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PubMed2001

Expression of CD31, Met/hepatocyte growth factor receptor and bone morphogenetic protein in bone metastasis of osteosarcoma.

The mechanism of metastasis of osteosarcoma cells to other bones has not yet fully been clarified. The purpose of the present study was to examine whether various factors involve the formation of osteosarcoma metastatic foci in other bones. Immunohistochemically, CD31 expression in osteosarcoma with no bone metastasis and osteosarcoma with bone metastasis was noted in 10 and 75% of cases, respectively. Met/hepatocyte growth factor (HGF) receptor expression in osteosarcoma with no bone metastasis and osteosarcoma with bone metastasis was noted in 90 and 25% of cases, respectively. Bone morphogenetic protein (BMP) expression in osteosarcoma with no bone metastasis and osteosarcoma with bone metastasis was noted in 20 and 75% of cases, respectively. Metastasis of osteosarcoma cells to other bones was significantly correlated with expression of BMP and CD31 and with no expression of Met/HGF receptor protein in osteosarcoma cells. In contrast, expression of insulin-like growth factor receptor in osteosarcoma cells did not correlate significantly with bone metastasis. These results suggest that formation of metastatic foci of osteosarcoma cells in other bones is regulated by CD31, which is associated with migration between endothelial cells, by BMP, which can induce and activate various mesenchymal cells affecting bone formation, and by escape of effect by HGF, which promotes differentiation of osteosarcoma cells.

Adolescent↗
PubMedDate not supplied

Heat-shock protein 72 in human osteosarcoma: T-lymphocyte reactivity and cytotoxicity.

Heat-shock proteins (hsp) have been shown to be involved in tumor immunity. The expression of hsp72, the inducible form of the 70-kDa family, is increased in human osteosarcoma and correlates with a good response to neoadjuvant chemotherapy. It is selectively expressed on the surface of osteosarcoma cell lines where it acts as a target molecule for natural killer cells. Because hsps are strongly immunogenic, this study investigates the role of hsps as antigens in human osteosarcoma. Osteosarcoma cells and infiltrating T lymphocytes were isolated from osteosarcoma specimens from 3 patients with high-grade osteosarcoma. Two of the tumors immunohistochemically expressed hsp72, whereas one did not. T-cell lines isolated from both hsp72-positive osteosarcomas had a significantly proliferative response upon stimulation with recombinant human hsp72, whereas the T lymphocytes from the hsp72-negative osteosarcoma did not recognize hsp72. The lines had a significantly proliferative response upon stimulation with autologous osteosarcoma cells and exerted cytotoxicity. Cytotoxicity and proliferation could be increased by heat treatment of the target cell in the hsp72 responsive lines. These results demonstrate that hsp72 is involved in the interaction of T lymphocytes and osteosarcoma cells in a specific group of osteosarcomas expressing hsp72. Because of the cytotoxic potential of these T lymphocytes, induction of hsp72 in osteosarcomas might lead to an increased immune response and rejection of the osteosarcoma.

Coculture Techniques↗
PubMed1982

The ultrastructure of conventional, parosteal, and periosteal osteosarcomas.

Twenty-seven osteosarcomas of bone were examined by electron microscopy. Eighteen cases were conventional osteosarcomas, one case was an osteosarcoma that developed in Paget's disease of bone, two cases were metastasis to the lungs of conventional osteosarcomas, five were parosteal osteosarcomas (and the recurrence of one of them), and one was periosteal osteosarcoma. In addition to the basic neoplastic cell, the osteoblast-like tumor cell, seven tumor cell types could be differentiated in varying numbers in the 27 cases examined: (1) chondroblast-like; (2) fibroblast-like; (3) histiocyte-like; (4) myofibroblast; (5) osteoclast-like; (6) malignant multinucleated osteoblast-like; and (7) atypical primitive mesenchymal cells. Moreover, endothelial cells and pericytes were also present. The tumor cells showed common neoplastic features in relation with general cell configuration and fine structures. No cytoplasmic organelle was considered to be cell-specific, and only the amount and distribution of the organelles allowed us to differentiate the above mentioned cell types. The presence of malignant appearing tumor cells with abundant and dilated cisternae of RER, in an intercellular matrix containing collagen fibers with areas of focal collections or puffs of hydroxyapatite crystals, are the most characteristic ultrastructural features of osteosarcoma. However, those features are not pathognomonic and do not allow in all cases the differential diagnosis with osteoid-osteoma and benign osteoblastoma. Fields of chondroblastic, fibroblastic, or fibrohitiocytic character are indistinguishable of chondrosarcomas, fibrosarcomas, or malignant fibrous histiocytoma of bone, respectively. The comparative study of parosteal and conventional osteosarcomas revealed a marked difference in the cell population: fibroblast-like cells and myofibroblasts were the main cell types in parosteal osteosarcoma; on the contrary, myofibroblasts were very scarce or absent in conventional osteosarcomas. This difference may correlate with the better outcome of parosteal osteosarcoma. The ultrastructural features of a periosteal osteosarcoma are reported for the first time. The tumor was comprised mostly of chondroblast-like tumor cells. However, in the more cellular peripheric areas of the neoplasm, the cells were predominantly of the fibroblast-like type and showed anaplastic features.

