Cartilage Cap Research Articles

Advantages in Vascular Tumors

The authors provide an extensive overview of the uses of whole-body magnetic resonance imaging (MRI) in manifold diseases. However, we wish to make two comments with regard to the use of whole-body MRI in benign or malignant tumors. It is correct to state that multiple cartilaginous exostoses entail the risk of malignant transformation (1). However, such transformations usually occur in elderly patients, and we agree that repeated radiographic examinations in young patients are certainly not advisable. However, the question arises whether all known exostoses should be subject to regular radiological (MRI) control examinations from childhood onwards. In our hospital, patients with clinically controllable exostoses on the peripheral skeletal system are fully informed about the fact that if these increase in size after patients have reached their full physical height, malignant transformation is the first diagnosis that springs to mind. In such cases, local MRI at the highest resolution should be conducted in order to determine the cartilage cap, so as to gain closer insights into a possible transformation. In exostoses that are close to the trunk and less easily clinically controlled, regular local MRI scanning is certainly a sensible option. Altogether, the question is whether in the cases mentioned above the more time-consuming and costlier whole-body MRI may lead to earlier detection of the transformation, thus conferring a prognostic advantage. As far as we are aware, no studies have been conducted in this regard. By contrast, we think that whole-body MRI offers a diagnostic advantage in patients with vascular tumors (for example, angiosarcomas). Because of their multifocality, these can often not be diagnosed by using conventional radiography or szintigraphy (2). In this setting, whole-body MRI can detect even smaller infiltrations of the bone marrow cavity, which will have to be made accessible to surgical treatment (3).

Giant Solitary Osteochondroma Arising from the Fifth Metatarsal Bone: A Case Report

Accounting for 20% to 50% of all benign forms, solitary osteochondroma is the most common bone tumor. The long bones of the lower extremity are most frequently affected, whereas the small bones of the hands, feet, pelvis, scapula, and spine are less common locations. Osteochondromas are benign osseous neoplasms with a distinct hyaline cartilage cap originating from the physis, and they cease to grow with skeletal maturity. Treatment of osteochondroma is usually conservative, unless symptoms, usually pain, are progressive or the lesion demonstrates rapid or new growth, or if enlargement after skeletal maturation is noted or malignant transformation is suspected. In this report, we describe the case of an adult with a giant, symptomatic osteochondroma localized to the fifth metatarsal. The lesion was treated with excision, and after more than 2 years of follow-up, no evidence of recurrence was noted. This case demonstrated that, despite the benign nature of the lesion, a large osteochondroma could localize to a metatarsal.

A splice‐site mutation leads to haploinsufficiency of EXT2 mRNA for a dominant trait in a large family with multiple osteochondromas

Multiple osteochondromas (MO) is an autosomal-dominant disorder and mutations in EXT1 and EXT2 account up to 78% of the cases studied, including missense, nonsense, frameshift, and splice-site mutations. EXT1 and EXT2 encode glycosyltransferases required for the synthesis of heparan sulfate (HS) chains. The molecular pathogenesis underlying these mutations is still largely unknown. A heterozygous c.1173 + 1G > T (EXT2) mutation was identified in a three-generation 34-member MO family and is present in all 19 affected members. The consequence of this mutation is exon 7 being spliced out, and the result is a shift in the codon-reading frame from position 360 (R360) of the amino acid sequence leading to a premature termination codon, and the mutant mRNA is degraded to an undetectable level. Interestingly, HS glycosaminoglycans were also undetectable in the cartilage cap of the tumors by immunostaining. Full penetrance of this mutation in all affected members ranging from 5 to 70 years of age suggests this primary defect in EXT2 mRNA level, in conjunction with other cellular changes such as enhanced heparanase expression, can produce profound effect on the synthesis of HS chains in cartilage, the consequence of which impacts on the regulation of chondrocyte proliferation and differentiation.

