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• W2167441405 abstract "Mesenchymal chondrosarcomas are small-cell malignancies named as chondrosarcomas due to the focal appearance of cartilage islands. In this study, the use of in situ detection techniques on a large series of mesenchymal chondrosarcoma specimens allowed the identification of tumor-cell differentiation pathways in these neoplasms. We were able to trace all steps of chondrogenesis within mesenchymal chondrosarcoma by using characteristic marker genes of chondrocytic development. Starting from undifferentiated cells, which were negative for vimentin and any other mesenchymal marker, a substantial portion of the cellular (undifferentiated) tumor areas showed a chondroprogenitor phenotype with an onset of expression of vimentin and collagen type IIA. Cells in the chondroid areas showed the full expression panel of mature chondrocytes including type X collagen indicating focal hypertrophic differentiation of the neoplastic chondrocytes. Finally, evidence was found for transdifferentiation of the neoplastic chondrocytes to osteoblast-like cells in areas of neoplastic bone formation. These results establish mesenchymal chondrosarcoma as the very neoplasm of differentiating premesenchymal chondroprogenitor cells. The potential of neoplastic bone formation in mesenchymal chondrosarcoma introduces a new concept of neoplastic (chondrocytic. osteogenesis in musculoskeletal malignant neoplasms, which qualifies the old dogma that neoplastic bone/osteoid formation automatically implies the diagnosis of osteosarcoma. Mesenchymal chondrosarcomas are small-cell malignancies named as chondrosarcomas due to the focal appearance of cartilage islands. In this study, the use of in situ detection techniques on a large series of mesenchymal chondrosarcoma specimens allowed the identification of tumor-cell differentiation pathways in these neoplasms. We were able to trace all steps of chondrogenesis within mesenchymal chondrosarcoma by using characteristic marker genes of chondrocytic development. Starting from undifferentiated cells, which were negative for vimentin and any other mesenchymal marker, a substantial portion of the cellular (undifferentiated) tumor areas showed a chondroprogenitor phenotype with an onset of expression of vimentin and collagen type IIA. Cells in the chondroid areas showed the full expression panel of mature chondrocytes including type X collagen indicating focal hypertrophic differentiation of the neoplastic chondrocytes. Finally, evidence was found for transdifferentiation of the neoplastic chondrocytes to osteoblast-like cells in areas of neoplastic bone formation. These results establish mesenchymal chondrosarcoma as the very neoplasm of differentiating premesenchymal chondroprogenitor cells. The potential of neoplastic bone formation in mesenchymal chondrosarcoma introduces a new concept of neoplastic (chondrocytic. osteogenesis in musculoskeletal malignant neoplasms, which qualifies the old dogma that neoplastic bone/osteoid formation automatically implies the diagnosis of osteosarcoma. Mesenchymal chondrosarcoma is an uncommon malignant chondrogenic neoplasm with an overall poor prognosis.1Salvador AH Beabout JW Dahlin DC Mesenchymal chondrosarcoma—observations on 30 new cases.Cancer. 1971; 28: 605-615Crossref PubMed Scopus (185) Google Scholar, 2Bertoni F Picci P Bacchini P Capanna R Innao V Bacci G Campanacci M Mesenchymal chondrosarcoma of bone and soft tissues.Cancer. 1983; 52: 533-541Crossref PubMed Scopus (95) Google Scholar, 3Dabska M Huvos AG Mesenchymal chondrosarcoma in the young. A clinicopathological study of 19 patients with explanation of histogenesis.Virchows Arch A Pathol Anat Histopathol. 1983; 399: 89-104Crossref PubMed Scopus (64) Google Scholar It represents about 1% of all chondrosarcomas1Salvador AH Beabout JW Dahlin DC Mesenchymal chondrosarcoma—observations on 30 new cases.Cancer. 