Peripheral Chondrosarcomas Research Articles

IDH1 and IDH2 mutations are frequent events in central chondrosarcoma and central and periosteal chondromas but not in other mesenchymal tumours

Somatic mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2 occur in gliomas and acute myeloid leukaemia (AML). Since patients with multiple enchondromas have occasionally been reported to have these conditions, we hypothesized that the same mutations would occur in cartilaginous neoplasms. Approximately 1200 mesenchymal tumours, including 220 cartilaginous tumours, 222 osteosarcomas and another ∼750 bone and soft tissue tumours, were screened for IDH1 R132 mutations, using Sequenom(®) mass spectrometry. Cartilaginous tumours and chondroblastic osteosarcomas, wild-type for IDH1 R132, were analysed for IDH2 (R172, R140) mutations. Validation was performed by capillary sequencing and restriction enzyme digestion. Heterozygous somatic IDH1/IDH2 mutations, which result in the production of a potential oncometabolite, 2-hydroxyglutarate, were only detected in central and periosteal cartilaginous tumours, and were found in at least 56% of these, ∼40% of which were represented by R132C. IDH1 R132H mutations were confirmed by immunoreactivity for this mutant allele. The ratio of IDH1:IDH2 mutation was 10.6 : 1. No IDH2 R140 mutations were detected. Mutations were detected in enchondromas through to conventional central and dedifferentiated chondrosarcomas, in patients with both solitary and multiple neoplasms. No germline mutations were detected. No mutations were detected in peripheral chondrosarcomas and osteochondromas. In conclusion, IDH1 and IDH2 mutations represent the first common genetic abnormalities to be identified in conventional central and periosteal cartilaginous tumours. As in gliomas and AML, the mutations appear to occur early in tumourigenesis. We speculate that a mosaic pattern of IDH-mutation-bearing cells explains the reports of diverse tumours (gliomas, AML, multiple cartilaginous neoplasms, haemangiomas) occurring in the same patient.

Abstract C3: Bcl-2 inhibition in Chondrosarcoma leads to increased apoptosis and is a promising therapeutic target

Abstract Chondrosarcomas are malignant cartilage-forming tumors of the bone and are notorious for their resistance to chemo- and radiotherapy. Chondrosarcomas consist of slowly dividing cells and show overexpression of BCL2. A correlation between BCL2 expression and malignant transformation of osteochondromas to peripheral chondrosarcomas has been found as well as BCL2 positivity in 30–67% of central chondrosarcomas, increasing with grade. As BCL2 is an anti-apoptotic protein, inhibition could lead to resensitization of tumor cells to conventional therapy. This study aims at inducing apoptosis in chondrosarcomas insensitive to conventional treatment measures. ABT737 is a BH3 mimetic which inhibits anti-apoptotic proteins. BCL2 inhibition has been proven to work in leukemia cells. Expression of pro- and anti-apoptotic genes was studied using Illumina human expression bead chip v3 microarrays on 23 solitary chondrosarcomas and 6 normal cartilage tissues for comparison using R software. ABT737 was tested for its ability to induce apoptosis in 4 chondrosarcoma cell lines and 4 primary cultures (SW1353, OUMS27, CH2879, JJ012, and L835, L869, L1081, L1250, respectively). HL60, an ALL cell line, was used as a positive control. ABT737 was also tested in combination with Doxorubicin and Cisplatin. Cell viability was assessed using WST assay measuring mitochondrial activity; cell count was performed with the Casey® cell counter. Induction of apoptosis was determined using Life Cell Imaging where apoptotic cells were labeled with Cy5-labelled AnnexinV. During Life Cell Imaging ABT737 was also combined with Roscovitine, an MCL1 inhibitor. FACS analysis on cell cycle was performed with DAPI staining. After comparing solitary chondrosarcomas to normal cartilage tissue, the anti-apoptotic MCL1 (logFc 0.6, p=0.02) and BAD (logFc=0.5, p=0.007) were overexpressed in chondrosarcoma. P-values were False Discovery Rate adjusted. A loss in cell number (IC50: 2 M) and viability (IC50: 20 M) after 72 hours incubation with ABT737 was achieved. 25µMABT737 in combination with 10µM Doxorubicin led to 85% reduction in cell viability in L869 and 65% reduction in other cultures. Life Cell Imaging showed a strong induction of apoptosis in cells treated with ABT737 alone (650%) over 72 hours of treatment. For Doxorubicin 10 M 560% increase in apoptotic cells was observed and for Roscovitine 10 M the total increase in apoptotic cells was 400%. Combining ABT737 with Roscovitine or Doxorubicin showed a total increase in apoptotic cell number of 430%. Combining ABT737 with doxorubicin showed no additional onset of apoptosis during the last 24 hours. By adding the BH3 mimic ABT737 to Doxorubicin treatment in chondrosarcoma cultures, an additional 20% decrease in cell viability can be obtained. However, by counting apoptotic cells, no such decrease could be observed, suggesting that the additional 20% is a cytostatic effect rather than a cytotoxic. Accordingly, preliminary data obtained with FACS analysis on cell cycle show a 10% increase of cells in G1 phase after ABT737 and Doxorubicin treatment, compared to ABT737 treatment alone. In conclusion, BCL2 overexpression seems to play an important part in chemoresistance in chondrosarcoma, and co-treatment of ABT737 with Doxorubicin causes the vast majority of chondrosarcoma cells to enter apoptosis while the remaining cells enter cell cycle arrest. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C3.

