NR4A3-Rearranged Soft-Tissue Sarcoma
- EXTRASKELETAL MYXOID CHONDROSARCOMA (EMC) is a RARE soft-tissue SARCOMA that, DESPITE its name, does NOT show true cartilaginous (hyaline-cartilage) differentiation - it is a distinct entity of uncertain differentiation, defined molecularly rather than by cartilage formation.
- It is characterised by NR4A3 GENE REARRANGEMENT - most commonly the EWSR1-NR4A3 fusion, with FUS-NR4A3 and other rarer variant partners (e.g. TAF15-NR4A3) - and this NR4A3 rearrangement is the molecular hallmark used to confirm the diagnosis.
- It typically presents as a DEEP soft-tissue MASS of the PROXIMAL LIMBS and limb GIRDLES (especially the THIGH) in adults, often slowly enlarging; the imaging is of a deep, often lobulated, myxoid (T2-bright) soft-tissue mass.
- HISTOLOGY shows a MYXOID matrix with a MULTILOBULAR architecture and CORDS, clusters or reticular arrays of relatively uniform eosinophilic OVOID-to-short-SPINDLE cells; immunohistochemistry is variable (e.g. variable CD117/S100), and morphological variants (rhabdoid, cellular/'high-grade', spindle) and rare non-EWSR1 fusions exist, so the molecular NR4A3 finding is valuable.
- PUT NUMBERS ON 'INDOLENT BUT RELAPSING' - AND NOTE THAT 'INDOLENT' UNDERSELLS IT. In a 117-case series with a median follow-up of 9 years (up to 22), estimated survival was 90 PERCENT at 5 years but 70 PERCENT at 10 and 60 PERCENT at 15; LOCAL RECURRENCE occurred in 48 percent (40 of 83), and 58 percent of those recurred MORE THAN ONCE; METASTASES occurred in 46 percent (35 of 76). The authors concluded that the high eventual death rate DISTINGUISHES EMC FROM LOW-GRADE SARCOMAS - so 'indolent' describes the tempo, not the eventual outcome, and prolonged surveillance follows from that.
- THE PROGNOSTIC FACTORS ARE CLINICAL, NOT HISTOLOGICAL. On multivariate analysis the adverse factors were OLDER AGE, LARGER TUMOUR SIZE and LOCATION IN THE PROXIMAL EXTREMITY OR LIMB GIRDLE - which is where 80 percent of these tumours arise, so the classic site is also the adverse one. METASTASIS reduced survival but LOCAL RECURRENCE did NOT. Critically, HISTOLOGIC GRADING WAS OF NO PROGNOSTIC VALUE in this series, so a report describing a 'cellular' or 'high-grade' variant should not be read as a worse prognosis; the cellular non-myxoid foci (seen in 29 percent) matter for RECOGNITION, since they mimic Ewing sarcoma, synovial sarcoma, fibrosarcoma and rhabdoid tumour.
- MANAGEMENT follows soft-tissue-sarcoma principles: MRI of the primary, a properly PLANNED BIOPSY at the treating sarcoma unit, and WIDE surgical RESECTION as the mainstay; EMC is relatively CHEMO/RADIO-RESISTANT, so radiotherapy/chemotherapy have a limited (selective) role, and LONG-TERM follow-up is essential because of late recurrence/metastasis - all within a specialist sarcoma multidisciplinary team.
- “Extraskeletal myxoid chondrosarcoma (EMC) = rare soft-tissue sarcoma; DESPITE the name it is NOT true cartilage. Defined by NR4A3 rearrangement (most often EWSR1-NR4A3; FUS/TAF15 variants).
- “Deep mass of the proximal limbs/girdles (thigh). Histology: myxoid + multilobular + cords/clusters of eosinophilic ovoid-spindle cells.
- “Indolent but RELAPSING long-term - local recurrence + LATE metastases (lung). Wide resection is the mainstay; chemo/radio-resistant; PROLONGED surveillance; sarcoma-centre care.
- “Quote the long tail: survival 90% at 5 years, 70% at 10, 60% at 15; local recurrence 48% (often repeated), metastases 46% (n=117, median follow-up 9 years). Adverse factors are older age, larger size and proximal-limb site - HISTOLOGIC GRADE has NO prognostic value, and local recurrence did not predict death.
