NUT midline carcinoma, thymic and upper respiratory tract carcinoma with t(15;19) translocation

Definition

A midline carcinoma with rearrangement of the nuclear protein in testis (NUT) gene on chromosome 15q14, most often with the BRD4 (bromodomain) gene on chromosome 19113.18.  The BRD4-NUT or other fusion products contribute to carcinogenesis by blocking cellular differentiation.  Among non-smokers, it is thought to constitute up to 20% of poorly differentiated carcinomsa of the upper aerodigestive tract.  Other than in this type of carcinoma, the NUT (Nuclear protein in Testis), normally only expressed in the testis5,6.

Synonym

Lethal midline carcinoma

Aetiology

There is no known association with EBV.

Epidemiology

This was initially identified as a tumour of children10 and young adults, predominantly female.  However, it probably also occurs in an older age group and goes unrecognised.  It may account for 20% of those undifferentiated carcinomas of the upper aerodigestive tract not associated with EBV infection7.

Clinical features

Although most often arising in the thymus1,3, this tumour has also been reported from the sinonasal region4,7, larynx4,7 and bladder. Widespread metastases are usual. There is commonly superior vena cava compression4.

Histopathology

In most cases, the tumours are morphologically undifferentiated, being composed of cells with relatively little cytoplasm, vesicular nuclei and prominent nucleoli forming syncytial sheets. There is extensive necrosis and a lymphoplasmacytic infiltrate. There may be focal abrupt keratinising squamous differentiation4,7.  In one case, the tumour showed mucoepidermoid differentiation4. The mitotic rate is high.  Large areas of coagulative necrosis may be present7.  Mucin stains are negative4.  

Immunohistochemistry

Ultrastructure

Electron microscopy shows rare intermediate junctions and basal lamina4.

Cytogenetics

In 80% of cases there is a BRD4-NUT fusion gene.  Variants include BRD3-NUT2.  NUT split-apart probes will demonstrate the involvement of NUT in a translocation9. A complex three-way translocation t(11;15;19) has been reported10.

Differential diagnosis

• Poorly differentiated squamous cell carcinoma
• t(15;19)-negative undifferentiated carcinoma
• Ewing sarcoma
• Sinonasal undifferentiated carcinoma
• Thymic carcinoma
• Lymphoepithelioma-like carcinoma
• Neuroblastoma
• Germ cell tumour
• Large cell lymphoma

Management

These tumours seem unresponsive to a range of modalities of treatment4.  They may respond to regimens designed for the treatment of Ewing sarcoma7.

Prognosis

This is a highly aggressive lethal tumour4 with an average survival of less than one year.  There is early widespread haematogenous dissemination with metastases occur to lymph nodes, lung, bone10, skin and soft tissues.

References

0 Tumours of the Lung, Pleura, Thymus and Heart. WHO Classification of Tumours. IARC Press 2004.

1 Kubonishi, I., N. Takehara, et al. (1991). "Novel t(15;19)(q15;p13) chromosome abnormality in a thymic carcinoma." Cancer Res 51(12): 3327-8.

2 Kees, U. R., M. T. Mulcahy, et al. (1991). "Intrathoracic carcinoma in an 11-year-old girl showing a translocation t(15;19)." Am J Pediatr Hematol Oncol 13(4): 459-64.

3 Lee, A. C., Y. I. Kwong, et al. (1993). "Disseminated mediastinal carcinoma with chromosomal translocation (15;19). A distinctive clinicopathologic syndrome." Cancer 72(7): 2273-6.

4 Vargas, S. O., C. A. French, et al. (2001). "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(5): 1195-203.

5 French, C. A., I. Miyoshi, et al. (2001). "BRD4 bromodomain gene rearrangement in aggressive carcinoma with translocation t(15;19)." Am J Pathol 159(6): 1987-92.

6 French, C. A., I. Miyoshi, et al. (2003). "BRD4-NUT fusion oncogene: a novel mechanism in aggressive carcinoma." Cancer Res 63(2): 304-7

7 AJSP 33:984

8 French CA, Ramirez CL, Kolmakova J, Hickman TT, Cameron MJ, Thyne ME, et al. BRD-NUT oncoproteins: a family of closely related nuclear proteins that block epithelial differentiation and maintain the growth of carcinoma cells. Oncogene. 2008 Apr 3;27(15):2237-42.

9 Stelow EB, Bellizzi AM, Taneja K, Mills SE, Legallo RD, Kutok JL, et al. NUT rearrangement in undifferentiated carcinomas of the upper aerodigestive tract. Am J Surg Pathol. 2008 Jun;32(6):828-34.

10 Toretsky JA, Jenson J, Sun CC, Eskenazi AE, Campbell A, Hunger SP, et al. Translocation (11;15;19): a highly specific chromosome rearrangement associated with poorly differentiated thymic carcinoma in young patients. Am J Clin Oncol. 2003 Jun;26(3):300-6.

This page last revised 15.8.2009

©SMUHT/PW Bishop