Original contributionThe CIC-DUX4 fusion transcript is present in a subgroup of pediatric primitive round cell sarcomas☆
Introduction
Pediatric soft tissue sarcomas are a diverse group of tumors arising in the connective tissues of the body and are generally found to be quite aggressive [1], [2]. Collectively, these tumors account for up to 20% of all pediatric solid tumors [3]. Sarcomas have long been a challenging group of tumors to diagnose and classify because of the morphological similarities between established subgroups, as well as the relative rarity of these neoplasms [4]. However, advances in immunohistochemical and molecular analyses have allowed for the accurate demarcation of different sarcoma subtypes [5].
Sarcomas can be subclassified at both morphological and genomic levels. Morphologically, sarcomas are divided into rhabdomyosarcomas (RMSs) and nonrhabdomyomatous sarcomas [6]. Examples of the latter category include Ewing sarcoma (ES)/primitive neuroectodermal tumor, malignant peripheral nerve sheath tumor, and synovial sarcoma (SS) [6]. At the genomic level, sarcomas are divided into 2 major groups. The first group is composed of sarcomas with simple, near-diploid karyotypes that consistently harbor recurrent chromosomal rearrangements [7]. Members of this group include ESs, which are associated with rearrangements of the EWS gene; alveolar RMSs, which are associated with PAX-FKHR rearrangements; and SSs, which are associated with SYT-SSX rearrangements [8]. The second group is composed of tumors that have very complex karyotypes but in which no reproducible chromosomal aberrations have been identified. This group includes malignant peripheral nerve sheath tumor, embryonal RMS, and osteosarcoma [7].
Despite the advancement of diagnostic applications that allow for the identification of sarcoma subtypes, approximately 5% of sarcomas remain unclassifiable [9], [10], [11]. These tumors, termed undifferentiated soft tissue sarcomas (USTSs), show no specific lineage differentiation and no well-established histologic or immunohistochemical profiles [9], [12]. Furthermore, the karyotypes of these sarcomas are largely variable, with some tumors having a very complex genomic makeup and other tumors harboring a near-diploid genome [13]. As such, a diagnosis of USTS is largely considered one of exclusion [5]. Morphologically, most of these tumors have a primitive round to plump spindle cell phenotype; however, a small percentage of USTSs exhibit a pure spindled/myxoid phenotype that likely represents a different entity [5], [9]. Recent case reports have linked tumors of primitive round cell morphology with a translocation involving 4q35 and 19q13.1 [11], [14], [15], [16]. In 4 such tumors, molecular and cytogenetic analyses determined that the translocation between 19q13.1 and 4q35 resulted in the fusion of the CIC gene on chromosome 19 and the DUX4 gene on chromosome 4 [11], [16].
In this study, we detail specific reverse transcriptase polymerase chain reaction (RT-PCR) assays that can be used to detect the CIC-DUX4 fusion transcript in both frozen and paraffin-embedded tissues and describe an additional 3 cases of CIC-DUX4–positive pediatric USTSs with primitive round cell morphology.
Section snippets
Tumor specimens
An electronic search of the pathology database at the Hospital for Sick Children was performed to identify children diagnosed with USTS between 1987 and 2007. Primary tumors involving viscera and bone, and intradural tumors, were excluded. Pretreatment biopsy specimens were studied if available, and all tumors underwent extensive immunohistochemical and molecular genetic screening before being included in the series of USTS (see Somers et al [9] for methodology used). Of the 19 USTSs, 10
Clinicopathologic features of tumor samples
In total, 19 USTSs were included in the study. Table 2 summarizes the clinicopathologic features of the tumors; for 1 patient, the age and sex was not available. Some of the clinicopathologic features have been previously described [9], [13], [17] (see also “Materials and methods”). Briefly, 15 cases comprised sheets of primitive round to plump spindle cells; 1 case comprised nests of primitive round cells; and 3 cases comprised pure spindle cells within a myxoid, collagenous, or cellular
Discussion
Pediatric sarcomas can be subdivided into specific categories based on morphological, immunohistochemical, and molecular genetic features. Recently, several groups have identified a novel subcategory of sarcoma with primitive round cell morphology and recurrent translocations involving chromosomes 4q35 and 19q13 [11], [14], [15], [16] (Table 4). One such study determined that, in 2 cases, this rearrangement resulted in the fusion of the CIC gene on chromosome 19q13.1 and the DUX4 gene on
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