Clinical & Experimental Metastasis

, Volume 33, Issue 2, pp 133–141 | Cite as

Increased lymphangiogenesis in lung metastases from colorectal cancer is associated with early lymph node recurrence and decreased overall survival

  • Thomas Schweiger
  • Christoph Nikolowsky
  • Thomas Graeter
  • Gernot Seebacher
  • Jürgen Laufer
  • Olaf Glueck
  • Christoph Glogner
  • Peter Birner
  • György Lang
  • Walter Klepetko
  • Hendrik Jan Ankersmit
  • Konrad HoetzeneckerEmail author
Research Paper


Pulmonary metastasectomy (PM) is an accepted treatment modality in colorectal cancer (CRC) patients with pulmonary tumor spread. Positive intrathoracic lymph nodes at the time of PM are associated with a poor prognosis and 5-year survival rates of <20 %. Increased lymphangiogenesis in pulmonary metastases might represent an initial step for a subsequent lymphangiogenic spreading. We aimed to evaluate the presence of lymphangiogenesis in clinically lymph node negative patients undergoing PM and its impact on outcome parameters. 71 patients who underwent PM for CRC metastases were included in this dual-center study. Tissue specimens of pulmonary metastases and available corresponding primary tumors were assessed by immunohistochemistry for lymphatic microvessel density (LMVD) and lymphovascular invasion (LVI). Results were correlated with clinical outcome parameters. LMVD was 13.9 ± 8.1 and 13.3 ± 8.5 microvessels/field (mean ± SD) in metastases and corresponding primary CRC; LVI was evident in 46.5 and 58.6 % of metastases and corresponding primary CRC, respectively. Samples with high LMVD had a higher likelihood of LVI. LVI was associated with early tumor recurrence in intrathoracic lymph nodes and a decreased overall survival (p < 0.001 and p = 0.029). Herein, we present first evidence in a well-defined patient collective that increased lymphangiogenesis is already present in a subtype of pulmonary metastases of patients staged as N0 at the time of PM. This lymphangiogenic phenotype has a strong impact on patients’ prognosis. Our findings may have impact on the post-surgical therapeutic management of CRC patients with pulmonary spreading.


Pulmonary metastasectomy Colorectal cancer Podoplanin Lymphangiogenesis Lymphovascular invasion 



The work was supported by Christian Doppler Laboratory for Cardiac and Thoracic Diagnosis and Regeneration.

Compliance with ethical standards

Conflict of interest

The authors declare no conflicts of interest.

Supplementary material

10585_2015_9763_MOESM1_ESM.jpg (415 kb)
Supplementary Fig. 1 Schematic description of the total study cohort (n = 71) and studied sub-groups (n = 56/n = 15). Supplementary material 1 (JPEG 415 kb)
10585_2015_9763_MOESM2_ESM.jpg (236 kb)
Supplementary Fig. 2 Pulmonary metastases (A) and corresponding primary CRC. (B) samples with evidence of LVI exhibited significantly higher values of LMVD. Supplementary material 2 (JPEG 236 kb)
10585_2015_9763_MOESM3_ESM.jpg (322 kb)
Supplementary Fig. 3 LMVD (A) and LVI (B) of primary CRC and paired pulmonary metastases dependent on the primary tumor site (colon vs rectum). Supplementary material 3 (JPEG 322 kb)


