【作者】 张华；

【导师】 王洲； 刘相燕；

【作者基本信息】 山东大学 ， 外科学， 2011， 硕士

【摘要】 背景与目的：胸腺上皮肿瘤(thymic epithelial tumors, TET)起源于胸腺上皮,是成人最常见的前纵隔肿瘤,临床上通常依据Masaoka分期及WHO组织学分型判定其良、恶性,但是有时缺乏敏感性,故探索识别良、恶性肿瘤的生物学标志有重要的临床意义。现在越来越多的证据表明JAK激酶/信号传导与转录激活因子(Janus protein tyrosine kinases/Signal transducers and activators of transcription, JAKs/STATs)在多种肿瘤的发生、发展中起着十分关键的作用。本研究通过检测分析胸腺上皮肿瘤中STAT3的表达情况,探索其表达与胸腺上皮肿瘤良、恶之间的关系及病人预后的相关性。方法：应用免疫组化法检测80例胸腺上皮肿瘤组织中STAT3蛋白的表达情况：STAT3蛋白染色结果以细胞质中出现棕黄色颗粒为阳性显色,按阳性细胞比例评定阳性表达。随机选取10个高倍视野(×400),每个视野计数100个癌细胞,计算阳性细胞百分比：切片中0～10%细胞染色棕黄色者判定为阴性(一),10%以上细胞染色为棕黄色者判定为阳性(+)。统计分析采用SPSS17.0,计数资料相关分析通过χ2检验,采用Kaplan-Meier法进行生存分析；用Log-rank检验判断生存差异性；用Cox回归多因素分析进行多因素分析判定独立预后危险因素。P<0.05表示差异有统计学意义。结果：(1)STAT3蛋白阳性表达与Masaoka分期(P<0.05)、WHO组织学分型(P<0.05)相关,未发现阳性表达与患者年龄、性别、肿瘤大小有相关性；(2) STAT3蛋白阳性表达与阴性表达者术后5年内发生复发／转移分别为12例(35.3%)与2例(4.3%),经检验存在显著性差异(P<0.05); (3) STAT3蛋白阳性表达者的5年生存率(61.1%)显著低于阴性表达者(97.7%)(P<0.01)；在MasaokaⅢ期、Ⅳ期及WHO B3、C型中STAT3蛋白阳性表达者的5年生存率(35%、35%)显著低于阴性表达者(92.31%、91.67%)(P<0.01)；(4)Cox回归多因素分析结果显示,STAT3蛋白阳性表达是胸腺上皮肿瘤独立的预后因素(HR=9.325,P=0.044)。结论：本研究应用免疫组化法检测80例TET组织和20例瘤旁正常组织中STAT3蛋白的表达情况,结果TET组织中阳性表达36例(45%),与瘤旁正常组织(5%)比较有显著性差异(P<0.05),提示STAT3蛋白可能在TET的发生发展过程中发挥作用,其可能成为诊断TET的一种分子生物学指标。统计表明STAT3蛋白表达与Masaoka分期(χ2=13.742,P<0.05)及WHO组织学分型(χ2=8.623,P<0.05)有明显相关性,STAT3蛋白阳性表达率随TET恶性程度的增高而增加,提示STAT3的过度表达可能促使胸腺肿瘤细胞的增殖、分化,并抑制其凋亡,其过度激活可能促进肿瘤细胞的形成及发展。统计显示STAT3蛋白阳性表达与患者的性别、年龄、肿瘤大小等因素无明显相关性。本组80例TET患者总的5年生存率为81.3%,STAT3蛋白阳性表达患者的5年生存率(61.1%)显著低于阴性表达者(97.7%)。术后随访结果显示,STAT3蛋白阳性表达者复发/转移率(35.5%)显著高于阴性表达者(4.3%),两者比较差异存在显著性(P<0.05),表明STAT3是判断术后复发／转移的重要指标。综上所述,STAT3是TET预后的重要指标：STAT3表达阳性者预后差,表达阴性者预后较好,其对判断复发／转移有良好的预测价值,可以作为胸腺上皮肿瘤患者的独立预后指标更多还原

