Clinical Presentation

Childhood nuclear protein of the testis (NUT) carcinomas (also known as midline tract carcinomas) arise in midline epithelial structures, typically the mediastinum and upper aerodigestive tract. These tumors present as very aggressive, undifferentiated carcinomas, with or without squamous differentiation.[1,2]

Although the original description of this neoplasm was reported in children and young adults, individuals of all ages can be affected.[3] A retrospective series with clinicopathological correlation of 54 patients found that the median age at diagnosis was 16 years (range, 0.1–78 years).[4] One study identified 11 patients younger than 18 years with NUT carcinoma in a German registry.[5] The median age was 13.2 years (range, 6.6–17.8 years). Thoracic and mediastinal tumors were found to be the primary site in six patients, head and neck tumors were the primary site in four patients, and one patient had a multifocal tumor with an unknown primary. All patients presented with regional lymph node involvement, and eight patients (72.7%) had distant metastases. Despite treatment with multiple therapies, the median event-free survival was 1.5 months, and the overall survival was 6.5 months.

References:

1. French CA, Kutok JL, Faquin WC, et al.: Midline carcinoma of children and young adults with NUT rearrangement. J Clin Oncol 22 (20): 4135-9, 2004.
2. Chau NG, Hurwitz S, Mitchell CM, et al.: Intensive treatment and survival outcomes in NUT midline carcinoma of the head and neck. Cancer 122 (23): 3632-3640, 2016.
3. French CA: NUT midline carcinoma. Cancer Genet Cytogenet 203 (1): 16-20, 2010.
4. Bauer DE, Mitchell CM, Strait KM, et al.: Clinicopathologic features and long-term outcomes of NUT midline carcinoma. Clin Cancer Res 18 (20): 5773-9, 2012.
5. Flaadt T, Wild H, Abele M, et al.: NUT carcinoma in pediatric patients: Characteristics, therapeutic regimens, and outcomes of 11 cases registered with the German Registry for Rare Pediatric Tumors (STEP). Pediatr Blood Cancer 71 (3): e30821, 2024.

Molecular Features

NUT carcinoma is a very rare and aggressive malignancy that is genetically defined by rearrangements of the NUTM1 gene. In most cases (75%), the NUTM1 gene on chromosome 15q14 is fused with the BRD4 gene on chromosome 19p13, creating chimeric genes that encode BRD4::NUT fusion proteins. In the remaining cases, NUTM1 is fused to other partners, most commonly BRD3 on chromosome 9q34 or NSD3 on chromosome 8p11.[1]

References:

1. French CA, Rahman S, Walsh EM, et al.: NSD3-NUT fusion oncoprotein in NUT midline carcinoma: implications for a novel oncogenic mechanism. Cancer Discov 4 (8): 928-41, 2014.

Prognosis

The outcomes of patients with NUT carcinomas are very poor, with a median survival of less than 1 year. Preliminary studies suggested that patients with NUT carcinomas without the typical BRD4::NUTM1 fusion gene may have a better prognosis than patients with other NUT carcinomas.[1,2] A retrospective analysis of 124 patients (including 47 patients younger than 18 years) reported that NUT carcinomas could be divided into three risk groups based on the anatomical location and specific NUTM1 fusion partner. The group with the best prognosis (median overall survival, 36.5 months) consisted of 12 patients (9.7%) with nonthoracic primary tumors and NUTM1 fusions with genes other than BRD4.[3]

References:

1. French CA, Kutok JL, Faquin WC, et al.: Midline carcinoma of children and young adults with NUT rearrangement. J Clin Oncol 22 (20): 4135-9, 2004.
2. French CA: NUT midline carcinoma. Cancer Genet Cytogenet 203 (1): 16-20, 2010.
3. Chau NG, Ma C, Danga K, et al.: An Anatomical Site and Genetic-Based Prognostic Model for Patients With Nuclear Protein in Testis (NUT) Midline Carcinoma: Analysis of 124 Patients. JNCI Cancer Spectr 4 (2): pkz094, 2020.

