Extraskeletal myxoid chondrosarcoma

Extraskeletal myxoid chondrosarcoma (EMC) is a rare malignant mesenchymal neoplasm of uncertain differentiation, classified by the WHO (5th edition, 2020) among tumors of uncertain differentiation rather than as a true cartilaginous neoplasm.[1] It is defined by recurrent NR4A3 gene rearrangements and arises predominantly in the deep soft tissues of the proximal extremities and limb girdles.[2][3] Despite its name, EMC lacks convincing cartilaginous differentiation; recent evidence supports a neuroendocrine lineage for at least a subset of cases.[4] The tumor follows a characteristically indolent yet persistent clinical course, with high rates of local recurrence and delayed distant metastasis.[5][6] On imaging, EMC typically presents as a well-circumscribed, lobulated soft-tissue mass with high water content reflecting its abundant myxoid matrix.[7][8] Wide surgical excision is the cornerstone of treatment for localized disease.[2][3]

Current Classification

The WHO Classification of Tumours of Soft Tissue and Bone (5th edition, 2020) places EMC under "tumors of uncertain differentiation," reflecting the absence of true chondrocytic lineage despite the historical name.[1]

Accepted Names and Aliases

• Extraskeletal myxoid chondrosarcoma (EMC) — the standard designation
• Chordoid sarcoma — an older synonym occasionally encountered in legacy literature

Obsolete and Potentially Confusing Terms

• EMC should not be confused with extraskeletal mesenchymal chondrosarcoma, a biologically and molecularly distinct entity defined by HEY1::NCOA2 fusion.[1][7]
• The term "myxoid chondrosarcoma" without the qualifier "extraskeletal" may cause confusion with conventional intraosseous chondrosarcoma showing myxoid change.[9]

• EMC accounts for approximately 1–3% of all soft-tissue sarcomas.[2][10]
• Median age at diagnosis is in the fifth to sixth decade (range reported from 6 to 89 years).[5][11]
• There is a consistent male predominance, with male-to-female ratios of approximately 1.7–2:1 across large series.[5][11][12]
• The vast majority arise in the deep soft tissues of the proximal lower extremity (thigh), followed by the trunk and limb girdles. Head and neck involvement is exceedingly rare, with only isolated case reports documenting EMC in the infratemporal fossa, buccal mucosa, nasal cavity, neck, jugular foramen, and mandible.[2][5][7][13][14][15][16][17][18]
• Rare osseous primary sites (bone-based EMC) have been documented.[19]

Presentation and Symptoms

• EMC most commonly presents as a slowly enlarging, deep-seated, painless mass in the proximal extremity. Duration of symptoms before diagnosis may range from weeks to several years.[2][5][7]
• In the rare head and neck location, presenting complaints depend on the site of origin and may include progressive swelling, nasal obstruction, or cranial nerve deficits.[13][16][18]
• Pain is variably reported and is not a dominant feature in most cases.

Tempo and Complications

• The clinical course is characteristically indolent but relentless: local recurrence rates range from 13–48%, and distant metastases develop in approximately 35–50% of patients, primarily to the lungs. Soft-tissue and lymph node metastases also occur.[2][5][8][11][20][21]
• Median time to distant metastasis is approximately 28 months, but metastases may appear many years after initial treatment.[2][8]
• Despite high recurrence rates, prolonged survival is common; 5-year overall survival ranges from 79–94% and 10-year overall survival from 70–88% across series.[2][11][20][22]

Red Flags

• Rapid enlargement, solid enhancement pattern on imaging, or tumor size >10 cm should raise concern for more aggressive behavior.[8][19]

EMC is overwhelmingly a soft-tissue neoplasm; primary involvement of the jaws is exceedingly rare, with only isolated case reports documenting mandibular or maxillary lesions.[7][23] The radiographic description below therefore focuses on the soft-tissue imaging characteristics most relevant when this tumor is encountered in the head and neck or adjacent to the jaws, supplemented by the rare jaw-related findings.