【Abstract】 Background& Objective:The thymic epithelial tumors(TET) originates from the thymic epidermis and is the most common mediastinum frontalis tumor in adult.we usually judge its nuture by Masaoka stage and WHO histologic subtype,but this way lacks sensibility for TET sometimes.So it is significant to explore a new biology marker which can discern the tumor nature-optimum or malignant.Nowdays more and more evidence indicates Janus protein tyrosine kinases/Signal transducers and activators of transcription(AKs/STATs) plays a very important role in arising and developing of many tumors.This study investigates the relationship between STAT3 protein expression and recurrence/metastasis and prognosis by immunohistochemical streptavidin peroxidase (SP) methods in 80 cases of thymic epithelial tumors. Methods:The expression of STAT3 protein in TET was detected in 80 cases of TET and 20 cases of paracarcinous normal thymic tissues by immunohistochemical streptavidin peroxidase (SP) methods.Methods:All 60 stageⅠNSCLC tissues and 30 paracarcinous normal lung tissues were obtained from the patients who underwent radical resection and lymph nodes in Provincial Hospital Affiliated to Shandong University. All the 90 specimens were examined by immuno-histochemistry to detect the expression of MTA1 protein. All statistic analyses were performed with SPSS 13.0 statistical software. According to the clinicopathologic factors, the difference of MTA1 protein expression was compared by X2 test. Kaplan-Meier method was performed to calculate the survival rate. Log-rank test was performed to compare the survival difference between the patients with and without MTA1 protein positive expression. Cox regression multivariate analysis was performed to determine independent prognostic factors.Results:(1)The positive expression of STAT3 protein was significantly associated with Masaoka stage (P< 0.05), WHO histologic subtype (P<0.05) while was unrelated with the age, sex, tumor diameter;(2)The recurrence/metastasis Postoperative follow-up observed the rate of recurrence/metastasis in TET patients with STAT3 protein positive expression(35.5%) was significantly higher than those negative expression(4.3%);(3)The 5-year survival rate in patients with positive STAT3 protein expression (61.1%) was significantly lower than that in patients with negative expression (97.7%); (4) The results of Cox multivariate regression analysis indicates STAT3 protein expression was an independent prognostic factor in TET (HR=15.265, P=0.013).Conclusions:The expression of STAT3 protein in TET was detected in 80 cases of TET and 20 cases of paracarcinous normal thymic tissues by immunohistochemical streptavidin peroxidase (SP) methods. There was a significant difference (P<0.05) with the positive expression between tumor tissues(45%) and paracarcinous normal thymic tissues (5%).This indicated the STAT3 protein play a role in the development process, which may be a diagnostic molecular markers of TET. Statistics show that STAT3 protein expression and Masaoka stage(X2=13.742, P<0.05) and WHO histological type (X2=8.623, P<0.05) correlated significantly, STAT3 protein expression rate increased with the malignant degree of TET increased, Suggesting that overexpression of STAT3 may promote thymic tumor cell proliferation, differentiation, and inhibition of apoptosis, and its excessive activation may promote tumor cell formation and development. Statistics show that there is no significant correlation between STAT3 protein expression and sex, age and tumor size.80 patients with TET in this group overall 5-year survival rate was 81.3%, STAT3 protein expression in patients with 5-year survival (61.1%) was significantly lower than the negative expression (97.7%). Postoperative follow-up results, STAT3 protein expression of recurrence/metastasis rate (35.5%) was significantly higher than negative expression (4.3%) and the difference was significant (P<0.05), so we considert STAT3 is the important indicator to determine recurrence/transfer of.tumor. In conclusion, STAT3 is an important prognostic indicator for TET:the positive expression was associated with poor outcome and the negative expression indicated well outcome.So STAT3 has good predictive value as an independent prognostic indicator to determine its recurrence/metastasis in patients with thymic epithelial tumors.更多还原