Improved Differentiation of Benign Osteochondromas from Secondary Chondrosarcomas with Standardized Measurement of Cartilage Cap at CT and MR Imaging

To validate a technique for reproducible measurement of the osteochondroma cartilage cap with computed tomography (CT) and magnetic resonance (MR) imaging and to reevaluate the correlation of the thickness of the cartilage cap with pathologic findings to improve noninvasive differentiation of benign osteochondromas from secondary chondrosarcomas. The institutional review board approved the study and waived the need for informed consent. HIPAA compliance was maintained. After validation of the measurement technique, 101 pathologically confirmed osteochondromas were retrospectively reviewed. Patient demographic data, histologic diagnosis, and chondrosarcoma grade were recorded. Two musculoskeletal radiologists used a standardized technique to independently measure the thicknesses of the cartilage caps on CT and MR images; these measurements were compared for interobserver agreement. Agreement between measurements with CT and MR imaging was also evaluated, as were the sensitivity and specificity of both modalities for differentiation of osteochondromas from chondrosarcomas. Evaluated were 67 benign osteochondromas (from 49 male patients and 18 female patients; mean age, 23.4 years) and 34 secondary chondrosarcomas (from 27 male patients and seven female patients; mean age, 33.2 years). On the basis of the proposed measuring technique, there was 88% interobserver measurement agreement with MR imaging (95% confidence interval [CI]: 80%, 94%) and 93% with CT (95% CI: 84%, 98%). The median difference between measurements of cap thickness at CT and MR imaging was 0 cm (25th and 75th percentiles, -3 mm and 1 mm, respectively). With 2 cm used as a cutoff for distinguishing benign osteochondromas from chondrosarcomas, the sensitivities and specificities were 100% and 98% for MR imaging and 100% and 95% for CT, respectively. The proposed measuring technique allows accurate and reproducible measurement of cartilage cap thickness with both CT and MR imaging. Cap thickness of 2 cm or greater strongly indicated secondary chondrosarcomas.

Solitary Pelvic Osteochondroma Causing L5 Nerve Root Compression

Osteochondroma is the most common benign bone tumor, accounting for more than one-third of all benign bone tumors. It usually develops at the metaphysis of the long bones, especially the distal femur and proximal tibia. Approximately 40% of osteochondromas are found around the knee. Osteochondroma commonly presents as a painless mass and is incidentally identified via plain radiographs. Thus, surgical excision is not routinely recommended unless the tumor causes clinical symptoms or cosmetic distress. Osteochondroma located in the pelvis is unusual. Spinal nerve root compressions due to pelvic osteochondroma are also rarely reported. We assessed the solitary pelvic osteochondroma of a 33-year-old man mimicking spinal disease. An exostotic bony projection composed of dense calcification of the cartilaginous cap arose from the iliac crest, which was located just lateral to the right sacroiliac joint in the paravertebral area, L5 level. Magnetic resonance imaging showed an irregular, exophytic outgrowing calcified mass with cartilage cap and exostotic mass compressed to the proximal part of the right L5 nerve root lateral to the nerve root foramen. The L5 nerve root was focally compressed and thinned.En bloc excision, the treatment of choice of symptomatic osteochondroma, was performed. The patient had complete resolution of symptoms postoperatively, and other neurologic symptoms may be expected to improve over time.

Identification of Four NovelEXT1andEXT2Mutations in Five Chinese Pedigrees with Hereditary Multiple Exostoses

Hereditary multiple exostoses (HME) is an autosomal dominant skeletal disorder most frequently caused by the EXT1 and EXT2 gene mutations resulting in reduction or absence of heparan sulfate (HS) in the exostotic cartilage cap. In this study, we investigated the molecular defects in five Chinese pedigrees with HME by direct sequencing analysis. Two novel EXT1 gene mutations and two novel EXT2 gene mutations were identified in two and three pedigrees, respectively. Of the four mutations identified, the c.651-664delinsTTT and c.680delG mutations in the exon 1 of EXT1 gene would cause frameshift (K218fs and R227fs) and introduce premature stop codon at amino acid site 220 and 251, respectively. The two missense mutations of c.398T > G in exon 2 and c.1016G > A in exon 6 of EXT2 gene result in the Leu133Arg and Cys339Tyr substitution, respectively. As HME is caused by defects in HS synthesis that is a complex process and not fully understood, these naturally occurring EXT mutations may provide important clues to future studies elucidating how EXT proteins contribute to HS biosynthesis.