Bone Neoplasms↗
PubMed1995

Analysis of oncogenes, tumor suppressor genes, autocrine growth-factor production, and differentiation state of human osteosarcoma cell lines.

Human osteosarcoma and fibrosarcoma cell lines were investigated for alterations in oncogenes, tumor suppressor genes, and growth factors, all of which have been implicated in tumor formation. Characterization of oncogenes that are involved in osteosarcoma formation, including the c-fos and c-myc oncogenes, indicated that all six osteosarcoma cell lines examined had 5- to 20-fold amplification of the c-myc oncogene, whereas neither of two fibrosarcoma cell lines c-myc amplification. Interestingly, only three of six osteosarcoma cell lines displayed altered c-myc immediate-early gene function. c-fos was found to be normal, both at the gene and functional levels, in all six osteosarcoma and both fibrosarcoma cell lines tested. Characterization of two tumor suppressor genes, p53 and RB1, that have been implicated in osteosarcoma formation indicated that p53 was altered in five of six osteosarcoma cell lines, whereas RB1 was altered in only two or six of these cell lines. Neither RB1 nor p53 was found to be altered in the fibrosarcoma cell lines tested. An additional transformation marker, autocrine growth-factor production, was observed in all six osteosarcoma cell lines and both fibrosarcoma cell lines examined. Finally, the differentiation state of the osteosarcoma cell lines was investigated via the bone differentiation markers alkaline phosphates and osteocalcin. Alkaline phosphatase activity was observed in four of six osteosarcoma cell lines but not in the two fibrosarcoma cell lines examined. The alkaline phosphatase activity was a result of the expression of the bone/liver/kidney alkaline phosphatase isoform. High-level osteocalcin expression was observed in one of the osteosarcoma cell lines but not in the two fibrosarcoma cell lines examined, although all cell lines demonstrated low-level osteocalcin expression. Together, these data demonstrate that relatively undifferentiated osteosarcomas commonly display c-myc amplification, p53 and RB1 mutation, and autocrine growth-factor production, all of which may play a role in osteosarcomagenesis.

Base Sequence↗
PubMed2000

Initial symptoms and clinical features in osteosarcoma and Ewing sarcoma.

