Skip to main content
SpringerLink
Log in

Lymphatic microvessel density as a prognostic factor in non-small cell lung carcinoma: a meta-analysis of the literature

  • Published:
Molecular Biology Reports Aims and scope Submit manuscript

Abstract

The role of lymphatic microvessel density (LVD) as a prognostic factor for survival of patients with non-small cell lung carcinoma (NSCLC) remains controversial. To evaluate this potential role, we performed a systematic review of the electronic databases PubMed and EMBASE for relevant literature to review and compile available survival results. To be eligible, a study had to assess LVD in patients with NSCLC and to compare survival based on LVD stratification. Among 12 eligible trials, all dealt with NSCLC, and 10 trials provided results for the meta-analysis of survival data (evaluable trials). In terms of survival, high LVD was reported to be an unfavorable prognostic factor for overall survival in 8 studies, whereas it was not in 4 studies. The overall survival hazard ratio for the 10 evaluable studies (1,426 patients) was calculated to be 1.41 (95% CI: 1.14–1.75) using a random effects model, indicating a poorer survival for NSCLC patients with high LVD. The hazard ratio was 1.52 (95% CI: 1.10–2.11) in 5 NSCLC studies where LVD was assessed based on D2-40 and 1.31 (95% CI: 1.08–1.60) in 4 studies where LVD was measured based on vascular endothelial growth factor receptor-3. This study supports the hypothesis that the lymphatic microvessel count or LVD, which reflects levels of lymphangiogenesis, is a poor prognostic factor for patient survival in surgically treated NSCLC. However, the present findings may overestimate the prognostic capacity of LVD because of publication and report bias. In addition, the standardization of lymphangiogenesis assessment by the lymphatic microvessel count is necessary.

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.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Hirsh V (2010) Systemic therapies in metastatic non-small-cell lung cancer with emphasis on targeted therapies: the rational approach. Curr Oncol 17:13–23

    PubMed  CAS  Google Scholar 

  2. Chansky K, Sculier JP, Crowley JJ, Giroux D, Van Meerbeeck J, Goldstraw P (2009) The International Association for the Study of Lung Cancer Staging Project: prognostic factors and pathologic TNM stage in surgically managed non-small cell lung cancer. J Thorac Oncol 4:792–801

    Article  PubMed  Google Scholar 

  3. Steels E, Paesmans M, Berghmans T, Branle F, Lemaitre F, Mascaux C, Meert AP, Vallot F, Lafitte JJ, Sculier JP (2001) Role of p53 as a prognostic factor for survival in lung cancer: a systematic review of the literature with a meta-analysis. Eur Respir J 18:705–719

    Article  PubMed  CAS  Google Scholar 

  4. Meert AP, Martin B, Delmotte P, Berghmans T, Lafitte JJ, Mascaux C, Paesmans M, Steels E, Verdebout JM, Sculier JP (2002) The role of EGF-R expression on patient survival in lung cancer: a systematic review with meta-analysis. Eur Respir J 20:975–981

    Article  PubMed  CAS  Google Scholar 

  5. Meert AP, Martin B, Paesmans M, Berghmans T, Mascaux C, Verdebout JM, Delmotte P, Lafitte JJ, Sculier JP (2003) The role of HER-2/neu expression on the survival of patients with lung cancer: a systematic review of the literature. Br J Cancer 89:959–965

    Article  PubMed  CAS  Google Scholar 

  6. Martin B, Paesmans M, Mascaux C, Berghmans T, Lothaire P, Meert AP, Lafitte JJ, Sculier JP (2004) Ki-67 expression and patients survival in lung cancer: systematic review of the literature with meta-analysis. Br J Cancer 91:2018–2025

    Article  PubMed  CAS  Google Scholar 

  7. Mascaux C, Martin B, Paesmans M, Berghmans T, Dusart M, Haller A, Lothaire P, Meert AP, Lafitte JJ, Sculier JP (2006) Has Cox-2 a prognostic role in non-small-cell lung cancer? A systematic review of the literature with meta-analysis of the survival results. Br J Cancer 95:139–145

    Article  PubMed  CAS  Google Scholar 

  8. Delmotte P, Martin B, Paesmans M, Berghmans T, Mascaux C, Meert AP, Steels E, Verdebout JM, Lafitte JJ, Sculier JP (2002) VEGF and survival of patients with lung cancer: a systematic literature review and meta-analysis. Rev Mal Respir 19:577–584

