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PubMed2002

Cytogenetic aberrations and their prognostic impact in chondrosarcoma.

Chondrosarcoma is the second most common primary malignancy of bone. Cytogenetic data are available from close to 100 cases, including all subtypes of chondrosarcoma. Specific chromosomal rearrangements have been identified only in extraskeletal myxoid chondrosarcoma (EMC). Strong prognostic factors are largely missing, although size and, in particular, histologic tumor grade have been implicated. In the present study, we investigated the genomic aberrations in 59 chondrosarcomas (six grade 1, 24 grade 2, and 29 grade 3, including dedifferentiated tumors), excluding EMC, by chromosome banding analysis and DNA flow cytometry and correlated the findings with clinical outcome. Hyperhaploid to near-diploid karyotypes were found in half of the cases, and there was a good correlation between cytogenetics and flow cytometry data; discrepancies were seen primarily in cases with normal karyotypes and in those with -Y as the sole anomaly. Abnormal karyotypes, excluding those with -Y as the only change, were found in 36 cases. No recurrent structural aberration was found, but a nonrandom pattern of aberrations was seen. Total or partial gains and losses were the dominant karyotypic features. Genomic imbalances found in at least 10 cases included -1p36, -1p13-p22, -4, -5q13-q31, -6q22-qter, +7p13-pter, -9p22-pter, -10p, -10q24-qter, -11p13-pter, -11q25, +12q15-qter, -13q21-qter, -14q24-qter, -18p, -18q22-qter, +19, +20pter-q11, +21q, and -22q13. At the latest follow-up, 19 patients had experienced distant metastases, and the 5-year metastasis-free survival rate was 0.69. By univariate analysis, malignancy grade and loss of material from 6q, 10p, 11p or 11q, 13q, and 22q were associated with impaired metastasis-free survival. Only -13q was an independent prognostic factor for metastasis, regardless of tumor grade or size.

Adolescent↗
PubMed1994

Dedifferentiated chondrosarcoma with t(9;22)(q34;q11-12).

Translocation t(9;22)(q22-31;q11-12) is associated with the myxoid variant of chondrosarcoma. We present here a report of a patient with a dedifferentiated grade IV chondrosarcoma, which originated from the iliac bone and contained areas of grade I chondrosarcoma. There was no evidence of myxoid differentiation. The tumor had the karyotype 46,X,-X,t(9;22)(q34;q11-12), + mar[5]/52-61,x?,2-3 min,inc[9]/46,XX[2]. It is possible that the different breakpoints in the t(9;22) may reflect different histopathologic subgroups of chondrosarcoma.

Aged↗
PubMed2001

Changes in p14(ARF) do not play a primary role in human chondrosarcoma tissues.

The locus encoding the tumor suppressor p16 has been found to code for a second, different protein. This protein, p14(ARF), has been shown to protect p53 from degradation. Like p16, its gene is often altered in different cancers. In this study, the first unique exon, exon 1 beta, of p14(ARF), has been studied in 22 chondrosarcoma tissues using polymerase chain reaction, DNA sequencing and methylation-specific polymerase chain reaction. One chondrosarcoma was found to have exon 1 beta homozygously deleted, but neither mutations nor methylations were found in any of the chondrosarcomas. This indicates that genetic changes of p14(ARF) are a rare event in chondrosarcoma.

Base Sequence↗
PubMed2002

Human chondrosarcoma secretes vascular endothelial growth factor to induce tumor angiogenesis and stores basic fibroblast growth factor for regulation of its own growth.

Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) are well-known factors that induce neovascularization in many tumors. The molecular mechanisms that regulate tumor angiogenesis in human chondrosarcoma are not clear. We assessed in this work the angiogenic activities of a human chondrosarcoma cell line (OUMS-27) in vivo and determined the efficacies of angiogenic factors derived from OUMS-27 cells on human umbilical vein endothelial cells (HUVECs) in vitro. Tumor xenografts induced an increase in the formation of neovessels, but the distributions of Ki-67 antigen, VEGF and bFGF were unaffected. We also demonstrated that OUMS-27 cells secreted VEGF(165) into the culture medium and that it was the maximal angiogenic factor to stimulate endothelial proliferation and migration in chondrosarcoma. Anti-VEGF antibodies induced an approximately 70% inhibition of these responses of HUVECs, but did not have any effect on OUMS-27 cells. Anti-bFGF antibodies suppressed not only the activities of HUVECs but also the growth of tumor cells in vitro. We indicate that angiogenesis is principally elicited by VEGF(165) and that tumorigenesis is mainly regulated by bFGF stored in the extracellular matrix of OUMS-27 cells. The present study may offer the availability of combination therapies for inhibition of VEGF and bFGF action on vascular endothelial cells and chondrosarcoma cells, respectively.

Animals↗
PubMed1991

Establishment from a human chondrosarcoma of a new immortal cell line with high tumorigenicity in vivo, which is able to form proteoglycan-rich cartilage-like nodules and to respond to insulin in vitro.

The human chondrosarcoma cell line (HCS-2/8) established by our group expresses cartilage phenotypes such as production of cartilage-type proteoglycans and collagen type II, but its tumorigenicity is low. To develop an in vitro experimental system for studies of human chondrosarcomas, a new immortal cell line of human chondrosarcoma, named HCS-2/A, was established from the same tumor. HCS-2/A cells proliferated with a doubling time of 3 1/2 days in a medium containing 20% fetal bovine serum (FBS). This growth rate was comparable to that of HCS-2/8 cells. However, HCS-2/A cells proliferated more rapidly than HCS-2/8 cells in the presence of 2-10% FBS. Like HCS-2/8 cells, HCS-2/A cells had a polygonal shape in sparse cultures and became spherical as they reached confluence, after which they formed nodules composed of multilayered cells and a large quantity of extracellular matrix showing strong metachromasia. The nodules formed by HCS-2/A cells were thicker and also larger in diameter than those formed by HCS-2/8 cells. Electron microscopically, the cells in the nodules resembled chondrocytes in vivo, but each cell had an irregular-shaped nucleus which is a characteristics of tumor cells. The cells actively synthesized "cartilage-specific" large proteoglycans and their level of proteoglycan synthesis was comparable to that of HCS-2/8 cells. Insulin, which stimulates proteoglycan and DNA syntheses in cultured chondrocytes, markedly increased proteoglycan synthesis in HCS-2/A cells. On the other hand, the hormone only slightly increased proteoglycan synthesis in HCS-2/8 cells. Insulin also stimulated DNA synthesis in cultured HCS-2/A cells, but not in HCS-2/8 cells. Immunostaining revealed that HCS-2/A cells produced type-II collagen but not type-I collagen. However, the level of collagen synthesis of HCS-2/A cells was lower than that of HCS-2/8 cells. Inoculation of HCS-2/A cells into athymic mice resulted in the formation of chondrosarcomas that grew faster than those arising from HCS-2/8 cells.

Aged↗
PubMed1998

Expression of cartilage extracellular matrix and potential regulatory genes in a new human chondrosarcoma cell line.

A human chondrosarcoma cell line has been established from an aggressive chondrosarcoma. The cells grow in a monolayer culture (doubling time: 2 days) and form aggregates. The aggregates consist of a rim of cells surrounding a hollow core. The cell line exhibits a unique pattern of mRNA expression with several molecules characteristic of the chondrocyte phenotype. Consistent with the chondrocyte phenotype, mRNAs encoding types IX and XI collagens were present along with an abundant expression of mRNAs encoding the core protein of the cartilage proteoglycans biglycan and aggrecan. No expression of mRNAs encoding types I or II fibrillar collagens or the proteoglycan decorin was observed. Sodium dodecyl sulfate-polyacrylamide gel electrophoretic analysis of [35S]sulfate-radiolabeled material confirmed the translation of proteoglycans containing glycosaminoglycan chains. The expression of molecules that contribute to cartilage development and tumorigenesis was examined. The cell line produces abundant mRNA that encodes transforming growth factor-beta1, a member of a family of cartilage and bone inductive proteins. The expression of mRNA encoding two proteins associated specifically with chondrogenesis was detected: Cart-1, a homeobox protein involved in cartilage differentiation, and CD-RAP, a secreted molecule restricted under normal conditions to differentiating chondrocytes and cartilage. Overexpression of p53, a tumor-suppressor gene, was detected. DNA analysis revealed a loss of heterozygosity at the chromosomal locus encoding p53, with the deletion of one p53 allele and the mutation of the remaining allele in both the parent tumor and the cell line. The malignant chondrosarcoma phenotype may be related to the unique gene expression pattern that is characteristic in many ways of differentiating chondroblasts, as well as to the inactivation of the p53 function that could contribute to the proliferative capacity of the cell line. This cell line may serve as a biological model for further investigation of the etiology of human chondrosarcomas and for the synthesis and regulation of cartilage-specific genes.