BACKGROUND: The time between the initial symptoms of osteosarcoma and Ewing sarcoma and the correct diagnosis and treatment is long. Over the last two decades, the prognosis for patients with these diseases has dramatically improved due to a new chemotherapy regimen. As a consequence, a limb-sparing operation has become an alternative to amputation. The aim of this study was to establish the initial symptoms and physical signs of osteosarcoma and Ewing sarcoma from the records of the first medical visit and to identify early characteristics of the diseases to shorten the delay to diagnosis. METHODS: A group of patients with osteosarcoma or Ewing sarcoma was identified from the Swedish Cancer Register of patients thirty years old and younger. Records from the first medical visit due to symptoms related to the bone tumor were obtained for 102 patients with osteosarcoma and forty-seven patients with Ewing sarcoma. RESULTS: Pain related to strain was reported by eighty-seven (85 percent) of the patients with osteosarcoma and thirty (64 percent) of those with Ewing sarcoma, but only twenty-one (21 percent) of the patients with osteosarcoma and nine (19 percent) of those with Ewing sarcoma reported pain at night. Forty-eight (47 percent) of the patients with osteosarcoma and twelve (26 percent) of those with Ewing sarcoma related the onset of symptoms to minor trauma occurring around the same time. A palpable mass was noted in forty (39 percent) of the patients with osteosarcoma and sixteen (34 percent) of those with Ewing sarcoma at the first visit, and in most cases the tumor diagnosis was suspected. There was a broad spectrum of misdiagnoses; the most common was tendinitis, which was the initial diagnosis in thirty-two (31 percent) of the patients with osteosarcoma and ten (21 percent) of those with Ewing sarcoma. The doctor's delay (the period from the first medical visit due to the symptoms to the correct diagnosis) was longer for Ewing sarcoma than for osteosarcoma (nineteen weeks and nine weeks, respectively; p < 0.0001). CONCLUSIONS: An initial symptom of both osteosarcoma and Ewing sarcoma was pain, which was intermittent and often related to strain but not frequently felt at night. A history of trauma was common, but the clinical course often diverged from what was expected from trauma. The clinical course of osteosarcoma and particularly of Ewing sarcoma was not steadily progressive but intermittent, which often misled the doctor into believing that the condition was temporary. The most important clinical feature was a palpable mass, which was noted in more than one-third of the patients at the first visit. This finding emphasizes that a thorough physical examination is absolutely necessary.

Adolescent↗
PubMed2003

[Pathomorphology of parosteal osteosarcoma. Experience with 125 cases in the Hamburg Register of Bone Tumors].

Parosteal osteosarcoma is a rare low-grade bone tumor. It occurs between the 2nd and 8th decade of life. In our own series of 125 parosteal osteosarcomas, most patients were aged between 30 and 40. The most frequent location was the distal dorsal femur. Until clearly proven otherwise, a bone-forming tumor in this location has to be regarded as a parosteal osteosarcoma. Of all parosteal osteosarcomas 77% are located in the lower extremity, with a female sex predominance in this location (62%); 18% are located in the upper extremity; 15% of all parosteal osteosarcomas are located in the humerus. Just 6% of all parosteal osteosarcomas are observed in the skull, the spine, and the pelvis. The tumor is characterized by hyalinized fibrous stroma with a low cell content without substantial nucleus polymorphism and variably dense bony trabeculae. The diagnosis can be difficult due to highly differentiated areas with fat tissue within the marrow and very uniformly bony structure. The operation material has to be analyzed very carefully, because the extent of dedifferentiated areas and most probably also the extent of invasion of the medullary cavity determine the prognosis and occurrence of recurrencies. The tumor is most commonly misinterpreted as osteochondroma or heterotopic ossification. Paying attention to all radiologic and histologic criteria,osteoblastic eccentrically located high-grade osteosarcomas can be clearly distinguished from parosteal osteosarcoma. An intramedullary located low-grade osteosarcoma,which is differentiated like a parosteal osteosarcoma,is histologically indistinguishable from the parosteal variant. This variant requires the synthesis of all available data to find the correct diagnosis. The parosteal osteosarcoma shows like no other tumor the necessity of close cooperation of all involved disciplines for diagnosis and therapy.

Adolescent↗
PubMed1988

DNA cytometry of osteosarcoma.