Dedifferentiated peripheral chondrosarcomas: regulation of EXT-downstream molecules and differentiation-related genes

Dedifferentiated peripheral chondrosarcoma is a rare subtype of chondrosarcoma arising superimposed on the cartilage cap of a preexisting osteochondroma. It consists of two clearly defined components, a low-grade malignant, well-differentiated cartilage component and a high-grade non-cartilaginous sarcoma. Signaling pathways having a role in normal cartilage development were analyzed in these tumors, and compared with available data of other cartilaginous tumors. Sixteen well-characterized dedifferentiated peripheral chondrosarcomas were immunohistochemically analyzed for parathyroid hormone-like hormone (PTHLH)-BCL-2, fibroblastic growth factor (FGF), and transforming growth factor-β signaling molecules, as well as matrix molecules and p53, comparing the chondrogenic component of dedifferentiated peripheral chondrosarcomas with the anaplastic component and with previously published data obtained from conventional grade I and II secondary peripheral chondrosarcomas. Results were correlated with clinical outcome. In the anaplastic component, various lines of differentiation could be found (collagen I (6/16), CD31 (1/16), smooth muscle actin (12/16), muscle-specific actin (12/16) and desmin (2/9)). Compared with the anaplastic component, the chondrogenic component of dedifferentiated peripheral chondrosarcomas shows more often expression of cyclin D1 (P=0.05), p53 (P=0.008), plasminogen activator inhibitor 1 (PAI-1) (P=0.005), and CD44 (P=0.030). Compared with secondary peripheral chondrosarcomas, more samples were positive in the chondrogenic component of dedifferentiated peripheral chondrosarcomas for FGF signaling (FGF receptor 3 P=0.000; bFGF P=0.003) and CD44 (P=0.000). Lower expression of BCL-2 (P=0.025) and absence of CD44v3 (P=0.000), a splice variant of CD44, was observed in the chondrogenic component of dedifferentiated peripheral chondrosarcomas compared with secondary peripheral chondrosarcomas. With regard to clinical data, PAI-1 expression in the chondrogenic component of dedifferentiated peripheral chondrosarcomas correlated with better survival (P=0.019). In conclusion, in the chondrogenic component of dedifferentiated peripheral chondrosarcomas, FGF signaling pathway is active, whereas PTHLH signaling seems to be low/downregulated. Interestingly, although the chondrogenic component of dedifferentiated peripheral chondrosarcoma is CD44+/CD44v3−, secondary peripheral chondrosarcomas is CD44−/CD44v3+, which suggest different splicing (preference). The prognostic value of PAI-1 in dedifferentiated peripheral chondrosarcomas might also be of interest for the more common dedifferentiated central chondrosarcomas.

Clinicopathologic features of osteochondroma with malignant transformation

To investigate the clinicopathologic, radiological and immunohistochemical characteristics of osteochondroma with malignant transformation. The clinical data, radiological imagings and hematoxylineosin stained histologic sections were reviewed in 463 cases of osteochondroma diagnosed in Shanghai 6th Hospital from 1991 to 2008, including 11 cases with malignant transformation. Immunohistochemical two-step staining was used to detect CK, vimentin, S-100 protein, p53 and c-myc expression in seven cases of osteochondroma with malignant transformation and 10 cases without malignant transformation. The relevant literature was reviewed. Among the 11 cases with malignant transformation, five were single osteochondroma (5/408, 1.2%), and six were multiple osteochondromas (6/55, 10.9%). The male to female ratio was 10:1. These 11 cases were derived from femur (4 cases), tibia (3 cases), ilium (3 cases), shoulder bone (1 case) and pubis (1 case). There was one case that showed malignant transformation in both the femur and ilium. The mean ages for the malignant and non-malignant cases were 39.8 years and 20.4 years respectively. All the malignant cases showed large sized lesions with prominent calcification in the thick cartilage caps. The malignant component was low grade, peripheral chondrosarcoma (grade I-II). In some areas the tumor cells infiltrated the peripheral soft tissue and bone marrow. Of the seven cases with malignant transformation that had immunohistochemical staining, all were positive for vimentin and S-100 protein; p53 protein was positive in 2 of 7 cases. Malignant transformation of osteochondroma was usually encountered in multiple lesions. Most patients were more than 30 years old with a long clinical history and with a male predominance. These tumors showed thick cartilage caps with prominent calcification. The lobulated nature of the tumors was evident and they infiltrated the surrounding soft tissue. The sarcomatoid component was peripheral type, well differentiated chondrosarcoma. p53 mutation may explain part of the molecular mechanism in the malignant transformation.