    PubMed  CAS  Google Scholar 

  9. Zhan P, Wang J, Lv XJ, Wang Q, Qiu LX, Lin XQ, Yu LK, Song Y (2009) Prognostic value of vascular endothelial growth factor expression in patients with lung cancer: a systematic review with meta-analysis. J Thorac Oncol 4:1094–1103

    Article  PubMed  Google Scholar 

  10. Mascaux C, Iannino N, Martin B, Paesmans M, Berghmans T, Dusart M, Haller A, Lothaire P, Meert AP, Noel S, Lafitte JJ, Sculier JP (2005) The role of RAS oncogene in survival of patients with lung cancer: a systematic review of the literature with meta-analysis. Br J Cancer 92:131–139

    Article  PubMed  CAS  Google Scholar 

  11. Meert AP, Paesmans M, Martin B, Delmotte P, Berghmans T, Verdebout JM, Lafitte JJ, Mascaux C, Sculier JP (2002) The role of microvessel density on the survival of patients with lung cancer: a systematic review of the literature with meta-analysis. Br J Cancer 87:694–701

    Article  PubMed  Google Scholar 

  12. Meert AP, Martin B, Paesmans M, Berghmans T, Mascaux C, Verdebout JM, Delmotte P, Lafitte JJ, Sculier JP (2003) Role of Bcl-2 as a prognostic factor for survival in lung cancer: a systematic review of the literature with meta-analysis. Br J Cancer 89:55–64

    Article  PubMed  Google Scholar 

  13. Tammela T, Alitalo K (2010) Lymphangiogenesis: molecular mechanisms and future promise. Cell 140:460–476

    Article  PubMed  CAS  Google Scholar 

  14. Lohela M, Bry M, Tammela T, Alitalo K (2009) VEGFs and receptors involved in angiogenesis versus lymphangiogenesis. Curr Opin Cell Biol 21:154–165

    Article  PubMed  CAS  Google Scholar 

  15. Cao Y (2005) Direct role of PDGF-BB in lymphangiogenesis and lymphatic metastasis. Cell Cycle 4:228–230

    Article  PubMed  CAS  Google Scholar 

  16. Chang LK, Garcia-Cardeña G, Farnebo F, Fannon M, Chen EJ, Butterfield C, Moses MA, Mulligan RC, Folkman J, Kaipainen A (2004) Dose-dependent response of FGF-2 for lymphangiogenesis. Proc Natl Acad Sci USA 101:11658–11663

    Article  PubMed  CAS  Google Scholar 

  17. Alitalo K, Tammela T, Petrova TV (2005) Lymphangiogenesis in development and human disease. Nature 438:946–953

    Article  PubMed  CAS  Google Scholar 

  18. Achen MG, Stacker SA (2006) Tumor lymphangiogenesis and metastatic spread-new players begin to emerge. Int J Cancer 119:1755–1760

    Article  PubMed  CAS  Google Scholar 

  19. Werynska B, Dziegiel P, Jankowska R (2009) Role of lymphangiogenesis in lung cancer. Folia Histochem Cytobiol 47:333–342

    Article  PubMed  CAS  Google Scholar 

  20. Feng Y, Wang W, Hu J, Ma J, Zhang Y, Zhang J (2010) Expression of VEGF-C and VEGF-D as significant markers for assessment of lymphangiogenesis and lymph node metastasis in non-small cell lung cancer. Anat Rec (Hoboken) 293:802–812

    Article  CAS  Google Scholar 

  21. Ran S, Volk L, Hall K, Flister MJ (2009) Lymphangiogenesis and lymphatic metastasis in breast cancer. Pathophysiology 17(4):229–251

    Article  PubMed  Google Scholar 

  22. Royston D, Jackson DG (2009) Mechanisms of lymphatic metastasis in human colorectal adenocarcinoma. J Pathol 217(5):608–619

    Article  PubMed  CAS  Google Scholar 

  23. Kodama M, Kitadai Y, Tanaka M, Kuwai T, Tanaka S, Oue N, Yasui W, Chayama K (2008) Vascular endothelial growth factor C stimulates progression of human gastric cancer via both autocrine and paracrine mechanisms. Clin Cancer Res 14:7205–7214

    Article  PubMed  CAS  Google Scholar 

  24. Benke EM, Ji Y, Patel V, Wang H, Miyazaki H, Yeudall WA (2010) VEGF-C contributes to head and neck squamous cell carcinoma growth and motility. Oral Oncol 46:e19–e24

