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Epidemiology, pathology, and molecular genetics of Ewing sarcoma

Epidemiology, pathology, and molecular genetics of Ewing sarcoma
Literature review current through: Jan 2024.
This topic last updated: Dec 07, 2022.

INTRODUCTION — Ewing sarcoma (ES) is a rare malignancy that most often presents as an undifferentiated primary bone tumor; less commonly, it arises in soft tissue (extraosseous ES [EES]).

The epidemiology, pathology, and molecular genetics of ES are presented here. The clinical features, diagnosis, and treatment of ES, diagnostic and biopsy techniques for bone tumors, principles of surgical management for bone sarcomas, and central nervous system embryonal tumors are discussed separately.

(See "Clinical presentation, staging, and prognostic factors of Ewing sarcoma".)

(See "Treatment of Ewing sarcoma" and "Radiation therapy for Ewing sarcoma family of tumors".)

(See "Bone tumors: Diagnosis and biopsy techniques".)

(See "Bone sarcomas: Preoperative evaluation, histologic classification, and principles of surgical management".)

(See "Uncommon brain tumors", section on 'CNS embryonal tumor NEC/NOS'.)

TERMINOLOGY — We use the term Ewing sarcoma (ES), based on nomenclature from the World Health Organization (WHO) pathology classification system. Several terms previously used to describe ES include the Ewing sarcoma family of tumors (EFT), peripheral primitive neuroectodermal tumor (PNET), peripheral neuroepithelioma, and small cell tumors of the chest wall (previously known as Askin tumor) [1].

ES was originally described as follows:

In 1918, Stout described a tumor of the ulnar nerve with the gross features of a sarcoma but composed of small round cells focally arranged as rosettes; this entity was historically designated as neuroepithelioma, and then peripheral primitive neuroectodermal tumor [2].

ES was described by James Ewing in 1921 as an undifferentiated tumor involving the diaphysis of long bones that, in contrast to osteosarcoma, was radiation sensitive. Although most often a primary bone tumor, ES was also reported to arise in soft tissue (extraosseous ES [EES]) [3,4].

However, it has become known that these entities comprise the same spectrum of neoplastic diseases known as ES, which also includes malignant small cell tumors of the chest wall (historically called Askin tumor) [5] and "atypical" ES [1,6]. These tumors likely derive from a common cell of origin because of their similar histologic and immunohistochemical characteristics and their shared nonrandom chromosomal translocations [7-14]. The histogenesis of the cell of origin is discussed below. (See 'Histogenesis' below.)

EPIDEMIOLOGY — Primary bone tumors are responsible for 6 percent of all childhood cancers [15]. Although rare, ES represents the second most common primary bone malignancy (table 1) affecting children and adolescents, after osteosarcoma [16,17]. Despite this, ES is responsible for only 3.5 percent of cancers in American children 10 to 14 years old and for 2.3 percent of those arising among 15 to 19 year olds. A similar incidence (2.8 percent of all tumors in children aged 15 to 19 years old) is described in adolescents in England [18].

In the United States, 650 to 700 children and adolescents younger than 20 years old are diagnosed with bone tumors every year, of which only 200 are ES and the remainder osteosarcomas [19]. The peak incidence is between 10 to 15 years of age. However, 30 percent of cases arise in children under the age of 10, and another 30 percent are in adults over the age of 20 [20,21]. As with many pediatric tumors, there is a slight male predominance.

Racial and ethnic factors are of epidemiologic importance. For unclear reasons, ES affects mainly White populations and are extremely uncommon in Black populations (both in the United States and Africa) and in populations from Asia (eg, Japan, Korea, China, Hong Kong, and Thailand). (figure 1) [21-24]. The reason for this striking ethnic distribution is not known. However, interethnic differences exist for certain alleles of the ES gene (the EWSR1 gene, MIM#133450), which is consistently disrupted in these tumors [25] (see 'EWSR1 translocations' below). Furthermore, genome-wide association studies have raised the possibility that genetic susceptibility factors may contribute to the observed geographical/ethnic differences in ES incidence [26].

RISK FACTORS — ES has not been consistently associated with specific familial or congenital syndromes [27,28]. However, at least one series reports an excess of congenital mesenchymal defects in affected patients [29], and another suggests an increase in neuroectodermal tumors and stomach cancer in the families of patients with ES [30].

