Biology and Management of High-Grade Chondrosarcoma: An Update on Targets and Treatment Options

Abstract

This review provides an overview of histopathology, clinical presentation, molecular pathways, and potential new systemic treatments of high-grade chondrosarcomas (CS), including grade 2–3 conventional, dedifferentiated, and mesenchymal CS. The diagnosis of CS combines radiological and histological data in conjunction with patient clinical presentations. Conventional CS is the most frequent subtype of CS (85%) and represents about 25% of primary bone tumors in adults; they can be categorized according to their bone location into central, peripheral, and periosteal chondrosarcomas. Central and peripheral CS differ at the molecular level with either IDH1/2 mutations or EXT1/2 mutations, respectively. CDKN2A/B deletions are also frequent in conventional CS, as well as COL2A1 mutations. Dedifferentiated CS develops when low-grade conventional CS transforms into a high-grade sarcoma and most frequently exhibits features of osteosarcoma, fibrosarcoma, or undifferentiated pleomorphic sarcoma. Their molecular characteristics are similar to conventional CS. Mesenchymal CS is a totally different pathological entity exhibiting recurrent translocations. Their clinical presentation and management are different too. The standard treatment of CSs is wide en-bloc resection. CS are relatively radiotherapy resistant; therefore, doses >60 Gy are needed in an attempt to achieve local control in unresectable tumors. Chemotherapy is possibly effective in mesenchymal chondrosarcoma and is of uncertain value in dedifferentiated chondrosarcoma. Due to resistance to standard anticancer agents, the prognosis is poor in patients with metastatic or unresectable chondrosarcomas. Recently, the refined characterization of the molecular profile, as well as the development of new treatments, allow new therapeutic options for these rare tumors. The efficiency of IDH1 inhibitors in other malignancies suggests that these inhibitors will be part of IDH1/2 mutated conventional CS management soon. Other treatment approaches, such as PIK3-AKT-mTOR inhibitors, cell cycle inhibitors, and epigenetic or immune modulators based on improving our understanding of CS molecular biology, are emerging.

Classification of Chondrosarcoma: From Characteristic to Challenging Imaging Findings

“…Developing an efficient treatment strategy requires a better understanding of the molecular survival pathways involved in chondrosarcomas and their chemotherapy and radiation resistance mechanisms [ 104 ]. Chondrosarcoma subtypes differ at the molecular genetic level ( Table 2 ) [ 105 ]. Recent studies have suggested several promising biomarkers and therapeutic targets for chondrosarcomas, with better understanding of chondrosarcoma genomic alterations and biology [ 103 , 105 , 106 , 107 , 108 , 109 , 110 ].…”

“…Chondrosarcoma subtypes differ at the molecular genetic level ( Table 2 ) [ 105 ]. Recent studies have suggested several promising biomarkers and therapeutic targets for chondrosarcomas, with better understanding of chondrosarcoma genomic alterations and biology [ 103 , 105 , 106 , 107 , 108 , 109 , 110 ]. As shown in Table 2 , the signaling pathways underpinning chondrosarcoma genesis such as IDH1/2 mutations, CDKN2A/B deletions, and TP53 mutations can be potential therapeutic targets [ 105 ].…”

“…Recent studies have suggested several promising biomarkers and therapeutic targets for chondrosarcomas, with better understanding of chondrosarcoma genomic alterations and biology [ 103 , 105 , 106 , 107 , 108 , 109 , 110 ]. As shown in Table 2 , the signaling pathways underpinning chondrosarcoma genesis such as IDH1/2 mutations, CDKN2A/B deletions, and TP53 mutations can be potential therapeutic targets [ 105 ]. The angiogenesis pathway is a potential effective target for preventing the growth and spread of chondrosarcoma [ 105 ].…”

“…As shown in Table 2 , the signaling pathways underpinning chondrosarcoma genesis such as IDH1/2 mutations, CDKN2A/B deletions, and TP53 mutations can be potential therapeutic targets [ 105 ]. The angiogenesis pathway is a potential effective target for preventing the growth and spread of chondrosarcoma [ 105 ]. Conventional chondrosarcomas are characterized by activation and/or overexpression of platelet-derived growth factor receptors PDGFR-alpha (PDGFRA) and PDGFR-beta (PDGFRB), and efforts to develop antiangiogenic therapies have produced many agents such as small molecule tyrosine kinase inhibitors and fully human monoclonal antibodies which affect angiogenesis [ 111 ].…”

Chondrosarcoma Resistance to Radiation Therapy: Origins and Potential Therapeutic Solutions

“…The expression of these factors, independently of O2 concentrations, will be responsible for tumor progression and radioresistance. In addition, chondrosarcoma cells are often EXT1/2 mutated and CDKN2A/B deletions are also frequent, as well as COL2A1 mutations [ 27 ]. In osteosarcoma, another rare malignant bone tumor, the expression of several repetitive elements was observed differentially expressed with normal bone.…”