Multiple Hereditary Exostosis, EXT Genes, and Skeletal Development

Multiple hereditary exostosis is an autosomal dominant inherited disease in which osteochondral growths occur on the periphery of bones. These growths are comprised of bone surrounded by a cap of cartilage. A small number of these exostoses proceed to a low-grade chondrosarcoma1,2. Although the disease can occur spontaneously, it has been estimated that 80% of affected individuals have a positive family history2. Research on the genetics of multiple hereditary exostosis over the past thirty years has been productive. Advances in the understanding of the disease have paralleled the methodological advances that have occurred in the field of molecular genetics. Initially, it was recognized that multiple hereditary exostosis is often inherited and that large families were available for genetic mapping. As techniques for gene mapping improved, regions of the chromosomes involved were identified, localized, and eventually subjected to DNA sequencing. The genes identified, the exostosins, were found to encode known enzymes whose function within the disease could be reasonably predicted. Mouse models were created, and the hypothesized function of these genes was verified. Many surprises were encountered along the way, which served to uncover important biological principles. The understanding of human multiple hereditary exostosis is a paradigm for the power of combining modern molecular biology, genetics, and clinical science. In the early 1990s, the clearly autosomal dominant inheritance of multiple hereditary exostosis was recognized by clinicians and DNA techniques became available to localize the inheritance patterns in the DNA. By genetic linkage analysis, Hecht et al. and Le Merrer et al. were able to localize the inheritance patterns of these families to three chromosomal locations: 8q24.1, 11p11-13, and 19p2,3. These genes were identified as tumor-suppressor genes, and loss of heterozygosity in these regions was associated with transformation into chondrosarcoma2, …

A comparison of open versus arthroscopic harvesting of osteochondral autografts

Osteochondral autograft transfer is a technique for treatment of traumatic and degenerative cartilage lesions. A graft in which the cartilage cap is oriented perpendicular to the long axis of the graft is ideal because it can both restore the cartilage tidemark and minimize articular step-off at the recipient site. This study determines if osteochondral harvest technique (arthroscopic versus mini-open) or donor site location affects suitable graft harvest. One hundred and twenty eight osteochondral grafts were harvested in 16 cadaver knees utilizing a 7 mm OATS chisel from four donor sites: lateral supracondylar ridge, lateral femoral condyle, lateral intercondylar notch and medial femoral condyle. Mini-open and arthroscopic harvesting techniques were equally employed. Radiographic methods were used to analyze graft perpendicularity. Statistical analysis comparing graft suitability based on technique and donor site location was performed. There were no statistically significant differences ( p > 0.05) in graft suitability regardless of the technique used or donor site location. 69% of arthroscopic and 56% of mini-open graft harvest were considered suitable, possessing a cartilage cap and graft axis angle that would create less than 1 mm of articular incongruity. Incongruity results when the angle between the subchondral bone plug long axis and cartilage interface is greater than 74°. There is no difference in the quality of osteochondral grafts harvested from the knee regardless of technique or donor site used. Osteochondral graft diameter should be kept at or less than 7 mm because of the high percentage of unacceptable grafts with increasing chisel sizes.