Special Considerations for the Treatment of Children With Cancer

Cancer in children and adolescents is rare, although the overall incidence has been slowly increasing since 1975.[1] Children and adolescents with cancer should be referred to medical centers that have a multidisciplinary team of cancer specialists with experience treating the cancers that occur during childhood and adolescence. This multidisciplinary team approach incorporates the skills of the following pediatric specialists and others to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life:

• Primary care physicians.
• Pediatric surgeons.
• Pathologists.
• Pediatric radiation oncologists.
• Pediatric medical oncologists and hematologists.
• Ophthalmologists.
• Rehabilitation specialists.
• Pediatric oncology nurses.
• Social workers.
• Child-life professionals.
• Psychologists.
• Nutritionists.

For specific information about supportive care for children and adolescents with cancer, see the summaries on Supportive and Palliative Care.

The American Academy of Pediatrics has outlined guidelines for pediatric cancer centers and their role in the treatment of children and adolescents with cancer.[2] At these centers, clinical trials are available for most types of cancer that occur in children and adolescents, and the opportunity to participate 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 current standard therapy. Other types of clinical trials test novel therapies when there is no standard therapy for a cancer diagnosis. Most of the progress in identifying curative therapies 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 2020, childhood cancer mortality decreased by more than 50%.[3,4,5] Childhood and adolescent cancer survivors require close monitoring because side effects of cancer therapy may persist or develop months or years after treatment. For information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors, see Late Effects of Treatment for Childhood Cancer.

Childhood cancer is a rare disease, with about 15,000 cases diagnosed annually in the United States in individuals younger than 20 years.[6] The U.S. Rare Diseases Act of 2002 defines a rare disease as one that affects populations smaller than 200,000 people in the United States. Therefore, all pediatric cancers are considered rare.

The designation of a rare tumor is not uniform among pediatric and adult groups. In adults, rare cancers are defined as those with an annual incidence of fewer than six cases per 100,000 people. They account for up to 24% of all cancers diagnosed in the European Union and about 20% of all cancers diagnosed in the United States.[7,8] In children and adolescents, the designation of a rare tumor is not uniform among international groups, as follows:

• A consensus effort between the European Union Joint Action on Rare Cancers and the European Cooperative Study Group for Rare Pediatric Cancers estimated that 11% of all cancers in patients younger than 20 years could be categorized as very rare. This consensus group defined very rare cancers as those with annual incidences of fewer than two cases per 1 million people. However, three additional histologies (thyroid carcinoma, melanoma, and testicular cancer) with incidences of more than two cases per 1 million people were also included in the very rare group due to a lack of knowledge and expertise in the management of these tumors.[9]
• The Children's Oncology Group defines rare pediatric cancers as those listed in the International Classification of Childhood Cancer subgroup XI, which includes thyroid cancers, melanomas and nonmelanoma skin cancers, and multiple types of carcinomas (e.g., adrenocortical carcinomas, nasopharyngeal carcinomas, and most adult-type carcinomas such as breast cancers and colorectal cancers).[10] These diagnoses account for about 5% of the cancers diagnosed in children aged 0 to 14 years and about 27% of the cancers diagnosed in adolescents aged 15 to 19 years.[4]

  Most cancers in subgroup XI are either melanomas or thyroid cancers, with other cancer types accounting for only 2% of the cancers diagnosed in children aged 0 to 14 years and 9.3% of the cancers diagnosed in adolescents aged 15 to 19 years.

These rare cancers are extremely challenging to study because of the relatively few patients with any individual diagnosis, the predominance of rare cancers in the adolescent population, and the low number of clinical trials for adolescents with rare cancers.

Information about these tumors may also be found in sources relevant to adults with cancer.

