Chondrosarcoma pathophysiology: Difference between revisions

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{{Chondrosarcoma}}
{{Chondrosarcoma}}
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{{CMG}}; {{AE}} {{Rohan}}


==Overview==
==Overview==
The exact [[pathogenesis]] of chondrosarcoama is not fully understood. Multiple genes have been implicated in [[pathogenesis]] of chondrosarcoma. [[Cytogenetics|Cytogenetic]] analysis of chondrosarcomas revealed that structural abnormalities of [[Chromosome 1|chromosomes 1]], [[Chromosome 6|6]], [[Chromosome 9|9]], [[Chromosome 12|12]] and [[Chromosome 15|15]] and  numerical abnormalities of chromosomes [[Chromosome 5|5]], [[Chromosome 7|7]], [[Chromosome 8|8]] and [[Chromosome 18|18]] are most frequent associated. Anomalies associated with [[chromosome 9]](9p12-22) are more commonly seen in central chondrosarcomas. [[Germline]] mutations in the exostosin (EXT1 or EXT2) genes,  [[TP53]] or [[Retinoblastoma protein|pRb]] pathway,  [[isocitrate dehydrogenase]]-1 and [[Isocitrate dehydrogenase|isocitrate dehydrogenase-]] 2 genes and gene encoding the receptor for [[Parathyroid gland|parathyroid]] have been implicated. On [[gross pathology]], greyish-white lobulated mass, [[necrosis]], [[calcification]], and mucoid degeneration are characteristic findings of chondrosarcoma. On microscopic [[Histopathology|histopathological]] analysis abnormal [[cartilage]], increased cellularity, and [[nuclear]] [[atypia]] are characteristic findings of chondrosarcoma. Chondrosarcoma may be divided into three grades based on cancer cells [[morphology]] under [[microscope]] and growth rate of [[tumor]].
==Pathophysiology==
==Pathophysiology==
===Physiology===
*[[Cartilaginous]] [[Tumor|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 of [[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 [[apoptosis]] resulting in invasion of [[vessels]] and [[Osteoblast|osteoblasts]] that start to form [[bone]] and lead to longitudinal [[bone]] growth.
*This [[Physiology|physiologic]] process is regulated by components of the Indian [[Hedgehog signaling pathway|hedgehog]] (IHH)/[[parathyroid hormone]] related (PTHRP) protein signaling pathway.
===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 [[Gene|genes]] have been implicated in [[pathogenesis]] of chondrosarcoma.
===Genetics===
*[[Cytogenetics|Cytogenetic]] analysis of chondrosarcomas revealed that structural abnormalities of [[Chromosome 1|chromosomes 1]], [[Chromosome 6|6]], [[Chromosome 9|9]], [[Chromosome 12|12]] and [[Chromosome 15|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 [[Chromosome 5|5]], [[Chromosome 7|7]], [[Chromosome 8|8]] and [[Chromosome 18|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>
*Anomalies 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>
*This result is decreased [[EXT1 gene|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]].
*Furthermore, the [[Genetics|genetic]] [[Mutation|mutations]] in the [[TP53]] or [[Retinoblastoma protein|pRb]] pathway are implied in the [[malignant]] transformation from [[osteochondroma]] to [[secondary]] peripheral chondrosarcoma.
*In [[Enchondroma|enchondromas]] and central chondrosarcomas, point [[Mutation|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 (genetics)|mosaic]] [[Mutation|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-ketoglutaric acid|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 Sarcoma|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|PTH-1]] receptor or PTH1R) has been associated to [[Enchondroma|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>
*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 [[Karyotype|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>
*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>
*[[Mutation|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, amplification of the [[c-myc]] and fos/[[Jun dimerization protein|jun]] protien 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 intra-chromosomal rearrangement of chromosome arm [[Chromosome 8|8]]<nowiki/>q result in [[mesenchymal]] chondrosarcoma.
*With extraskeletal myxoid chondrosarcomas, the t(9;22)(q22;q12) [[Translocations|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>
===Gross Pathology===
Characteristic features of chondrosarcoma on gross pathology are:<ref name="pmid8478391">{{cite journal| author=Simon MA, Biermann JS| title=Biopsy of bone and soft-tissue lesions. | journal=J Bone Joint Surg Am | year= 1993 | volume= 75 | issue= 4 | pages= 616-21 | pmid=8478391 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8478391  }} </ref><ref name="pmid26883651">{{cite journal| author=Roitman PD, Farfalli GL, Ayerza MA, Múscolo DL, Milano FE, Aponte-Tinao LA| title=Is Needle Biopsy Clinically Useful in Preoperative Grading of Central Chondrosarcoma of the Pelvis and Long Bones? | journal=Clin Orthop Relat Res | year= 2017 | volume= 475 | issue= 3 | pages= 808-814 | pmid=26883651 | doi=10.1007/s11999-016-4738-y | pmc=5289157 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26883651  }} </ref>
*Greyish-white lobulated mass
*[[Necrosis]]
*[[Calcification]]
*Mucoid degeneration
===Microscopic Pathology===
===Microscopic Pathology===
In general chondrosarcomas are multilobulated (due to hyaline cartilage nodules) with central high water content and peripheral enchondral ossification. Each chondrosarcoma subtype has specific characteristics:
In general chondrosarcomas are multi-lobulated (due to [[hyaline cartilage]] [[Nodule (medicine)|nodules]]) with central high water content and peripheral enchondral [[ossification]]. Characteristic features on microscopic analysis are variable depending on the chondrosarcoma subtype:
====Mesenchymal chondrosarcoma====
Mesenchymal chondrosarcoma is a [[malignant tumor]] with a characteristic biphasic pattern:
*Poorly differentiated small round blue cells.
*Islands of well-differentiated [[hyaline cartilage]].
**Progressive maturation of [[cartilage]] towards the center.
**Central [[calcification]] or bone formation.
*Can have a hemangiopericytomatous vascular pattern.
{| align
|-valign="top"
| [[Image:800px-Bone Chondrosarcoma Mesenchymal MP5 PA.JPG|thumb|350px|Islands of cartilage in a background of small blue cells]]
|}


