Skip to main content
Log in

AFP, AFP-L3, DCP, and GP73 as markers for monitoring treatment response and recurrence and as surrogate markers of clinicopathological variables of HCC

  • Original Article—Liver, Pancreas, and Biliary Tract
  • Published:
Journal of Gastroenterology Aims and scope Submit manuscript

Abstract

Background

Alpha-fetoprotein (AFP), lens culinaris agglutinin-reactive fraction of AFP (AFP-L3), des-γ-carboxy prothrombin (DCP), and Golgi protein-73 (GP73) have been used or proposed as tumor markers for hepatocellular carcinoma (HCC).

Methods

They were measured in 96 patients undergoing hepatectomy for HCC to investigate their treatment response and association with variables linked with tumor invasiveness and/or prognosis. Values at 1 month post-surgery in the 77 patients without recurrence within 6 postoperative months were adopted as those after surgery.

Results

GP73 levels did not change after hepatectomy, but levels of other markers decreased and areas under receiver operating characteristic curves (95% CI) were: 0.64 (0.56–0.72), 0.63 (0.55–0.71), 0.79 (0.73–0.86), and 0.63 (0.55–0.71) for AFP, AFP-L3, DCP, and combination of AFP and AFP-L3, respectively. Cutoff points giving specificities of 96.1% (sensitivities at these points) were: 124 ng/mL (28.1%), 10% (21.9%), and 60 mAU/mL (52.1%), for AFP, AFP-L3, and DCP, respectively. The combination of AFP and AFP-L3 provided a sensitivity of 26.0% at a specificity of 96.1%. The increased DCP value was, or tended to be, associated with a larger tumor, vascular invasion, intrahepatic metastases, and a lower grade of tumor cell differentiation. Although similar associations were found between AFP and vascular invasion as well as a lower grade of tumor cell differentiation, no such relationship was found with AFP-L3.

Conclusions

DCP is a more effective tumor marker than AFP and AFP-L3. AFP-L3 showed comparable accuracy to AFP but no benefit was found in their combination. GP73 did not play a significant role in this context. Indices of tumor invasiveness were most closely associated with DCP.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Abbreviations

AFP:

Alpha-fetoprotein

AFP-L3:

Lens culinaris agglutinin-reactive fraction of AFP

AUROC:

Areas under ROC curve

CI:

Confidence interval

DCP:

Des-γ-carboxy prothrombin

GP73:

Golgi protein-73

HCC:

Hepatocellular carcinoma

ROC curve:

Receiver operating characteristic curve

References

  1. El-Serag HB. Hepatocellular carcinoma: recent trends in the United States. Gastroenterology. 2004;127:S27–34.

    Article  PubMed  Google Scholar 

  2. Bruix J, Sherman M, Practice Guidelines Committee, American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma. Hepatology. 2005;42:1208–36.

    Article  PubMed  Google Scholar 

  3. Liebman HA, Furie BC, Tong MJ, Blanchard RA, Lo KJ, Lee SD, et al. Des-gamma-carboxy (abnormal) prothrombin as a serum marker of primary hepatocellular carcinoma. N Eng J Med. 1984;310:1427–31.

    Article  CAS  Google Scholar 

  4. Nomura F, Ishijima M, Kuwa K, Tanaka N, Nakai T, Ohnishi K. Serum des-gamma-carboxy prothrombin levels determined by a new generation of sensitive immunoassays in patients with small-sized hepatocellular carcinoma. Am J Gastroenterol. 1999;94:650–4.

    Article  CAS  PubMed  Google Scholar 

  5. Aoyagi Y, Isemura M, Suzuki Y, Sekine C, Soga K, Ozaki T, et al. Fucosylated alpha-fetoprotein as marker of early hepatocellular carcinoma. Lancet. 1985;2:1353–4.

    Article  CAS  PubMed  Google Scholar 

  6. Taketa K, Endo Y, Sekiya C, Tanikawa K, Koji T, Taga H, et al. A collaborative study for the evaluation of lectin-reactive alpha-fetoprotein in early detection of hepatocellular carcinoma. Cancer Res. 1993;53:5419–23.

