|Written||2005-03||Yvonne M Schrage, Judith VMG Bovée|
|Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands|
|ICD-Topo||C400-C403,C408-C414,C418-C419 BONES & JOINTS|
|Note|| Primary skeletal neoplasms account for 0,2% of human tumors, whereas involvement of skeletal tissue by metastatic disease is much more common. Their soft tissue-related counterparts outnumber bone tumors by a margin of approximately 10:1. Because of their rarity, not much is known about the etiology and risk factors of bone tumors, although a difference in ethnical distribution has been observed.
Bone tumors are mostly of mesenchymal origin, though for example Ewing sarcoma is thought to have neuroectodermal precursor cells. Classification of the World Health Organization will be followed in this overview. Grading of bone tumors is roughly based on the cellularity of the lesion compared to the amount of extracellulair matrix, nuclear features, the presence of mitotic figures and necrosis. Staging via the TNM system is normally not used, because metastases in lymph nodes are not frequent in these lesions. Therefore staging is based on degree of differentiation of the tumor tissue and local and distant spread of the tumor.
Genetic information and references are provided for tumors investigated in more than a single case.
| Cartilage tumors
Ewing sarcoma/Primitive neuroectodermal tumor
Giant cell tumors
Myogenic, lipogenic, neural and epithelial tumors
Tumors of undefined neoplastic nature
|Clinics and Pathology|
|Cytogenetics|| Cartilage tumors |
Germ line mutations in the tumorsupressor genes Exostosin-1 (EXT-1) located at 8q24 and Exostosin-2 (EXT-2) located at 11p11-p12 have been found in hereditary multiple osteochondromas (MO). Somatic mutations are extremely rare in these tumors. In four tumors aberrations involving the region 1p13-p22 were shown.
Although a dozen of case reports have been published, no specific alterations were found in these rare benign tumors.
Structural rearrangements of chromosome 6 are found to be non-random, particularly involving the long arm (q13 and q25) and p25 on the short arm.
In a comparative study, 19 of 20 peripheral chondrosarcoma showed LOH at the loci for EXT, EXTL, 13q14, 17p14, 17p13, 9p21 and chromosome 10, while only 3 of 12 central chondrosarcoma did. In addition the ploidy status in peripheral chondrosarcoma showed wide variation (0,56-2,01), whereas central chondrosarcomas were predominantly periploid.
|Cytogenetics|| Osteogenic tumors |
Involvement of band 22q13 and loss of the distal part of arm 17q were detected in two out of three analyzed cases.
No consistent aberrations have been detected in four cases, although clues are leading to deregulation of the cell cycle. No telomerase activity could be found.
|Cytogenetics|| Fibrogenic tumors |
Like in desmoid tumors, trisomies 8 and 20 are commonly found.
No cytogenetic investigations on fibrosarcoma have been published.
|Cytogenetics|| Fibrohistiocytic tumors |
Of the benign form of this tumor, no cytogenetic information is available. Its malignant counterpart shows LOH at chromosome 9p21-22, which has also been shown by CGH before.
|Cytogenetics|| Ewing sarcoma/Primitive neuroectodermal tumor|
The most common rearrangement (85%) in this tumor is translocation t(11;22)(q24;q12). Consequently, this leads to the fusion protein EWS/FLI1. Other translocations found in the Ewing Sarcoma gene are listed below:
|Cytogenetics|| Giant cell tumors |
Reduction in length of the telomeres, as well as telomeric association, has been demonstrated in these tumors. Most commonly 11p, 13p, 14p, 15p, 19q, 20q and 21p are affected.
|Cytogenetics|| Notochordal tumors |
Nine of sixteen investigated chordomas were hypodiploid with a chromosome number ranging from 33 to 44. Chromosomes 3, 4, 10, and 13 are most commonly lost, and in half of the cases the following segments are lost up to the telomere: 1p31, 3p21, 3q21, 9p24, 17q11. Because LOH is found at band 1p36, a tumor suppressor gene is thought to exist on distal 1p.
|Cytogenetics|| Vascular tumors |
No cytogenetic investigations reported.
