Bovée, J.V.M.G.

Hogendoorn, P.C.W.

Leiden University Scholary Publications

Letter to the EditorRe. Review Article entitled `The neoplastic pathogenesisof solitary and multiple osteochondromas'In a recent Review Article, Porter and Simpsonsummarize the many theories proposed over the yearsto explain the pathogenesis of osteochondroma andspeculate about the underlying genetic changes [1].Based on progress that we have recently made inunderstanding the genetics of the neoplastic pathogen-esis of osteochondroma, and the multistep modeltowards secondary chondrosarcoma, we would like tosupplement their article with some very recent data.Based on the available literature, the authorscorrectly conclude that a neoplastic pathogenesis forosteochondroma should be suspected. In our opinion,the most important support for a clonal origin ofosteochondroma lies in the clonal karyotypic abnorm-alities described [2,3]. In support of this, we haverecently obtained data demonstrating loss of hetero-zygosity (LOH) in the cartilaginous cap of 6 of 14osteochondromas and DNA aneuploidy in 4 of 10osteochondromas [4], strongly pointing towards aclonal, and thus neoplastic, origin for the cartilaginoustissue of osteochondroma. Although we understandthe temptation of Porter and Simpson to speculate thatthe osteal part of osteochondroma may be consideredreactive tumour stroma, there are no data frommolecular or immunohistochemical studies availablefrom the literature to support this view. We feel thatfurther molecular genetic studies are required tocon®rm their statement.To date, it is unclear whether complete inactivationof an EXT gene (according to the Knudson tumoursuppressor model) is required for osteochondromadevelopment, or whether a single EXT germlinemutation acts in a dominant negative way, resultingin multiple benign osteochondromas. In the latter,inactivation of the remaining allele would be aprerequisite for malignant transformation. The authorspropose ®ve speculative and, to us, unconvincingarguments for a `dominant negative' effect of theEXT tumour suppressor genes in hereditary multipleexostoses. We describe two patients with multipleosteochondromas demonstrating a germline EXT1mutation [4]. This is combined with loss of theremaining wild-type allele in three osteochondromas,indicating that, in cartilaginous cells of the growthplate, inactivation of both copies of the EXT1 gene isrequired for osteochondroma formation in hereditarycases [4]. This was also suggested by others [5] andexcludes a dominant negative effect of the EXT1 genein hereditary osteochondroma.Their comparison of the `stepwise' process ofoncogenesis for the osteochondroma±chondrosarcomasequence to the colorectal adenoma±carcinomasequence (Table II [1]) is interesting, but requiresfurther comment. We do not believe that it is justi®edto subdivide osteochondroma into pre-neoplastic andneoplastic categories, since there is now suf®cientevidence that at least the cartilaginous cap of osteo-chondroma is a true neoplasm. They correctly spec-ulate that both copies of an EXT gene are inactivated,which indicates neoplastic growth. Furthermore, thereis no indication that additional genetic alterations inosteochondroma occur, since both cytogenetic studies[2,3] and our own study [4] show alterations mainlyrestricted to the EXT loci, especially EXT1.We agree with the authors that in sporadic osteo-chondroma, somatic inactivation of both copies of anEXT gene could be expected. So far, only one somaticmutation in the EXT1 gene has been described in asporadic chondrosarcoma [6]. We did not ®nd anysomatic EXT1 cDNA alterations in eight sporadicosteochondromas and 14 sporadic chondrosarcomas.Future studies on a larger panel of tumours shouldreveal whether the situation is similar to the BRCA1gene, for