Clinical and molecular characterization of primary sclerosing epithelioid fibrosarcoma of bone and review of the literature

Abstract

Sclerosing epithelioid fibrosarcoma (SEF) is a rare sarcoma subtype characterized by monomorphic epithelioid cells embedded in a densely sclerotic collagenous matrix. The overwhelming majority of tumors arise in soft tissues; however, rare cases have been documented to occur primarily in bone. The hallmarks of soft tissue SEF include MUC4 immunoreactivity and the presence of an EWSR1-CREB3L1 fusion. Rare cases with alternative fusions have also been reported such as EWSR1-CREB3L2 and FUS-CREB3L2 transcripts. The molecular alterations of skeletal SEF have not been well-defined, with only rare cases analyzed to date. In this study we investigated the clinicopathologic and molecular features of seven patients presenting with primary osseous SEF. There were 3 males and 4 females, with a mean age at diagnosis of 38 years. All cases had microscopic features within the histologic spectrum of SEF and showed strong and diffuse MUC4 positivity, while lacking SATB2 expression. However, due to its unusual presentation within bone, four cases were initially misinterpreted as either osteosarcoma, Ewing sarcoma or chondroblastoma. Half of the patients with follow-up data developed metastasis. The cases were tested by targeted RNA sequencing, MSK-IMPACT, and/or fluorescence in situ hybridization, showing EWSR1-CREB3L1 in six cases and EWSR1-CREB3L2 in one case. The fusion transcripts were composed of EWSR1 exon 11 to either exon 6 of CREB3L1 or CREB3L2. In summary, due to their rarity in the bone, skeletal SEF are often misdiagnosed, resulting in inadequate treatment modalities. Similar to their soft tissue counterpart, bone SEF follow an aggressive clinical behavior and show similar EWSR1-CREB3L1/CREB3L2 fusions.

Keywords: CREB3L1; CREB3L2; EWSR1; fusions; sclerosing epithelioid fibrosarcoma.

Figure 1.. Imaging studies demonstrating a primary bone lesion.

A) X-ray showing a destructive right femur lesion (Case# 1). B) MRI T2 weighted image showing a mass in the right femur with bone marrow edema (Case# 1). C) X-ray showing a left proximal femur lytic lesion associated with pathologic fracture (Case# 2). D) CT showing lytic skull mass with bone destruction and extra-osseous extension (Case# 5). E) CT showing a left mandibular destructive mass with extra-osseous extension (Case# 6).

Figure 2.. Histologic features of skeletal SEF.

Classic morphologic appearance with uniform epithelioid cells separated by wiry collagen bundles in cord and columns (A); alternating markedly hyalinized hypocellular areas suggesting a benign/reactive process are noted (B). An abrupt transition between the more cellular, sometimes with a spindling phenotype, and hypocellular areas can be noted (C). Some tumors show highly cellular/primitive areas, almost completely devoid of fibrotic stroma, arranged in sheets of nests, reminiscent of an undifferentiated round cell sarcoma or Ewing sarcoma (D,E). In other tumors, the lesional cells have a more plasmacytoid or rhabdoid phenotype, with densely eosinophilic cytoplasm and eccentric round nuclei (F). This tumor showed a densely hyalinized matrix s/p neoadjuvant chemotherapy, highly suggestive of osteoid matrix deposition (G); however, the tumor cells were negative for SATB2 (with good internal positive control the adjacent osteoblasts), while being strongly positive for MUC4.

Figure 3.. Diagrammatic representation of the EWSR1-CREB3L1 and EWSR1-CREB3L2 fusions studied by targeted RNA sequencing.

Upper and middle panel show chromosomal localization of EWSR1 on 22q12.2, CREB3L1 on 11p11.2 and CREB3L2 on 7q33. Red vertical lines depict the genomic breakpoints. Orange arrows and bars show the direction of transcription of each gene and the exonic breaks, respectively. The protein domains of each gene are shown below. Fusion variants are depicted at the bottom of each panel showing EWSR1 exon 11 fused to CREB3L1 exon 6 and EWSR1 exon 11 to CREB3L2 exon 6.