Author: PathologyMCQ Editorial Team
Category: Soft Tissue and Bone Pathology
Last Updated: October 2026
Read Time: 16 minutes
Difficulty: Moderate to difficult (FRCPath, NEET-SS, MD/DNB)

At a glance

• What they are: Ewing-like small round cell sarcomas without an EWSR1/FUS–ETS fusion, defined by CIC, BCOR, NFATC2 or PATZ1 alterations.
• Key IHC clues: WT1 + ETV4 (CIC), BCOR + SATB2 + CCNB3 (BCOR), CD99 + NKX2.2 + AGGRECAN (NFATC2), myogenic + neural co-expression (PATZ1).
• Behaviour differs: CIC sarcoma is the most aggressive; BCOR::CCNB3 behaves like Ewing sarcoma; NFATC2 is often more indolent but chemoresistant.
• WHO update: the 6th edition (2026 beta) lists NFATC2-rearranged sarcoma separately and moves PATZ1-rearranged sarcoma to tumours of uncertain differentiation.

What are undifferentiated round cell sarcomas?

Undifferentiated small round cell sarcomas are malignant mesenchymal tumours of primitive round to oval cells with no clear line of differentiation on routine histology. For years most were labelled “atypical Ewing sarcoma” or “Ewing-like sarcoma”. Molecular testing showed that many lack the canonical EWSR1/FUS–ETS fusion of Ewing sarcoma and instead carry distinct drivers, each with its own morphology, immunoprofile, behaviour and treatment response.

They sit in the broad “small round blue cell tumour” group alongside Ewing sarcoma, rhabdomyosarcoma, lymphoblastic lymphoma, neuroblastoma, desmoplastic small round cell tumour, poorly differentiated synovial sarcoma and small cell carcinoma, so a careful IHC panel and molecular confirmation are essential.

WHO classification: 5th vs 6th edition

WHO 5th edition (2020) “Undifferentiated small round cell sarcomas of bone and soft tissue”	WHO 6th edition (2026 online beta) “Undifferentiated spindle and small round cell sarcomas”
Ewing sarcoma	Ewing sarcoma
Round cell sarcoma with EWSR1–non-ETS fusions (NFATC2 and PATZ1 grouped together)	NFATC2-rearranged sarcoma (own entity). PATZ1-rearranged sarcoma moves to “tumours of uncertain differentiation”
CIC-rearranged sarcoma	CIC-rearranged sarcoma
Sarcoma with BCOR genetic alterations	Sarcomas with BCOR genetic alterations

The chapter name now includes “spindle” because several of these tumours, especially BCOR sarcomas, often show spindle-cell morphology. Exams will follow the 5th edition until boards switch, so learn both names.

Side-by-side comparison of the four entities

	CIC-rearranged	BCOR-altered	NFATC2-rearranged	PATZ1-rearranged
Patient and site	Young adults; deep soft tissue of limbs and trunk (bone rare)	BCOR::CCNB3: adolescent boys, bone (pelvis, long bones). BCOR ITD: infants, soft tissue and kidney	Young adult men; long bones (metaphysis/diaphysis)	All ages; chest wall and abdomen, also CNS
Morphology	Sheets of round cells, vesicular chromatin, prominent nucleoli, mild pleomorphism, myxoid areas, geographic necrosis	Uniform round to spindle cells, fine chromatin, delicate capillary network, myxoid stroma	Cords, nests and trabeculae of round to epithelioid cells in myxohyaline stroma	Round to spindle cells in sheets with fibrous stroma; variable
IHC	WT1 (N-terminal), ETV4, DUX4 nuclear; CD99 patchy; NKX2.2 usually negative	BCOR, SATB2, CCNB3 (in CCNB3 fusion), cyclin D1, TLE1; CD99 variable	CD99, NKX2.2 (often), PAX7, AGGRECAN	Polyphenotypic: desmin, MyoD1, myogenin with S100, SOX10, GFAP; CD99 variable
Molecular	CIC::DUX4 (most), CIC::FOXO4, CIC::NUTM1	BCOR::CCNB3, BCOR::MAML3, ZC3H7B::BCOR, BCOR ITD	EWSR1::NFATC2, FUS::NFATC2; EWSR1 amplification common	EWSR1::PATZ1 (22q inversion)
Behaviour	Highly aggressive; early lung metastasis	Similar to Ewing sarcoma (CCNB3); ITD tumours can be aggressive	Locally aggressive, often indolent; chemoresistant	Variable; limited data

CIC-rearranged sarcoma

• The commonest non-Ewing round cell sarcoma; most cases carry CIC::DUX4.
• Round cells with vesicular chromatin and prominent nucleoli, more pleomorphism than Ewing sarcoma, myxoid foci and geographic necrosis.
• Nuclear WT1 and ETV4 (and DUX4) are the best surrogates; CD99 is patchy, NKX2.2 usually negative.
• Aggressive, with early metastasis and poor response to Ewing-type chemotherapy.