====Myxoid chondrosarcoma====
*Myxoid background.
*small cells with eosinophilic cytoplasm.
{| align
|-valign="top"
| [[Image:790px-Bone Chondrosarcoma Myxoid MP2 PA.JPG|thumb|350px|Anastomizing chords of small neoplastic cells surround mucin pools]]
| [[Image:800px-Bone Chondrosarcoma Myxoid MP PA.JPG|thumb|350px|Chords of neoplastic cells surround mucin pools]]
|}
====Clear cell chondrosarcoma====
====Clear cell chondrosarcoma====
*Lobules of uniform to polymorphic densely-packed large cells.
*[[Lobules]] of uniform to [[polymorphic]] densely-packed large cells.<ref>McCarthy EF, Hogendoorn PCW. Clear cell chondrosarcoma. In: World Health Organization classification of tumours of soft tissue and bone, 4th, Fletcher CDM, Bridge JA, Hogendoorn PCW, Mertens F (Eds), IARC, Lyon 2013. p.273.</ref><ref name="pmid17522879">{{cite journal| author=Donati D, Yin JQ, Colangeli M, Colangeli S, Bella CD, Bacchini P et al.| title=Clear cell chondrosarcoma of bone: long time follow-up of 18 cases. | journal=Arch Orthop Trauma Surg | year= 2008 | volume= 128 | issue= 2 | pages= 137-42 | pmid=17522879 | doi=10.1007/s00402-007-0353-4 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17522879  }} </ref><ref name="pmid16239809">{{cite journal| author=Itälä A, Leerapun T, Inwards C, Collins M, Scully SP| title=An institutional review of clear cell chondrosarcoma. | journal=Clin Orthop Relat Res | year= 2005 | volume= 440 | issue=  | pages= 209-12 | pmid=16239809 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16239809  }} </ref>
*Well defined pushing borders.
*Well defined pushing borders.
*Clear to intensively acidophilic granular cytoplasm with vacuoles.
*Clear to intensively [[acidophilic]] granular [[cytoplasm]] with [[Vacuole|vacuoles]].
*Central nuclei with occasional prominent nucleoli.
*Central [[nuclei]] with occasional prominent [[nucleoli]].
*Low mitotic rate.
*Low mitotic rate.
*Clear cell areas lack production of hyaline chondroid matrix.
*Clear cell areas lack production of [[hyaline]] chondroid matrix.
*Areas with osteoclast-type giant cells mixed with small trabeculae of reactive bone.
*Areas with [[osteoclast]]-type [[giant cells]] mixed with small [[Trabecula|trabeculae]] of reactive bone.
*May contain conventional low-grade chondrosarcoma.
*May contain conventional low-grade chondrosarcoma.
*May have secondary aneurysmal bone cyst changes.
*May have secondary [[aneurysmal bone cyst]] changes.
{| align
{| align=""
|-valign="top"
|- valign="top"
| [[Image:800px-Bone Chondrosarcoma ClearCell HP PA.jpg|thumb|350px|High grade round cells with cytoplasmic clearing]]
| [[Image:800px-Bone Chondrosarcoma ClearCell HP PA.jpg|thumb|350px|High grade round cells with cytoplasmic clearing. Source Wikimedia common.]]
| [[Image:800px-Bone Chondrosarcoma ClearCell MP PA.jpg|thumb|350px|The lesion also had areas of more conventional chondrosarcoma]]
| [[Image:800px-Bone Chondrosarcoma ClearCell MP PA.jpg|thumb|350px|The lesion also had areas of more conventional chondrosarcoma. Source Wikimedia common.]]
|}
|}


