Radiation Oncology Journal

The Korean Society for Radiation Oncology (대한방사선종양학회)
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Molecular biomarkers in extrahepatic bile duct cancer patients undergoing chemoradiotherapy for gross residual disease after surgery

  • Koh, Hyeon Kang (Department of Radiation Oncology, Seoul National University College of Medicine) ;
  • Park, Hae Jin (Department of Radiation Oncology, Soonchunhyang University Hospital) ;
  • Kim, Kyubo (Department of Radiation Oncology, Seoul National University College of Medicine) ;
  • Chie, Eui Kyu (Department of Radiation Oncology, Seoul National University College of Medicine) ;
  • Min, Hye Sook (Department of Pathology, Seoul National University College of Medicine) ;
  • Ha, Sung W. (Department of Radiation Oncology, Seoul National University College of Medicine)
  • Received : 2012.09.17
  • Accepted : 2012.10.22
  • Published : 2012.12.30
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Abstract

Purpose: To analyze the outcomes of chemoradiotherapy for extrahepatic bile duct (EHBD) cancer patients who underwent R2 resection or bypass surgery and to identify prognostic factors affecting clinical outcomes, especially in terms of molecular biomarkers. Materials and Methods: Medical records of 21 patients with EHBD cancer who underwent R2 resection or bypass surgery followed by chemoradiotherapy from May 2001 to June 2010 were retrospectively reviewed. All surgical specimens were reevaluated by immunohistochemical staining using phosphorylated protein kinase B (pAKT), CD24, matrix metalloproteinase 9 (MMP9), survivin, and ${\beta}$-catenin antibodies. The relationship between clinical outcomes and immunohistochemical results was investigated. Results: At a median follow-up of 20 months, the actuarial 2-year locoregional progression-free, distant metastasis-free and overall survival were 37%, 56%, and 54%, respectively. On univariate analysis using clinicopathologic factors, there was no significant prognostic factor. In the immunohistochemical staining, cytoplasmic staining, and nuclear staining of pAKT was positive in 10 and 6 patients, respectively. There were positive CD24 in 7 patients, MMP9 in 16 patients, survivin in 8 patients, and ${\beta}$-catenin in 3 patients. On univariate analysis, there was no significant value of immunohistochemical results for clinical outcomes. Conclusion: There was no significant association between clinical outcomes of patients with EHBD cancer who received chemoradiotherapy after R2 resection or bypass surgery and pAKT, CD24, MMP9, survivin, and ${\beta}$-catenin. Future research is needed on a larger data set or with other molecular biomarkers.

