Skip to main content
SpringerLink
Log in

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

  • Original Paper
  • Published:
Journal of Cancer Research and Clinical Oncology Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  • Asamura H, Kameya T, Matsuno Y, Noguchi M, Tada H, Ishikawa Y, Yokose T, Jiang SX, Inoue T, Nakagawa K, Tajima K, Nagai K (2006) Neuroendocrine neoplasms of the lung: a prognostic spectrum. J Clin Oncol Off J Am Soc Clin Oncol 24(1):70–76. doi:10.1200/JCO.2005.04.1202

    Article  Google Scholar 

  • Bhowmick NA, Neilson EG, Moses HL (2004) Stromal fibroblasts in cancer initiation and progression. Nature 432(7015):332–337. doi:10.1038/nature03096

    Article  PubMed  CAS  Google Scholar 

  • Bremnes RM, Donnem T, Al-Saad S, Al-Shibli K, Andersen S, Sirera R, Camps C, Marinez I, Busund LT (2011) The role of tumor stroma in cancer progression and prognosis: emphasis on carcinoma-associated fibroblasts and non-small cell lung cancer. J Thorac Oncol Off Publ Int Assoc Study Lung Cancer 6(1):209–217. doi:10.1097/JTO.0b013e3181f8a1bd

    Google Scholar 

  • Carvalho FM, Zaganelli FL, Almeida BGL, Goes JCS, Baracat EC, Carvalho JP (2010) Prognostic value of podoplanin expression in intratumoral stroma and neoplastic cells of uterine cervical carcinomas. Clinics 65(12):1279–1283. doi:10.1590/s1807-59322010001200009

    Article  PubMed  Google Scholar 

  • Chen X, Oppenheim JJ (2011) Resolving the identity myth: key markers of functional CD4 + FoxP3 + regulatory T cells. Int Immunopharmacol 11(10):1489–1496. doi:10.1016/j.intimp.2011.05.018

    Article  PubMed  CAS  Google Scholar 

  • Dimitrakopoulos FI, Papadaki H, Antonacopoulou AG, Kottorou A, Gotsis AD, Scopa C, Kalofonos HP, Mouzaki A (2011) Association of FOXP3 expression with non-small cell lung cancer. Anticancer Res 31(5):1677–1683

    PubMed  CAS  Google Scholar 

  • Ding ZY, Zou XL, Wei YQ (2012) Cancer Microenvironment and Cancer Vaccine. Cancer Microenviron Off J Int Cancer Microenviron Soc. doi:10.1007/s12307-012-0107-x

  • Erler BS, Presby MM, Finch M, Hodges A, Horowitz K, Topilow AA, Matulewicz T (2011) CD117, Ki-67, and p53 predict survival in neuroendocrine carcinomas, but not within the subgroup of small cell lung carcinoma. Tumour Biol J Int Soc Oncodev Biol Med 32(1):107–111. doi:10.1007/s13277-010-0104-y

    Article  CAS  Google Scholar 

  • Gudermann T, Roelle S (2006) Calcium-dependent growth regulation of small cell lung cancer cells by neuropeptides. Endocr Relat Cancer 13(4):1069–1084. doi:10.1677/erc.1.01302

    Article  PubMed  CAS  Google Scholar 

  • Hoshino A, Ishii G, Ito T, Aoyagi K, Ohtaki Y, Nagai K, Sasaki H, Ochiai A (2011) Podoplanin-positive fibroblasts enhance lung adenocarcinoma tumor formation: podoplanin in fibroblast functions for tumor progression. Cancer Res 71(14):4769–4779. doi:10.1158/0008-5472.CAN-10-3228

    Article  PubMed  CAS  Google Scholar 

  • Igawa S, Watanabe R, Ito I, Murakami H, Takahashi T, Nakamura Y, Tsuya A, Kaira K, Naito T, Endo M, Yamamoto N, Kameya T (2010) Comparison of chemotherapy for unresectable pulmonary high-grade non-small cell neuroendocrine carcinoma and small-cell lung cancer. Lung Cancer 68(3):438–445. doi:10.1016/j.lungcan.2009.07.003

    Article  PubMed  Google Scholar 

  • Ito M, Ishii G, Nagai K, Maeda R, Nakano Y, Ochiai A (2012a) Prognostic impact of cancer-associated stromal cells in stage I lung adenocarcinoma patients. Chest. doi:10.1378/chest.11-2458