====Mesenchymal chondrosarcoma====
Mesenchymal chondrosarcoma is a [[malignant tumor]] with a characteristic biphasic pattern:<ref>Nakashima Y, de Pinieux G, Ladanyi M. Mesenchymal chondrosarcoma. In: WHO classification of tumours of soft tissue and bone, 4th, Fletcher CDM, Bridge JA, Hogendoorn CDW, Mertens F (Eds), IARC, Lyon 2013. p.271.</ref><ref name="pmid25529371">{{cite journal| author=Frezza AM, Cesari M, Baumhoer D, Biau D, Bielack S, Campanacci DA et al.| title=Mesenchymal chondrosarcoma: prognostic factors and outcome in 113 patients. A European Musculoskeletal Oncology Society study. | journal=Eur J Cancer | year= 2015 | volume= 51 | issue= 3 | pages= 374-81 | pmid=25529371 | doi=10.1016/j.ejca.2014.11.007 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25529371  }} </ref><ref name="pmid18438777">{{cite journal| author=Dantonello TM, Int-Veen C, Leuschner I, Schuck A, Furtwaengler R, Claviez A et al.| title=Mesenchymal chondrosarcoma of soft tissues and bone in children, adolescents, and young adults: experiences of the CWS and COSS study groups. | journal=Cancer | year= 2008 | volume= 112 | issue= 11 | pages= 2424-31 | pmid=18438777 | doi=10.1002/cncr.23457 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18438777  }} </ref>
*Poorly differentiated small round blue cells
*Islands of well-differentiated [[hyaline cartilage]]
**Progressive [[maturation]] of [[cartilage]] towards the center
**Central [[calcification]] or bone formation
*Can have a hemangiopericytomatous vascular pattern.
====Myxoid chondrosarcoma====
*It shows [[myxoid]] background.<ref name="pmid9781944">{{cite journal| author=Antonescu CR, Argani P, Erlandson RA, Healey JH, Ladanyi M, Huvos AG| title=Skeletal and extraskeletal myxoid chondrosarcoma: a comparative clinicopathologic, ultrastructural, and molecular study. | journal=Cancer | year= 1998 | volume= 83 | issue= 8 | pages= 1504-21 | pmid=9781944 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9781944  }} </ref>
*In addition, small cells with eosinophilic [[cytoplasm]] are seen.<ref name="pmid14657948">{{cite journal| author=Aigner T, Oliveira AM, Nascimento AG| title=Extraskeletal myxoid chondrosarcomas do not show a chondrocytic phenotype. | journal=Mod Pathol | year= 2004 | volume= 17 | issue= 2 | pages= 214-21 | pmid=14657948 | doi=10.1038/modpathol.3800036 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14657948  }} </ref>
{| align=""
|- valign="top"
| [[Image:790px-Bone Chondrosarcoma Myxoid MP2 PA.JPG|thumb|350px|Anastomizing chords of small neoplastic cells surround mucin pools. Source Wikimedia common.]]
| [[Image:800px-Bone Chondrosarcoma Myxoid MP PA.JPG|thumb|350px|Chords of neoplastic cells surround mucin pools. Source Wikimedia common.]]
|}


