Central Chondrosarcoma, Grades 2 and 3

Staging is according to bone sarcoma protocols (see TNM staging of tumors of bone). See also the information on staging in section Bone tumors: Introduction.

About half of these tumors carry IDH1 or IDH2 mutations, suggesting that they have progressed from enchondroma and ACT/CS1. Grade 2 and 3 central chondrosarcomas are characterized by aneuploidy and complex karyotypes. Polyploidization of an initially hyperhaploid/hypodiploid cell population is a common mechanism of progression in a subset. Alterations in the p53 and RB1 signaling pathways are involved in tumor progression; the RB1 pathway is affected in 86% of high-grade chondrosarcomas, including by loss of p16 and overexpression and/or amplification of CDK4. TP53 is mutated in 20–49% of the cases, whereas mutations in CDKN2A (encoding p16) are infrequent. For central chondrosarcoma, several active signaling pathways have been identified, which might provide novel treatment options, such as hedgehog signaling, mTOR signaling, SRC and AKT, and metabolic pathways. Members of the BCL2 family seem to play an important role in the chemoresistance of chondrosarcoma.

Resection specimens reveal a translucent, often lobular, bluish-grey or white cut surface. Cystic changes can be seen, as well as areas of myxoid material. Calcification can be visible as yellowish-white chalky areas. Erosion and destruction of the cortex with soft tissue extension are frequently present. Extensive sampling is needed to rule out areas of dedifferentiation and chondroblastic osteosarcoma.

The tumors are cellular with an overall lobular configuration in which the tumor lobules permeate and entrap the pre-existing bone trabeculae. The tumor cells are embedded within the cartilaginous matrix, which can still be hyaline but most often shows myxoid changes to a variable extent. The cellularity is higher than in ACT/CS1 and mitoses are present. The nuclei can still be small and condensed, and severe condensation of the nuclei may hamper the detection of mitoses. More often the nuclei vary in size, with open chromatin and a visible nucleolus. Nuclear atypia can be present but is usually not severe. Binucleation can be seen and necrosis can be present. In grade 3 chondrosarcomas, mitoses are more easily found, and the cells at the periphery of the mostly myxoid, highly cellular tumor lobules are spindled and less differentiated. These spindled cells gradually merge with the fibrous cells in the fibrous septations surrounding the lobules that contain numerous small vascular channels and immune cells. The tumors often destroy and grow through the cortex.

Not clinically relevant

Patients are usually treated with en bloc resection to obtain negative margins. The reported 5-year overall survival rate for grade 2 chondrosarcoma is 74–99% and for grade 3 tumors 31–77%. The 10-year overall survival rate for grade 2 is 58–86% and for grade 3 tumors 26–55%. Even after 10 years, deaths due to disease can still occur. Local recurrence rates are 19% for grade 2 and 26% for grade 3 chondrosarcoma; 10–30% of the grade 2 tumors and 32–71% of the grade 3 tumors metastasize. Chondrosarcomas with axial localization have a significantly lower survival than extremity chondrosarcoma. It is unclear at present whether the IDH mutation is associated with outcome.

Molecular analysis is not needed for diagnosis in most cases. Detection of mutations in the isocitrate dehydrogenase genes IDH1 and IDH2 may be helpful in distinguishing these tumors from chondroblastic osteosarcoma.

Essential: origin in the medulla of the bone; lobulated cartilaginous tumor with entrapment of pre-existing host bone; increased cellularity, myxoid matrix, and presence of mitoses; absence of osteoid deposition associated with malignant cells.