Clinicopathological Significance of Osteopontin in Cholangiocarcinoma Cases

  • Laohaviroj, Marut (Department of Pathology, Faculty of Medicine, Khon Kaen University) ;
  • Chamgramol, Yaovalux (Department of Pathology, Faculty of Medicine, Khon Kaen University) ;
  • Pairojkul, Chawalit (Department of Pathology, Faculty of Medicine, Khon Kaen University) ;
  • Mulvenna, Jason (Infectious Disease and Cancer, QIMR Berghofer Medical Research Institute) ;
  • Sripa, Banchob (Department of Pathology, Faculty of Medicine, Khon Kaen University)
  • Published : 2016.02.05


Cholangiocarcinoma (CCA) is generally a rare primary liver tumor of the bile duct with extremely poor clinical outcomes due to late diagnosis. Osteopontin (OPN) is the most abundant expressed gene in intrahepatic CCA and its involvement in tumor aggressiveness suggests it could be a useful prognostic biomarker. However, the prognostic significance of OPN expression in CCA is still controversial. We therefore immunohistochemically studied OPN expression in 354 resected CCAs and correlated the results with patient clinicopathological parameters. OPN expression was separately scored according to the percentage of cancer cells or degree of stromal tissue staining and classified as low (score 0-1) and high (score 2-3). OPN expression in CCA cells was found in 177 out of 354 patients (56.5%), whereas stroma was positive in 185 out of 354 patients (52.3%). Univariate analysis with several of the aforementioned parameters revealed that stromal but not cancer cell OPN expression was significantly associated with tumor size, tumor direct invasion into normal liver parenchyma, regional lymph node metastasis and higher staging. The combination of cancer cell and stromal OPN expression demonstrated a positive trend for linkage with lymph node metastasis. Multivariate analysis identified gender, the presence of lymphatic permeation and lymph node metastasis, but not OPN expression, as independent prognostic factors. This study confirms the presence of stromal OPN expression in tumor aggressiveness but not survival in CCA patients.


Cholangiocarcinoma;osteopontin;biomarker;prognostic marker;immunohistochemistry


Supported by : Thailand Research Fund (TRF), National Cancer Institute, National Institute of Allergy and Infectious Diseases (NIAID), NIH