Furthermore, a minority of cases may be associated with an inherited cancer predisposition. In a study that used next-generation sequencing to determine the contribution of germline predisposition mutations in 1120 children with cancer, mutations that were deemed to be pathogenic or probably pathogenic were identified in 5 out of 46 (11 percent) patients with ES [31]. Three of the germline mutations were in TP53, the gene associated with Li-Fraumeni syndrome, two were in the RET gene, which is associated with multiple endocrine neoplasia type 2 (MEN2), and one was in the PMS2 gene, which is involved in DNA mismatch repair. Importantly, family history did not predict the presence of an underlying predisposition syndrome in most patients. Despite these data, a causative/pathogenic role for these inherited germline mutations in the development of ES has not been demonstrated. (See "Li-Fraumeni syndrome" and "Classification and genetics of multiple endocrine neoplasia type 2" and "Clinical manifestations and diagnosis of multiple endocrine neoplasia type 2".)

Specific environmental exposures have not been identified as risk factors [28,32]. ES develops rarely after treatment of a primary cancer during childhood, but most cases do not appear to be related to radiation therapy [33,34]. An association has been suggested between a parental occupation of farming (particularly if the mother farmed) and the development of ES [35].

ES may be more common in children who have hernias [35-39]. A meta-analysis of three case-control studies (totaling 357 patients with ES and 745 controls [37-39]) showed that affected children were more likely to have had a hernia in childhood (odds ratio 3.2, 95% CI 1.9-5.7) [35]. The association was strongest for umbilical hernias. The mechanism underlying a possible association between hernias and ES is unclear.

HISTOGENESIS — The histogenic origin of ES has been debated. Both neuroectodermal cells and mesenchymal progenitor cells have been suggested as possible cells or origin. Additional data will be required to draw a final conclusion as to the cell of origin in ES. (See 'EWSR1 translocations' below.)

Neuroectodermal cells – A neuroectodermal origin had been proposed based upon variable expression of neuronal immunohistochemical markers, cytogenetic, and ultrastructural features, as well as the ability of ES cell lines to differentiate along neural pathways in vitro [11-13,40,41].

Mesenchymal progenitor cells – An alternative theory supported by other data suggests that ES arises from mesenchymal progenitor or mesenchymal stem cells (MSC) [14,42]. MSCs isolated from bone marrow can differentiate into osteogenic, chondrogenic, or adipogenic lineages. Expression of the ES-specific oncoprotein EWS-FLI blocks MSC differentiation [43], while removal of EWS-FLI from patient-derived ES cell lines allows the cells to gain the ability to differentiate into multiple lineages and adapt a gene expression profile that resembles that of MSCs [14].

HISTOLOGIC FEATURES — The morphologic appearance of classic ES is that of a primitive, undifferentiated neoplasm. On hematoxylin and eosin-stained sections, there are sheets of uniform, small, round, blue cells with a high nuclear cytoplasmic ratio, hyperchromatic nuclei with finely dispersed chromatin, and scant cytoplasm with variable cytoplasmic clearing due to the presence of abundant glycogen (picture 1) [44]. There is usually extensive necrosis, with preservation of viable tumor around blood vessels. Some tumors historically referred to as peripheral primitive neuroectodermal tumor (PNET) exhibit rosette-like structures and a more prominent neuroectodermal differentiation. Mitotic figures are typically infrequent, and aneuploidy is uncommon on flow cytometry studies [45].

"Atypical" ES represents a histologic variant of ES; they are described as having larger cells, greater nuclear pleomorphism, prominent nucleoli, and a higher mitotic rate.

DIFFERENTIAL DIAGNOSIS — Morphologically, the appearance of ES overlaps that of other small round blue cell tumors (SRBCTs) involving bone and soft tissue, including lymphoma, small cell osteosarcoma, mesenchymal chondrosarcoma, undifferentiated neuroblastoma, poorly differentiated synovial sarcoma, desmoplastic small round cell tumors, rhabdomyosarcoma, and sarcomas with CIC-DUX4 or BCOR genetic alterations. As a group, these tumors can pose difficult diagnostic problems when examined by light microscopy alone. There is little in the routine histologic appearance of ES to relate it to a component of normal bone or other tissue from which it might have arisen. Even the determination of bone versus soft tissue origin can be challenging because ES involving bone often have an extensive soft tissue component, while extraosseous tumors may invade bone secondarily.

