Lung adenocarcinomas in situ (AISs) often occur in individuals who have never smoked, although smoking is one of the main causes of lung cancer. To characterize AIS and, in particular, determine how AIS might be related to smoking, we collected a large number of AIS cases and examined clinicopathologic features, EGFR and KRAS mutation status, and activation status of receptor tyrosine kinase downstream signal pathways, including pAkt, pERK, and pStat3, using immunohistochemistry. We identified 110 AISs (36 smokers and 74 nonsmokers) among 1549 adenocarcinomas resected surgically during 1995 to 2010. Between the AIS of smokers and nonsmokers, only the sex ratio was significantly different; all the other clinicopathologic factors including TTF-1 and driver mutations were not significantly different: EGFR and KRAS mutation rates (smokers:nonsmokers) were 61:58 (%) (P=0.7) and 6.1:1.4 (%) (P=0.2), respectively, whereas, in invasive adenocarcinomas, the rates were 41:69 (%) (P<0.001) and 9.4:2.3 (%) (P<0.04), respectively. For pAkt and pERK, around 40% to 50% of AISs were positive, and for pStat3, >80% were positive, with no significant differences between smokers and nonsmokers with AIS. Mucinous AIS (n=8) rarely harbored KRAS mutations and expressed significantly less pStat3 (P<0.001) than nonmucinous AIS. Taken together, AIS occurs predominantly in female individuals and nonsmokers. However, characteristics of AIS arising in smokers and nonsmokers were similar in terms of cell lineage, driver mutations, and receptor tyrosine kinase pathway activation. Our results suggest that smoking is not a major cause of AIS. Rather, smoking may play a role in progression of AIS to invasive adenocarcinoma with AIS features.
虽然吸烟是肺癌的主要病因之一，肺原位腺癌（AISs）常常发生于从不吸烟的人群。为了研究AIS特点，尤其是明确AIS与吸烟的相关性，我们收集了大样本的AIS病例，观察其临床病理特征，检测其EGFR和KRAS突变状态，并用免疫组化方法研究pAkt、pERK、pSTAT3等受体酪氨酸激酶信号通路的下游因子激活状态。我们从1995年到2010年1549肺腺癌手术切除标本中确定了110例AIS（36吸烟者和74名不吸烟者）。AIS吸烟者和非吸烟者相比，只有性别比例有显著差异；其他临床病理特征，包括TTF-1表达和驱动基因突变都没有显著差异性：EGFR和KRAS突变率（吸烟者：非吸烟者）分别为61:58（%）（P = 0.7）和6.1:1.4（%）（P = 0.2）；在浸润性腺癌，EGFR和KRAS突变率（吸烟者：非吸烟者）分别是41:69（%）（P＜0.001）和9.4:2.3（%）（P＜0.04）。约40%到50%AIS阳性表达pAkt和pERK，PSTAT3阳性率＞80%，吸烟者和非吸烟者之间的差异无显著性。与非粘液型AIS相比，黏液型AIS（n = 8）很少有KRAS基因突变且pStat3表达显著降低（P＜0.001）。总之，AIS主要发生于女性和非吸烟者。然而，发生于吸烟者和非吸烟者AIS的细胞谱系、驱动基因突变和受体酪氨酸激酶信号通路激活等特征均有相似性。我们的研究结果表明，吸烟不是AIS的主要病因。相反，吸烟可能在AIS演进到伴有AIS特征的浸润性腺癌中发挥了作用。