The biology and management of cartilaginous tumors: a role for targeting isocitrate dehydrogenase.

Chondrosarcomas are rare mesenchymal neoplasms defined by the production of abnormal cartilaginous matrix. Conventional chondrosarcoma is the most common histology. The management of primary conventional chondrosarcoma generally is surgical with the possible addition of radiation therapy. Treatment of conventional chondrosarcoma is problematic in unresectable or metastatic disease because the tumors tend to be resistant to standard sarcoma chemotherapy regimens. Previous attempts at targeted therapy, including inhibitors of Hedgehog signaling, the mTOR pathway, and platelet-derived growth factor receptor (PDGFR) have been largely disappointing. However, heterozygous mutations in isocitrate dehydrogenase (IDH) enzymes recently have been identified in chondrogenic neoplasms, with mutations reported in approximately 87% of benign enchondromas, 70% of conventional chondrosarcomas, and 54% of dedifferentiated chondrosarcomas. The normal IDH protein continues to produce alpha-ketoglutarate (alpha-KG) whereas the mutant IDH protein converts KG to the oncometabolite 2-hydroxyglutarate (2-HG). Clinical trials of novel IDH inhibitors are ongoing, with evidence of early activity in IDH-mutant leukemias. IDH inhibitors show antitumor effects against IDH-mutant chondrosarcoma cell lines, supporting the inclusion of patients with chondrosarcoma with IDH mutations on IDH inhibitor clinical trials for solid tumors. Targeting IDH mutations may offer hope of a novel antineoplastic strategy not only for patients with chondrosarcomas, but also for other solid tumors with aberrant IDH activity.

Squamous cell carcinoma arising in dedifferentiated chondrosarcoma proved by isocitrate dehydrogenase mutation analysis.

Dedifferentiated chondrosarcoma is a primary bone tumor characterized by the presence of both low-grade cartilaginous and high-grade malignant noncartilaginous components. The high-grade noncartilaginous component is typically a pleomorphic fibroblastic spindle cell sarcoma. Dedifferentiation into a malignant epithelial component is extremely rare. In this report, we present a 74-year-old woman who developed a metastatic squamous cell carcinoma in the right inguinal area 1 year after wide resection of her right proximal femur for a dedifferentiated chondrosarcoma. The dedifferentiated component was composed of poorly differentiated epithelioid cells with foci of squamous cell carcinoma. Mutational analysis was performed, and the isocitrate dehydrogenase 1 R132C mutation was detected in the low-grade chondrosarcoma, dedifferentiated chondrosarcoma as well as the metastatic squamous cell carcinoma. And this mutation was not detected in patient's normal tissue. Our study supports the theory that both the chondrosarcoma cells and dedifferentiated epithelioid tumor cells arose from the same clonal origin.