Chondrosarcoma pathophysiology
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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.[1]
- There is hypertrophy of the resting zone chondrocytes due to proliferation and differentiation within the normal growth plate.[1]
- These cells the undergo apoptosis resulting 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
- The exact pathogenesis of chondrosarcoma is not full understood.[2]
- Multiple genes have been implicated in pathogenesis of chondrosarcoma.
Genetics
- Cytogenetic analysis chondrosarcomas revealed that structural abnormalities of chromosomes 1, 6, 9, 12 and 15.[3]
- Also, numerical abnormalities of chromosomes 5, 7, 8 and 18 were most frequent associated with chondrosarcoma.[4]
- Anomlaies associated with chromosome 9(9p12-22) are more commonly seen in central chondrosarcomas.[5]
- Patients with multiple osteochondromas seem to have germline mutations in the exostosin (EXT1 or EXT2) genes.[6]
- This result is decreased EXT expression and decreased biosynthesis and release of heparan sulfate proteoglycans (HSPGs), which are essential for cell signaling through IHH/PTHLH pathways.[7][8][9]
- This in turn decreases normal chondrocyte proliferation and differentiation within the normal human growth plate.
- Furthermore, the genetic mutations in the TP53 or pRb pathway are implied in the malignant transformation from osteochondroma to secondary peripheral chondrosarcoma.
- In enchondromas and central chondrosarcomas, point mutations in isocitrate dehydrogenase-1 and isocitrate dehydrogenase 2 genes IDH1 and IDH2 have been suggested.
- In addition, the Ollier disease and Maffucci syndrome are also result of somatic mosaic mutations in IDH1 and IDH2. [10]
- Isocitrate dehydrogenase is the necessary enzyme required for conversion of isocitrate to alpha-ketoglutarate in the tricarboxylic acid cycle.
- Mutations in IDH1 and IDH2 cause elevated levels of the oncometabolite D-2-hydroxyglutarate (D-2-HG) which promotes chondrogenesis and inhibit osteogenic differentiation of mesenchymal stem cells as well as causes DNA hypermethylation and histone modification, all resulting in decreased differentiation.[11]
- A missense mutation (R150C) in the gene encoding the receptor for PTHRP (PTH-1 receptor or PTH1R) has been associated to enchondromatosis in patients with Ollier disease, and decreased receptor function.[12][13][14]
- Low-grade chondrosarcomas are near-diploid and have very few karyotypic abnormalities.[15]
- On the other hand, high grade chondrosarcomas are aneuploid and have complex karyotypes.[15]
- The progression of chondrosarcoma has been linked to the CDKN2A (p16) tumor suppressor gene present at 9p21 and by mutation in p53.[16][17]
- Mutations in COL2A1 have also been hypothesized in pathogenesis of chondrosarcomas.[18]
- In addition, amplification of the c-myc and fos/jun has also been implicated in the pathogenesis of chondrosarcoma.[19][20]
- A specific HEY1-NCOA2 fusion product due to an intrachromosomal rearrangement of chromosome arm 8q result in mesenchymal chondrosarcoma.
- With extraskeletal myxoid chondrosarcomas, the t(9;22)(q22;q12) translocation is common.[21]
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].
References
- ↑ 1.0 1.1 Bovée JV, Hogendoorn PC, Wunder JS, Alman BA (2010). "Cartilage tumours and bone development: molecular pathology and possible therapeutic targets". Nat Rev Cancer. 10 (7): 481–8. doi:10.1038/nrc2869. PMID 20535132.
- ↑ Peabody, Terrance (2014). Orthopaedic oncology : primary and metastatic tumors of the skeletal system. Cham: Springer. ISBN 9783319073224.
- ↑ Bovée JV, Cleton-Jansen AM, Kuipers-Dijkshoorn NJ, van den Broek LJ, Taminiau AH, Cornelisse CJ; et al. (1999). "Loss of heterozygosity and DNA ploidy point to a diverging genetic mechanism in the origin of peripheral and central chondrosarcoma". Genes Chromosomes Cancer. 26 (3): 237–46. PMID 10502322.
- ↑ Bovée JV, Cleton-Jansen AM, Rosenberg C, Taminiau AH, Cornelisse CJ, Hogendoorn PC (1999). "Molecular genetic characterization of both components of a dedifferentiated chondrosarcoma, with implications for its histogenesis". J Pathol. 189 (4): 454–62. doi:10.1002/(SICI)1096-9896(199912)189:4<454::AID-PATH467>3.0.CO;2-N. PMID 10629543.
- ↑ Bovée JV, Sciot R, Dal Cin P, Debiec-Rychter M, van Zelderen-Bhola SL, Cornelisse CJ; et al. (2001). "Chromosome 9 alterations and trisomy 22 in central chondrosarcoma: a cytogenetic and DNA flow cytometric analysis of chondrosarcoma subtypes". Diagn Mol Pathol. 10 (4): 228–35. PMID 11763313.
- ↑ de Andrea CE, Reijnders CM, Kroon HM, de Jong D, Hogendoorn PC, Szuhai K; et al. (2012). "Secondary peripheral chondrosarcoma evolving from osteochondroma as a result of outgrowth of cells with functional EXT". Oncogene. 31 (9): 1095–104. doi:10.1038/onc.2011.311. PMID 21804604.