Overview & Epidemiology
Extraskeletal myxoid chondrosarcoma (EMC) is a rare soft-tissue sarcoma of uncertain differentiation. Despite its name it shows no true cartilage differentiation, and it is defined molecularly by NR4A3 rearrangement. It accounts for only a small minority of soft-tissue sarcomas and has no established population incidence figure.
Who gets it, and where. The demographics come from the largest series (Meis-Kindblom 1999, n=117):
- Sex: male-to-female ratio 2 to 1
- Age: median 52 years (range 6-89), a tumour of adults
- Size: median 7 cm (range 1.1-25)
- Site: all deep (deep subcutis or deeper), 80 percent in the proximal extremities or limb girdles and 20 percent in the trunk, with the thigh the classic location
The tempo. The defining clinical fact is an indolent but relentlessly relapsing course, quantified under Complications & Prognosis below.
Pathophysiology & Molecular Basis
The gene. NR4A3 (also known as CHN, NOR1 or TEC) is a nuclear orphan-receptor transcription factor on chromosome 9q22. In EMC a chromosomal translocation fuses it to a strong transactivation partner.
The fusions. The partner varies:
- EWSR1-NR4A3, from t(9;22)(q22;q12): the classic fusion, in about two-thirds of cases, first characterised by Clark 1996
- TAF15-NR4A3, from t(9;17)
- TCF12-NR4A3, from t(9;15)
- FUS-NR4A3
- Recently reported novel fusions such as ACTB-NR4A3 and FUS-NR4A2 (Chen 2026)
How the fusion drives the tumour. The fusion protein replaces the RNA-binding domain of the partner with the entire NR4A3 protein. An intact orphan nuclear receptor is placed under an aberrantly strong promoter, and the constitutive, dysregulated transcription that follows is the oncogenic mechanism.
A misleading name. The tumour's lineage is genuinely uncertain. The "chondrosarcoma" label records historical morphology rather than biology, which is why EMC sits in the WHO chapter on tumours of uncertain differentiation. The bone tumour whose name it borrows, chondrosarcoma, shares nothing with it but a word.
Why EWSR1 alone is not enough. EWSR1 is a promiscuous fusion gene, rearranged in many sarcomas, so an EWSR1 break-apart result alone is not diagnostic and the NR4A3 partner must be demonstrated. Among the other EWSR1-rearranged tumours:
- Ewing sarcoma: EWSR1-FLI1
- Clear cell sarcoma: EWSR1-ATF1
- Desmoplastic small round cell tumour: EWSR1-WT1
- Angiomatoid fibrous histiocytoma: EWSR1-CREB1
Histology
The pattern. EMC shows a myxoid matrix with a multilobular architecture, the lobules separated by fibrous septa. Within it lie cords, clusters or reticular arrays of relatively uniform eosinophilic, ovoid-to-short-spindle cells.
Variants. Morphological variants exist (rhabdoid, cellular or "high-grade", and spindle), as do rare non-EWSR1 fusions, so the molecular NR4A3 finding is valuable. In the largest series cellular, solid, non-myxoid foci were found in 29 percent of cases and resembled chondroblastoma, Ewing sarcoma, synovial sarcoma, fibrosarcoma and rhabdoid tumour.
Why the cellular foci matter. Their importance is diagnostic, not prognostic. Recognising them prevents the tumour being misclassified as one of those mimics, which would lead to quite different treatment.
Clinical Presentation
The mass. The typical patient is an adult with a deep, slowly enlarging, usually painless soft-tissue mass, most often in the thigh or another proximal limb or limb-girdle site. Growth is indolent, and patients may report a mass present for years, which is exactly why the eventual behaviour surprises the unwary.
Symptoms. When the mass is symptomatic, the symptoms relate to its size and site: mechanical discomfort, a palpable lump, occasionally venous or neural compression. Systemic symptoms are uncommon at presentation.
The deep mass. Any deep mass larger than 5 cm should be treated as a sarcoma until proven otherwise and referred before any excision, along the route set out in soft-tissue masses and sarcoma referral. In the largest series most initial excisions were intralesional or marginal, a pattern that feeds the 48 percent local-recurrence rate.
Investigations
MRI of the primary is the imaging mainstay, interpreted as in MRI of soft-tissue lesions. EMC appears as a deep, lobulated, T2-bright (myxoid) intramuscular mass with low T1 signal, typically with peripheral and septal enhancement after contrast.