An identical translocation of chromosomes 1 and 3 has been reported in two epithelioid haemangioendotheliomas.
|Cytogenetics|| Myogenic, lipogenic, neural and epithelial tumors |
5 Grade IIB tumors demonstrated a rate of genomic loss of 90%, whereas high micro satellite instability was not observed. Allelotyping revealed loss of pRb in the tumors. In addition, chromosomal loss was noticed in human telomerase subunit-linked markers.
Only one case study is published about the benign form of this tumor. On its malignant counterpart, liposarcoma of bone, no genetic information has been published.
Cumulating evidence indicates that classic adamantinomas derive from their osteofibrous dysplasia (OFD)-like counterparts. OFD and adamantinoma show common cytogenetic abnormalities. In 15 cases of adamantinoma (n=11) and OFD (n=4) trisomies of chromosomes 7, 8, 12, 19 and 21 were detected. These findings further substantiate the clonal origin of OFD and the common histogenesis of OFD and adamantinoma.
|Cytogenetics|| Tumors of undefined neoplastic nature |
Aneurysmal bone cysts can be primary or secondary to other bone lesions. Chromosome bands 16q22 and/or 17p13 (USP6 gene) are non-randomly rearranged in ABC, regardless of tumor type (classic and solid) and of location (osseous and extraosseous). However, rearrangements are absent in secondary ABC. A recurrent t(16;17)(q22;p13) has been identified, but other chromosomal segments as translocation partner for each chromosome have been described.
Only one case report describes structural rearrangements.
Two fibrous dysplasia cases exhibited either a completely normal karyotype or single cell aberrations. Evidence that this lesion is neoplastic comes from the fact that clonal chromosomal aberrations have been found. In monostotic as well as polyostotic lesions activating GNAS1(20q13.2) mutations, known from the McCune-Albright syndrome, have been demonstrated.
Studies of X-chromosome inactivation demonstrated that LCH is clonal.
|Cytogenetics|| Congenital and inherited syndromes |
This syndrome, which is caused by heterogenic genetic changes on 11q15, is subject to genomic imprinting. 3 Beckwith-Wiedemann syndrome chromosome regions (BWSCR) have been identified: BWSC1 near INS/IGF2, BWSC2 5 Mb proximal to BWSC1, and BWSC3 2 Mb even more proximal.
These syndromes are non-hereditary although a case of familial clustering has been reported. Mutations in the PTH receptor 1 have been found in two cases, but these results could not be confirmed in a larger series of 31 patients, suggesting that PTHR1 is not the culprit for enchondromatosis.
Mutations in the GNAS1 gene, located on 20q13, change the structure of the G-protein a-stimulatory subunit. Dysfunctions of the heterotrimeric G-protein complexes lead to this non-familial occurring disorder.
Mutations in one of the two exostosin (EXT) genes are responsible for this autosomal dominant syndrome. EXT1 is located at 8q24 and EXT2 at 11p11-p12. Most mutations are either nonsense, frame shift or splice-site mutations, leading to premature termination of the EXT proteins. This causes alteration of the gene products, which are functioning in the endoplasmatic reticulum as transmembrane glycoproteins, and will affect the biosynthesis of heparan sulphate proteoglycans, leading to altered growth factor signaling.
Familial Paget Disease of Bone (PDB) demonstrates linkage to chromosome 18q. Some cases (PDB type 2) are caused by mutations in the TNFRSF11A gene on chromosome 18q22.1, which encodes RANK, a protein essential in osteoclast formation. The phenotype linked to chromosome 5q35 (PDB type 3) is caused by mutations in the SQSTM1 gene, the product of which is associated with the RANK pathway.
