Tumor Biology

, Volume 35, Issue 6, pp 5511–5518 | Cite as

RETRACTED ARTICLE: Relationship between VEGF protein expression and lymph node metastasis in papillary thyroid carcinoma among Asians: a meta-analysis

  • De-Feng Chang
  • Zhong-Qing Xu
  • Bin Sun
Research Article


We carried out the current meta-analysis of relevant cohort studies in an attempt to investigate the relationships between vascular endothelial growth factor (VEGF) protein expression and lymph node (LN) metastasis in papillary thyroid carcinoma (PTC) among Asians. A range of electronic databases were searched, including Web of Science (1945 ∼ 2013), the Cochrane Library Database (Issue 12, 2013), MEDLINE (1966 ∼ 2013), EMBASE (1980 ∼ 2013), CINAHL (1982 ∼ 2013), and Chinese Biomedical Database (CBM) (1982 ∼ 2013) with cross-referencing without language restrictions. Meta-analysis was conducted using the STATA 12.0 software. Crude odds ratio (OR) with their 95 % confidence interval (95 %CI) was calculated. Twelve clinical cohort studies with a total of 1,045 PTC patients were included in our meta-analysis, The results of our meta-analysis revealed that patients with VEGF-positive tumors had a 3.02-fold higher risk of LN metastasis than that of patients with VEGF-negative tumors (OR = 3.02, 95 %CI = 2.05 ∼ 4.43, P < 0.001). Furthermore, subgroup analysis by country suggested that VEGF-positive expression was associated with an increased risk of LN metastasis in PTC patients among Chinese populations (OR = 3.33, 95 %CI = 2.30 ∼ 4.83, P < 0.001), but not among Korean, Turkish, and Japanese populations (all P > 0.05). Our findings support the view that VEGF protein expression may be correlated with LN metastasis in PTC patients, especially among Chinese populations.


Vascular endothelial growth factor Papillary thyroid carcinoma Lymph node metastasis Meta-analysis 



We would like to acknowledge the reviewers for their helpful comments on this paper.

