title: Pulmonary adenocarcinoma in situ: analyses of a large series with reference to smoking, driver mutations, and receptor tyrosine kinase pathway activation.
abstract: 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.
authors.affiliation: *Division of Pathology, The Cancer Institute, Department of Pathology, The Cancer Institute Hospital †Department of Thoracic Surgical Oncology, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo ‡Division of Thoracic and Cardiovascular Surgery, Niigata University Hospital, Niigata, Japan.
authors.forename: Seijiro
authors.initials: S
authors.lastname: Sato
authors.forename: Noriko
authors.initials: N
authors.lastname: Motoi
authors.forename: Miyako
authors.initials: M
authors.lastname: Hiramatsu
authors.forename: Eisaku
authors.initials: E
authors.lastname: Miyauchi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ono
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Saito
authors.forename: Hiroko
authors.initials: H
authors.lastname: Nagano
authors.forename: Hironori
authors.initials: H
authors.lastname: Ninomiya
authors.forename: Kentaro
authors.initials: K
authors.lastname: Inamura
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Uehara
authors.forename: Mingyon
authors.initials: M
authors.lastname: Mun
authors.forename: Yukinori
authors.initials: Y
authors.lastname: Sakao
authors.forename: Sakae
authors.initials: S
authors.lastname: Okumura
authors.forename: Masanori
authors.initials: M
authors.lastname: Tsuchida
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Ishikawa
mesh_terms: D065311:Adenocarcinoma in Situ / Q000209:etiology* / Q000235:genetics; D005260:Female; D018773:Genes, erbB-1 / Q000235:genetics*; D006801:Humans; D008175:Lung Neoplasms / Q000209:etiology* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D020794:Receptor Protein-Tyrosine Kinases / Q000502:physiology*; D012189:Retrospective Studies; D015398:Signal Transduction; D012907:Smoking / Q000009:adverse effects*; D018631:ras Proteins / Q000235:genetics*
chemical_list: C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D020794:Receptor Protein-Tyrosine Kinases; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins