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Midline Carcinoma of Children and Young Adults With NUT Rearrangement

From the Department of Pathology, Brigham and Women’s Hospital; Department of Pathology, Massachusetts General Hospital; Department of Pathology, Children’s Hospital; and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA; Department of Pediatrics, University of Maryland School of Medicine; and Departments of Pathology and Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD; Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY; Department of Pediatric Hematology-Oncology, Aghi Sofia Children’s Hospital, Athens University, Athens, Greece; and Department of Medicine, Kochi Medical School, Kochi, Japan

Address reprint requests to Christopher A. French, MD, Department of Pathology, Brigham and Women’s Hospital, 75 Francis St, Boston, MA 02115; e-mail: Cfrench{at}partners.org

PURPOSE: A balanced chromosomal translocation, t(15;19), resulting in the BRD4-NUT oncogene, has been identified in a lethal carcinoma of young people, a disease described primarily in case reports. We sought to amass a more definitive series of tumors with NUT and/or BRD4 gene rearrangements and to determine distinct clinicopathologic features.

PATIENTS AND METHODS: Carcinomas (N = 98) in young individuals (median age, 32.5 years) were screened for NUT and BRD4 rearrangements using dual-color fluorescence in situ hybridization. Four published carcinomas with BRD4 and NUT rearrangements were also evaluated. Immunophenotypic analyses were performed.

RESULTS: Eleven tumors had NUT gene rearrangements, including eight with BRD4-NUT fusions and three with novel rearrangements, which were designated as NUT variant. All NUT-rearranged carcinomas (NRCs) arose from midline epithelial structures, including the first example arising below the diaphragm. Patients were young (median age, 17.6 years). Squamous differentiation (seen in 82% of NRCs) was particularly striking in NUT-variant cases. In this first description of NUT-variant carcinomas, the average survival (96 weeks, n = 3) was longer than for BRD4-NUT carcinomas (28 weeks, n = 8). Strong CD34 expression was found in six of 11 NRCs but in zero of 45 NUT wild-type carcinomas.

CONCLUSION: NRCs arise from midline structures in young people, and NRCs with BRD4-NUT are highly lethal, despite intensive therapies. NUT-variant carcinomas might have a less fulminant clinical course than those with BRD4-NUT fusions. CD34 expression is characteristic in NRCs and, therefore, holds promise as a diagnostic test for this distinctive clinicopathologic entity.

Supported by the National Institutes of Health National Cancer Institute Mentored Clinical Scientist Award 1 KO8 CA92158-01 (C.A.F.)

Authors’ disclosures of potential conflicts of interest are found at the end of this article.

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