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Undifferentiated small round cell sarcoma of bone and soft tissue

Round cell sarcomas with EWSR1 / FUS::NFATC2


Borislav A. Alexiev, M.D.
Lawrence J. Jennings, M.D., Ph.D.

Last author update: 6 March 2025
Last staff update: 6 March 2025

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PubMed Search: Round cell sarcomas with EWSR1 / FUS::NFATC2

Borislav A. Alexiev, M.D.
Lawrence J. Jennings, M.D., Ph.D.
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Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Pathophysiology | Etiology | Diagrams / tables | Clinical features | Diagnosis | Radiology description | Radiology images | Prognostic factors | Case reports | Treatment | Gross description | Gross images | Frozen section description | Microscopic (histologic) description | Microscopic (histologic) images | Cytology description | Cytology images | Immunofluorescence description | Immunofluorescence images | Positive stains | Negative stains | Molecular / cytogenetics description | Sample pathology report | Differential diagnosis | Additional references | Practice question #1 | Practice answer #1 | Practice question #2 | Practice answer #2
Cite this page: Alexiev BA, Jennings LJ. Round cell sarcomas with EWSR1 / FUS::NFATC2. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/boneroundcellsarcomaewsr1.html. Accessed September 18th, 2025.
Definition / general
  • NFATC2 rearranged sarcomas are infrequent round cell tumors characterized by EWSR1::NFATC2 and FUS::NFATC2 fusions (Mod Pathol 2020;33:2087)
Essential features
  • Spindled to rounded cell morphology, mostly low grade features
  • Fibromyxoid and hyaline stromal changes
  • EWSR1::NFATC2 and FUS::NFATC2 fusions
  • Sarcomas with NFATC2 fusions do not respond to Ewing sarcoma chemotherapy regimens (Hum Pathol 2019;90:45)
Terminology
  • Not recommended: Ewing-like sarcoma
ICD coding
  • ICD-O: 9366/3 - round cell sarcoma with EWSR1 non-ETS fusions
Epidemiology
Sites
Pathophysiology
  • Translocation event results in fusion of NFATC2 (20q13.2) and EWSR1 (22q12.2) or FUS (16p11.2), respectively (Clin Cancer Res 2009;15:2259, Cancer Genet Cytogenet 2007;172:12)
    • Fusion activates the NFATC2 transcription factor following the loss of the N terminal regulatory domain, which results in the relocation of the chimeric transcription factor to the nucleus
  • In contrast to EWSR1::NFATC2, the FUS::NFATC2 fusion gene has not demonstrated amplification
  • Clustering analyses suggest that FUS::NFATC2 sarcomas are a transcriptionally distinct form of EWSR1::NFATC2 sarcomas (J Pathol 2018;245:29)
Etiology
  • Unknown
Diagrams / tables

Contributed by Lawrence J. Jennings, M.D., Ph.D.
FUS::NFATC2 fusion transcript

FUS::NFATC2 fusion transcript



Images hosted on other servers:
Distribution of round cell sarcomas

Distribution of round cell sarcomas

Clinical features
  • EWSR1::NFATC2 and FUS::NFATC2 sarcomas frequently manifest as painful, locally destructive bone lesions that may invade surrounding soft tissue
  • A subset of patients experience symptoms including slow growing mass for years before diagnosis (Hum Pathol 2018;81:281, Hum Pathol 2019;90:45)
Diagnosis
  • Round cell sarcoma
  • Identification of the EWSR1::NFATC2 and FUS::NFATC2 fusion transcripts remains the gold standard
Radiology description
Radiology images

Contributed by Borislav A. Alexiev, M.D.
Magnetic resonance imaging (MRI)

