Multiple osteochondromas, formerly called multiple hereditary exostoses, is an autosomal dominant heterogeneous disorder that occurs in 1 in 50,000 births1 and is associated with mutations of the exostosin-1 (EXT1) and exostosin-2 (EXT2) genes. Both genes are putative tumor suppressors that encode glycosyltransferases, also known as exostosins, involved in the biosynthesis of heparin sulfate. Penetrance is very high: 96% in female patients and 100% in male patients. In 10% of affected individuals, hereditary multiple osteochondromas is the result of a new mutation2. Clinical manifestations of this disease result in exostoses that generally involve the long bones and result in varying degrees of skeletal deformity and growth disturbances.
Malignant transformation, chondrosarcoma that arises in the cartilage cap, occurs in 5% of patients with multiple osteochondromas. Although certain risk and protective factors such as sex, number of lesions, the presence of EXT2 mutations, and the absence of EXT1 or EXT2 correlate with clinical disease severity, none predict malignant transformation3.
In the article by Goud and colleagues, the observation that central chondroid tumors are associated with multiple osteochondromas is surprising, as, to my knowledge, it has not been previously reported. Central chondroid tumors, enchondromas, occur in association with exostoses in patients with metachondromatosis, a rare disease that generally affects the hands and feet and is not associated with growth disturbances. Unlike multiple osteochondromas, metachondromatosis is not associated with EXT1 or EXT2 mutations. Although peripheral chondrosarcomas are not uncommon in patients with multiple osteochondromas, there is only one case report of a patient with presumed metachondromatosis who developed a central chondrosarcoma4. Interestingly, this patient was not tested for the EXT1 or EXT2 mutation, which, in light of the findings presented in the study by Goud et al., raises the possibility of this case actually being multiple osteochondromas. Until this study by Goud and colleagues, to my knowledge, there had been no association between multiple osteochondromas and central chondroid tumors. Therefore, the findings that central chondroid tumors are observed in up to 3.6% of patients in this large series and that these lesions were thought to represent low-grade chondrosarcomas deserve further scrutiny. Why has this association not been appreciated before? The reason may be that this is a very large collection of patients with multiple osteochondromas, and all subjects had confirmed EXT1 or EXT2 mutations. Furthermore, the search focused on individuals with genetically confirmed multiple osteochondromas and an associated malignancy. As a result of that query, a subset of patients with central low-grade chondrosarcoma was identified, which is another unexpected and somewhat controversial aspect of this investigation.
The application of genetic testing in the entire group and the radiographic observation of central chondroid tumors is compelling evidence that exostoses and central chondroid tumors are connected. After all, they both arise from abnormalities of the physis. Unfortunately, on the basis of the study design, the true incidence of central cartilage neoplasia in patients with multiple osteochondromas is unknown, and only the incidence of what the authors believed were malignant central chondroid tumors is included in this study.
However, the distinction between benign and malignant cartilage tumors is more vexing. Murphey et al.5 studied 187 patients and reported that the presence and degree of endosteal scalloping were the most important discriminating factors in predicting benign or malignant cartilage tumors. In the present study, endosteal changes were subtle and were observed in only two patients. Furthermore, two additional patients deferred surgery, and the radiographic changes over time were described as minimal in one patient after five years and in another patient after two years of observation. Other investigators have determined that only axial location and >5-cm tumors were deemed to be significant in distinguishing enchondromas from grade-1 chondrosarcomas and found no correlation between morphologic changes on radiographs and the presence or absence of clinical symptoms in predicting benign cartilage from low-grade cartilage tumors6. In this study by Goud and colleagues, all tumors were in the appendicular skeleton and varied greatly in tumor size from 8 mm to 170 mm.
The reliability of both radiographic and histologic grading of cartilaginous neoplasms in long bones is relatively poor. In one study (Skeletal Lesions Interobserver Correlation among Expert Diagnosticians [SLICED] Study Group), kappa coefficients for interpreter reliability were 0.443 for pathologists and, slightly worse, 0.345 for radiologists7. In another study, Eefting et al.8 assessed interobserver variability in determining malignant from benign cartilage tumors. Even with clinical and radiographic correlation, they found considerable variation among experienced pathologists, especially in distinguishing enchondroma from low-grade chondrosarcoma8. Only when defining specific diagnostic parameters (high cellularity, presence of host bone entrapment, open chromatin, mucoid matrix quality, and patient age of more than forty-five years) did agreement between observers improve. What these observations mean clinically or how they change the therapeutic approach to the lesion remains unclear.