====Dedifferentiated chondrosarcoma====
====Dedifferentiated chondrosarcoma====
*Poorly differentiated [[mesenchymal]] [[malignancy]].<ref>Inwards C, Hogendoorn PCW. Dedifferentiated chondrosarcoma In: WHO classification of tumours of soft tissue and bone, 4th, Fletcher CDM, Bridge JA, Hogendoorn PCW, Mertens F (Eds), IARC, Lyon 2013. p.269.</ref>
*Well-differentiated [[cartilaginous]] component


*Poorly differentiated (mesenchymal) malignancy.
==Histological Grading==
*Well-differentiated cartilaginous component.
*Chondrosarcomas can be classified into the following three [[Histologic|histologic grades]], depending on findings of cellularity, [[atypia]], and [[pleomorphism]]:<ref name="pmid17260660">{{cite journal| author=Ryzewicz M, Manaster BJ, Naar E, Lindeque B| title=Low-grade cartilage tumors: diagnosis and treatment. | journal=Orthopedics | year= 2007 | volume= 30 | issue= 1 | pages= 35-46; quiz 47-8 | pmid=17260660 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17260660  }} </ref><ref name="pmid4064409">{{cite journal| author=Mirra JM, Gold R, Downs J, Eckardt JJ| title=A new histologic approach to the differentiation of enchondroma and chondrosarcoma of the bones. A clinicopathologic analysis of 51 cases. | journal=Clin Orthop Relat Res | year= 1985 | volume=  | issue= 201 | pages= 214-37 | pmid=4064409 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=4064409  }} </ref>


'''Grade 1'''
*Chondrosarcoma grows relatively slowly, has cells whose [[histological]] appearance is quite similar to cells of normal [[cartilage]].
*Mostly chondroid [[matrix]], little if any myxoid.
*Mild-to-moderate increase of cellularity +/- binucleated cells.
*Have much less aggressive [[invasive]] and [[metastatic]] properties.
{| align=""
|- valign="top"
| [[Image:800px-Bone Chondrosarcoma Grade1 HP2 PA.JPG|thumb|350px|Grade 1 - Somewhat cellular cartilage with binucleation. Source Wikimedia common.]]
|}


'''Grade 2'''
*Intermediate grade chondrosarcoma
*Little chondroid [[matrix]], [[necrosis]] and more common prominent myxoid.
{| align=""
|- valign="top"
| [[Image:800px-Bone Chondrosarcoma Grade2 HP PA.jpg|thumb|350px|Grade 2 - Very cellular cartilage with obvious hyperchromasia and nuclear atypia. Source Wikimedia common.]]
|}


Shown below is a micrograph of chondrosarcoma.(H&E stain)
'''Grade 3'''
 