References:

1. Smith MA, Seibel NL, Altekruse SF, et al.: Outcomes for children and adolescents with cancer: challenges for the twenty-first century. J Clin Oncol 28 (15): 2625-34, 2010.
2. American Academy of Pediatrics: Standards for pediatric cancer centers. Pediatrics 134 (2): 410-4, 2014. Also available online. Last accessed August 23, 2024.
3. Smith MA, Altekruse SF, Adamson PC, et al.: Declining childhood and adolescent cancer mortality. Cancer 120 (16): 2497-506, 2014.
4. National Cancer Institute: NCCR*Explorer: An interactive website for NCCR cancer statistics. Bethesda, MD: National Cancer Institute. Available online. Last accessed August 23, 2024.
5. Surveillance Research Program, National Cancer Institute: SEER*Explorer: An interactive website for SEER cancer statistics. Bethesda, MD: National Cancer Institute. Available online. Last accessed March 6, 2024.
6. Ward E, DeSantis C, Robbins A, et al.: Childhood and adolescent cancer statistics, 2014. CA Cancer J Clin 64 (2): 83-103, 2014 Mar-Apr.
7. Gatta G, Capocaccia R, Botta L, et al.: Burden and centralised treatment in Europe of rare tumours: results of RARECAREnet-a population-based study. Lancet Oncol 18 (8): 1022-1039, 2017.
8. DeSantis CE, Kramer JL, Jemal A: The burden of rare cancers in the United States. CA Cancer J Clin 67 (4): 261-272, 2017.
9. Ferrari A, Brecht IB, Gatta G, et al.: Defining and listing very rare cancers of paediatric age: consensus of the Joint Action on Rare Cancers in cooperation with the European Cooperative Study Group for Pediatric Rare Tumors. Eur J Cancer 110: 120-126, 2019.
10. Pappo AS, Krailo M, Chen Z, et al.: Infrequent tumor initiative of the Children's Oncology Group: initial lessons learned and their impact on future plans. J Clin Oncol 28 (33): 5011-6, 2010.

Treatment of Childhood NUT Carcinoma

Treatment options for childhood NUT carcinoma include the following:

1. Chemotherapy.
2. Surgery.
3. Radiation therapy.

Treatment of childhood NUT carcinoma includes a multimodal approach with systemic chemotherapy, surgery, and radiation therapy. Cisplatin, taxanes, and alkylating agents have been used with some success. While early response to these agents is common, tumor progression occurs early in the course of the disease.[1]; [2][Level of evidence C1]

In a report from the NUT Midline Carcinoma Registry, 40 patients with primary tumors in the head and neck were evaluable. The 2-year overall survival rate was 30%. The three long-term survivors (with survivals of 35, 72, and 78 months) underwent primary gross-total resection and received adjuvant therapy.[3]; [4][Level of evidence C1]

Because of the presence of the BRD4::NUTM1 gene fusion in NUT carcinomas, there has been increased interest in evaluating BET bromodomain inhibitors for adults and children with this malignancy.[5] Unfortunately, activity for this class of agents has been limited in reported clinical trials:

• In a phase I study of the BET inhibitor molibresib, confirmed objective responses were observed in 2 of the 19 patients who were treated with a daily dose of 60 mg or higher.[6]
• A subsequent phase II study of molibresib used a daily dose of 75 mg in patients with NUT carcinomas. Only 1 of the 12 patients achieved an objective response, which did not meet the prespecified bar for activity.[7]
• In a phase I study of the BET inhibitor birabresib, three of the nine patients achieved responses, but only one response lasted longer than 2 months.[8]

References:

1. Lemelle L, Pierron G, Fréneaux P, et al.: NUT carcinoma in children and adults: A multicenter retrospective study. Pediatr Blood Cancer 64 (12): , 2017.
2. Bauer DE, Mitchell CM, Strait KM, et al.: Clinicopathologic features and long-term outcomes of NUT midline carcinoma. Clin Cancer Res 18 (20): 5773-9, 2012.
3. Sopfe J, Greffe B, Treece AL: Metastatic NUT Midline Carcinoma Treated With Aggressive Neoadjuvant Chemotherapy, Radiation, and Resection: A Case Report and Review of the Literature. J Pediatr Hematol Oncol 43 (1): e73-e75, 2021.
4. Chau NG, Hurwitz S, Mitchell CM, et al.: Intensive treatment and survival outcomes in NUT midline carcinoma of the head and neck. Cancer 122 (23): 3632-3640, 2016.
5. Pearson AD, DuBois SG, Buenger V, et al.: Bromodomain and extra-terminal inhibitors-A consensus prioritisation after the Paediatric Strategy Forum for medicinal product development of epigenetic modifiers in children-ACCELERATE. Eur J Cancer 146: 115-124, 2021.
6. Piha-Paul SA, Hann CL, French CA, et al.: Phase 1 Study of Molibresib (GSK525762), a Bromodomain and Extra-Terminal Domain Protein Inhibitor, in NUT Carcinoma and Other Solid Tumors. JNCI Cancer Spectr 4 (2): pkz093, 2020.
7. Cousin S, Blay JY, Garcia IB, et al.: Safety, pharmacokinetic, pharmacodynamic and clinical activity of molibresib for the treatment of nuclear protein in testis carcinoma and other cancers: Results of a Phase I/II open-label, dose escalation study. Int J Cancer 150 (6): 993-1006, 2022.
8. Lewin J, Soria JC, Stathis A, et al.: Phase Ib Trial With Birabresib, a Small-Molecule Inhibitor of Bromodomain and Extraterminal Proteins, in Patients With Selected Advanced Solid Tumors. J Clin Oncol 36 (30): 3007-3014, 2018.

Treatment Options Under Clinical Evaluation for Childhood NUT Carcinoma

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, see the ClinicalTrials.gov website.

The following are examples of national and/or institutional clinical trials that are currently being conducted:

• NCT05019716 (Testing the Safety and Efficacy of the Addition of A New Anti-cancer Drug, ZEN003694, to Chemotherapy Treatment [Etoposide and Cisplatin] for Adult and Pediatric Patients [Aged 12–17 Years] With NUT Carcinoma): This phase I/II trial will determine the maximum tolerated dose of the BET bromodomain inhibitor ZEN-3694 added to cisplatin and etoposide to treat patients with NUT carcinoma. This trial will also evaluate the efficacy of this treatment regimen.
• NCT05372640 (Testing the Safety and Efficacy of the Combination of Two Anticancer Drugs, ZEN003694 and Abemaciclib, for Adult and Pediatric Patients [Aged 12–17 years] With Metastatic or Unresectable NUT Carcinoma, Breast Cancer, and Other Solid Tumors): This phase I trial will determine the maximum tolerated dose of the BET bromodomain inhibitor ZEN003694 given with abemaciclib to treat patients with metastatic or unresectable NUT carcinoma, breast cancer, or other solid tumors.

Latest Updates to This Summary (08 / 07 / 2024)

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.

This summary was comprehensively reviewed.

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® Cancer Information for Health Professionals pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood NUT carcinoma. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

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).

Board members review recently published articles each month to determine whether an article should:

• be discussed at a meeting,
• be cited with text, or
• replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Childhood NUT Carcinoma Treatment are:

• Denise Adams, MD (Children's Hospital Boston)
• Karen J. Marcus, MD, FACR (Dana-Farber Cancer Institute/Boston Children's Hospital)
• William H. Meyer, MD
• Paul A. Meyers, MD (Memorial Sloan-Kettering Cancer Center)
• Thomas A. Olson, MD (Aflac Cancer and Blood Disorders Center of Children's Healthcare of Atlanta - Egleston Campus)
• Alberto S. Pappo, MD (St. Jude Children's Research Hospital)
• D. Williams Parsons, MD, PhD (Texas Children's Hospital)
• Arthur Kim Ritchey, MD (Children's Hospital of Pittsburgh of UPMC)
• Carlos Rodriguez-Galindo, MD (St. Jude Children's Research Hospital)
• Stephen J. Shochat, MD (St. Jude Children's Research Hospital)

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

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The preferred citation for this PDQ summary is:

PDQ® Pediatric Treatment Editorial Board. PDQ Childhood NUT 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>. [PMID: 29337479]

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Last Revised: 2024-08-07