MRI

Prognostic factors
  • Potential for local recurrence and distant metastasis
  • In terms of prognosis, EWSR1 / FUS::NFATC2 sarcoma typically requires treatment such as surgical resection, radiation therapy and chemotherapy
  • Some studies have shown that the prognosis of EWSR1 / FUS::NFATC2 sarcoma is related to factors such as age, tumor size, lymph node metastasis and surgical resection (Diagn Pathol 2024;19:19)
  • Lung, cutaneous and bone metastases have been reported as long as 10 years after initial diagnosis and clinical indolence (Am J Surg Pathol 2019;43:1112)
  • Little or no histological response has been observed in patients treated with neoadjuvant chemotherapy (Hum Pathol 2019;90:45)
Case reports
Treatment
Gross description
  • Well circumscribed and lobulated, gray-white, fleshy masses with variably necrotic and hemorrhagic areas (Mod Pathol 2020;33:1930)
  • Most cases have a large extraosseous component
  • Cortical breakthrough and soft tissue invasion (Mod Pathol 2020;33:2087)
  • Large, fleshy mass with hemorrhagic areas and multilobular contours (Mod Pathol 2020;33:2087)
Gross images

Contributed by Borislav A. Alexiev, M.D.
Distal femur mass

Distal femur mass



Images hosted on other servers:
Primary bone tumor

Primary bone tumor

Frozen section description
  • Monotonous proliferation of small to medium sized round or oval cells with eosinophilic or clear cytoplasm arranged in nests, cords, trabeculae or pseudoglandular patterns (Hum Pathol 2019;90:45, Mod Pathol 2020;33:2087)
Microscopic (histologic) description
  • Monotonous proliferation of small to medium sized round or oval cells arranged in nests, cords, trabeculae or pseudoglandular patterns (Diagn Pathol 2024;19:19, Mod Pathol 2020;33:2087)
  • Eosinophilic or clear cytoplasm
  • Small, round, monotonous to markedly pleomorphic nuclei with smooth or irregular nuclear contours, dense hyperchromatic or vesicular chromatin and small or prominent nucleoli
  • Other findings include spindle cells, epithelioid round cell morphology, cartilaginous differentiation, osteoid-like matrix and eosinophilic infiltration (Mod Pathol 2020;33:2087, Hum Pathol 2018;81:281)
  • Variable amounts of fibrohyaline to myxohyaline stroma (Mod Pathol 2020;33:2087)
  • A focal hemangiopericytic vascular network may be present
  • Variable mitotic activity and tumor necrosis
Microscopic (histologic) images

Contributed by Borislav A. Alexiev, M.D.
Round cell sarcoma

Round cell sarcoma

Permeative growth pattern

Permeative growth pattern

Round nuclei

Round nuclei

Clear cytoplasm

Clear cytoplasm


Tumor necrosis

Tumor necrosis

Hemangiopericytic vascular network

Hemangiopericytic vascular network

Cartilaginous differentiation

Cartilaginous differentiation

CD99

CD99

Cytology description
Cytology images

Contributed by Borislav A. Alexiev, M.D.
Diff-Quik   Diff-Quik

Diff-Quik

Immunofluorescence description
  • Rearrangement of EWSR1 in all EWSR1::NFATC2 cases with gains of the 5' portion of the probe (suggestive of an unbalanced translocation) or gains of both the 5' and 3' portions of the EWSR1 probe (Mod Pathol 2020;33:2087)
  • Unbalanced pattern with signal gains of the 5' portion of the FUS gene was seen in the single tested case with a FUS::NFATC2 fusion (Mod Pathol 2020;33:2087)
Immunofluorescence images