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.

Aberrant Heparan Sulfate Proteoglycan Localization, Despite Normal Exostosin, in Central Chondrosarcoma

The tumor suppressor genes EXT1 and EXT2 are involved in the formation of multiple osteochondromas, which can progress to become secondary peripheral chondrosarcomas. The most common chondrosarcoma subtype is primary central chondrosarcoma, which occurs in the medullar cavity of bone. The EXT1/EXT2 protein complex is involved in heparan sulfate proteoglycan (HSPG) biosynthesis, which is important for signal transduction of Indian hedgehog (IHH), WNT, and transforming growth factor (TGF)-beta. The role of EXT and its downstream targets in central chondrosarcomas is currently unknown. EXT1 and EXT2 were therefore evaluated in central chondrosarcomas at both the DNA and mRNA levels. Immunohistochemistry was used to assess HSPG (CD44v3 and SDC2), WNT (beta-catenin), and TGF-beta (PAI-1 and phosphorylated Smad2) signaling, whereas IHH signaling was studied both by quantitative polymerase chain reaction and in vitro. mRNA levels of both EXT1 and EXT2 were normal in central chondrosarcomas; genomic alterations were absent in these regions and in 30 other HSPG-related genes. Although HSPGs were aberrantly located (CD44v3 in the Golgi and SDC2 in cytoplasm and nucleus), this was not caused by mutation. WNT signaling negatively correlated with increasing histological grade, whereas TGF-beta positively correlated with increasing histological grade. IHH signaling was active, and inhibition decreased cell viability in one of six cell lines. Our data suggest that, despite normal EXT in central chondrosarcomas, HSPGs and HSPG-dependent signaling are affected in both central and peripheral chondrosarcomas.

Decreased EXT expression and intracellular accumulation of heparan sulphate proteoglycan in osteochondromas and peripheral chondrosarcomas

Mutational inactivation of EXT1 or EXT2 is the cause of hereditary multiple osteochondromas. These genes function in heparan sulphate proteoglycan (HSPG) biosynthesis in the Golgi apparatus. Loss of heterozygosity of the EXT1 locus at 8q24 is frequently found in solitary osteochondromas, whereas somatic mutations are rarely found. We investigated the expression of EXT1 and EXT2 (quantitative RT-PCR) and of different HSPGs (immunohistochemistry) in solitary and hereditary osteochondromas and in cases with malignant progression to secondary peripheral chondrosarcoma, in relation to possible mutations and promoter methylation. The mutation status of patients with multiple osteochondromas correlated with decreased EXT1 or EXT2 expression found in their resected tumours. We could not show somatic point mutations or promoter hypermethylation in 17 solitary tumours; however, EXT1 expression was decreased in 15 cases, whereas EXT2 was not. Intracellular accumulation of syndecan-2 and heparan sulphate-bearing isoforms of CD44 (CD44v3) was found in most tumours, which concentrated in the Golgi apparatus as shown by confocal microscopy. This contrasted with the extracellular expression found in normal growth plates. In conclusion, mutational inactivation of either EXT1 or EXT2 leads to loss of mRNA expression of the corresponding gene. We hypothesize that loss of EXT expression disrupts the function of the EXT1/2 complex in HSPG biosynthesis, resulting in the intracellular accumulation of HSPG core proteins that we found in these tumours.

