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Journal of Clinical Oncology, Vol 22, No 20 (October 15), 2004: pp. 4135-4139 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.02.107 Midline Carcinoma of Children and Young Adults With NUT RearrangementFrom 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.
Rare reports have described a carcinoma with translocation t(15;19)(q13, p13.1), which occurs in young people and seems to be associated with a highly lethal clinical course.1-7 Interest in this cancer derives from its unique chromosomal translocation, which is the sole identifier of the disease. The simplicity of the karyotype in these carcinomas is striking because most carcinomas have highly complex karyotypes and lack diagnostic balanced translocations.8 In this respect, the cytogenetic profile in t(15;19) carcinoma is more akin to those in many lymphomas and sarcomas. We recently reported that the t(15;19) results in a novel fusion oncogene, BRD4-NUT.9 The limited literature on t(15;19) carcinoma suggests that this entity arises from thymic or respiratory epithelium and is invariably lethal and unresponsive to aggressive chemoradiotherapy.1-7 To better define the clinicopathologic features of this disease, we sought to characterize a larger series comprised of both new cases identified by screening 98 carcinomas with a dual-color fluorescence in situ hybridization (FISH) assay for NUT and BRD4 rearrangements, and cases with known t(15;19).1,5-7
Patients Hematoxylin and eosin-stained or unstained, 4-µm, formalin-fixed, paraffin-embedded sections of malignant tumors were collected based on one or more of the following criteria: epithelial differentiation, patient age less than 40 years, poorly differentiated histomorphology, rapid clinical progression, or cytogenetic evidence of chromosome 15q or 19p rearrangement. Histomorphology was reviewed in all cases. Mitotic counts (per 10 high-power fields) were performed for all NUT-rearranged carcinomas (NRCs). Hospitals from which tissue was obtained included Brigham and Women’s Hospital, Massachusetts General Hospital, and Children’s Hospital (Boston, MA), University of Maryland School of Medicine, The Johns Hopkins University School of Medicine (Baltimore, MD), Memorial Sloan-Kettering Cancer Center (New York, NY), Aghi Sofia Children’s Hospital/Athens University (Athens, Greece), and Kochi Medical School (Kochi, Japan). Clinical history and follow-up for patients harboring NUT rearrangements were obtained from hospital computer records or from the patient’s oncologist. These studies were performed in accordance with Institutional Review Board protocol 2000-P-001990/3 of the Brigham and Women’s Hospital.
FISH
Immunohistochemistry
The FISH studies revealed NUT rearrangement in 11 patients. Seven of these were new unpublished cases from the group of 98 screened tumors (7.1%). Only one of the NUT-rearranged tumors from the screened group, a patient with the t(15;19), had karyotyping performed before selection for this study. The clinicopathologic characteristics of the 98 patients with tumors who were screened are listed in Table 1. Most patients were young (median age, 32.5 years) and often had poorly differentiated carcinomas (43%). Primary sites were entirely from the head, neck, or trunk, predominantly midline (73%), and were frequently within the respiratory tract (47%).
Clinicopathologic features of the 11 patients with tumors with NUT break points are listed in Table 2. All NUT-rearranged tumors were carcinomas, as defined by squamous differentiation or expression of epithelial keratins (Table 2). In contrast to the NUT wild-type (NUTwt) group of tumors (n = 91; median age, 33.4 years), NUT-rearranged tumors were diagnosed exclusively in adolescents and young adults (median age, 17.6 years). Notably, our FISH screening method revealed the first case of BRD4-NUT-rearranged carcinoma in a toddler (age, 3 years), who succumbed rapidly despite chemotherapy and radiation therapy, with adrenal and renal metastases from a bladder primary (patient 4). Eight of the NRCs also harbored the BRD4 gene break point, which is consistent with BRD4-NUT fusion. Three patients harbored the NUT but not BRD4 translocation break point, which identified, for the first time, the existence of variant rearrangements involving NUT.
Histologic features of NRCs (Fig 1A, 1B, and 1D) included varying degrees of squamous differentiation (n = 9, 82%) and absence of glandular differentiation (n = 11). All BRD4-NUT carcinomas were poorly differentiated, whereas the NUT-variant carcinomas had more pronounced squamous differentiation. All NUT-variant carcinomas had multifocal keratinization, and one (patient 9) was extensively keratinized (Fig 1B), warranting the diagnosis of well-differentiated squamous cell carcinoma. As a group, NRCs showed considerable morphologic overlap with typical NUTwt squamous cell carcinomas (Fig 1C).
