title: The association of intravascular stromal cells with prognosis in high-grade neuroendocrine carcinoma of the lung.
abstract: OBJECTIVE
  Histological vascular invasion (VI) is major predictor of recurrence after surgery for several cancer types. We previously reported that VI with abundant stromal cell infiltrates was a negative prognostic factor in lung adenocarcinoma. This study examined whether stromal cell infiltrates within VI are associated with prognosis in high-grade neuroendocrine carcinoma (HGNEC) of the lung.
  
  
  METHODS
  We investigated the relationship between the frequency and density of VI and recurrence-free survival (RFS) of 60 resected HGNEC patients without adjuvant chemotherapy. We examined prognostic effects of CD204 (+) macrophages, CD34 (+) microvessels and α-smooth muscle actin (+) myofibroblasts within VI. Correlation between expressions of stem cell-related molecules (ALDH-1, Notch 1, CD44) and epithelial-mesenchymal transition-related molecules (E-cadherin, S100A4) in cancer cells within VI and RFS was also analyzed.
  
  
  RESULTS
  Among 60 cases, 51 cases showed VI. Although the presence of VI was a significant predictor for worse RFS (P = 0.04), the frequency and density of VI were not correlated with RFS. The number of CD204 (+) macrophage, CD34 (+) microvessels and α-smooth muscle actin (+) myofibroblasts within VI did not influence on the RFS. On the contrary, cases with higher Notch 1 expression in cancer cells in the VI displayed significantly shorter RFS than lower expression group (7.6 vs. 29.4 months, P = 0.02).
  
  
  CONCLUSIONS
  The current study revealed the presence of stromal cells within VI was not significant predictor for recurrence in HGNEC. This suggests that in HGNEC, unlike adenocarcinoma, intravascular stromal cells are not major contributors to metastasis.
authors.affiliation: Division of Pathology, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.|Division of Thoracic Surgery, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.
authors.forename: Keigo
authors.initials: K
authors.lastname: Sekihara
authors.affiliation: Division of Thoracic Surgery, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Hishida
authors.affiliation: Division of Pathology, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.|Division of Thoracic Oncology, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.
authors.forename: Shinnosuke
authors.initials: S
authors.lastname: Ikemura
authors.affiliation: Division of Pathology, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.|Division of Thoracic Oncology, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Saruwatari
authors.affiliation: Division of Pathology, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.|Division of Thoracic Oncology, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Morise
authors.affiliation: Division of Pathology, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kuwata
authors.affiliation: Division of Pathology, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Fujii
authors.affiliation: Division of Pathology, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.
authors.forename: Motohiro
authors.initials: M
authors.lastname: Kojima
authors.affiliation: Division of Pathology, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Ochiai
authors.affiliation: First Department of Surgery, Hamamatsu University School of Medicine, 1-20-1, Handayama, Hamamatsu, Shizuoka, 431-3192, Japan.
authors.forename: Kazuhito
authors.initials: K
authors.lastname: Funai
authors.affiliation: Division of Thoracic Surgery, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.
authors.forename: Keiju
authors.initials: K
authors.lastname: Aokage
authors.affiliation: Division of Thoracic Surgery, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.
authors.forename: Junji
authors.initials: J
authors.lastname: Yoshida
authors.affiliation: Division of Thoracic Surgery, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Tsuboi
authors.affiliation: Division of Pathology, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan. gishii@east.ncc.go.jp.
authors.forename: Genichiro
authors.initials: G
authors.lastname: Ishii
mesh_terms: D000199:Actins / Q000378:metabolism; D000230:Adenocarcinoma / Q000098:blood supply / Q000188:drug therapy / Q000473:pathology*; D000368:Aged; D018952:Antigens, CD34 / Q000378:metabolism; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism; D018278:Carcinoma, Neuroendocrine / Q000098:blood supply / Q000188:drug therapy / Q000473:pathology*; D017024:Chemotherapy, Adjuvant; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007124:Immunoenzyme Techniques; D008175:Lung Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000473:pathology*; D008264:Macrophages / Q000473:pathology; D008297:Male; D058628:Myofibroblasts / Q000473:pathology; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology*; D011379:Prognosis; D051117:Scavenger Receptors, Class A / Q000378:metabolism; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology; D015996:Survival Rate
chemical_list: C541116:ACTA2 protein, human; D000199:Actins; D018952:Antigens, CD34; D014408:Biomarkers, Tumor; D015820:Cadherins; C495139:MSR1 protein, human; D051117:Scavenger Receptors, Class A
keywords: High-grade neuroendocrine carcinoma; Intravascular microenvironment; Large cell neuroendocrine carcinoma; Notch1; Small cell lung cancer; Stromal cells; Vascular invasion