteins. In the remaining cases, NUT is fused to BRD3 or an unknown partner gene; these tumors are termed NUT-variant. Diagnosis of NMC is made by demonstration of expression of the NUT-fusion protein using a monoclonal antibody to NUT for immunohistochemistry, and confirmation of the fusion (BRD-NUT or NUT-variant) by fluorescent in situ hybridization or reverse transcriptase-polymerase chain reaction. BRD-NUT functions to block cellular differentiation and promote uncontrolled growth of carcinoma cells. Because the reagents and expertise required to diagnose NMC are not available in most laboratories, and because of incomplete awareness of this disease, NMC is frequently undiagnosed or misdiagnosed, and its actual prevalence is unknown. NUT midline carcinoma does not arise from any specific tissue type or organ. It presents as a poorly differentiated carcinoma originating from midline locations such as the head, neck or mediastinum. Although rare, NMCs occur throughout life, and advanced local disease is frequently accompanied by distant hematogenous metastases. There still is no effective treatment for NMC, there are no guidelines, and current approaches to treatment are based on discussions among a few oncologists who each have had a single experience treating this disease.