All NRCs involved midline structures, including sinus/orbit, nasopharynx, trachea, thymus, mediastinum, lung, and bladder. No sex predilection was seen. All patients (except patient 10, NUT variant) succumbed to disease despite aggressive treatment with multimodality intensive chemotherapies and/or radiation therapy. The average survival time for NUT-variant carcinomas was 96.3 weeks, almost four-fold greater than for BRD4-NUT carcinomas (28 weeks; P < .0001). All 11 NRCs developed hematogenous metastases, although lymphatic spread was seen only in NUT-variant carcinomas. Despite these apparent clinical differences, there was no difference in mitotic counts between the BRD4-NUT (10.5 mitoses/10 hpf) and NUT-variant (12.7 mitoses/10 hpf) carcinomas. To evaluate the possibility that NRCs have distinctive phenotypic features, additional immunohistochemical studies were performed (Table 2). The results were notable for the frequent (seven of 11 tumors, 64%) expression of the stem-cell and vascular marker CD34 on NRCs. This was in contrast to the nonreactivity (n = 43) or, at most, focal weak reactivity (n = 2) of NUTwt neoplasms for CD34. In contrast, stains for placental alkaline phosphatase, a sensitive marker for germ cell tumors, were completely negative in 10 of 11 NUT-rearranged tumors, with the remaining tumor showing only weak focal staining. Most NRCs were reactive for CK7 (six of seven tumors). CK20 immunostaining was either negative (two of seven tumors) or showed only focal reactivity (five of seven tumors).
The midline carcinoma with NUT rearrangement is the only known carcinoma defined by its molecular signature. The consistency of the NUT break point is herein demonstrated in the largest series (11 patients) reported to date, underscoring the molecular genetic uniformity of these tumors. An unexpected and important finding in this series of NRCs is the discovery of tumors with NUT-variant rearrangements, in which NUT is fused apparently with an oncogene other than BRD4. Like tumors with the BRD4-NUT, all cases with NUT-variant rearrangement(s) were carcinomas. However, our preliminary evidence suggests that NUT-variant carcinomas are histologically better differentiated; clinically, the pattern of tumor spread differed from BRD4-NUT carcinomas, and patients lived almost four-fold longer. The significance of these differences has yet to be determined in a larger series; nevertheless, there may be a critical prognostic difference between BRD4-NUT and NUT-variant tumors. We hypothesize that, like t(15;19), the t(15;variant) results in formation of a fusion oncogene between NUT and an unknown partner gene. It is possible that the variant partner gene encodes a bromodomain protein similar to BRD4. The BRD4-NUT fusion oncogene contains a promoter that results in ubiquitous expression and two bromodomains of BRD4 capable of binding chromatin constitutively.10,11 We hypothesize that the BRD4 promoter and bromodomains drive aberrant NUT expression and chromatin binding. The variant partner gene may also serve these functions and, thus, belong to a similar family as BRD4. Our discovery of the NUT-variant subgroup establishes the NUT oncogene as the common denominator in midline carcinoma of young people, and we propose that such carcinomas (whether having BRD4-NUT or NUT-variant rearrangements) be designated as midline carcinoma with NUT rearrangement. The NUT-variant subgroup is also relevant in demonstrating that these carcinomas can arise without rearrangement of the chromosome 19p13.1 region containing NOTCH3. It has been hypothesized that NOTCH3, because of its proximity to the chromosome 19p13.1 break point, is the oncogene responsible for the t(15;19) carcinoma.4 Because the 19p13.1 break point is lacking in variant carcinomas with NUT rearrangement, it is unlikely that NOTCH3 plays a critical role in the t(15;19) carcinoma, where a BRD4-NUT fusion oncogene is expressed. Although t(15;19) carcinomas were previously hypothesized to originate from respiratory tract or thymus, our finding of a bladder carcinoma with BRD4-NUT suggests that NRCs can arise from various midline epithelial surfaces. It is possible that NRCs arise from early epithelial progenitor-cell rests that are greatest in number during the first two to three decades of life. The CD34 reactivity might also be relevant, in that some epithelial cell precursors, including hair follicle and hepatobiliary stem-like cells, express CD34,12,13,14 a marker previously associated with hematopoietic stem cells; vascular endothelium and soft tissue tumors (angiomyolipoma, gastrointestinal stromal tumors, and some neural and fibrous tumors) are also reactive for CD34. If NUT carcinomas indeed arise from early epithelial stem cells, they might contain a large percentage of self-renewing cells, accounting for their distinctly aggressive biology. However, this hypothesis will need to be evaluated formally because poorly differentiated tumors are known to express antigens uncharacteristic for their supposed lineage and which have no obvious relevance to their biology. Although the biologic significance of CD34 reactivity is unclear, our findings show that it is a specific marker for carcinomas harboring the NUT rearrangements and should be a helpful adjunct in identifying future cases for both clinical and investigative purposes. The most consistent clinical findings described in previous reports and confirmed in this series of NRCs are the young ages of the patients and the aggressive, rapidly lethal nature of tumors with the BRD4-NUT fusion. Therefore, the BRD4-NUT fusion conveys important prognostic information with potential therapeutic relevance, underscoring the importance of assaying poorly differentiated squamous carcinomas in young people for the t(15;19).