The relationship between cytochemical features and histomorphology in osteosarcoma, and the clinical significance of DNA content were investigated by microspectrophotometry (MSP) of tissue sections and flow cytophotometry (FCM) of cell suspensions. MSP of tissue sections entails the methodological error of determining the DNA content of sectioned cell nuclei. By analyzing 184 normal mesenchymal cell populations, an upper limit of diploidy (normal DNA content) was deduced. Applying this upper limit for 42 sarcomas, 6 were diploid and 36 hyperploid. Comparative analysis of the same lesions by MSP of imprint preparations and by FCM disclosed complete agreement in ploidy classification (diploid versus hyperploid). Retrospective MSP analysis of bone tumors is often impeded by previous demineralization in acid, which destroys DNA. EDTA as an alternative was found to slightly reduce Feulgen DNA stainability of osteosarcomas, but did not affect tumor ploidy determination. Hence, EDTA offers a means of retaining DNA stainability of bone tumors requiring demineralization. MSP analysis of different histologic areas, and comparative FCM analysis of biopsy and surgical specimens, dislosed that individual osteosarcomas are cytochemically uniform despite morphologic heterogeneity. Hence, a single tumor sample for DNA analysis can be relied upon as representative for the tumor as a whole. In a consecutive series of 83 osteosarcoma patients treated by surgery and adjuvant Interferon, the 7-year survival rate was 0.44. MSP DNA analysis gave no significant prognostic information. Multivariate analysis identified 3 risk factors for tumor related death, i.e., male sex, proximal tumor location, and histologic grade IV. In a prognostication model, the 7-year survival rates, for patients with 0, 1, 2, or 3 risk factors, were 0.80, 0.59, 0.42, and 0.13, respectively. Hence, it is possible to identify subgroups of high grade osteosarcoma patients with different prognosis. In a study of 166 primary bone tumors, the applicability of DNA analysis for differential diagnostic purposes was investigated. The series included high grade osteosarcomas, parosteal osteosarcomas and benign bone tumors, which may be mixed up histologically with osteosarcoma. Out of 166 tumors, 149 (90%) were histologically noncontroversial, whereas 17 (10%) posed diagnostic difficulties. In the diagnostically noncontroversial group, all benign tumors and parosteal osteosarcomas were diploid, whereas 97 of 102 osteosarcomas were hyperploid. Hence, hyperploidy seems to be a characteristic feature of high grade osteosarcoma.(ABSTRACT TRUNCATED AT 400 WORDS)

Bone Neoplasms↗
PubMed2002

[Expressions of CD44s, MMP-9, and Ki-67: possible association with invasion, metastasis, and recurrence of osteosarcoma].

BACKGROUND & OBJECTIVE: Recent research had showed that tumor cell adhesion molecular CD44 and matrix metalloproteinases (MMP) were expressed strongly in many tumors, and was associated closely with invasion and metastasis of the tumors. Ki-67 was one of the proliferative markers, which indicated the growth rate of tumor cells. However, the relationship among these markers and the invasion, metastasis, and recurrence of osteosarcoma was unclear yet. In this research the authors studied the expression of standard-type CD44(CD44s), MMP-9, and Ki-67 in osteosarcoma, and their relation to the invasion, metastasis, and recurrence of the tumor. METHODS: Immunohistochemistry staining(SP method) was used to detect CD44s, MMP-9, and Ki-67 in cases of osteosarcoma. Bone benign disease or normal connective tissue were used as the control. The results were treated with semi-quantitative method and analyzed by using non-parameter rank sum test. RESULTS: The positive rates of CD44s, MMP-9, and Ki-67 in osteosarcoma were 71.0%, 75.8%, and 35.5%, respectively, which were significantly higher than that in control tissue. The positive rate of Ki-67 in recurrent osteosarcoma was 81.8%, which was significantly higher than that in primary tumor. CD44s and Ki-67 positive rates were 88.9% and 66.7% respectively in osteosarcoma with lung metastasis, which were both significantly higher than that in osteosarcoma without lung metastasis. In poorly differentiated osteosarcoma positive rates of CD44s and MMP-9 were 76.3% and 79.7%, respectively, which were significantly higher than that in well differentiated tumor. Spearman correlation analysis proved that the expression of CD44s, MMP-9, and Ki-67 had significant relation to another. CONCLUSIONS: Increase of CD44s, MMP-9, and Ki-67 were involved in the growth and local invasion of osteosarcoma. The recurrence of osteosarcoma was associated with the proliferative rate of tumor cells. Whether there were early lung metastasis or not was affected by the amount of CD44s and the proliferative rate of the tumor cell. The poorer differentiation of osteosarcoma cells, the higher level of CD44s and MMP-9.

Adolescent↗
PubMed2004

[Significance of stathmin gene overexpression in osteosarcoma cells].