- ↑ Hameetman L, Szuhai K, Yavas A, Knijnenburg J, van Duin M, van Dekken H; et al. (2007). "The role of EXT1 in nonhereditary osteochondroma: identification of homozygous deletions". J Natl Cancer Inst. 99 (5): 396–406. doi:10.1093/jnci/djk067. PMID 17341731.
- ↑ McCormick C, Leduc Y, Martindale D, Mattison K, Esford LE, Dyer AP; et al. (1998). "The putative tumour suppressor EXT1 alters the expression of cell-surface heparan sulfate". Nat Genet. 19 (2): 158–61. doi:10.1038/514. PMID 9620772.
- ↑ Hameetman L, David G, Yavas A, White SJ, Taminiau AH, Cleton-Jansen AM; et al. (2007). "Decreased EXT expression and intracellular accumulation of heparan sulphate proteoglycan in osteochondromas and peripheral chondrosarcomas". J Pathol. 211 (4): 399–409. doi:10.1002/path.2127. PMID 17226760.
- ↑ Pansuriya TC, van Eijk R, d'Adamo P, van Ruler MA, Kuijjer ML, Oosting J; et al. (2011). "Somatic mosaic IDH1 and IDH2 mutations are associated with enchondroma and spindle cell hemangioma in Ollier disease and Maffucci syndrome". Nat Genet. 43 (12): 1256–61. doi:10.1038/ng.1004. PMC 3427908. PMID 22057234.
- ↑ Amary MF, Bacsi K, Maggiani F, Damato S, Halai D, Berisha F; et al. (2011). "IDH1 and IDH2 mutations are frequent events in central chondrosarcoma and central and periosteal chondromas but not in other mesenchymal tumours". J Pathol. 224 (3): 334–43. doi:10.1002/path.2913. PMID 21598255.
- ↑ Bovée JV, van den Broek LJ, Cleton-Jansen AM, Hogendoorn PC (2000). "Up-regulation of PTHrP and Bcl-2 expression characterizes the progression of osteochondroma towards peripheral chondrosarcoma and is a late event in central chondrosarcoma". Lab Invest. 80 (12): 1925–34. PMID 11140704.
- ↑ Rozeman LB, Hameetman L, Cleton-Jansen AM, Taminiau AH, Hogendoorn PC, Bovée JV (2005). "Absence of IHH and retention of PTHrP signalling in enchondromas and central chondrosarcomas". J Pathol. 205 (4): 476–82. doi:10.1002/path.1723. PMID 15685701.
- ↑ Hopyan S, Gokgoz N, Poon R, Gensure RC, Yu C, Cole WG; et al. (2002). "A mutant PTH/PTHrP type I receptor in enchondromatosis". Nat Genet. 30 (3): 306–10. doi:10.1038/ng844. PMID 11850620.
- ↑ 15.0 15.1 Tallini G, Dorfman H, Brys P, Dal Cin P, De Wever I, Fletcher CD; et al. (2002). "Correlation between clinicopathological features and karyotype in 100 cartilaginous and chordoid tumours. A report from the Chromosomes and Morphology (CHAMP) Collaborative Study Group". J Pathol. 196 (2): 194–203. doi:10.1002/path.1023. PMID 11793371.
- ↑ van Beerendonk HM, Rozeman LB, Taminiau AH, Sciot R, Bovée JV, Cleton-Jansen AM; et al. (2004). "Molecular analysis of the INK4A/INK4A-ARF gene locus in conventional (central) chondrosarcomas and enchondromas: indication of an important gene for tumour progression". J Pathol. 202 (3): 359–66. doi:10.1002/path.1517. PMID 14991902.
- ↑ Rozeman LB, Hogendoorn PC, Bovée JV (2002). "Diagnosis and prognosis of chondrosarcoma of bone". Expert Rev Mol Diagn. 2 (5): 461–72. doi:10.1586/14737159.2.5.461. PMID 12271817.
- ↑ Tarpey PS, Behjati S, Cooke SL, Van Loo P, Wedge DC, Pillay N; et al. (2013). "Frequent mutation of the major cartilage collagen gene COL2A1 in chondrosarcoma". Nat Genet. 45 (8): 923–6. doi:10.1038/ng.2668. PMC 3743157. PMID 23770606.
- ↑ Castresana JS, Barrios C, Gómez L, Kreicbergs A (1992). "Amplification of the c-myc proto-oncogene in human chondrosarcoma". Diagn Mol Pathol. 1 (4): 235–8. PMID 1342971.
- ↑ Franchi A, Calzolari A, Zampi G (1998). "Immunohistochemical detection of c-fos and c-jun expression in osseous and cartilaginous tumours of the skeleton". Virchows Arch. 432 (6): 515–9. PMID 9672192.
- ↑ Panagopoulos I, Mertens F, Isaksson M, Domanski HA, Brosjö O, Heim S; et al. (2002). "Molecular genetic characterization of the EWS/CHN and RBP56/CHN fusion genes in extraskeletal myxoid chondrosarcoma". Genes Chromosomes Cancer. 35 (4): 340–52. doi:10.1002/gcc.10127. PMID 12378528.