本文選題：肺鱗狀細(xì)胞癌　切入點(diǎn)：手術(shù)　出處：《天津醫(yī)科大學(xué)》2017年博士論文　論文類型：學(xué)位論文

【摘要】：肺癌是目前世界上發(fā)病率和死亡率最高的惡性腫瘤。在病理分類中,約30%左右的患者為肺鱗狀細(xì)胞癌,是第二大肺癌病理亞型,擁有獨(dú)立的臨床病理特點(diǎn),并且治療手段有限。目前,手術(shù)治療肺鱗癌效果最佳,然而,臨床上過(guò)半數(shù)的肺鱗癌患者診斷時(shí)已屬晚期或局部晚期,增加了手術(shù)風(fēng)險(xiǎn)和難度,手術(shù)治療局部晚期肺鱗癌目前仍充滿爭(zhēng)議,還存在許多值得探索和研究的問(wèn)題。本研究回顧了我科室170例肺鱗狀細(xì)胞癌病例,包括局部晚期肺鱗癌手術(shù)患者病例,總結(jié)其臨床特點(diǎn),隨訪術(shù)后病情,治療,生存時(shí)間及去世原因。研究因素包括手術(shù)方式,性別、ECOG評(píng)分、年齡、腫瘤位置、合并癥、吸煙指數(shù)、腫瘤直徑、T分期、N分期、胸腔積液情況、系統(tǒng)淋巴結(jié)清掃/縱膈淋巴結(jié)采樣、術(shù)后切緣是否殘留、血管癌栓等臨床特點(diǎn),采用COX模型推斷預(yù)后因素,用壽命表法計(jì)算生存率,用Kaplar-Meire評(píng)價(jià)中位生存期和總生存期。對(duì)此170例肺鱗癌患者血清CEA、NSE、CYFRA21-1,SCC-Ag數(shù)據(jù),并與臨床資料相結(jié)合,分析其與臨床分期,診療和預(yù)后的關(guān)系。最后,本研究探索性的利用二代測(cè)序技術(shù),精選肺癌相關(guān)56個(gè)靶基因,對(duì)臨床特征和預(yù)后因素相似,但生存期有明顯差異的兩組(A組:生存期大于3年;B組:生存期小于1年)局部晚期肺鱗癌患者進(jìn)行深度測(cè)序,探索不同驅(qū)動(dòng)基因特點(diǎn)與其術(shù)后生存期的關(guān)系,探討分子分型用于指導(dǎo)局部晚期肺鱗狀細(xì)胞癌手術(shù)治療的可能。同時(shí)對(duì)突變率較高的TP53基因進(jìn)行meta分析,探討TP53基因突變與肺鱗狀細(xì)胞生存期間的關(guān)系。結(jié)果顯示,患者總的1年生存率為78.2%,中位生存期約為62個(gè)月,5年生存期為15.3%。在單因素分析結(jié)果中,ECOG-PS(P=0.000)、T分期(P=0.000)、N分期(P=0.000)、手術(shù)切除方式(P=0.001)、淋巴清掃方式(P=0.001)、切緣殘留情況(P=0.001)、有無(wú)血管癌栓(P=0.012)和胸腔積液(P=0.003)是影響預(yù)后的重要因素且具有統(tǒng)計(jì)學(xué)意義。應(yīng)用Cox回歸模型,分析預(yù)后相關(guān)因素,結(jié)果顯示吸煙指數(shù)(P=0.002)、ECOG-PS(P=0.000)、T分期(P=0.005)以及N分期(P=0.000)是影響預(yù)后的獨(dú)立因素。同時(shí),治療前肺鱗癌患者肺腫瘤標(biāo)志物表達(dá)情況如下:CEA表達(dá)濃度3.06(0.57,486.42)ng/ml,陽(yáng)性率22.9%,在不同T、N分期中均無(wú)顯著差異;NSE表達(dá)濃度15.03(0.83,86.94)ng/L,陽(yáng)性率44.7%,其表達(dá)水平不同T分期組間有差異,相關(guān)系數(shù)0.214;CYFRA21-1表達(dá)濃度3.76(0.32,57.46)ng/ml,陽(yáng)性率57.6%,陽(yáng)性率最高。