BACKGROUND & OBJECTIVE: Stathmin, a signal transduction regulatory factor, plays a crucial role in cell division and malignant tumor development. This study was designed to analyze stathmin gene expression in the tissue of osteosarcoma, and to explore the growth inhibition by blocking stathmin expression with Stathmin antisense oligodeoxynucleotide (ASODN) on cultured human osteosarcoma cell line with stathmin gene overexpression. METHODS: Reverse transcriptase polymerase chain reaction (RT-PCR) and in situ hybridization methods were used to determine the expression of stathmin in two human osteosarcoma cell lines and 45 osteosarcoma tissue specimens. Using stathmin gene overexpression in human osteosarcoma cell line SOSP-9607 as target cell and stathmin ASODN as gene expression blocking agent, cell growth inhibition of stathmin ASODN was determined by MTT method, and cell growth and mitotic character was analyzed by flow cytometry. RESULTS: Both osteosarcoma cell lines of SOSP-9607 and SOSP-9901 showed stathmin gene overexpression by RT-PCR method and 24 of 45 osteosarcoma specimens were stathmin positive by in situ hybridization, while there were only 2 in 10 normal tissues with mild positive signal. There was significant difference in stathmin gene expression between human osteosarcoma tissues and normal tissues (P< 0.05). The growth of osteosarcoma cells were suppressed by ASODN (P< 0.05,P< 0.01). The cell cycle of SOSP-9607 was blocked in metaphase and cell apoptosis was found. CONCLUSION: Stathmin gene displays high level expression in osteosarcoma, which may become a new target for the bio-treatment for osteosarcoma.

Adolescent↗
PubMed1996

Analysis of the presence of osteocalcin, S-100 protein, and proliferating cell nuclear antigen in cells of various types of osteosarcomas.

Osteosarcomas are characterized by different histologic subtypes that are composed of heterogeneous tumor cells. Although the histological origin of the malignant cells is unknown, it has been speculated that osteoblasts lead to the malignant cells. In the current study, the osteosarcoma cells in 27 lesions were assessed by means of immunohistochemical staining for osteocalcin (OC), S-100 protein (S-100) and proliferating cell nuclear antigen (PCNA). PCNA labeling indices were the highest in osteoblastic and stromal areas, and significantly lower in chondroblastic areas (p < 0.01). Cells that were positive for both PCNA and OC were abundant in osteoblastic and stromal areas, while cells that were positive for both PCNA and S-100 were rarely observed. These results were almost similar for conventional, parosteal and periosteal osteosarcomas. In contrast, OC reactivity was poor in fibroblastic osteosarcoma, in osteosarcoma with giant cells, and in telangiectatic osteosarcoma. Pulmonary metastatic osteosarcoma lesions weakly expressed OC (p < 0.01), but showed high values for the PCNA labeling indices. In conclusion, immunohistochemical staining for OC, S-100, and PCNA are useful to analyze the proliferating cells in osteosarcomas. The main proliferating cells in most osteosarcomas are mature osteoblast-like cells. OC-negative tumor cells predominate in some of osteosarcoma subtypes, and these tumors therefore probably represent a distinct osteosarcoma variant. OC expression in pulmonary metastatic lesions may be suppressed.

Adolescent↗
PubMed2002

Human osteosarcoma expresses specific ephrin profiles: implications for tumorigenicity and prognosis.

BACKGROUND: The molecular mechanisms underlying malignancy of osteosarcoma are unknown. It has been reported that eph receptor protein tyrosine kinases and their ligands, ephrins, are associated with increased tumorigenicity in patients with breast carcinoma and melanoma. The expression and role of eph/ephrins in human osteosarcoma has not yet been characterized. METHODS: Ephrin-A1, ephrin-A3, ephrin-A4, ephrin-A5, ephrin-B1, ephrin-B2, and ephrin-B3 mRNA expression was examined by reverse transcription polymerase chain reaction analysis in nine specimens of human osteosarcoma tissue and five human osteosarcoma cell lines. Ephrin-B1 protein expression was detected immunohistochemically in human osteosarcoma tissue. Clinicopathologic correlation was made between the osteosarcoma specimens and their ephrin expression profiles. RESULTS: Normal bone specimens, osteosarcoma tissue specimens, and osteosarcoma cell lines expressed a distinct mRNA profile of ephrin-A1, ephrin-A4, and ephrin-B2. A second mRNA profile that included ephrin-A3, ephrin-A5, and ephrin-B1 was expressed by a subset of tumors. The expression of ephrin-B1 was correlated with a poorer clinical prognosis. Ephrin-B1 protein was expressed by osteosarcoma cells and blood vessels. CONCLUSIONS: The results of this study suggest that ephrin-B1 expressed by osteosarcoma may be a poor prognostic marker through increased tumorigenicity.

