title: Drastic morphological and molecular differences between lymph node micrometastatic tumors and macrometastatic tumors of lung adenocarcinoma.
abstract: OBJECTIVE
  The expansion of micrometastatic tumors to macrometastatic ones is thought to be tightly regulated by several microenvironmental factors. The aim of this study was to elucidate the morphological and phenotypical differences between micrometastatic and macrometastatic tumors.
  
  
  METHODS
  We first examined the morphological characteristics of 66 lymph node (LN) micrometastatic tumors (less than 2 mm in size) and 51 macrometastatic tumors (more than 10 mm in size) in 42 lung adenocarcinoma cases. Then, we evaluated the expression level of E-cadherin, S100A4, ALDH1, and Geminin in cancer cells and the number of smooth muscle actin (SMA), CD34, and CD204 (+) stromal cells in the primary tumors, matched micrometastatic tumors, and macrometastatic tumors (n = 34, each).
  
  
  RESULTS
  Tumor budding reflects the process of EMT, and stromal reactions were observed more frequently in macrometastatic tumors (P < 0.001). E-cadherin staining score for the micrometastatic tumors was significantly higher than that for the primary tumors (P < 0.001). In contrast, the E-cadherin staining score for the macrometastatic tumors was significantly lower than that for the micrometastatic tumors (P = 0.017). As for the stromal cells, the numbers of SMA (+) fibroblasts, CD34 (+) microvessels, and CD204 (+) macrophages were significantly higher for the macrometastatic tumors and primary tumors than for the micrometastatic tumors (P < 0.001, all).
  
  
  CONCLUSIONS
  The present study clearly showed that dynamic microenvironmental changes (e.g., EMT-related changes in cancer cells and structural changes in stromal cells) occur during the growth of micrometastases into macrometastases.
authors.affiliation: Division of Pathology, Research Center for Innovative Oncology, National Cancer Center Hospital East, Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.|Division of Thoracic Surgery, National Cancer Center Hospital East, Chiba, Japan.|Division of General Thoracic Surgery, Department of Surgery, Tokyo Medical University School of Medicine, Tokyo, Japan.
authors.forename: Nao
authors.initials: N
authors.lastname: Aramaki
authors.affiliation: Division of Pathology, Research Center for Innovative Oncology, National Cancer Center Hospital East, Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan. gishii@east.ncc.go.jp.
authors.forename: Genichiro
authors.initials: G
authors.lastname: Ishii
authors.affiliation: Division of Thoracic Surgery, National Cancer Center Hospital East, Chiba, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Yamada
authors.affiliation: Division of Pathology, Research Center for Innovative Oncology, National Cancer Center Hospital East, Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Morise
authors.affiliation: Division of Thoracic Surgery, National Cancer Center Hospital East, Chiba, Japan.
authors.forename: Keiju
authors.initials: K
authors.lastname: Aokage
authors.affiliation: Division of Pathology, Research Center for Innovative Oncology, National Cancer Center Hospital East, Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.
authors.forename: Motohiro
authors.initials: M
authors.lastname: Kojima
authors.affiliation: Division of Thoracic Surgery, National Cancer Center Hospital East, Chiba, Japan.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Hishida
authors.affiliation: Division of Thoracic Surgery, National Cancer Center Hospital East, Chiba, Japan.
authors.forename: Junji
authors.initials: J
authors.lastname: Yoshida
authors.affiliation: Division of General Thoracic Surgery, Department of Surgery, Tokyo Medical University School of Medicine, Tokyo, Japan.
authors.forename: Norihiko
authors.initials: N
authors.lastname: Ikeda
authors.affiliation: Division of Thoracic Surgery, National Cancer Center Hospital East, Chiba, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Tsuboi
authors.affiliation: Division of Pathology, Research Center for Innovative Oncology, National Cancer Center Hospital East, Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Ochiai
mesh_terms: D000230:Adenocarcinoma / Q000556:secondary*; D002291:Carcinoma, Papillary / Q000556:secondary*; D006801:Humans; D016130:Immunophenotyping; D008175:Lung Neoplasms / Q000473:pathology*; D008207:Lymphatic Metastasis; D009361:Neoplasm Invasiveness; D061206:Neoplasm Micrometastasis; D009367:Neoplasm Staging; D011379:Prognosis
keywords: Cancer microenvironment; Lung adenocarcinoma; Macrometastasis; Micrometastasis