Adult↗
PubMed1998

Up-regulation of inducible nitric oxide synthase and production of nitric oxide by the Swarm rat and human chondrosarcoma.

Production of nitric oxide by solid tumors may have important ramifications regarding tumor growth and potential metastasis. This study demonstrated that the chondrosarcoma of the Swarm rat has upregulated mRNA for inducible nitric oxide synthase and produces nitric oxide. These results were confirmed by (a) the presence of a 4.4-kb band of mRNA detected by Northern blot using a probe for inducible nitric oxide synthase, (b) a 133-kDa band of protein that was detected with either a polyclonal or monoclonal antibody to the inducible nitric oxide synthase of the murine macrophage, and (c) the detection of nitrites from the culture medium of freshly cultured, isolated chondrosarcoma cells. This study showed that the expression of inducible nitric oxide synthase and the production of nitric oxide by the tumor can be increased by stimulation with endotoxin lipopolysaccharide and can be inhibited by inducible nitric oxide synthase inhibitors (L-N(g)-monomethyl arginine and aminoguanidine). Immunostaining confirmed the presence of inducible nitric oxide synthase within the tumor cells and appeared to localize the enzyme to the cytoplasm of the cells. A human chondrosarcoma was also shown to have an upregulated inducible nitric oxide synthase by both the detection of mRNA for inducible nitric oxide synthase and the presence of nitrites from the culture medium of the tumor in organ culture. Because the chondrosarcoma of the Swarm rat is a well differentiated solid tumor that rarely metastasizes, nitric oxide may be produced by the tumor to promote local growth by effects on vascular supply.

Animals↗
PubMed2004

Identification of a single nucleotide polymorphism in the MMP-1 promoter in chondrosarcoma.

Matrix metalloproteinases (MMPs) are a group of at least 26 enzymes that facilitate cellular invasion via the degradation of the extracellular matrix. Specifically, the ability to degrade collagen types III and I is important in tumor invasion and metastasis. Over expression of the MMP-1 gene has been shown to correlate with poorer outcome in GI tract and gynecological tumors. This level of expression of this gene has been shown to be significantly increased by the presence of a single nucleotide polymorphism in the MMP-1 promoter sequence as a result of the creation of an ETS binding site. This SNP results from the addition of a single guanine base at -1,607 bp 24. Two chondrosarcoma cell lines and a series of 10 resected chondrosarcoma specimens underwent DNA extraction, purification, polymerase chain reaction, and sequencing. The presence of the single nucleotide polymorphism at -1,607 bp was confirmed within the promoter region for MMP-1 in human chondrosarcoma. Because all three genotypes were found in the clinical samples, the SNP may indeed provide a mechanistic explanation for a more aggressive biologic behavior locally and distally for a subset of chondrosarcomas.

Cell Line, Tumor↗
PubMed1994

Chondrosarcoma of bone: oncologic and functional results.