    Article  PubMed  CAS  Google Scholar 

  25. Banerji S, Ni J, Wang SX, Clasper S, Su J, Tammi R, Jones M, Jackson DG (1999) LYVE-1, a new homologue of the CD44 glycoprotein, is a lymph-specific receptor for hyaluronan. J Cell Biol 144:789–801

    Article  PubMed  CAS  Google Scholar 

  26. Breiteneder-Geleff S, Soleiman A, Kowalski H, Horvat R, Amann G, Kriehuber E, Diem K, Weninger W, Tschachler E, Alitalo K, Kerjaschki D (1999) Angiosarcomas express mixed endothelial phenotypes of blood and lymphatic capillaries: podoplanin as a specific marker for lymphatic endothelium. Am J Pathol 154:385–394

    Article  PubMed  CAS  Google Scholar 

  27. Wigle JT, Oliver G (1999) Prox1 function is required for the development of the murine lymphatic system. Cell 98:769–778

    Article  PubMed  CAS  Google Scholar 

  28. Kahn HJ, Bailey D, Marks A (2002) Monoclonal antibody D2-40, a new marker of lymphatic endothelium, reacts with Kaposi’s sarcoma and a subset of angiosarcomas. Mod Pathol 15:434–440

    Article  PubMed  Google Scholar 

  29. Van den Eynden GG, Van der Auwera I, Van Laere SJ, Huygelen V, Colpaert CG, van Dam P, Dirix LY, Vermeulen PB, Van Marck E (2006) Induction of lymphangiogenesis in and around axillary lymph node metastases of patients with breast cancer. Br J Cancer 95:1362–1366

    Article  PubMed  Google Scholar 

  30. Arinaga M, Noguchi T, Takeno S, Chujo M, Miura T, Uchida Y (2003) Clinical significance of vascular endothelial growth factor C and vascular endothelial growth factor receptor 3 in patients with nonsmall cell lung carcinoma. Cancer 97:457–464

    Article  PubMed  CAS  Google Scholar 

  31. Renyi-Vamos F, Tovari J, Fillinger J, Timar J, Paku S, Kenessey I, Ostoros G, Agocs L, Soltesz I, Dome B (2005) Lymphangiogenesis correlates with lymph node metastasis, prognosis, and angiogenic phenotype in human non-small cell lung cancer. Clin Cancer Res 11:7344–7353

    Article  PubMed  CAS  Google Scholar 

  32. Chen X, Wan J, Liu J, Xie W, Diao X, Xu J, Zhu B, Chen Z (2010) Increased IL-17-producing cells correlate with poor survival and lymphangiogenesis in NSCLC patients. Lung Cancer 69(3):348–354

    Article  PubMed  Google Scholar 

  33. Okudera K, Kamata Y, Takanashi S, Hasegawa Y, Tsushima T, Ogura Y, Nakanishi K, Sato H, Okumura K (2006) Small adenocarcinoma of the lung: prognostic significance of central fibrosis chiefly because of its association with angiogenesis and lymphangiogenesis. Pathol Int 56:494–502

    Article  PubMed  Google Scholar 

  34. Parmar MK, Torri V, Stewart L (1998) Extracting summary statistics to perform meta-analyses of the published literature for survival endpoints. Stat Med 17:2815–2834

    Article  PubMed  CAS  Google Scholar 

  35. Yusuf S, Peto R, Lewis J, Collins R, Sleight P (1985) Beta blockade during and after myocardial infarction: an overview of the randomized trials. Prog Cardiovasc Dis 27:335–371

    Article  PubMed  CAS  Google Scholar 

  36. Chen F, Takenaka K, Ogawa E, Yanagihara K, Otake Y, Wada H, Tanaka F (2004) Flt-4-positive endothelial cell density and its clinical significance in non-small cell lung cancer. Clin Cancer Res 10:8548–8553

    Article  PubMed  CAS  Google Scholar 

  37. Sun JG, Liao RX, Qiu J, Jin JY, Wang XX, Duan YZ, Chen FL, Hao P, Xie QC, Wang ZX, Li DZ, Chen ZT, Zhang SX (2009) Detection of lymphangiogenesis in non-small cell lung cancer and its prognostic value. J Exp Clin Cancer Res 28:21