Peripheral chondrosarcoma progression is accompanied by decreased Indian Hedgehog signalling

Hedgehog (HH) signalling is important for specific developmental processes, and aberrant, increased activity has been described in various tumours. Disturbed HH signalling has also been implicated in the hereditary syndrome, Multiple Osteochondromas. Indian Hedgehog (IHH), together with parathyroid hormone-like hormone (PTHLH), participates in the organization of growth plates in long bones. PTHLH signalling is absent in osteochondromas, benign tumours arising adjacent to the growth plate, but is reactivated when these tumours undergo malignant transformation towards secondary peripheral chondrosarcoma. We describe a gradual decrease in the expression of Patched (PTCH) and glioma-associated oncogene homologue 1 (GLI1) (both transcribed upon IHH activity), and GLI2 with increasing malignancy, suggesting that IHH signalling is inactive and PTHLH signalling is IHH independent in secondary peripheral chondrosarcomas. cDNA expression profiling and immunohistochemical studies suggest that transforming growth factor-beta (TGF-beta)-mediated proliferative signalling is active in high-grade chondrosarcomas since TGF-beta downstream targets were upregulated in these tumours. This is accompanied by downregulation of energy metabolism-related genes and upregulation of the proto-oncogene jun B. Thus, the tight regulation of growth plate organization by IHH signalling is still seen in osteochondroma, but gradually lost during malignant transformation to secondary peripheral chondrosarcoma and subsequent progression. TGF-beta signalling is stimulated during secondary peripheral chondrosarcoma progression and could potentially regulate the retained activity of PTHLH.

Surgical treatment and outcome of conventional pelvic chondrosarcoma

We reviewed 124 patients with a conventional pelvic chondrosarcoma who had been treated over a period of 20 years. We recorded the type of tumour (central or peripheral), type of operation (limb salvage surgery or hemipelvectomy), the grade of tumour, local recurrence and/or metastases, in order to identify the factors which might influence survival. More satisfactory surgical margins were achieved for central tumours or in those patients treated by hemipelvectomy. However, grade 1 tumours, whatever the course, did not develop metastases or cause death, while grade 3 tumours had the worst outcome and prognosis. Central, high-grade tumours require aggressive surgical treatment in order to achieve adequate surgical margins, particularly in those lesions located close to the sacroiliac joint. By contrast, grade 1 peripheral chondrosarcomas may be treated with contaminated margins in order to reduce operative morbidity, but without reducing survival.

Expression of the chondromodulin-I gene in chondrosarcomas

We investigated the expression of the Chondromodulin-I (ChM-I) gene, a putative tumor suppressor gene in cartilaginous tumors, by quantitative RT-PCR in 15 chondrosarcomas (CSs). Eight CSs expressed the ChM-I gene at the level higher than those in articular cartilage (positive cases), whereas the expression of the ChM-I gene in the remaining seven CSs was lower than those in articular cartilage (negative cases). All of five peripheral CS were positive, and the ChM-I positive tumors shared expression profiles of cartilage-related genes with articular cartilage cells. On the other hand, all of four central CSs without extramedullary lesions were negative, and the ChM-I negative tumors expressed the parathyroid hormone-related peptide gene at the lower level and the COL10A1 genes at the higher level than articular cartilage cells. Neither the histological grade nor the rate of recurrence showed clear association with the level of ChM-I gene expression. These results suggested that the expression of ChM-I gene in CS has no direct role in tumorigenesis but rather reflects the site of tumor development and therefore precursor of tumor cells.

Chromosome 9 alterations and trisomy 22 in central chondrosarcoma: a cytogenetic and DNA flow cytometric analysis of chondrosarcoma subtypes.

Chondrosarcomas are malignant cartilaginous tumors. Most are located in the medullar cavity (central chondrosarcoma), and a minority develop in a preexisting osteochondroma (peripheral chondrosarcoma). The authors present karyotypes for 37 central, peripheral, juxtacortical, and dedifferentiated chondrosarcomas. Using loss of heterozygosity (LOH) analysis and DNA flow cytometry, the authors previously showed that central and peripheral chondrosarcomas probably evolve by different genetic mechanisms. Peripheral chondrosarcoma is characterized by genetic instability, as was previously shown by a high percentage of LOH and a broad range in DNA ploidy. The authors now show that all peripheral chondrosarcomas tested are aneuploid, combined with many nonspecific chromosomal aberrations. Two juxtacortical chondrosarcomas showed normal chromosome numbers combined with limited structural alterations, substantiating that juxtacortical and peripheral chondrosarcomas are two clinicopathologically different entities with a different genetic background. Central chondrosarcomas were previously found to be peridiploid with limited LOH, most frequent at 9p21. In the current study, chromosome 9 was involved in five of seven central chondrosarcomas compared with only one of four peripheral chondrosarcomas. Three central tumors showed involvement of the 9pl2-22 region, suggesting an important role for chromosome 9 in the oncogenesis of central chondrosarcoma. Moreover, trisomy 22 was found in four central chondrosarcomas only.