|Chromosome 9 alterations and trisomy 22 in central chondrosarcoma: a cytogenetic and DNA flow cytometric analysis of chondrosarcoma subtypes.|
|Bovée JV, Sciot R, Cin PD, Debiec-Rychter M, van Zelderen-Bhola SL, Cornelisse CJ, Hogendoorn PC|
|Diagnostic molecular pathology : the American journal of surgical pathology, part B. 2001 ; 10 (4) : 228-235.|
|Biologic and clinical significance of cytogenetic and molecular cytogenetic abnormalities in benign and malignant cartilaginous lesions.|
|Bridge JA, Bhatia PS, Anderson JR, Neff JR|
|Cancer genetics and cytogenetics. 1993 ; 69 (2) : 79-90.|
|Clonal chromosomal abnormalities in osteofibrous dysplasia. Implications for histopathogenesis and its relationship with adamantinoma.|
|Bridge JA, Dembinski A, DeBoer J, Travis J, Neff JR|
|Cancer. 1994 ; 73 (6) : 1746-1752.|
|Cytogenetic findings in 73 osteosarcoma specimens and a review of the literature.|
|Bridge JA, Nelson M, McComb E, McGuire MH, Rosenthal H, Vergara G, Maale GE, Spanier S, Neff JR|
|Cancer genetics and cytogenetics. 1997 ; 95 (1) : 74-87.|
|Clonal karyotypic aberrations in enchondromas.|
|Bridge JA, Persons DL, Neff JR, Bhatia P|
|Cancer detection and prevention. 1992 ; 16 (4) : 215-219.|
|Recurrent chromosome aberrations in fibrous dysplasia of the bone: a report of the CHAMP study group. CHromosomes And MorPhology.|
|Dal Cin P, Sciot R, Brys P, De Wever I, Dorfman H, Fletcher CD, Jonsson K, Mandahl N, Mertens F, Mitelman F, Rosai J, Rydholm A, Samson I, Tallini G, Van den Berghe H, Vanni R, Willen H|
|Cancer genetics and cytogenetics. 2000 ; 122 (1) : 30-32.|
|Mesenchymal chondrosarcoma. A cytogenetic, immunohistochemical and ultrastructural study.|
|Dobin SM, Donner LR, Speights VO Jr|
|Cancer genetics and cytogenetics. 1995 ; 83 (1) : 56-60.|
|Cytogenetic and molecular cytogenetic evidence of recurrent 8q24.1 loss in osteochondroma.|
|Feely MG, Boehm AK, Bridge RS, Krallman PA, Neff JR, Nelson M, Bridge JA|
|Cancer genetics and cytogenetics. 2002 ; 137 (2) : 102-107.|
|WHO Classification of tumours. Pathology & Genetics. Tumours of Bone and Soft tissue.|
|Fletcher CDM, Unni KK, and Mertens F|
|IARC Press. : page L.|
|The pericentromeric inversion, inv (6)(p25q13), is a novel diagnostic marker in chondromyxoid fibroma.|
|Granter SR, Renshaw AA, Kozakewich HP, Fletcher JA|
|Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc. 1998 ; 11 (11) : 1071-1074.|
|Clonal chromosome abnormalities in enchondromas and chondrosarcomas.|
|Gunawan B, Weber M, Bergmann F, Wildberger J, Niethard FU, Füzesi L|
|Cancer genetics and cytogenetics. 2000 ; 120 (2) : 127-130.|
|Cytogenetic analysis of a scapular chondromyxoid fibroma.|
|Halbert AR, Harrison WR, Hicks MJ, Davino N, Cooley LD|
|Cancer genetics and cytogenetics. 1998 ; 104 (1) : 52-56.|
|Multiple Osteochondromas: Clinicopathological and Genetic Spectrum and Suggestions for Clinical Management.|
|Hameetman L, Bovée JVMG, Taminiau AHM, Kroon HM, and Hogendoorn PCW|
|Hereditary Cancer in Clinical Practice. 2004 ; 2 : 161-173.|
|Molecular Cytogenetics in Ewing Tumors: Diagnostic and Prognostic Information.|
|Hattinger CM, Zoubek A, Ambros PF|
|Onkologie. 2000 ; 23 (5) : 416-422.|
|DNA aberrations in the epithelial cell component of adamantinoma of long bones.|
|Hazelbag HM, Fleuren GJ, Cornelisse CJ, van den Broek LJ, Taminiau AH, Hogendoorn PC|
|The American journal of pathology. 1995 ; 147 (6) : 1770-1779.|