1971; 28: 605-615Crossref PubMed Scopus (185) Google Scholar, 4Huvos AG Rosen G Dabska M Marcove RC Mesenchymal chondrosarcoma—a clinicopathologic analysis of 35 patients with emphasis on treatment.Cancer. 1983; 51: 1230-1237Crossref PubMed Scopus (204) Google Scholar, 5Nakashima Y Unni KK Shives TC Swee RG Dahlin DC Mesenchymal chondrosarcoma of bone and soft tissue—a review of 111 cases.Cancer. 1986; 57: 2444-2453Crossref PubMed Scopus (312) Google Scholar and affects all ages (5 to 74 years) with a peak occurrence in the second decade of life.3Dabska M Huvos AG Mesenchymal chondrosarcoma in the young. A clinicopathological study of 19 patients with explanation of histogenesis.Virchows Arch A Pathol Anat Histopathol. 1983; 399: 89-104Crossref PubMed Scopus (64) Google Scholar As a peculiarity of this neoplasm, about one third of the cases develop outside the bone including a significant number arising in the meninges.1Salvador AH Beabout JW Dahlin DC Mesenchymal chondrosarcoma—observations on 30 new cases.Cancer. 1971; 28: 605-615Crossref PubMed Scopus (185) Google Scholar, 5Nakashima Y Unni KK Shives TC Swee RG Dahlin DC Mesenchymal chondrosarcoma of bone and soft tissue—a review of 111 cases.Cancer. 1986; 57: 2444-2453Crossref PubMed Scopus (312) Google Scholar, 6Guccion JG Font RL Enzinger FM Zimmerman LE Extraskeletal mesenchymal chondrosarcoma.Arch Pathol Lab Med. 1973; 95: 336-340Google Scholar, 7Rollo JL Green WR Kahn LB Primary meningeal mesenchymal chondrosarcoma.Arch Pathol Lab Med. 1979; 103: 239-243PubMed Google Scholar, 8Seth HN Singh M Intracranial mesenchymal chondrosarcoma.Acta Neuropathol. 1973; 24: 86-89Crossref PubMed Scopus (17) Google Scholar, 9Scheithauer BW Rubinstein LJ Meningeal mesenchymal chondrosarcoma.Cancer. 1978; 42: 2744-2752Crossref PubMed Scopus (116) Google Scholar Mesenchymal chondrosarcoma was first described as mesenchymoma/polyhistioma by Jacobson10Jacobson SA Polyhistioma.Cancer. 1977; 40: 2116-2130Crossref PubMed Scopus (38) Google Scholar and is composed of two characteristic tumor components: one being highly cellular and the other showing cartilage formation with abundant extracellular matrix. So far, only histological and ultrastructural studies have been performed5Nakashima Y Unni KK Shives TC Swee RG Dahlin DC Mesenchymal chondrosarcoma of bone and soft tissue—a review of 111 cases.Cancer. 1986; 57: 2444-2453Crossref PubMed Scopus (312) Google Scholar, 11Dobin SM Donner LR Speights VO Mesenchymal chondrosarcoma. A cytogentic, immunohistochemical and ultrastructural study.Cancer Genet Cytogenet. 1995; 83: 56-60Abstract Full Text PDF PubMed Scopus (28) Google Scholar, 12Fu Y-S Kay S A comparative ultrastructural study of mesenchymal chondrosarcoma and myxoid chondrosarcoma.Cancer. 1974; 33: 1531-1542Crossref PubMed Scopus (88) Google Scholar, 13Kurotaki H Takeoka H Takeuchi M Yagihashi S Kamata Y Nagai K Primary mesenchymal chondrosarcoma of the lung: a case report with immunohistochemical and ultrastructural studies.Acta Pathol Jpn. 1992; 42: 353-358PubMed Google Scholar, 14Steiner GC Mirra JM Bullough PG Mesenchymal chondrosarcoma—a study of the ultrastructure.Cancer. 1973; 32: 926-939Crossref PubMed Scopus (66) Google Scholar and no studies on the biochemical composition of the extracellular tumor matrix and pattern of cell differentiation in mesenchymal chondrosarcomas are available. Hence, cell differentiation is so far poorly understood.15Huvos AG Bone Tumors. W. B. Saunders, Philadelphia1991: 1-784Google Scholar To define a phenotypic profile of these heterogeneous tumors, techniques allowing in situ analysis on the cellular level are required. This is not possible with conventional biochemical or molecular techniques. Here, therefore, besides conventional histological and histochemical techniques we used in situ localization methods for both, protein and mRNA, enabling identification of matrix components and their gene expression pattern in correlation to the different tumor compartments. More importantly, these techniques enable the identification of the cellular differentiation pattern in situ. This is particularly practical for studying chondrogenesis because distinct markers of different developmental stages of chondrogenic cell differentiation have been identified (for review see Cancedda and colleagues16Cancedda R Descalzi-Cancedda F Castagnola P Chondrocyte differentiation.Int Rev Cytol. 