局部晚期肺鳞癌手术预后因素分析和分子分型初步探讨

发布时间：2018-03-06 03:08

  本文选题：肺鳞状细胞癌　切入点：手术　出处：《天津医科大学》2017年博士论文　论文类型：学位论文

【摘要】：肺癌是目前世界上发病率和死亡率最高的恶性肿瘤。在病理分类中,约30%左右的患者为肺鳞状细胞癌,是第二大肺癌病理亚型,拥有独立的临床病理特点,并且治疗手段有限。目前,手术治疗肺鳞癌效果最佳,然而,临床上过半数的肺鳞癌患者诊断时已属晚期或局部晚期,增加了手术风险和难度,手术治疗局部晚期肺鳞癌目前仍充满争议,还存在许多值得探索和研究的问题。本研究回顾了我科室170例肺鳞状细胞癌病例,包括局部晚期肺鳞癌手术患者病例,总结其临床特点,随访术后病情,治疗,生存时间及去世原因。研究因素包括手术方式,性别、ECOG评分、年龄、肿瘤位置、合并症、吸烟指数、肿瘤直径、T分期、N分期、胸腔积液情况、系统淋巴结清扫/纵膈淋巴结采样、术后切缘是否残留、血管癌栓等临床特点,采用COX模型推断预后因素,用寿命表法计算生存率,用Kaplar-Meire评价中位生存期和总生存期。对此170例肺鳞癌患者血清CEA、NSE、CYFRA21-1,SCC-Ag数据,并与临床资料相结合,分析其与临床分期,诊疗和预后的关系。最后,本研究探索性的利用二代测序技术,精选肺癌相关56个靶基因,对临床特征和预后因素相似,但生存期有明显差异的两组(A组:生存期大于3年;B组:生存期小于1年)局部晚期肺鳞癌患者进行深度测序,探索不同驱动基因特点与其术后生存期的关系,探讨分子分型用于指导局部晚期肺鳞状细胞癌手术治疗的可能。同时对突变率较高的TP53基因进行meta分析,探讨TP53基因突变与肺鳞状细胞生存期间的关系。结果显示,患者总的1年生存率为78.2%,中位生存期约为62个月,5年生存期为15.3%。在单因素分析结果中,ECOG-PS(P=0.000)、T分期(P=0.000)、N分期(P=0.000)、手术切除方式(P=0.001)、淋巴清扫方式(P=0.001)、切缘残留情况(P=0.001)、有无血管癌栓(P=0.012)和胸腔积液(P=0.003)是影响预后的重要因素且具有统计学意义。应用Cox回归模型,分析预后相关因素,结果显示吸烟指数(P=0.002)、ECOG-PS(P=0.000)、T分期(P=0.005)以及N分期(P=0.000)是影响预后的独立因素。同时,治疗前肺鳞癌患者肺肿瘤标志物表达情况如下:CEA表达浓度3.06(0.57,486.42)ng/ml,阳性率22.9%,在不同T、N分期中均无显著差异;NSE表达浓度15.03(0.83,86.94)ng/L,阳性率44.7%,其表达水平不同T分期组间有差异,相关系数0.214;CYFRA21-1表达浓度3.76(0.32,57.46)ng/ml,阳性率57.6%,阳性率最高。其表达水平不同T分期组间对比存有差异,相关系数0.206。SCC-Ag浓度0.90(0.10,89)ng/L,阳性率30%,表达水平不同N分期组间对比有明显差异,相关系数0.020。最后,两组生存期差异患者二代测序结果显示,不同组织中共有21例(87.5%)样本检测出不同类型的变异。12例(50%)存在PI3K/AKT通路突变;7例(29.1%)存在ERBB家族突变;3例(12.5%)存在CDKN2A/RB1通路突变;6例(25.0%)存在NOTCH1突变;3例(12.5%)存在JAK家族突变。与正常组织对比筛选出肿瘤组织驱动基因的突变,其中A组突变基因较多的NOTCH1(N=3),其次为EGFR(N=2),除此之外检测到TP53、JAK2、ERBB4、MET突变(N=1);B组突变较多的基因分别为TP53、CCND1(N=4),其次为FGF3(N=3),NOTCH1、AKT1、PIK3CA(N=2),MET(N=1)。而对TP53进行meta分析结果显示:总共纳入了9篇文献研究肺鳞癌患者中TP53基因突变率。其合并后的RR值为0.69(95%CI,0.54-0.87),P=0.002。总共有6篇文章分析了肺鳞癌患者TP53基因突变引起的总生存率变化。其合并后的HR值为1.28(95%CI,1.07-1.53),P=0.006。这俩个分析结果说明,在鳞癌患者中,野生型TP53基因占多数,但是与野生型TP53基因相对,突变型TP53基因的生存率HR值接近1,俩者差异不明显,但具有统计学意义。上述结果提示肺鳞癌手术治疗患者的中位生存期约为62个月,1年生存率为78.2%,5年生存期为15.3%。而吸烟指数、ECOG-PS、T分期以及N分期是影响预后的独立因素。术前检验肺肿瘤标志物有明确的临床意义,然而,CEA的对于肺鳞癌的临床指导意义较弱,CYFRA21-1,NSE,SCC-Ag对肺鳞状细胞癌临床意义更为明显。在临床工作中CEA阳性患者应更多考虑诊断非鳞状细胞癌或混合型肿瘤。TP53单独作为指导肺鳞癌预后的分子标志物仍有待更大样本的研究,但TP53错义突变,特别是与NOTCH1错义突变共同存在时或者存在CCND1、FGF3、PIK3CA基因扩增,都可能提示肺鳞癌手术预后不佳。如果术前通过穿刺、气管镜、血检等方式检测到上述基因突变,此类肺鳞癌患者,特别是局部晚期肺鳞癌患者手术治疗需谨慎。这些指标有望通过后续扩大样本的研究成为指导肺鳞癌手术的预后指标。同时,对肺鳞癌患者,仍有EGFR突变可能,在条件允许的情况下可行EGFR基因检测,争取EGFR-TKI治疗的机会。
[Abstract]:Lung cancer is currently the world's highest morbidity and mortality of malignant tumors. In pathological classification, about 30% of the patients with lung squamous cell carcinoma, second lung cancer pathological subtypes, clinical and pathological features of independent, and treatment is limited. At present, surgical treatment of lung squamous carcinoma is best, however, lung squamous cell carcinoma more than half of the patients with clinical diagnosis of locally advanced or late stage, increase the operation risk and the difficulty of surgical treatment of locally advanced squamous cell carcinoma of the lung is still controversial, there are still many problems that are worth exploring and studying. This study reviews our department 170 cases of lung squamous cell carcinoma patients, including patients with locally advanced squamous cell carcinoma of the lung surgery cases, summarized the clinical characteristics, postoperative illness, treatment, survival time and death reason. Study on factors including surgery, ECOG score, age, gender, tumor location, comorbidities, smoking index, swollen The diameter of tumor, T staging, N staging, pleural effusion, lymph node dissection / mediastinal lymph node sampling, postoperative residual margin, clinical features of vascular cancer embolus, using factor COX model to infer the prognosis, the survival rate was calculated by life table method, using Kaplar-Meire to evaluate median survival and overall survival this period. 