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Serum CYFRA 21-1 in Biliary Tract Cancers: A Reliable Biomarker for Gallbladder Carcinoma and Intrahepatic Cholangiocarcinoma

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Abstract

Background

Biliary tract cancers encompass gallbladder carcinoma, and intrahepatic, perihilar and distal cholangiocarcinoma. Upregulated serum CYFRA 21-1 has been reported in intrahepatic cholangiocarcinoma.

Aims

The present study aimed to explore the clinical significance of serum CYFRA 21-1 in all biliary tract cancer subtypes.

Methods

Serum CYFRA 21-1, carbohydrate antigen 19-9 and carcinoembryonic antigen were quantitated preoperatively, postoperatively and during follow-up in 134 malignant and 52 benign patients. Receiver operator characteristic curves of biomarkers were analyzed. Level of CYFRA 21-1 was correlated with patients’ clinicopathological features and follow-up data.

Results

CYFRA 21-1 was significantly upregulated in biliary malignancies, and expressional difference existed between these subtypes. Based on the maximal Youden’s index, cutoff values were selected (ng/mL): 2.61 for biliary tract cancers (sensitivity 74.6 % and specificity 84.6 %); 3.27 for intrahepatic cholangiocarcinoma (75.6 and 96.2 %) and gallbladder carcinoma (93.7 and 96.2 %); 2.27 for perihilar cholangiocarcinoma (71.0 and 71.2 %); and 2.61 for distal cholangiocarcinoma (63.3 and 84.6 %). CYFRA 21-1 showed better diagnostic performance than other biomarkers in gallbladder carcinoma and intrahepatic cholangiocarcinoma; its performance was not inferior to that of the combination of these three biomarkers and declined after curative resection and re-elevated when tumor recurred, which was correlated with tumor aggressiveness and TNM stage; it was an independent predictor for 1-year recurrence-free survival and overall survival on multivariate analysis.

Conclusion

Serum CYFRA 21-1 represents a reliable biomarker for gallbladder carcinoma and intrahepatic cholangiocarcinoma.

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References

  1. Hezel AF, Zhu AX. Genetics of biliary tract cancers and emerging targeted therapies. J Clin Oncol. 2010;28:3531–3540.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  2. Rizvi S, Gores GJ. Pathogenesis, diagnosis, and management of cholangiocarcinoma. Gastroenterology. 2013;145:1215–1229.

    Article  CAS  PubMed  Google Scholar 

  3. Liu LN, Xu HX, Lu MD, et al. Contrast-enhanced ultrasound in the diagnosis of gallbladder diseases a multi-center experience. PLoS ONE. 2012;7:e48371.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  4. Alvaro D. Serum and bile biomarker for cholangiocarcinoma. Curr Opin Gastroenterol. 2009;25:279–284.

    Article  CAS  PubMed  Google Scholar 

  5. Moll R, Franke WW, Schiller DL, Geiger B, Krepler R. The catalog of human cytokeratins: patterns of expression in normal epithelia, tumors and cultured cells. Cell. 1982;31:11–24.

    Article  CAS  PubMed  Google Scholar 

  6. Stieber P, Bodenmüller H, Banauch D, et al. Cytokeratin 19 fragments: a new marker for non-small-cell lung cancer. Clin Biochem. 1993;26:301–304.

    Article  CAS  PubMed  Google Scholar 

  7. Rastel D, Ramaioli A, Cornillie F, Thirion B. CYFRA 21-1, a sensitive and specific new tumour marker for squamous cell lung cancer. Report of the first European multicentre evaluation. CYFRA 21-1 Multicentre Study Group. Eur J Cancer. 1994;30A:601–606.

    Article  CAS  PubMed  Google Scholar 

  8. Kashihara T, Ohki A, Kobayashi T, et al. Intrahepatic cholangiocarcinoma with increased serum CYFRA 21-1 level. J Gastroenterol. 1998;33:447–453.

    Article  CAS  PubMed  Google Scholar 

  9. Uenishi T, Kubo S, Hirohashi K, et al. Cytokeratin-19 fragments in serum (CYFRA 21-1) as a marker in primary liver cancer. Br J Cancer. 2003;88:1894–1899.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. Uenishi T, Yamazaki O, Tanaka H, et al. Serum cytokeratin 19 fragment (CYFRA21-1) as a prognostic factor in intrahepatic cholangiocarcinoma. Ann Surg Oncol. 2008;15:583–589.

    Article  PubMed  Google Scholar 

  11. Chapman MH, Sandanayake NS, Andreola F, et al. Circulating CYFRA 21-1 is a Specific Diagnostic and Prognostic Biomarker in Biliary Tract Cancer. J Clin Exp Hepatol. 2011;1:6–12.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. Edge S, Byrd D, Compton C, Fritz A, Greene F, Trotti A, eds. AJCC Cancer Staging Manual. 2010.

  13. Youden WJ. Index for rating diagnostic tests. Cancer. 1950;3:32–35.

    Article  CAS  PubMed  Google Scholar 

  14. Wu JC, Martin AF, Raghu NK. Measures, uncertainties, and significance test in operational ROC analysis. J Res Natl Inst Stand Technol. 2011;116:517–537.

    Article  Google Scholar 

  15. Malaguarnera G, Paladina I, Giordano M, Malaguarnera M, Bertino G, Berretta M. Serum markers of intrahepatic cholangiocarcinoma. Dis Markers. 2013;34:219–228.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  16. Schweizer J, Bowden PE, Coulombe PA, et al. New consensus nomenclature for mammalian keratins. J Cell Biol. 2006;174:169–174.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  17. Wu PC, Fang JW, Lau VK, Lai CL, Lo CK, Lau JY. Classification of hepatocellular carcinoma according to hepatocellular and biliary differentiation markers. Clinical and biological implications. Am J Pathol. 1996;149:1167–1175.

