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Microvessel density correlates with lymph node metastases and prognosis in hilar cholangiocarcinoma

  • Liver, Pancreas, and Biliary Tract
  • Published:
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Abstract

Background

Neovascularization was shown to be critically involved in the progression of multiple cancers, and treatment approaches targeting tumor-associated neovascularization provide convincing results in recent years in some tumor entities. However, little is known about the tumor-associated neovascularization in hilar cholangiocarcinoma. The present study was conducted to analyze tumor-associated neovascularization in hilar cholangiocarcinoma and to determine its influence on tumor growth, metastasis, recurrence, and prognosis.

Methods

We analyzed tissue specimens of hilar cholangiocarcinoma (n = 60) by immunohistochemistry using the endothelial-specific antibody CD31 and subsequently quantified the microvessel density (MVD). The MVD was correlated with clinicopathological characteristics and recurrence pattern of the tumors as well as survival of patients.

Results

Hilar cholangiocarcinoma revealed a high degree of vascularization, with a calculated mean MVD of 28.1 ± 14.5 vessels. Tumors with a high MVD had a significant higher incidence of lymph node involvement (P = 0.009) and local recurrence (P < 0.001). Furthermore, a high MVD was identified to be a significant overall survival disadvantage (3-year, 28% vs. 93%; 5-year, 8% vs. 78%; P < 0.001) as well as disease-free survival disadvantage (3-year, 7% vs. 88%, 5-year, 7% vs. 72%; P < 0.001), with MVD representing an independent prognostic factor for survival.

Conclusions

Neovascularization is associated with nodal spread as well as local recurrence and serves as an independent prognostic factor for survival after curative resection of hilar cholangiocarcinoma. Therefore, tumor-associated neovascularization seems to be critically involved in the progression of this tumor entity. In addition, neovascularization may represent a potential target in he development of new therapeutic approaches in hilar cholangiocarcinoma.

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References

  1. de Groen PC, Gores GJ, LaRusso NF, Gunderson LL, Nagorney DM. Biliary tract cancers. N Engl J Med 1999;341:1368–1378.

    Article  PubMed  Google Scholar 

  2. Patel T. Cholangiocarcinoma. Nat Clin Pract Gastroenterol Hepatol 2006;3:33–42.

    Article  PubMed  Google Scholar 

  3. Neuhaus P, Jonas S, Bechstein WO, Lohmann R, Radke C, Kling N, et al. Extended resections for hilar cholangiocarcinoma. Ann Surg 1999;230:808–819.

    Article  PubMed  CAS  Google Scholar 

  4. Nimura Y, Kamiya J, Kondo S, Nagino M, Uesaka K, Oda K, et al. Aggressive preoperative management and extended surgery for hilar cholangiocarcinoma: Nagoya experience. J Hepatobiliary Pancreat Surg 2000;7:155–162.

    Article  PubMed  CAS  Google Scholar 

  5. Jarnagin WR, Fong Y, DeMatteo RP, Gonen M, Burke EC, Bodniewicz BS J, et al. Staging, resectability, and outcome in 225 patients with hilar cholangiocarcinoma. Ann Surg 2001;234:507–517.

    Article  PubMed  CAS  Google Scholar 

  6. Jarnagin WR, Shoup M. Surgical management of cholangiocarcinoma. Semin Liver Dis 2004;24:189–199.

    Article  PubMed  Google Scholar 

  7. Ortner ME, Caca K, Berr F, Liebetruth J, Mansmann U, Huster D, et al. Successful photodynamic therapy for nonresectable cholangiocarcinoma: a randomized prospective study. Gastroenterology 2003;125:1355–1363.

    Article  PubMed  Google Scholar 

  8. Furuya M, Nishiyama M, Kasuya Y, Kimura S, Ishikura H. Pathophysiology of tumor neovascularization. Vasc Health Risk Manag 2005;1:277–290.

    Article  PubMed  CAS  Google Scholar 

  9. Sasano H, Suzuki T. Pathological evaluation of angiogenesis in human tumor. Biomed Pharmacother 2005;59(suppl 2):334–336.

    Article  Google Scholar 

  10. Rhee J, Hoff PM. Angiogenesis inhibitors in the treatment of cancer. Expert Opin Pharmacother 2005;6:1701–1711.

    Article  PubMed  CAS  Google Scholar 

  11. Thelen A, Scholz A, Benckert C, Weichert W, Dietz E, Wiedenmann B, et al. Tumor-associated lymphangiogenesis correlates with lymph node metastases and prognosis in hilar cholangiocarcinoma. Ann Surg Oncol 2008;15:791–799.

    Article  PubMed  Google Scholar 

  12. Sobin LH, Wittekind CH, editors. UICC: TNM classification of malignant tumors. 6th ed. New York: Wiley-Liss; 2002.

    Google Scholar 

  13. Parums DV, Cordell JL, Micklem K, Heryet AR, Gatter KC, Mason DY. JC70: a new monoclonal antibody that detects vascular endothelium associated antigen on routinely processed tissue sections. J Clin Pathol 1990;43:752–757.

