【摘要】：目的：探討肺伴粘液分泌的腺癌臨床病理特征,預(yù)后與ALK重排、KRAS和EGFR基因突變的相關(guān)性。材料和方法：1、選取2002年10月至2014年9月之間經(jīng)根治性手術(shù)切除,病理診斷為肺伴粘液分泌的腺癌(簡稱粘液腺癌)的病例75例進行回顧性分析。按照2011年國際肺癌研究學(xué)會、美國胸科學(xué)會和歐洲呼吸學(xué)會(IASLC/ATS/ERS)公布的肺腺癌國際多學(xué)科分類方法(簡稱新分類)進行重新分類。總結(jié)粘液腺癌的臨床病理特征,并分析臨床病理各因素與預(yù)后和基因突變的關(guān)系。2、EnVision免疫組織化學(xué)方法檢測TTF-1、NapsinA抗體的表達(dá)。使用Benchmark XT自動免疫組化染色儀檢測ALK蛋白D5F3抗體的表達(dá)。采用擴增阻滯突變系統(tǒng)(ARMS法)法檢測EGFR和KRAS基因突變。3、對75例粘液腺癌患者進行電話隨訪。4、運用SPSS(17.0)統(tǒng)計軟件對數(shù)據(jù)進行統(tǒng)計分析。結(jié)果：1、共75例粘液腺癌患者,其中男性36例(48%),女性39例(52%)。按照新分類分為浸潤性粘液腺癌(IMA)24例(32%),腺泡或乳頭為主伴粘液分泌腺癌(A/P)21例(28%),實體為主伴粘液分泌腺癌(SA)20例(26.7%),粘液型微小浸潤性腺癌(m-MIA)6例(8.0%),膠樣癌4例(5.3%)2、 75例粘液腺癌中ALK蛋白總陽性檢出率為33.3%(25/75),較常見于不吸煙、腫瘤位于上葉或中葉、中晚期(Ⅲ-Ⅳ期)、淋巴結(jié)轉(zhuǎn)移陽性患者中,并主要存在于SA和具有特定組織結(jié)構(gòu)如印戒細(xì)胞、篩狀結(jié)構(gòu)和微乳頭狀結(jié)構(gòu)的病例中。KRAS突變率為22.7%(17/75),主要存在于浸潤性粘液腺癌、腫瘤位于下葉和不具有印戒細(xì)胞結(jié)構(gòu)的患者中。而EGFR突變少見,突變率僅為6.7%(5/75)。ALK重排陽性病例中檢測出2例KRAS突變,未檢測到EGFR突變。僅有1例檢測到KRAS與EGFR聯(lián)合突變。3、免疫組化抗體TTF-1、NapsinA在SA中表達(dá)陽性率明顯高于其他亞型,而在IMA中表達(dá)明顯低于其他亞型。但二者表達(dá)與粘液腺癌的預(yù)后無明顯相關(guān)性。4、粘液腺癌1年、3年、5年無進展生存率分別為85%、64%、38%,總生存率分別為90%、67%、50%。較大腫瘤、晚期分期、淋巴結(jié)轉(zhuǎn)移陽性因素與預(yù)后差相關(guān)。KRAS突變是術(shù)后進展的陽性因素。不同亞型粘液腺癌預(yù)后差異有統(tǒng)計學(xué)意義,其中預(yù)后最好者為m-MIA,其他依次為IMA、SA、A/P.結(jié)論：1、不同組織亞型的粘液腺癌具有不同的分子表型,SA和具有印戒細(xì)胞、篩狀結(jié)構(gòu)和微乳頭狀結(jié)構(gòu)的粘液腺癌患者ALK重排陽性率較高；IMA和不具有印戒細(xì)胞結(jié)構(gòu)的患者KRAS突變率高。該結(jié)果為篩選粘液腺癌患者靶向治療提供了形態(tài)學(xué)和分子學(xué)依據(jù)。2、不同組織學(xué)亞型的粘液腺癌臨床病理特征、免疫標(biāo)志物表達(dá)、基因突變率的差別具有統(tǒng)計學(xué)意義,該結(jié)果為粘液腺癌組織亞型的鑒別診斷提供依據(jù).3、粘液腺癌的預(yù)后與腫瘤大小、分期和淋巴結(jié)轉(zhuǎn)移相關(guān),較大腫瘤、晚期分期、淋巴結(jié)轉(zhuǎn)移陽性患者預(yù)后差。KRAS突變是術(shù)后進展的陽性因素。不同亞型粘液腺癌預(yù)后差異有統(tǒng)計學(xué)意義,其中預(yù)后最好者為m-MIA,其他依次為IMA、SA、A/P。4、新分類未將A/P單獨列為一種亞型,A/P單獨列出具有重要臨床意義。
[Abstract]:Objective: To investigate the clinicopathological features and prognosis of lung adenocarcinoma with mucus secretion, and the correlation between ALK rearrangement, KRAS and EGFR gene mutation.Materials and Methods: 1. 75 cases of lung adenocarcinoma with mucus secretion (referred to as mucinous adenocarcinoma) were retrospectively analyzed. According to the International Multidisciplinary Classification of Lung Adenocarcinoma (IASLC/ATS/ERS) published by the International Society for Lung Cancer Research in 2011, the American Thoracic Society and the European Respiratory Society (IASLC/ATS/ERS), the clinical and pathological characteristics of mucinous adenocarcinoma were summarized and the relationship between clinical and pathological factors, prognosis and gene mutation was analyzed. TTF-1 and NapsinA antibodies were detected by chemical methods. The expression of ALK protein D5F3 antibodies was detected by Benchmark XT automatic immunohistochemical staining. EGFR and KRAS gene mutations were detected by amplification blocking mutation system (ARMS method). 75 patients with mucinous adenocarcinoma were followed up by telephone. 