Round cell sarcoma with EWSR1–non-ETS fusions is an evolving family of neoplasms that now includes round cell sarcomas with fusions involving FET family members (EWSR1 or, less commonly, FUS) and genes outside of the ETS family, including NFATC2 and PATZ1. 

Sarcomas with EWSR1::NFATC2 or FUS::NFATC2 fusions are very rare, and they have a strong predilection for males, with a wide age distribution and a median age at presentation of about 30 years. ¹

EWSR1::PATZ1-rearranged sarcoma also has a wide age distribution, with a median age at presentation of about 40 years. ² It occurs with equal frequency in males and females.

EWSR1::NFATC2-rearranged sarcoma most commonly occurs in bone (about 80%), while about 20% occur in soft tissue. ¹ Patients typically present with a painful mass, although patients with soft tissue primary tumors can present with a slow-growing painless mass.

EWSR1::PATZ1-rearranged sarcoma occurs in soft tissue; most are located in the chest wall, with the remainder having a wide body site distribution.² Patients typically present with pain or a palpable mass.

EWSR1::NFATC2-rearranged sarcoma exhibits an infiltrative growth pattern in bone and is composed of nests of round or spindle cells with moderate amounts of eosinophilic to clear cytoplasm and with finely dispersed chromatin and variably conspicuous nucleoli. The nested architecture and variably clear cytoplasm can resemble myoepithelial carcinoma, presenting a potential diagnostic pitfall. Some examples show linear growth of tumor cells, mimicking lobular breast carcinoma or sclerosing epithelioid fibrosarcoma. 

EWSR1::PATZ1-rearranged sarcoma is a round and spindle cell sarcoma that exhibits sheet-like growth of tumor cells with intervening fibrous septa and/or dense collagenous stroma. Tumor cells are small, with small to moderate amounts of palely eosinophilic cytoplasm and primitive-appearing nuclei with fine chromatin and small conspicuous nucleoli. EWSR1::PATZ1-rearranged sarcoma exhibits multifocal spindle cell-morphology, which would be unusual in Ewing sarcoma.

EWSR1::NFATC2-rearranged sarcoma shares significant immunophenotypic overlap with Ewing sarcoma, with diffuse CD99 expression in about 50% of cases and occasional nuclear expression of NKX2.2. ^3,4

EWSR1::PATZ1-rearranged sarcoma has been described as a "polyphenotypic" sarcoma due to its expression of proteins associated with disparate lineages, including myogenic proteins (desmin, myogenin, MyoD1), nerve sheath proteins (SOX10, S100, GFAP), and, in some cases, CD34 or CD99.

There is limited information regarding clinical behavior of these tumor types, which have only recently been defined. Based on limited follow-up, it seems that 70-80% of EWSR1::NFATC2/FUS::NFATC2-rearranged sarcomas have not recurred or metastasized following surgery, although there are reports of recurrence and metastasis.¹ Treatment response to conventional systemic chemotherapy has been generally poor, supporting the notion that EWSR1::NFATC2/FUS::NFATC2-rearranged sarcomas should be considered distinct from Ewing sarcoma.^3,5-7

EWSR1::PATZ1-rearranged sarcoma appears to behave aggressively based on limited clinical follow-up data.²Treatment response to conventional systemic chemotherapy has been modest to poor.^2,8

• EWSR1::NFATC2 gene fusion results from t(20;22)(q13.2;q12.2), and amplification of the fusion gene as the result of r(20;22) is a consistent and distinctive finding. ^5,9-11 Thus, in clinical practice, the finding of 5’ EWSR1 amplification using EWSR1 break-apart probes strongly supports the presence of an underlying EWSR1::NFATC2 fusion (Fig. 1). Similarly, NFATC2 amplification can be demonstrated using NFATC2 break-apart probes (Fig. 2).

• EWSR1::NFATC2-rearranged sarcoma shows recurrent losses on chromosome 9q and segmental gains on 20q13 and 22q12 involving the NFATC2 and EWSR1 loci, respectively.¹²

• EWSR1::PATZ1 gene fusion was first identified in 2000, as result of a cryptic intra-chromosomal rearrangement of chromosome 22. ¹³Because PATZ1 is located in close proximity to EWSR1 on chromosome 22, interpretation of EWSR1 break-apart FISH signals is challenging. ²

• EWSR1::PATZ1-rearranged sarcomas harbor CDKN2A/CDKN2B loss in about 70% of cases and, they rarely show MDM2 amplification.²

Figure 1. 5' EWSR1 amplification in EWSR1::NFATC2-rearranged sarcoma. This cytogenetic finding distinguishes EWSR1::NFATC2-rearranged sarcoma from Ewing sarcoma, the latter of which does not show EWSR1 amplification. This image is provided courtesy of Dr. Cristina Antonescu (Memorial Sloan Kettering Cancer Center, New York City, NY, USA).

Figure 2. 3' NFATC2 amplification in EWSR1::NFATC2-rearranged sarcoma. Break-apart probes demonstrate amplification of the 3' end of NFATC2 (red probe), relative to the 5' end (green probe). This image is provided courtesy of Dr. Cristina Antonescu (Memorial Sloan Kettering Cancer Center, New York City, NY, USA).