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==Pathophysiology==
==Pathophysiology==
===Physiology===
===Physiology===
*Cartilaginous tumors are seen in bones that arise from enchondral ossification.  
*Cartilaginous tumors are seen in bones that arise from enchondral ossification.<ref name="pmid20535132">{{cite journal| author=Bovée JV, Hogendoorn PC, Wunder JS, Alman BA| title=Cartilage tumours and bone development: molecular pathology and possible therapeutic targets. | journal=Nat Rev Cancer | year= 2010 | volume= 10 | issue= 7 | pages= 481-8 | pmid=20535132 | doi=10.1038/nrc2869 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20535132  }} </ref>
*There is hypertrophy of the resting zone chondrocytes due to proliferation and differentiation within the normal growth plate.
*There is hypertrophy of the resting zone chondrocytes due to proliferation and differentiation within the normal growth plate.<ref name="pmid20535132">{{cite journal| author=Bovée JV, Hogendoorn PC, Wunder JS, Alman BA| title=Cartilage tumours and bone development: molecular pathology and possible therapeutic targets. | journal=Nat Rev Cancer | year= 2010 | volume= 10 | issue= 7 | pages= 481-8 | pmid=20535132 | doi=10.1038/nrc2869 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20535132  }} </ref>
*These cells the undergo apoptosisresulting in invasion of vessels and osteoblasts that start to form bone and lead to longitudinal bone growth.  
*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.
*This physiologic process is regulated by components of the Indian hedgehog (IHH)/parathyroid hormone related (PTHRP) protein signaling pathway.


===Pathogenesis===
===Pathogenesis===
*The exact pathogenesis of chondrosarcoma is not full understood.<ref>{{cite book | last = Peabody | first = Terrance | title = Orthopaedic oncology : primary and metastatic tumors of the skeletal system | publisher = Springer | location = Cham | year = 2014 | isbn = 9783319073224 }}</ref>
*Multiple genes have been implicated in pathogenesis of chondrosarcoma.


 
===Genetics===
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].
*Cytogenetic analysis chondrosarcomas revealed that structural abnormalities of chromosomes 1, 6, 9, 12 and 15.<ref name="pmid10502322">{{cite journal| author=Bovée JV, Cleton-Jansen AM, Kuipers-Dijkshoorn NJ, van den Broek LJ, Taminiau AH, Cornelisse CJ et al.| title=Loss of heterozygosity and DNA ploidy point to a diverging genetic mechanism in the origin of peripheral and central chondrosarcoma. | journal=Genes Chromosomes Cancer | year= 1999 | volume= 26 | issue= 3 | pages= 237-46 | pmid=10502322 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10502322  }} </ref>
 
*Also, numerical abnormalities of chromosomes 5, 7, 8 and 18 were most frequent associated with chondrosarcoma.<ref name="pmid10629543">{{cite journal| author=Bovée JV, Cleton-Jansen AM, Rosenberg C, Taminiau AH, Cornelisse CJ, Hogendoorn PC| title=Molecular genetic characterization of both components of a dedifferentiated chondrosarcoma, with implications for its histogenesis. | journal=J Pathol | year= 1999 | volume= 189 | issue= 4 | pages= 454-62 | pmid=10629543 | doi=10.1002/(SICI)1096-9896(199912)189:4<454::AID-PATH467>3.0.CO;2-N | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10629543  }} </ref>
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.
*Anomlaies associated with chromosome 9(9p12-22) are more commonly seen in central chondrosarcomas.<ref name="pmid11763313">{{cite journal| author=Bovée JV, Sciot R, Dal Cin P, Debiec-Rychter M, van Zelderen-Bhola SL, Cornelisse CJ et al.| title=Chromosome 9 alterations and trisomy 22 in central chondrosarcoma: a cytogenetic and DNA flow cytometric analysis of chondrosarcoma subtypes. | journal=Diagn Mol Pathol | year= 2001 | volume= 10 | issue= 4 | pages= 228-35 | pmid=11763313 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11763313  }} </ref>
 
