title: Identification of prognostic immunophenotypic features in cancer stromal cells of high-grade neuroendocrine carcinomas of the lung.
abstract: OBJECTIVE
  The immunophenotypes of cancer stromal cells have been recognized as prognostic factors of cancer. The purpose of this study was to analyze the prognostic markers of high-grade neuroendocrine carcinomas of the lung (HGNEC; both small cell carcinoma and large cell neuroendocrine carcinoma) by examining the immunophenotypes of cancer stromal cells.
  
  
  METHODS
  One hundred and fifteen patients who underwent a complete resection of HGNEC were included in this study. We examined the presence of CD204-positive tumor-associated macrophages (TAMs), Foxp3-positive regulatory T cells (Tregs), and podoplanin-positive cancer-associated fibroblasts (CAFs) to evaluate the prognostic values of these markers.
  
  
  RESULTS
  The number of CD204-positive TAMs and Foxp3-positive Tregs did not influence the overall survival (OS) or the relapse-free survival (RFS) of the patients. However, patients with podoplanin-positive CAFs had a significantly better prognosis than those with podoplanin-negative CAFs [OS: p = 0.002, RFS: p = 0.002, 5-year overall survival (5YR): 74 vs. 45 %]. According to subgroup analyses, patients with podoplanin-positive CAFs displayed a better prognosis for both small cell carcinoma (OS: p = 0.046, 5YR: 74 vs. 46 %) and large cell neuroendocrine carcinoma (OS: p = 0.020, 5YR: 74 vs. 45 %). Moreover, in multivariate analyses, the podoplanin status of the CAFs was shown to be a statistically significant independent predictor of recurrence.
  
  
  CONCLUSIONS
  The presence of podoplanin-positive CAFs had a favorable prognostic value, suggesting that the evaluation of podoplanin expression by CAFs would lead to a novel risk classification of patients.
authors.affiliation: Pathology Division, Department of Pathology, Research Center for Innovative Oncology, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa-City, Chiba, 277-8577, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Takahashi
authors.forename: Genichiro
authors.initials: G
authors.lastname: Ishii
authors.forename: Tomonari
authors.initials: T
authors.lastname: Kinoshita
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Yoshida
authors.forename: Shigeki
authors.initials: S
authors.lastname: Umemura
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Hishida
authors.forename: Kiyotaka
authors.initials: K
authors.lastname: Yoh
authors.forename: Seiji
authors.initials: S
authors.lastname: Niho
authors.forename: Koichi
authors.initials: K
authors.lastname: Goto
authors.forename: Hironobu
authors.initials: H
authors.lastname: Ohmatsu
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Ohe
authors.forename: Kanji
authors.initials: K
authors.lastname: Nagai
authors.forename: Atsushi
authors.initials: A
authors.lastname: Ochiai
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018278:Carcinoma, Neuroendocrine / Q000276:immunology* / Q000473:pathology; D005260:Female; D051858:Forkhead Transcription Factors / Q000096:biosynthesis; D006801:Humans; D007150:Immunohistochemistry; D016130:Immunophenotyping; D008175:Lung Neoplasms / Q000276:immunology* / Q000473:pathology; D008297:Male; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D008875:Middle Aged; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D012189:Retrospective Studies; D051117:Scavenger Receptors, Class A / Q000096:biosynthesis; D017154:Stromal Cells / Q000276:immunology* / Q000473:pathology; D055815:Young Adult; D000098853:Podoplanin
chemical_list: D051858:Forkhead Transcription Factors; D008562:Membrane Glycoproteins; D051117:Scavenger Receptors, Class A; C418974:FOXP3 protein, human; C495139:MSR1 protein, human; C117468:PDPN protein, human; D000098853:Podoplanin