Mesenchymal Chondrosarcoma from Diagnosis to Clinical Trials

Simple Summary Mesenchymal chondrosarcoma (MCS) is a subtype of chondrosarcoma with rare occurrence and poor survival rates. MCS stains positive for S-100 and SOX9 as well as CD99, ezrin, and NKX2.2. Recurring fusion of the HEY1 and NCOA2 genes-involved in epigenetic modifications-was reported in MSC. MCS may also be positive for IRF2BP2-CDX1 fusion, loss of the cyclin-dependent kinase inhibitor 2A (CDKN2A)/p16 or loss of TP53. Treatment of these tumors is difficult and there is lack of therapeutical options for patients with advanced and metastatic disease due to the unknown pathogenesis of MCS. Despite the limited efficacy of conventional chemotherapy in an advanced setting, young patients may be considered for chemotherapy combined with aggressive local treatment and/or RT. The data of other therapeutic options, including immunotherapy efficacy, are limited. If available, patients with MCS should be considered potential candidates for clinical trials.Abstract Mesenchymal chondrosarcoma (MCS) is a rare subtype of chondrosarcoma with a poor prognosis. Although these tumors are sensitive to radiotherapy/chemotherapy, the standard treatment for localized MCS is only surgical resection, and there are no established treatment guidelines for patients with advanced and metastatic MCS. Due to the low incidence of MCS, the pathology of these tumors is still unknown, and other therapeutic options are lacking. Some studies show the potential role of the PDGF/PPI3K/AKT, PKC/RAF/MEK/ERK, and pRB pathways, and BCL2 overexpression in the pathogenesis of MCS. These findings provide an opportunity to use protein kinases and BCL2 inhibitors as potential therapy in MCS. In this review, we summarize the current knowledge about MCS diagnosis and treatment options. We show the immunological and molecular biomarkers used in the diagnosis of MCS. In addition, we discuss the known prognostic and predictive factors in MCS. Finally, we present the novel trends, including targeted therapies and ongoing clinical trials using protein kinase inhibitors and the death receptor 5 (DR5) agonist, which may be the focus of future MCS treatment studies.