Conflicts of interest



  1. 1.
    LiVolsi VA. Papillary thyroid carcinoma: an update. Mod Pathol. 2011;24 Suppl 2:S1–9.CrossRefPubMedGoogle Scholar
  2. 2.
    Mazzaferri EL, Doherty GM, Steward DL. The pros and cons of prophylactic central compartment lymph node dissection for papillary thyroid carcinoma. Thyroid. 2009;19(7):683–9.CrossRefPubMedGoogle Scholar
  3. 3.
    Lukas J, Drabek J, Lukas D, Dusek L, Gatek J. The epidemiology of thyroid cancer in the Czech Republic in comparison with other countries. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2013;157(3):266–75.PubMedGoogle Scholar
  4. 4.
    Swierniak M, Wojcicka A, Czetwertynska M, Stachlewska E, Maciag M, Wiechno W, et al. In-depth characterization of the microrna transcriptome in normal thyroid and papillary thyroid carcinoma. J Clin Endocrinol Metab. 2013;98(8):E1401–9.CrossRefPubMedGoogle Scholar
  5. 5.
    Liao S, Song W, Liu Y, Deng S, Liang Y, Tang Z, et al. Familial multinodular goiter syndrome with papillary thyroid carcinomas: mutational analysis of the associated genes in 5 cases from 1 Chinese family. BMC Endocr Disord. 2013;13(1):48.PubMedCentralCrossRefPubMedGoogle Scholar
  6. 6.
    Chen AY, Jemal A, Ward EM. Increasing incidence of differentiated thyroid cancer in the United States, 1988–2005. Cancer. 2009;115(16):3801–7.CrossRefPubMedGoogle Scholar
  7. 7.
    Wartofsky L. Increasing world incidence of thyroid cancer: increased detection or higher radiation exposure? Horm (Athens). 2010;9(2):103–8.CrossRefGoogle Scholar
  8. 8.
    Kabat GC, Kim MY, Wactawski-Wende J, Lane D, Wassertheil-Smoller S, Rohan TE. Menstrual and reproductive factors, exogenous hormone use, and risk of thyroid carcinoma in postmenopausal women. Cancer Causes Control. 2012;23(12):2031–40.CrossRefPubMedGoogle Scholar
  9. 9.
    Jebreel A, England J, Bedford K, Murphy J, Karsai L, Atkin S. Vascular endothelial growth factor (VEGF), VEGF receptors expression and microvascular density in benign and malignant thyroid diseases. Int J Exp Pathol. 2007;88(4):271–7.PubMedCentralCrossRefPubMedGoogle Scholar
  10. 10.
    Erdem H, Gundogdu C, Sipal S. Correlation of E-cadherin, VEGF, Cox-2 expression to prognostic parameters in papillary thyroid carcinoma. Exp Mol Pathol. 2011;90(3):312–7.CrossRefPubMedGoogle Scholar
  11. 11.
    Yasuoka H, Nakamura Y, Zuo H, Tang W, Takamura Y, Miyauchi A, et al. VEGF-D expression and lymph vessels play an important role for lymph node metastasis in papillary thyroid carcinoma. Mod Pathol. 2005;18(8):1127–33.CrossRefPubMedGoogle Scholar
  12. 12.
    Tian X, Cong M, Zhou W, Zhu J, Liu Q. Relationship between protein expression of VEGF-C, MMP-2 and lymph node metastasis in papillary thyroid cancer. J Int Med Res. 2008;36(4):699–703.CrossRefPubMedGoogle Scholar
  13. 13.
    Bates DO. Vascular endothelial growth factors and vascular permeability. Cardiovasc Res. 2010;87(2):262–71.PubMedCentralCrossRefPubMedGoogle Scholar
  14. 14.
    Poh CK, Shi Z, Lim TY, Neoh KG, Wang W. The effect of VEGF functionalization of titanium on endothelial cells in vitro. Biomaterials. 2010;31(7):1578–85.CrossRefPubMedGoogle Scholar
  15. 15.
    Miller JW, Le Couter J, Strauss EC, Ferrara N. Vascular endothelial growth factor a in intraocular vascular disease. Ophthalmology. 2013;120(1):106–14.CrossRefPubMedGoogle Scholar
  16. 16.
    Doi K, Noiri E, Fujita T. Role of vascular endothelial growth factor in kidney disease. Curr Vasc Pharmacol. 2010;8(1):122–8.CrossRefPubMedGoogle Scholar
  17. 17.
    Hsueh C, Lin JD, Wu IC, Chao TC, Yu JS, Liou MJ, et al. Vascular endothelial growth factors and angiopoietins in presentations and prognosis of papillary thyroid carcinoma. J Surg Oncol. 2011;103(5):395–9.CrossRefPubMedGoogle Scholar
  18. 18.
    Saharinen P, Eklund L, Pulkki K, Bono P, Alitalo K. Vegf and angiopoietin signaling in tumor angiogenesis and metastasis. Trends Mol Med. 2011;17(7):347–62.CrossRefPubMedGoogle Scholar
  19. 19.
    Ferrara N. Pathways mediating VEGF-independent tumor angiogenesis. Cytokine Growth Factor Rev. 2010;21(1):21–6.CrossRefPubMedGoogle Scholar
  20. 20.
    Salajegheh A, Pakneshan S, Rahman A, Dolan-Evans E, Zhang S, Kwong E, et al. Co-regulatory potential of vascular endothelial growth factor-a and vascular endothelial growth factor-c in thyroid carcinoma. Hum Pathol. 2013;44(10):2204–12.CrossRefPubMedGoogle Scholar
  21. 21.
    Kamat A, Rajoria S, George A, Suriano R, Shanmugam A, Megwalu U, et al. Estrogen-mediated angiogenesis in thyroid tumor microenvironment is mediated through VEGF signaling pathways. Arch Otolaryngol Head Neck Surg. 2011;137(11):1146–53.CrossRefPubMedGoogle Scholar
  22. 22.
