Extragastrointestinal stromal tumor (EGIST) is a unique tumor that occurs outside the gastrointestinal tract. EGIST shows a c-kit expression and histologic appearance similar to those of gastrointestinal stromal tumor (GIST). Most GISTs have gain-of-functional mutation of the c-kit gene, and some have mutation of the platelet-derived growth factor receptor-alpha (PDGFRA) gene. However, the frequency of mutation of those genes in EGISTs remains unclear. We examined the clinicopathologic features, prognostic factors, and c-kit and PDGFRA mutation in 39 cases of EGIST. Tumors with high mitotic counts (>or=5/50 high power fields) or a high Ki-67 labeling index (>or=10%) were significantly correlated with worse prognoses. The c-kit mutation was found in the juxtamembrane domain (exon 11) and the extracellular domain (exon 9) in 12 of 29 cases (41.4%) and 2 of 29 cases (6.9%), respectively. The PDGFRA gene mutation was found at the juxtamembrane domain (exon 12) and the tyrosine kinase domain (exon 18) in one case each. The pattern of kit and PDGFRA mutation in EGIST was essentially similar to that in GIST. Our results suggest that the c-kit and PDGFRA mutations play an important role in the tumorigenesis of EGIST. High mitotic counts and a high Ki-67 labeling index may be useful for predicting the aggressive biologic behavior in EGIST. Furthermore, STI-571, targeting c-kit and PDGFR tyrosine kinase, seems to be a possible therapeutic strategy for EGISTs, especially advanced cases.
The chemokine, CXCL12, and its receptor, CXCR4, have recently been shown to play an important role in metastasis of several kinds of carcinoma. It has also been demonstrated that VEGF regulates both the expression of CXCR4 and invasiveness in breast cancer cell lines. We compared the immunohistochemical expression of CXCR4 and VEGF between the primary site and a concordant pulmonary metastatic site in 30 osteosarcoma patients, all of which had undergone thoracotomy. Microvessel density (MVD) as shown by immunostaining of CD34 and proliferative activity with MIB-1 monoclonal antibody was also evaluated. CXCR4 expression (primary, 33.3% positive vs metastatic, 66.6% positive; P ¼ 0.0097) and MVD (primary, 29.8676 ; P ¼ 0.0015) in the metastatic site were both significantly increased compared with those in the primary site, whereas no difference between primary and metastatic sites was observed with regard to VEGF expression. There was a significant positive correlation between immunohistochemical CXCR4 and VEGF expression (P ¼ 0.0269). In total population, the MIB-1-labeling index (LI) was significantly higher in tumors, which showed immunoreactivity for VEGF (MIB-1-LI in VEGF-positive tumors, 24.2975.4 vs VEGF-negative tumors, 18.3374.16; P ¼ 0.034). Furthermore, those patients with VEGFpositive primary tumors had a significantly worse prognosis compared with the patients with VEGF-negative primary tumors (P ¼ 0.0053). Our results suggested that CXCR4 expression was associated with metastatic progression, and immunohistochemical VEGF expression in the primary site had predictive value for the osteosarcoma patients, who developed lung metastasis. It has been demonstrated that certain chemokines can serve as tissue-specific attractant molecules for tumor cells, promoting tumor cell migration to particular sites in vivo. Among chemokines and their receptors, the stromal cell-derived factor-1 (SDF-1/CXCL12)/CXCR4 system has been demonstrated to be involved in the lymph node metastasis or distant metastasis of several types of cancer. [1][2][3][4][5][6][7][8][9][10][11][12] Osteosarcoma is the most frequent primary bone tumor in young adults and adolescents. Despite recent advances in multimodality treatments consisting of adjuvant chemotherapy and surgical-wide resection, pulmonary metastasis occurs in approximately 40-50% of the patients. 13 In such cases, the overall 5-year survival rate is only 28%, despite the multidisciplinary therapy.14 Involvement of the CXCR4/SDF-1 pathway in the metastatic process in the lung has also been demonstrated in osteosarcoma cell lines.
15Immunohistochemical VEGF expression in the untreated primary site has been reported to be correlated with pulmonary metastasis and microvessel density (MVD) in osteosarcoma.16 Wang
This study addresses the immunohistochemical expression of the E-cadherin and catenin families and mutations of the beta-catenin gene detected by PCR-SSCP in synovial sarcoma. Immunohistochemical analysis was performed for 72 cases, with follow-up data available on 62. The prognostic value of the expression of these proteins was evaluated. Reduced immunoreactivity for E-cadherin and alpha-catenin was significantly correlated with a poor survival rate (p=0.0040 and 0.0053, respectively). According to multivariate analysis, low AJC stage (stages I and II: p<0.0001), the preservation of alpha-catenin expression (p=0.0001), and a low necrotic rate (<50%: p=0.0139) were independent favourable prognostic factors. Widespread aberrant staining of beta-catenin protein within cytoplasm and/or nuclei was observed in 28 cases (38.9%) and was significantly correlated with poor survival (p=0.0122). In addition, there was a trend towards a correlation between widespread aberrant staining of beta-catenin and the MIB-1 labelling index (p=0.0535). Mutational analysis of exon 3 of the beta-catenin gene was performed for 49 cases. Nucleotide sequencing analysis revealed that four (8.2%) contained point mutations (three in codon 32, GAC to TAC; one in codon 37, TCT to TTT). Survival data were available for three out of four cases with beta-catenin mutations; two of these patients died within 1 year (died of disease at 6 and 11 months, respectively). These results suggest that E-cadherin and alpha-catenin undertake important roles as intercellular adhesion molecules; their preserved expression is associated with a better overall survival rate in synovial sarcoma and may have prognostic value. Abnormal levels of beta-catenin, with or without mutation, could contribute to the development and progression of synovial sarcoma, through increasing the proliferative activity of the tumour cells.
The immunohistochemical expression of beta-catenin, cyclin D1, Ki-67 and PCNA was Examined in 38 cases of sporadic extra-abdominal or abdominal-wall desmoid tumours without familial adenomatous polyposis (FAP), to evaluate the hypothesis that the accumulated beta-catenin within the nuclei could affect the regulation of the cyclin D1 gene. There was a statistically significant correlation between beta-catenin accumulation and cyclin D1 overexpression (p=0.029). Each group with beta-catenin accumulation or cyclin D1 overexpression showed a higher PCNA-LI than those without, the difference being statistically significant (p=0.007, p=0.004, respectively). Differential PCR was also performed to detect amplification of the cyclin D1 gene and mutational analysis was undertaken for exon 3 of the beta-catenin gene. Amplification of the cyclin D1 gene was observed in 13 out of 22 cases (59.1%). There were nine-point mutations in 7 out of 18 cases (38.9%). The distribution of beta-catenin mutation fell within a wide range, from codon 21 to codon 67. In conclusion, beta-catenin nuclear expression correlated with cyclin D1 overexpression in sporadic desmoid tumours, which could be an in vivo model system for the APC-beta-catenin-Tcf pathway. In addition, beta-catenin mutations in desmoid tumours occurred at an unusually wide range of sites within the gene.
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