Sarcomas with BCOR genetic alterations

• BCOR::CCNB3 sarcoma: adolescent boys, mostly bone; uniform round to spindle cells with a delicate vascular network.
• BCOR ITD: infants; includes undifferentiated round cell sarcoma of infancy, primitive myxoid mesenchymal tumour of infancy and clear cell sarcoma of kidney.
• Nuclear BCOR, SATB2 and CCNB3 (in CCNB3 fusions) are characteristic; cyclin D1 and TLE1 can be positive, a pitfall with synovial sarcoma.
• Outcome of BCOR::CCNB3 sarcoma is broadly similar to Ewing sarcoma and better than CIC sarcoma.

NFATC2-rearranged sarcoma

• Young adult men, usually in long bones; may mimic myoepithelial tumour or extraskeletal myxoid chondrosarcoma.
• Cords and nests of small round to epithelioid cells in a myxohyaline stroma.
• CD99 and often NKX2.2 positive; AGGRECAN and PAX7 are useful markers.
• EWSR1::NFATC2 (often with EWSR1 amplification) or FUS::NFATC2. Usually indolent but locally aggressive and poorly responsive to Ewing chemotherapy, so surgery is key.

PATZ1-rearranged sarcoma

• Wide age range; chest wall, abdomen and CNS; sheets of round to spindle cells with fibrous stroma.
• Polyphenotypic: co-expresses myogenic (desmin, MyoD1, myogenin) and neural (S100, SOX10, GFAP) markers, so it can mimic rhabdomyosarcoma or MPNST.
• EWSR1::PATZ1 results from a small inversion on 22q: EWSR1 break-apart FISH can be falsely negative, so RNA-based NGS is preferred.
• Listed under tumours of uncertain differentiation in the WHO 6th edition beta.

Diagnostic approach and molecular pitfalls

1. Confirm a small round cell tumour and exclude non-sarcomas: CD45, TdT, CD20/CD3 (lymphoma); keratin, TTF-1, INSM1 (carcinoma); S100, SOX10 (melanoma).
2. First-line sarcoma panel: CD99, NKX2.2, desmin, myogenin, WT1 (C- and N-terminal), keratin, TLE1 or SS18-SSX.
3. Surrogates for the new entities: ETV4/WT1/DUX4 (CIC), BCOR/SATB2/CCNB3 (BCOR), AGGRECAN/PAX7 (NFATC2).
4. Molecular confirmation: RNA-based NGS fusion panel is preferred. EWSR1 FISH is positive in Ewing, NFATC2 and PATZ1 sarcomas (and DSRCT), so it cannot separate them; CIC FISH can miss some CIC::DUX4 fusions, and BCOR ITD needs sequencing.

Remember: strong CD99 alone is never diagnostic. It is positive in lymphoblastic lymphoma, synovial sarcoma, mesenchymal chondrosarcoma, DSRCT and many others.

Differential diagnosis of small round cell tumours

Tumour	Key IHC	Molecular
Ewing sarcoma	Strong diffuse membranous CD99, NKX2.2, FLI1 or ERG	EWSR1::FLI1, EWSR1::ERG, FUS::ERG
Alveolar rhabdomyosarcoma	Desmin, diffuse strong myogenin, MyoD1	PAX3/PAX7::FOXO1
Lymphoblastic lymphoma	TdT, CD99, CD43, CD3 or CD79a	Clonal rearrangements
Neuroblastoma	PHOX2B, synaptophysin; CD99 negative	MYCN amplification
Desmoplastic small round cell tumour	Keratin + dot-like desmin + WT1 (C-terminal)	EWSR1::WT1
Poorly differentiated synovial sarcoma	TLE1, SS18-SSX fusion antibody, focal keratin/EMA	SS18::SSX1/2/4
Mesenchymal chondrosarcoma	CD99, NKX2.2, SOX9; islands of hyaline cartilage	HEY1::NCOA2
Small cell carcinoma, Merkel cell carcinoma	Keratin (dot-like), INSM1, TTF-1 or CK20	Not applicable

Prognosis and treatment

Entity	Prognosis	Practical notes
CIC-rearranged	Poor (5-year survival below about 50%)	Early lung metastasis; limited response to Ewing regimens; trials of other approaches
BCOR::CCNB3	Similar to Ewing sarcoma	Usually treated with Ewing-type multimodal therapy
BCOR ITD (infants)	Variable, can be aggressive	Complete surgical resection important
NFATC2-rearranged	Often indolent, locally aggressive	Poor chemotherapy response; wide resection is the mainstay
PATZ1-rearranged	Variable	Limited data; managed individually

More practice: round cell sarcoma quiz

Exam pearls and key takeaways

• Small round blue cell tumour ≠ Ewing sarcoma. CD99 is sensitive but not specific; NKX2.2 is more specific but still not perfect.
• WT1 + ETV4 nuclear in a round cell sarcoma of a young adult: think CIC::DUX4, the most aggressive.
• BCOR + SATB2 + CCNB3 in an adolescent boy’s bone tumour: BCOR::CCNB3, behaves like Ewing.
• Cords in myxohyaline stroma, long bone, AGGRECAN+: NFATC2-rearranged sarcoma, chemoresistant.
• Myogenic + neural markers together: think EWSR1::PATZ1, and use RNA NGS because FISH can miss it.
• Key takeaway: these are molecularly defined tumours. Morphology and IHC narrow the field, but an integrated diagnosis needs fusion testing, ideally by RNA-based NGS.