*Grade 3 chondrosarcoma is increasingly faster-growing cancer, with more varied and abnormal-looking cells.
[[Image:Chondrosarcoma_(1).jpg‎|200px]]
*Characterized by myxoid [[stroma]], [[nuclear]] [[pleomorphism]] and [[mitoses]].
===Video===
*Absent chondroid [[matrix]].
Below is a video of Extraskeletal Myxoid chondrosarcoma
*These are much more likely to infiltrate surrounding tissues, [[lymph nodes]], and [[organs]].
{{#ev:youtube|DxljkFd9xew}}
{| align=""
|- valign="top"
| [[Image:800px-Bone Chondrosarcoma Grade3 HP PA.JPG|thumb|350px|Grade 3 - Even more cellular neoplastic cartilage with high grade nuclear atypia. Source Wikimedia common.]]
|}


==References==
==References==
{{reflist|2}}
{{Reflist|2}}
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Latest revision as of 18:47, 1 June 2019

Chondrosarcoma Microchapters

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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 chondrosarcoama is not fully understood. Multiple genes have been implicated in pathogenesis of chondrosarcoma. Cytogenetic analysis of chondrosarcomas revealed that structural abnormalities of chromosomes 1, 6, 9, 12 and 15 and numerical abnormalities of chromosomes 5, 7, 8 and 18 are most frequent associated. Anomalies associated with chromosome 9(9p12-22) are more commonly seen in central chondrosarcomas. Germline mutations in the exostosin (EXT1 or EXT2) genes, TP53 or pRb pathway, isocitrate dehydrogenase-1 and isocitrate dehydrogenase- 2 genes and gene encoding the receptor for parathyroid have been implicated. On gross pathology, greyish-white lobulated mass, necrosis, calcification, and mucoid degeneration are characteristic findings of chondrosarcoma. On microscopic histopathological analysis abnormal cartilage, increased cellularity, and nuclear atypia are characteristic findings of chondrosarcoma. Chondrosarcoma may be divided into three grades based on cancer cells morphology under microscope and growth rate of tumor.

Pathophysiology

Physiology

Pathogenesis

Genetics

Gross Pathology

Characteristic features of chondrosarcoma on gross pathology are:[22][23]

Microscopic Pathology

In general chondrosarcomas are multi-lobulated (due to hyaline cartilage nodules) with central high water content and peripheral enchondral ossification. Characteristic features on microscopic analysis are variable depending on the chondrosarcoma subtype:

Clear cell chondrosarcoma

High grade round cells with cytoplasmic clearing. Source Wikimedia common.
The lesion also had areas of more conventional chondrosarcoma. Source Wikimedia common.

Mesenchymal chondrosarcoma

Mesenchymal chondrosarcoma is a malignant tumor with a characteristic biphasic pattern:[27][28][29]

Myxoid chondrosarcoma

Anastomizing chords of small neoplastic cells surround mucin pools. Source Wikimedia common.
Chords of neoplastic cells surround mucin pools. Source Wikimedia common.

Dedifferentiated chondrosarcoma

Histological Grading

Grade 1

  • Chondrosarcoma grows relatively slowly, has cells whose histological appearance is quite similar to cells of normal cartilage.
  • Mostly chondroid matrix, little if any myxoid.
  • Mild-to-moderate increase of cellularity +/- binucleated cells.
  • Have much less aggressive invasive and metastatic properties.
Grade 1 - Somewhat cellular cartilage with binucleation. Source Wikimedia common.

Grade 2

  • Intermediate grade chondrosarcoma
  • Little chondroid matrix, necrosis and more common prominent myxoid.
Grade 2 - Very cellular cartilage with obvious hyperchromasia and nuclear atypia. Source Wikimedia common.

Grade 3

  • Grade 3 chondrosarcoma is increasingly faster-growing cancer, with more varied and abnormal-looking cells.
  • Characterized by myxoid stroma, nuclear pleomorphism and mitoses.
  • Absent chondroid matrix.
  • These are much more likely to infiltrate surrounding tissues, lymph nodes, and organs.
Grade 3 - Even more cellular neoplastic cartilage with high grade nuclear atypia. Source Wikimedia common.

