Synovial chondromatosis and soft tissue chondroma: extraosseous cartilaginous tumor defined by FN1 gene rearrangement

Abstract

A fusion between fibronectin 1 (FN1) and activin receptor 2A (ACVR2A) has been reported previously in isolated cases of the synovial chondromatosis. To analyse further and validate the findings, we performed FISH and demonstrated recurrent FN1-ACVR2A rearrangements in synovial chondromatosis (57%), and chondrosarcoma secondary to synovial chondromatosis (75%), showing that FN1 and/or AVCRA2 gene rearrangements do not distinguish between benign and malignant synovial chondromatosis. RNA sequencing revealed the presence of the FN1-ACVR2A fusion in several cases that were negative by FISH suggesting that the true prevalence of this fusion is potentially higher than 57%. In soft tissue chondromas, FN1 alterations were detected by FISH in 50% of cases but no ACVR2A alterations were identified. RNA sequencing identified a fusion involving FN1 and fibroblast growth factor receptor 2 (FGFR2) in a case of soft tissue chondroma and FISH confirmed recurrent involvement of both FGFR1 and FGFR2. These fusions were present in a subset of soft tissue chondromas characterised by grungy calcification a feature reminiscent of phosphaturic mesenchymal tumour. However, unlike the latter, fibroblast growth factor 23 (FGF23) mRNA expression was not elevated in soft tissue chondromas harbouring the FN1-FGFR1 fusion. The mutual exclusivity of ACVR2A rearrangements observed in synovial chondromatosis and FGFR1/2 in soft tissue chondromas suggests these represent separate entities. There have been no reports of malignant soft tissue chondromas, therefore differentiating these lesions will potentially alter clinical management by allowing soft tissue chondromas to be managed more conservatively.

Chondrogenic Bone Tumors: The Importance of Imaging Characteristics

“…Das Chondroblastom und das Chondromyxoidfibrom wurden im Rahmen der aktuellen WHO-Klassifikation von 2020 von der intermediären in die benigne Gruppe verschoben. Die synoviale Chondromatose wurde von der benignen in die intermediäre Gruppe verschoben, um das lokal aggressive Wachstumsmuster und das hohe Risiko für Lokalrezidive abzubilden [8]. Zu der intermediären Gruppe gehört aufgrund des lokal aggressiven Wachstumsmusters auch der atypische kartilaginäre Tumor (ACT) der Extremitäten [9].…”

Calcified chondroid mesenchymal neoplasms with FN1-receptor tyrosine kinase gene fusions including MERTK, TEK, FGFR2, and FGFR1: a molecular and clinicopathologic analysis

“…Chimeric transcripts and proteins detected in the cohort of soft tissue chondroma of this study and related tumors in the literature, showing the retained exons and functional domains of the fusion genes of FN1, FGFR2, FGFR1, MERTK , and PLAG1 . Case 102 is the only case with FN1-FGFR2 characterized by RNA-seq previously (2). *PMTs = Phosphaturic Mesenchymal Tumors with FN1-FGFR1 fusions and range of breakpoints reported in the literature (3,12,25,27,28).…”

“…Specifically, synovial chondromatosis, characterized by multinodular growth of mature cartilaginous tissue with clustering of chondrocytes has recently been shown as frequently harboring the FN1-ACVR2 translocation (2). Fusion of FN1 to FGFR1 or FGFR2 has also been described in soft tissue chondroma, particularly in examples showing grungy to lacy (chondroblastoma-like) calcification (2). Phosphaturic mesenchymal tumor, frequently harboring FN1-FGFR1 or FN1-FGF1 fusions, shows variable histologic features, and is generally characterized as a proliferation of bland spindled to stellate cells with associated flocculent-appearing calcified, chondroid or ossified matrix within a highly vascularized stroma (3,4).…”

Updates from the 2020 World Health Organization Classification of Soft Tissue and Bone Tumours

“…Furthermore, recurrent rearrangements of FN1 and/or ACVR2A have been characterised in 57% of cases 52,87,88 . Synovial chondromatosis therefore joins a growing list of mesenchymal tumours with fibronectin gene ( FN1 ) rearrangements outlined earlier that show chondroid matrix production 52,87 . It is important to note that FN1 / ACVR2A rearrangement may also be detected in chondrosarcomas that can rarely develop from synovial chondromatosis 88 …”