4. SPSS (17.0) statistical software was used to analyze the data. Results: 1. There were 75 cases of mucinous adenocarcinoma, 36 males (48%) and 39 females (52%). According to the new classification, there were 24 cases (32%) of invasive mucinous adenocarcinoma (IMA), 21 cases (28%) of acinar or papillary adenocarcinoma with mucinous secretion (A/P), 20 cases (26.7%) of solid adenocarcinoma with mucinous secretion (SA), 6 cases (8.0%) of mucinous minimal invasive adenocarcinoma (m-MIA). The total positive rate of ALK protein was 33.3% (25/75) in 4 cases (5.3%) of gelatinous carcinoma and 75 cases of mucinous adenocarcinoma. KR was more common in non-smoking, upper or middle lobe, middle and advanced stage (stage III-IV), lymph node metastasis, and mainly existed in SA and cases with specific histological structures such as signet ring cells, cribriform and micropapillary structures. The mutation rate of AS was 22.7% (17/75), mainly found in invasive mucinous adenocarcinoma, tumor located in the lower lobe and without signet ring cell structure. EGFR mutation was rare, and the mutation rate was only 6.7% (5/75). Two KRAS mutations were detected in ALK rearrangement positive cases, but no EGFR mutation was detected. Only one case detected KRAS and EGFR combined mutation.3, immunohistochemistry. The positive rates of antibody TTF-1 and NapsinA in SA were significantly higher than those in other subtypes, but the positive rates in IMA were significantly lower than those in other subtypes. However, there was no significant correlation between the expression of TTF-1 and NapsinA and the prognosis of mucinous adenocarcinoma. KRAS mutation is a positive factor for postoperative progression. The prognosis of different subtypes of mucinous adenocarcinoma is statistically significant. The best prognosis is m-MIA. The others are IMA, SA, A/P. Conclusion: 1. Different subtypes of mucinous adenocarcinoma have different molecular phenotypes, SA and signet ring cells, cribriform. The positive rate of ALK rearrangement was higher in mucinous adenocarcinoma patients with structure and micropapillary structure, and KRAS mutation was higher in IMA and non-signet ring cell structure patients. KRAS mutation is a positive factor for the progression of mucinous adenocarcinoma. The prognosis of mucinous adenocarcinoma is related to tumor size, stage and lymph node metastasis. The prognosis of patients with large tumor, advanced stage and positive lymph node metastasis is poor. The prognosis of liquid adenocarcinoma was significantly different. The best prognosis was m-MIA, followed by IMA, SA, A/P.4. The new classification did not classify A/P as a subtype, and A/P was listed separately as an important clinical significance.
【學(xué)位授予單位】：中國人民解放軍醫(yī)學(xué)院
【學(xué)位級別】：博士
【學(xué)位授予年份】：2016
【分類號】：R734.2

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