A retrospective review of 27 patients (21 males and 6 females) with chondrosarcoma of bone was performed to evaluate the oncologic and functional results. The average age of the patients was 48 years (range: 17-76). The tumor sites were pelvis in 10 cases, distal femur in 2, proximal tibia in 3, rib in 2, and other in 10. One patient with Ollier's disease had chondrosarcoma at two different sites simultaneously. Surgical stages were I A in 8 cases, I B in 8, II A in 1, and II B in 10. Two patients had no surgical treatment. Amputation was performed in 5 cases and en bloc resection in 20. An uncontaminated radical or wide surgical margin was achieved in 13 of 25 cases. Additional surgery was performed in seven cases; for deep infection in one case and for local recurrence or metastasis in six. Local recurrence developed in seven patients (26%). At follow-up, four patients had died of disease (15%), one patient had died of another cause, and two patients were alive with disease (7%). No evidence of disease was found in 20 patients (74%). The oncologic results of limb salvage and amputation in chondrosarcoma of the limbs were good, although there was one failure of limb salvage, caused by infection. Due to surgical inaccessibility, results of the management of chondrosarcoma of the pelvis were poor. The average functional evaluation of 16 patients (average follow-up: 104 months) was 75% (range: 30-100). The Musculoskeletal Tumor Society ratings were excellent in four cases, good in seven, fair in four, and poor in one.

Adolescent↗
PubMed1987

Dedifferentiated chondrosarcoma of bone. An immunohistochemical and lectin-histochemical study.

Ten cases of dedifferentiated chondrosarcoma (DCS) were immunohistochemically and histochemically compared with 12 de novo malignant fibrous histiocytomas, 10 osteoblastic osteosarcomas, 9 conventional chondrosarcomas, and 4 fibrosarcomas (all of bone or soft tissues), in order to discern similarities and differences in the immunophenotypes of these neoplasms. All cases of DCS and malignant fibrous histiocytoma were reactive for alpha-1-antichymotrypsin, and several examples of both tumor types bound peanut agglutinin, and expressed positivity for alpha-1-antitrypsin and lysozyme. None of these four cellular markers was observed in de novo osteosarcoma and fibrosarcoma; in addition, conventional chondrosarcoma lacked all of them except for peanut agglutinin receptors. S100 protein reactivity and binding of wheat germ agglutinin were detectable in conventional chondrosarcomas and in rare cells of the anaplastic components of primary DCS, but not in malignant fibrous histiocytoma arising ab initio and the other sarcomas. These results suggest the evolution of a second neoplastic cellular clone in DCS, with primitive morphological and phenotypic characteristics.

Adult↗
PubMed1995

Dedifferentiated chondrosarcoma.

We reviewed 74 cases of dedifferentiated central and peripheral chondrosarcoma. Histologically these tumours consist of an underlying cartilaginous component (either benign or malignant) juxtaposed to a high-grade non-cartilaginous component, with a typically abrupt transition between the two tissue types. The non-cartilaginous component may constitute a very small or a very large proportion of the tumour, so diagnosis often requires histological evaluation of the entire tumour. The diagnosis is often suspected on the basis of the clinical course and careful evaluation of the radiographic characteristics. Central dedifferentiated chondrosarcoma can be classified radiographically into three types. In type I (36 cases in our review) the radiographic features are the same as those of a central chondrosarcoma, with the addition of a region with very aggressive radiographic features. Type 2 lesions (20 cases) resemble the underlying benign enchondroma but also have destructive changes and/or a large soft tissue mass. Type 3 lesions (8 cases) are not distinctive radiographically and present as a very high grade destructive lesion of bone. These cases are diagnosed following biopsy or tumour resection. The prognosis of these tumours is extremely poor, with 13% overall 5-year survival in this series. Improved survival was found in those cases where diagnosis was prompt and surgical treatment with a wide or radical margin was attained. No benefit was found from the use of adjuvant chemotherapy or radiotherapy. Thus, early recognition of the characteristic radiographic features, adequate histological sampling, and wide or radical surgical margins are necessary for satisfactory management of this highly malignant variant of chondrosarcoma.

Adult↗
PubMed1992

Cellular variant of extraskeletal myxoid chondrosarcoma of abdominal wall--a case report with comparative immunohistochemical study on cartilaginous collagenous proteins in various myxoid mesenchymal tumors.

