Case report
A t(4;19) pediatric undifferentiated sarcoma with a novel variant of the CIC-DUX4 fusion transcript

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Abstract

We report cytogenetic and molecular genetic analysis of a pediatric tumor positive for the CIC-DUX4 fusion. The tumor belongs to a rare, diagnostically challenging subgroup of undifferentiated small round cell sarcomas. A balanced t(4;19)(q35;q13.1-2) was identified by G-banding, as a sole cytogenetic finding. The translocation was also identified by the M-FISH technique. After RT-PCR, the tumor sample was positive for the CIC-DUX4 fusion. The PCR product contains a novel, so far unreported variant of the CIC-DUX4 fusion transcript, with a fusion of the exon 20 from the CIC gene and the exon 1 from the DUX4 gene.

Introduction

Pediatric soft tissue sarcomas with undifferentiated morphology are difficult to diagnose and classify because they show no specific lineage differentiation and no well- established histologic or immunohistochemical profiles [1], [2]. Originally, several groups have identified a novel subcategory with primitive round cell morphology and a recurrent cytogenetic translocation t(4;19)(q35;q13.1). Later, this rearrangement was found to result in a fusion of the CIC gene on chromosome 19q13.1 and DUX4 gene on chromosome 4q35 [3]. Subsequent sequence analysis revealed that the genetic breakpoint at 19q13 was located inside CIC exon 20 and that of 4q35 was within the coding region of the DUX4 double homeodomain gene. The breakpoint is variable in both CIC and DUX4 genes. Recognition of the cytogenetic and molecular features is necessary to avoid misdiagnosing this entity, originally termed “atypical Ewing sarcoma” or “Ewing-like sarcoma”, especially in small biopsies [4], [5]. Due to its rarity, only few cases have been reported so far and clinical features have not been well defined. Unlike Ewing sarcoma, CIC-DUX4 sarcoma appears to quickly develop chemoresistance and has a more aggressive clinical course than Ewing sarcoma [6].

Section snippets

Clinical summary

In September 2004, a 17-year-old boy was referred to the local surgery department with one year history of a slowly growing painless mass arising in the perineal region. There were no other abnormalities on physical examination. Blood count and serum biochemistry were unremarkable. For further investigations, the patient underwent CT scan of the pelvis that showed subcutaneous a round well circumscribed lesion, suspected of a fibroma. Radical resection of the lesion was performed. Histological

Histology and immunohistochemistry

The histopathological analysis of the primary tumor showed an undifferentiated small round cell sarcoma with occasional spindling of the tumor cells (Fig. 2). The cytoplasm of the tumor cells was PAS positive with granules being diastase sensitive revealing thus cytoplasmic glycogen.

The immunohistochemical analysis revealed positivity with antibodies against CD99 (Fig. 3a) and vimentin. WT1 showed diffuse strong cytoplasmatic expression (Fig. 3b). Other antibodies including myogenic markers,

Discussion

Small round cell sarcomas have distinctive morphological features and most of them carry specific chromosomal rearrangements. A small portion of undifferentiated sarcomas remains unclassified, which leads to problems with histopathological diagnosis and subsequent treatment. Recent studies have identified specific chromosomal rearrangements with fusion genes in a subset of unclassified undifferentiated sarcomas, which are considered to be of diagnostic value: CIC-DUX4 fusion transcript with

Conflict of interest

The authors declare no conflict of interest.

Acknowledgements

The study was supported by the Research Project of the Ministry of Health No 00064203 and OPPK CZ.2.16/3.1.00/24022.

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