    Pasquali D, Santoro A, Bufo P, Conzo G, Deery WJ, Renzullo A, et al. Upregulation of endocrine gland-derived vascular endothelial growth factor in papillary thyroid cancers displaying infiltrative patterns, lymph node metastases, and BRAF mutation. Thyroid. 2011;21(4):391–9.CrossRefPubMedGoogle Scholar
  23. 23.
    de Araujo-Filho VJ, Alves VA, de Castro IV, Lourenco SV, Cernea CR, Brandao LG, et al. Vascular endothelial growth factor expression in invasive papillary thyroid carcinoma. Thyroid. 2009;19(11):1233–7.CrossRefPubMedGoogle Scholar
  24. 24.
    Yu XM, Lo CY, Lam AK, Lang BH, Leung P, Luk JM. The potential clinical relevance of serum vascular endothelial growth factor (VEGF) and VEGF-C in recurrent papillary thyroid carcinoma. Surgery. 2008;144(6):934–40. discussion 40-1.CrossRefPubMedGoogle Scholar
  25. 25.
    Kim BH, Lee CH, Kim SJ, Jeon YK, Kim SS, Kim YK, et al. Clinicopathologic characteristics of synchronous primary thyroid cancer detected by initial staging (18)F-FDG PET-CT examination in patients with underlying malignancy. Thyroid. 2013;23(11):1431–6.PubMedCentralCrossRefPubMedGoogle Scholar
  26. 26.
    Li J, Teng L, Jiang H. Relationship between preoperative serum TSH levels and expression of VEGF in papillary thyroid carcinoma. Asia Pac J Clin Oncol. 2013;40(5):455–8.Google Scholar
  27. 27.
    Stang A. Critical evaluation of the newcastle-ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol. 2010;25(9):603–5.CrossRefPubMedGoogle Scholar
  28. 28.
    Zintzaras E, Ioannidis JP. Hegesma: genome search meta-analysis and heterogeneity testing. Bioinformatics. 2005;21(18):3672–3.CrossRefPubMedGoogle Scholar
  29. 29.
    Peters JL, Sutton AJ, Jones DR, Abrams KR, Rushton L. Comparison of two methods to detect publication bias in meta-analysis. JAMA. 2006;295(6):676–80.CrossRefPubMedGoogle Scholar
  30. 30.
    Miao AL, Wan MZ, Cheng L. Expression of Cox-2 and VEGF-C in papillary thyroid carcinoma and their relationship to cervical lymph metastases. J Clin Otorhinolaryngol Head Neck Surg. 2009;23(19):881–3.Google Scholar
  31. 31.
    Lee SH, Lee SJ, Jin SM, Lee NH, Kim DH, Chae SW, et al. Relationships between lymph node metastasis and expression of CD31, D2-40, and vascular endothelial growth factors A and C in papillary thyroid cancer. Clin Exp Otorhinolaryngol. 2012;5(3):150–5.PubMedCentralCrossRefPubMedGoogle Scholar
  32. 32.
    Jiang HG, Gao M, Tang WP, Li FH, Cai QZ. Expression and significance of VEGF, VEGF-C, and VEGF-D in papillary thyroid carcinoma. Chin J Cancer. 2005;24(9):1136–9.Google Scholar
  33. 33.
    Luo HJ, Li JP, Yang TF, Wang JD. Expression and significance of VEGF-C and VEGF-D in differentiated thyroid carcinoma. J Clin Otorhinolaryngol Head Neck Surg. 2009;12:531–4.Google Scholar
  34. 34.
    Yu XM, Lo CY, Chan WF, Lam KY, Leung P, Luk JM. Increased expression of vascular endothelial growth factor c in papillary thyroid carcinoma correlates with cervical lymph node metastases. Clin Cancer Res. 2005;11(22):8063–9.CrossRefPubMedGoogle Scholar
  35. 35.
    Wang T, Jiang CX, Li Y, Liu X. Pathologic study of expression and significance of matrix metalloproteinases-9, tissue inhibitor of metalloproteinase-1, vascular endothelial growth factor and transforming growth factor beta-1 in papillary carcinoma and follicular carcinoma of thyroid. Chin J Pathol. 2009;38(12):824–8.Google Scholar
  36. 36.
    Wang YQ, Hua QQ. Clinical significance of HIF-1 alpha, VEGF and VEGF-C expression in papillary thyroid carcinoma. J Clin Otorhinolaryngol Head Neck Surg. 2007;21(5):204–6,8.Google Scholar
  37. 37.
    Tanaka K, Kurebayashi J, Sonoo H, Otsuki T, Yamamoto Y, Ohkubo S, et al. Expression of vascular endothelial growth factor family messenger rna in diseased thyroid tissues. Surg Today. 2002;32(9):761–8.CrossRefPubMedGoogle Scholar
  38. 38.
    Karpanen T, Egeblad M, Karkkainen MJ, Kubo H, Yla-Herttuala S, Jaattela M, et al. Vascular endothelial growth factor c promotes tumor lymphangiogenesis and intralymphatic tumor growth. Cancer Res. 2001;61(5):1786–90.PubMedGoogle Scholar
  39. 39.
    Freeman R, Girsh J, Jou AF, Ho JA, Hug T, Dernedde J, et al. Optical aptasensors for the analysis of the vascular endothelial growth factor (VEGF). Anal Chem. 2012;84(14):6192–8.CrossRefPubMedGoogle Scholar
  40. 40.
    Ebos JM, Lee CR, Cruz-Munoz W, Bjarnason GA, Christensen JG, Kerbel RS. Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis. Cancer Cell. 2009;15(3):232–9.PubMedCentralCrossRefPubMedGoogle Scholar
  41. 41.
    Thangarajah H, Yao D, Chang EI, Shi Y, Jazayeri L, Vial IN, et al. The molecular basis for impaired hypoxia-induced VEGF expression in diabetic tissues. Proc Natl Acad Sci U S A. 2009;106(32):13505–10.PubMedCentralCrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2014

Authors and Affiliations

  1. 1.Department of General SurgeryHeilongjiang HospitalHarbinPeople’s Republic of China

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