The molecular and cellular basis of exostosis formation in hereditary multiple exostoses

The molecular and cellular basis of exostosis formation in hereditary multiple exostoses

Concurrent Osteochondroma and Osteoblastoma of the Proximal Humeral Shaft

We present what we believe is the first reported case of synchronous osteochondroma and osteoblastoma, occurring in the proximal humerus of a young man. A 15-year-old boy presented with a painful left arm mass for 3 months. A firm mass was palpable in the proximal medial arm, and he had mild triceps weakness secondary to pain. Imaging showed an eccentric lesion involving the proximal one-third of the humerus, with central lysis, surrounding sclerosis and edema, endosteal scalloping, and cortical thinning and expansion. The humeral diaphysis contained a bony exostosis with corticomedullary continuity, consistent with an osteochondroma with a cartilage cap <5 mm thick. Within the proximal portion of the osteochondroma was a 2-cm, edematous, rim-enhancing cystic lesion, concerning for a secondary process such as malignant transformation. On open biopsy, the mass grossly appeared to be a sessile osteochondroma, and was removed with a rongeur. The cystic lesion was curetted out of the bone. Pathology confirmed that the raised lesion was an osteochondroma. The cystic lesion contained osteoblasts in a matrix of osteoid and immature bone, characteristic of an osteoblastoma. The multidisciplinary team agreed that this was an osteoblastoma within an exostosis. At follow-up, the patient's pain had fully resolved and radiographs showed good early healing. We wished to document the extraordinary, simultaneous existence of an osteochondroma and adjacent osteoblastoma in the proximal humerus of a young patient. Although similar in presentation, the tumors consist of cells of different origins, making the pathogenesis unclear.

Osteochondritis Dissecans of the Elbow

Osteochondritis dissecans of the elbow is a disorder noted in young, repetitive-motion athletes. Although often characterized by inflammation, pain, and loss of motion, the pathological changes within the bone involve no inflammatory cells. Nonoperative management includes elimination of the secondary inflammatory changes, by rest and the use of anti-inflammatory modalities, combined with elimination of the stress to the capitellum by rest and the use of an off-loading hinged elbow brace. Nonoperative management is most effective when the cartilage cap overlying the lesion is intact. Surgical intervention may take several forms when the disorder either does not respond to nonoperative management or is discovered in a later stage. Percutaneous fixation of nondisplaced lesions, when there is enough bone in the loose fragment to allow purchase of the fixation device, is an attractive option. Arthroscopic removal of loose bodies, excision of an inflamed posterolateral plica, and microfracture of the residual defect may be of benefit in the intermediate stages. Patients in which these options fail, or in which there is extensive destruction of the bone and involvement of the extreme lateral cortex or “shoulder” of the capitellum, osteochondral grafting may be indicated. Results of each treatment modality are quite good, with success rates reported between 66% and 95%. The primary complications include loss of motion, early arthritis, and a failure to return to the same level of competition.

Skeletal Osteochondromas Revisited

Skeletal osteochondromas or osteocartilaginous exostoses represent the most common of all benign bone tumors and 10% to 15% of all bone tumors. Osteochondromas are solitary or multiple, pedunculated or sessile exophytic outgrowths from the bone surface that are composed of cortical and medullary bone with an overlying hyaline cartilage cap. Marrow and cortical continuity with the underlying parent bone defines the lesion. Osteochondromas usually occur in children or adolescents between 10 and 15 years, and increase in size throughout childhood, ranging from 1 to 10 cm. After adolescence and skeletal maturity, osteochondromas usually exhibit no further growth. In adults, growth or imaging alterations of an osteochondroma suggest the rare diagnosis of malignant transformation; however, extensive growth of osteochondromas without histological evidence of malignancy has been reported

Osteochondral Fragmentation in the Synovial Pad of the Fetlock in Warmblood Horses

To determine clinical and arthroscopic characteristics associated with fragments in the synovial pad of the fetlock and to characterize their morphology. Retrospective study. Warmblood horses (n=104) with fragment(s) in the synovial pad. Signalment and results of radiographic and clinical examination were collected before surgery. After arthroscopic fragment removal and joint evaluation for synovial and/or cartilage abnormalities, fragments were measured, and evaluated by histopathology. Synovial pad fragments (n=142) were removed from 127 fetlocks. Two older horses had lameness. During arthroscopy, abnormalities were observed in 40 joints (31.5%) and multivariate logistic regression analysis showed a significant correlation between the observed arthroscopic abnormalities and the presence of large fragments (P=.016). Fragments were osteochondral bodies completely surrounded by fibrous tissue. At the edges of the hyaline cartilage cap an underlying fibrous structure was obvious in the extracellular matrix giving it a reactive pattern. Although the impact on lameness was minimal, there was a significant correlation between arthroscopic abnormalities and presence of large synovial pad fragments. On histopathology, these osteochondral fragments are embedded in fibrous tissue and show a reactive pattern. They are not a manifestation of any well-described joint pathology. Large synovial pad fragments in Warmblood horses can be associated with synovial and cartilage abnormalities, but further studies are warranted to determine their origin and clinical importance.