Biopsy. A planned biopsy is taken at the treating sarcoma unit, along a track the surgeon can excise, according to biopsy principles.
Molecular confirmation is the clincher. NR4A3 rearrangement (most often EWSR1-NR4A3) is demonstrated by FISH, RT-PCR or NGS; do not rely on an EWSR1 break-apart result alone.
Immunohistochemistry supports but does not define. EMC is CD117 (c-KIT)-positive in a proportion (about 30%), variably S100-positive and INI1 (SMARCB1)-retained. It is negative for keratins/EMA and brachyury. That profile, with the NR4A3 rearrangement, separates it from the tumours that share its cords or strands of cells in a myxoid matrix:
- Chordoma and myoepithelioma: keratin/EMA-positive, and chordoma is also brachyury-positive
- Myxoid liposarcoma: DDIT3 (FUS-DDIT3) fusion, "chicken-wire" vasculature and lipoblasts
- Myxofibrosarcoma: curvilinear vessels and pleomorphism, no NR4A3
- Low-grade fibromyxoid sarcoma: FUS-CREB3L2, MUC4-positive
- Intramuscular myxoma and ossifying fibromyxoid tumour: benign, no NR4A3
The two most often confused with EMC have their own pages: myxofibrosarcoma and, for the myxoid subtype, liposarcoma.
Staging. Chest CT images the lungs, the dominant metastatic site, alongside cross-sectional imaging of the primary. Metastases can appear late, so staging is repeated through surveillance.
Management
Setting. Management follows soft-tissue-sarcoma principles within a specialist sarcoma multidisciplinary team: MRI of the primary and a planned biopsy before any definitive surgery. Unplanned excision of an undiagnosed deep mass is the error to avoid.
Surgery. Wide resection with clear margins is the mainstay. Wide resection of a deep proximal mass can sacrifice muscle compartments or neurovascular structures.
Radiotherapy and chemotherapy. EMC is relatively resistant to cytotoxic chemotherapy and radiotherapy, so adjuvant therapy has a limited, selective role. When it is used it adds toxicity with limited proven benefit.
Pazopanib in advanced disease. The one systematic qualification comes from the first prospective trial in this disease (Stacchiotti 2019), in which the antiangiogenic pazopanib produced RECIST objective responses in 4 of 22 evaluable patients (18 percent) with advanced NR4A3-confirmed EMC. In unresectable or metastatic disease after anthracycline failure there is therefore a reasonable systemic option, but that is an advanced-disease setting, not an adjuvant one. The commonest grade 3 events were hypertension (35%), raised ALT (23%) and raised AST (19%), with no grade 4 events.
Surveillance. Long-term follow-up, including the chest, is essential because of late local recurrence and metastasis; in the Meis-Kindblom series both accumulated well beyond five years. No surveillance interval or duration has been validated in EMC, so the schedule is consensus-based sarcoma practice rather than trial-derived. What the evidence does establish is that the follow-up horizon must be measured in decades, not years.
Complications & Prognosis
The long tail. In Meis-Kindblom's series of 117 cases, with a median follow-up of 9 years (range 2 months to 22 years), estimated survival was 90 percent at 5 years, 70 percent at 10 and 60 percent at 15. "Indolent" describes how slowly the tumour moves, not how it ends.
Local recurrence occurred in 48 percent (40 of 83), and 58 percent of those recurred more than once. Unplanned excision is the driver to avoid, given how the initial excisions in that series were done (see Clinical Presentation). Local recurrence did not independently predict death.
Metastasis occurred in 46 percent (35 of 76), often late and predominantly pulmonary. It reduced survival, yet survival after metastasis can still be prolonged, which is unusual among sarcomas.
The authors' own conclusion is the one to quote: the high rate of local recurrence, the prolonged survival even after metastasis, and the eventual high rate of death distinguish EMC from low-grade sarcomas. A five-year disease-free interval is therefore an interim result, not a discharge.
Prognostic factors. On multivariate analysis the adverse factors are all clinical, and the classic site is also an adverse one.