其表達(dá)水平不同T分期組間對(duì)比存有差異,相關(guān)系數(shù)0.206。SCC-Ag濃度0.90(0.10,89)ng/L,陽(yáng)性率30%,表達(dá)水平不同N分期組間對(duì)比有明顯差異,相關(guān)系數(shù)0.020。最后,兩組生存期差異患者二代測(cè)序結(jié)果顯示,不同組織中共有21例(87.5%)樣本檢測(cè)出不同類型的變異。12例(50%)存在PI3K/AKT通路突變;7例(29.1%)存在ERBB家族突變;3例(12.5%)存在CDKN2A/RB1通路突變;6例(25.0%)存在NOTCH1突變;3例(12.5%)存在JAK家族突變。與正常組織對(duì)比篩選出腫瘤組織驅(qū)動(dòng)基因的突變,其中A組突變基因較多的NOTCH1(N=3),其次為EGFR(N=2),除此之外檢測(cè)到TP53、JAK2、ERBB4、MET突變(N=1);B組突變較多的基因分別為T(mén)P53、CCND1(N=4),其次為FGF3(N=3),NOTCH1、AKT1、PIK3CA(N=2),MET(N=1)。而對(duì)TP53進(jìn)行meta分析結(jié)果顯示:總共納入了9篇文獻(xiàn)研究肺鱗癌患者中TP53基因突變率。其合并后的RR值為0.69(95%CI,0.54-0.87),P=0.002�？偣灿�6篇文章分析了肺鱗癌患者TP53基因突變引起的總生存率變化。其合并后的HR值為1.28(95%CI,1.07-1.53),P=0.006。這倆個(gè)分析結(jié)果說(shuō)明,在鱗癌患者中,野生型TP53基因占多數(shù),但是與野生型TP53基因相對(duì),突變型TP53基因的生存率HR值接近1,倆者差異不明顯,但具有統(tǒng)計(jì)學(xué)意義。上述結(jié)果提示肺鱗癌手術(shù)治療患者的中位生存期約為62個(gè)月,1年生存率為78.2%,5年生存期為15.3%。而吸煙指數(shù)、ECOG-PS、T分期以及N分期是影響預(yù)后的獨(dú)立因素。術(shù)前檢驗(yàn)肺腫瘤標(biāo)志物有明確的臨床意義,然而,CEA的對(duì)于肺鱗癌的臨床指導(dǎo)意義較弱,CYFRA21-1,NSE,SCC-Ag對(duì)肺鱗狀細(xì)胞癌臨床意義更為明顯。在臨床工作中CEA陽(yáng)性患者應(yīng)更多考慮診斷非鱗狀細(xì)胞癌或混合型腫瘤。TP53單獨(dú)作為指導(dǎo)肺鱗癌預(yù)后的分子標(biāo)志物仍有待更大樣本的研究,但TP53錯(cuò)義突變,特別是與NOTCH1錯(cuò)義突變共同存在時(shí)或者存在CCND1、FGF3、PIK3CA基因擴(kuò)增,都可能提示肺鱗癌手術(shù)預(yù)后不佳。如果術(shù)前通過(guò)穿刺、氣管鏡、血檢等方式檢測(cè)到上述基因突變,此類肺鱗癌患者,特別是局部晚期肺鱗癌患者手術(shù)治療需謹(jǐn)慎。這些指標(biāo)有望通過(guò)后續(xù)擴(kuò)大樣本的研究成為指導(dǎo)肺鱗癌手術(shù)的預(yù)后指標(biāo)。同時(shí),對(duì)肺鱗癌患者,仍有EGFR突變可能,在條件允許的情況下可行EGFR基因檢測(cè),爭(zhēng)取EGFR-TKI治療的機(jī)會(huì)。
[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紿佸彉;3渚，

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