    Google Scholar 

  • Ito S, Ishii G, Hoshino A, Hashimoto H, Neri S, Kuwata T, Higashi M, Nagai K, Ochiai A (2012b) Tumor promoting effect of podoplanin-positive fibroblasts is mediated by enhanced RhoA activity. Biochem Biophys Res Commun 422(1):194–199. doi:10.1016/j.bbrc.2012.04.158

    Article  PubMed  CAS  Google Scholar 

  • Iyoda A, Hiroshima K, Moriya Y, Mizobuchi T, Otsuji M, Sekine Y, Shibuya K, Iizasa T, Saitoh Y, Fujisawa T (2004) Pulmonary large cell neuroendocrine carcinoma demonstrates high proliferative activity. Ann Thorac Surg 77(6):1891–1895. doi:10.1016/j.athoracsur.2003.10.119 Discussion 1895

    Article  PubMed  Google Scholar 

  • Iyoda A, Hiroshima K, Moriya Y, Takiguchi Y, Sekine Y, Shibuya K, Iizasa T, Kimura H, Nakatani Y, Fujisawa T (2006) Prospective study of adjuvant chemotherapy for pulmonary large cell neuroendocrine carcinoma. Ann Thorac Surg 82(5):1802–1807. doi:10.1016/j.athoracsur.2006.05.109

    Article  PubMed  Google Scholar 

  • Karagoz B, Bilgi O, Gumus M, Erikci AA, Sayan O, Turken O, Kandemir EG, Ozturk A, Yaylaci M (2010) CD8 + CD28- cells and CD4 + CD25 + regulatory T cells in the peripheral blood of advanced stage lung cancer patients. Med Oncol 27(1):29–33. doi:10.1007/s12032-008-9165-9

    Article  PubMed  Google Scholar 

  • Kawase A, Ishii G, Nagai K, Ito T, Nagano T, Murata Y, Hishida T, Nishimura M, Yoshida J, Suzuki K, Ochiai A (2008) Podoplanin expression by cancer associated fibroblasts predicts poor prognosis of lung adenocarcinoma. IJC Int J cancer 123(5):1053–1059. doi:10.1002/ijc.23611

    Article  CAS  Google Scholar 

  • Komohara Y, Hasita H, Ohnishi K, Fujiwara Y, Suzu S, Eto M, Takeya M (2011) Macrophage infiltration and its prognostic relevance in clear cell renal cell carcinoma. Cancer Sci 102(7):1424–1431. doi:10.1111/j.1349-7006.2011.01945.x

    Article  PubMed  CAS  Google Scholar 

  • Koyama K, Kagamu H, Miura S, Hiura T, Miyabayashi T, Itoh R, Kuriyama H, Tanaka H, Tanaka J, Yoshizawa H, Nakata K, Gejyo F (2008) Reciprocal CD4 + T-cell balance of effector CD62Llow CD4 + and CD62LhighCD25 + CD4 + regulatory T cells in small cell lung cancer reflects disease stage. Clin Cancer Res Off J Am Assoc Cancer Res 14(21):6770–6779. doi:10.1158/1078-0432.CCR-08-1156

    Article  CAS  Google Scholar 

  • Kurahara H, Shinchi H, Mataki Y, Maemura K, Noma H, Kubo F, Sakoda M, Ueno S, Natsugoe S, Takao S (2011) Significance of M2-polarized tumor-associated macrophage in pancreatic cancer. J Surg Res 167(2):e211–e219. doi:10.1016/j.jss.2009.05.026

    Article  PubMed  Google Scholar 

  • Liang P, Hong JW, Ubukata H, Liu G, Katano M, Motohashi G, Kasuga T, Watanabe Y, Nakada I, Tabuchi T (2005) Myofibroblasts correlate with lymphatic microvessel density and lymph node metastasis in early-stage invasive colorectal carcinoma. Anticancer Res 25(4):2705–2712

    PubMed  Google Scholar 

  • Ohtaki Y, Ishii G, Nagai K, Ashimine S, Kuwata T, Hishida T, Nishimura M, Yoshida J, Takeyoshi I, Ochiai A (2010) Stromal macrophage expressing CD204 is associated with tumor aggressiveness in lung adenocarcinoma. J Thorac Oncol Off Publ Int Assoc Study Lung Cancer 5(10):1507–1515. doi:10.1097/JTO.0b013e3181eba692

