Other entities represented in this entry:NEUROEPITHELIOMA, PERIPHERAL, INCLUDED; PNE, INCLUDEDASKIN TUMOR, INCLUDED▼ DescriptionThe Ewing sarcoma family of tumor...
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The Ewing sarcoma family of tumors (primitive neuroectodermal tumors; PNET) comprise morphologically heterogeneous tumors that are characterized by nonrandom chromosomal translocations involving the EWS gene on chromosome 22q12 and one of several members of the ETS family of transcription factors. The tumors include Ewing sarcoma, peripheral neuroepithelioma, and Askin tumor. In approximately 90% of cases of ESFT, the FLI1 gene (193067) on chromosome 11 is the fusion partner of EWS; in approximately 10%, the EWS fusion partner is the ERG gene (165080) on chromosome 22. Many other ETS family members have been identified as fusion partners of EWS, but these cases are rare (Khoury, 2005).
▼ Clinical Features
Ewing sarcoma is a highly malignant, metastatic, primitive small round cell tumor of bone and soft tissue that affects children and adolescents. It was first described by Ewing (1921) as a diffuse endothelioma of bone.
In a study of 5 Ewing sarcoma cell lines established from 4 patients, Turc-Carel et al. (1984) found a consistent reciprocal translocation t(11;22)(q24;q12). In 4 patients, Aurias et al. (1984) studied fresh tumor cells derived by biopsy of primary or metastatic tumors. Abnormal karyotypes with translocations involving 22q12 were found in all. In 2 cases, t(11;22)(q24;q12) was found. Histologic differentiation of ES from several other childhood tumors is often difficult; the marker chromosome may be very useful to precise diagnosis.
Among 13 cases of Ewing sarcoma, Douglass et al. (1986) found that 9 had t(11;22) and that 2 additional cases had only a deleted chromosome 22. Griffin et al. (1986) could distinguish the cytologically indistinguishable tumor-related t(11;22) by doing in situ hybridization with probes for the constant region of the lambda light chain located at 22q11 and the ETS1 oncogene (164720) located at 11q23.3-q24.
In a case of secondary ES presenting 11 years after treatment of acute lymphoblastic leukemia in childhood, Tilly et al. (1984) found the same t(11;22)(q24;q12) rearrangement described in cases of primary ES.
In somatic cell hybrids obtained by fusion of translocation (11;22)-positive Ewing sarcoma cells and Chinese hamster fibroblasts, van Kessel et al. (1985) confirmed the cytogenetic observation that the Ewing sarcoma-associated breakpoint in chromosome 22 is distal to that in translocation (8;22)-positive Burkitt lymphoma and that in translocation (9;22)-positive chronic myeloid leukemia.
In a study of 23 cases of Ewing sarcoma, Turc-Carel et al. (1987) found that all had reciprocal translocations involving 11q24 and 22q12. Turc-Carel et al. (1988) corroborated the remarkable consistency of t(11;22)(q24;q12) in all but 1 of their own 31 cases and in the majority of 54 cases reported by other investigators. The translocation mentioned was present in 83% of the total series. In 4% of cases, variant translocations involved 22q12, but with a chromosome other than number 11. Among 43 cases of Ewing sarcoma analyzed for numerical changes, trisomy 8 was observed consistently in half; an unbalanced t(1;16) was found in 18% of 82 cases analyzed for structural changes (Mugneret et al., 1988).
Budarf et al. (1989) stated that the balanced reciprocal translocation t(11;22)(q23;q11) is the most common non-Robertsonian constitutional translocation in humans.
Burchill et al. (1997) used RT-PCR for evaluation of EWS/FLI1 fusion transcripts in 18 neurally derived small round cell tumors. These included 6 tumors of the Ewing family and 12 neuroblastomas. EWS/FLI1 fusion transcripts were identified in all 6 Ewing tumors, but also in 2 of the 12 neuroblastomas.
Lin et al. (1999) stated that the translocation resulting in the formation of the EWS/FLI1 fusion gene is present in up to 95% of cases of Ewing sarcoma. Alternative forms of the chimeric gene exist because of variations in the locations of the EWS and FLI1 genomic breakpoints. The most common form, designated type 1, consists of the first 7 exons of EWS joined to exons 6-9 of FLI1 and accounts for approximately 60% of cases. The type 2 EWS/FLI1 fusion includes FLI1 exon 5 also and is present in another 25%. Lin et al. (1999) observed that the type 1 fusion is associated with a significantly better prognosis than the other fusion types. They found that the type 1 EWS/FLI1 fusion encodes a less active chimeric transcription factor, thus providing a molecular explanation of clinical heterogeneity in Ewing sarcoma.
Bielack et al. (2004) described a 14-year-old girl without a family history of cancer who initially presented with a Ewing sarcoma of the atlas in which they identified a chimeric EWS/ERG (165080) fusion transcript characteristic of the t(21;22)(q22;q21) translocation. Four and a half years later, the girl was found to have a second Ewing sarcoma, of the right proximal humerus, in which an EWS/FLI1 type 5 translocation was identified. Bielack et al. (2004) stated that this was the first report of such molecular heterogeneity in specimens of Ewing sarcoma from a single patient.
Jeon et al. (1995) identified Ewing sarcoma resulting from a t(7;22)(p22;q12) translocation that fused EWS to the ETV1 gene (600541). Jeon et al. (1995) found that the N-terminal domain of the EWS gene was fused to a portion of the ETV1 gene encoding the ETS domain, which has sequence-specific DNA-binding activity. They noted that conservation of the ETS domain also occurs in the more common fusion genes involving EWS with FLI1 and ERG.