1995; 159: 265-358Crossref PubMed Scopus (351) Google Scholar). Thus, chondroprogenitor cells in the limb-bud mesenchyme start to express a specific splice variant of collagen type II (COL2A)17Sandell LJ Morris NP Robbins JR Goldring MB Alternatively spliced type II procollagen mRNAs define distinct populations of cells during vertebral development: differential expression of the amino-propeptide.J Cell Biol. 1991; 114: 1307-1319Crossref PubMed Scopus (301) Google Scholar, 18Sandell LJ Nalin AM Reife RA The alternative splice form of type II procollagen mRNA (IIA) is predominant in skeletal precursors and non-cartilaginous tissues during early mouse development.Dev Dys. 1994; 199: 129-140Crossref Scopus (165) Google Scholar even before any cartilage matrix formation is observable. Differentiated chondrocytes form abundant, histologically visible extracellular cartilage matrix by expressing collagen types II (COL2B), IX (COL9), and XI (COL11) as well as the cartilage-typical large aggregating proteoglycan aggrecan.19Vornehm SI Dudhia J von der Mark K Aigner T Expression of collagen types IX and XI as well as other major cartilage matrix components by human fetal chondrocytes in vivo.Matrix Biol. 1996; 15: 91-98Crossref PubMed Scopus (58) Google Scholar In the terminal phase of chondrocyte differentiation, the cells become hypertrophic and start to express type X collagen (COL10).20Linsenmayer TF Chen Q Gibney E Gordon MK Marchant JK Mayne R Schmid TM Collagen types IX and X in the developing chick tibiotarsus: analyses of mRNAs and proteins.Development. 1991; 111: 191-196Crossref PubMed Google Scholar, 21Reichenberger E Aigner T von der Mark K Stöβ H Bertling W In situ hybridization studies on the expression of type X collagen in fetal human cartilage.Dev Biol. 1991; 148: 562-572Crossref PubMed Scopus (117) Google Scholar Most of the terminally differentiated chondrocytes in the fetal growth plate subsequently undergo apoptotic cell death. More recent experimental evidence suggests, however, that at least part of these cells can transdifferentiate to osteoblast-like cells.22Roach HI Erenpreisa J Aigner T Osteogenic differentiation of hypertrophic chondrocytes involves asymmetric cell divisions and apoptosis.J Cell Biol. 1995; 131: 483-494Crossref PubMed Scopus (251) Google Scholar, 23Cancedda FD Gentili C Manduca P Cancedda R Hypertrophic chondrocytes undergo further differentiation in culture.J Cell Biol. 1992; 117: 427-435Crossref PubMed Scopus (183) Google Scholar Transdifferentiated chondrocytes can be identified by the onset of the expression of type I collagen (COL1) and the deposition of bone matrix. Thus, chondrogenesis and endochondral bone formation can be traced on the basis of specific marker gene products such as COL2A for chondroprogenitor cells and COL10 for terminally differentiated hypertrophic chondrocytes. In our recent work, we were able to phenotype neoplastic cells of conventional and clear cell chondrosarcomas using these marker genes.24Aigner T Dertinger S Vornehm SI Dudhia J von der Mark K Kirchner T Phenotypic diversity of neoplastic chondrocytes and extracellular matrix gene expression in cartilaginous neoplasms.Am J Pathol. 1997; 150: 2133-2141PubMed Google Scholar, 25Aigner T Dertinger S Belke J Kirchner T Chondrocytic cell differentiation in clear cell chondrosarcoma.Hum Pathol. 