Although ES can exhibit a variable degree of neural differentiation, this is usually subtle and often only detected by immunohistochemical staining for markers of neural differentiation or by ultrastructural examination. Although no routinely used histochemical or immunohistochemical stain can positively distinguish ES from other undifferentiated small round cell tumors of childhood, the vast majority of ES express high levels of a cell surface glycoprotein (designated CD99, MIC2 surface antigen or p30/32MIC2) that is encoded by the CD99 (MIC2X) gene [7,46]. The finding of membrane-localized MIC2 expression is a sensitive diagnostic marker for the ES; however, it lacks specificity since other tumors (eg, rhabdomyosarcoma, which is often in the differential diagnosis) and some normal tissues can also be immunoreactive with anti-MIC2 antibodies [47]. Another potential immunohistochemical marker for ES is NKX2.2, the protein product of the NKX2-2 gene [48].

EWSR1-fusion-negative SRBCTs have been further characterized by several novel translocations. These include SRBCTs with CIC-DUX4 gene fusions and those with BCOR fusions. These tumors, some of which in the past were called "atypical" ES, are better identified as Ewing-like sarcoma, an entity different from ES. SRBCTs with CIC-DUX4 gene fusions result from either a t(4;19) or t(10;19) translocation and is the most common genetic abnormality detected in EWSR1 fusion-negative SRBCTs. These are associated with an aggressive clinical course [49]. SRBCTs with BCOR fusions tend to occur in males, with a predilection for older children and adolescents as the most commonly affected population [50]. They appear to be more chemosensitive and have a more favorable clinical outcome than the CIC-rearranged sarcomas [51]. Patients with these novel translocations should also be referred for evaluation at sarcoma centers of excellence.

Cytogenetic or molecular genetic studies looking for particular chromosomal translocations and/or their fusion transcripts are usually required to secure the diagnosis. (See 'Molecular diagnostics' below.)

MOLECULAR GENETICS — Remarkable progress has been made in defining and classifying bone and soft tissue tumors on the basis of characteristic chromosomal abnormalities (table 2). Because of their unique shared chromosomal translocations, ES has become a model system for nonmorphologic approaches to diagnosis and subclassification using both cytogenetic and molecular techniques. These translocations interrupt specific genes and recombine them to create novel fusion genes, whose products are tumor specific and present in virtually all cases of an individual tumor category. Thus, their characterization not only yields profound insights into tumor biology, but also holds great promise for diagnostic and therapeutic approaches. (See "Pathogenetic factors in soft tissue and bone sarcomas", section on 'Chromosomal translocations'.)

EWSR1 translocations — The unique shared pattern of nonrandom chromosomal translocations in ES provides one of the most compelling arguments for a common cellular origin. Virtually all cases express one of several different reciprocal translocations, most of which involve breakpoints that are clustered within a single gene locus, designated the EWSR1 gene on chromosome 22q12 (table 2) [8,9,44,52-55].

The EWSR1 gene normally encodes a widely expressed protein, the EWS protein, whose amino terminal domain shares some homology with eukaryotic RNA polymerase II and whose carboxy terminus (which is replaced by tumor-specific translocations) contains an RNA recognition motif. The EWS protein is a member of a family of highly conserved RNA binding proteins that are believed to mediate interaction with RNA or single-stranded DNA [56,57].

In 85 to 90 percent of cases of ES, a recurrent chromosomal translocation, t(11;22)(q24;q12), fuses the 5' portion of the EWSR1 gene on chromosome 22 to the 3' portion of the FLI1 gene on chromosome 11 [52,53]. This can be detected using fluorescence in situ hybridization (FISH) (image 1).

FLI1 encodes the FLI protein, a member of the ETS family of transcription factors, and is involved in the control of cellular proliferation, development, and tumorigenesis [58]. Members of the ETS family are defined by the presence of a highly conserved 85-amino acid domain, termed the erythroblastosis virus-transforming sequence (ETS) domain, which mediates specific binding to purine-rich DNA sequences [59]. As a result of the t(11;22), the EWS-FLI fusion protein is expressed. EWS-FLI binds DNA via its FLI-derived ETS domain and regulates gene expression through the EWS portion of the fusion.

In ES that lack the EWSR1-FLI1 translocation, analogous translocations fuse the EWSR1 gene to other genes of the ETS family (ie, ERG, ETV1, ETV4, or FEV) that have structural homology to FLI1, forming t(21;22)(q22;q12), t(7;22)(p22;q12), t(17;22)(q12;q12), or t(2;22)(q35;q12) translocations, respectively [60-63]. The EWSR1-ERG translocation [t(21;22) (q22;q12)] is present in 5 to 10 percent of ES, while the others are less common [63-66].