Giant Solitary Osteochondroma of the Inferior Medial Calcaneal Tubercle: A Case Report and Review of the Literature

Small osteophytes are frequently encountered in the foot and ankle, and are not to be confused with true osteochondromas, which are relatively uncommon in this region. They most often affect long bones of the appendicular skeleton but may involve flat bones as well. Osteochondromas are benign osseous neoplasms with a distinct hyaline cartilage cap originating from the physis and cease growing with skeletal maturity. Osteochondroma are often treated conservatively unless they become symptomatic, painful, demonstrate rapid or new growth, enlarge after skeletal maturity, and/or exhibit signs of malignant transformation. In this report, we present a case of a giant (8 cm x 4.2 cm x 2.1 cm) osteochondroma in an adult occurring on the inferior medial tubercle of the calcaneus that underwent excision, with 3.5 years of follow-up without recurrence. To our knowledge this is the largest osteochondroma affecting the inferior medial tubercle of the calcaneus. This case demonstrates that large osteochondromas may occur in the foot, and also confirms that benign osteochondroma growth may occur in adulthood. A detailed review of osteochondroma occurrence in the foot is presented along with a review of the diagnostic work-up to evaluate for malignant transformation. 4.

Glenoid labrum ossification and mechanical restriction of joint motion: extraosseous manifestations of melorheostosis

We report a case of a 47-year-old man who presented with progressive loss of motion and pain in the right shoulder. Radiographs of the shoulder demonstrated dense ossification in the glenoid and humeral head with extension into the periarticular soft tissues. CT and MRI scans confirmed the radiographic findings and also revealed ossification of the glenoid labrum. A radiographic diagnosis of melorheostosis, an uncommon benign sclerosing bone dysplasia, was made. Because of the patient's severe symptomatology, he underwent total shoulder arthroplasty. Histological analysis of the resected masses was consistent with melorheostosis with a few areas covered by a cartilage cap. This case illustrates several uncommon but important features of melorheostosis, including mechanical obstruction of joint motion requiring joint replacement, ossification of the glenoid labrum, and cartilage-covering portions of the intra-articular masses, not to be confused with cartilage-producing tumors.

Contribution of EXT1, EXT2, and EXTL3 to Heparan Sulfate Chain Elongation

The exostosin (EXT) family of genes encodes glycosyltransferases involved in heparan sulfate biosynthesis. Five human members of this family have been cloned to date: EXT1, EXT2, EXTL1, EXTL2, and EXTL3. EXT1 and EXT2 are believed to form a Golgi-located hetero-oligomeric complex that catalyzes the chain elongation step in heparan sulfate biosynthesis, whereas the EXTL proteins exhibit overlapping glycosyl-transferase activities in vitro, so that it is not apparent what reactions they catalyze in vivo. We used gene-silencing strategies to investigate the roles of EXT1, EXT2, and EXTL3 in heparan sulfate chain elongation. Small interfering RNAs (siRNAs) directed against the human EXT1, EXT2, or EXTL3 mRNAs were introduced into human embryonic kidney 293 cells. Compared with cells transfected with control siRNA, those transfected with EXT1 or EXT2 siRNA synthesized shorter heparan sulfate chains, and those transfected with EXTL3 siRNA synthesized longer chains. We also generated human cell lines overexpressing the EXT proteins. Overexpression of EXT1 resulted in increased HS chain length, which was even more pronounced in cells coexpressing EXT2, whereas overexpression of EXT2 alone had no detectable effect on heparan sulfate chain elongation. Mutations in either EXT1 or EXT2 are associated with hereditary multiple exostoses, a human disorder characterized by the formation of cartilage-capped bony outgrowths at the epiphyseal growth plates. To further investigate the role of EXT2, we generated human cell lines overexpressing mutant EXT2. One of the mutations, EXT2-Y419X, resulted in a truncated protein. Interestingly, the capacity of wild type EXT2 to enhance HS chain length together with EXT1 was not shared by the EXT2-Y419X mutant.