Ephrin-A1↗
PubMed2006

Primary versus radiation-associated craniofacial osteosarcoma: Biologic and clinicopathologic comparisons.

BACKGROUND: Craniofacial osteosarcoma differs from long bone osteosarcoma in that patients are older, tumors are often low grade, and prognosis is more favorable. Although most are sporadic, some tumors occur in association with prior radiation therapy. The purpose of the current study was to compare clinicopathologic and prognostic features of primary and radiation-associated osteosarcoma. METHODS: The study group consisted of 15 primary and 6 radiation-associated osteosarcomas. Clinical and follow-up data were obtained in every case. Tissue microarrays were immunohistochemically stained for p53, pRB, Ki-67 (MIB-1), and ezrin. DNA was sequenced for TP53 mutations. RESULTS: All radiation-associated osteosarcomas were high grade and half were fibroblastic. In contrast, 47% of primary craniofacial osteosarcomas were high grade and only 1 was fibroblastic. All radiation-associated osteosarcomas recurred, half the patients died of disease, 2 were alive with unresectable tumors, whereas only 1 was alive without disease. In contrast, 80% of patients with primary tumors were alive without disease, 33% had local recurrences, and 13% died of disease. Radiation-associated tumors overexpressed p53 more often (33% vs. 13%), more often had TP53 mutations (33% vs. 8%), had higher proliferative activity (67% vs. 0% showing >50% MIB-1 staining), and expressed ezrin more frequently (83% vs. 40%) than primary tumors. Compared with a control group of 24 high- and 7 low-grade primary extremity osteosarcomas, radiation-associated tumors marked as the high-grade tumors. CONCLUSIONS: Craniofacial radiation-associated osteosarcomas are high-grade tumors that behave more aggressively than most primary craniofacial osteosarcomas. In addition, they demonstrate higher expression rates of adverse prognostic indicators, further highlighting the distinction.

Adolescent↗
PubMed1995

Osteosarcoma oncogene expression detected by in situ hybridization.

Fifteen archival human osteosarcoma specimens were examined by in situ hybridization for the expression of human and mouse transforming growth factor-beta (isoforms 1, 2, and 3), c-fos, and metalloproteinase (stromelysin-3 and matrilysin). Osteosarcoma subtypes were confirmed by review of patients' radiographs, histopathology, and age at diagnosis. The outcome and method of treatment were documented. The subtypes of osteosarcoma consisted of nine conventional osteosarcomas and two each of fibroblastic, telangiectatic, and post-radiation osteosarcomas. Each specimen was histologically examined under light microscopy, and then adjacent paraffin sections were assayed with sense and anti-sense RNA probes by in situ hybridization. The probes localized to the neoplastic cells, confirming the methodology of the technique. Human transforming growth factor-beta 1 had the most uniform binding affinity to the osteosarcomas examined and was more specific in binding than mouse transforming growth factor-beta 1. Specific mRNA encoding for the transforming growth factor-beta s, c-fos, and metalloproteinases are detectable in patterns within osteosarcoma cells, and collectively, their expression parallels the different histopathologic subtypes. The less differentiated subtypes (telangiectatic and post-radiation osteosarcomas) expressed the fewest molecular markers. Osteosarcoma is a heterogeneous tumor. Differential expression of matrilysin in osteosarcoma is the first reported detection of metalloproteinase activity in human skeletal sarcoma.

Adult↗
PubMed1994

Cytogenetic aberrations in osteosarcomas. Nonrandom deletions, rings, and double-minute chromosomes.