In addition to EWSR1-based translocations, rare cases of ES are associated with translocations involving a related gene, FUS (also called TLS) [67,68]. Tumors exhibiting t(16;21)(p11;q24) or t(2;16)(q35;p11) translocations express FUS-ERG or FUS-FEV fusions, respectively. Because EWS and FUS proteins are highly similar, it is believed that FUS-based fusion proteins function similarly to EWS-based fusions. It is important to note that tumors with these translocations can be a source of diagnostic confusion. (See 'Molecular diagnostics' below.)

Ultimately, specific translocations are important diagnostic features of ES, and the protein products of the fusion genes are believed to play an important role in tumor development and biology. A growing body of evidence suggests that these proteins function as transcriptional regulators, although their transcriptional targets are just beginning to be identified. (See 'Molecular pathogenesis' below.)

EWSR1 translocations in other soft tissue tumors — Although translocations involving the EWSR1 and ETS families of genes are specific for ES, translocations that involve fusion of the EWSR1 gene to other genes have been observed in many other tumors (eg, clear cell sarcoma/malignant melanoma of soft parts, desmoplastic small round cell tumor [69-71]). The structure of these resultant fusion genes is analogous to that of EWSR1-FLI1 (ie, all result in the fusion of the 5' portions of the EWSR1 gene or an EWSR1-like gene [eg, the FUS gene] to 3' portions of genes encoding transcription factors). The resulting chimeric proteins presumably have a similar function to the EWS-FLI fusion protein, and it is thought that disruption of transcriptional control contributes to their transforming potential [44]. (See 'Molecular pathogenesis' below.)

With few exceptions, a clinicopathologically distinct tumor entity has been consistently associated with each specific translocation involving a unique class of transcription factors. This tumor specificity is most likely related to cell-specific influences on DNA recombination, target genes of the fusion transcription factor involved, chimeric gene expression, and intrinsic proteins that are necessary to complement the action of the chimeric protein.

Other genetic changes — In addition to the characteristic reciprocal translocations described above, other numerical and structural chromosomal aberrations are occasionally found in ES. These include a gain of chromosomes 1q, 2, 8, and 12, losses of 9p and 16q, and the nonreciprocal translocation t(1;16)(q12;q11.2) [72-74]. In addition, alterations in known tumor suppressor genes have been identified in some cases. As an example, homozygous deletion of the CDKN2A gene has been described in 12 to 30 percent of cases, and TP53 mutations are detected in 5 to 20 percent [44,75-77]. Finally, loss-of-function mutations in STAG2 have also been identified in more than 15 percent of cases [78-81].

The biologic implications of these findings are incompletely understood and are somewhat controversial, with some studies suggesting an adverse prognostic impact of some of these alterations [77-80], while others have failed to confirm such a correlation [82]. More recently, loss-of-function alterations in STAG2 have been identified and have also been suggested to be predictive of poor outcome in patients with ES, particularly when concurrent with TP53 mutations [78]. At this time, however, these data are preliminary, and they require validation before any molecular test can be used to change clinical decision-making.

Molecular pathogenesis — ES-associated translocations result in the production of chimeric proteins that contain the amino-terminal domain of the normal EWS protein fused to the nucleic acid-binding domain of the transcription factor translocation partner. Because of their ubiquitous presence in ES, they are thought to be intimately connected to the biology of these tumors.

The available data suggest two possible mechanisms by which these unique chimeric proteins may contribute to neoplastic transformation and/or cell growth:

Chimeric proteins such as EWS-FLI may influence transcription of some of the same genes that are normally regulated by native FLI, but because the chimeric molecule is expressed in either a different temporal or quantitative manner, the downstream targets are deregulated, leading to uncontrolled cellular growth.

EWS-FLI may affect target genes that are different from those regulated by the native FLI or EWS proteins. This would explain why the chimeric gene product (EWS-FLI) has transforming properties that are not shared by either the EWS or FLI wild-type counterparts [83].

