Chondrosarcoma pathophysiology
Chondrosarcoma Microchapters |
Diagnosis |
---|
Treatment |
Case Studies |
Chondrosarcoma pathophysiology On the Web |
American Roentgen Ray Society Images of Chondrosarcoma pathophysiology |
Risk calculators and risk factors for Chondrosarcoma pathophysiology |
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rohan A. Bhimani, M.B.B.S., D.N.B., M.Ch.[2]
Overview
The exact pathogenesis of [disease name] is not fully understood.
OR
It is thought that [disease name] is the result of / is mediated by / is produced by / is caused by either [hypothesis 1], [hypothesis 2], or [hypothesis 3].
OR
[Pathogen name] is usually transmitted via the [transmission route] route to the human host.
OR
Following transmission/ingestion, the [pathogen] uses the [entry site] to invade the [cell name] cell.
OR
[Disease or malignancy name] arises from [cell name]s, which are [cell type] cells that are normally involved in [function of cells].
OR
The progression to [disease name] usually involves the [molecular pathway].
OR
The pathophysiology of [disease/malignancy] depends on the histological subtype.
Pathophysiology
Physiology
- Cartilaginous tumors are seen in bones that arise from enchondral ossification.
- There is hypertrophy of the resting zone chondrocytes due to proliferation and differentiation within the normal growth plate.
- These cells the undergo apoptosisresulting in invasion of vessels and osteoblasts that start to form bone and lead to longitudinal bone growth.
- This physiologic process is regulated by components of the Indian hedgehog (IHH)/parathyroid hormone related (PTHRP) protein signaling pathway.
Pathogenesis
Patients with multiple osteochondromas (previously called hereditary multiple exostoses) have germline mutations in the exostosin (EXT1 or EXT2) genes [75-77], with loss of the remaining wild type allele in the cartilage cap of the osteochondroma [78]. The end result is decreased EXT expression. Loss of expression of the EXT genes through homozygous deletion of EXT1 is also seen in solitary osteochondromas that are unassociated with the hereditary syndrome [79,80]. The EXT gene products are involved in the biosynthesis of heparan sulfate proteoglycans (HSPGs), which are essential for cell signaling through IHH/PTHLH and other pathways [81].
In osteochondromas where EXT is inactivated, the HSPGs seem to accumulate in the cytoplasm and Golgi apparatus instead of being transported to the cell surface [80]. This hampers multiple growth signaling pathways (including the IHH/PTHRP protein pathways), which, as noted above, are important for normal chondrocyte proliferation and differentiation within the normal human growth plate.
In secondary peripheral chondrosarcomas arising in osteochondromas, EXT is usually wild type, suggesting that the wild type cells in osteochondroma are prone to malignant transformation through EXT independent mechanisms [82]. Using a mouse model, it was shown that additional genetic alterations involving the TP53 or pRb pathway are involved in the progression from osteochondroma to secondary peripheral chondrosarcoma [83]. In addition, a role for IHH signaling has been suggested, although the data are not entirely consistent [84-88]:
●PTHRP signaling, which is downstream of IHH and is involved in chondrocyte proliferation, is absent in osteochondromas, but upregulated with malignant transformation towards secondary peripheral chondrosarcoma, especially in high-grade lesions [85,86,89-92].
●There is decreased expression of downstream targets in the IHH signaling cascade during tumor progression in peripheral chondrosarcomas, while they are still active in central chondrosarcomas [93].
●Data from in vitro and in vivo models show that treatment of central chondrosarcoma cells with recombinant Hedgehog increases proliferation, whereas treatment with Hedgehog signaling inhibitors inhibits tumor proliferation and growth in a small subset of tumors and chondrosarcoma cell cultures [88,93,94].
A multistep genetic model for the development of secondary (peripheral) chondrosarcomas has been proposed (figure 2) [14].
With regards to the molecular genetics of enchondromas and the far more common primary (central) chondrosarcomas, point mutations in isocitrate dehydrogenase-1 and isocitrate dehydrogenase 2 genes IDH1 and IDH2 have been identified in 40 to 56 percent of cases, and seem to be an early event [24,95]. Also, Ollier disease and Maffucci syndrome are caused by somatic mosaic mutations in IDH1 and IDH2 [24,25]. The identification of IDH1 and IDH2 mutations in four chondrosarcoma cell lines provides an in vitro model to study the role of these mutations in tumorigenesis [24]. Isocitrate dehydrogenase is an enzyme that converts isocitrate to alpha-ketoglutarate in the TCA (tricarboxylic acid) cycle. Mutations in IDH1 and IDH2 cause elevated levels of the oncometabolite D-2-hydroxyglutarate (D-2-HG), which competitively inhibits alpha-ketoglutarate dependent enzymes, such as TET2, thereby inducing epigenetic changes, including DNA hypermethylation and histone modification, probably affecting differentiation [96]. Increased levels of D-2-HG promote chondrogenic and inhibit osteogenic differentiation of mesenchymal stem cells. Thus, mutations in IDH1 or -2 lead to a local block in osteogenic differentiation during skeletogenesis, causing the development of benign cartilaginous tumors [97,98]. Indeed, also in mice, mutant IDH or D-2-HG causes persistence of chondrocytes, giving rise to rests of growth-plate cells that persist in the bone as enchondromas [99].
In addition, although EXT is not involved, involvement of the IHH/PTHLH signaling pathway is suggested by the observations that PTHRP signaling is active in enchondromas [89,92], and hedgehog signaling is active in central chondrosarcomas [93]. Moreover, a mutation in the gene encoding the receptor for PTHRP (PTH-1 receptor or PTH1R) has been identified in enchondromatosis that is claimed to lead to constitutive activation of IHH signaling [87,100]. Three new heterozygous missense mutations have been described in the PTH1R gene in patients with Ollier disease, which result in reduced receptor function [101]. Mutations in PTH1R have not been found in sporadic chondrosarcomas, nor in Maffucci syndrome [24,25,102]; this gene may contribute to pathogenesis in only a very small subset (<5 percent) of patients with Ollier disease. Moreover, using whole exome sequencing, mutations were found in different genes involved in hedgehog signaling [103].
●While enchondromas and low-grade chondrosarcomas are near-diploid and carry few karyotypic abnormalities, high grade chondrosarcomas are aneuploid and have complex karyotypes [43,104]. Some of the few consistent genetic aberrations include 12q13-15 and 9p21 rearrangements [43,104-107].
●Chondrosarcoma progression has been linked to the CDKN2A (p16) tumor suppressor gene, located at 9p21 [108,109] and by alterations in p53 [110].
●Mutations in COL2A1 are found in a subset of chondrosarcomas, the meaning of which is as yet unknown [103].
●Activation and/or overexpression of platelet-derived growth factor receptor-alpha (PDGFRA) and beta (PDGFRB) has been described in conventional primary chondrosarcomas, although activating mutations have not been found [111,112]. The therapeutic implications of this finding are discussed below. (See 'Novel therapies' below.)
A multistep genetic model for development of primary chondrosarcomas has been proposed (figure 3) [14].
Dedifferentiated chondrosarcomas also contain IDH1 or IDH2 mutations in approximately 50 percent of cases [24,49,95].
The majority of mesenchymal chondrosarcomas was shown to harbor a specific HEY1-NCOA2 fusion product caused by an intrachromosomal rearrangement of chromosome arm 8q [113]. Alternatively, a IRF2BP2-CDX1 fusion gene brought about by translocation t(1;5)(q42;q32) was described [114].
Gross Pathology
On gross pathology, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].
Microscopic Pathology
On microscopic histopathological analysis, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].