Relatively few karyotypes have been reported from short-term cultures and/or direct harvests of osteosarcomas. We describe clonal aberrations in 17 high-grade osteosarcoma specimens and in one low-grade osteosarcoma. The high-grade osteosarcomas were karyotyped after direct harvest (four cases) or after short-term culture periods of < 1 week (13 cases). Three of these specimens, a primary osteosarcoma and two lung metastases, were from the same patient and shared a number of clonal aberrations. No consistent chromosome translocations were identified in the overall group of high-grade osteosarcomas, but potential nonrandom deletions involved 6q21-->qter, 9p21-->pter, chromosome 10, chromosome 13, 17p12-pter, and chromosome 20. Ring chromosomes were detected in three cases, and double-minute (dmin) chromosomes were detected in six. All high-grade osteosarcomas had numerous nonclonal chromosome aberrations superimposed on complex clonal events. The single low-grade osteosarcoma was characterized by a balanced, nonconstitutional, t(5;10) (p13;p14-15), together with an addition to the short arm of chromosome X. This is the first translocation reported in low-grade osteosarcoma, and the simplicity of the karyotype contrasts strikingly with those in the high-grade osteosarcomas.

Adolescent↗
PubMed1985

Biological characterization of human bone tumors. IV. Combined biochemical and histological analyses of different osteosarcomas.

A new technique was applied to the study of human osteosarcoma. Ten slices of 10 micron were cut serially from 2 X 2 X 6 mm shock frozen blocks of human osteosarcoma for chemical analysis. Before and after each series of 10 slices, one slice of 10 micron was separated for morphological analysis. Four different types of osteosarcoma were investigated: Case 1 was an atypical osteoblastic osteosarcoma, case 2 a small cell sclerosing osteosarcoma, case 3 a well-differentiated parosteal osteosarcoma grade I, and case 4 a highly malignant anaplastic osteosarcoma. Alkaline phosphatase, acid phosphatase, beta-glucuronidase and proteolytic activities were analysed as well as matrix collagen and hexosamine, phosphorus (Pi and Po), protein, DNA, and water content. In accordance with the morphology, the obtained data illustrate the great heterogeneity of osteosarcomas. Although case 1, 2 and 3 all represent calcifying types of the tumor, characteristic differences exist with regard to the matrix and the degree of calcification. In contrast to these three, case 4 presents a noncalcified type of osteosarcoma whose matrix contains relatively high amounts of hexosamine and low amounts of collagen, whereas DNA and water contents are high. The data from the analysis of osteosarcoma were compared with previous results from the calf epiphyseal growth plate in order to define differences and similarities between the formation of tumor bone and the physiological formation of hard tissue.

Acid Phosphatase↗
PubMed1998

Evaluation of HLA-DR expression and T-lymphocyte infiltration in osteosarcoma.

Although in recent years the outcome of patients with osteosarcoma has considerably been improved by combining neoadjuvant chemotherapy with radical surgery, there still remains the problem of nonresponse to chemotherapy. T-lymphocytes play a critical role in tumor immunology, and MHC molecules are of central importance in the regulation of the immune response. It is the aim of this study to investigate whether T-lymphocyte infiltration of osteosarcomas and HLA-DR expression on tumor cells and infiltrating immune cells are of predictive or diagnostic value. Expression of CD3, CD8 and HLA-II was evaluated immunohistochemically on paraffin-embedded sections of 35 patients with high-grade osteosarcoma at the time of biopsy before chemotherapy and correlated with histologic response to chemotherapy, tumor size, age, alkaline-phosphatase serum levels and duration of symptoms. Thirty-four patients with osteoblastoma (n = 7), osteoid osteoma (n = 7) or fibrous dysplasia (n = 20) served as controls. Osteosarcomas were infiltrated by CD3+ (33/35, 95%) and CD8+ T-lymphocytes (24/35, 68%), non malignant bone tumors by CD3+ in 91% (31/34) and CD8+ T-lymphocytes in 74% (25/34), respectively. T-lymphocytes were positive for HLA-DR expression in 29% (10/35) in osteosarcomas and in 11% (4/34) in non-malignant controls. Osteosarcoma cells were positive for HLA-DR in 11/35 (31%) and non-malignant tumor cells in only 9% (3/34). Therefore, HLA-DR is overexpressed in osteosarcoma (p < 0.05). HLA-DR expression on osteosarcoma cells showed a positive correlation with HLA-DR expression on lymphocytes (p < 0.001) as well as with duration of symptoms and age (p < 0.05). Response to preoperative chemotherapy, gender, tumor size and serum alkaline-phosphatase levels did not correlate with the expression of the molecules tested. Our results show that HLA-DR is overexpressed in osteosarcoma cells compared to non-malignant bone-tumors. This overexpression, however, fails to serve as a predictive marker for response to neoadjuvant chemotherapy. The same is also true for tumor-infiltrating lymphocytes expressing CD3, CD8 and HLA-DR. Increased HLA-DR expression in osteosarcoma is most likely due to the immune response against the tumor.

