NUT midline carcinoma is a very rare and aggressive malignancy genetically defined by rearrangements of the NUT gene. In most cases (75%), the NUT gene on chromosome 15q14 is fused with the BRD4 gene on chromosome 19p13, creating chimeric genes that encode the BRD-NUT fusion proteins. In the remaining cases, NUT is fused to BRD3 on chromosome 9q34 or to NSD3 on chromosome 8p11;  these tumors are termed NUT-variant. 
The tumors arise in midline epithelial structures, typically mediastinum and upper aerodigestive tract, and present as very aggressive undifferentiated carcinomas, with or without squamous differentiation.   Although the original description of this neoplasm was made in children and young adults, individuals of all ages can be affected.  A retrospective series with clinicopathologic correlation found that the median age at diagnosis of 54 patients was 16 years (range, 0.1–78 years). 
The outcome is very poor, with an average survival of less than 1 year. Preliminary data seem to indicate that NUT-variant tumors may have a more protracted course.  
Treatment of childhood midline tract carcinoma involving the NUT gene (NUT midline carcinoma) has included a multimodal approach with systemic chemotherapy, surgery, and radiation therapy. Cisplatin, taxanes, and alkylating agents have been used with some success; however, while early response is common, tumors progress early in the course of the disease. [Level of evidence: 3iiiB] In a report from the NUT Midline Carcinoma Registry, 40 patients with primary tumors in the head and neck were evaluable. Two-year overall survival was 30%. The three long-term survivors (35, 72, and 78 months) underwent primary gross-total resection and received adjuvant therapy. [Level of evidence: 3iiA]
Preclinical studies have shown that the NUT-BRD4 fusion is associated with globally decreased histone acetylation and transcriptional repression; studies have also shown that this acetylation can be restored with histone deacetylase inhibitors, resulting in squamous differentiation and arrested growth in vitro and growth inhibition in xenograft models. Response to vorinostat has been reported in two separate cases of children with refractory disease, suggesting a potential role for this class of agents in the treatment of this malignancy.   The BET bromodomain inhibitors represent a promising class of agents that is being investigated for adults with this malignancy. 
Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.
The following are examples of national and/or institutional clinical trials that are currently being conducted:
Tumor tissue from progressive or recurrent disease must be available for molecular characterization. Patients with tumors that have molecular variants addressed by treatment arms included in the trial will be offered treatment on Pediatric MATCH. Additional information can be obtained on the ClinicalTrials.gov website for APEC1621 (NCT03155620).
Cancer in children and adolescents is rare, although the overall incidence of childhood cancer has been slowly increasing since 1975.  Referral to medical centers with multidisciplinary teams of cancer specialists experienced in treating cancers that occur in childhood and adolescence should be considered for children and adolescents with cancer. This multidisciplinary team approach incorporates the skills of the following health care professionals and others to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life:
(Refer to the PDQ Supportive and Palliative Care summaries for specific information about supportive care for children and adolescents with cancer.)
Guidelines for pediatric cancer centers and their role in the treatment of pediatric patients with cancer have been outlined by the American Academy of Pediatrics.  At these pediatric cancer centers, clinical trials are available for most types of cancer that occur in children and adolescents, and the opportunity to participate in these trials is offered to most patients and their families. Clinical trials for children and adolescents diagnosed with cancer are generally designed to compare potentially better therapy with therapy that is currently accepted as standard. Most of the progress made in identifying curative therapy for childhood cancers has been achieved through clinical trials. Information about ongoing clinical trials is available from the NCI website.
Dramatic improvements in survival have been achieved for children and adolescents with cancer. Between 1975 and 2010, childhood cancer mortality decreased by more than 50%.  Childhood and adolescent cancer survivors require close monitoring because cancer therapy side effects may persist or develop months or years after treatment. (Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.)
Childhood cancer is a rare disease, with about 15,000 cases diagnosed annually in the United States in individuals younger than 20 years.  The U.S. Rare Diseases Act of 2002 defines a rare disease as one that affects populations smaller than 200,000 persons and, by definition, all pediatric cancers are considered rare. The designation of a pediatric rare tumor is not uniform among international groups, as follows:
These rare cancers are extremely challenging to study because of the low incidence of patients with any individual diagnosis, the predominance of rare cancers in the adolescent population, and the lack of clinical trials for adolescents with rare cancers.
Information about these tumors may also be found in sources relevant to adults with cancer.
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
Clinical Presentation and Outcome
Added Chau et al. as reference 2.
Treatment of Childhood Midline Tract Carcinoma
Added text to state that in a report from the NUT Midline Carcinoma Registry, 40 patients with primary tumors in the head and neck were evaluable. Two-year overall survival was 30%. The three long-term survivors underwent primary gross-total resection and received adjuvant therapy (cited Chau et al. as reference 2 and level of evidence 3iiA).
This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood midline tract carcinoma involving the NUT gene (NUT midline carcinoma). It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.
This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
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The lead reviewers for Childhood Midline Tract Carcinoma Involving the NUT Gene (NUT Midline Carcinoma) Treatment are:
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PDQ® Pediatric Treatment Editorial Board. PDQ Childhood Midline Tract Carcinoma Involving the NUT Gene (NUT Midline Carcinoma) Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/midline/hp-child-midline-tract-carcinoma-treatment-pdq. Accessed <MM/DD/YYYY>.
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Date first published: 2018-01-10 Date last modified: 2018-01-26
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