Midline carcinoma of children and young adults with NUT rearrangement.
OBJECTIVE
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.


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.


CONCLUSIONS
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.
French
Christopher A
CA
Department of Pathology, Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115, USA. Cfrench@partners.org
Kutok
Jeffery L
JL
Faquin
William C
WC
Toretsky
Jeffrey A
JA
Antonescu
Cristina R
CR
Griffin
Constance A
CA
Nose
Vania
V
Vargas
Sara O
SO
Moschovi
Mary
M
Tzortzatou-Stathopoulou
Fotini
F
Miyoshi
Isao
I
Perez-Atayde
Antonio R
AR
Aster
Jon C
JC
Fletcher
Jonathan A
JA
D000293:Adolescent; D000328:Adult; D000368:Aged; D018952:Antigens, CD34 / Q000032:analysis; D002294:Carcinoma, Squamous Cell; D018797:Cell Cycle Proteins; D002648:Child; D002675:Child, Preschool; D002884:Chromosomes, Human, Pair 15; D002888:Chromosomes, Human, Pair 19; D005260:Female; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000235:genetics*; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion / Q000032:analysis / Q000235:genetics*; D015996:Survival Rate; D014157:Transcription Factors; D014178:Translocation, Genetic; D000092468:Bromodomain Containing Proteins
D018952:Antigens, CD34; D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; D014157:Transcription Factors; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins; C471990:BRD4-NUT fusion oncogene protein, human