Location and Distribution

• EMC characteristically arises in the deep soft tissues (subfascial) of the proximal extremities. In the head and neck, reported sites include the infratemporal fossa, buccal mucosa, nasopharynx, nasal cavity, anterior neck, jugular foramen, and mandible.[5][7][8][13][14][15][16][17][18]
• When arising adjacent to the jaws, the tumor occupies the deep soft tissues rather than originating within bone.[7]

Periphery and Shape

• EMC is characteristically well circumscribed with smooth or lobulated margins. In the largest MRI series, all 44 lesions demonstrated well-circumscribed margins.[8][17]
• A multinodular or multilobulated architecture is typical, reflecting the underlying histologic lobular growth pattern.[7]

Internal Architecture

• The abundant myxoid matrix produces a mass of low density on CT (commonly 20–40 HU), which may mimic a cystic lesion.[7]
• Calcification is uncommon in EMC, distinguishing it from conventional chondrosarcoma. When present, calcifications are typically streaky or punctate and may reflect secondary dystrophic change rather than chondroid matrix mineralization. One case report documented extensive calcifications as an unusual variant.[7][17]
• On CT with contrast, most EMCs show minimal or no enhancement, consistent with the hypovascular, mucin-rich stroma. Moderate or heterogeneous enhancement may be seen in recurrent tumors with increased cellularity.[7]
• Internal fibrous septa dividing the mass into lobules are a characteristic feature, appearing as low-signal bands on MRI and as internal septations on cross-sectional imaging.[7][8]

Effects on Adjacent Structures

• EMC is typically a displacing rather than infiltrating mass. Bone erosion or destruction from direct pressure may occur when the tumor abuts osseous structures, but primary intraosseous origin is rare.[7][19]
• In the single reported mandibular case, the tumor appeared as a soft-tissue mass adjacent to the right lower jaw without the typical lobulated MRI pattern seen in extremity lesions.[7]

Growth Pattern and Extent

• Tumors are often large at presentation; mean maximal dimension in the largest MRI series was 8.8 cm (range 1.7–36 cm).[8]
• Despite well-defined margins, EMC has a high propensity for local recurrence after excision, suggesting microscopic extension beyond the apparent capsule.[5][24]

Recognized Variants

• Tumors arising in unusual locations (vertebral canal, carpal tunnel, jaw) may lack the classic lobulated architecture on imaging, making radiographic recognition more difficult.[7]

MRI Signal Characteristics

• On T1-weighted images, EMC is typically isointense to hypointense relative to skeletal muscle. Occasional cases show areas of T1 hyperintensity, which may correspond to hemorrhage or proteinaceous content.[7]
• On T2-weighted and STIR sequences, the tumor demonstrates markedly high signal intensity, reflecting the abundant myxoid matrix; this was observed in 93% of lesions in the largest series.[7][8]
• Internal septations appear as hypointense bands on T2-weighted images, dividing the mass into a characteristic lobulated or multinodular pattern.[7][8]

Enhancement Patterns

• Post-contrast enhancement is variable and has prognostic significance:
  • Mixed enhancement (20–80% of the lesion) is the most common pattern.[8]
  • Solid enhancement (>80%) occurs in a minority but is significantly associated with metastatic disease.[8]
• Enhancement is characteristically peripheral and septal, with the myxoid tumor stroma remaining unenhanced.[7]

CT Characteristics

• CT demonstrates a low-attenuation mass (typically 15–40 HU), which may be mistaken for a cystic lesion.[7]
• CT is more sensitive than MRI for detecting calcifications, which are occasionally present.[7][9]

PET

• FDG-PET data for EMC are limited. FDG uptake is variable and may be low in indolent tumors, limiting its utility for initial characterization but potentially useful for staging and surveillance.[1]

When a well-circumscribed, lobulated, myxoid soft-tissue mass is identified in or adjacent to the head and neck or jaws, the differential diagnosis centers on other myxoid and cartilaginous neoplasms. The abundant myxoid matrix and cyst-like low density of EMC overlap with several entities; molecular confirmation is often required for definitive diagnosis.[10][25]

The highest-risk diagnostic pitfall is misclassification as a benign myxoid lesion (e.g., intramuscular myxoma) or as another EWSR1-rearranged sarcoma, given that EMC shares EWSR1 involvement with several entities. NR4A3 break-apart FISH is the most practical single confirmatory assay and should be pursued whenever a deep myxoid soft-tissue mass lacks definitive lineage markers.[2][25]

Classic Morphology

• EMC is a multinodular neoplasm composed of uniform, small ovoid to short spindle cells with deeply eosinophilic cytoplasm, arranged in anastomosing cords, strands, and reticular patterns within an abundant chondromyxoid matrix.[5][10][27]
• Cellularity is typically greater at the periphery of lobules, with the central zones dominated by myxoid stroma.[10]

Morphologic Variants

• Cellular/solid variant: increased cellularity with diminished myxoid matrix, sometimes forming sheets; may mimic round cell sarcomas.[5][30]
• Rhabdoid/anaplastic variant: moderate to severe cytologic atypia with rhabdoid cytomorphology; associated with TAF15::NR4A3 fusion.[19][27]
• Non-myxoid solid variant: sheet-like proliferation of round to epithelioid cells without chondromyxoid stroma; requires molecular testing for recognition.[30]