    Google Scholar 

  • Ono S, Ishii G, Nagai K, Takuwa T, Yoshida J, Nishimura M, Hishida T, Aokage K, Fujii S, Ikeda N, Ochiai A (2013) Podoplanin-positive cancer-associated fibroblasts could have prognostic value independent of cancer cell phenotype in stage I lung squamous cell carcinoma: usefulness of combining analysis of both cancer cell phenotype and cancer-associated fibroblast phenotype. Chest 143(4):963–970. doi:10.1378/chest.12-0913

    Article  PubMed  Google Scholar 

  • Petersen RP, Campa MJ, Sperlazza J, Conlon D, Joshi MB, Harpole DH Jr, Patz EF Jr (2006) Tumor infiltrating Foxp3 + regulatory T-cells are associated with recurrence in pathologic stage I NSCLC patients. Cancer 107(12):2866–2872. doi:10.1002/cncr.22282

    Article  PubMed  Google Scholar 

  • Pollard JW (2004) Tumour-educated macrophages promote tumour progression and metastasis. Nat Rev Cancer 4(1):71–78. doi:10.1038/nrc1256

    Article  PubMed  CAS  Google Scholar 

  • Pula B, Jethon A, Piotrowska A, Gomulkiewicz A, Owczarek T, Calik J, Wojnar A, Witkiewicz W, Rys J, Ugorski M, Dziegiel P, Podhorska-Okolow M (2011) Podoplanin expression by cancer-associated fibroblasts predicts poor outcome in invasive ductal breast carcinoma. Histopathology 59(6):1249–1260. doi:10.1111/j.1365-2559.2011.04060.x

    Article  PubMed  Google Scholar 

  • Rossi G, Cavazza A, Marchioni A, Longo L, Migaldi M, Sartori G, Bigiani N, Schirosi L, Casali C, Morandi U, Facciolongo N, Maiorana A, Bavieri M, Fabbri LM, Brambilla E (2005) Role of chemotherapy and the receptor tyrosine kinases KIT, PDGFRalpha, PDGFRbeta, and Met in large-cell neuroendocrine carcinoma of the lung. J Clin Oncol Off J Am Soc Clin Oncol 23(34):8774–8785. doi:10.1200/JCO.2005.02.8233

    Article  CAS  Google Scholar 

  • Ryuge S, Sato Y, Jiang SX, Wang G, Matsumoto T, Katono K, Inoue H, Iyoda A, Satoh Y, Yoshimura H, Masuda N (2012) Prognostic impact of nestin expression in resected large cell neuroendocrine carcinoma of the lung. Lung Cancer. doi:10.1016/j.lungcan.2012.03.025

    PubMed  Google Scholar 

  • Sarkaria IS, Iyoda A, Roh MS, Sica G, Kuk D, Sima CS, Pietanza MC, Park BJ, Travis WD, Rusch VW (2011) Neoadjuvant and adjuvant chemotherapy in resected pulmonary large cell neuroendocrine carcinomas: a single institution experience. Ann Thorac Surg 92(4):1180–1186. doi:10.1016/j.athoracsur.2011.05.027 Discussion 1186–1187

    Article  PubMed  Google Scholar 

  • Schoppmann SF, Berghoff A, Dinhof C, Jakesz R, Gnant M, Dubsky P, Jesch B, Heinzl H, Birner P (2012) Podoplanin-expressing cancer-associated fibroblasts are associated with poor prognosis in invasive breast cancer. Breast Cancer Res Treat. doi:10.1007/s10549-012-1984-x

  • Shimizu K, Nakata M, Hirami Y, Yukawa T, Maeda A, Tanemoto K (2010) Tumor-infiltrating Foxp3 + regulatory T cells are correlated with cyclooxygenase-2 expression and are associated with recurrence in resected non-small cell lung cancer. J Thorac Oncol Off Publ Int Assoc Study of Lung Cancer 5(5):585–590. doi:10.1097/JTO.0b013e3181d60fd7

    Google Scholar 

  • Sun JM, Ahn MJ, Ahn JS, Um SW, Kim H, Kim HK, Choi YS, Han J, Kim J, Kwon OJ, Shim YM, Park K (2012) Chemotherapy for pulmonary large cell neuroendocrine carcinoma: Similar to that for small cell lung cancer or non-small cell lung cancer? Lung Cancer. doi:10.1016/j.lungcan.2012.04.009