    CAS  PubMed  Google Scholar 

  7. Marrero JA, Romano PR, Nikolaeva O, Steel L, Mehta A, Fimmel CJ, et al. GP73, a resident Golgi glycoprotein, is a novel serum marker for hepatocellular carcinoma. J Hepatol. 2005;43:1007–12.

    Article  CAS  PubMed  Google Scholar 

  8. Hu JS, Wu DW, Liang S, Miao XY. GP73, a resident Golgi glycoprotein, is sensibility and specificity for hepatocellular carcinoma of diagnosis in a hepatitis B-endemic Asian population. Med Oncol. 2009;27:339–45.

    Article  PubMed  Google Scholar 

  9. Yuen MF, Lai CL. Serological markers of liver cancer. Best Pract Res Clin Gastroenterol. 2005;19:91–9.

    Article  CAS  PubMed  Google Scholar 

  10. Makuuchi M, Kosuge T, Takayama T, Yamazaki S, Kakazu T, Miyagawa S, et al. Surgery for small liver cancers. Semin Surg Oncol. 1993;9:298–304.

    Article  CAS  PubMed  Google Scholar 

  11. Takayama T, Sekine T, Makuuchi M, Yamasaki S, Kosuge T, Yamamoto J, et al. Adoptive immunotherapy to lower postsurgical recurrence rate of hepatocellular carcinoma: a randomized trial. Lancet. 2000;356:802–7.

    Article  CAS  PubMed  Google Scholar 

  12. Shimizu K, Taniichi T, Satomura S, Matsuura S, Taga H, Taketa K. Establishment of assay kits for the determination of microheterogeneities of alpha-fetoprotein using lectin-affinity electrophoresis. Clin Chim Acta. 1993;214:3–12.

    Article  CAS  PubMed  Google Scholar 

  13. Toyoda H, Kumada T, Kaneoka Y, Osaki Y, Kimura T, Arimoto A, et al. Prognostic value of pretreatment levels of tumor markers for hepatocellular carcinoma on survival after curative treatment of patients with HCC. J Hepatol. 2008;49:223–32.

    Article  CAS  PubMed  Google Scholar 

  14. Durazo FA, Blatt LM, Corey WG, Lin JH, Han S, Saab S, et al. Des-gamma-carboxyprothrombin, alpha-fetoprotein and AFP-L3 in patients with chronic hepatitis, cirrhosis and hepatocellular carcinoma. J Gastroenterol Hepatol. 2008;23:1541–8.

    Article  CAS  PubMed  Google Scholar 

  15. Bruix J, Sherman M, Llovet JM, Beaugrand M, Lencioni R, Burroughs AK, et al. Clinical management of hepatocellular carcinoma. Conclusions of the Barcelona-2000 EASL conference. European Association for the Study of the Liver. J Hepatol. 2001;35:421–30.

    Article  CAS  PubMed  Google Scholar 

  16. Liver Cancer Study Group In Japan. The general rules for the clinical and pathological study of primary liver cancer. 5th ed. Tokyo: Kanehara; 2008.

    Google Scholar 

  17. Metz CE. Basic principles of ROC analysis. Semin Nucl Med. 1978;8:283–98.

    Article  CAS  PubMed  Google Scholar 

  18. Tateishi R, Yoshida H, Matsuyama Y, Mine N, Kondo Y, Omata M. Diagnostic accuracy of tumor markers for hepatocellular carcinoma: a systematic review. Hepatol Int. 2008;2:17–30.

    Article  PubMed  Google Scholar 

  19. Tateishi R, Shiina S, Yoshida H, Teratani T, Obi S, Yamashiki N, et al. Prediction of recurrence of hepatocellular carcinoma after curative ablation using three tumor markers. Hepatology. 2006;44:1518–27.

