Koichi Saruwatari1, Shinnosuke Ikemura2, Keigo Sekihara3, Takeshi Kuwata2, Satoshi Fujii2, Shigeki Umemura4, Keisuke Kirita4, Shingo Matsumoto4, Kiyotaka Yoh4, Seiji Niho4, Hironobu Ohmatsu2, Atsushi Ochiai2, Hirotsugu Kohrogi5, Masahiro Tsuboi6, Koichi Goto4, Genichiro Ishii7. 1. 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. 2. Division of Pathology, Exploratory Oncology Research & Clinical Trial Center, Japan. 3. Division of Pathology, Exploratory Oncology Research & Clinical Trial Center, Japan; Department of Thoracic Surgery, National Cancer Center Hospital East, Japan. 4. Department of Thoracic Oncology, National Cancer Center Hospital East, Japan. 5. Department of Respiratory Medicine, Kumamoto University Hospital, Japan. 6. Department of Thoracic Surgery, National Cancer Center Hospital East, Japan. 7. Division of Pathology, Exploratory Oncology Research & Clinical Trial Center, Japan. Electronic address: gishii@east.ncc.go.jp.
Abstract
INTRODUCTION: 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. CONCLUSION: 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.
INTRODUCTION: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. CONCLUSION: 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.