*Patients with multiple osteochondromas seem to have germline mutations in the exostosin (EXT1 or EXT2) genes.<ref name="pmid21804604">{{cite journal| author=de Andrea CE, Reijnders CM, Kroon HM, de Jong D, Hogendoorn PC, Szuhai K et al.| title=Secondary peripheral chondrosarcoma evolving from osteochondroma as a result of outgrowth of cells with functional EXT. | journal=Oncogene | year= 2012 | volume= 31 | issue= 9 | pages= 1095-104 | pmid=21804604 | doi=10.1038/onc.2011.311 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21804604  }} </ref>
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]:
*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.<ref name="pmid17341731">{{cite journal| author=Hameetman L, Szuhai K, Yavas A, Knijnenburg J, van Duin M, van Dekken H et al.| title=The role of EXT1 in nonhereditary osteochondroma: identification of homozygous deletions. | journal=J Natl Cancer Inst | year= 2007 | volume= 99 | issue= 5 | pages= 396-406 | pmid=17341731 | doi=10.1093/jnci/djk067 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17341731  }} </ref><ref name="pmid9620772">{{cite journal| author=McCormick C, Leduc Y, Martindale D, Mattison K, Esford LE, Dyer AP et al.| title=The putative tumour suppressor EXT1 alters the expression of cell-surface heparan sulfate. | journal=Nat Genet | year= 1998 | volume= 19 | issue= 2 | pages= 158-61 | pmid=9620772 | doi=10.1038/514 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9620772  }} </ref><ref name="pmid17226760">{{cite journal| author=Hameetman L, David G, Yavas A, White SJ, Taminiau AH, Cleton-Jansen AM et al.| title=Decreased EXT expression and intracellular accumulation of heparan sulphate proteoglycan in osteochondromas and peripheral chondrosarcomas. | journal=J Pathol | year= 2007 | volume= 211 | issue= 4 | pages= 399-409 | pmid=17226760 | doi=10.1002/path.2127 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17226760  }} </ref>
 
*This in turn decreases normal chondrocyte proliferation and differentiation within the normal human growth plate.
●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].
*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.
●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].
*In addition, the Ollier disease and Maffucci syndrome are also result of somatic mosaic mutations in IDH1 and IDH2. <ref name="pmid22057234">{{cite journal| author=Pansuriya TC, van Eijk R, d'Adamo P, van Ruler MA, Kuijjer ML, Oosting J et al.| title=Somatic mosaic IDH1 and IDH2 mutations are associated with enchondroma and spindle cell hemangioma in Ollier disease and Maffucci syndrome. | journal=Nat Genet | year= 2011 | volume= 43 | issue= 12 | pages= 1256-61 | pmid=22057234 | doi=10.1038/ng.1004 | pmc=3427908 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22057234  }} </ref>
 
*Isocitrate dehydrogenase is the necessary enzyme required for  conversion of isocitrate to alpha-ketoglutarate in the tricarboxylic acid cycle.  
●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].
*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.<ref name="pmid21598255">{{cite journal| author=Amary MF, Bacsi K, Maggiani F, Damato S, Halai D, Berisha F et al.| title=IDH1 and IDH2 mutations are frequent events in central chondrosarcoma and central and periosteal chondromas but not in other mesenchymal tumours. | journal=J Pathol | year= 2011 | volume= 224 | issue= 3 | pages= 334-43 | pmid=21598255 | doi=10.1002/path.2913 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21598255  }} </ref>
 
*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.<ref name="pmid11140704">{{cite journal| author=Bovée JV, van den Broek LJ, Cleton-Jansen AM, Hogendoorn PC| title=Up-regulation of PTHrP and Bcl-2 expression characterizes the progression of osteochondroma towards peripheral chondrosarcoma and is a late event in central chondrosarcoma. | journal=Lab Invest | year= 2000 | volume= 80 | issue= 12 | pages= 1925-34 | pmid=11140704 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11140704  }} </ref><ref name="pmid15685701">{{cite journal| author=Rozeman LB, Hameetman L, Cleton-Jansen AM, Taminiau AH, Hogendoorn PC, Bovée JV| title=Absence of IHH and retention of PTHrP signalling in enchondromas and central chondrosarcomas. | journal=J Pathol | year= 2005 | volume= 205 | issue= 4 | pages= 476-82 | pmid=15685701 | doi=10.1002/path.1723 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15685701  }} </ref><ref name="pmid11850620">{{cite journal| author=Hopyan S, Gokgoz N, Poon R, Gensure RC, Yu C, Cole WG et al.| title=A mutant PTH/PTHrP type I receptor in enchondromatosis. | journal=Nat Genet | year= 2002 | volume= 30 | issue= 3 | pages= 306-10 | pmid=11850620 | doi=10.1038/ng844 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11850620  }} </ref>
A multistep genetic model for the development of secondary (peripheral) chondrosarcomas has been proposed (figure 2) [14].
*Low-grade chondrosarcomas are near-diploid and have very few karyotypic abnormalities.<ref name="pmid11793371">{{cite journal| author=Tallini G, Dorfman H, Brys P, Dal Cin P, De Wever I, Fletcher CD et al.| title=Correlation between clinicopathological features and karyotype in 100 cartilaginous and chordoid tumours. A report from the Chromosomes and Morphology (CHAMP) Collaborative Study Group. | journal=J Pathol | year= 2002 | volume= 196 | issue= 2 | pages= 194-203 | pmid=11793371 | doi=10.1002/path.1023 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11793371  }} </ref>
 