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.
  22. ↑ Simon MA, Biermann JS (1993). "Biopsy of bone and soft-tissue lesions". J Bone Joint Surg Am. 75 (4): 616–21. PMID 8478391.
  23. ↑ Roitman PD, Farfalli GL, Ayerza MA, Múscolo DL, Milano FE, Aponte-Tinao LA (2017). "Is Needle Biopsy Clinically Useful in Preoperative Grading of Central Chondrosarcoma of the Pelvis and Long Bones?". Clin Orthop Relat Res. 475 (3): 808–814. doi:10.1007/s11999-016-4738-y. PMC 5289157. PMID 26883651.
  24. ↑ McCarthy EF, Hogendoorn PCW. Clear cell chondrosarcoma. In: World Health Organization classification of tumours of soft tissue and bone, 4th, Fletcher CDM, Bridge JA, Hogendoorn PCW, Mertens F (Eds), IARC, Lyon 2013. p.273.
  25. ↑ Donati D, Yin JQ, Colangeli M, Colangeli S, Bella CD, Bacchini P; et al. (2008). "Clear cell chondrosarcoma of bone: long time follow-up of 18 cases". Arch Orthop Trauma Surg. 128 (2): 137–42. doi:10.1007/s00402-007-0353-4. PMID 17522879.
  26. ↑ Itälä A, Leerapun T, Inwards C, Collins M, Scully SP (2005). "An institutional review of clear cell chondrosarcoma". Clin Orthop Relat Res. 440: 209–12. PMID 16239809.
  27. ↑ Nakashima Y, de Pinieux G, Ladanyi M. Mesenchymal chondrosarcoma. In: WHO classification of tumours of soft tissue and bone, 4th, Fletcher CDM, Bridge JA, Hogendoorn CDW, Mertens F (Eds), IARC, Lyon 2013. p.271.
  28. ↑ Frezza AM, Cesari M, Baumhoer D, Biau D, Bielack S, Campanacci DA; et al. (2015). "Mesenchymal chondrosarcoma: prognostic factors and outcome in 113 patients. A European Musculoskeletal Oncology Society study". Eur J Cancer. 51 (3): 374–81. doi:10.1016/j.ejca.2014.11.007. PMID 25529371.
  29. ↑ Dantonello TM, Int-Veen C, Leuschner I, Schuck A, Furtwaengler R, Claviez A; et al. (2008). "Mesenchymal chondrosarcoma of soft tissues and bone in children, adolescents, and young adults: experiences of the CWS and COSS study groups". Cancer. 112 (11): 2424–31. doi:10.1002/cncr.23457. PMID 18438777.
  30. ↑ Antonescu CR, Argani P, Erlandson RA, Healey JH, Ladanyi M, Huvos AG (1998). "Skeletal and extraskeletal myxoid chondrosarcoma: a comparative clinicopathologic, ultrastructural, and molecular study". Cancer. 83 (8): 1504–21. PMID 9781944.
  31. ↑ Aigner T, Oliveira AM, Nascimento AG (2004). "Extraskeletal myxoid chondrosarcomas do not show a chondrocytic phenotype". Mod Pathol. 17 (2): 214–21. doi:10.1038/modpathol.3800036. PMID 14657948.
  32. ↑ Inwards C, Hogendoorn PCW. Dedifferentiated chondrosarcoma In: WHO classification of tumours of soft tissue and bone, 4th, Fletcher CDM, Bridge JA, Hogendoorn PCW, Mertens F (Eds), IARC, Lyon 2013. p.269.
  33. ↑ Ryzewicz M, Manaster BJ, Naar E, Lindeque B (2007). "Low-grade cartilage tumors: diagnosis and treatment". Orthopedics. 30 (1): 35–46, quiz 47-8. PMID 17260660.
  34. ↑ Mirra JM, Gold R, Downs J, Eckardt JJ (1985). "A new histologic approach to the differentiation of enchondroma and chondrosarcoma of the bones. A clinicopathologic analysis of 51 cases". Clin Orthop Relat Res (201): 214–37. PMID 4064409.
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