The prognostic impact of lymph node metastasis in patients with non-small cell lung cancer and distant organ metastasis

  • Jie Yang
  • Aimei Peng
  • Bo Wang
  • Aaron M. Gusdon
  • Xiaoting Sun
  • Gening JiangEmail author
  • Peng ZhangEmail author
Research Paper


This study aimed to identify the prognostic value of lymph node metastasis in patients with non-small cell lung cancer (NSCLC) and distant organ metastasis. A total of 42,613 NSCLC patients with distant metastasis from the surveillance, epidemiology, and end results database between 2010 and 2013 were included for analysis. The proportion of N0 stage in M1a patients was significantly higher than that in M1b patients, 34.0% and 22.7% respectively (P < 0.001). Compared with N0 patients, patients had higher odds of experiencing multiorgan metastases (MOM) if they had higher N stage at diagnoses (P < 0.001). The Kaplan–Meier curves suggested both M1a and M1b groups patients at stage N0 had better survival than those at higher N stage (P < 0.001). Further analysis indicated that better survival was observed in N0 stage compared with N2 or N3 stage if patients had bone metastasis, brain metastasis, or MOM (P < 0.001, P < 0.001, and P = 0.002, respectively), but there was no significant difference in survival among each N stage patients with liver metastasis only. Cox regression analysis showed that compared with N0 patients, higher hazard for disease-specific mortality was observed for patients with higher N stage. Among NSCLC patients with distant organ metastasis, lymph node metastasis was associated with higher odds of experiencing MOM and a worse prognosis in terms of longer survival except patients with liver metastasis. Better understandings of the role of lymphatic metastasis in M1 NSCLC could help clinicians with better management of the disease.


Non-small cell lung cancer Lymph node metastasis Distant metastasis Prognosis SEER 





American Joint Committee on Cancer


Hazard ratios


International Association for the Study of Lung Cancer


Interquartile range


Multiorgan metastases


Non-small cell lung cancer


Odds ratios


Surveillance, epidemiology and end results


Squamous cell carcinoma


Tumor, node, and metastasis



We would like to thank all the staff of National Cancer Institute for their effort to the SEER program.

Author Contributions

Conception and design: J.Y., G.J., and P.Z.; Acquisition, statistical analysis or interpretation of the data: All authors; Drafting of the manuscript: J.Y., A.P., and B.W.; All authors reviewed and approved the final version of the manuscript.


This work was supported by National Natural Science Foundation of China No. 81600052 (J. Y.) and the Fundamental Research Funds for the Central Universities No. 22120180022 (J. Y.).

Compliance with ethical standards

Conflicts of interest

The authors disclose no potential conflicts of interest related to this study.

Ethical approval

Our study was approved by the ethical committee board of Shanghai Pulmonary Hospital and complied with 1964 Helsinki declaration and its later amendments or comparable ethical standards.


