title: Aggressive tumor microenvironment of solid predominant lung adenocarcinoma subtype harboring with epidermal growth factor receptor mutations.
abstract: BACKGROUND
  Tumor microenvironment critically affects cancer progression. This study aimed to identify differences in microenvironments of lung adenocarcinomas with epidermal growth factor receptor (EGFR) mutations by histological subtypes.
  
  
  METHODS
  The study cohort included 214 lung adenocarcinomas harboring EGFR mutations. We analyzed clinicopathological characteristics of lepidic (LPA), papillary (PPA), acinar (APA), and solid-predominant adenocarcinoma (SPA) subtypes, and examined expression levels of EGFR, E-cadherin, ezrin, laminin-5, ALDH1, and PD-L1 in cancer cells, and of CD34, CD204, podoplanin (PDPN), and FoxP3 in stromal cells in 4 subtypes (n=20 each).
  
  
  RESULTS
  SPA displayed significantly more frequent lymph node metastasis, lymphovascular invasion, and worse prognosis than the other subtypes. Ezrin expression levels in SPA were also significantly higher than in LPA, PPA, or APA (P<0.05, all). Laminin-5 and PD-L1 expression levels in SPA were significantly higher than in LPA (P<0.01 for both) and PPA (P<0.01 for both) and tended to be higher than in APA (laminin-5: P=0.096, PD-L1: P=0.081). Furthermore, SPA displayed higher levels of PDPN (+) cancer-associated fibroblasts (P<0.01) and CD204 (+) tumor-associated macrophages (P<0.05) than the other subtypes.
  
  
  CONCLUSIONS
  Compared with other predominant subtypes with EGFR mutations, the microenvironment of SPA with EGFR mutations is characterized by cancer cells with higher invasive and immune evasion potential and more abundant stromal cells with tumor-promoting functions, which would contribute to the more aggressive behavior of SPA.
authors.affiliation: Division of Pathology, Exploratory Oncology Research & Clinical Trial Center, Japan; Department of Thoracic Oncology, National Cancer Center Hospital East, Japan; Department of Respiratory Medicine, Kumamoto University Hospital, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Saruwatari
authors.affiliation: Division of Pathology, Exploratory Oncology Research & Clinical Trial Center, Japan.
authors.forename: Shinnosuke
authors.initials: S
authors.lastname: Ikemura
authors.affiliation: Division of Pathology, Exploratory Oncology Research & Clinical Trial Center, Japan; Department of Thoracic Surgery, National Cancer Center Hospital East, Japan.
authors.forename: Keigo
authors.initials: K
authors.lastname: Sekihara
authors.affiliation: Division of Pathology, Exploratory Oncology Research & Clinical Trial Center, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kuwata
authors.affiliation: Division of Pathology, Exploratory Oncology Research & Clinical Trial Center, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Fujii
authors.affiliation: Department of Thoracic Oncology, National Cancer Center Hospital East, Japan.
authors.forename: Shigeki
authors.initials: S
authors.lastname: Umemura
authors.affiliation: Department of Thoracic Oncology, National Cancer Center Hospital East, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Kirita
authors.affiliation: Department of Thoracic Oncology, National Cancer Center Hospital East, Japan.
authors.forename: Shingo
authors.initials: S
authors.lastname: Matsumoto
authors.affiliation: Department of Thoracic Oncology, National Cancer Center Hospital East, Japan.
authors.forename: Kiyotaka
authors.initials: K
authors.lastname: Yoh
authors.affiliation: Department of Thoracic Oncology, National Cancer Center Hospital East, Japan.
authors.forename: Seiji
authors.initials: S
authors.lastname: Niho
authors.affiliation: Division of Pathology, Exploratory Oncology Research & Clinical Trial Center, Japan.
authors.forename: Hironobu
authors.initials: H
authors.lastname: Ohmatsu
authors.affiliation: Division of Pathology, Exploratory Oncology Research & Clinical Trial Center, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Ochiai
authors.affiliation: Department of Respiratory Medicine, Kumamoto University Hospital, Japan.
authors.forename: Hirotsugu
authors.initials: H
authors.lastname: Kohrogi
authors.affiliation: Department of Thoracic Surgery, National Cancer Center Hospital East, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Tsuboi
authors.affiliation: Department of Thoracic Oncology, National Cancer Center Hospital East, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Goto
authors.affiliation: Division of Pathology, Exploratory Oncology Research & Clinical Trial Center, Japan. Electronic address: gishii@east.ncc.go.jp.
authors.forename: Genichiro
authors.initials: G
authors.lastname: Ishii
mesh_terms: D000230:Adenocarcinoma / Q000201:enzymology / Q000235:genetics* / Q000473:pathology*; D000077192:Adenocarcinoma of Lung; D000368:Aged; D000080924:Aldehyde Dehydrogenase 1 Family; D060890:B7-H1 Antigen / Q000096:biosynthesis; D015820:Cadherins / Q000096:biosynthesis; D015815:Cell Adhesion Molecules / Q000096:biosynthesis; D015331:Cohort Studies; D003598:Cytoskeletal Proteins / Q000096:biosynthesis; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008175:Lung Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology*; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D009154:Mutation; D050697:Retinal Dehydrogenase / Q000235:genetics / Q000378:metabolism; D012189:Retrospective Studies; D016019:Survival Analysis; D059016:Tumor Microenvironment / Q000235:genetics*; D000097794:Kalinin; D000099149:Ezrin
chemical_list: D000080924:Aldehyde Dehydrogenase 1 Family; D060890:B7-H1 Antigen; D015820:Cadherins; D015815:Cell Adhesion Molecules; D003598:Cytoskeletal Proteins; D066246:ErbB Receptors; D007527:Isoenzymes; D050697:Retinal Dehydrogenase; D000097794:Kalinin; D000099149:Ezrin; C423236:CD274 protein, human; C510223:ALDH1A1 protein, human; C512478:EGFR protein, human
keywords: Cancer cells; Immunohistochemical staining; Lung adenocarcinoma with EGFR mutation; Microenvironment; Solid predominant adenocarcinoma; Stromal cells