Undifferentiated small round cell sarcomas of bone and soft tissue
2022-12-06 David Papke, MD Affiliation1.Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
Classification
Definition
Round cell sarcomas are among the most aggressive soft tissue tumors, and they often affect children or young adults. The identification of novel molecular alterations has greatly contributed to the classification of these tumors, enabling precise definition of Ewing sarcoma and, more recently, the identification of diagnostic classes within the former waste-basket category of so-called “Ewing-like sarcomas”. The 2020 WHO Bone and Soft Tissue Tumours categorized three distinctive entities from the former "Ewing-like-sarcoma" category: CIC-rearranged sarcoma, sarcoma with BCOR genetic alterations, and round cell sarcoma with EWSR1–non-ETS fusions. Although they show some morphologic overlap, these tumor types nevertheless exhibit characteristic morphologic and immunophenotypic features that predict their underlying molecular alterations.1-4
| Tumor type | Genetic information |
|---|---|
| Ewing sarcoma | t(11;22)(q24;q12) is associated with EWSR1::FLI1,5 the gene fusion in ~85% of Ewing sarcomas.6,7 |
| t(21;22)(q22;q21) is associated with EWSR1::ERG, the second most frequent fusion in Ewing sarcoma. This fusion is not always detectable by FISH using break-apart EWSR1 probe,8 because it typically does not result from a simple balanced translcoation. Instead, it is associated with chromoplexy and concurrent TP53 alterations.9 | |
| Alternative rare translocation variants (bigger of 10%) include: t(2;12)(q35;q12)/EWR1::FEV,t(7;22)(p21;q12)/EWSR1::ETV1 and t(17;22)(q21;q12)/EWSR1::ETV4}.10 Occasionally FUS rearrangements instead of EWSR1 have been described.11 EWSR1::FEV and FUS::FEV fusions show a predilection for extra-skeletal sites and aggressive behavior.12 | |
| Recurrent additional chromosomal aberrations include gain of chromosomes 8, 2, 1q and 2, and deletion of 9p involving CDKN2A.13 | |
| Mutations in STAG2 and TP53 have been also observed.13,14 | |
| Round cell sarcoma with EWSR1–non-ETS fusions | EWSR1::NFATC2 gene fusion results from t(20;22) (q13.2;q12.2), and amplification of the fusion gene appears to be a consistent concommittant finding.11,15-17 In clinical practice, the diagnosis of EWSR1::NFATC2-translocated sarcoma is strongly supported by amplification of 5’EWSR1 break apart probe, a specific finding among EWSR1-rearranged neoplasms. Occasionally FUS rearrangements instead of EWSR1 have been described. 11,18 So far, the FUS::NFATC2 fusion is not associated with FUS amplification, suggesting that there is a different structure of the fusion product.18 |
| While EWSR1::NFATC2 and FUS::NFATC2 fusion tumors can show linear proliferations of neoplastic cells in sclerotic stroma, the range of morphologic findings remains broad, and more work is needed to better define these features.18 | |
| EWSR1::PATZ1 gene fusion results from intra-chromosomal rearrangement of 22q area.19 Because PATZ1 mapped close to EWSR1 on 22q12, interpretation of EWSR1 break-apart FISH has imperfect sensitivity for detecting this fusion.20 EWSR1::PATZ1 sarcomas can additionally harbor CDKN2A/CDKN2B loss in about 70% of cases, and occasionally MDM2 amplification.20 | |
| CIC-rearranged sarcoma | The CIC::DUX4 gene fusion most often results from either cryptic t(4;19(q35;q13) or, less frequently, from t(10;19)(q26;q13), the latter involving the DUX4 paralogDUX4.21 Other gene fusion partners include FOXO4, NUTM1 and NUTM2A.22-25 CIC break apart FISH has imperfect sensitivity at detected CIC rearrangements.26 |