  1. 1.
    United States Cancer Statistics (2014) 1999–2011 Incidence and Mortality Web-based Report. U.S. Cancer Statistics Working GroupGoogle Scholar
  2. 2.
    Mitry E et al (2010) Epidemiology, management and prognosis of colorectal cancer with lung metastases: a 30-year population-based study. Gut 59(10):1383–1388CrossRefPubMedGoogle Scholar
  3. 3.
    Kruger M et al (2014) Optimal timing of pulmonary metastasectomy-is a delayed operation beneficial or counterproductive? Eur J Surg Oncol 40(9):1049–1055CrossRefPubMedGoogle Scholar
  4. 4.
    Treasure T et al (2009) Pulmonary metastasectomy in colorectal cancer: time for a trial. Eur J Surg Oncol 35(7):686–689CrossRefPubMedGoogle Scholar
  5. 5.
    Pfannschmidt J, Hoffmann H, Dienemann H (2010) Reported outcome factors for pulmonary resection in metastatic colorectal cancer. J Thorac Oncol 5(6):S172–S178CrossRefPubMedGoogle Scholar
  6. 6.
    Schweiger T et al (2014) Prognostic factors in pulmonary metastasectomy: spotlight on molecular and radiological markers. Eur J Cardiothorac Surg 45(3):408–416CrossRefPubMedGoogle Scholar
  7. 7.
    Garcia-Yuste M, Cassivi S, Paleru C (2010) Thoracic lymphatic involvement in patients having pulmonary metastasectomy: incidence and the effect on prognosis. J Thorac Oncol 5(6):S166–S169CrossRefPubMedGoogle Scholar
  8. 8.
    Zabaleta J et al (2011) Survival after lung metastasectomy for colorectal cancer: importance of previous liver metastasis as a prognostic factor. Eur J Surg Oncol 37(9):786–790CrossRefPubMedGoogle Scholar
  9. 9.
    Hamaji M et al (2012) Is lymph node dissection required in pulmonary metastasectomy for colorectal adenocarcinoma? Ann Thorac Surg 94(6):1796–1800CrossRefPubMedGoogle Scholar
  10. 10.
    He Y et al (2004) Preexisting lymphatic endothelium but not endothelial progenitor cells are essential for tumor lymphangiogenesis and lymphatic metastasis. Cancer Res 64(11):3737–3740CrossRefPubMedGoogle Scholar
  11. 11.
    Beasley NJ et al (2002) Intratumoral lymphangiogenesis and lymph node metastasis in head and neck cancer. Cancer Res 62(5):1315–1320PubMedGoogle Scholar
  12. 12.
    Choi WW et al (2005) Angiogenic and lymphangiogenic microvessel density in breast carcinoma: correlation with clinicopathologic parameters and VEGF-family gene expression. Mod Pathol 18(1):143–152CrossRefPubMedGoogle Scholar
  13. 13.
    Nishida T et al (2014) Predictors of lymph node metastasis in T1 colorectal carcinoma: an immunophenotypic analysis of 265 patients. Dis Colon Rectum 57(8):905–915CrossRefPubMedGoogle Scholar
  14. 14.
    Gertler R et al (2009) Defining a high-risk subgroup with colon cancer stages I and II for possible adjuvant therapy. Eur J Cancer 45(17):2992–2999CrossRefPubMedGoogle Scholar
  15. 15.
    Matsumoto K et al (2007) Lymphatic microvessel density is an independent prognostic factor in colorectal cancer. Dis Colon Rectum 50(3):308–314CrossRefPubMedGoogle Scholar
  16. 16.
    Ishii M et al (2009) Lymphatic vessel invasion detected by monoclonal antibody D2-40 as a predictor of lymph node metastasis in T1 colorectal cancer. Int J Colorectal Dis 24(9):1069–1074CrossRefPubMedGoogle Scholar
  17. 17.
    Weidner N et al (1992) Tumor angiogenesis: a new significant and independent prognostic indicator in early-stage breast carcinoma. J Natl Cancer Inst 84(24):1875–1887CrossRefPubMedGoogle Scholar
  18. 18.
    Schoppmann A et al (2011) Comparison of lymphangiogenesis between primary colorectal cancer and corresponding liver metastases. Anticancer Res 31(12):4605–4611PubMedGoogle Scholar
  19. 19.
