| Objective: Gastrointestinal stromal tumors(GISTs) is the most common mesenchymal tumors of the gastrointestinal tract. They occur throughout the GI tract but predominantly arise from stomach wall,which represent 39~50% of all GISTs. About 25~37% GISTs occur in the small intestine which made the small intestine the secondary popular site of GISTs. The pathogenesis of GISTs is the gain-of-function mutation of c-kit and platelet derived growth factor alpha (PDGFRA) which cause sustained activity of the signal transduction of the type Ⅲ tyrosine kinase . STI-571 is the competitive inhibitor of ATP and can block the enzymatic activity of KIT and PDGFRA. Patients with metastastic or recurrent GISTs have excellent response to STI-571 especially the one harbored the mutation of c-kit exon 11. People are exploring the use of STI-571 in neoadjuvant, adjuvant clinical trails. But the obscure biological behavior of GISTs' make the outcome of the tumor unpredictable. The predictors for GISTs are become more and more important. The epidemiologic research of GISTs reveals that the incidence and mortality is different between different races and different regions. Such as the Africa-American has the highest incedence and mortality, the incedence of Asian-American is lower than Africa-American but higher than the White, and they have the lowest mortality. Different region shows different incedence. Hawaii is the highest, reaching 1.06/100,000 and Alaska is the lowest, 0. Until now most of the literature about the biolobical behavior of GISTs is English literature, and mainly based on Europeans and American. The native literature about prognostic factors is rare. Our research analysed the influence of 8 basic clinicopathologic factors on patients survival, including gender, age, tumor location, clinic staging, tumor diameter, mitotic index, necrosis and histologicgrade. We also detected the differentiation markers such as smooth muscle actin (SMA), S-100 protein, the tumor suppressor genes such as PTEN and FHIT, and other markers like CD44, MMP-9, TIMPs, and Ki-67. We analysed all the 16 factors statistically by Kaplan-Meier plots and COX proportional hazard model, expecting to find some markers related to the biological behavior of GSITs. We also detected the mutation of c-kit exon 11 and analyzed its relationship with the prognosis of the tumor.Matetials and Methords: 156 cases of gastric and small intestinal GISTs were collected and reviewed from the archives of the Chinese PLA General Hospital during the time period from 1996 to 2003. 105 cases with complete clinical and follow-up information were evaluated to identify valuable prognostic factors. 105 cases of primary tumor tissue and 19 cases of metastatic or recurrent tumors were used in the immunohistochemical study.Envision procedure of immunohistochemistry was applied to detect the expression of CD117, SMA, S-100, PTEN, FHIT, CD44, MMP-9, TIMP-1 and Ki-67 on the formalin-fixed and paraffin-embedded tissue sections.Somatic mutations in exon 11 of c-kit genomic DNA was detected using PCR analysis. PCR was carried out in a mixture of 20 μl, primer annealing at 56℃ . The amplification was performed for 45 cycles. PCR products were separated in 2% agrose gels.The mutation was detected by denaturing high-performance liquid chromatography (DHPLC). Compared with the wild type exon 11, the samples with different wave type were sequenced to confirm the mutation.Results: 156 cases GISTs contained 83 cases of gastric GISTs and 73 cases of small intestinal GISTs. The average age was 53.4 years, male (112 cases ) was predominant over female (44 cases). The average of gastric GISTs was 55.4 years with the range from 13 to 82 years. Male was affected 2.1 folds more than female. 62 cases was fully followed-up. The longest survival time of the patient who died of the tumor was 132 months, the shortest was 6 months. Overall 17 casesdeveloped metastasis or recurrence. The one-year survival rate for patients with gastric GISTs was 78%, the 5-year survival rate was 67.1%. The mean age of patients with small intestinal GISTs was 50.6 years, which affected male 3.3 folds more than female. The oldest patient was 77 years and the youngest was 20. Overall 43 cases had the follow-up data, the longest survival time was 230 months, the shortest was 3 month and 22 cases developed metastasis and recurrence. 1-year survival rate was 72.4%, 5-year survival rate was 50.9%. The GISTs arising from the small intestine was more aggressive than the gastric GISTs (x2= 6.131, P=0.013). Two cases showed good response to the therapy of STI-571 and one case did not response at all during follow up.Statistic analysis found that gastric GISTs patients with age younger than 50 years (P=0.046), large tumor diameter (P=0.000), high mitotic index (P=0.000), necrosis(P=0.000) late clinical stage (P=O.OOO) and high histologic grade (P=0.004) had low survival rate. The COX analysis revealed that large diameter (P=0.000), high mitotic index (P=0.002), late clinical stage (P=0.001) and high histologic grade (P=0.018) were significantly correlate to prognosis, but no independent factors were found. Necrosis (P=0.046) and high clinical stage (P=0.01) was associated with low survival rate of the small intestinal GISTs, in which cinical stage was independent.The expression of SMA (P=0.004), MMP-9 (P=0.042), the loss of CD44 expression (P=0.006), the fraction of PTEN-positive cells lower than 50% (P=0.006) and the Ki-67 index higher than 5% were associated with lower survival rate of gastric GISTs patients. Only Ki-67 index over 15% was the independent prognostic factor. Ki-67 index higher than 5% was associated with lower survival rate of small intestinal GISTs pateints.We successfully amplified 97samples of c-kit exonll and found 16 kinds of wave type different from wild-type c-kit exon 11. 15 kinds of wave types were caused by mutation after DNA sequencing. The accuracy of DHPLC was 93.7%. Overall 24 samples harbored mutations. The hot spot of mutation cluster was in...
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