| CIC-rearranged sarcomas occurring outside of soft tissue and been described,27 and these can have higher frequencies alternate CIC fusion partners; for example, CNS CIC-rearranged sarcomas often have NUTM1 fusion partners, in addition to DUX4, LEUTX, and more recently ATXN1. 28 When the diagnosis of CIC-rearranged sarcoma is suspected, immunohostochemistry for WT1 and ETV4 can help support the diagnosis.29 | |
| CIC-rearranged sarcomas also can exhibit trisomy 8 and MYC amplification.30,31 | |
| Sarcoma with BCOR genetic alteration | BCOR::CCNB3 gene fusion results from a cryptic paracentric inversion on the Xp chromosome, inv(X)(p11.4p11.22).32,33 |
| Alternative BCOR fusions include BCOR::MAML3, ZC3H7B::BCOR, KMT2D::BCOR, CIITA::BCOR, BCOR::CHD9 and RTL9::BCOR.34-37 | |
| BCOR internal tandem duplications (ITD), which occur in exon 15, result in upregulation of BCOR, which has oncogenic properties.38 | |
| BCOR-ITD is a common genetic alteration in a wide range of cancers,39 including pediatric sarcomas.40 | |
| There are several BCOR aberrations in oncology such as the internal tandem duplications, different gene fusions, and loss of function mutations, in a large variety of mesenchymal, epithelial, neural and hematological tumors, suggesting a central role in cancer evolution.41 |
Article Bibliography
| Reference Number | Pubmed ID | Last Year | Title | Authors |
|---|---|---|---|---|
| 1 | 29661713 | 2018 | Review with novel markers facilitates precise categorization of 41 cases of diagnostically challenging, "undifferentiated small round cell tumors". A clinicopathologic, immunophenotypic and molecular analysis. | Machado I et al |
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| 3 | 31802230 | 2020 | Ewing sarcoma and Ewing-like tumors. | Sbaraglia M et al |
| 4 | 34763921 | 2022 | From the ashes of "Ewing-like" sarcoma: A contemporary update of the classification, immunohistochemistry, and molecular genetics of round cell sarcomas. | Kallen ME et al |
| 5 | 6877319 | 1983 | Chromosomal translocations in Ewing's sarcoma. | |
| 6 | 1522903 | 1992 | Gene fusion with an ETS DNA-binding domain caused by chromosome translocation in human tumours. | Delattre O et al |
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| 8 | 26690869 | 2016 | Ewing sarcoma with ERG gene rearrangements: A molecular study focusing on the prevalence of FUS-ERG and common pitfalls in detecting EWSR1-ERG fusions by FISH. | Chen S et al |
| 9 | 30166462 | 2018 | Rearrangement bursts generate canonical gene fusions in bone and soft tissue tumors. | Anderson ND et al |
| 10 | 21872822 | 2011 | Promiscuous partnerships in Ewing's sarcoma. | Sankar S et al |
| 11 | 31078563 | 2019 | EWSR1/FUS-NFATc2 rearranged round cell sarcoma: clinicopathological series of 4 cases and literature review. | Diaz-Perez JA et al |
| 12 | 31756779 | 2020 | Ewing sarcoma with FEV gene rearrangements is a rare subset with predilection for extraskeletal locations and aggressive behavior. | Tsuda Y et al |
| 13 | 29977059 | 2018 | Ewing sarcoma. | Grünewald TGP et al |
| 14 | 25186949 | 2014 | The genomic landscape of pediatric Ewing sarcoma. | Crompton BD et al |
| 15 | 17175374 | 2007 | Detection and molecular cytogenetic characterization of a novel ring chromosome in a histological variant of Ewing sarcoma. | Szuhai K et al |
| 16 | 19318479 | 2009 | The NFATc2 gene is involved in a novel cloned translocation in a Ewing sarcoma variant that couples its function in immunology to oncology. | Szuhai K et al |
| 17 | 30994538 | 2019 | EWSR1-NFATC2 Translocation-associated Sarcoma Clinicopathologic Findings in a Rare Aggressive Primary Bone or Soft Tissue Tumor. | Wang GY et al |
| 18 | 31049020 | 2019 | EWSR1-NFATC2 and FUS-NFATC2 Gene Fusion-Associated Mesenchymal Tumors: Clinicopathologic Correlation and Literature Review. | Bode-Lesniewska B et al |
