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Bone: Osteochondroma

Written2002-09Liesbeth Hameetman, Judith VMG Bovée
Department of Pathology, Leiden University Medical Center, P1-30, Albinusdreef 2, 2333 ZA Leiden, The Netherlands
Updated2008-09Christianne Reijnders, Liesbeth Hameetman, Judith VMG Bovée
Department of Pathology, Leiden University Medical Center, P1-30, Albinusdreef 2, 2333 ZA Leiden, The Netherlands

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ICD-Topo C400-C403,C408-C414,C418-C419 BONES & JOINTS
ICD-Morpho 9210/0 Osteochondroma
Atlas_Id 5146
Phylum Bones::Osteochondroma
Note Osteochondroma (osteocartilaginous exostosis) is a cartilage capped bony neoplasm arising on the external surface of bone containing a marrow cavity that is continuous with that of the underlying bone. It arises in bones preformed by endochondral ossification and the most common site of involvement is the metaphyseal region of the long bone of the limbs, like the distal femur, upper humerus, upper tibia and fibula. They also frequently occur in the flat bones, in particular the ilium and scapula. Osteochondromas can occur as a solitary lesion (solitary osteochondromas) or within the context of Multiple Osteochondromas (MO). The literature indicates slight male sex predominance (male/female ratio 1.5:1). Most osteochondromas are prone to arise in the first 3 decades of life. Osteochondromas hardly occur in the craniofacial bones. This might be explained by the fact that these bones are not formed by endochondral ossification.

Clinics and Pathology

Epidemiology Osteochondromas are the most common benign bone tumors. They represent 35% of the benign and 8% of all bone tumours, although this is probably an underestimation since the majority are asymptomatic. Approximately 15% of patients with osteochondromas have multiple osteochondromas (MO).
Clinics The growth of the osteochondroma ceases at skeletal maturation or shortly thereafter. Patients may have a swelling of year's causing symptoms related to the location and site of the lesion such as mechanical obstruction, nerve impingement, pseudoaneurysm of an overlying vessel, fracture at the stalk of the lesion, or the formation of a bursa over the osteochondroma. However most lesions are asymptomatic and found accidentally. The most serious complication is malignant transformation towards secondary peripheral chondrosarcoma, which is estimated to occur in <1% of solitary cases and 0.5-5% of MO cases.
Pathology Pedunculated osteochondromas contain a stalk and are long and slender, while sessile ones are flat. Many osteochondromas are cauliflower shaped (figure 1). A fibrous perichondrium covers the cartilage cap and is continuous with the periosteum of the underlying bone. The cartilage cap is less than 2 cm thick and this is decreasing with age. A thick (greater than 2 cm) and irregular cap may indicate malignant transformation of the tumor. The cap covers the entire elevated surface of a sessile tumor, while it only covers the distal part of a pedunculated one. The cartilage cap merges into the underlying spongiosa. Here the chondrocytes are arranged according to an epiphyseal growth plate. A typical benign chondrocyte has a single small nucleus. During active bone growth, binucleated chondrocytes may be seen in benign tumors. The spongiosa of the stalk is continuous with the underlying cancellous bone. Fractures within the stalk may produce fibroblastic proliferation and even new bone formation. A bursa may develop over the osteochondroma and is usually attached to the perichondrium of the cap. The bursal wall is lined by synovium that may show inflammatory changes.
Figure 1: Histological appearance of an osteochondroma. A perichondrium (Bellaiche et al., 1998) covers the cartilage cap (Bernard et al., 2001). The cap merges into the underlying spongiosa (Bornemann et al., 2004), where the chondrocytes are arranged according to an epiphyseal growth plate (Bovée et al., 1999).
Treatment The low rate of malignant transformation (<1%) is insufficient reason for resection. Osteochondromas are usually removed for cosmetic reasons, when symptoms of pain, limitation of motion, or impingement on adjacent structures such as nerves and blood vessels occur, or when roentogenographic features or an abnormal increase in tumor size suggest progression towards malignancy. When surgical resection is needed, the entire lesion should be removed, including the complete cartilaginous cap, to avoid recurrence. Multiple recurrence or recurrence in a well-excised lesion should raise suspicion of malignancy.
Evolution Until recently, there has been a lot of debate about whether an osteochondroma is a developmental disorder or a true neoplasm. It was for long considered to be a perversion in the direction of bone growth. However, recent studies have shown osteochondroma to be a true neoplasm, since presence of loss of heterozygosity (LOH) and aneuploidy in osteochondromas indicate a clonal origin for the cartilaginous tissue of osteochondromas. Inactivation of both alleles of EXT1 in cartilaginous cells of the cap is required for the formation of solitary and multiple osteochondromas.
Prognosis Complete excision of osteochondroma is usually curative. Failure to remove the entire cartilaginous cap or its overlying periosteum is the basis for most recurrences. Recurrence could also suggest malignancy.


