Chondroid Soft Tissue Tumors With FOS :: PABPN1 Fusion: A New Entity? About Two Cases

Abstract

Soft tissue tumors with chondroid matrix represent a heterogeneous group with persistent diagnostic challenges. Advances in molecular diagnostics have identified recurrent gene fusions in several chondroid neoplasms, predominantly involving FN1. Here, we report two cases of chondroid tumors harboring a novel FOS::PABPN1 fusion. The patients were young and presented with small, deep, peri-osseous nodules located in the extremities. Histologically, the tumors were well-circumscribed and lobulated. Both cases presented fibro-cartilaginous and spindle cell areas. No cytonuclear atypia, mitoses, or necrosis were observed. Immunohistochemistry (performed in Case 2) revealed positivity for S100, CD34, and FOS, with negativity for MDM2, HMGA2, PLAG1, and desmin. RNA sequencing identified an identical in-frame FOS::PABPN1 fusion transcript in both tumors. Unsupervised transcriptomic clustering positioned the cases near synovial chondromatoses and other chondroid lesions, despite the absence of FN1 rearrangements. Massive overexpression of the WIF1 (Wnt Inhibitory Factor1) gene was also observed. To our knowledge, this is the first description of FOS rearrangement in mesenchymal tumors exhibiting chondroid differentiation. The FOS::PABPN1 fusion expands the spectrum of FOS-altered neoplasms beyond osteoblastic and vascular lesions and defines a potential new molecular subset of benign chondroid tumors. These findings highlight the utility of RNA sequencing in the diagnosis of chondroid neoplasms in order to identify rearrangement (of FN1, THBS1 or FOS) or IDH1/2. The consistent upregulation of WIF1 may represent a potential diagnostic biomarker.