  1. 1.
    Siegel RL, Miller KD, Jemal A (2017) Cancer statistics, 2017. CA Cancer J Clin 67(1):7–30. CrossRefGoogle Scholar
  2. 2.
    Siegel R, Desantis C, Jemal A (2014) Colorectal cancer statistics, 2014. CA Cancer J Clin 64(2):104–117. CrossRefGoogle Scholar
  3. 3.
    Bray F, Jemal A, Grey N, Ferlay J, Forman D (2012) Global cancer transitions according to the Human Development Index (2008–2030): a population-based study. Lancet Oncol 13(8):790–801. CrossRefGoogle Scholar
  4. 4.
    Detterbeck FC, Boffa DJ, Kim AW, Tanoue LT (2017) The eighth edition lung cancer stage classification. Chest 151(1):193–203. CrossRefGoogle Scholar
  5. 5.
    Morgensztern D, Ng SH, Gao F, Govindan R (2010) Trends in stage distribution for patients with non-small cell lung cancer: a National Cancer Database survey. J Thorac Oncol 5(1):29–33. CrossRefGoogle Scholar
  6. 6.
    Rami-Porta R, Asamura H, Travis WD, Rusch VW (2017) Lung cancer—major changes in the American Joint Committee on Cancer eighth edition cancer staging manual. CA Cancer J Clin 67(2):138–155. CrossRefGoogle Scholar
  7. 7.
    Yang J, Zhang Y, Sun X, Gusdon AM, Song N, Chen L, Jiang G, Huang Y (2018) The prognostic value of multiorgan metastases in patients with non-small cell lung cancer and its variants: a SEER-based study. J Cancer Res Clin Oncol 144(9):1835–1842. CrossRefGoogle Scholar
  8. 8.
    Ren Y, Dai C, Zheng H, Zhou F, She Y, Jiang G, Fei K, Yang P, Xie D, Chen C (2016) Prognostic effect of liver metastasis in lung cancer patients with distant metastasis. Oncotarget 7(33):53245–53253. CrossRefGoogle Scholar
  9. 9.
    Dai C, Ren Y, Xie D, Zheng H, She Y, Fei K, Jiang G, Chen C (2016) Does lymph node metastasis have a negative prognostic impact in patients with NSCLC and M1a disease? J Thorac Oncol 11(10):1745–1754. CrossRefGoogle Scholar
  10. 10.
    Johnson KK, Rosen JE, Salazar MC, Boffa DJ (2016) Outcomes of a highly selective surgical approach to oligometastatic lung cancer. Ann Thorac Surg 102(4):1166–1171. CrossRefGoogle Scholar
  11. 11.
    Ettinger DS, Wood DE, Akerley W, Bazhenova LA, Borghaei H, Camidge DR, Cheney RT, Chirieac LR, D’Amico TA, Demmy TL, Dilling TJ, Dobelbower MC, Govindan R, Grannis FW Jr, Horn L, Jahan TM, Komaki R, Krug LM, Lackner RP, Lanuti M, Lilenbaum R, Lin J, Loo BW Jr, Martins R, Otterson GA, Patel JD, Pisters KM, Reckamp K, Riely GJ, Rohren E, Schild SE, Shapiro TA, Swanson SJ, Tauer K, Yang SC, Gregory K, Hughes M, National Comprehensive Cancer Network (2015) Non-small cell lung cancer, Version 6.2015. J Natl Compr Cancer Netw 13(5):515–524CrossRefGoogle Scholar
  12. 12.
    Asamura H, Chansky K, Crowley J, Goldstraw P, Rusch VW, Vansteenkiste JF, Watanabe H, Wu YL, Zielinski M, Ball D, Rami-Porta R, International Association for the Study of Lung Cancer S, Prognostic Factors Committee ABM, Participating I (2015) The International Association for the Study of Lung Cancer Lung Cancer Staging Project: proposals for the revision of the N descriptors in the forthcoming 8th edition of the TNM classification for lung cancer. J Thorac Oncol 10(12):1675–1684. CrossRefGoogle Scholar
  13. 13.
    Leung E, Xue A, Wang Y, Rougerie P, Sharma VP, Eddy R, Cox D, Condeelis J (2017) Blood vessel endothelium-directed tumor cell streaming in breast tumors requires the HGF/C-Met signaling pathway. Oncogene 36(19):2680–2692. CrossRefGoogle Scholar
  14. 14.
    Wong SY, Hynes RO (2006) Lymphatic or hematogenous dissemination: how does a metastatic tumor cell decide? Cell Cycle 5(8):812–817. CrossRefGoogle Scholar