1996; 27: 1301-1305Abstract Full Text PDF PubMed Scopus (35) Google Scholar In this study, we analyzed the expression of these marker genes in a large series of mesenchymal chondrosarcomas to establish matrix biochemistry and cell differentiation pattern in these neoplasms. Forty-eight specimens of 25 patients with mesenchymal chondrosarcomas from the Mayo bone tumor registry (Rochester, MN) and the Department of Pathology, University of Erlangen-Nürnberg, Germany, were used for the study. Twenty-nine specimens derived from primary, six specimens from recurrences, and 10 specimens from metastatic lesions. Nineteen specimens derived from primary skeletal lesions and seven from primary soft-tissue lesions (one of them meningeal). The material was routinely fixed with 10% formalin, decalcified, and embedded in paraffin. Five-μm-thick paraffin sections were cut and stored at room temperature until use. Conventional hematoxylin and eosin (H&E) staining was performed to establish the diagnosis according to diagnostic criteria described elsewhere26Unni KK Dahlin's bone tumors. Lippincott-Raven, Philadelphia-New York1996: 1-463Google Scholar and to evaluate histomorphological features of the neoplasms. Histochemical techniques were used to estimate the total content of cartilage-typical glycosaminoglycans and collagens on a semiquantitative basis (see Table 2).Table 2Distribution of Cytoproteins and Extracellular Matrix Components in Matrix-Poor and Matrix-Rich Small-Cell, Cartilaginous, and Bone-Forming Tumor Compartments in Mesenchymal ChondrosarcomasAreasVimS-100ColGAGs AggCOL1COL2COL2ACOL3COL6COL10Matrix-poor small cell areas−−−−(+)(+)(++)(+)(+)−Matrix-rich small cell areas+−*Only single large rounded cells positive.++(+)(+)+++++(+)(+)−*Only single large rounded cells positive.Cartilaginous++++++++++(+)++++(+)++pc(+++)†In particular calcified areas.Bony++(+)+++(pc)+++(pc)(pc)pcpc(pc)+++, strongly positive; ++, positive; +, weakly positive; −, negative; 0, focally positive; vim, vimentin; col, collagen content; GAGs, glycosaminoglycans; agg, aggrecan; I (II, IIA, III, VI, X); collagen type I (II, IIA, III, VI, X).* Only single large rounded cells positive.† In particular calcified areas. Open table in a new tab +++, strongly positive; ++, positive; +, weakly positive; −, negative; 0, focally positive; vim, vimentin; col, collagen content; GAGs, glycosaminoglycans; agg, aggrecan; I (II, IIA, III, VI, X); collagen type I (II, IIA, III, VI, X). The cartilage-typical glycosaminoglycans were visualized by toluidine blue staining (10 minutes, 0.3% toluidine blue [Merck, Germany]; pH 3.65, room temperature).27Shepard N Mitchell NS Simultaneous localization of proteoglycan by light and electron microscopy using toluidine blue O—a study of epiphyseal cartilage.J Histochem Cytochem. 1976; 24–5: 621-629Crossref Scopus (90) Google Scholar The presence of collagens in the extracellular tumor matrix was demonstrated by Masson-Goldner's stain. Deparaffinized sections were enzymatically pretreated (Table 1), incubated with primary antibodies (Table 1) overnight at 4°C, and visualized using a streptavidin-biotin-complex technique (Super Sensitive Immunodetection System for mouse or rabbit primary antibodies; Biogenex, Mainz, Germany) with alkaline phosphatase as detection enzyme and 3-hydroxy-2-naphthylacid 2,4-dimethylanilid as substrate. Nuclei were counterstained with hematoxylin.Table 1Primary Antibodies and Enzymatic Pretreatments Used for Immunohistochemical AnalysisAntigenTypeDilutionDigestionSourceVimentin (V9.1) (human)m1:200PtDako (Denmark)S-100 protein (bovine)r1:20000PDako (Denmark)Collagen I (human)r1:200H, PtSynbio (Germany)Collagen II (chick)m1:50H, PDr. Holmdahl53 (Uppsala, Sweden)Collagen IIA (human)p1:1000H, PtDr. L. Sandell54Collagen III (human)r1:2000H, PDr. Günzler (Höchst, Frankfurt, FRG) (prepared and characterized according to Nowack et al55)Collagen VI (human)r1:5000H, PDr. R. Timpl (MPI for Biochemistry, Munich, FRG)56Collagen X (X-36, X-54) (human)m1:100H, PtDr. von der Mark (Erlangen, Germany)57Aggrecan (5G5) (human)m1:5000H, PtDr. R. Perris (Avioli, Italy; manuscript in preparation)m, mouse monoclonal; r, rabbit polyclonal; H, hyaluronidase (ovine testis in 2 mg/ml, phosphate-buffered saline, pH 