| 19 | 10949935 | 2000 | A novel zinc finger gene is fused to EWS in small round cell tumor. | Mastrangelo T et al |
| 20 | 31189996 | 2019 | Clinical, pathological, and genomic features of EWSR1-PATZ1 fusion sarcoma. | Bridge JA et al |
| 21 | 28346326 | 2017 | Sarcomas With CIC-rearrangements Are a Distinct Pathologic Entity With Aggressive Outcome: A Clinicopathologic and Molecular Study of 115 Cases. | Antonescu CR et al |
| 22 | 25007147 | 2014 | A novel CIC-FOXO4 gene fusion in undifferentiated small round cell sarcoma: a genetically distinct variant of Ewing-like sarcoma. | Sugita S et al |
| 23 | 28188754 | 2017 | NUTM2A-CIC fusion small round cell sarcoma: a genetically distinct variant of CIC-rearranged sarcoma. | Sugita S et al |
| 24 | 29700887 | 2018 | CIC-NUTM1 fusion: A case which expands the spectrum of NUT-rearranged epithelioid malignancies. | Schaefer IM et al |
| 25 | 30407212 | 2019 | Clinicopathologic Features of CIC-NUTM1 Sarcomas, a New Molecular Variant of the Family of CIC-Fused Sarcomas. | Le Loarer F et al |
| 26 | 35093696 | 2022 | CIC rearranged sarcomas: A single institution experience of the potential pitfalls in interpreting CIC FISH results. | Cocchi S et al |
| 27 | 31870501 | 2020 | Undifferentiated round cell sarcomas with CIC-DUX4 gene fusion: expanding the clinical spectrum. | Brčić I et al |
| 28 | 33550509 | 2021 | A novel ATXN1-DUX4 fusion expands the spectrum of 'CIC-rearranged sarcoma' of the CNS to include non-CIC alterations. | Pratt D et al |
| 29 | 27443513 | 2016 | Evaluation of ETV4 and WT1 expression in CIC-rearranged sarcomas and histologic mimics. | Hung YP et al |
| 30 | 23887164 | 2013 | Undifferentiated small round cell sarcoma with t(4;19)(q35;q13.1) CIC-DUX4 fusion: a novel highly aggressive soft tissue tumor with distinctive histopathology. | Choi EY et al |
| 31 | 24947144 | 2015 | CIC-DUX sarcomas demonstrate frequent MYC amplification and ETS-family transcription factor expression. | Smith SC et al |
| 32 | 22387997 | 2012 | A new subtype of bone sarcoma defined by BCOR-CCNB3 gene fusion. | Pierron G et al |
| 33 | 29300189 | 2018 | BCOR-CCNB3 Fusion Positive Sarcomas: A Clinicopathologic and Molecular Analysis of 36 Cases With Comparison to Morphologic Spectrum and Clinical Behavior of Other Round Cell Sarcomas. | Kao YC et al |
| 34 | 29431183 | 2018 | Transcriptomic definition of molecular subgroups of small round cell sarcomas. | Watson S et al |
| 35 | 31647130 | 2020 | Expanding the clinicopathologic and molecular spectrum of BCOR-associated sarcomas in adults. | Yoshida A et al |
| 36 | 32034283 | 2020 | NTRK3 overexpression in undifferentiated sarcomas with YWHAE and BCOR genetic alterations. | Kao YC et al |
| 37 | 34331570 | 2022 | Novel RGAG1-BCOR gene fusion revealed in a somatic soft tissue sarcoma with a long follow-up. | Vasella M et al |
| 38 | 26098867 | 2015 | Consistent in-frame internal tandem duplications of BCOR characterize clear cell sarcoma of the kidney. | Ueno-Yokohata H et al |
| 39 | 33718245 | 2021 | Specific and Sensitive Diagnosis of BCOR-ITD in Various Cancers by Digital PCR. | Barets D et al |
| 40 | 34325058 | 2021 | Assessment of BCOR Internal Tandem Duplications in Pediatric Cancers by Targeted RNA Sequencing. | Al-Ibraheemi A et al |
| 41 | 31150281 | 2019 | BCOR involvement in cancer. | Astolfi A et al |
Citation
David Papke, MD
Undifferentiated small round cell sarcomas of bone and soft tissue
Atlas Genet Cytogenet Oncol Haematol. 2022-12-06
Online version: http://atlasgeneticsoncology.org/solid-tumor/208992/undifferentiated-small-round-cell-sarcomas-of-bone-and-soft-tissue
