An Anatomical Site and Genetic-Based Prognostic Model for Patients With Nuclear Protein in Testis (NUT) Midline Carcinoma: Analysis of 124 Patients

Abstract

Background NUT midline carcinoma, renamed NUT carcinoma (NC), is an aggressive squamous cancer defined by rearrangement of the NUTM1 gene. Although a subset of patients can be cured, for the majority of patients the prognosis is grim. We sought to classify patients into risk groups based on molecular and clinicopathologic factors at the time of diagnosis. Methods Clinicopathologic variables and survival outcomes were extracted for a total of 141 NC patients from the NUT midline carcinoma Registry using questionnaires and medical records. Translocation type was identified by molecular analyses. Survival tree regression analysis was performed to determine risk factors associated with overall survival (OS). Results For 141 patients, the median age at diagnosis was 23.6 years. Fifty-one percent had thoracic origin compared with 49% nonthoracic sites (41% head and neck, 6% bone or soft tissue, 1% other). The median OS was 6.5 months (95% confidence interval [CI] = 5.8 to 9.1 months). Most patients had the BRD4-NUTM1 fusion (78%), followed by BRD3-NUTM1 (15%) and NSD3-NUTM1 (6%). Survival tree regression identified three statistically distinct risk groups among 124 patients classified by anatomical site and genetics: group A is nonthoracic primary, BRD3-, or NSD3-NUT (n = 12, median OS = 36.5 months, 95% CI = 12.5 to not reported months); group B is nonthoracic primary, BRD4-NUT (n = 45, median OS = 10 months, 95% CI = 7 to 14.6 months); and group C is thoracic primary (n = 67, median OS = 4.4 months, 95% CI = 3.5 to 5.6 months). Only groups A and B had long-term (≥3 years, n = 12) survivors. Conclusions We identify three risk groups defined by anatomic site and NUT fusion type. Nonthoracic primary with non-BRD4-NUT fusion confers the best prognosis, followed by nonthoracic primary with BRD4-NUT. Thoracic NC patients, regardless of the NUT fusion, have the worst survival.

YAP1-NUTM1 Gene Fusion in Porocarcinoma of the External Auditory Canal

“…As the study by Sekine et al [10] was not published at the time of reporting Case 1, we initially considered this unusual genetic alteration of uncertain significance. Accordingly, we emphasized the clear-cut difference between our case and conventional NUT carcinoma in the pathology report to avoid overtreatment [1,2,6]. Strong and specific nuclear NUT expression confirmed the genetic finding and is in line with an oncogenically active NUTM1 fusion.…”

“…This has led to a wider inclusion of the NUT IHC in the panel used for classifying undifferentiated or unclassified neoplasms irrespective of site. In the vast majority of cases, the recurrent genomic translocation t(15;19) (q13;p13.1) results in fusion of NUTM1 to the gene Bromodomain Containing 4 (BRD4), a member of the bromodomain gene family in 78% of cases [2,6]. Rarely, other fusion partners have been described, including BRD3 (15%) as well as non-bromodomain family members like NSD3 (6%) and ZNF532 (< 1%) [2,6].…”

P63-Negative Pulmonary NUT Carcinoma Arising in the Elderly: A Case Report.

“…Nuclear mitoses and necrosis are frequently reported [11]. Squamous differentiation may be present in some cases [11], but not in others [2]. Although NUT carcinoma shows no speci c ndings on general immunostaining, carcinoma cells express the p63 protein in most cases.…”

“…It was initially considered to occur in the midline organs (the mediastinum and upper aerodigestive tract) of children or adolescents [1]. However, with the recognition of NUT midline carcinoma and emergence of novel NUT monoclonal antibodies, case numbers are now increasing in all ages and organs, including extra-midline sites (resulting in the name NUT carcinoma) [2]. The International NUT Midline carcinoma registry (www.nmcregistry.org) [3] was established in 2010 for the purpose of obtaining more information on this disease [4].…”

P63-negative pulmonary NUT carcinoma arising in the elderly: a case report

“…It was initially considered to occur in the midline organs (the mediastinum and upper aerodigestive tract) of children or adolescents [1]. However, with the recognition of NUT midline carcinoma and emergence of novel NUT monoclonal antibodies, case numbers are now increasing in all ages and organs, including extra-midline sites (resulting in the name NUT carcinoma) [2]. The International NUT Midline carcinoma registry (www.…”