|Rearrangement of band q13 on both chromosomes 12 in a periosteal chondroma.|
|Mandahl N, Willén H, Rydholm A, Heim S, Mitelman F|
|Genes, chromosomes & cancer. 1993 ; 6 (2) : 121-123.|
|Malignant fibrous histiocytoma: inherited and sporadic forms have loss of heterozygosity at chromosome bands 9p21-22-evidence for a common genetic defect.|
|Martignetti JA, Gelb BD, Pierce H, Picci P, Desnick RJ|
|Genes, chromosomes & cancer. 2000 ; 27 (2) : 191-195.|
|Translocation der(13;21)(q10;q10) in skeletal and extraskeletal mesenchymal chondrosarcoma.|
|Naumann S, Krallman PA, Unni KK, Fidler ME, Neff JR, Bridge JA|
|Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc. 2002 ; 15 (5) : 572-576.|
|USP6 and CDH11 oncogenes identify the neoplastic cell in primary aneurysmal bone cysts and are absent in so-called secondary aneurysmal bone cysts.|
|Oliveira AM, Perez-Atayde AR, Inwards CY, Medeiros F, Derr V, Hsi BL, Gebhardt MC, Rosenberg AE, Fletcher JA|
|The American journal of pathology. 2004 ; 165 (5) : 1773-1780.|
|Cytogenetic distinction among benign fibro-osseous lesions of bone in children and adolescents: value of karyotypic findings in differential diagnosis.|
|Parham DM, Bridge JA, Lukacs JL, Ding Y, Tryka AF, Sawyer JR|
|Pediatric and developmental pathology : the official journal of the Society for Pediatric Pathology and the Paediatric Pathology Society. 2004 ; 7 (2) : 148-158.|
|Genetic and epigenetic alterations in tumor progression in a dedifferentiated chondrosarcoma.|
|Röpke M, Boltze C, Neumann HW, Roessner A, Schneider-Stock R|
|Pathology, research and practice. 2003 ; 199 (6) : 437-444.|
|Enchondromatosis (Ollier disease, Maffucci syndrome) is not caused by the PTHR1 mutation p.R150C.|
|Rozeman LB, Sangiorgi L, Briaire-de Bruijn IH, Mainil-Varlet P, Bertoni F, Cleton-Jansen AM, Hogendoorn PC, Bovée JV|
|Human mutation. 2004 ; 24 (6) : 466-473.|
|Recurrent anomalies of 6q25 in chondromyxoid fibroma.|
|Safar A, Nelson M, Neff JR, Maale GE, Bayani J, Squire J, Bridge JA|
|Human pathology. 2000 ; 31 (3) : 306-311.|
|Updates on the cytogenetics and molecular genetics of bone and soft tissue tumors: chondrosarcoma and other cartilaginous neoplasms.|
|Sandberg AA, Bridge JA|
|Cancer genetics and cytogenetics. 2003 ; 143 (1) : 1-31.|
|Evidence of an association between 6q13-21 chromosome aberrations and locally aggressive behavior in patients with cartilage tumors.|
|Sawyer JR, Swanson CM, Lukacs JL, Nicholas RW, North PE, Thomas JR|
|Cancer. 1998 ; 82 (3) : 474-483.|
|Recurring breakpoints of 1p13 approximately p22 in osteochondroma.|
|Sawyer JR, Thomas EL, Lukacs JL, Swanson CM, Ding Y, Parham DM, Thomas JR, Nicholas RW|
|Cancer genetics and cytogenetics. 2002 ; 138 (2) : 102-106.|
|Genome-wide analysis of sixteen chordomas by comparative genomic hybridization and cytogenetics of the first human chordoma cell line, U-CH1.|
|Scheil S, Brüderlein S, Liehr T, Starke H, Herms J, Schulte M, Möller P|
|Genes, chromosomes & cancer. 2001 ; 32 (3) : 203-211.|
|Telomeric associations and consistent growth factor overexpression detected in giant cell tumor of bone.|
|Schwartz HS, Butler MG, Jenkins RB, Miller DA, Moses HL|
|Cancer genetics and cytogenetics. 1991 ; 56 (2) : 263-276.|
|Frequent loss of 9p21 (p16(INK4A)) and other genomic imbalances in human malignant fibrous histiocytoma.|