The authors indicated no potential conflicts of interest.
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.
1. Kubonishi I, Takehara N, Iwata J, et al: Novel t(15;19)(q15;p13) chromosome abnormality in a thymic carcinoma. Cancer Res 51: 3327-3328, 1991 2. Kees UR, Mulcahy MT, Willoughby ML: Intrathoracic carcinoma in an 11-year-old girl showing a translocation t(15;19). Am J Pediatr Hematol Oncol 13: 459-464, 1991[Medline] 3. Lee AC, Kwong YI, Fu KH, et al: Disseminated mediastinal carcinoma with chromosomal translocation (15;19): A distinctive clinicopathologic syndrome. Cancer 72: 2273-2276, 1993[CrossRef][Medline]
4. Dang TP, Gazdar AF, Virmani AK, et al: Chromosome 19 translocation, over-expression of Notch3, and human lung cancer. J Natl Cancer Inst 92: 1355-1357, 2000 5. Vargas SO, French CA, Faul PN, et al: Upper respiratory tract carcinoma with chromosomal translocation 15;19: Evidence for a distinct disease entity of young patients with a rapidly fatal course. Cancer 92: 1195-1203, 2001[CrossRef][Medline]
6. French CA, Miyoshi I, Aster JC, et al: BRD4 bromodomain gene rearrangement in aggressive carcinoma with translocation t(15;19). Am J Pathol 159: 1987-1992, 2001 7. Toretsky JA, Jenson J, Sun CC, et al: Translocation (11;15:19): A highly specific chromosome rearrangement associated with poorly differentiated thymic carcinoma in young patients. Am J Clin Oncol 26: 300-306, 2003[CrossRef][Medline] 8. Artandi SE, Chang S, Lee SL, et al: Telomere dysfunction promotes non-reciprocal translocations and epithelial cancers in mice. Nature 406: 641-645, 2000[CrossRef][Medline]
9. French CA, Miyoshi I, Kubonishi I, et al: BRD4-NUT fusion oncogene: A novel mechanism in aggressive carcinoma. Cancer Res 63: 304-307, 2003
10. Dey A, Ellenberg J, Farina A, et al: A bromodomain protein, MCAP, associates with mitotic chromosomes and affects G(2)-to-M transition. Mol Cell Biol 20: 6537-6549, 2000
11. Dey A, Chitsaz F, Abbasi A, et al: The double bromodomain protein Brd4 binds to acetylated chromatin during interphase and mitosis. Proc Natl Acad Sci U S A 100: 8758-8763, 2003 12. Blakolmer K, Jaskiewicz K, Dunsford HA, et al: Hematopoietic stem cell markers are expressed by ductal plate and bile duct cells in developing human liver. Hepatology 21: 1510-1516, 1995[CrossRef][Medline] 13. Trempus CS, Morris RJ, Bortner CD, et al: Enrichment for living murine keratinocytes from the hair follicle bulge with the cell surface marker CD34. J Invest Dermatol 120: 501-511, 2003[CrossRef][Medline] 14. Crosby HA, Kelly DA, Strain AJ: Human hepatic stem-like cells isolated using c-kit or CD34 can differentiate into biliary epithelium. Gastroenterology 120: 534-544, 2001[CrossRef][Medline] Submitted February 17, 2004; accepted July 26, 2004. This article has been cited by other articles:
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
