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Midline carcinoma with t(15;19) and BRD4-NUTfusion oncogene in a 30-year-old female with response to docetaxel and radiotherapy
© Engleson et al; licensee BioMed Central Ltd. 2006
Received: 07 November 2005
Accepted: 16 March 2006
Published: 16 March 2006
Poorly differentiated midline carcinoma with a translocation between chromosomes 15 and 19, i.e. t(15;19), has been recognized as a distinct clinical entity for over a decade. This tumor affects young individuals, shows a rapidly fatal clinical course despite intensive therapy. The t(15;19) results in the fusion oncogene BRD4-NUT. Information concerning treatment of this rare disorder is scarce.
A 30-year-old woman was admitted with a rapidly progressing tumor in the mediastinum, cervical lymph nodes, vertebral column and the epidural space. Pathological, cytogenetic, FISH and PCR analysis revealed a glycogenated carcinoma rarely expressing cytokeratins and showing t(15;19) and BRD4-NUT gene rearrangement. The patient was initially treated with a Ewing sarcoma chemotherapy regimen, but had rapid progression after two cycles. She then received docetaxel and radiotherapy, which resulted in almost complete disappearance of the tumor.
Docetaxel may be considered for initial chemotherapy in young patients presenting with a midline carcinoma with bone marrow involvement and cytogenetic and molecular genetic finding of a t(15;19)/BRD4-NUT-rearrangement. We herein describe, in detail, the laboratory methods by which the BRD4-NUT -rearrangement can be detected.
In 1991, midline carcinoma associated with a (15;19) translocation was identified in young individuals as a rare but clinically distinct subgroup of poorly differentiated carcinoma [1, 2]. It has recently been shown that the translocation results in a novel fusion gene, BRD4-NUT . BRD4 (bromodomain containing 4) is a bromodomain protein with an important role in cell cycle regulation inhibiting cell cycle progression from G1 to S, whereas NUT (nuclear protein in testis) is a protein of unknown function, normally only expressed in testis tissue . In a recent series, 8 cases with BRD4-NUT fusion oncogene were reviewed. Typically, the patients were children or young adults, and all but one of the tumors originated from the respiratory tract or thymus. Clinically, the patients have shown an average overall survival of only 28 weeks with rapid disease progression and dissemination in spite of intensive chemo- and radiotherapy . In the present report we describe cyto- and molecular genetic methods for the diagnosis of these rare tumors and detailed information about the clinical pathology findings. We also report a remarkable effect of docetaxel chemotherapy in this patient.
A 30-year-old woman presented with a history of one month of accelerating back pain, 15% weight loss and night sweats. At admission she had palpable cervical lymph nodes. Chest x-ray showed an enlarged mediastinum. A laboratory screening showed a markedly elevated lactate dehydrogenase (LD) of 32.2 μkat/L. The following day she developed the superior vena cava syndrome (VCS) with swelling of the upper extremities and the face. A CT scan confirmed tumor growth compressing the superior vena cava and bilateral pleural effusion. MRI of the spinal cord showed tumor infiltrates in all vertebrae, with epidural tumor growth extending from Th9 to L3. Fine-needle aspiration of a palpable lymph node revealed uncharacteristic largely dissociated medium-sized polygonal tumor cells with clear to eosinophilic cytoplasm and small paranuclear vacuoles. Flow cytometry of a bone marrow aspirate was negative for all hematopoietic markers including CD34. While awaiting definitive pathological diagnosis, the patient was treated with cyclophosphamide, 200 mg/m2/day for two days. Steroids and a caval stent alleviated VCS symptoms.
Cytogenetic and FISH-analysis
RT-PCR was carried out for the detection of the BRD4-NUT chimeric transcript. Total RNA was extracted using the Trizol reagent according to the manufacturer's instructions (Invitrogen, Stockholm, Sweden), and 5 μg were reverse-transcribed in a 20 μL reaction volume containing 50 mM Tris-HCl pH 8.3 (at 25°C), 75 mM KCl, 3 mM MgCl2, 10 mM DTT, 1 mM of each dNTP, 20 units RNA guard (Amersham Biosciences, Uppsala, Sweden), 10 pmol random hexamers, and 400 units M-MLV Reverse Transcriptase (Invitrogen). The reaction was carried out at 37°C for 60 minutes, heated for 10 minutes at 65°C, and then kept at 4°C until analysis.
The few previously described cases of midline carcinoma were all aggressive tumors with a rapidly fatal clinical course, occurring in young patients. The present case confirms the clinical picture. This rare entity should be considered in the differential diagnosis in young patients with aggressively growing mediastinal tumors, and it may not be initially recognized as a carcinoma, especially if cytokeratin staining is spotty. The diagnosis of such midline tumors requires chromosomal or molecular analysis. The FISH analysis described in this paper may serve as a diagnostic tool in this regard. However, as variant NUT-rearrangements have been described , FISH techniques that detect both BRD4-NUT fusions and variant NUT-rearrangements should also be considered. If no fresh tissue is available, interphase FISH analysis on formalin-fixed tissue is a possibility (Figure 4).
There is scarce information concerning treatment in this disorder. Our patient was initially treated with VIDE, based on a clinical and morphological similarity to metastatic Ewing's sarcoma. The patient was improved initially on this regimen, but rapidly worsened after two cycles. The regimen was then altered to weekly docetaxel and there was a remarkable tumor regression after only two weekly courses of docetaxel, the first course given concomitantly with radiation therapy to the mediastinum. The effect was evident both within and outside of the irradiated volume. It is important that new cases with this rare and lethal tumor are reported. Possibly, the BRD4-NUT fusion protein may provide a rational therapeutic target that may improve the prognosis in the future. At present, an initial attempt with docetaxel chemotherapy may be justified.
We thank the relatives of the patient who gave kindly gave consent to the publishing of the case. This work was supported by grants from The Swedish Cancer Foundation and The Gunnar Nilsson's Cancer Foundation.
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