5, 60 minutes at 37°C; Sigma, Deisenhofer, Germany); P, pronase (2 mg/ml, phosphate-buffered saline, pH 7.3, 60 minutes at 37°C; Boehringer Mannheim); P, pepsin (0.4% in 0.01N HCl; Sigma); Pt, protease XXIV (0.02 mg/ml, phosphate-buffered saline, pH 7.3, 60 minutes at RT; Sigma). Open table in a new tab m, mouse monoclonal; r, rabbit polyclonal; H, hyaluronidase (ovine testis in 2 mg/ml, phosphate-buffered saline, pH 5, 60 minutes at 37°C; Sigma, Deisenhofer, Germany); P, pronase (2 mg/ml, phosphate-buffered saline, pH 7.3, 60 minutes at 37°C; Boehringer Mannheim); P, pepsin (0.4% in 0.01N HCl; Sigma); Pt, protease XXIV (0.02 mg/ml, phosphate-buffered saline, pH 7.3, 60 minutes at RT; Sigma). As negative control for immunohistochemical stainings, the primary antibody was replaced by nonimmune mouse or rabbit serum (BioGenex, San Ramon, CA) or Tris-buffered saline (pH 7.2) in selected cases. Specificity of antibodies was tested by using test tissues (eg, fetal growth-plate cartilage) with established staining pattern in parallel experiments. Suitable fragments of human collagen chains α1(I), α1(II), and α1(X), and aggrecan core protein mRNA were selected and transcribed in vitro to generate digoxigenin-labeled antisense and sense riboprobes as described previously.19Vornehm SI Dudhia J von der Mark K Aigner T Expression of collagen types IX and XI as well as other major cartilage matrix components by human fetal chondrocytes in vivo.Matrix Biol. 1996; 15: 91-98Crossref PubMed Scopus (58) Google Scholar, 28Aigner T Neureiter D Müller S Küspert G Belke J Kirchner T Extracellular matrix composition and gene expression in collagenous colitis.Gastroenterology. 1997; 113: 136-143Abstract Full Text PDF PubMed Scopus (144) Google Scholar The rather long (>1 kb) primary transcripts for aggrecan core protein and type X collagen were reduced to an average length of 300 bp by standard alkaline hydrolysis. To control probe specificity, all probes were tested on fetal growth-plate specimens in parallel experiments.19Vornehm SI Dudhia J von der Mark K Aigner T Expression of collagen types IX and XI as well as other major cartilage matrix components by human fetal chondrocytes in vivo.Matrix Biol. 1996; 15: 91-98Crossref PubMed Scopus (58) Google Scholar A probe for 18S rRNA29Aigner T Stöβ H Weseloh G Zeiler G von der Mark K Activation of collagen type II expression in osteoarthritic and rheumatoid cartilage.Virchows Arch B Cell Pathol. 1992; 62: 337-345Crossref Scopus (127) Google Scholar was used as a positive control. Negative samples were discarded from in situ mRNA analysis. In situ hybridization was performed as described elsewhere.28Aigner T Neureiter D Müller S Küspert G Belke J Kirchner T Extracellular matrix composition and gene expression in collagenous colitis.Gastroenterology. 1997; 113: 136-143Abstract Full Text PDF PubMed Scopus (144) Google Scholar Briefly, deparaffinized and rehydrated sections were digested with proteinase K (200 μg/ml in 50 mmol/L Tris), postfixed in paraformaldehyde, acetylated, and dehydrated. The sections were hybridized for 12 to 16 hours at 44°C with riboprobes (final concentration, 1 ng/ml) in ECL-gold-hybridization buffer (Amersham, Freiburg, Germany) supplemented with 0.3 mol/L NaCl. After hybridization, the tissue sections were washed at 40°C in 1× standard saline citrate (SSC) and 0.3× SSC, treated with RNases A and T1, and washed again at 50°C in 0.1× SSC. The immunological detection of the digoxigenin-labeled probes was performed using the Digoxigenin-Detection-Kit (Boehringer-Mannheim, Mannheim, Germany). The exposure time was 3 days for all three probes. For the detection of in situ DNA breaks, the TUNEL-reaction was applied using the Apoptosis-Detection Kit from Oncor (Gaithersburg, MD). According to the suggestions of the manufacturer, the proteinase K pretreatment as well as the terminal deoxytransferase concentration was carefully titrated to ensure specificity and sensitivity of the procedure. Control