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Round Cell Sarcoma FactFile

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Overview of Round Cell Sarcoma

Malignancy:    Malignant

Type of bone tumour: Mesenchymal tumour

Grade: Varies

Location:

  • Upper limbs: humerus and radius
  • Lower limbs: Tibia, Femur
  • Rare in viscera/abdomen/belly
  • Other locations are affected and depend on the type of round cell sarcoma.

Onset: Varies with type of round cell sarcoma

Risk Factors Of Round Cell Sarcoma

A) Genetics:

EWSR1::NFATC2 and FUS::NFATC2 fusions

EWS RNA-binding protein 1 (EWSR1) is a member of the FET or TET family and is found on chromosome 22 (22q12).

It undergoes rearrangement with the ETS family gene, like FLI1, to form a fusion and increases the risk of Ewing Sarcoma.

However, a fusion between EWSR1 and Nuclear factor of activated T cells 2 (NFATC2), a type of transcription factor, can form a rare bone cancer called round cell sarcoma of the bone.

In some fusions, another member of the FET/TET family called FUS replaces EWSR1 to form a fusion with NFATC2. FUS is on chromosome 16p11.2, and NFATC2 is on chromosome 20q13.2.

This leads to a FUS::NFATC2 fusion.

This image is by Al-Obaidy et al. (2021) and is subdivided into three. Part A graphically presents the coding regions called exons of the EWSR1 (light blue) and PATZ1 dark blue) genes fuse together. It was detected by Archer analysis software that the fusion occurs between exon 8 of EWSR1 and exon 1 of PATZ. Part B presents the structure of the EWSR1 transcript. The lines are the boundaries of the exons, and there are also conserved domains. The dotted lines present the start and end of the coding sequence. The red arrow indicates the fusion point. The TAD domain is the transactivation domain containing a consensus sequence of the repeated QGSY peptide. The three RGG domains are rich in the amino acids arginine and glycine. The function of the RCG domain is to help recognise the RNA and facilitate binding. The RMM domain consists of two domains: the zinc (Zn) finger domain and the RNA recognition domain. PY is a C-terminal nuclear-localization domain. The Zinc finger domain is a small functional protein that plays a major role in gene regulation. It coordinates one or more zinc ions to stabilize its structure. They have a finger-like shape where they bind to specific molecules, often DNA or RNA. Part C presents the transcript of PATZ1. The lines are the boundaries of the exons, and there are also conserved domains. The dotted lines present the start and end of the coding sequence. The red arrow presents the fusion point. There are several domains: BTB/POZ, AT, and Zn. BTB/POZ is a protein/protein interaction motif. AT is a DNA-binding motif, and there is a zinc finger domain. The partial nucleotide and amino acid sequence underneath the PATZ1 transcript shows the position of the breakpoints for cases 1, 2, and 3 in PATZ1 exon 1. To create a transcriptional activator, the fusion removes the BTB/POZ putative transcriptional repressor domain and the AT-hook domain at the N-terminus of PATZ1 and converts the transcriptional repressor into a transcriptional activator.

Other risk factors of Round Cell Sarcoma

Age

Ewing sarcoma and BCOR-sarcoma occur predominantly in children and adolescents <20 years old.

CIC-sarcoma, NFATC2-sarcoma, and PATZ1-sarcoma à young- to middle-aged adults (<50 years).

In older adults, a tumor displaying rhabdomyosarcomatous.

B) Gender

Males are mainly affected, as there is a slight increase than female.            

Most have an equal distribution between sex/gender.

Appearance Under Microscope

Cell Morphology:

  • Small- to medium-sized round cells
  • Monotonous nuclei
  • High nuclear-to-cytoplasmic ratio, giving a blue colour to the tumour.
  • Fibromyxoid and hyaline stromal changes
  • EWSR1::NFATC2 and FUS::NFATC2 fusions
Locally destructive bone lesions that may invade surrounding soft tissue (Alexiev and Jennings)

Recommended reading

Unravelling Round cell bone sarcomasDownload

References

Al-Obaidy, K.I., Bridge, J.A., Cheng, L., Janos Sumegi, Reuter, V.E., Ryma Benayed, Hameed, M., Williamson, S.R., Hes, O., Alruwaii, F.I., Segal, J.P., Pankhuri Wanjari, Idrees, M.T., Nassiri, M., Eble, J.N. and Grignon, D.J. (2021). EWSR1-PATZ1 fusion renal cell carcinoma: a recurrent gene fusion characterizing thyroid-like follicular renal cell carcinoma. Modern Pathology, 34(10), pp.1921–1934. doi:10.1038/s41379-021-00833-7.

Alexiev, B. and Jennings, L. (2026) Bone & joints Undifferentiated spindle and small round cell sarcomas of soft tissue and bone NFATC2 rearranged sarcoma. Available at: https://www.pathologyoutlines.com/topic/boneroundcellsarcomaewsr1.html (Accessed: 26th April 2026)

Bădilă, A.E., Rădulescu, D.M., Niculescu, A.-G., Grumezescu, A.M., Rădulescu, M. and Rădulescu, A.R. (2021). Recent Advances in the Treatment of Bone Metastases and Primary Bone Tumors: An Up-to-Date Review. Cancers, [online] 13(16), p.4229. Doi: https://doi.org/10.3390/cancers13164229.

Biermann, J.S., Hirbe, A., Ahlawat, S., Bernthal, N.M., Binitie, O., Boles, S., Brigman, B., Callan, A.K., Cipriano, C., Cranmer, L.D., Davis, J., Donnelly, E., Ferguson, M., Graham, A., Groundland, J., Hess, M., Hiniker, S.M., Hoover-Regan, M.L., Hornick, J.L. and Jonard, B. (2025). Bone Cancer, Version 2.2025, NCCN Clinical Practice Guidelines in Oncology. Journal of the National Comprehensive Cancer Network, [online] 23(4). does: https://doi.org/10.6004/jnccn.2025.0017.

Cancer Research UK (2025a) Types of bone cancer. Available at:  https://www.cancerresearchuk.org/about-cancer/bone-cancer/types (Accessed 3rd April 2026)

Cowan, P., Launico, M. and Kahai, P. (2024) Anatomy, Bones. Available at: https://www.ncbi.nlm.nih.gov/books/NBK537199/ (Accessed: 9th April 2026)

Gerrand, C., Amary, F., Anwar, H.A., Brennan, B., Dileo, P., Kalkat, M.S., McCabe, M.G., McCullough, A.L., Parry, M.C., Patel, A., Seddon, B.M., Sherriff, J.M., Tirabosco, R. and Strauss, S.J. (2024). UK guidelines for the management of bone sarcomas. British Journal of Cancer. doi:https://doi.org/10.1038/s41416-024-02868-4.

Hosseini, H., Heydari, S., Kiavash Hushmandi, Salman Daneshi and Rasoul Raesi (2025). Bone tumors: a systematic review of prevalence, risk determinants, and survival patterns. BMC Cancer, 25(1). doi:https://doi.org/10.1186/s12885-025-13720-0.

Pullan, J.E., and Lotfollahzadeh, S. (2024) Primary Bone Cancer Available at: https://www.ncbi.nlm.nih.gov/books/NBK560830/ (Accessed: 9th April 2026)

‌WHO Editorial Board. WHO classification of bone tumours. In WHO Classification of Tumours Editorial Board. Soft tissue and bone tumours. Bovee J, Flanagan AM, Lazar AJ, Nielsen GP and Yoshida A (eds) pp 338. International Agency for Research on Cancer (2020)

Updated July 2026 Next Review July 2028

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