Mesenchymal Tumors with EWSR1 Gene Rearrangements

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Overview

Approximately one-third of soft tissue sarcomas harbor characteristic, recurrent, chromosomal translocations. These translocations are usually balanced and reciprocal and mostly associated with simple karyotypes. Chromosomal translocations involve the exchange of genetic material between 2, usually nonhomologous, chromosomes and lead to tumorigenesis via a variety of mechanisms, generating neoplasms with distinct clinical and pathologic features.1 Pathogenic translocations are usually initial

The EWSR1 gene

The EWSR1 gene is a member of the TET (translocated in liposarcoma [TLS]/fused in sarcoma [FUS], EWSR1, TATA-binding protein-associated factor 15 [TAF15]) family,34 a group of genes involved in several translocation-associated sarcomas.35, 36, 37, 38, 39 EWSR1, sited between base-pairs 29,663,998 and 29,696,515 on chromosome 22q12, was first noted to be rearranged in ES40 and encodes a multifunctional protein involved in a variety of cellular mechanisms, including gene expression, meiotic and

Ewing Sarcoma

ES is an aggressive bone and soft tissue tumor predominantly occurring in children and young adults. ES comprises a group of round cell neoplasms with common morphologic, immunohistochemical, and molecular features, including balanced reciprocal translocations between EWSR1 and, most frequently, genes encoding various members of the ETS family of transcription factors (most commonly FLI1 and ERG). ES is now considered a single disease entity,54 encompassing neoplasms previously described as

Desmoplastic Small Round Cell Tumor

DSRCT is an aggressive small round cell neoplasm predominantly arising within the abdominal cavity (including the pelvis, retroperitoneum, omentum, and mesentery,54, 104 often with widespread serosal involvement) in adolescents and young adults with a male predisposition. DSRCT can more rarely arise in older (including elderly) patients105 and occur as a primary tumor in rarer sites, including intrascrotally/paratesticularly, intrathoracically,106 and within the head and neck (including the

Myxoid Liposarcoma

MLPS most frequently occurs within the deep soft tissues of proximal extremities and trunk in young to middle-aged adults, with rare cases arising in children. MLPS is exceptional within the retroperitoneum or abdominal cavity, and metastatic disease should first be excluded at these sites. Metastases occur in up to one-third of patients, typically to other soft tissue sites, the lungs, or bones,122 and metastatic risk is related to the proportion of round cell change present.123

Extraskeletal Myxoid Chondrosarcoma

This neoplasm arises most frequently in extremity deep soft tissues of adults, particularly the limbs and limb girdles, as well as the head and neck, the abdomen, retroperitoneum and pelvic cavity, and rarely, primarily in the bone (osseous myxochondroid sarcoma).132, 133, 134, 135 EMC is associated with high rates of both local recurrence and distant metastases, with overall 5-, 10-, and 15-year survival rates of 90%, 70%, and 60%, respectively.134 Metastases often occur many years after

Tumors with EWSR1-CREB1 or EWSR1-ATF1 fusions

The ATF1 gene encodes the cyclic AMP-dependent transcription factor ATF1. This gene is a member of the cyclic-AMP response element binding protein (CREB)-ATF transcription factor family, which binds to cyclic adenosine monophosphate (cAMP)-inducible promoters. CREB proteins are related in functional terms to ATF, with CREB1 serving as an alternative gene to ATF1 in AFH and CCS.16 EWSR1-ATF1 and/or EWSR1-CREB1 gene fusions are characteristically associated with 5 clinically and pathologically

EWSR1-CREM Fusions

Recently, a novel group of myxoid mesenchymal neoplasms has been described,33 predominantly at intracranial sites in children or young adults with equal gender distribution, although one case has been described in perirectal soft tissues. These tumors are circumscribed and lobulated, typically comprising cords or reticular distributions of bland, uniform ovoid cells dispersed in a prominent myxoid/microcystic matrix. Mitoses are infrequent, and necrosis is absent.213 Most are associated with

Myoepithelial Tumors with EWSR1 Rearrangements

Myoepithelial neoplasms are a heterogeneous group that shows morphologic, immunohistochemical, and ultrastructural features suggestive of myoepithelial differentiation. These tumors are well characterized within the salivary glands, but are also described in soft tissue, bone, and visceral locations. Mixed tumors have similar features but in addition show apocrine or eccrine ductular or tubular differentiation and are associated with recurrent PLAG1 rearrangements, similar to those occurring in

Summary

The EWSR1 gene is notable for its ability to rearrange with a wide variety of fusion partners to generate an array of distinct, mostly mesenchymal tumors that show a variety of morphologic features and clinical behaviors. It is evident that the finding of an EWSR1 gene rearrangement in isolation by FISH is nonspecific, and although the use of RT-PCR in conjunction may identify specific fusion transcripts, even this may not be a diagnostic finding. Both of these routine ancillary molecular

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    Disclosures: The authors have no conflicts of interest or funding to disclose.

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