EWSR1/FUS-NFATc2 rearranged round cell sarcoma: clinicopathological series of 4 cases and literature review

Abstract

Background: The classification of bone neoplasms composed of small round cells is experiencing a transformation after the discovery of various gene fusion rearrangements that determine diagnosis, behavior, and response to therapy. Aim: We present herein four new cases of small round cell tumor of the bone that harbor NFATc2 rearrangements involving either EWSR1 or FUS genes. Materials and methods: We studied the clinical presentation, pathologic features, genetics (FISH, targeted RNA sequencing) and outcome in these four patients. We also reviewed the literature describing similar cases. Results: All our patients were male. The median age at diagnosis was 33.5 years. All tumors presented in long bones of the extremities as a large destructive mass with a mean size of 12.5 cm. All cases were hypercellular with prominent collagenous stroma and consisted of small to medium size round cells arranged in cords, thin trabeculae, and pseudoacinar structures. Most cases showed focal or diffuse membrane staining for CD99; whereas S100, synaptophysin and chromogranin were negative. EMA showed cytoplasmic staining in one case. Genetic studies identified EWSR1-NFATc2 fusion in three cases, and FUS-NFATc2 fusion in one case. The patients were treated with chemotherapy using Ewing sarcoma regimens and surgical excision was performed on three patients; necrosis was minimal. Follow-up is limited; after a median follow-up of 8.7 months one patient developed local recurrence and metastases to the lungs. Conclusion: Poorly differentiated round cell sarcoma with EWSR1/FUS-NFATc2 fusions are uncommon. The tumors have consistent clinical findings, morphology, and immunoprofile that in combination are distinctive and differ from that of Ewing sarcoma. Importantly, these tumors do not respond to Ewing sarcoma chemotherapy regimens.

A morphologic and molecular reappraisal of myoepithelial tumors of soft tissue, bone, and viscera with EWSR1 and FUS gene rearrangements

“…Our results further emphasize the significant challenges in diagnosing myoepithelial tumors, especially at the malignant/high‐grade end of the spectrum, without a comprehensive molecular analysis. A particular pitfall is an overlap with the increasing family of round cell sarcomas, in particular with Ewing sarcoma‐like tumors, which now encompass variant morphologies and immunoprofiles . In fact, three tumors occurring in children were initially misinterpreted as Ewing sarcoma at the outside institution based on an EWSR1 gene rearrangement positive result and treated with Ewing sarcoma regimens.…”

Identification of EWSR1–NFATC2 fusion in simple bone cysts

“…The breakpoints of EWSR1 and NFATC2 in the three simple bone cysts were identical to those in an EWSR1-NFATC2 sarcoma that we had previously analysed. 15,20 Whereas the EWSR1-NFATC2 fusion reads in the three simple bone cysts were 23-40 times lower than that in the EWSR1-NFATC2 sarcoma, the EWSR1-NFATC2 fusion reads appeared to be specific and were not detected in 288 additional bone/soft tissue tumours analysed. Although EWSR1 FISH performed on the three EWSR1-NFATC2 simple bone cysts were all technically negative (Table 1), rare split signals of the shows a recurrent expansile lytic lesion with intact metallic hardware from the prior procedure.…”

“…15 As illustrated in several case series, [14][15][16][17][18] EWSR1-NFATC2 and FUS-NFATC2 sarcomas frequently involve the long bones of extremities, and less commonly soft tissue, with local recurrence and/or metastasis occurring in approximately 40% of patients. 17 NFATC2-rearranged sarcomas appear not to respond to neoadjuvant osteosarcoma or Ewing sarcoma-based chemotherapy regimens, [15][16][17] with patients having worse overall survival than those with EWSR1-FLI1 Ewing sarcoma. 29 Microscopically, NFATC2-rearranged sarcomas are characterised by cords, trabeculae, and pseudoacinar groups of round-to-epithelioid cells in a collagenous-to-myxohyaline stroma, mimicking Ewing sarcoma, myoepithelial carcinoma, extraskeletal myxoid chondrosarcoma, and sclerosing epithelioid fibrosarcoma.…”

“…29 Microscopically, NFATC2-rearranged sarcomas are characterised by cords, trabeculae, and pseudoacinar groups of round-to-epithelioid cells in a collagenous-to-myxohyaline stroma, mimicking Ewing sarcoma, myoepithelial carcinoma, extraskeletal myxoid chondrosarcoma, and sclerosing epithelioid fibrosarcoma. [14][15][16] Cartilaginous differentiation or osteoid-like matrix can be seen. 17 Immunohistochemically, NFATC2-rearranged sarcomas show patchy-to-diffuse CD99 staining, [15][16][17] occasionally show dot-like keratin staining, and are positive for PAX7, 30 NKX2.2, 16 and AGGRECAN, 17 but lack FLI1 and ERG expression.…”

“…NFATC2 rearrangements, which are characteristic of a subset of aggressive round cell sarcomas, [12][13][14][15][16][17][18] have been recently described in benign-appearing bone cysts. 14,19 Bode-Lesniewska et al reported a bone cyst in the humerus of a 12-year-old boy, showing aneurysmal bone cyst-like histology and harbouring an FUS-NFATC2 fusion.…”