  15. 15.
    Podgrabinska S, Skobe M (2014) Role of lymphatic vasculature in regional and distant metastases. Microvasc Res 95:46–52. CrossRefGoogle Scholar
  16. 16.
    Brakenhielm E, Burton JB, Johnson M, Chavarria N, Morizono K, Chen I, Alitalo K, Wu L (2007) Modulating metastasis by a lymphangiogenic switch in prostate cancer. Int J Cancer 121(10):2153–2161. CrossRefGoogle Scholar
  17. 17.
    Burton JB, Priceman SJ, Sung JL, Brakenhielm E, An DS, Pytowski B, Alitalo K, Wu L (2008) Suppression of prostate cancer nodal and systemic metastasis by blockade of the lymphangiogenic axis. Cancer Res 68(19):7828–7837. CrossRefGoogle Scholar
  18. 18.
    Roberts N, Kloos B, Cassella M, Podgrabinska S, Persaud K, Wu Y, Pytowski B, Skobe M (2006) Inhibition of VEGFR-3 activation with the antagonistic antibody more potently suppresses lymph node and distant metastases than inactivation of VEGFR-2. Cancer Res 66(5):2650–2657. CrossRefGoogle Scholar
  19. 19.
    Brown M, Assen FP, Leithner A, Abe J, Schachner H, Asfour G, Bago-Horvath Z, Stein JV, Uhrin P, Sixt M, Kerjaschki D (2018) Lymph node blood vessels provide exit routes for metastatic tumor cell dissemination in mice. Science 359(6382):1408–1411. CrossRefGoogle Scholar
  20. 20.
    Pereira ER, Kedrin D, Seano G, Gautier O, Meijer EFJ, Jones D, Chin SM, Kitahara S, Bouta EM, Chang J, Beech E, Jeong HS, Carroll MC, Taghian AG, Padera TP (2018) Lymph node metastases can invade local blood vessels, exit the node, and colonize distant organs in mice. Science 359(6382):1403–1407. CrossRefGoogle Scholar
  21. 21.
    Osarogiagbon RU, Allen JW, Farooq A, Berry A, Spencer D, O’Brien T (2010) Outcome of surgical resection for pathologic N0 and Nx non-small cell lung cancer. J Thorac Oncol 5(2):191–196. CrossRefGoogle Scholar
  22. 22.
    Osarogiagbon RU, Allen JW, Farooq A, Berry A, O’Brien T (2011) Pathologic lymph node staging practice and stage-predicted survival after resection of lung cancer. Ann Thorac Surg 91(5):1486–1492. CrossRefGoogle Scholar
  23. 23.
    Ohta Y, Oda M, Wu J, Tsunezuka Y, Hiroshi M, Nonomura A, Watanabe G (2001) Can tumor size be a guide for limited surgical intervention in patients with peripheral non-small cell lung cancer? Assessment from the point of view of nodal micrometastasis. J Thorac Cardiovasc Surg 122(5):900–906. CrossRefGoogle Scholar
  24. 24.
    Tamura T, Kurishima K, Nakazawa K, Kagohashi K, Ishikawa H, Satoh H, Hizawa N (2015) Specific organ metastases and survival in metastatic non-small-cell lung cancer. Mol Clin Oncol 3(1):217–221. CrossRefGoogle Scholar
  25. 25.
    Riihimaki M, Hemminki A, Fallah M, Thomsen H, Sundquist K, Sundquist J, Hemminki K (2014) Metastatic sites and survival in lung cancer. Lung Cancer 86(1):78–84. CrossRefGoogle Scholar

Copyright information

© Springer Nature B.V. 2019

Authors and Affiliations

  1. 1.Department of Thoracic Surgery, Shanghai Pulmonary HospitalTongji University School of MedicineShanghaiChina
  2. 2.Department of Respiratory Medicine, Shanghai Tenth People’s HospitalTongji UniversityShanghaiChina
  3. 3.Department of Thoracic Surgery, Shanghai Tenth People’s HospitalTongji University School of MedicineShanghaiChina
  4. 4.Department of Neurology, Division of Neurocritical CareJohns Hopkins University School of MedicineBaltimoreUSA
  5. 5.Department of Health Services Research & AdministrationUniversity of Nebraska Medical CenterOmahaUSA

Personalised recommendations