Peripheral neuroepithelioma (PNE; peripheral neuroblastoma) is an uncommon malignant tumor of the peripheral nervous system with a histologic appearance similar to that of classic childhood neuroblastoma. In contrast to neuroblastoma, however, it typically presents in older children and young adults, can be associated with peripheral nerves, and spares the adrenal glands and sympathetic ganglia. In both tumor specimens and tumor cell lines from 2 patients with PNE, Whang-Peng et al. (1984) found a reciprocal 11;22 translocation indistinguishable from that reported in Ewing sarcoma (Turc-Carel et al., 1983). The findings support the hypothesis that these 2 neoplasms have a common histogenesis and that the malignant transformation leading to these 2 tumors has a common basis.
By both in situ hybridization and somatic cell hybrids, Zhang et al. (1990) showed that the recurrent translocation breakpoint on chromosome 22 of neuroepithelioma lies between 2 probes, D22S1 and D22S15. The 2 probes were genetically linked with a lod score of 5.3 at theta = 0.0. Furthermore, they were unaffected by a partial deletion of 22q occurring with meningioma (607174), showing that the meningioma locus is distal to that of neuroepithelioma.
Askin tumor, a malignancy of the thoracopulmonary region, also has been found to have t(11;22) (Whang-Peng et al., 1986) and is a neuroepithelioma of the chest wall (Triche and Askin, 1983).
▼ Biochemical Features
Kovar et al. (1990) noted that Ewing sarcoma and other PNE tumors express high amounts of a glycoprotein on their cell surface, which could be specifically detected by the monoclonal antibody HBA-71. They identified this glycoprotein as the product of the pseudoautosomal gene MIC2 (CD99; 313470). Kovar et al. (1990) presented evidence that CD99 is expressed at low levels in most, if not all, human cells and normal tissues. Because expression of CD99 is significantly enhanced in ES and PNET cells, they suggested that detection of the antigen by immunocytochemical analysis might be a useful tool in tumor diagnosis. Khoury (2005) stated that strong diffuse CD99 immunostaining constitutes a useful positive marker for ESFT.
Using a competitive PCR technique, Tanaka et al. (1997) showed that there might be a correlation between the expression levels of the EWS/FLI1 fusion gene and the proliferative activity of Ewing sarcoma and primitive neuroectodermal tumor cells. Furthermore, when the EWS/FLI1 expression was inhibited by antisense oligodeoxynucleotides against the fusion RNA, the growth of tumor cells was significantly reduced both in vitro and in vivo. Their data further indicated that the growth inhibition of the cells by the antisense sequence might be mediated by G0/G1 block in the cell cycle progression.
Gorthi et al. (2018) showed that Ewing sarcoma cells show alterations in regulation of damage-induced transcription, accumulation of R-loops, and increased replication stress. In addition, homologous recombination is impaired in Ewing sarcoma owing to an enriched interaction between BRCA1 (113705) and the elongating transcription machinery. Finally, Gorthi et al. (2018) uncovered a role for EWSR1 (133450) in the transcriptional response to damage, suppressing R-loops and promoting homologous recombination. Gorthi et al. (2018) concluded that their findings improved the understanding of EWSR1 function, elucidated the mechanistic basis of the sensitivity of Ewing sarcoma to chemotherapy (including PARP1 (173870) inhibitors), and highlighted a class of BRCA-deficient-like tumors.
▼ Genotype/Phenotype Correlations
Ginsberg et al. (1999) investigated whether the 2 alternative gene fusion products, EWS/FLI1 and EWS/ERG (165080), defined different clinical subsets within the Ewing sarcoma family of tumors. They studied 30 cases of Ewing sarcoma with EWS/ERG gene fusion and 106 cases with EWS/FLI1 fusion. No significant clinical differences were observed between the 2 groups in age of diagnosis, sex, metastasis at diagnosis, primary site, event-free survival, or overall survival.
Honoki et al. (2007) performed a metaanalysis of 6 studies representing 188 patients with Ewing sarcoma. Presence of a p16(INK4a) (600160) mutation was associated with a poor prognosis, as assessed by likelihood of 2-year survival. The estimated pooled relative risk for p16(INK4a) alteration for 2-year survival was statistically significant (2.17; 95% confidence interval 1.55-3.03). There was no statistically significant difference in the pooled estimated risk ratios of p16(INK4a) alteration for disease outcome between patients with or without metastasis at diagnosis.
Esthesioneuroblastoma (ENB; olfactory neuroblastoma) is an exceedingly rare malignancy that originates in the neuroectodermal stem cells of the olfactory epithelium. In a malignant lesion from 1 such patient, Whang-Peng et al. (1987) found a reciprocal translocation, t(11;22)(q24;q12), indistinguishable from the one that had been reported in Ewing sarcoma and Askin tumor. Later cytogenetic and molecular data concerning the presence of a typical t(11;22) translocation or of trisomy 8 in ENB were controversial. Mezzelani et al. (1999) presented evidence suggesting that ENB is not a member of the ES/PNE tumor group. They analyzed 5 ENB tumor specimens for trisomy 8 by FISH, for the presence of EWS gene rearrangements by FISH, RT-PCR, and Southern blot analysis, as well as for the expression of ES-associated MIC2 antigen by immunohistochemistry. Neither EWS gene rearrangements nor MIC expression was found in any tumor, whereas trisomy 8 was found in 1 case only. They stated that the translocation described by Whang-Peng et al. (1987) probably represented a metastatic lesion derived from a primary ES/PNE in the chest wall to the nasal cavity.