Bone: Osteochondroma

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Bone: Osteochondroma

Identity

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 osteochondroma) or within the context of hereditary multiple exostoses (HME). The literature indicates a slight male sex predominance (male/female ratio 1.5:1) and most osteochondromas are prone to attention in the first three decades of life. Osteochondromas pratically never 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 underestimate since the majority are asymptomatic. Approximately 15% of patients with osteochondromas have multiple lesions (HME).

Clinics The growth of the osteochondroma ceases at skeletal maturation or shortly thereafter. Patients may have a swelling of years duration 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 accidentially. The most serious complication is malignant transformation towards secondary peripheral chondrosarcoma, which is estimated to occur in <1% of solitary cases and 1-3% of hereditary cases.

Pathology Pedunculated osteochondromas contain a stalk and are long and slender, while sessile ones are flat. Many exostoses are cauliflower shaped (figure). 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 decreases 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 a osteochondroma. A perichondrium (1) covers the cartilage cap (2). The cap merges into the underlying spongiosa, where the chondrocytes are arranged according to an epiphyseal growth plate (4).

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 adjecent 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 copies of an EXT gene in cartilaginous cells in the growth plate is required for the formation of osteochondromas in hereditary cases.

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.

Cytogenetics

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 hereditary osteochondromas. In one sporadic case deletion of 11p11-12 was found.

Cytogenetics Molecular
Loss of heterozygosity (LOH) was found almost exclusively at the EXT1 locus in both sporadic and hereditary osteochondromas using microsatellite analysis. Fluorescence in situ hybridization revealed loss of the 8q24 locus. The EXT genes, involved in HME, 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 hereditary 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). In chondrocytes these HS proteoglycans are important amongst others in the growth plate signaling and remodeling. EXT mutations would affect the HS synthesis and thereby disturb the intracellular signaling involving Indian Hedgehog (IHh) and parathyroid hormone-related protein (PTHrP), which regulate proliferation, organization and differentiation in the growth plate. These downstream effectors of EXT are indeed almost absent in sporadic and hereditary osteochondromas.
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.

Bibliography

Loss of chromosome band 8q24 in sporadic osteocartilaginous exostoses.

Mertens F, Rydholm A, Kreicbergs A, Willˆ©n H, Jonsson K, Heim S, Mitelman F, Mandahl N

Genes, chromosomes & cancer. 1994 ; 9 (1) : 8-12.

PMID 7507706

Chondrosarcoma (Primary, Secondary, Dedifferentiated, and Clear Cell).

K..

Osteochondroma (Osteocartilaginous Exostosis).

Unni KK

Dahlin's bone tumors. General aspects and data on 11,087 cases, Philadelphia Lippincot-Raven Publishers. 1996 ; 5 : 71-108.

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

Cancer. 1998 ; 82 (9) : 1657-1663.

PMID 9576285

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

Cancer. 1998 ; 82 (9) : 1657-1663.

PMID 9576285

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, CletonJansen AM, Hogendoorn PCW

Lab.Invest.

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, Lˆºdecke HJ, Lovett M, Van Winkle WB, Hecht JT

Cell motility and the cytoskeleton. 2001 ; 48 (2) : 149-162.

PMID 11169766

Cartilaginous tumors: fast contrast-enhanced MR imaging.

Geirnaerdt MJ, Hogendoorn PC, Bloem JL, Taminiau AH, van der Woude HJ

Radiology. 2000 ; 214 (2) : 539-546.

PMID 10671608

Heparan sulfate abnormalities in exostosis growth plates.

Hecht JT, Hall CR, Snuggs M, Hayes E, Haynes R, Cole WG

Bone. 2002 ; 31 (1) : 199-204.

PMID 12110435

REVIEW articles automatic search in PubMed

Last year publications automatic search in PubMed

Contributor(s)

Written 09-2002 L Hameetman, JVMG Bovée

Department of Pathology, Leiden University Medical Center, P1-30, Albinusdreef 2, 2333 ZA Leiden, The Netherlands

Citation

This paper should be referenced as such :
Hameetman L, Bovée JVMG . Bone: Osteochondroma. Atlas Genet Cytogenet Oncol Haematol. Septem ber 2002 .
URL : http://AtlasGeneticsOncology.org/Genes/OsteochondromaID5146.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology
indexed on : Mon Aug 11 21:22:21 2008

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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 underestimate since the majority are asymptomatic. Approximately 15% of patients with osteochondromas have multiple lesions (HME).
Clinics	The growth of the osteochondroma ceases at skeletal maturation or shortly thereafter. Patients may have a swelling of years duration 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 accidentially. The most serious complication is malignant transformation towards secondary peripheral chondrosarcoma, which is estimated to occur in <1% of solitary cases and 1-3% of hereditary cases.
Pathology	Pedunculated osteochondromas contain a stalk and are long and slender, while sessile ones are flat. Many exostoses are cauliflower shaped (figure). 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 decreases 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 a osteochondroma. A perichondrium (1) covers the cartilage cap (2). The cap merges into the underlying spongiosa, where the chondrocytes are arranged according to an epiphyseal growth plate (4).

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 adjecent 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 copies of an EXT gene in cartilaginous cells in the growth plate is required for the formation of osteochondromas in hereditary cases.
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.

REVIEW articles	automatic search in PubMed
Last year publications	automatic search in PubMed

Written	09-2002	L Hameetman, JVMG Bovée
		Department of Pathology, Leiden University Medical Center, P1-30, Albinusdreef 2, 2333 ZA Leiden, The Netherlands