Keywords

References

  1. Ganeshan D, Moron FE, Szklaruk J. Extrahepatic biliary cancer: new staging classification. World J Radiol 2012;4:345-52. https://doi.org/10.4329/wjr.v4.i8.345
  2. Seyama Y, Makuuchi M. Current surgical treatment for bile duct cancer. World J Gastroenterol 2007;13:1505-15. https://doi.org/10.3748/wjg.v13.i10.1505
  3. Vauthey JN, Blumgart LH. Recent advances in the management of cholangiocarcinomas. Semin Liver Dis 1994;14:109-14. https://doi.org/10.1055/s-2007-1007302
  4. Nathan H, Pawlik TM, Wolfgang CL, Choti MA, Cameron JL, Schulick RD. Trends in survival after surgery for cholangiocarcinoma: a 30-year population-based SEER database analysis. J Gastrointest Surg 2007;11:1488-96. https://doi.org/10.1007/s11605-007-0282-0
  5. Witzigmann H, Berr F, Ringel U, et al. Surgical and palliative management and outcome in 184 patients with hilar cholangiocarcinoma: palliative photodynamic therapy plus stenting is comparable to r1/r2 resection. Ann Surg 2006;244:230-9. https://doi.org/10.1097/01.sla.0000217639.10331.47
  6. Reding R, Buard JL, Lebeau G, Launois B. Surgical management of 552 carcinomas of the extrahepatic bile ducts (gallbladder and periampullary tumors excluded): results of the French Surgical Association Survey. Ann Surg 1991;213:236-41. https://doi.org/10.1097/00000658-199103000-00010
  7. Yamaguchi K, Chijiiwa K, Saiki S, Shimizu S, Takashima M, Tanaka M. Carcinoma of the extrahepatic bile duct: mode of spread and its prognostic implications. Hepatogastroenterology 1997;44:1256-61.
  8. Nagorney DM, Donohue JH, Farnell MB, Schleck CD, Ilstrup DM. Outcomes after curative resections of cholangiocarcinoma. Arch Surg 1993;128:871-7. https://doi.org/10.1001/archsurg.1993.01420200045008
  9. Kim JW, Jo S, Moon HJ, et al. Prognostic factors after major resection for distal extrahepatic cholangiocarcinoma. Korean J Gastroenterol 2006;47:144-52.
  10. Kloek JJ, Ten Kate FJ, Busch OR, Gouma DJ, van Gulik TM. Surgery for extrahepatic cholangiocarcinoma: predictors of survival. HPB (Oxford) 2008;10:190-5. https://doi.org/10.1080/13651820801992575
  11. Fingas CD, Katsounas A, Kahraman A, et al. Prognostic assessment of three single-nucleotide polymorphisms (GNB3 825C>T, BCL2-938C>A, MCL1-386C>G) in extrahepatic cholangiocarcinoma. Cancer Invest 2010;28:472-8. https://doi.org/10.3109/07357900903095714
  12. Mobius C, Demuth C, Aigner T, et al. Evaluation of VEGF A expression and microvascular density as prognostic factors in extrahepatic cholangiocarcinoma. Eur J Surg Oncol 2007;33:1025-9. https://doi.org/10.1016/j.ejso.2007.02.020
  13. Tamada S, Shibahara H, Higashi M, et al. MUC4 is a novel prognostic factor of extrahepatic bile duct carcinoma. Clin Cancer Res 2006;12:4257-64. https://doi.org/10.1158/1078-0432.CCR-05-2814
  14. Li S, Jo YS, Lee JH, et al. L1 cell adhesion molecule is a novel independent poor prognostic factor of extrahepatic cholangiocarcinoma. Clin Cancer Res 2009;15:7345-51. https://doi.org/10.1158/1078-0432.CCR-09-0959
  15. Chung JY, Hong SM, Choi BY, Cho H, Yu E, Hewitt SM. The expression of phospho-AKT, phospho-mTOR, and PTEN in extrahepatic cholangiocarcinoma. Clin Cancer Res 2009;15:660-7. https://doi.org/10.1158/1078-0432.CCR-08-1084
  16. Hori H, Ajiki T, Mita Y, et al. Frequent activation of mitogenactivated protein kinase relative to Akt in extrahepatic biliary tract cancer. J Gastroenterol 2007;42:567-72. https://doi.org/10.1007/s00535-007-2055-7
  17. Itatsu K, Zen Y, Yamaguchi J, et al. Expression of matrix metalloproteinase 7 is an unfavorable postoperative prognostic factor in cholangiocarcinoma of the perihilar, hilar, and extrahepatic bile ducts. Hum Pathol 2008;39:710-9. https://doi.org/10.1016/j.humpath.2007.09.016
  18. Qin XL, Xue HZ, Wang ZR, Liu HS, Zhou HB, Ma W. Expression of Survivin protein in extrahepatic cholangiocarcinoma and its relationship with the prognosis. Zhonghua Wai Ke Za Zhi 2009;47:1852-6.
  19. Tanno S, Yanagawa N, Habiro A, et al. Serine/threonine kinase AKT is frequently activated in human bile duct cancer and is associated with increased radioresistance. Cancer Res2004;64:3486-90. https://doi.org/10.1158/0008-5472.CAN-03-1788
  20. Javle MM, Yu J, Khoury T, et al. Akt expression may predict favorable prognosis in cholangiocarcinoma. J Gastroenterol Hepatol 2006;21:1744-51. https://doi.org/10.1111/j.1440-1746.2006.04373.x
  21. Kristiansen G, Sammar M, Altevogt P. Tumour biological aspects of CD24, a mucin-like adhesion molecule. J Mol Histol 2004;35:255-62.
  22. Keeratichamroen S, Leelawat K, Thongtawee T, et al. Expression of CD24 in cholangiocarcinoma cells is associated with disease progression and reduced patient survival. Int J Oncol 2011;39:873-81.
  23. Agrawal S, Kuvshinoff BW, Khoury T, et al. CD24 expression is an independent prognostic marker in cholangiocarcinoma. J Gastrointest Surg 2007;11:445-51. https://doi.org/10.1007/s11605-007-0091-5
  24. Coussens LM, Fingleton B, Matrisian LM. Matrix metalloproteinase inhibitors and cancer: trials and tribulations. Science 2002;295:2387-92. https://doi.org/10.1126/science.1067100
  25. Shirabe K, Shimada M, Kajiyama K, et al. Expression of matrix metalloproteinase-9 in surgically resected intrahepatic cholangiocarcinoma. Surgery 1999;126:842-6. https://doi.org/10.1016/S0039-6060(99)70024-3
  26. Ambrosini G, Adida C, Altieri DC. A novel anti-apoptosis gene, survivin, expressed in cancer and lymphoma. Nat Med 1997;3:917-21. https://doi.org/10.1038/nm0897-917
  27. Chang Q, Liu ZR, Wang DY, Kumar M, Chen YB, Qin RY. Survivin expression induced by doxorubicin in cholangiocarcinoma. World J Gastroenterol 2004;10:415-8. https://doi.org/10.3748/wjg.v10.i3.415
  28. Javle MM, Tan D, Yu J, et al. Nuclear survivin expression predicts poor outcome in cholangiocarcinoma. Hepatogastroenterology 2004;51:1653-7.
  29. Thompson MD, Monga SP. WNT/beta-catenin signaling in liver health and disease. Hepatology 2007;45:1298-305. https://doi.org/10.1002/hep.21651
  30. Nault JC, Zucman-Rossi J. Genetics of hepatobiliary carcinogenesis. Semin Liver Dis 2011;31:173-87. https://doi.org/10.1055/s-0031-1276646
  31. Hsu HP, Shan YS, Jin YT, Lai MD, Lin PW. Loss of E-cadherin and beta-catenin is correlated with poor prognosis of ampullary neoplasms. J Surg Oncol 2010;101:356-62.
  32. Ben-David MA, Griffith KA, Abu-Isa E, et al. External-beam radiotherapy for localized extrahepatic cholangiocarcinoma. Int J Radiat Oncol Biol Phys 2006;66:772-9. https://doi.org/10.1016/j.ijrobp.2006.05.061
  33. Oh D, Lim do H, Heo JS, et al. The role of adjuvant radiotherapy in microscopic tumor control after extrahepatic bile duct cancer surgery. Am J Clin Oncol 2007;30:21-5. https://doi.org/10.1097/01.coc.0000245467.97180.78

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