Immunohistochemistry

• EMC has a limited and variable immunophenotype: S-100 protein is positive in approximately 20% of cases; synaptophysin and neuron-specific enolase (NSE) show occasional positivity.[10][31]
• INSM1 is positive in approximately 90% of EMCs and is a useful diagnostic marker, supporting neuroendocrine differentiation.[4]
• CD117 shows variable expression in over half of cases but does not reflect activating KIT mutations in most instances.[19][32]
• Cytokeratins, EMA, desmin, and CD34 are characteristically negative.[10][32]

Molecular Findings

• The defining molecular feature is rearrangement of the NR4A3 gene on chromosome 9q22:[1][2]
  • EWSR1::NR4A3 — most common (approximately 75–80% of cases)
  • TAF15::NR4A3 — second most common (approximately 16%); associated with larger tumor size and potentially more aggressive behavior[11][19][33]
  • TCF12::NR4A3 and TFG::NR4A3 — rare[1]
  • Novel partners including FUS, HSPA8, ACTB, and substitution of NR4A2 for NR4A3 have been reported[30][32][34]
• NR4A3 break-apart FISH is the recommended single-assay diagnostic tool.[2]

Radiologic-Pathologic Correlation

The abundant myxoid matrix accounts for the low CT density, high T2 signal, and minimal enhancement seen on imaging. The fibrous septa dividing histologic lobules correspond to the hypointense internal septations on MRI.[7] Cellular or solid variants with reduced myxoid stroma may show atypical imaging features, including more heterogeneous enhancement and loss of the classic lobulated pattern.[7]

Workup and Referral

• Any deep-seated myxoid soft-tissue mass should prompt referral to a sarcoma center for multidisciplinary evaluation.[1][3]
• Staging includes cross-sectional imaging of the primary site (MRI preferred) and CT chest for pulmonary metastases. Nodal metastases occur in approximately 9% of cases, warranting attention to regional lymph nodes.[1][8]

Definitive Treatment

• Wide surgical excision with negative margins is the cornerstone of treatment for localized EMC. R0 resection is associated with substantially lower rates of local recurrence and distant metastasis compared with R1/R2 margins.[2][3][12][24]
• Adjuvant radiotherapy improves local control when margins are close or positive, or when tumors are large.[2][3]

Systemic Therapy for Advanced Disease

• Anthracycline-based chemotherapy has limited activity in EMC.[2][12][21]
• The NCCN Guidelines list pazopanib as the preferred systemic agent for EMC, with sunitinib and cabozantinib as other recommended options. In a phase 2 trial, pazopanib achieved an objective response rate of 18% and median progression-free survival of 19 months.[1][2][21]

Recurrence and Prognosis

• Local recurrence rates range from 13–48% across series; distant metastases develop in 35–50% of patients, predominantly in the lungs.[2][5][20]
• Despite high recurrence rates, overall survival is prolonged: 5-year OS 79–94%, 10-year OS 70–88%. However, with extended follow-up (>10 years), the majority of patients eventually develop metastatic disease, and long-term mortality is substantial.[2][5][6][11][20][22]
• Adverse prognostic factors include older age, tumor size >10 cm, proximal extremity location, TAF15::NR4A3 fusion type, and metastasis at presentation.[5][11][19]

Surveillance

• Prolonged surveillance is essential, as metastases may develop years to decades after initial treatment. NCCN guidelines recommend periodic MRI of the primary site and CT chest, with consideration of ultrasound for detecting small local recurrences.[1][6][8]

Molecular Stratification

• The type of NR4A3 fusion partner may influence prognosis. TAF15::NR4A3-positive tumors are associated with larger size, higher-grade morphology, and a trend toward worse disease-free and metastasis-free survival compared with EWSR1::NR4A3-positive tumors. This distinction may become clinically actionable as molecular stratification criteria evolve.[11][19][33]

Neuroendocrine Phenotype

• A subset of EMCs exhibits a complete neuroendocrine immunophenotype (synaptophysin, INSM1, chromogranin), which may lead to misdiagnosis as a neuroendocrine neoplasm, particularly on small biopsies. Awareness of this phenotypic overlap is essential to avoid misclassification.[4][34]

Pediatric Occurrence

• EMC is exceedingly rare in children and adolescents. Isolated pediatric cases have been reported in the jugular foramen and maxilla. The same diagnostic and treatment principles apply, though long-term surveillance is especially important given the decades-long risk of recurrence.[18][23]