Secondary peripheral chondrosarcoma evolving from osteochondroma as a result of outgrowth of cells with functional EXT

Abstract

Secondary peripheral chondrosarcoma is the result of malignant transformation of a pre-existing osteochondroma, the most common benign bone tumor. Osteochondromas are caused by genetic abnormalities in EXT1 or EXT2: homozygous deletion of EXT1 characterizes sporadic osteochondromas (non-familial/solitary), and germline mutations in EXT1 or EXT2 combined with loss of heterozygosity define hereditary multiple osteochondromas. While cells with homozygous inactivation of EXT and wild-type cells shape osteochondromas, the cellular composition of secondary peripheral chondrosarcomas and the role of EXT in their formation have remained unclear. We report using a targeted-tiling-resolution oligo-array-CGH (array comparative genomic hybridization) that homozygous deletions of EXT1 or EXT2 are much less frequently detected (2/17, 12%) in sporadic secondary peripheral chondrosarcomas than expected based on the assumption that they originate in sporadic osteochondromas, in which homozygous inactivation of EXT1 is found in B80% of our cases. FISH with an EXT1 probe confirmed that, unlike sporadic osteochondromas, cells from sporadic secondary peripheral chondrosarcomas predominantly retained one (hemizygous deleted loci) or both copies (wild-type) of the EXT1 locus. By immunohistochemistry, we confirm the presence of cells with dysfunctional EXT1 in sporadic osteochondromas and show cells with functional EXT1 in sporadic secondary peripheral chondrosarcomas. These immuno results were verified in osteochondromas and secondary peripheral chondrosarcomas in the setting of hereditary multiple osteochondromas. Our data therefore point to a model of oncogenesis in which the osteochondroma creates a niche in which wild-type cells with functional EXT are predisposed to acquire other mutations giving rise to secondary peripheral chondrosarcoma, indicating that EXT-independent mechanisms are involved in the pathogenesis of secondary peripheral chondrosarcoma.

Dedifferentiated peripheral chondrosarcoma: a clinicopathologic, immunohistochemical, and molecular analysis of four cases

“…Inactivation of the EXT1 and/or the EXT2 genes is a well-known event in the development of osteochondromas [6], but it is likely not involved in the pathogenesis of secondary peripheral CS [7]. An immunohistochemical analysis of cell signaling pathways that are known to have an important role in normal chondrocyte proliferation showed that the FGF signaling pathway is more frequently active than in the chondrogenic component of conventional secondary peripheral CS, whereas PTHLH signaling seems to be low/downregulated [5].…”

Epiphyseal growth plate and secondary peripheral chondrosarcoma: the neighbours matter

“…It indicates that homozygous inactivation of Ext1 in a small fraction of chondrocytes is required and sufficient for the initiation of osteochondromas in this model. In human osteochondromas, it has been shown by fluorescence in situ hybridization (FISH) with an EXT1 probe that cells with homozygous deletion of EXT1 constitute the major population of cells in the tumour [67]. It is plausible to foresee that number of wild-type cells in the osteochondroma cap varies depending on the patient's age, decreasing upon osteochondroma maturation.…”

“…The role of the micro-environment in secondary peripheral chondrosarcoma formation has been recently described (Figure 2) [67]. Secondary peripheral chondrosarcoma is a malignant cartilage-producing tumour that arises from the cartilage cap of an osteochondroma [75].…”

“…Secondary peripheral chondrosarcoma is a malignant cartilage-producing tumour that arises from the cartilage cap of an osteochondroma [75]. It has been shown that, while homozygous mutations in EXT1/EXT2 are crucial for the formation of an osteochondroma, genetic alteration(s) in other gene(s) than EXT1/EXT2 is(are) the causing event(s) of a subset of secondary peripheral chondrosarcoma [67]. Additionally, IDH1/IDH2 mutations are shown not to be involved in secondary peripheral chondrosarcomas formation [76].…”

“…Hypothetically, secondary peripheral chondrosarcomas may arise from clonal growth of committed stem cells/wild-type chondrocytes or cells with homozygous inactivation of EXT1/EXT2 (Figure 2). Osteochondromas cells originating chondrosarcoma is a rare event, base on the fact that very few secondary peripheral chondrosarcomas display homozygous deletion of EXT1/EXT2 [67].…”