sections of fetal growth-plate cartilage were processed in parallel revealing specific apoptotic labeling selectively in the lower hypertrophic zone. The main results of the study are summarized in Table 2. These results were consistent among the specimens examined demonstrating a high consistency regarding the various phases of mesenchymal differentiation in between the different specimens. Histomorphologically, the investigated mesenchymal chondrosarcomas showed the typical morphological features of this tumor entity. In principle, in most samples two tumor compartments could be distinguished as described previously:5Nakashima Y Unni KK Shives TC Swee RG Dahlin DC Mesenchymal chondrosarcoma of bone and soft tissue—a review of 111 cases.Cancer. 1986; 57: 2444-2453Crossref PubMed Scopus (312) Google Scholar, 26Unni KK Dahlin's bone tumors. Lippincott-Raven, Philadelphia-New York1996: 1-463Google Scholar First, the noncartilaginous compartment showed either loose sheets of small neoplastic cells (Figure 1A, lower part) or small cells located around sinusoidal vascular proliferates (hemangiopericytoma-like pattern; Figure 1A, upper part). The abundance of the extracellular tumor matrix varied in these areas from hardly any to moderate (Figure 1h). Notably, rarely single larger round cells surrounded by a rim of hyaline matrix forming a lacunar space were found in the areas showing more abundant extracellular matrix (Figure 2a).Figure 2Analysis of single chondrocytic tumor cells in otherwise matrix-rich small-cell areas. a: Conventional H&E staining. b: Histochemical demonstration of pericellular glycosaminoglycans (toluidine blue). c, e, f: Immunodetection of aggrecan (c), COL2 (e), and COL10 (f) in the extracellular tumor matrix. d: Immunodetection of S-100 protein selectively in the neoplastic chondrocytic cells. Original magnification, ×100.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Secondly, areas of cartilaginous matrix formation with cells sitting in lacunae similar to chondrocytes in physiological fetal cartilage were found (Figure 3e). Within the cartilaginous compartment of some samples, focal calcification and areas of bone formation occurred. The presence of mature bone matrix was confirmed by polarized light microscopy. The transition in between small-cell areas and cartilage and bone formation was either rather sharp or smooth. Histochemical matrix analysis showed the absence of glycosaminoglycan staining in the cellular areas. Focal staining was found in the matrix-rich small-cell areas, in particular around the large single cells (Figure 2b). Abundant staining was seen in the cartilaginous tumor areas (Figure 3e). Collagen staining was not significant in the cellular matrix-poor areas and moderate to high in the matrix-rich cellular and cartilaginous areas, respectively. The highest amount of collagens was seen in areas of bone matrix formation (Figure 4d). Here some cells showed pericellular staining for glycosaminoglycans (Figure 4f) whereas others as well as the bone matrix were negative in the toluidine blue reaction. No principal difference in matrix composition was found in the different small-cell tumor areas irrespective of their morphological appearance, hemangiopericytoma-like or not. Cellular areas, in which hardly any collagen could be detected histochemically, showed no or only minor amounts of COL1, COL2, COL2A, COL3, and COL6 (Figure 1d, 1e) and were consistently negative for COL10. Cellular areas, in which histochemically significant intercellular collagen was detectable, significant staining for COL2 (Figure 1i), in particular COL2A (Figure 1j), was detectable together with some staining for COL1, COL3, and COL6. COL10 was again not detectable. The large round single cells in these areas were surrounded by a COL6 pericellular matrix. Further away from the cells, but still in their immediate neighborhood, COL2 (Figure 2c) and less often COL10 (Figure 2f) were found. The cartilaginous tumor