Another important observation is the concomitant finding of peripheral chondrosarcoma that was diagnosed in five of the seven patients with low-grade central chondrosarcoma. This discovery may help to identify a genetic subpopulation of patients with multiple osteochondromas who are at greater risk for malignant transformation. Stratification of risk, based on genetic alterations that lead to malignant transformation, would be of great value in surveying patients over time. The ability to identify a group of patients at risk would limit the amount of testing and the associated cost for those with low-risk genetic profiles and would compel closer observation and timely intervention in those individuals at the highest risk. These evocative findings should compel others to validate the association between multiple osteochondromas and central chondroid tumors. The distinction between benign and low-grade malignant tumors is blurred, and the term “low-grade chondrosarcoma” should be used with caution and for patients with tumors that have real malignant potential. It would be helpful to know the overall incidence of central chondroid tumors in patients with multiple osteochondromas. One wonders why these lesions were biopsied in the first place, as the lesions appeared benign on radiographs. Is it possible that central chondroid lesions in patients with multiple osteochondromas are histologically more aggressive than pedestrian enchondromas despite having a nonaggressive radiographic appearance and an indolent clinical course? If so, they do not appear to behave in an aggressive way on the basis of the radiographic survey and the clinical course in at least two of the patients who elected not to undergo surgical excision and did not appear to progress.
1. Schmale GA, Conrad EU 3rd, Raskind WH. The natural history of hereditary multiple exostoses. J Bone Joint Surg Am. 1994 Jul;76(7):986-92.
2. Wuyts W, Schmale GA, Chansky HA, Raskind WH. Hereditary multiple osteochondromas. In: Pagon RA, Adam MP, Ardinger HH, Bird TD, Dolan CR, Fong CT, Smith RJH, Stephens K, editors. GeneReviews®. Seattle, WA: University of Washington; 2000.
3. Pedrini E, Jennes I, Tremosini M, Milanesi A, Mordenti M, Parra A, Sgariglia F, Zuntini M, Campanacci L, Fabbri N, Pignotti E, Wuyts W, Sangiorgi L. Genotype-phenotype correlation study in 529 patients with multiple hereditary exostoses: identification of “protective” and “risk” factors. J Bone Joint Surg Am. 2011 Dec 21;93(24):2294-302.
4. Mavrogenis AF, Skarpidi E, Papakonstantinou O, Papagelopoulos PJ. Chondrosarcoma in metachondromatosis: a case report. J Bone Joint Surg Am. 2010 Jun;92(6):1507-13.
5. Murphey MD, Flemming DJ, Boyea SR, Bojescul JA, Sweet DE, Temple HT. Enchondroma versus chondrosarcoma in the appendicular skeleton: differentiating features. Radiographics. 1998 Sep-Oct;18(5):1213-37; quiz 1244-5.
6. Geirnaerdt MJ, Hermans J, Bloem JL, Kroon HM, Pope TL, Taminiau AH, Hogendoorn PC. Usefulness of radiography in differentiating enchondroma from central grade 1 chondrosarcoma. AJR Am J Roentgenol. 1997 Oct;169(4):1097-104.
7. Skeletal Lesions Interobserver Correlation among Expert Diagnosticians (SLICED) Study Group. Reliability of histopathologic and radiologic grading of cartilaginous neoplasms in long bones. J Bone Joint Surg Am. 2007 Oct;89(10):2113-23.
8. Eefting D, Schrage YM, Geirnaerdt MJ, Le Cessie S, Taminiau AH, Bovée JV, Hogendoorn PC; EuroBoNeT consortium. Assessment of interobserver variability and histologic parameters to improve reliability in classification and grading of central cartilaginous tumors. Am J Surg Pathol. 2009 Jan;33(1):50-7.