Up-Regulation of PTHrP and Bcl-2 Expression Characterizes the Progression of Osteochondroma towards Peripheral Chondrosarcoma and Is a Late Event in Central Chondrosarcoma

Chondrosarcomas are malignant cartilage-forming tumors arising centrally in bone (central chondrosarcoma) or within the cartilaginous cap of osteochondroma (peripheral chondrosarcoma). For hereditary multiple osteochondromas, two responsible genes, EXT1 and EXT2, have been cloned. Their recently elucidated role in heparan sulfate biosynthesis and Hedgehog diffusion leads to the hypothesis that EXT inactivation affects fibroblast growth factor (FGF) and Indian Hedgehog (IHh)/parathyroid hormone-related peptide (PTHrP) signaling, two important pathways in chondrocyte proliferation and differentiation. The expression of PTHrP, PTHrP-receptor, Bcl-2, FGF2, FGFR1, FGFR3, and p21 is investigated by immunohistochemistry in osteochondromas (n = 24) and peripheral (n = 29) and central (n = 20) chondrosarcomas. IHh/PTHrP and FGF signaling molecules are mostly absent in osteochondromas. Although no somatic EXT mutations were found in sporadic osteochondromas, the putative EXT downstream targets are affected similarly in sporadic and hereditary tumors. In chondrosarcomas, re-expression of FGF2, FGFR1, PTHrP, Bcl-2, and p21 is found. Expression levels increase with increasing histological grade. Up-regulation of PTHrP and Bcl-2 characterizes malignant transformation of osteochondroma because PTHrP and Bcl-2 expression is significantly higher in borderline and grade I peripheral chondrosarcomas compared with osteochondromas. In contrast, up-regulation of PTHrP and Bcl-2 seems to be a late event in central cartilaginous tumorigenesis because expression is mainly restricted to high-grade central tumors.

Near-Haploidy and Subsequent Polyploidization Characterize the Progression of Peripheral Chondrosarcoma

Chondrosarcomas are malignant cartilaginous tumors arising centrally in bone (central chondrosarcoma), or secondarily within the cartilaginous cap of osteochondroma (peripheral chondrosarcoma). We previously used DNA flow cytometry to demonstrate that near-haploidy is relatively frequent in peripheral chondrosarcomas. We performed fluorescence in situ hybridization (FISH) to interphase nuclei using centromeric probes, a genome wide loss of heterozygosity (LOH) analysis, and comparative genomic hybridization on five peripheral chondrosarcomas. We demonstrated near-haploidy in two low-grade tumors with only one copy and LOH of most chromosomes. Few chromosomes are disomic, with retention of heterozygosity and overrepresentation at comparative genomic hybridization. One tumor contains both a near-haploid clone with chromosomes in monosomic and disomic state, and an exactly duplicated clone. Two high-grade tumors clearly demonstrate polyploidization because most chromosomes show LOH and two copies at FISH, whereas few chromosomes have four copies with retention of heterozygosity. Using DNA from a relative, we demonstrate that chromosome loss is random regardless of parental origin. Using FISH on paraffin slides, we exclude near-haploidy to result from meiosis-like division in binucleated cells, characteristic for chondrosarcoma. In conclusion, our results indicate that near-haploidy characterizes the progression from osteochondroma toward low-grade chondrosarcoma. Moreover, further progression toward high-grade chondrosarcoma is characterized by polyploidization.