  1. Bourguignon LY, Zhu H, Shao L, et al (1999). Rho-kinase (ROK) promotes CD44v(3,8-10)-ankyrin interaction and tumor cell migration in metastatic breast cancer cells. Cell Motil Cytoskeleton, 43, 269-87.<269::AID-CM1>3.0.CO;2-5
  2. Fedor HL, De Marzo AM (2005). Practical methods for tissue microarray construction. Methods Mol Med, 103, 89-101.
  3. Ghouri YA, Mian I, Blechacz B (2015). Cancer review: Cholangiocarcinoma. J Carcinog, 14, 1.
  4. Grunnet M, Mau-Sorensen M (2014). Serum tumor markers in bile duct cancer--a review. Biomarkers, 19, 437-43.
  5. Hass HG, Nehls O, Jobst J, et al (2008). Identification of osteopontin as the most consistently over-expressed gene in intrahepatic cholangiocarcinoma: detection by oligonucleotide microarray and real-time PCR analysis. World J Gastroenterol, 14, 2501-10.
  6. Huang Q, Liu L, Liu CH, et al (2012). Expression of Smad7 in cholangiocarcinoma: prognostic significance and implications for tumor metastasis. Asian Pac J Cancer Prev, 13, 5161-5.
  7. Iguchi T, Yamashita N, Aishima S, et al (2009). A comprehensive analysis of immunohistochemical studies in intrahepatic cholangiocarcinoma using the survival tree model. Oncol, 76, 293-300.
  8. Irby RB, McCarthy SM, Yeatman TJ (2004). Osteopontin regulates multiple functions contributing to human colon cancer development and progression. Clin Exp Metastasis, 21, 515-23.
  9. Juntavee A, Sripa B, Pugkhem A, et al (2005). Expression of sialyl Lewis(a) relates to poor prognosis in cholangiocarcinoma. World J Gastroenterol, 11, 249-54.
  10. Khan SA, Taylor-Robinson SD, Toledano MB, et al (2002). Changing international trends in mortality rates for liver, biliary and pancreatic tumours. J Hepatol, 37, 806-13.
  11. Khuntikeo N, Pugkhem A, Titapun A, et al (2014). Surgical management of perihilar cholangiocarcinoma: a Khon Kaen experience. J Hepatobiliary Pancreat Sci, 21, 521-4.
  12. Macri A, Versaci A, Lupo G, et al (2009). Role of osteopontin in breast cancer patients. Tumori, 95, 48-52.
  13. Nakanuma Y, Sato Y, Harada K, et al (2010). Pathological classification of intrahepatic cholangiocarcinoma based on a new concept. World J Hepatol, 2, 419-27.
  14. Qiu Y, Hu Y, Zhang ZY, et al (2014). Genetic association of osteopontin (OPN) and its receptor CD44 genes with susceptibility to Chinese gastric cancer patients. J Cancer Res Clin Oncol, 140, 2143-56.
  15. Shaib Y, El-Serag HB (2004). The epidemiology of cholangiocarcinoma. Semin Liver Dis, 24, 115-25.
  16. Shin HR, Oh JK, Masuyer E, et al (2010). Comparison of incidence of intrahepatic and extrahepatic cholangiocarcinoma--focus on East and South-Eastern Asia. Asian Pac J Cancer Prev, 11, 1159-66.
  17. Silsirivanit A, Araki N, Wongkham C, et al (2011). A novel serum carbohydrate marker on mucin 5AC: values for diagnostic and prognostic indicators for cholangiocarcinoma. Cancer, 117, 3393-403.
  18. Sirica AE, Dumur CI, Campbell DJ, et al (2009). Intrahepatic cholangiocarcinoma progression: prognostic factors and basic mechanisms. Clin Gastroenterol Hepatol, 7, 68-78.
  19. Sripa B, Bethony JM, Sithithaworn P, et al (2011). Opisthorchiasis and Opisthorchis-associated cholangiocarcinoma in Thailand and Laos. Acta Trop, 120, 158-68.
  20. Sripa B, Kaewkes S, Intapan PM, et al (2010). Food-borne trematodiases in Southeast Asia epidemiology, pathology, clinical manifestation and control. Adv Parasitol, 72, 305-50.
  21. Sriputtha S, Khuntikeo N, Promthet S, et al (2013). Survival rate of intrahepatic cholangiocarcinoma patients after surgical treatment in Thailand. Asian Pac J Cancer Prev, 14, 1107-10.
  22. Standal T, Borset M, Sundan A (2004). Role of osteopontin in adhesion, migration, cell survival and bone remodeling. Exp Oncol, 26, 179-84.
  23. Subraman V, Thiyagarajan M, Malathi N, et al (2015). OPN -Revisited. J Clin Diagn Res, 9, 10-3.
  24. Sulpice L, Rayar M, Desille M, et al (2013). Molecular profiling of stroma identifies osteopontin as an independent predictor of poor prognosis in intrahepatic cholangiocarcinoma. Hepatol, 58, 1992-2000.
  25. Terashi T, Aishima S, Taguchi K, et al (2004). Decreased expression of osteopontin is related to tumor aggressiveness and clinical outcome of intrahepatic cholangiocarcinoma. Liver Int, 24, 38-45.
  26. Uttaravichien T, Bhudhisawasdi V, Pairojkul C, et al (1999). Intrahepatic cholangiocarcinoma in Thailand. J Hepatobiliary Pancreat Surg, 6, 128-35.
  27. Yonglitthipagon P, Pairojkul C, Chamgramol Y, et al (2010). Up-regulation of annexin A2 in cholangiocarcinoma caused by Opisthorchis viverrini and its implication as a prognostic marker. Int J Parasitol, 40, 1203-12.
  28. Zhao XQ, Dong JH, Zhang WZ, et al (2011). Prognosis of ampullary cancer based on immunohistochemical type and expression of osteopontin. Diagn Pathol, 6, 98.

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