170 cases of squamous cell carcinoma patients with serum CEA, NSE, CYFRA21-1, SCC-Ag data, and combined with clinical data, analyze its relationship with clinical stage, treatment and prognosis. Finally, this study explores the use of the two generation sequencing technology, selection of lung cancer related 56 genes, factors of clinical characteristics and prognosis similar, but the survival of two group was significantly difference (A group: the survival of more than 3 years; group B: the survival of less than 1 years) in patients with locally advanced squamous cell carcinoma of the lung by deep sequencing, explore relationship of different driving characteristics and gene survival after surgery, and to investigate the molecular typing for guidance Surgical treatment of locally advanced squamous cell carcinoma of the lung may. At the same time, the mutation rate of TP53 gene was higher in meta analysis, to explore the relationship between TP53 gene mutation and survival of lung squamous cell. The results showed that the patients overall 1 year survival rate was 78.2%, the median survival period of about 62 months, 5 years survival was 15.3%. in the univariate analysis, ECOG-PS (P=0.000), T stage (P=0.000), N stage (P=0.000), surgical lymph node dissection (P=0.001), (P=0.001), way of residual margin (P=0.001), there is no vascular tumor thrombus (P=0.012) and pleural effusion (P=0.003) is an important influence prognostic factors and have statistical significance. By Cox regression analysis of prognostic factors, results showed that smoking index (P=0.002), ECOG-PS (P=0.000), T stage (P=0.005) and N stage (P=0.000) were independent factors affecting the prognosis. At the same time, before the treatment of lung squamous cell carcinoma patients with lung tumor markers The expression is as follows: the expression of CEA was 3.06 (0.57486.42) ng/ml, the positive rate was 22.9%, in different T stages of N were no significant differences; the expression of NSE was 15.03 (0.83,86.94) ng/L, the positive rate was 44.7%, the expression level of different T groups are different, the correlation coefficient is 0.214; the expression of CYFRA21-1 was 3.76 (0.32,57.46 ng/ml), the positive rate was 57.6%, the highest positive rate. The expression level of T between the groups of different stages are different, the correlation coefficient 0.206.SCC-Ag was 0.90 (0.10,89) ng/L, the positive rate was 30%, the expression level of N between the groups of different stages have obvious difference, the correlation coefficient 0.020., finally, two groups of survival between patients with two generation sequencing the results showed that different tissues were found in 21 cases (87.5%) samples to detect mutation in.12 patients with different types of (50%) PI3K/AKT pathway mutations; 7 cases (29.1%) of the ERBB family mutation; 3 cases (12.5%) CDKN2A/RB1 pathway mutations; 6 cases (25%) NOTC H1绐佸彉;3渚，

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