    Schweiger T et al (2014) EGFR, BRAF and KRAS status in patients undergoing pulmonary metastasectomy from primary colorectal carcinoma: a prospective follow-up study. Ann Surg Oncol 21(3):946–954CrossRefPubMedGoogle Scholar
  20. 20.
    Pfannschmidt J, Dienemann H, Hoffmann H (2007) Surgical resection of pulmonary metastases from colorectal cancer: a systematic review of published series. Ann Thorac Surg 84(1):324–338CrossRefPubMedGoogle Scholar
  21. 21.
    Okumura S et al (1996) Pulmonary resection for metastatic colorectal cancer: experiences with 159 patients. J Thorac Cardiovasc Surg 112(4):867–874CrossRefPubMedGoogle Scholar
  22. 22.
    Hwang MR et al (2010) Early intrapulmonary recurrence after pulmonary metastasectomy related to colorectal cancer. Ann Thorac Surg 90(2):398–404CrossRefPubMedGoogle Scholar
  23. 23.
    Zampino MG et al (2014) Lung metastases from colorectal cancer: analysis of prognostic factors in a single institution study. Ann Thorac Surg 98(4):1238–1245CrossRefPubMedGoogle Scholar
  24. 24.
    Internullo E et al (2008) Pulmonary metastasectomy: a survey of current practice amongst members of the European Society of Thoracic Surgeons. J Thorac Oncol 3(11):1257–1266CrossRefPubMedGoogle Scholar
  25. 25.
    Renaud S et al (2014) Does nodal status influence survival? Results of a 19-year systematic lymphadenectomy experience during lung metastasectomy of colorectal cancer. Interact CardioVasc Thorac Surg 18(4):482–487PubMedCentralCrossRefPubMedGoogle Scholar
  26. 26.
    Loehe F et al (2001) Value of systematic mediastinal lymph node dissection during pulmonary metastasectomy. Ann Thorac Surg 72(1):225–229CrossRefPubMedGoogle Scholar
  27. 27.
    Zhang Z et al (2015) Can lymph node evaluation be performed well by video-assisted thoracic surgery? J Cancer Res Clin Oncol 141(1):143–151CrossRefPubMedGoogle Scholar
  28. 28.
    Seebacher G et al (2014) Unexpected Lymph Node Disease in Resections for Pulmonary Metastases. Ann Thorac Surg 99:231–236CrossRefPubMedGoogle Scholar
  29. 29.
    Bolukbas S et al (2014) Risk factors for lymph node metastases and prognosticators of survival in patients undergoing pulmonary metastasectomy for colorectal cancer. Ann Thorac Surg 97(6):1926–1932CrossRefPubMedGoogle Scholar
  30. 30.
    Shiono S et al (2005) Histopathologic prognostic factors in resected colorectal lung metastases. Ann Thorac Surg 79(1):278–282CrossRefPubMedGoogle Scholar
  31. 31.
    Wang H et al (2010) Patterns of lymph node metastasis are different in colon and rectal carcinomas. World J Gastroenterol 16(42):5375–5379PubMedCentralCrossRefPubMedGoogle Scholar
  32. 32.
    Li M et al (2007) Colorectal cancer or colon and rectal cancer? Clinicopathological comparison between colonic and rectal carcinomas. Oncology 73(1–2):52–57CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2015

Authors and Affiliations

  • Thomas Schweiger
    • 1
    • 2
  • Christoph Nikolowsky
    • 1
    • 2
  • Thomas Graeter
    • 3
  • Gernot Seebacher
    • 3
  • Jürgen Laufer
    • 4
  • Olaf Glueck
    • 1
    • 2
  • Christoph Glogner
    • 1
    • 2
  • Peter Birner
    • 5
  • György Lang
    • 1
  • Walter Klepetko
    • 1
  • Hendrik Jan Ankersmit
    • 1
    • 2
  • Konrad Hoetzenecker
    • 1
    Email author
  1. 1.Department of Thoracic SurgeryMedical University of ViennaViennaAustria
  2. 2.Christian Doppler Laboratory for Cardiac and Thoracic Diagnosis and RegenerationMedical University of ViennaViennaAustria
  3. 3.Department of Thoracic and Vascular SurgeryKlinik LoewensteinLoewensteinGermany
  4. 4.Institute for PathologySLK-Kliniken HeilbronnHeilbronnGermany
  5. 5.Department of PathologyMedical University of ViennaViennaAustria

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