Adolescent↗
PubMedDate not supplied

Submicroscopic and immunohistochemical profile of surface osteosarcomas.

While the analysis of the clinical, radiologic, and histopathologic features of surface osteosarcomas has been the subject of several papers, identification of the phenotypic features of these tumors has so far received little attention. The aim of the present study was to characterize the neoplastic cells of surface osteosarcomas using an ultrastructural and immunohistochemical approach. Glutaraldehyde-fixed, epoxy resin-embedded archival pieces of tissue from 8 surface osteosarcomas (4 parosteal low-grade osteosarcomas, 3 dedifferentiated parosteal osteosarcomas, 1 periosteal osteosarcoma) were investigated using transmission electron microscopy. Sections of formalin-fixed, paraffin-embedded tumor specimens were employed for the immunohistochemical analysis of osteonectin and osteocalcin, two markers of cells of osteoblastic lineage, and sigma-smooth muscle actin and muscle specific actin. By electron microscopy, the tumors were composed of a mixture of neoplastic cells with varied differentiation, i.e., osteoblast-like, fibroblast-like, myofibroblast-like, and chondroblast-like. The latter were particularly abundant in the periosteal osteosarcoma. Osteocalcin expression was detected in the cytoplasm of neoplastic cells in 6 cases (66.6%), while osteonectin was expressed at least focally in all cases. The expression of the noncollagenous bone proteins was higher in low-grade osteosarcomas than in dedifferentiated osteosarcomas. sigma-Smooth muscle actin and muscle-specific actin expression were detected in 4 (44.4%) and 5 (55.5%) cases respectively, and the distribution was similar in both low-grade and dedifferentiated lesions. The results do not confirm previous observations regarding the prevalence of a specific cellular phenotype in surface osteosarcomas. Further, the myofibroblast-like cells that are present in variable numbers in these tumors are probably modified osteoblasts, since they co-express actin, osteonectin, and osteocalcin.

Actins↗
PubMed2005

Hematogenous micrometastases in osteosarcoma patients.

Bone marrow and peripheral blood samples from 60 patients with suspected bone sarcoma were examined for the presence and number of micrometastatic osteosarcoma cells by a sensitive immunomagnetic detection assay, using in parallel two osteosarcoma-associated antibodies. Forty-nine of the patients had osteosarcoma, and of these, as many as 31 (63%) had tumor cells in bone marrow, in many cases with a high number of cells. Only four (8%) were positive also in blood. None of 38 control bone marrow samples were positive, including 11 from patients with suspected bone sarcoma at time of sampling who later were found not to have osteosarcoma. Fifteen of 28 patients without overt metastases at primary diagnosis (54%) were positive, 12 of whom had localized high-grade primary tumors in the extremity. Four of these have relapsed compared with none of 10 negative patients. In the group of 22 patients with extremity localized nonmetastatic osteosarcoma, information was available on the histologic response to preoperative chemotherapy in 15 patients. None of the three patients in the bone marrow-negative group who had a poor response to chemotherapy have relapsed, whereas two of the four poor responders in the bone marrow-positive cohort are dead of disease. Among 12 patients with overt metastasis at primary diagnosis, 11 (92%) were positive in bone marrow with a very high number of osteosarcoma cells. The immunomagnetically isolated cells were further characterized by the use of fluorescent latex microparticles with surface-bound antibodies targeting different membrane markers. Moreover, in cases with numerous osteosarcoma cells in bone marrow attempts to grow the selected cells in vitro were successful in two of eight attempts, and in two of five cases, isolated cells produced tumors with osteosarcoma characteristics in nude mice. In conclusion, already at primary diagnosis, a very high fraction of osteosarcoma patients had malignant cells in bone marrow, and a correlation between the presence of tumor cells, clinical stage, and disease progression was found. The data show the clinical potential of this immunomagnetic method. Attempts to subgroup osteosarcoma patients for more individualized treatment based on the presence of micrometastatic cells should be studied in a larger cohort of patients.

Adolescent↗