A rare cellular variant of recurrent extraskeletal myxoid chondrosarcoma occurring in the right lower abdominal wall of a 70-year-old man, is presented with emphasis on a characteristic distribution pattern of cartilaginous collagen proteins in the stroma. While the primary and the first recurrent tumors showed the typical histology of extraskeletal myxoid chondrosarcoma, the later tumor, which recurred 14 years after the first resection, comprised mostly compact nodules of proliferating anaplastic cells with little mucoid stroma. Some areas presented a hemangiopericytomatous pattern. A few nodules possessed abundant myxoid stroma. Immunohistochemically, type II collagen was demonstrated in the stroma of some cellular areas, and type VI collagen was intensely stained around individual tumor cells both in cellular and myxoid areas. In a comparative immunohistochemical study, the same distribution pattern of cartilaginous collagen proteins was observed only in skeletal myxoid chondrosarcomas, but not in other mesenchymal tumors with abundant myxoid stroma. These findings seem to support the cartilaginous nature of extraskeletal myxoid chondrosarcoma, and will facilitate the differential diagnosis of soft-tissue tumors with myxoid stroma.

Abdominal Muscles↗
PubMed1994

A case of metastatic chondrosarcoma of the stomach.

A case of metastatic chondrosarcoma of the stomach in a 34-year-old female is reported. This patient had been diagnosed as having chondrosarcoma of the right knee and was operated on in 1984. Thereafter, there was repeated local recurrence and operations were performed on multiple metastases, including those of the lung, brain, ovary and spleen. In September, 1990, the patient was readmitted because of advanced anemia. Gastroendoscopy disclosed a firm elevated lesion with central irregular erosion. Histologically, there was cellular atypical cartilage with pleomorphic chondrocytes, which showed the same staining reactions as those in the primary lesion. Therefore this case was diagnosed as metastatic chondrosarcoma. This may be the first documentation of a case of gastric metastasis of chondrosarcoma.

Adult↗
PubMed2003

Radiation therapy for chordoma and chondrosarcoma of the skull base and the cervical spine. Prognostic factors and patterns of failure.

BACKGROUND: Prospective analysis of local tumor control, survival and treatment complications in 67 consecutive patients treated with fractionated photon and proton radiation for chordoma or chondrosarcoma of the base of the skull and the cervical spine. PATIENTS AND METHODS: Between December 1995 and January 2000, 67 patients with a median age of 52 years (range: 14-85 years), were treated at the Centre de Protonthérapie d'Orsay (CPO), France, using the 201-MeV proton beam, 49 for chordoma and 18 for chondrosarcoma. Irradiation combined high-energy photons and protons. Photons represented two thirds of the total dose and protons one third. The median total dose delivered within gross tumor volume (GTV) was 67 Cobalt Gray Equivalents (CGE; range: 60-70 CGE). RESULTS: Within a median follow-up of 29 months (range: 4-71 months), the 3-year local control rates were 71% and 85% for chordomas and chondrosarcomas, respectively, and the 3-year overall survival rates 88% and 75%, respectively. 14 tumors (21.5%) failed locally (eight within the GTV, four within the clinical target volume [CTV], and two without further assessment). Seven patients died from their tumor and another one from a nonrelated condition (pulmonary embolism). The maximum tumor diameter and, similarly, the GTV were larger in relapsing patients, compared with the rest of the population: 56 mm vs 44 mm (p = 0.024) and 50 ml vs 22 ml (p = 0.0083), respectively. In univariate analysis, age < or = 52 years at the time of radiotherapy (p = 0.002), maximum diameter < 45 mm (p = 0.02), and GTV < 28 ml (p = 0.02) impacted positively on local control. On multivariate analysis, only age was an independent prognostic factor of local control. CONCLUSION: In chordomas and chondrosarcomas of the skull base and cervical spine, combined photon and proton radiation therapy offers excellent chances of cure. In two thirds of the cases, relapses are located in the GTV. Maximum diameter, GTV, and age are prognostic indicators of local control. These results should be confirmed during a longer follow-up.

