Identification of EWSR1–NFATC2 fusion in simple bone cysts

Abstract

Identification of EWSR1-NFATC2 fusion in simple bone cystsAims: Simple bone cysts are benign intramedullary tumours primarily involving the long bones in skeletally immature individuals. Several mechanisms have been proposed for their pathogenesis. Although the diagnosis is typically straightforward, the interpretation can be problematic, because of superimposed fracture causing them to resemble aneurysmal bone cysts and other tumours. EWSR1-NFATC2 or FUS-NFATC2 fusions, which are characteristic of a subset of aggressive round cell sarcomas, have been recently detected in simple bone cysts. The aim of this study was to examine the clinicopathological and molecular features in a series of simple bone cysts. Methods and results: Using RNA-based next-generation sequencing and/or fluorescence in-situ hybridisation, we investigated the presence of EWSR1 or FUS rearrangements in nine simple bone cysts. The patients were five females and four males, aged 3-23 years (median, 14 years); the tumours ranged from 19 mm to 160 mm (median, 46 mm) in size, and involved the femur (n = 3), humerus (n = 2), fibula (n = 2), tibia (n = 1), and iliac wing (n =1). We identified three cases with EWSR1-NFATC2 fusion (showing identical breakpoints to those in EWSR1-NFATC2 sarcomas) and one additional case with FUS rearrangement. Unlike in EWSR1-NFATC2 sarcomas, immunohistochemical expression of NKX3.1 and NKX2.2 was absent in two simple bone cysts tested. Conclusions: More than 40% of simple bone cysts harbour genetic alterations confirming that they are neoplastic, investigation of EWSR1 and/or FUS rearrangement may help to distinguish simple bone cysts from mimics, and NFATC2 rearrangement is not pathognomonic of malignancy.

EWSR1—The Most Common Rearranged Gene in Soft Tissue Lesions, Which Also Occurs in Different Bone Lesions: An Updated Review

“…SBC was initially reported by Rudolf Virchow in 1876 [179][180][181]. It is a benign intramedullary cystic lesion involving the long bones in skeletally immature individuals.…”

“…Symptoms can be pain and swelling. A unilocular expansile cyst showing double-density fluid levels is radiologically characteristic [5,179,180,182].…”

“…Secondary changes as hemorrhage with resorption with chronic inflammation can be found after fracture. This can camouflage the classical microscopical features [5,179,180,182]. In 2002, the translocation (16;20)(p11.2;q13) was identified as the sole cytogenetic abnormality in a SBC case [183].…”

“…In 2002, the translocation (16;20)(p11.2;q13) was identified as the sole cytogenetic abnormality in a SBC case [183]. Recently, the corresponding FUS1-NFATC2 or alternatively EWSR1-NFATC2 fusion have been demonstrated in a subset of cases proving that SBC is a neoplasm [5,180,182] Besides ABC, other differential diagnoses are cystic fibrous dysplasia, intraosseous ganglion, or lipoma (Table 14) [5,180]. Conservative and surgical treatment are discussed in the literature.…”

“…Conservative and surgical treatment are discussed in the literature. The recurrence rate is low but fractures are a known complication [5,179,180].…”