    Article  PubMed  Google Scholar 

  38. Guo X, Chen Y, Xu Z, Qian Y, Yu X (2009) Prognostic significance of VEGF-C expression in correlation with COX-2, lymphatic microvessel density, and clinicopathologic characteristics in human non-small cell lung cancer. Acta Biochim Biophys Sin (Shanghai) 41:217–222

    Article  CAS  Google Scholar 

  39. Ming J, Zhang Q, Qiu X, Wang E (2009) Interleukin 7/interleukin 7 receptor induce c-Fos/c-Jun-dependent vascular endothelial growth factor-D up-regulation: a mechanism of lymphangiogenesis in lung cancer. Eur J Cancer 45:866–873

    Article  PubMed  CAS  Google Scholar 

  40. Faoro L, Hutto JY, Salgia R, El-Zayaty SA, Ferguson MK, Cheney RT, Reid ME, Armato SG III, Krausz T, Husain AN (2008) Lymphatic vessel density is not associated with lymph node metastasis in non-small cell lung carcinoma. Arch Pathol Lab Med 132:1882–1888

    PubMed  Google Scholar 

  41. Kadota K, Huang CL, Liu D, Ueno M, Kushida Y, Haba R, Yokomise H (2008) The clinical significance of lymphangiogenesis and angiogenesis in non-small cell lung cancer patients. Eur J Cancer 44:1057–1067

    Article  PubMed  CAS  Google Scholar 

  42. Kojima H, Shijubo N, Yamada G, Ichimiya S, Abe S, Satoh M, Sato N (2005) Clinical significance of vascular endothelial growth factor-C and vascular endothelial growth factor receptor 3 in patients with T1 lung adenocarcinoma. Cancer 104:1668–1677

    Article  PubMed  CAS  Google Scholar 

  43. Iwakiri S, Nagai S, Katakura H, Takenaka K, Date H, Wada H, Tanaka F (2009) D2-40-positive lymphatic vessel density is a poor prognostic factor in squamous cell carcinoma of the lung. Ann Surg Oncol 16:1678–1685

    Article  PubMed  Google Scholar 

  44. Diederich S, Engeser P, Junker K, Passlick B, Pfluger T, Pottgen C, Reck M (2009) Response judgement—conventional versus new methods. Onkologie 32(Suppl 1):9–17

    Article  PubMed  Google Scholar 

  45. Metzner C, Noldge G, Delling G, Oehler U, Nawroth P, Kasperk C (2006) Bone metastasis of prostatic cancer imitating Paget’s sarcoma. Dtsch Med Wochenschr 131:2524–2528

    Article  PubMed  CAS  Google Scholar 

  46. Ueda K, Nawata S, Esato K, Sakano H, Tanaka T, Matsuoka T, Sudo M, Hayashi M, Hamano K (2003) Subjective criteria of chest CT findings for predicting pathological features and postoperative outcomes of small peripheral lung cancer (< or =2 cm). Kyobu Geka 56:841–845

    PubMed  CAS  Google Scholar 

  47. Ikegami H, Nakamura S, Horai T, Matsuda M (1983) Chemotherapy of small cell carcinoma of the lung in relation to lymph node metastasis and extending pattern of tumor. Gan To Kagaku Ryoho 10:750–755

    PubMed  CAS  Google Scholar 

  48. Wang Y, Sun JG, Ye MF, Chen ZT (2006) Clinical and prognostic significance of podoplanin-positive lymphatic vessel density in non-small cell lung carcinoma. Zhonghua Jie He He Hu Xi Za Zhi 29:758–761

    PubMed  Google Scholar 

  49. Kadota K, Huang CL, Liu D, Nakashima N, Yokomise H, Ueno M, Haba R (2010) The clinical significance of the tumor cell D2-40 immunoreactivity in non-small cell lung cancer. Lung Cancer 70(1):88–93

    Article  PubMed  Google Scholar 

  50. Takanami I, Abiko T, Koizumi S (2008) Expression of periostin in patients with non-small cell lung cancer: correlation with angiogenesis and lymphangiogenesis. Int J Biol Markers 23:182–186

    PubMed  CAS  Google Scholar 

  51. Egger M, Davey Smith G, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315:629–634

    Article  PubMed  CAS  Google Scholar 

  52. Begg CB, Mazumdar M (1994) Operating characteristics of a rank correlation test for publication bias. Biometrics 50:1088–1101

    Article  PubMed  CAS  Google Scholar 

  53. Laakkonen P, Porkka K, Hoffman JA, Ruoslahti E (2002) A tumor-homing peptide with a targeting specificity related to lymphatic vessels. Nat Med 8:751–755