Note Cytogenetic aberrations involving 8q22-24.1, where the EXT1 gene is located, have been found in ten out of 30 sporadic and in 1 out of 13 multiple osteochondromas. In one sporadic case deletion of 11p11-12 was found. In 7 out of 8 solitary osteochondromas homozygous deletions of EXT1 were identified. Aberrations of chromosome 1p (1p13-p22) were found in five of seven osteochondromas.
Cytogenetics Molecular Loss of heterozygosity (LOH) was found almost exclusively at the EXT1 locus in both sporadic and multiple osteochondromas using microsatellite analysis. Fluorescence in situ hybridization revealed loss of the 8q24 locus. The EXT genes, involved in MO, are hypothesized to be tumor suppressor genes. Germline EXT1 mutations, resulting in a truncated EXT1 protein, together with the loss of the remaining wild type allele was demonstrated in both sporadic and multiple osteochondromas. These findings suggest that inactivation of both copies of the EXT1 gene is required for the development of osteochondromas. The EXT proteins are involved in the biosynthesis of heparan sulphate (HS). Heparan sulphate proteoglycans (HSPG) are large macromolecules composed of heparan sulphate glycosaminoglycan chains linked to a protein core. Four HSPG families are syndecan, glypican, perlecan and isoforms of CD44. HSPGs are required for high-affinity binding of fibroblast growth factor to its receptor. Furthermore, studies in Drosophila have shown that EXT (tout-velu, Ttv) is required for the diffusion of the morphogens: Hedgehog (Hh, human homologues Indian Hedgehog ( IHh ) and Sonic Hedgehog ( SHh ), decapentaplegic (dpp, human homologues TGB-beta and BMP) and wingless (human homologue Wnt). It was therefore hypothesized that EXT mutations affect IHh / PTHLH, TGF-beta/BMP and Wnt signaling pathways within the normal growth plate. Indeed, altered levels of the EXT1 and EXT2 protein and of their putative downstream effectors (IHh/PTHrP, TGF-beta/BMP and Wnt signalling pathways) were demonstrated in both solitary and multiple osteochondromas. In addition, due to impaired EXT1/EXT2 function the HSPGs appear to be retained in the Golgi apparatus and cytoplasm of the tumour cell, instead of being transported to the cell surface and/or extra cellular matrix where they normally exert their function. Moreover, EXT mutations were described to induce cytoskeletal abnormalities (altered actin distribution) in osteochondroma chondrocytes.
Malignant transformation of osteochondroma is characterized at the DNA level by chromosomal instability, as demonstrated by a high percentage of LOH and aneuploidy in chondrosarcomas compared to LOH restricted to 8q24 and diploidy or mild aneuploidy in osteochondroma. At the protein level, upregulation of PTHrP and BCL2 is found in grade I peripheral chondrosarcomas as compared to osteochondromas.


Tout-velu is a drosophila homologue of the putative tumour suppressor EXT1 and is needed for Hh diffusion.
Bellaiche Y, The I, Perrimon N.
Nature. 1998 Jul 2; 394(6688): 85-88.
PMID 9665133
Diminished levels of the putative tumor suppressor proteins EXT1 and EXT2 in exostosis chondrocytes.
Bernard MA, Hall CE, Hogue DA, Cole WG, Scott A, Snuggs MB, Clines GA, Ludecke HJ, Lovett M, Van Winkle WB, Hecht JT.
Cell Motil Cytoskeleton. 2001 Feb; 48(2): 149-162.
PMID 11169766
Abrogation of heparan sulfate synthesis in Drosophila disrupts the Wingless, Hedgehog and Decapentaplegic signaling pathways.
Bornemann DJ, Duncan JE, Staatz W, Selleck S, Warrior R.
Development. 2004 May; 131(9): 1927-1938. Epub 2004 Mar 31.
PMID 15056609
Up-regulation of PTHrP and Bcl-2 expression characterizes the progression of osteochondroma towards peripheral chondrosarcoma and is a late event in central chondrosarcoma.
Bovee JVMG, Van den Broek LJCM, Cleton-Jansen AM, Hogendoorn PCW.
Lab Invest. 2000 Dec; 80(12): 1925-1934.
PMID 11140704
Clonal karyotypic abnormalities of the hereditary multiple exostoses chromosomal loci 8q24.1 (EXT1) and 11p11-12 (EXT2) in patients with sporadic and hereditary osteochondromas.
Bridge JA, Nelson M, Orndal C, Bhatia P, Neff JR.
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PMID 9576285
Cartilaginous tumors: fast contrast-enhanced MR imaging.
Geirnaerdt MJ, Hogendoorn PCW, Bloem JL, Taminiau AHM, Van der Woude HJ.
Radiology. 2000 Feb; 214(2): 539-546.
PMID 10671608
The role of EXT1 in nonhereditary osteochondroma: identification of homozygous deletions.
Hameetman L, Szuhai K, Yavas A, Knijnenburg J, van Duin M, Van Dekken H, Taminiau AH, Cleton-Jansen AM, Bovee JV, Hogendoorn PC.
J Natl Cancer Inst. 2007 Mar 7;99(5):396-406.
PMID 17341731
Heparan sulfate abnormalities in exostosis growth plates.
Hecht JT, Hall CR, Snuggs M, Hayes E, Haynes R, Cole WG.
Bone. 2002 Jul; 31(1): 199-204.
PMID 12110435
Loss of chromosome band 8q24 in sporadic osteocartilaginous exostoses.
Mertens F, Rydholm A, Kreicbergs A, Willen H, Jonsson K, Heim S, Mitelman F, Mandahl N.
Genes Chromosomes Cancer. 1994 Jan; 9(1): 8-12.
PMID 7507706
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 Genet Cytogenet. 2002 Oct 15; 138(2): 102-106.
PMID 12505252
Chondrosarcoma (Primary, Secondary, Dedifferentiated, and Clear Cell).
Unni KK.
Dahlin's bone tumors. General aspects and data on 11,087 cases. 1996; pp 71-108.


This paper should be referenced as such :
Reijnders, C ; Hameetman, L ; Bove, JVMG
Bone: Osteochondroma
Atlas Genet Cytogenet Oncol Haematol. 2009;13(9):678-680.
Free journal version : [ pdf ]   [ DOI ]
On line version :
History of this paper:
Hameetman, L ; Bove, JVMG. Bone: Osteochondroma. Atlas Genet Cytogenet Oncol Haematol. 2003;7(1):41-43.

Other genes implicated (Data extracted from papers in the Atlas) [ 1 ]

Genes IDH2

External links

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