which only germline mutations in hereditarybreast cancer are described [7].The authors' suggestion that progression to a low-grade chondrosarcoma is accompanied by chromo-some 3q and 10q deletion may be an oversimpli®ca-tion. We compared LOH patterns of peripheralchondrosarcomas secondary to osteochondromas withthose of primary central chondrosarcomas [8,9]. Nine-teen of 20 peripheral chondrosarcomas showed LOHat all loci tested (EXT genes, EXT-like genes, and at9p21, 13q14, 17p13, and chromosome 10), while only 3of 12 central chondrosarcomas exhibited LOH,restricted to 9p21, 10, 13q14, and 17p13. DNA ¯owcytometry demonstrated a wide variation in the ploidystatus in peripheral chondrosarcomas (DNA indices0.56±2.01), whereas central chondrosarcomas werepredominantly peridiploid. Remarkably, near-haploidywas found in peripheral chondrosarcomas, which couldexplain some of the high LOH percentages. Also,polyploidization of a near-haploid clone had occurredin two high-grade peripheral chondrosarcomas. In allstudies reported in the literature so far, no separationhas been made between central and peripheral chon-drosarcoma; LOH data presented in this way shouldtherefore be interpreted with caution [8,9].In conclusion, it seems to be more appropriate topropose a genetic progression model for peripheralcartilaginous tumourigenesis based on recently avail-able data. First, inactivation of both copies of theEXT1 gene in cartilaginous cells of the growth plate isrequired for osteochondroma formation, as demon-Journal of PathologyJ Pathol 2000; 190: 516±517.Copyright # 2000 John Wiley & Sons, Ltd.strated by loss of the remaining wild-type allele inhereditary osteochondromas [4]. Whether completeinactivation occurs in sporadic cases remains to beinvestigated. One or more additional genetic altera-tions may then be required for a peripheral chondro-sarcoma to arise within its benign precursor. Theprocess of malignant transformation is geneticallyrepresented by chromosomal instability with severeaneuploidy and a high LOH incidence in peripheralchondrosarcoma [8,9].Finally, in their discussion of the physiologicalfunction of the EXT gene family, the authors omit theimportant ®nding that an EXT1 homologue in Droso-phila (tout-velu) was demonstrated to be required fordiffusion of the morphogen Hedgehog [10]. Remark-ably, in humans, Indian Hedgehog is normally expressedin the growth zone and pre-hypertrophic chondrocytesof cartilage [11]. Furthermore, not only the EXT1 butalso the EXT2 gene products were shown to beglycosyltransferases required for the biosynthesis ofheparan sulphate [12,13]. The role of the resultingaltered heparan sulphate expression on the cell surfaceand the abnormal diffusion of Hedgehog within chon-drocytes of the growth plate caused by EXT mutationswill be an interesting ®eld of study in the future, furtherrevealing the pathogenesis of osteochondroma.Judith V. M. G. BoveÂe and Pancras C. W. HogendoornDepartment of Pathology, Leiden University Medical Center,P.O. Box 9600, L1-Q, 2300 RC Leiden, The NetherlandsReferences1. Porter DE, Simpson AHRW. The neoplastic pathogenesis ofsolitary and multiple osteochondromas. J Pathol 1999; 188:119±125.2. Bridge JA, Nelson M, Orndal C, Bhatia P, Neff JR. Clonalkaryotypic abnormalities of the hereditary multiple exostoseschromosomal loci 8q24.1 (EXT1) and 11p11±12 (EXT2) inpatients with sporadic and hereditary osteochondromas. Cancer1998; 82: 1657±1663.3. Mertens F, Rydholm A, Kreicbergs A, et al. Loss of chromo-some band 8q24 in sporadic osteocartilaginous exostoses. GenesChromosomes Cancer 1994; 9: 8±12.4. Bovee JVMG, Cleton-Jansen AM, Wuyts W, et al. EXTmutation analysis and loss of heterozygosity in sporadic andhereditary osteochondromas and secondary chondrosarcomas.Am J Hum Genet 1999; 65: 