Images hosted on other servers:
EWSR1 FISH

EWSR1 FISH

FISH with EWSR1::NFATC2 probe

FISH with EWSR1::NFATC2 probe

EWSR1 break apart FISH results

Positive stains
Molecular / cytogenetics description
  • Round cell sarcomas with EWSR1::NFATC2 fusion share a distinct DNA methylation signature and carry characteristic copy number alterations, which emphasizes that these sarcomas should be considered separately from Ewing sarcoma (J Cancer Res Clin Oncol 2019;145:1273)
  • Recurrent losses of chromosome 9q and segmental gains on 20q13 and 22q12 involving the EWSR1 and NFATC2 loci, respectively
  • EWSR1::NFATC2 tumors are strongly enriched in genes associated with inflammatory and immune responses (J Pathol 2018;245:29)
  • FUS::NFATC2 tumors are enriched in proliferation and drug resistance signatures (J Pathol 2018;245:29)
  • In accordance with the potential areas of cartilaginous differentiation, genes involved in the extracellular matrix of cartilaginous tissues (such as ACAN, COL9A2, MATN3, COMP and CILP2) or encoding secreted proteins (PTN, DKK3, ANGPTL2, SBSPON and WNT5B) are preferentially expressed in FUS::NFATC2 positive tumors
  • FUS::NFATC2 sarcomas are different from EWSR1::NFATC2 tumors and transcriptionally resemble CIC fused tumor entities (J Pathol 2018;245:29)
  • Morphologic correlation is essential; identical gene fusions have also been reported in both solitary bone cysts (SBC) and vascular malformations, which show entirely different morphology and clinical behavior (Am J Surg Pathol 2021;45:1669, ScienceDirect: Vascular Anomaly [Accessed 27 January 2025])
Sample pathology report
  • Left tibia, core biopsy:
    • Round cell sarcoma with FUS::NFATC2 fusion (see comment)
    • Comment: H&E stained tissue sections show a cellular neoplasm composed of small to medium sized round cells with eosinophilic and clear cytoplasm and round nuclei with smooth or irregular nuclear contours, hyperchromatic or vesicular chromatin and small nucleoli. Few mitoses and focal necrosis (~20%) are seen. Immunohistochemical stain for CD99 is positive in tumor cells. The targeted solid tumor next generation sequencing (NGS) fusion panel identified a FUS::NFATC2 fusion. Overall, these pathologic findings are consistent with round cell sarcoma with FUS::NFATC2 fusion. Sarcomas with NFATC2 fusions have potential for local and distant recurrence and are resistant to Ewing sarcoma specific chemotherapy.
Differential diagnosis
Practice question #1


A 56 year old patient has a 10 cm mass in the diaphysis of the femur with evidence of extraosseous extension. Immunohistochemical stains show positivity for CD99 and NKX2.2 and are negative for SOX10, desmin and pancytokeratins. On FISH testing, a gene rearrangement of the NFATC2 gene is noted. Which of the following is true about this lesion?

  1. NFATC2 sarcomas are resistant to Ewing sarcoma specific chemotherapy
  2. NFATC2 sarcomas have been reported exclusively in soft tissue
  3. Patients with NFATC2 sarcomas show a younger median age at diagnosis compared to those with EWSR1::FLI1
  4. Predominantly arise in children
  5. Strong female predominance
Practice answer #1
A. NFATC2 sarcomas are resistant to Ewing sarcoma specific chemotherapy. Answer D is incorrect because while NFATC2 fusion sarcomas occur in children and adults (age range: 12 - 67 years), the median age is 33 years old. Answer E is incorrect because NFATC2 fusion sarcomas have a strong male predominance. Answer B is incorrect because NFATC2 fusion sarcomas are predominantly located in bones, with a 4:1 ratio over soft tissue. Answer C is incorrect because patients with NFATC2 fusion sarcomas show an older median age at diagnosis compared to those with EWSR1::FLI1.

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Reference: Round cell sarcomas with EWSR1 / FUS::NFATC2
Practice question #2
Which of the following is true about NFATC2 rearranged sarcomas?

  1. CD99+
  2. Frequently present in the upper trunk / back of the neck in adults
  3. Lack the ability to metastasize
  4. Loss of INI1
  5. Show a predilection to metastasize to soft tissue sites
Practice answer #2
A. CD99+. NFATC2 sarcomas are positive for CD99. Answer B is incorrect because NFATC2 sarcomas are most commonly found in the bones, particularly the long bones, such as the femur, humerus, radius and tibia. Answer D is incorrect because INI1 expression is retained. Answer C is incorrect because NFATC2 sarcomas have a potential for local recurrence and distant metastasis. Answer E is incorrect because lung, cutaneous and bone metastases have been reported as long as 10 years after initial diagnosis and clinical indolence.

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Reference: Round cell sarcomas with EWSR1 / FUS::NFATC2
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