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Small round cell sarcomas

Nature Reviews Disease Primers volume 8, Article number: 66 (2022) Cite this article

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Abstract

Undifferentiated small round cell sarcomas (SRCSs) of bone and soft tissue comprise a heterogeneous group of highly aggressive tumours associated with a poor prognosis, especially in metastatic disease. SRCS entities mainly occur in the third decade of life and can exhibit striking disparities regarding preferentially affected sex and tumour localization. SRCSs comprise new entities defined by specific genetic abnormalities, namely EWSR1–non-ETS fusions, CIC-rearrangements or BCOR genetic alterations, as well as EWSR1–ETS fusions in the prototypic SRCS Ewing sarcoma. These gene fusions mainly encode aberrant oncogenic transcription factors that massively rewire the transcriptome and epigenome of the as yet unknown cell or cells of origin. Additional mutations or copy number variants are rare at diagnosis and, depending on the tumour entity, may involve TP53, CDKN2A and others. Histologically, these lesions consist of small round cells expressing variable levels of CD99 and specific marker proteins, including cyclin B3, ETV4, WT1, NKX3-1 and aggrecan, depending on the entity. Besides locoregional treatment that should follow standard protocols for sarcoma management, (neo)adjuvant treatment is as yet ill-defined but generally follows that of Ewing sarcoma and is associated with adverse effects that might compromise quality of life. Emerging studies on the molecular mechanisms of SRCSs and the development of genetically engineered animal models hold promise for improvements in early detection, disease monitoring, treatment-related toxicity, overall survival and quality of life.

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Fig. 1: Anatomical distribution of SRCSs.
Fig. 2: Potential cellular origin of SRCSs.
Fig. 3: Fusion oncogenes in SRCSs and related malignancies.
Fig. 4: Models of metastasis in SRCSs.
Fig. 5: The tumour microenvironment in SRCSs.
Fig. 6: Radiological presentation in SRCSs.
Fig. 7: Proposed algorithm for molecular diagnosis of SRCS.
Fig. 8: Pathology and histomorphology of SRCS.

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Acknowledgements

T.G.P.G. was supported by the Matthias-Lackas Foundation, the Dr. Leopold and Carmen Ellinger Foundation, the German Cancer Aid (DKH-70114278 and DKH-70114111), the Gert und Susanna Mayer Foundation, the Boehringer-Ingelheim Foundation, the Federal Ministry of Education and Research (BMBF: SMART-CARE; HEROES-AYA), the Deutsche Forschungsgemeinschaft (DFG-458891500), the SMARCB1 association, and the Barbara und Wilfried Mohr Foundation. F.C.-A. was supported by grants from the Barbara & Hubertus Trettner Foundation, and the Dr. Rolf M. Schwiete Foundation, and the German Cancer Aid. The authors express their apologies to all authors whose valuable work could not be cited owing to space constraints.

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Authors and Affiliations

  1. Division of Translational Paediatric Sarcoma Research, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Heidelberg, Germany

    Florencia Cidre-Aranaz & Thomas G. P. Grünewald

  2. Hopp-Children’s Cancer Center (KiTZ), Heidelberg, Germany

    Florencia Cidre-Aranaz & Thomas G. P. Grünewald

  3. Department of Medical Oncology, Institut Curie Hospital, Paris, France

    Sarah Watson

  4. INSERM U830, Diversity and Plasticity of Childhood Tumors Lab, PSL Research University, SIREDO Oncology Center, Institut Curie Research Center, Paris, France

    Sarah Watson & Olivier Delattre

  5. Cancer and Blood Disease Institute, Children’s Hospital Los Angeles, Los Angeles, CA, USA

    James F. Amatruda

  6. Departments of Paediatrics and Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    James F. Amatruda

  7. Institute of Medical Science, Tokyo Medical University, Tokyo, Japan

    Takuro Nakamura

  8. Institute of Biomedicine of Sevilla (IBiS), Virgen del Rocio University Hospital/CSIC/University of Sevilla/CIBERONC, Seville, Spain

    Enrique de Alava

  9. Department of Normal and Pathological Cytology and Histology, School of Medicine, University of Seville, Seville, Spain

    Enrique de Alava

  10. Department of Paediatrics, University Hospital Essen, Essen, Germany

    Uta Dirksen

  11. Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany

    Thomas G. P. Grünewald

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  1. Florencia Cidre-Aranaz
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  2. Sarah Watson
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  8. Thomas G. P. Grünewald
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Contributions

Introduction (F.C.-A., T.G.P.G); Epidemiology (F.C.-A. and T.G.P.G); Mechanisms/pathophysiology (E.deA., O.D., T.N., J.F.A., F.C.-A. and T.G.P.G); Diagnosis, screening and prevention (E.deA., U.D., S.W., F.C.-A. and T.G.P.G); Management (U.D., J.F.A., S.W., F.C.-A. and T.G.P.G); Quality of life (U.D., J.F.A., S.W., F.C.-A. and T.G.P.G); Outlook (U.D., J.F.A., F.C.-A. and T.G.P.G).

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Correspondence to Florencia Cidre-Aranaz or Thomas G. P. Grünewald.

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Nature Reviews Disease Primers thanks K. Thway, P. Rutkowski and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Cidre-Aranaz, F., Watson, S., Amatruda, J.F. et al. Small round cell sarcomas. Nat Rev Dis Primers 8, 66 (2022). https://doi.org/10.1038/s41572-022-00393-3

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