areas showed strong staining for COL2 throughout the extracellular tumor matrix (Figure 3f). Notably, a much less intense or absent staining was found in these areas for the isoform COL2A (Figure 3b) indicating a switch to predominantly the COL2B variant in these areas, which is characteristic for fully differentiated chondrocytes. The cells were mostly lying in cell lacunae and were surrounded by a COL6 positive pericellular matrix (Figure 3c). Multifocally, COL10 deposition was found including the areas of matrix calcification (Figure 3g), which expression of COL10 seemed to precede. In areas of bone formation, the bone matrix was, as expected, positive for COL1, but negative for COL2 or COL10. This was easily seen in one of the cases which showed areas of organoid bone formation (Figure 4a). Also here, the bone matrix was positive for COL1 (Figure 4b) and largely negative for COL2 and COL10. But both collagen types were, however, found in the pericellular matrix of some cells within the bone (Figure 4h, 4i) suggesting the chondrocytic origin of these cells. COL3 and COL6 were found in the pericellular area of the newly formed bone, but not within the bone matrix itself. Immunodetection for aggrecan proteoglycan showed a distribution of aggrecan core protein virtually identical to the histochemical glycosaminoglycan staining. No aggrecan was detectable in the matrix-poor cellular areas (Figure 1f). Focal staining was visible in the matrix-rich, histochemically glycosaminoglycan-positive areas (Figure 1g), in particular around the single round cells (Figure 2e). Overall, clearly less staining for aggrecan (Figure 1g) was found compared to type II collagen in the small-cell areas (Figure 1i). The extracellular matrix in cartilaginous areas was strongly stained for aggrecan (Figure 3d). The neoplastic bone was again negative for aggrecan except the pericellular area around some tumor cells (Figure 4g). In situ hybridization analysis on the mRNA level confirmed the expression pattern found by immunoanalysis. COL2 mRNA expression was localized to the matrix-rich small-cell and in the cartilaginous areas (Figure 3i). COL10 mRNA was restricted to the cartilaginous areas, in particular the foci of beginning or ongoing matrix calcification (Figure 3j). Type I collagen mRNA expression was seen in areas of bone formation (Figure 4c). Aggrecan mRNA expression was observed mostly in the chondrocytic cells of cartilaginous areas (Figure 3h). Most small cells as well as all nonneoplastic cells were negative for aggrecan mRNA. Immunodetection of vimentin was positive in the matrix-rich noncartilaginous small-cell (Figure 1c), cartilaginous, and osteoid areas, but not in the cellular matrix-poor areas (Figure 1b). S-100 protein was positive in the single rounded cells in the matrix-rich small-cell areas (Figure 2d) and in most cells of the cartilaginous areas (Figure 3a) as well as some cells in the areas of neoplastic bone formation (Figure 4e). Small cells and the majority of osteoblast-like cells were negative for S-100 protein. DNA fragmentation detected by the TUNEL-reaction, indicated apoptotic cell death throughout the tumor, but was most prominent in the chondroid tumor areas (Figure 3k, 3l). This study identifies mesenchymal chondrosarcoma as the neoplasm of very early prechondrogenic cells, which multifocally undergo full chondrocytic differentiation analogous to limb bud development. The most undifferentiated cells are even vimentin-negative and express none of the chondrocytic marker genes and hardly any matrix components at all. A large proportion of the morphologically undifferentiated cells, however, expresses the marker of chondroprogenitor cells, COL2A17Sandell LJ Morris NP Robbins JR Goldring MB Alternatively spliced type II procollagen mRNAs define distinct populations of cells during vertebral development: differential expression of the amino-propeptide.J Cell Biol. 1991; 114: 1307-1319Crossref PubMed Scopus (301) Google Scholar and also vimentin. The expression of COL2B together with aggrecan proteoglycan is the hallmark of differentiated chondrocytes in the areas of microscopically visible cartilaginous matrix formation. In these areas, cells are positive for S-100 protein, which is one marker for physiological and neoplastic chondrocytic differentiation.30Nakamura Y Becker LE Marks A S-100 protein in tumors of cartilage and bone.Cancer. 