New fusion sarcomas: histopathology and clinical significance of selected entities

Abstract

Many sarcomas contain gene fusions that can be pathogenetic mechanisms and diagnostic markers. In this article we review selected fusion sarcomas and techniques for their detection. CIC-DUX4 fusion sarcoma is a round cell tumor now considered an entity separate from Ewing sarcoma with a more aggressive clinical course, occurrence in older age, and predilection to soft tissues. It is composed of larger cells than Ewing sarcoma and often has prominent necrosis. Nuclear DUX4 expression is a promising immuno histochemical marker. BCOR-CCNB3 fusion sarcoma is cyclin B3-positive, usually occurs in bone or soft tissue of children, and may mimic a poorly differentiated synovial sarcoma. EWSR1-NFATC2 sarcoma may present in bone or soft tissue. It is typically composed of small round cells in a trabecular pattern in a myxoid matrix resembling myoepithelioma. ACTB-GLI1 fusion sarcoma may mimic a skin adnexal carcinoma, showing focal expression of epithelial markers and S100 protein. NTRK-fusion sarcomas include, in addition to infantile fibrosarcoma with ETV6-NTRK3 fusion, LMNA-NTRK1 fusion sarcoma, a low-grade spindle cell sarcoma seen in peripheral soft tissues in children and young adults. Methods to detect gene fusions include next-generation sequencing panels, anchored multiplex polymerase chain reaction systems to detect partner for a known fusion gene, and comprehensive RNA sequencing to detect virtually all gene fusions. In situ hybridization testing using probes for both fusion partners can be used as an alternative confirmation technique, especially in the absence of satisfactory RNA yield. In addition, fusion protein-related and other immunohistochemical markers can have a high specificity for fusion sarcomas.

Keywords: ACTB-GLI1; Anchored multiplex PCR; BCOR-CCNB3; CIC-DUX4; EWSR1-NFATC2; Fusion sarcoma; LMNA-NTRK1.

Fig. 1

CIC-DUX4 fusion sarcoma. A, Extensive tumor necrosis is common. B and C, Tumors are composed of round cells larger than typical Ewing sarcoma cells with prominent nucleoli. Tumor cells show nuclear positivity for DUX4, which is considered a useful marker for these fusion sarcomas.

Fig. 2

CIC-FOXO1 fusion sarcoma resembles a classic Ewing sarcoma and is composed of uniform small round cells.

Fig. 3

A BCOR-CCNB3 fusion sarcoma is composed of spindled cells resembling a poorly differentiated synovial sarcoma.

Fig. 4

EWSR1-NFATC2 fusion sarcoma has often a corded cellular pattern with myxoid matrix between the cellular cords composed of uniform round cells.

Fig. 5

A and B, ACTB-GLI1 fusion sarcoma shows histologic resemblance to skin adnexal tumors such as myoepithelioma. Tumor cells show variable positivity for S100 protein and CD99.

Fig 6

A-C, LMNA-NTRK1 fusion sarcoma shown here grows permeatively in subcutaneous fat and is composed of uniform spindled to ovoid cells with low mitotic activity. The tumor cells are immunohistochemically positive for S100 protein and often CD34. Immunoreactivity for NTRK is a consistent although not totally specific feature.