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|Title:||Avaliação imuno-histoquímica da expressão das proteínas p53, Bcl-2, Bcl-x e caspase-3 clivada em neurofibromas e tumores malignos da bainha do nervo periférico: correlação clínico-patológica|
|Keywords:||Tumores malignos da bainha do nervo periférico; Neurofibromas; Neurofibromatose Tipo 1; Proteína p53; Proteína Bcl-2; Proteína Bcl-x; Caspase-3 clivada; imunohistoquímica; Neurofibroma; Malignant peripheral nerve sheath tumor; apoptosis; p53 protein; Bcl-2 protein; Bcl-x protein; Cleaved caspase-3; Immunohistochemistry|
|Abstract:||Malignant peripheral nerve sheath tumors are rare and highly aggressive neoplasms. Neurofibromatosis type 1, a syndrome caused by mutations in the NF1 gene, is the major risk factor for the development of these tumors. Malignant peripheral nerve sheath tumors may appear de novo or may develop from the transformation of a benign neural neoplasm, mainly from a plexiform neurofibroma, which occurs almost exclusively in Neurofibromatosis type 1 patients. Nowadays, the knowledge of the factors involved in the oncogenesis of malignant peripheral nerve sheath tumors is still modest. It is believed that the loss of heterozygosity of NF1 gene is sufficient for the development of neurofibromas, but studies have been demonstrated that the pathogenesis of malignant peripheral nerve sheath tumors is a multistage process, involving many molecular alterations in addition to biallelic inactivation of NF1 gene. Many authors have been evaluated alterations in cell proliferation control genes, but the knowledge of apoptosis alterations in these tumors is still scarce. With the aim to evaluate the expression of apoptosis-associated proteins in malignant peripheral nerve sheath tumors, the immunoreactivity of p53, Bcl-2, Bcl-x and cleaved caspase-3 proteins was investigated in 28 malignant peripheral nerve sheath tumors, using tissue microarray, and compared with their immunoreactivity in 38 neurofibromas. The correlation of the expression of these proteins with clinicopathological features and prognosis of malignant peripheral nerve sheath tumors was also investigated. P53, Bcl-2, Bcl-x and cleaved caspase-3 proteins were expressed in 64,3%, 78,6%, 75,0% and 100% of malignant peripheral nerve sheath tumors, respectively, and in 2,6%, 32,4%, 43,2% and 100% of neurofibromas, respectively. Comparing the immunopositive cases, malignant perihperal nerve sheath tumores showed higher positivity indexes for Bcl-2, Bcl-x and cleaved caspase-3 than neurofibromas. In neurofibromas, cleaved caspase-3 expression was only observed in the nucleus of the cells, whereas 50% of malignant peripheral nerve sheath tumors showed nuclear expression and the other 50% expressed cleaved caspase-3 in the nucleus and in the cytoplasm of the cells. There was a correlation between the cytoplasmatic expression of cleaved caspase-3 and the high histological grade, high mitotic index and necrosis. In multivariate Cox analysis, necrosis was an independent predictor factor for lower overall survival and high positivity index for cleaved caspase-3 was an independent risk factor for worse disease-free survival. Our results suggest that alterations of p53, Bcl-2, Bcl-x and cleaved caspase-3 expression are possibly associated to the development of malignant peripheral nerve sheath tumors|
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