Some chimeric fusion proteins can act as transcriptional activators, deregulating many genes associated with cell signaling, proliferation, apoptosis, tissue invasion, and metastasis [44,83-90]. It is likely that this ability to regulate transcriptional activity is associated with their oncogenic potential. EWS-FLI and other chimeric fusion proteins are all capable of transforming cell lines equally well. As an example, expression of either the EWS-FLI or EWS-ERG cDNAs can transform mouse NIH3T3 fibroblasts so that they acquire tumor-like properties (eg, growth in soft agar or in immunodeficient mice) [83,91]. Notably, EWS-FLI can only transform cells in which insulin-like growth factor signaling is intact, and thus, there is a potential role for insulin-like growth factor 1 receptor (IGF1R) inhibitors in the treatment of ES [92-94].

The protein products of the fused genes are also important for maintaining the growth characteristics of ES cell lines, and emerging data suggest the potential for molecularly targeted therapy [95]:

Introduction of EWS-FLI RNA antisense molecules or short-interfering or short-hairpin RNAs (such as RNAi that mediate RNA-interference) into ES cells decreases the expression of the EWS-FLI fusion protein and results in growth inhibition and/or loss of oncogenic potential, both in vitro and in vivo [96-100].

Likewise, inhibition of the interaction between EWS-FLI and its cellular binding partner RNA helicase A (RHA) by a small peptide or small molecule inhibitor reduces the growth of ES orthotopic xenografts [101].

Truncated ETS domain-binding molecules can act as competitive inhibitors and have a dominant negative effect on cell growth [102]. p21(WAF1/CIP1), which is important in cell cycle regulation, might be one of the direct targets of EWS-FLI, suggesting that this molecule could serve as a target for a molecularly based therapy for ES [95].

Because EWS-FLI and related fusions are thought to function primarily as transcriptional regulators, a number of studies have sought to define the genes that are regulated by the fusion proteins [98-100,103,104]. Some of the EWS-FLI-regulated genes are involved in the oncogenic phenotype of ES model systems (eg, IGFBP3, CAV1, NKX2.2, NR0B1, GSTM4, and others) [85,98-100,105,106]. While many of the details are still being worked out, some of these gene targets and associated pathways may prove to be future targets for molecularly targeted therapy.

Another mechanism whereby EWS-FLI may exert a tumorigenic effect is via deregulation of programmed cell death (apoptosis). Cancer is believed, in part, to represent an imbalance between cell growth and cell death. Expression of EWS-FLI1 or EWS-ERG in NIH3T3 cells inhibits the apoptosis that would normally occur with serum deprivation or calcium ionophore treatment [107], while antisense inhibition of EWS-FLI increases susceptibility to chemotherapy-induced apoptosis in ES cell lines. Similarly, reduced expression of EWS-FLI using RNAi-based approaches also resulted in increased apoptosis [99].

EWS-ETS fusion proteins also activate human telomerase activity in Ewing tumors through upregulation of the telomerase reverse transcriptase gene expression, probably by acting as a transcriptional coactivator [108]. Telomerase is a ribonucleoprotein enzyme that compensates for telomere shortening during cell division by synthesizing telomeric DNA, thereby maintaining telomere length. In normal somatic cells, telomerase activity is usually undetectable, with the exception of some cell types, such as hematopoietic cells, hair follicles, intestinal crypt cells, and basal cells of the epidermis. Upregulated telomerase activity in cancer cells correlates with the stabilization of telomere length and cellular immortalization (ie, the ability of the cells to divide indefinitely). This raises the possibility of therapeutic approaches using telomerase inhibitors.

Molecular diagnostics — The translocations that characterize ES are exquisitely sensitive and specific tumor markers that have rapidly become the standard for confirming the diagnosis, particularly for cases in which morphology is inconclusive [8,109]. Standard cytogenetic analysis can reveal a wide variety of chromosomal alterations, but technical constraints and variant translocations may complicate the interpretation, and results are often obtained too late to influence therapy. Molecular assays are more attractive because of the small amount of tissue required, rapid results, and higher sensitivity than traditional cytogenetics.

Both the fusion genes and their hybrid transcripts can be identified in tumor cells using molecular genetic approaches. Two techniques are in use, FISH and reverse transcriptase polymerase chain reaction (RT-PCR), and both are more rapid than cytogenetic analysis [110-113]. In particular, RT-PCR to detect the presence of fusion transcripts in tumor cells has become a mainstay in molecular diagnosis of ES. It is extremely sensitive and specific, and allows detection of very low levels of tumor cells, even among large numbers of normal cells (eg, peripheral blood and bone marrow), providing an extremely robust method for molecular staging and monitoring treatment response.