|Simons A, Schepens M, Jeuken J, Sprenger S, van de Zande G, Bjerkehagen B, Forus A, Weibolt V, Molenaar I, van den Berg E, Myklebost O, Bridge J, van Kessel AG, Suijkerbuijk R|
|Cancer genetics and cytogenetics. 2000 ; 118 (2) : 89-98.|
|EXT genes are differentially expressed in bone and cartilage during mouse embryogenesis.|
|Stickens D, Brown D, Evans GA|
|Developmental dynamics : an official publication of the American Association of Anatomists. 2000 ; 218 (3) : 452-464.|
|Significance of abnormalities of chromosomes 5 and 8 in chondroblastoma.|
|Swarts SJ, Neff JR, Johansson SL, Nelson M, Bridge JA|
|Clinical orthopaedics and related research. 1998 : 189-193.|
|Correlation between clinicopathological features and karyotype in 100 cartilaginous and chordoid tumours. A report from the Chromosomes and Morphology (CHAMP) Collaborative Study Group.|
|Tallini G, Dorfman H, Brys P, Dal Cin P, De Wever I, Fletcher CD, Jonson K, Mandahl N, Mertens F, Mitelman F, Rosai J, Rydholm A, Samson I, Sciot R, Van den Berghe H, Vanni R, Willén H|
|The Journal of pathology. 2002 ; 196 (2) : 194-203.|
|Gains and losses of DNA sequences in osteosarcomas by comparative genomic hybridization.|
|Tarkkanen M, Karhu R, Kallioniemi A, Elomaa I, Kivioja AH, Nevalainen J, Bhling T, Karaharju E, Hyytinen E, Knuutila S|
|Cancer research. 1995 ; 55 (6) : 1334-1338.|
|Analysis of the p16INK4, p14ARF, p15, TP53, and MDM2 genes and their prognostic implications in osteosarcoma and Ewing sarcoma.|
|Tsuchiya T, Sekine K, Hinohara S, Namiki T, Nobori T, Kaneko Y|
|Cancer genetics and cytogenetics. 2000 ; 120 (2) : 91-98.|
|Genetic instability in primary leiomyosarcoma of bone.|
|Verelst SJ, Hans J, Hanselmann RG, Wirbel RJ|
|Human pathology. 2004 ; 35 (11) : 1404-1412.|
|Langerhans'-cell histiocytosis (histiocytosis X)--a clonal proliferative disease.|
|Willman CL, Busque L, Griffith BB, Favara BE, McClain KL, Duncan MH, Gilliland DG|
|The New England journal of medicine. 1994 ; 331 (3) : 154-160.|
|Positional cloning of a gene involved in hereditary multiple exostoses.|
|Wuyts W, Van Hul W, Wauters J, Nemtsova M, Reyniers E, Van Hul EV, De Boulle K, de Vries BB, Hendrickx J, Herrygers I, Bossuyt P, Balemans W, Fransen E, Vits L, Coucke P, Nowak NJ, Shows TB, Mallet L, van den Ouweland AM, McGaughran J, Halley DJ, Willems PJ|
|Human molecular genetics. 1996 ; 5 (10) : 1547-1557.|
|This paper should be referenced as such :|
|Schrage, YM ; Bovée, JVMG|
|Bone tumors: an overview|
|Atlas Genet Cytogenet Oncol Haematol. 2005;9(2):166-170.|
|Free journal version : [ pdf ] [ DOI ]|
|On line version : http://AtlasGeneticsOncology.org/Tumors/BoneTumorID5143.html|
|Other genes implicated (Data extracted from papers in the Atlas) [ 10 ]|
|arrayMap||Topo ( C40,C41) arrayMap ((UZH-SIB Zurich) [auto + random 100 samples .. if exist ] [tabulated segments]|
|Other database||ICGC Data Portal - [BOCA-UK] Bone Cancer - UK|
|Other database||Sarcoma (SARC) TCGA Copy Number Portal|
|Other database||Bone Cancer Overview - Disease Synopsis [canSAR]|
|Other database||Sarcoma [ Genomic Data Commons - NCI TCGA-SARC]|
|Disease database||Bone tumors: an overview|
|REVIEW articles||automatic search in PubMed|
|Last year articles||automatic search in PubMed|
|© Atlas of Genetics and Cytogenetics in Oncology and Haematology||indexed on : Mon Dec 14 18:30:18 CET 2020|
For comments and suggestions or contributions, please contact us