689±698.5. Hogue DA, Cole WG, Hecht JT. Mutational steps leading to thedevelopment of bony exostoses. Am J Hum Genet 1998; 63: A365(Abstract).6. Hecht JT, Hogue D, Wang Y, et al. Hereditary multipleexostoses (EXT): mutational studies of familial EXT1 cases andEXT-associated malignancies. Am J Hum Genet 1997; 60: 80±86.7. Futreal PA, Liu Q, Stattuck-Eidens D, et al. BRCA1 mutationsin primary breast and ovarian carcinomas. Science 1994; 266:120±122.8. BoveÂe JVMG, Cleton-Jansen AM, Taminiau AHM, et al.Peripheral and central chondrosarcoma; loss of heterozygosityand DNA-ploidy point to a different genetic background. AmJ Hum Genet 1998; 63: A63 (Abstract).9. BoveÂe JVMG, Cleton-Jansen AM, Kuipers-Dijkshoorn N, et al.Loss of heterozygosity and DNA-ploidy point to a diverginggenetic mechanism in the origin of peripheral and centralchondrosarcoma. Genes Chromosomes Cancer 1999; 26: 237±246.10. Bellaiche Y, The I, Perrimon N. Tout-velu is a Drosophilahomologue of the putative tumour suppressor EXT1 and isneeded for Hh diffusion. Nature 1998; 394: 85±88.11. Hammerschmidt M, Brook A, McMahon AP. The worldaccording to hedgehog. TIG 1997; 13: 14±21.12. McCormick C, Leduc Y, Martindale D, et al. The putativetumour suppressor EXT1 alters the expression of cell-surfaceheparan sulfate. Nature Genet 1998; 19: 158±161.13. Lind T, Tufaro F, McCormick C, Lindahl U, Lidholt K. Theputative tumor suppressors EXT1 and EXT2 are glycosyltrans-ferases required for the biosynthesis of heparan sulfate. J BiolChem 1998; 273: 26265±26268.Authors' replyWe are grateful for the comments on our review fromDrs BoveÂe and Hogendoorn.Our suggestion that the `osteal' part of the osteo-chondroma may be reactive or supportive, rather thantruly neoplastic, re¯ects the surgical fact that ablationof the cartilage cap alone will ablate further growth ofthe osteochondroma.We agree that it is unclear whether complete inacti-vation of the EXT gene is required for osteochondromadevelopment. Despite this, our review emphasizes thatno research to date indicates any features of EXTactivity other than those which suggest a recessivetumour suppressor gene function. Unfortunately, dueto an oversight in manuscript preparation for which weapologize, we on one occasion describe the function ofthe EXT gene as `dominant negative'. The ®ve featureswhich we attribute to EXT behaviour do, of course,suppose an entirely `recessive' and not `dominantnegative' action of the gene.Our review deals at length with the problems ofde®ning the cartilage cap of an osteochondroma as aneoplasm on the traditional model. We justify ourclassi®cation of the childhood osteochondroma, whichossi®es at the end of skeletal growth, as `pre-neoplastic'to overcome these traditional objections. We believethat this is entirely consistent with the molecular data.We agree that non-EXT gene changes have not beenidenti®ed in osteochondromas in any signi®cantnumber. Major genetic abnormalities would not beexpected to occur in simple `pre-neoplastic' childhoodosteochondromas. We suggest that reactivated, adult-type osteochondromas, which are much less common,would be the best candidates to investigate theincidence of non-EXT genetic changes in accordancewith a step-wise model of osteochondroma±chondro-sarcoma carcinogenesis.D. E. Porter and A. H. R. W. SimpsonNuf®eld Department of Orthopaedic Surgery, University of Oxford,Headington, Oxford OX3 7LD, UKLetter to the Editor 517Copyright # 2000 John Wiley & Sons, Ltd. J Pathol 2000; 190: 516±517.

Re. Review Article entitled `The neoplastic pathogenesis of solitary and multiple osteochondromas'

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Re. Review Article entitled `The neoplastic pathogenesis of solitary and multiple osteochondromas'

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