Dysplasia epiphysealis hemimelica (Trevor disease): a rare developmental disorder of bone mimicking osteochondroma of long bones

Dysplasia epiphysealis hemimelica (DEH) is a rare developmental disorder of childhood and is characterized by asymmetric enlargement of the epiphyseal cartilage of the long bones. After 4 to 5 years of age, the lesions histologically resemble osteochondroma. To our knowledge, only one publication of this entity is available in an English pathology journal. The clinical, radiographic, and histologic features of 9 cases of DEH were retrospectively reviewed. The patients' age ranged from 3 to 15 years with single or multiple lesions of the femur, fibula, tibia, and talus. The etiology and pathogenesis of DEH are not known. Its origin and evolution has initially apparent similarities to the development and growth of epiphyseal secondary ossification centers. DEH can be differentiated from osteochondroma of long bones using clinical, radiologic, and pathologic parameters. DEH occurs in young children and adolescents manifesting as lesions that arise particularly from the epiphysis of the lower extremities and tarsus. Osteochondroma, in contrast, occurs most frequently between 10 and 30 years of age and originates from the metaphysis of long bones. Although the DEH cartilage resembles osteochondroma, there are several significant histologic differences. During infancy, lesions of DEH histologically reveal osteocartilaginous nodules that resemble secondary ossification centers. Usually after 4 to 5 years of age they develop into osteochondroma-like lesions. Although all cases of DEH contain small areas of calcified cartilage beneath the cartilage cap, a significant percentage of osteochondromas show large amounts. The nodules and cartilage cap of DEH contain bands of cartilage separating areas of cancellous bone; these bands are not present in osteochondroma. Among the other distinguishable features, recent molecular studies of DEH demonstrated normal expression levels of EXT1 and EXT2 genes, comparable to that of normal growth plate. Osteochondroma, in contrast, has low levels of EXT1 and EXT2 gene expression due to gene mutation. The histologic differences in combination with the distinct clinical and radiographic features should enable a pathologist to differentiate these entities.

The Role of EXT1 in Nonhereditary Osteochondroma: Identification of Homozygous Deletions

Multiple osteochondromas is a hereditary syndrome that is characterized by the formation of cartilage-capped bony neoplasms (osteochondromas), for which exostosis (multiple)-1 (EXT1) has been identified as a causative gene. However, 85% of all osteochondromas present as solitary (nonhereditary) lesions in which somatic mutations in EXT1 are extremely rare, but loss of heterozygosity and clonal rearrangement of 8q24 (the chromosomal locus of EXT1) are common. We examined whether EXT1 might act as a classical tumor suppressor gene for nonhereditary osteochondromas. Eight nonhereditary osteochondromas were subjected to high-resolution array-based comparative genomic hybridization (array-CGH) analysis for chromosome 8q. The array-CGH results were validated by subjecting tumor DNA to multiple ligation-dependent probe amplification (MLPA) analysis for EXT1. EXT1 locus-specific fluorescent in situ hybridization (FISH) was performed on nuclei isolated from the three tissue components of osteochondroma (cartilage cap, perichondrium, bony stalk) to examine which parts of the tumor are of clonal origin. Array-CGH analysis of tumor DNA revealed that all eight osteochondromas had a large deletion of 8q; five tumors had an additional small deletion of the other allele of 8q that contained the EXT1 gene. MLPA analysis of tumor DNA confirmed these findings and identified two additional deletions that were smaller than the limit of resolution of array-CGH. FISH analysis of the cartilage cap, perichondrium, and bony stalk showed that these homozygous EXT1 deletions were present only in the cartilage cap of osteochondroma. EXT1 functions as a classical tumor suppressor gene in the cartilage cap of nonhereditary osteochondromas.