  • Tao H, Mimura Y, Aoe K, Kobayashi S, Yamamoto H, Matsuda E, Okabe K, Matsumoto T, Sugi K, Ueoka H (2012) Prognostic potential of FOXP3 expression in non-small cell lung cancer cells combined with tumor-infiltrating regulatory T cells. Lung Cancer 75(1):95–101. doi:10.1016/j.lungcan.2011.06.002

    Article  PubMed  Google Scholar 

  • Travis WD (2010) Advances in neuroendocrine lung tumors. Ann Oncol Off J Eur Soc Med Oncol/ESMO 21(Suppl 7):65–71. doi:10.1093/annonc/mdq380

    Google Scholar 

  • Travis WD, Linnoila RI, Tsokos MG, Hitchcock CL, Cutler GB Jr, Nieman L, Chrousos G, Pass H, Doppman J (1991) Neuroendocrine tumors of the lung with proposed criteria for large-cell neuroendocrine carcinoma. An ultrastructural, immunohistochemical, and flow cytometric study of 35 cases. Am J Surg Pathol 15(6):529–553

    Article  PubMed  CAS  Google Scholar 

  • Usuda K, Saito Y, Sagawa M, Sato M, Kanma K, Takahashi S, Endo C, Chen Y, Sakurada A, Fujimura S (1994) Tumor doubling time and prognostic assessment of patients with primary lung cancer. Cancer 74(8):2239–2244

    Article  PubMed  CAS  Google Scholar 

  • Usuda J, Ichinose S, Ishizumi T, Ohtani K, Inoue T, Saji H, Kakihana M, Kajiwara N, Uchida O, Nomura M, Ohira T, Ikeda N (2011a) Klotho predicts good clinical outcome in patients with limited-disease small cell lung cancer who received surgery. Lung Cancer 74(2):332–337. doi:10.1016/j.lungcan.2011.03.004

    Article  PubMed  Google Scholar 

  • Usuda J, Ichinose S, Ishizumi T, Ohtani K, Inoue T, Saji H, Kakihana M, Kajiwara N, Uchida O, Nomura M, Tsutsui H, Ohira T, Ikeda N (2011b) Klotho is a novel biomarker for good survival in resected large cell neuroendocrine carcinoma of the lung. Lung Cancer 72(3):355–359. doi:10.1016/j.lungcan.2010.10.008

    Article  PubMed  Google Scholar 

  • Wang W, Hodkinson P, McLaren F, Mackinnon A, Wallace W, Howie S, Sethi T (2012) Small cell lung cancer tumour cells induce regulatory T lymphocytes, and patient survival correlates negatively with FOXP3(+) cells in tumour infiltrate. IJC J Int Cancer. doi:10.1002/ijc.27613

  • Yamazaki S, Sekine I, Matsuno Y, Takei H, Yamamoto N, Kunitoh H, Ohe Y, Tamura T, Kodama T, Asamura H, Tsuchiya R, Saijo N (2005) Clinical responses of large cell neuroendocrine carcinoma of the lung to cisplatin-based chemotherapy. Lung Cancer 49(2):217–223. doi:10.1016/j.lungcan.2005.01.008

    Article  PubMed  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

  1. 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

    Akiko Takahashi, Genichiro Ishii, Tatsuya Yoshida & Atsushi Ochiai

  2. Department of Thoracic Oncology, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa-City, Chiba, 277-8577, Japan

    Akiko Takahashi, Tomonari Kinoshita, Tatsuya Yoshida, Shigeki Umemura, Tomoyuki Hishida, Kiyotaka Yoh, Seiji Niho, Koichi Goto, Hironobu Ohmatsu, Yuichiro Ohe & Kanji Nagai

Authors
  1. Akiko Takahashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Genichiro Ishii
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tomonari Kinoshita
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tatsuya Yoshida
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Shigeki Umemura
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Tomoyuki Hishida
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Kiyotaka Yoh
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Seiji Niho
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Koichi Goto
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Hironobu Ohmatsu
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Yuichiro Ohe
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Kanji Nagai
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Atsushi Ochiai
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Genichiro Ishii or Atsushi Ochiai.

Electronic supplementary material

Below is the link to the electronic supplementary material.

432_2013_1502_MOESM1_ESM.pdf

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)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Takahashi, A., Ishii, G., Kinoshita, T. et al. Identification of prognostic immunophenotypic features in cancer stromal cells of high-grade neuroendocrine carcinomas of the lung. J Cancer Res Clin Oncol 139, 1869–1878 (2013). https://doi.org/10.1007/s00432-013-1502-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00432-013-1502-5

Keywords

Search

Navigation