Subtitle: EWSR1-rearranged tumours (WHO 5th edition): Ewing sarcoma, DSRCT, extraskeletal myxoid chondrosarcoma, angiomatoid fibrous histiocytoma, clear cell sarcoma, myoepithelial tumours, round cell sarcomas with EWSR1-non-ETS fusions and more, with fusion partners, IHC and 8 MCQs.
Author: PathologyMCQ Editorial Board
Category: Soft Tissue Pathology
Last Updated: October 2026
Read Time: 6 minutes
At-a-Glance
- EWSR1 sits at 22q12; FUS is a related FET gene that can replace it.
- The partner gene, not EWSR1, defines the tumour; FISH break-apart only shows EWSR1 is rearranged.
- Same fusion, different tumours: EWSR1::ATF1 in clear cell sarcoma, AFH and hyalinising clear cell carcinoma.
- WHO 5th edition: round cell sarcomas with EWSR1-non-ETS fusions (NFATC2, PATZ1) are separate from Ewing sarcoma.
- Morphology and IHC must match the fusion.
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Fusion Table
| Tumour | Fusion | Translocation / key IHC |
|---|---|---|
| Ewing sarcoma | EWSR1::FLI1 (~85%), EWSR1::ERG (~10%), others (FEV, ETV1, ETV4) | t(11;22)(q24;q12); CD99 membranous, NKX2.2 |
| Desmoplastic small round cell tumour | EWSR1::WT1 | t(11;22)(p13;q12); keratin, desmin dot-like, WT1 (C-terminal) |
| Round cell sarcoma, EWSR1-non-ETS | EWSR1::NFATC2; EWSR1/FUS::PATZ1 | CD99 variable; NKX2.2 (NFATC2); PATZ1: desmin, myogenin, S100 variable |
| Extraskeletal myxoid chondrosarcoma | EWSR1::NR4A3 | t(9;22)(q22;q12); cords in myxoid stroma |
| Angiomatoid fibrous histiocytoma | EWSR1::CREB1 (most), EWSR1::ATF1, FUS::ATF1 | Desmin, EMA, CD99; lymphoid cuff, blood-filled spaces |
| Clear cell sarcoma (soft tissue) | EWSR1::ATF1 (also EWSR1::CREB1) | t(12;22)(q13;q12); S100, SOX10, HMB45 |
| Clear cell sarcoma-like tumour of GI tract (GNET) | EWSR1::ATF1 or EWSR1::CREB1 | S100, SOX10; melanocytic markers negative |
| Primary pulmonary myxoid sarcoma | EWSR1::CREB1 | Reticular cords in myxoid stroma |
| Myoepithelial tumours of soft tissue | EWSR1::POU5F1, ::PBX1, ::ZNF444 | Keratin/EMA, S100, GFAP |
| Sclerosing epithelioid fibrosarcoma | EWSR1::CREB3L1 (most) | MUC4 positive |
| Myxoid liposarcoma (rare) | EWSR1::DDIT3 (FUS::DDIT3 in ~90%) | t(12;22)(q13;q12); lipoblasts, chicken-wire vessels |
| EWSR1::SMAD3 fibroblastic tumour | EWSR1::SMAD3 | Acral, superficial; ERG positive |
| Hyalinising clear cell carcinoma (salivary) | EWSR1::ATF1 (>80%) | Clear cells in hyalinised stroma; p63 |
| Mesothelioma (rare) | EWSR1::YY1, EWSR1::ATF1 | Young patients, peritoneum |
Tumour Notes
- Ewing sarcoma: small round blue cells, glycogen (PAS+), membranous CD99 and nuclear NKX2.2.
- DSRCT: young men, intra-abdominal, nests in desmoplastic stroma; polyphenotypic IHC.
- AFH: children and young adults; multinodular histiocytoid cells, pseudoangiomatous spaces, thick lymphoplasmacytic cuff.
- Clear cell sarcoma: melanocytic, but BRAF wild type and EWSR1 rearranged, unlike melanoma.
- EWSR1-non-ETS round cell sarcomas: see undifferentiated round cell sarcoma →; EWSR1::SMAD3 fibroblastic tumour: see EWSR1::SMAD3 →
FISH vs NGS
EWSR1 break-apart FISH confirms that EWSR1 is rearranged but does not identify the partner, and many different tumours share EWSR1. RNA-based NGS (fusion panels) identifies the exact partner and is preferred when morphology and IHC are not decisive. A negative EWSR1 FISH does not exclude a FUS-rearranged counterpart (for example FUS::ERG Ewing sarcoma or FUS::DDIT3 myxoid liposarcoma).
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EWSR1-rearranged tumours: 8 MCQs
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Exam Pearls
- EWSR1::FLI1 = Ewing; EWSR1::WT1 = DSRCT; EWSR1::NR4A3 = EMC.
- EWSR1::ATF1 = clear cell sarcoma, AFH, salivary hyalinising clear cell carcinoma.
- AFH: EWSR1::CREB1 most common.
- Partner gene defines the entity; use NGS when needed.
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Related reads: Undifferentiated round cell sarcoma → · Soft tissue and bone MCQs →
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References
- WHO Classification of Tumours Editorial Board. Soft Tissue and Bone Tumours. 5th ed. IARC; 2020.
- Flucke U, et al. EWSR1: the most common rearranged gene in soft tissue lesions, which also occurs in different bone lesions: an updated review. Diagn Pathol. 2021;16:91.
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