    PubMed Central  CAS  PubMed  Google Scholar 

  18. Uenishi T, Kubo S, Yamamoto T, et al. Cytokeratin 19 expression in hepatocellular carcinoma predicts early postoperative recurrence. Cancer Sci. 2003;94:851–857.

    Article  CAS  PubMed  Google Scholar 

  19. Ding SJ, Li Y, Tan YX, et al. From proteomic analysis to clinical significance: overexpression of cytokeratin 19 correlates with hepatocellular carcinoma metastasis. Mol Cell Proteomics. 2004;3:73–81.

    Article  CAS  PubMed  Google Scholar 

  20. Uenishi T, Yamazaki O, Yamamoto T, et al. Clinical significance of serum cytokeratin-19 fragment (CYFRA 21-1) in hepatocellular carcinoma. J Hepatobiliary Pancreat Surg. 2006;13:239–244.

    Article  PubMed  Google Scholar 

  21. Dohmoto K, Hojo S, Fujita J, et al. The role of caspase 3 in producing cytokeratin 19 fragment (CYFRA21-1) in human lung cancer cell lines. Int J Cancer. 2001;91:468–473.

    Article  CAS  PubMed  Google Scholar 

  22. Karantza V. Keratins in health and cancer: more than mere epithelial cell markers. Oncogene. 2011;30:127–138.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Alix-Panabières C, Vendrell JP, Slijper M, et al. Full-length cytokeratin-19 is released by human tumor cells a potential role in metastatic progression of breast cancer. Breast Cancer Res. 2009;11:R39.

    Article  PubMed Central  PubMed  Google Scholar 

  24. Fuks D, Regimbeau JM, Le Treut YP, et al. Incidental gallbladder cancer by the AFC-GBC-2009 study group. World J Surg. 2011;35:1887–1897.

    Article  PubMed  Google Scholar 

  25. Jarnagin WR, Ruo L, Little SA, et al. Patterns of initial disease recurrence after resection of gallbladder carcinoma and hilar cholangiocarcinoma: implications for adjuvant therapeutic strategies. Cancer. 2003;98:1689–1700.

    Article  PubMed  Google Scholar 

  26. Brabon AC, Williams JF, Cardiff RD. A monoclonal antibody to a human breast tumor protein released in response to estrogen. Cancer Res. 1984;44:2704–2710.

    CAS  PubMed  Google Scholar 

  27. Ito F, Agni R, Rettammel RJ, et al. Resection of hilar cholangiocarcinoma: concomitant liver resection decreases hepatic recurrence. Ann Surg. 2008;248:273–279.

    Article  PubMed  Google Scholar 

  28. Ito K, Ito H, Allen PJ, et al. Adequate lymph node assessment for extrahepatic bile duct adenocarcinoma. Ann Surg. 2010;251:675–681.

    Article  PubMed  Google Scholar 

  29. Li SQ, Liang LJ, Hua YP, et al. Long-term outcome and prognostic factors of intrahepatic cholangiocarcinoma. Chin Med J (Engl). 2010;122:2286–2291.

    Google Scholar 

  30. Pilgrim CH, Groeschl RT, Turaga KK, Gamblin TC. Key factors influencing prognosis in relation to gallbladder cancer. Dig Dis Sci. 2013;58:2455–2462.

    Article  CAS  PubMed  Google Scholar 

  31. Jensen LH. Biliary-tract cancer: improving therapy by adding molecularly targeted agents. Lancet Oncol. 2012;13:118–119.

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

The authors thank Prof. Dong Wang and Dr. Dubo Chen (Department of Clinical Laboratory, the First Affiliated Hospital of Sun Yat-sen University) for providing advice and technical assistance in measuring biomarkers. We also thank Prof. Yuantao Hao (Department of Medical Statistics and Epidemiology, School of Public Health, Sun Yat-sen University) for careful review and statistical advice. This work was supported by the National Natural Science Foundation of China (81201919), the Science and Technology Planning Project of Guangdong Province (2012B050600016) and the Medical Scientific Research Foundation of Guangdong Province (B2012087).

Conflict of interest

The authors of this manuscript have no financial arrangements to disclose.

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Correspondence to Jiaming Lai or Lijian Liang.

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10620_2014_3472_MOESM1_ESM.jpg

Supplementary material 1 Distributions of serum CYFRA 21-1 in TNM stage of each biliary tract cancers subtype. Data are presented as median (horizontal line) and interquartile range. Analysis of serum CYFRA 21-1 in different TNM stage of biliary tract cancers (BTCs) and all subtypes revealed significant difference (Kruskal–Wallis test, P < 0.001). (1a) biliary tract cancers (BTCs); (1b) intrahepatic cholangiocarcinoma (ICC); (1c) gallbladder carcinoma (GBC); (1d) perihilar cholangiocarcinoma (Perihilar-CC); (1e) distal cholangiocarcinoma (Distal-CC) (JPEG 267 kb)

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Huang, L., Chen, W., Liang, P. et al. Serum CYFRA 21-1 in Biliary Tract Cancers: A Reliable Biomarker for Gallbladder Carcinoma and Intrahepatic Cholangiocarcinoma. Dig Dis Sci 60, 1273–1283 (2015). https://doi.org/10.1007/s10620-014-3472-0

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  • DOI: https://doi.org/10.1007/s10620-014-3472-0

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