*On the other hand, high grade chondrosarcomas are aneuploid and have complex karyotypes.<ref name="pmid11793371">{{cite journal| author=Tallini G, Dorfman H, Brys P, Dal Cin P, De Wever I, Fletcher CD et al.| title=Correlation between clinicopathological features and karyotype in 100 cartilaginous and chordoid tumours. A report from the Chromosomes and Morphology (CHAMP) Collaborative Study Group. | journal=J Pathol | year= 2002 | volume= 196 | issue= 2 | pages= 194-203 | pmid=11793371 | doi=10.1002/path.1023 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11793371  }} </ref>
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].
*The progression of chondrosarcoma has been linked to the CDKN2A (p16) tumor suppressor gene present at 9p21 and by mutation in p53.<ref name="pmid14991902">{{cite journal| author=van Beerendonk HM, Rozeman LB, Taminiau AH, Sciot R, Bovée JV, Cleton-Jansen AM et al.| title=Molecular analysis of the INK4A/INK4A-ARF gene locus in conventional (central) chondrosarcomas and enchondromas: indication of an important gene for tumour progression. | journal=J Pathol | year= 2004 | volume= 202 | issue= 3 | pages= 359-66 | pmid=14991902 | doi=10.1002/path.1517 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14991902  }} </ref><ref name="pmid12271817">{{cite journal| author=Rozeman LB, Hogendoorn PC, Bovée JV| title=Diagnosis and prognosis of chondrosarcoma of bone. | journal=Expert Rev Mol Diagn | year= 2002 | volume= 2 | issue= 5 | pages= 461-72 | pmid=12271817 | doi=10.1586/14737159.2.5.461 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12271817  }} </ref>
 
*Mutations in COL2A1 have also been hypothesized in pathogenesis of chondrosarcomas.<ref name="pmid23770606">{{cite journal| author=Tarpey PS, Behjati S, Cooke SL, Van Loo P, Wedge DC, Pillay N et al.| title=Frequent mutation of the major cartilage collagen gene COL2A1 in chondrosarcoma. | journal=Nat Genet | year= 2013 | volume= 45 | issue= 8 | pages= 923-6 | pmid=23770606 | doi=10.1038/ng.2668 | pmc=3743157 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23770606  }} </ref>
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].
*In addition, amplification of the c-myc and fos/jun has also been implicated in the pathogenesis of chondrosarcoma.<ref name="pmid1342971">{{cite journal| author=Castresana JS, Barrios C, Gómez L, Kreicbergs A| title=Amplification of the c-myc proto-oncogene in human chondrosarcoma. | journal=Diagn Mol Pathol | year= 1992 | volume= 1 | issue= 4 | pages= 235-8 | pmid=1342971 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1342971  }} </ref><ref name="pmid9672192">{{cite journal| author=Franchi A, Calzolari A, Zampi G| title=Immunohistochemical detection of c-fos and c-jun expression in osseous and cartilaginous tumours of the skeleton. | journal=Virchows Arch | year= 1998 | volume= 432 | issue= 6 | pages= 515-9 | pmid=9672192 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9672192  }} </ref>
 
*A specific HEY1-NCOA2 fusion product due to an intrachromosomal rearrangement of chromosome arm 8q result in mesenchymal chondrosarcoma.  
●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].
*With extraskeletal myxoid chondrosarcomas, the t(9;22)(q22;q12) translocation is common.<ref name="pmid12378528">{{cite journal| author=Panagopoulos I, Mertens F, Isaksson M, Domanski HA, Brosjö O, Heim S et al.| title=Molecular genetic characterization of the EWS/CHN and RBP56/CHN fusion genes in extraskeletal myxoid chondrosarcoma. | journal=Genes Chromosomes Cancer | year= 2002 | volume= 35 | issue= 4 | pages= 340-52 | pmid=12378528 | doi=10.1002/gcc.10127 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12378528  }} </ref>
 
●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==
==Gross Pathology==

Revision as of 18:58, 22 January 2019

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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. ↑ 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.
  2. ↑ Peabody, Terrance (2014). Orthopaedic oncology : primary and metastatic tumors of the skeletal system. Cham: Springer. ISBN 9783319073224.
  3. ↑ 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.
  4. ↑ 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.
  5. ↑ 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.
  6. ↑ 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.
  7. ↑ 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.
  8. ↑ 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.
  9. ↑ 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.
  10. ↑ 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.
  11. ↑ 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.
  12. ↑ 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.
  13. ↑ 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.
  14. ↑ 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. ↑ 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.
  16. ↑ 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.
  17. ↑ 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.
  18. ↑ 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.
  19. ↑ 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.
  20. ↑ 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.
  21. ↑ 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.

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