Extraskeletal Myxoid Chondrosarcoma

The American Joint Committee on Cancer (AJCC) or Union for International Cancer Control (UICC) TNM system may be used.

Molecular characterization of the t(9;22) and subsequently also of the t(9;17) variant translocation has shown that they result in gene fusions in which the NR4A3 gene is fused with either EWSR1 at 22q12.2 or TAF15 at 17q12. The NR4A3 fusions, which are present in > 90% of EMCs, have not been found in any other sarcoma and may therefore be considered a hallmark of this disease. NR4A3 (also known as TEC, CHN, and NOR1) encodes an orphan nuclear receptor belonging to the steroid/thyroid receptor gene family, whereas EWSR1 and TAF15 – also known as TAF2N, RBP56, and TAF(II)68 – belong to the TET family of multifunctional proteins that bind both RNA and DNA. Two additional gene fusions, TCF12-NR4A3 and TFG-NR4A3, have also been identified in isolated cases of EMC.

The molecular consequences of the NR4A3 gene fusions in EMC have only been partially elucidated. The EWSR1-NR4A3 and TAF15-NR4A3 fusion proteins are strong transcriptional activators. There is evidence suggesting that coexpression of native NR4A3 and its coactivator SIX3 may be an alternative mechanism to gene fusion. The orphan receptor NR4A3 is a transcriptional target of p53 and interacts with the antiapoptotic BCL2 protein, presumably promoting apoptosis.

Cytogenetically, EMC is characterized by a t(9;22)(q22;q12) translocation or less frequently a t(9;17)(q22;q11) or t(9;15)(q22;q21) translocation. Although the t(9;22) has been found as the sole anomaly, most cases also show other chromosome changes, including trisomy for 1q25-qter, 7, 8, 12, and 19.

EMCs form large, well-demarcated tumors. Tumor size is variable and some very large tumors can reach 30 cm. On cut surface, EMC has a well-defined multinodular architecture comprising glistening, gelatinous areas separated by fibrous septa. Intratumoral hemorrhage, cystic cavities, and geographical areas of necrosis are common. Highly cellular tumors are fleshy.

EMC has a multinodular architecture defined by fibrous septa that divide the tumor into hypocellular lobules with abundant pale-blue myxoid or chondromyxoid matrix. Well-formed hyaline cartilage is virtually never seen. The stroma is strikingly hypovascular. The cells characteristically interconnect with one another to form cords, small clusters, and complex trabecular or cribriform arrays. The cells have a modest amount of deeply eosinophilic to vacuolated cytoplasm, as well as uniform round to oval nuclei, and delicate elongated cytoplasmic processes are common. The chromatin is evenly distributed, often with a small, inconspicuous nucleolus. Mitotic activity is usually low. Some tumors have prominent rhabdoid cytoplasmic inclusions. Rare cases are hypercellular with decreased myxoid matrix and have higher-grade, often epithelioid cytomorphology.

S100 is positive in as many as 20% of cases, and KIT (CD117, c-KIT) is positive in as many as 30%. Expression of synaptophysin and NSE has been demonstrated in some tumors. Tumors with rhabdoid features are often negative for SMARCB1 (INI1). Notably, tumor cells only very rarely express keratins or GFAP, and muscle markers are negative.

Not clinically relevant

Although often associated with prolonged survival, EMC has high rates of distant recurrence and disease-associated death. Metastases are usually pulmonary; however, extrapulmonary and disseminated metastases also occur. Interestingly, prolonged survival even in the face of metastatic disease is not uncommon. Two large retrospective series report 5-year, 10-year, and 15-year overall survival rates of 82–90%, 65–70%, and 58–60%, respectively. Older age, large tumor size (especially > 10 cm), and proximal location are adverse prognostic factors. Some studies suggest that tumors with increased cellularity and atypia are more aggressive. Others suggest that the presence of rhabdoid cells represents an adverse histological finding. EMCs with variant non-EWSR1 gene fusions tend to show a higher incidence of rhabdoid phenotype, high-grade morphology, and aggressive outcome than the EWSR1-NR4A3–positive tumors.

Identification of NR4A3 gene rearrangement is diagnostically helpful.

Essential: generally bland cells with eosinophilic cytoplasm disposed in strands or cords in a predominantly myxoid stroma.

Desirable: NR4A3 rearrangement (in selected cases).