    Article  PubMed  CAS  Google Scholar 

  14. Sarraf-Yazdi S, Mi J, Clary BM. Hepatic tumor growth: target for angiogenesis inhibition? World J Surg 2005;29:287–292.

    Article  PubMed  Google Scholar 

  15. Ribatti D, Vacca A, Nico B, Sansonno D, Dammacco F. Angiogenesis and anti-angiogenesis in hepatocellular carcinoma. Cancer Treat Rev 2006;32:437–444.

    Article  PubMed  CAS  Google Scholar 

  16. Jonas S, Bechstein WO, Steinmuller T, Herrmann M, Radke C, Berg T, et al. Vascular invasion and histopathologic grading determine outcome after liver transplantation for hepatocellular carcinoma in cirrhosis. Hepatology 2001;33:1080–1086.

    Article  PubMed  CAS  Google Scholar 

  17. Imamura H, Matsuyama Y, Tanaka E, Ohkubo T, Hasegawa K, Miyagawa S, et al. Risk factors contributing to early and late phase intrahepatic recurrence of hepatocellular carcinoma after hepatectomy. J Hepatol 2003;38:200–207.

    Article  PubMed  Google Scholar 

  18. Benckert C, Jonas S, Cramer T, Von Marschall Z, Schafer G, Peters M, et al. Transforming growth factor beta 1 stimulates vascular endothelial growth factor gene transcription in human cholangiocellular carcinoma cells. Cancer Res 2003;63:1083–1092.

    PubMed  CAS  Google Scholar 

  19. Mobius C, Demuth C, Aigner T, Wiedmann M, Wittekind C, Mossner J, et al. Evaluation of VEGF-A expression and microvessel density as prognostic factors in extrahepatic cholangiocarcinoma. Eur J Surg Oncol 2007;33:1025–1029.

    PubMed  CAS  Google Scholar 

  20. Otto G, Thies J, Hoppe-Lotichius M, Bittinger F, Pitton MB, Hadian A. Hilar cholangiocarcinoma: results of en bloc resection of tumor and liver (in German with English abstract). Chirurg 2004;75:59–65.

    Article  PubMed  CAS  Google Scholar 

  21. Ebata T, Nagino M, Kamiya J, Uesaka K, Nagasaka T, Nimura Y. Hepatectomy with portal vein resection for hilar cholangiocarcinoma: audit of 52 consecutive cases. Ann Surg 2003;238:720–727.

    Article  PubMed  Google Scholar 

  22. Mittal B, Deutsch M, Iwatsuki S. Primary cancers of extrahepatic biliary passages. Int J Radiat Oncol Biol Phys 1985;11:849–854.

    PubMed  CAS  Google Scholar 

  23. Shayan R, Achen MG, Stacker SA. Lymphatic vessels in cancer metastasis: bridging the gaps. Carcinogenesis (Oxf) 2006;27:1729–1738.

    Article  CAS  Google Scholar 

  24. Saaristo A, Karpanen T, Alitalo K. Mechanisms of angiogenesis and their use in the inhibition of tumor growth and metastasis. Oncogene 2000;19:6122–6129.

    Article  PubMed  CAS  Google Scholar 

  25. Jain RK. Tumor angiogenesis and accessibility: role of vascular endothelial growth factor. Semin Oncol 2002;29:3–9.

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  27. Schoppmann SF, Birner P, Stöckl J, Kalt R, Ullrich R, Cauciq C, et al. Tumor-associated macrophages express lymphatic endothelial growth factors and are related to peritumoral lymphangiogenesis. Am J Pathol 2002;161:947–956.

    PubMed  CAS  Google Scholar 

  28. Rea DJ, Heimbach JK, Rosen CB, Haddock MG, Alberts SR, Kremers WK, et al. Liver transplantation with neoadjuvant chemoradiation is more effective than resection for hilar cholangiocarcinoma. Ann Surg 2005;242:451–458.

    PubMed  Google Scholar 

  29. Heimbach JK, Gores GJ, Haddock MG, Alberts SR, Pedersen R, Kremers W, et al. Predictors of disease recurrence following neoadjuvant chemoradiotherapy and liver transplantation for unresectable perihilar cholangiocarcinoma. Transplantation 2006;82:1703–1707.

    Article  PubMed  CAS  Google Scholar 

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Thelen, A., Scholz, A., Benckert, C. et al. Microvessel density correlates with lymph node metastases and prognosis in hilar cholangiocarcinoma. J Gastroenterol 43, 959–966 (2008). https://doi.org/10.1007/s00535-008-2255-9

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  • DOI: https://doi.org/10.1007/s00535-008-2255-9

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