1983; 52: 1820-1824Crossref PubMed Scopus (109) Google Scholar, 31Stefansson K Wollmann RL Moore BW Arnason BGW S-100 protein in human chondrocytes.Nature. 1982; 295: 63-64Crossref PubMed Scopus (223) Google Scholar The formed cartilage shows histochemically and immunohistochemically all features of fetal hyaline cartilage, thus, confirming previous morphological and ultrastructural studies.14Steiner GC Mirra JM Bullough PG Mesenchymal chondrosarcoma—a study of the ultrastructure.Cancer. 1973; 32: 926-939Crossref PubMed Scopus (66) Google Scholar, 32Martinez-Tello FJ Navas-Palacios JJ Ultrastructural study of conventional chondrosarcomas and myxoid- and mesenchymal-chondrosarcomas.Virchows Arch A Pathol Anat Histopathol. 1982; 396: 197-211Crossref Scopus (39) Google Scholar, 33Sato NL Minase T Yoshida Y Narimatsu E Muroya K Asaishi K Kikuchi K An ultrastructural study of extraskeletal mesenchymal chondrosarcoma.Acta Pathol Jpn. 1984; 34: 1355-1366PubMed Google Scholar Also, type VI collagen is concentrated pericellularly in these areas, which is characteristic for cartilage and most likely involved into the formation of the cartilage-typical cell lacunae found in the cartilaginous tumor areas.34Poole CA Ayad S Schofield JR Chondrons fro" @default.
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• W2167441405 date "2000-04-01" @default.
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• W2167441405 title "Cell Differentiation and Matrix Gene Expression in Mesenchymal Chondrosarcomas" @default.
• W2167441405 cites W166547449 @default.
• W2167441405 cites W1796439827 @default.
• W2167441405 cites W1834208879 @default.
• W2167441405 cites W1964519636 @default.
• W2167441405 cites W1966550670 @default.
• W2167441405 cites W1978943338 @default.
• W2167441405 cites W1979866682 @default.
• W2167441405 cites W1980221316 @default.
• W2167441405 cites W1984156394 @default.
• W2167441405 cites W1989406187 @default.
• W2167441405 cites W1998176866 @default.
• W2167441405 cites W2002419387 @default.
• W2167441405 cites W2004989299 @default.
• W2167441405 cites W2007372407 @default.
• W2167441405 cites W2012495993 @default.
• W2167441405 cites W2022486398 @default.
• W2167441405 cites W2022862437 @default.
• W2167441405 cites W2028442510 @default.
• W2167441405 cites W2029591566 @default.
• W2167441405 cites W2030535921 @default.
• W2167441405 cites W2030684193 @default.
• W2167441405 cites W2030695940 @default.
• W2167441405 cites W2037254430 @default.
• W2167441405 cites W2037536272 @default.
• W2167441405 cites W2039737840 @default.
• W2167441405 cites W2045631728 @default.
• W2167441405 cites W2046355511 @default.
• W2167441405 cites W2048007275 @default.
• W2167441405 cites W2050785319 @default.
• W2167441405 cites W2051349620 @default.
• W2167441405 cites W2051847271 @default.
• W2167441405 cites W2067200032 @default.
• W2167441405 cites W2067310864 @default.
• W2167441405 cites W2067591602 @default.
• W2167441405 cites W2071905570 @default.
• W2167441405 cites W2075698606 @default.
• W2167441405 cites W2078744277 @default.
• W2167441405 cites W2089860867 @default.
• W2167441405 cites W2103461739 @default.
• W2167441405 cites W2104923858 @default.
• W2167441405 cites W2110881366 @default.
• W2167441405 cites W2122284111 @default.
• W2167441405 cites W2122309353 @default.
• W2167441405 cites W2126931608 @default.
• W2167441405 cites W2141186116 @default.
• W2167441405 cites W2275996370 @default.
• W2167441405 cites W2299382724 @default.
• W2167441405 cites W2398143325 @default.
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