Adolescent↗
PubMed1997

Dedifferentiated chondrosarcoma in patients with multiple osteochondromatosis: report of a case and review of the literature.

Multiple osteochondromatosis (MOS) is a familial disorder of autosomal dominant transmission characterized by the development of multiple exostoses and often derangements of epiphyseal cartilage, sometimes resulting in long bone growth retardation. Patients with the disorder appear to be at increased risk for developing secondary chondrosarcomas. Rarely, dedifferentiated chondrosarcomas may also occur. We report a single case of a 27-year-old man with multiple osteochondromatosis who developed a fatal dedifferentiated chondrosarcoma. Radiographically, the neoplasm arose from the pelvis completely destroying the left pubic ramus. Subsequently, the patient underwent preoperative chemotherapy followed by a left external hemipelvectomy. On pathologic examination, the tumor was characterized by high-grade pleomorphic sarcoma sharply juxtaposed to a low-grade chondrosarcoma. The patient ultimately died of widespread metastatic sarcoma.

Adult↗
PubMed1997

Extraskeletal mesenchymal chondrosarcoma of the rectus sheath.

Mesenchymal chondrosarcomas (MSCs) are a rare form of chondrosarcoma which usually arise in bone. Extraskeletal chondrosarcomas constitute a minority (14-25%) of MSCs. We describe the imaging features of an extraskeletal mesenchymal chondrosarcoma that arose from the rectus abdominus muscle.

Adult↗
PubMed2004

FDG PET imaging for grading and prediction of outcome in chondrosarcoma patients.

The aims of this study were to assess the potential of fluorine-18 fluorodeoxyglucose positron emission tomography (FDG PET) for tumor grading in chondrosarcoma patients and to evaluate the role of standardized uptake value (SUV) as a parameter for prediction of patient outcome. FDG PET imaging was performed in 31 patients with chondrosarcoma prior to therapy. SUV was calculated for each tumor and correlated to tumor grade and size, and to patient outcome in terms of local relapse or metastatic disease with a mean follow-up period of 48 months. Chondrosarcomas were detectable in all patients. Tumor SUV was 3.38 +/- 1.61 for grade I (n = 15), 5.44 +/- 3.06 for grade II (n = 13), and 7.10 +/- 2.61 for grade III (n =3). Significant differences were found between patients with and without disease progression: SUV was 6.42 +/- 2.70 (n = 10) in patients developing recurrent or metastatic disease compared with 3.74 +/- 2.22 in patients without relapse (P = 0.015). Using a cut-off of 4 for SUV, sensitivity, specificity, and positive and negative predictive values for a relapse were 90%, 76%, 64%, and 94%, respectively. Combining tumor grade and SUV, these parameters improved to 90%, 95%, 90%, and 95%, respectively. Pretherapeutic tumor SUV obtained by FDG PET imaging was a useful parameter for tumor grading and prediction of outcome in chondrosarcoma patients. The combination of SUV and histopathologic tumor grade further improved prediction of outcome substantially, allowing identification of patients at high risk for local relapse or metastatic disease.

Adult↗
PubMed1996

[Comparative DNA cytometric and cytogenetic ploidy determination of chondrosarcoma and osteosarcoma].

10 chondrosarcomas and 10 osteosarcomas were examined using cytogenetics and DNA-image-cytometry. Cytogenetically 6 of 10 chondrosarcomas and 4 of 10 osteosarcomas showed hyperdiploid tumorcells. By DNA-cytometry in 8 of 10 chondrosarcomas and 9 of 10 osteosarcomas hyperdiploid tumorcells resp. hyperdiploid stemlines were detected. This discrepancy reflects an in-vitro-selection depending on the different entities. In 7 aneuploid clones of chondrosarcomas the chromosomal ploidy was calculated using the relative length of the chromosomes and compared with the DNA-ploidy of the native tumor. There was a close relation between both parameters of nuclear DNA-content. The interpretation of cytogenetic results is improved using a combination of karyotypic and DNA-cytometric examination. This is particularly important for the search for relations between numeric chromosomal aberrations and morphological parameters (grading).

Aneuploidy↗