Loss of heterozygosity and DNA ploidy point to a diverging genetic mechanism in the origin of peripheral and central chondrosarcoma

Chondrosarcomas are malignant cartilaginous tumors arising centrally in bone (central chondrosarcoma), or secondarily within the cartilaginous cap of a hereditary or sporadic exostosis (peripheral chondrosarcoma). Loss of heterozygosity (LOH) was studied by microsatellite analysis at the loci harboring the EXT genes (implicated in hereditary multiple exostoses), the EXT-like genes, and at 9p21, 13q14, 17p13, and chromosome 10. Nineteen of 20 peripheral chondrosarcomas showed LOH at all loci tested, while only 3 of 12 central chondrosarcomas exhibited LOH, restricted to 9p21, 10, 13q14, and 17p13. LOH at 9p21 did not appear to involve the CDKN2A gene, as assessed by SSCP analysis. DNA flow cytometry demonstrated a wide variation in the ploidy status in peripheral chondrosarcomas (DNA indexes, 0.56-2.01), whereas central chondrosarcomas were predominantly peridiploid. Near-haploidy found in peripheral chondrosarcomas could explain part of the high LOH percentages. Ki-67 immunohistochemistry suggested a higher proliferation rate in peripheral chondrosarcomas. Our results indicate that peripheral chondrosarcomas, arising secondarily to an exostosis, may obtain genetic alterations during malignant transformation, with subsequent genetic instability as demonstrated by a high percentage of LOH and a wide variation in ploidy status. In contrast, peridiploidy and a low percentage of LOH in central tumors suggest that a different oncogenic molecular mechanism may be operative.

EXT-Mutation Analysis and Loss of Heterozygosity in Sporadic and Hereditary Osteochondromas and Secondary Chondrosarcomas

Osteochondromas occur as sporadic solitary lesions or as multiple lesions, characterizing the hereditary multiple exostoses syndrome (EXT). Approximately 15% of all chondrosarcomas arise within the cartilaginous cap of an osteochondroma. EXT is genetically heterogeneous, and two genes, EXT1 and EXT2, located on 8q24 and 11p11-p12, respectively, have been cloned. It is still unclear whether osteochondroma is a developmental disorder or a true neoplasm. Furthermore, it is unclear whether inactivation of both alleles of an EXT gene, according to the tumor-suppressor model, is required for osteochondroma development, or whether a single EXT germline mutation acts in a dominant negative way. We therefore studied loss of heterozygosity and DNA ploidy in eight sporadic and six hereditary osteochondromas. EXT1- and EXT2-mutation analysis was performed in a total of 34 sporadic and hereditary osteochondromas and secondary peripheral chondrosarcomas. We demonstrated osteochondroma to be a true neoplasm, since aneuploidy was found in 4 of 10 osteochondromas. Furthermore, LOH was almost exclusively found at the EXT1 locus in 5 of 14 osteochondromas. Four novel constitutional cDNA alterations were detected in exon 1 of EXT1. Two patients with multiple osteochondromas demonstrated a germline mutation combined with loss of the remaining wild-type allele in three osteochondromas, indicating that, in cartilaginous cells of the growth plate, inactivation of both copies of the EXT1 gene is required for osteochondroma formation in hereditary cases. In contrast, no somatic EXT1 cDNA alterations were found in sporadic osteochondromas. No mutations were found in the EXT2 gene.

Diagnostic imaging of malignant cartilage tumors

We compared the diagnostic capabilities of CT and MRI in the study of malignant cartilage tumors. Information about the characterization and the intra-/extraosseous spread of these lesions is of primary importance in the preoperative planning. Besides peripheral chondrosarcomas, arising from an osteochondroma and central chondrosarcomas, which are the most common malignant cartilaginous tumors, we also considered secondary, periosteal, dedifferentiated, clear cells and mesenchymal chondrosarcomas. Our study was performed using a standard MRI and CT protocol; in some cases, the examination was completed by the intravenous administration of a contrast agent. High contrast T2-weighted GE images can perfectly depict and differentiate the cartilage cap of an osteochondroma from the adjacent soft tissues. Evaluation of the growth of exostosis and of the thickness of its cap is essential in the assessement of malignant transformation. Both CT and MRI provide important information about peculiar aspects of the cartilaginous matrix such as the shape of calcifications-ossifications and lobulated growth, septa, septal enchancement and necrotic intratumoral areas, furthermore, CT perfectly shows the patterns of bone destruction. MRI should be considered as the most reliable imaging technique for the locoregional staging of malignant bone tumors thanks to its spatial and contrast resolution. CT plays a major role in the characterization of most bone tumors, especially those with a cartilaginous matrix.

Quantitative analysis of solitary lesions of bone.