- Effect on survival
- Adverse, on multivariate analysis
- Note
- One of only three independent factors
- Effect on survival
- Adverse, on multivariate analysis
- Note
- Independent factor
- Effect on survival
- Adverse, on multivariate analysis
- Note
- Also the commonest site
- Effect on survival
- Adverse
- Note
- Yet survival after metastasis was prolonged in some patients
- Effect on survival
- NOT associated with worse survival
- Note
- Common (48 percent) and often repeated, but did not predict death
- Effect on survival
- NO prognostic value
- Note
- Prognosis is dictated by clinical features, not by grading
Reading the pathology report. Because grading carried no prognostic value, a report describing a cellular or "high-grade-looking" area should not be read as a worse prognosis. The series is retrospective and predates routine NR4A3 testing, so some cases were classified morphologically.
Mnemonics & Memory Aids
MYXOID
Hook:MYXOID: Myxoid/multilobular, Y not truly cartilage, NR4A3 (X) fusion, Often deep thigh, Indolent but relapsing, Do wide resection + surveillance.
ASP
Hook:ASP - the three multivariate adverse factors in EMC are all CLINICAL: Age, Size, Place (proximal). Histologic grade is NOT among them.
CHORD
Hook:CHORD - the myxoid differential: separate by keratin/brachyury status and by which fusion (DDIT3, CREB3L2, or NR4A3) is present.
Clinical Decision Scenarios
Practise clinical reasoning and management decisions out loud
“A deep thigh sarcoma is reported as extraskeletal myxoid chondrosarcoma. What does the name actually mean, and how would you manage it?”
What it is
- Rare soft-tissue sarcoma; NOT true cartilage despite the name
- Defined by NR4A3 rearrangement (EWSR1-NR4A3 most common; FUS/TAF15 variants)
- Uncertain differentiation
Presentation & histology
- Deep mass of proximal limbs/limb girdles (thigh), adults
- Myxoid matrix, multilobular architecture
- Cords/clusters of eosinophilic ovoid-to-short-spindle cells (variants exist)
Behaviour
- Survival 90 percent at 5 years, 70 at 10, 60 at 15 (n=117, median follow-up 9 years)
- Local recurrence 48 percent (often repeated); metastases 46 percent - often late, to lung
- Adverse: older age, larger size, proximal-limb site. Grade has NO prognostic value; local recurrence did not predict death
- Short-term disease-free status is not reassurance
Management
- Planned biopsy + NR4A3 confirmation; MRI primary
- Wide resection is the mainstay (chemo/radio-resistant)
- Prolonged surveillance (incl. chest); sarcoma-centre care
Evidence & Key Studies
A series of extraskeletal myxoid chondrosarcomas with rare morphological and molecular variations
- Extraskeletal myxoid chondrosarcoma is a rare soft-tissue sarcoma characterised by a myxoid matrix, multilobular architecture, and eosinophilic ovoid-to-short-spindle cells arranged in cords, clusters or reticular patterns, with NR4A3 gene rearrangement.
- Five variant cases in adults (24-59 years, median 49) in the dorsal region, buttock, thigh, paravertebral region and elbow (4.0-16.0 cm, median 6.5); morphological variants included solid, rhabdoid, biphasic and spindle-cell patterns; all showed variable CD117 expression.
- NGS identified EWSR1-NR4A3, two FUS-NR4A3 fusions, and the novel fusions FUS-NR4A2 and ACTB-NR4A3, expanding the genetic spectrum; none of the five patients had local recurrence or metastasis at follow-up.
The defining features of extraskeletal myxoid chondrosarcoma - the myxoid matrix, multilobular architecture, cords/clusters of eosinophilic ovoid-to-short-spindle cells, the NR4A3 rearrangement (EWSR1-NR4A3 most common, with variant fusion partners), the adult age and deep proximal/limb-girdle sites, and the morphological variants - come from the cited Chen series. The fact that EMC does not show true cartilage differentiation despite its name, its indolent-but-relapsing long-term behaviour with late metastasis, its chemo/radio-resistance, and wide resection with prolonged surveillance as management are standard, well- established teaching. The survival rates, recurrence and metastasis proportions, demographics, prognostic factors and the finding that histologic grading carries no prognostic value come from the Meis-Kindblom series, which is retrospective, single-centre and predates routine NR4A3 testing. No randomised trial compares any adjuvant regimen in EMC, no systemic agent has an established survival benefit, and no surveillance interval or duration has been validated - so although the late-relapse pattern justifies long follow-up, no schedule is quoted here as though it were evidence-based.