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Journal of Cancer Research and Clinical Oncology

, Volume 139, Issue 11, pp 1869–1878 | Cite as

Identification of prognostic immunophenotypic features in cancer stromal cells of high-grade neuroendocrine carcinomas of the lung

  • Akiko Takahashi
  • Genichiro IshiiEmail author
  • Tomonari Kinoshita
  • Tatsuya Yoshida
  • Shigeki Umemura
  • Tomoyuki Hishida
  • Kiyotaka Yoh
  • Seiji Niho
  • Koichi Goto
  • Hironobu Ohmatsu
  • Yuichiro Ohe
  • Kanji Nagai
  • Atsushi OchiaiEmail author
Original Paper

Abstract

Purpose

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.

Materials and 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.

Conclusion

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.

Keywords

Small cell carcinoma Large cell neuroendocrine carcinoma High-grade neuroendocrine carcinomas Cancer-associated fibroblasts Tumor-associated macrophages Regulatory T cells 

Notes

Acknowledgments

This work was supported by National Cancer Center Research and Development Fund (23-A-12 and 23-K-18), the Foundation for the Promotion of Cancer Research, 3rd-Term Comprehensive 10-Year Strategy for Cancer Control, Program for the Promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation, and JSPS KAKENHI (24659185).

Conflict of interest

None.

Supplementary material

432_2013_1502_MOESM1_ESM.pdf (119 kb)
Fig. S1 Survival analysis of HGNEC patients with podoplanin expression in CAFs. (a) Overall survival curves for p-stage I patients. (b) Relapse-free survival curves for p-stage I patients. (c) Overall survival curves for SCLC patients. (d) Relapse-free survival curves for SCLC patients. (e) Overall survival curves for LCNEC patients. (f) Relapse-free survival curves for LCNEC patients. Supplementary material 1 (PDF 118 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Akiko Takahashi
    • 1
    • 2
  • Genichiro Ishii
    • 1
    Email author
  • Tomonari Kinoshita
    • 2
  • Tatsuya Yoshida
    • 1
    • 2
  • Shigeki Umemura
    • 2
  • Tomoyuki Hishida
    • 2
  • Kiyotaka Yoh
    • 2
  • Seiji Niho
    • 2
  • Koichi Goto
    • 2
  • Hironobu Ohmatsu
    • 2
  • Yuichiro Ohe
    • 2
  • Kanji Nagai
    • 2
  • Atsushi Ochiai
    • 1
    Email author
  1. 1.Pathology Division, Department of Pathology, Research Center for Innovative OncologyNational Cancer Center Hospital EastKashiwa-CityJapan
  2. 2.Department of Thoracic OncologyNational Cancer Center Hospital EastKashiwa-CityJapan

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