To quantitate the radiographic features of common solitary lesions of bone using vector analysis to optimize their radiographic description. Plain radiographs of 709 solitary bone lesions were reviewed. Relevant demographic, anatomic, and structural data were cataloged. These data were used to approximate the vector space defined by all possible solitary lesions of bone. Vector space analysis on the entire set of lesions was performed to determine similarities among and between lesion types. The 709 lesions generated 614 separate vectors within the appearance vector space. Only 10 vectors were represented more than 3 times, indicating great variability among and between most lesion types. Osteochondromas (with two vectors repeated 10 and 15 times, respectively) and peripheral chondrosarcomas (with one vector repeated 5 times) were relatively uniform in appearance. Gender bias was present for multiple types of lesions. Larger lesions that involved more than one anatomic center were more likely to be malignant. Lesions occurring in the femoral diaphysis and pelvic flat bones were statistically more likely to be malignant. Analysis shows that most lesions have highly varied vectors in the appearances within the vector space. More in-depth analysis of each lesion type using this quantitative technique is required to better define individual lesion subspaces and hence their radiographic appearances with respect to other bone lesions.

Dedifferentiated peripheral chondrosarcomas. A report of seven cases.

Peripheral dedifferentiated chondrosarcoma (CS) is an exceedingly rare variant of the highly malignant entity of dedifferentiated chondrosarcoma. Only five such cases have previously been reported. Seven cases are analyzed and evaluated for the presentation and natural history of this highly malignant lesion when it arises in a tumor that was previously an osteochondroma. Both peripheral and central dedifferentiated chondrosarcomas are high-grade malignant lesions and require wide or radical surgical margins for adequate treatment. Despite adequate resection, survival is poor; five of the seven cases presented herein died of metastatic spread of their disease. These cases of the peripheral variant of dedifferentiated chondrosarcoma occurred in patients who were younger than patients with central dedifferentiated chondrosarcomas and may be present with longer duration of symptoms because they occur in previously long-standing benign osteochondromas. As such, they may be easily overlooked clinically and radiographically. Therefore, careful histologic analysis of all cartilage lesions arising on the surface of bone is essential to prevent overlooking foci of high-grade sarcomatous dedifferentiation.

Does chondroid chordoma exist?

The existence of chondroid chordoma (CC), initially described in 1973, has remained controversial. Since the antigenic profiles of both chordoma (CD) and cartilaginous (chondroid) lesions have been well characterized, we decided to study chondroid chordoma immunohistochemically. Our hypothesis was that chondroid chordoma should display a hybrid or mixed pattern of staining: chordomatous areas with an epithelial phenotype and cartilaginous areas with a mesenchymal (non-epithelial) phenotype. An analysis of CC (seven cases) was performed and compared with results obtained on notochord, cartilage, classic CD (18 cases), peripheral chondromas (two cases), and peripheral chondrosarcomas (CS, eight cases). Four epithelial markers were employed: MKER and AE-1 (both monoclonal antibodies to cytokeratin); PKER (a polyclonal antibody to cytokeratin); and, EMA (epithelial membrane antigen). In addition, selected cases were tested for the presence of neurofilament (NF) and glial fibrillary acidic protein (GFAP). All 18 CD's exhibited the expected epithelial immunophenotype - MKER+, AE-1+, PKER+, and EMA+ - a reaction pattern nearly identical to that found in fetal notochord. This reinforced the importance of the growth pattern in assessing the presence of chordomatous elements. All chondromas and CS's failed to express any of the epithelial markers studied and contained only S-100 immunoreactivity, like cartilage. Chondroid chordoma resembled cartilaginous tumors immunohistochemically; no mixed pattern with even focal epithelial marker reactivity was identified. All CC tested were also NF and GFAP negative. We conclude that CC either does not exist or is extremely rare and that these tumors are cartilaginous in nature.(ABSTRACT TRUNCATED AT 250 WORDS)

Radiographic hallmarks of peripheral chondrosarcoma.

Ten peripheral chondrosarcomas, nine arising in the cap of an osteochondroma and one developing as a primary periosteal tumor, are reported. The radiological and histological features of these tumors are compared with those of 203 benign osteochondromas and two soft-tissue chondrosarcomas. In 3 of the 10 cases, cytological evidence of malignancy could not be demonstrated, although the size of the tumors and the presence of extension into adjacent soft tissues indicated that they were low-grade chondrosarcomas. In all of the 10 cases there was radiological evidence of scattered calcifications in the cartilaginous part of the tumor, and this is regarded as an important radiological indication of malignancy. Histological studies indicate that calcification of tumor cartilage, followed by replacement of the calcified cartilage by endochrondral bone, is responsible for the opacities that, in clinical radiographs, are characteristic of chondrosarcoma.