A molecular study of synovial chondromatosis

Abstract

Synovial chondromatosis (SC) is a rare benign cartilaginous neoplasm in which recurrent fibronectin 1 (FN1) and activin receptor 2A (ACVR2A) gene rearrangements have been recently reported. Triggered by a case of malignant transformation in SC (synovial chondrosarcoma) showing a novel KMT2A‐BCOR gene fusion by targeted RNA sequencing, we sought to evaluate the molecular abnormalities in a cohort of 27 SC cases using a combined methodology of fluorescence in situ hybridization (FISH) and/or targeted RNA sequencing. Results showed that FN1 and /or ACVR2A gene rearrangements were noted in 18 cases (67%), with an FN1‐ACVR2A fusion being confirmed in 15 (56%) cases. Two cases showed only FN1 gene rearrangement, without other abnormalities. A novel FN1‐NFATc2 gene fusion was noted in one case by RNA sequencing. The remaining nine cases showed no abnormalities in FN1 and ACVR2A genes. No additional cases showed BCOR gene alterations. In conclusion, this study confirms that FN1‐ACVR2A fusion is the leading pathogenetic event in SC, at even higher frequency than previously reported. FISH methodology emerges as an appropriate tool in the identification of FN1 and ACVR2A gene abnormalities, which can be used in challenging cases. Further studies are needed to determine the recurrent potential of BCOR abnormalities in this disease.

Synovial chondrosarcoma: a single‐institution experience with molecular investigations and review of the literature

“…As IDH1/IDH2 mutations seem to be exclusively found in central and periosteal cartilaginous tumours, and are early events in the pathogenesis of these subtypes of cartilaginous tumour, 16,37 we molecularly analysed seven synovial chondrosarcoma cases; however, we did not identify any mutation. To the best of our knowledge, this is the first report of IDH/IDH2 mutations in synovial chondrosarcomas; on the basis of our results, it can be suggested that this molecular marker is not useful in the distinction between synovial chondromatosis and synovial chondrosarcoma.…”

“…Interestingly recent studies 38 reported the presence of FN1-ACVR2A and ACVR2A-FN1 in-frame fusions in 31 of 57 (54%) cases of synovial chondromatosis and in two of three secondary synovial chondrosarcomas. 37 These data would indeed support a link between these tumour entities, but unfortunately they cannot help in separating synovial chondromatosis from synovial chondrosarcoma.…”

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

“…Synovial chondromatosis was previously considered to be benign, but it is now classed as having intermediate (locally aggressive) biological potential. 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 .…”

“…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 Chondromyxoid fibroma is now classified as a benign entity (with a local recurrence rate of approximately 10-15%).…”

“…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 …”