    PubMed  CAS  Google Scholar 

  54. Valtola R, Salven P, Heikkilä P, Taipale J, Joensuu H, Rehn M, Pihlajaniemi T, Weich H, deWaal R, Alitalo K (1999) VEGFR-3 and its ligand VEGF-C are associated with angiogenesis in breast cancer. Am J Pathol 154:1381–1390

    Article  PubMed  CAS  Google Scholar 

  55. Pepper MS (2002) Lymphangiogenesis and tumor metastasis: myth or reality? Clin Cancer Res 7:462–468

    Google Scholar 

  56. Pusztaszeri MP, Seelentag W, Bosman FT (2006) Immunohistochemical expression of endothelial markers CD31, CD34, von Willebrand factor, and Fli-1 in normal human tissues. J Histochem Cytochem 54:385–395

    Article  PubMed  CAS  Google Scholar 

  57. Fiedler U, Christian S, Koidl S, Kerjaschki D, Emmett MS, Bates DO, Christofori G, Augustin HG (2006) The sialomucin CD34 is a marker of lymphatic endothelial cells in human tumors. Am J Pathol 168:1045–1053

    Article  PubMed  CAS  Google Scholar 

  58. Beasley NJ, Prevo R, Banerji S, Leek RD, Moore J, van Trappen P, Cox G, Harris AL, Jackson DG (2002) Intratumoral lymphangiogenesis and lymph node metastasis in head and neck cancer. Cancer Res 62:1315–1320

    PubMed  CAS  Google Scholar 

  59. Trivella M, Pezzella F, Pastorino U, Harris AL, Altman DG (2007) Microvessel density as a prognostic factor in non-small-cell lung carcinoma: a meta-analysis of individual patient data. Lancet Oncol 8:488–499

    Article  PubMed  Google Scholar 

  60. Uzzan B, Nicolas P, Cucherat M, Perret GY (2004) Microvessel density as a prognostic factor in women with breast cancer: a systematic review of the literature and meta-analysis. Cancer Res 64:2941–2955

    Article  PubMed  CAS  Google Scholar 

  61. Des Guetz G, Uzzan B, Nicolas P, Cucherat M, Morere JF, Benamouzig R, Breau JL, Perret GY (2006) Microvessel density and VEGF expression are prognostic factors in colorectal cancer. Meta-analysis of the literature. Br J Cancer 94(12):1823–1832

    Article  PubMed  Google Scholar 

  62. Padera TP, Kadambi A, di Tomaso E, Carreira CM, Brown EB, Boucher Y, Choi NC, Mathisen D, Wain J, Mark EJ, Munn LL, Jain RK (2002) Lymphatic metastasis in the absence of functional intratumor lymphatics. Science 296:1883–1886

    Article  PubMed  CAS  Google Scholar 

  63. Leu AJ, Berk DA, Lymboussaki A, Alitalo K, Jain RK (2000) Absence of functional lymphatics within a murine sarcoma: a molecular and functional evaluation. Cancer Res 60:4324–4327

    PubMed  CAS  Google Scholar 

  64. Padera TP, Stoll BR, Tooredman JB, Capen D, di Tomaso E, Jain RK (2004) Pathology: cancer cells compress intratumour vessels. Nature 427:695

    Article  PubMed  CAS  Google Scholar 

  65. Achen MG, McColl BK, Stacker SA (2005) Focus on lymphangiogenesis in tumor metastasis. Cancer Cell 7:121–127

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This study was supported by the National Nature Science Foundation of China (30901788) and Shandong Provincial Nature Science Foundation (ZR2010HQ038 and ZR2010HM059).

Conflict of interest

The authors declare no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Oncology, General Hospital, Jinan Command of People’s Liberation Army, Shifan Street 25, Tianqiao District, Jinan, 250031, China

    Jun Wang, Kainan Li, Baocheng Wang & Jingwang Bi

Authors
  1. Jun Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kainan Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Baocheng Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jingwang Bi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Baocheng Wang.

Additional information

J. Wang and K. Li contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wang, J., Li, K., Wang, B. et al. Lymphatic microvessel density as a prognostic factor in non-small cell lung carcinoma: a meta-analysis of the literature. Mol Biol Rep 39, 5331–5338 (2012). https://doi.org/10.1007/s11033-011-1332-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11033-011-1332-y

Keywords

Search

Navigation