In addition to providing diagnostic support for challenging cases, the identification of specific types of transcripts was at one time thought to have prognostic significance [72,114,115]. As an example, in one report, the presence of type 1 EWS-FLI transcripts (EWSR1 exon 7 fused with FLI1 exon 6) was associated with a threefold reduction in the risk of developing metastatic disease as compared with non-type 1 transcripts [114]. However, more recent independent studies from both the United States and Europe do not support the prognostic value of translocation type [116,117]. It appears that current intensive treatment protocols may have eliminated this apparent difference in prognosis. (See "Clinical presentation, staging, and prognostic factors of Ewing sarcoma", section on 'Prognostic factors'.)

While molecular tests for ES-associated translocations are important and often useful adjuncts in the diagnostic workup, in most cases, molecular pathology laboratories do not test for all of the "alternate" translocations (such as those that encode EWSR1-ETV1, EWSR1-ETV4, EWSR1-FEV, FUS-ERG, and FUS-FEV). Thus, a "negative" FISH or RT-PCR result does not necessarily rule out the diagnosis of ES. Physicians are strongly advised to consult with their molecular diagnostic laboratory to understand exactly what tests are performed and the sensitivity and specificity of those tests for ES. Ultimately, the diagnosis of ES is based upon a combination of histopathology, immunohistochemical stains, and molecular diagnostics that are interpreted in the context of the patient's clinical presentation.

Molecular staging — Disease stage as determined by standard imaging modalities constitutes the most powerful predictor of prognosis for patients with ES. However, some patients considered to have localized disease have an unfavorable outcome, even with multimodality therapy, and this may be related to the persistence of minimal metastatic disease that is not detected by traditional methods. (See "Clinical presentation, staging, and prognostic factors of Ewing sarcoma", section on 'Prognostic factors'.)

Minimal disease (ie, circulating ES cells) can be detected in peripheral blood and bone marrow using PCR-based methods in up to 30 percent of patients with apparently localized disease and in approximately 50 percent of those with advanced or relapsed disease [118-122]. However, the prognostic significance of this finding, particularly in patients with localized disease, is controversial [119,121,122], and the ultimate contribution of this finding to patient management is unclear [121,122]. Further prospective studies using molecular methods to detect the presence of minimal residual disease are needed in order to assess its impact on outcome.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Soft tissue sarcoma".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topic (see "Patient education: Bone cancer (The Basics)")

SUMMARY

Epidemiology – Although rare, Ewing sarcoma (ES) represents the second most common primary bone malignancy (table 1) affecting children and adolescents. (See 'Epidemiology' above.)

Risk factors – ES has not been consistently associated with any familial or congenital syndromes, and specific environmental exposures have not been identified as risk factors. (See 'Risk factors' above.)

Histologic features and differential diagnosis – The morphologic appearance of classic ES is that of a primitive, undifferentiated neoplasm (picture 1), which overlaps with that of other small, round, blue cell tumors (SBCTs) involving bone and soft tissue. Such tumors include lymphoma, small cell osteosarcoma, mesenchymal chondrosarcoma, undifferentiated neuroblastoma, poorly differentiated synovial sarcoma, desmoplastic small round cell tumors, and rhabdomyosarcoma, and sarcomas with CIC-DUX4 or BCOR genetic alterations. (See 'Histologic features' above and 'Differential diagnosis' above.)

Molecular diagnostics – ES often poses difficult diagnostic problems when examined by light microscopy alone. Cytogenetic or molecular genetic studies looking for particular chromosomal translocations and/or their fusion transcripts are usually required to secure the diagnosis (table 2). (See 'Molecular diagnostics' above.)

Characteristic molecular translocations – Virtually all cases of ES express one of several different reciprocal translocations. Most involve breakpoints that are clustered within a single gene locus, designated the EWSR1 gene on chromosome 22q12. (See 'EWSR1 translocations' above.)

Molecular pathogenesis – ES-associated translocations result in the production of chimeric proteins that contain the amino-terminal domain of the normal EWS protein fused to the nucleic acid-binding domain of the transcription factor translocation partner. Because of their ubiquitous presence in ES, these chimeric proteins are thought to be intimately connected to the biology of these tumors. (See 'Molecular pathogenesis' above.)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Henry J Mankin, MD; Stephen L Lessnick, MD, PhD; and Thomas F DeLaney, MD, who contributed to earlier versions of this topic review.

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Topic 7742 Version 36.0

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