    Article  CAS  PubMed  Google Scholar 

  20. Makuuchi M, Kokudo N, Arii S, Futagawa S, Kaneko S, Kawasaki S, et al. Development of evidence-based clinical guidelines for the diagnosis and treatment of hepatocellular carcinoma in Japan. Hepatol Res. 2008;38:37–51.

    Article  PubMed  Google Scholar 

  21. Johnson PJ. The role of serum alpha-fetoprotein estimation in the diagnosis and management of hepatocellular carcinoma. Clin Liver Dis. 2001;5:145–59.

    Article  CAS  PubMed  Google Scholar 

  22. Hasegawa K, Imamura H, Ijichi M, Matsuyama Y, Sano K, Sugawara Y, et al. Inclusion of tumor markers improves the correlation of the Milan criteria with vascular invasion and tumor cell differentiation in patients with hepatocellular carcinoma undergoing liver resection (#JGSU-D-07–00462). J Gastrointest Surg. 2008;12:858–66.

    Article  PubMed  Google Scholar 

  23. Gu Y, Chen W, Zhao Y, Chen L, Peng T. Quantitative analysis of elevated serum Golgi protein-73 expression in patients with liver diseases. Ann Clin Biochem. 2009;46:38–43.

    Article  CAS  PubMed  Google Scholar 

  24. Riener MO, Stenner F, Liewen H, Soll C, Breitenstein S, Pestalozzi BC, et al. Golgi phosphoprotein 2 (GOLPH2) expression in liver tumors and its values as a serum marker in hepatocellular carcinomas. Hepatology. 2009;49:1602–9.

    Article  CAS  PubMed  Google Scholar 

  25. Leerapun A, Suravarapu SV, Bida JP, Clark RJ, Sanders EL, Mettler TA, et al. The utility of Lens culinaris agglutinin-reactive alpha-fetoprotein in the diagnosis of hepatocellular carcinoma: evaluation in a United States referral population. Clin Gastroenterol Hepatol. 2007;5:394–402.

    Article  CAS  PubMed  Google Scholar 

  26. Sterling RK, Jeffers L, Gordon F, Sherman M, Venook AP, Reddy KR, et al. Clinical utility of AFP-L3% measurement in North American patients with HCV-related cirrhosis. Am J Gastroenterol. 2007;102:2196–205.

    Article  PubMed  Google Scholar 

  27. Marrero JA, Su GL, Wei W, Sherman M, Venook AP, Reddy KR, et al. Des-gamma carboxyprothrombin can differentiate hepatocellular carcinoma from nonmalignant chronic liver disease in American patients. Hepatology. 2003;37:1114–21.

    Article  CAS  PubMed  Google Scholar 

  28. Wang CS, Lin CL, Lee HC, Chen KY, Chiang MF, Chen HS, et al. Usefulness of serum des-gamma-carboxy prothrombin in detection of hepatocellular carcinoma. World J Gastroenterol. 2005;11:6115–9.

    CAS  PubMed  Google Scholar 

  29. Nakamura S, Nouso K, Sakaguchi K, Ito YM, Ohashi Y, Kobayashi Y, et al. Sensitivity and specificity of des-gammma-carboxy prothrombin for diagnosis of patients with hepatocellular carcinoma varies according to tumor size. Am J Gastroenterol. 2006;101:2038–43.

    Article  CAS  PubMed  Google Scholar 

  30. Kim do Y, Paik YH, Ahn SH, Youn YJ, Choi JW, Kim JK, et al. PIVKA-II is a useful tumor marker for recurrent hepatocellular carcinoma after surgical resection. Oncology. 2007;72:52–7.

    Article  PubMed  Google Scholar 

  31. Yamamoto K, Imamura H, Matsuyama Y, Hasegawa K, Beck Y, Sugawara Y, et al. Significance of alpha-fetoprotein and des-γ-carboxy prothrombin in patients with hepatocellular carcinoma undergoing hepatectomy. Ann Surg Oncol. 2009;16:1795–804.

    Article  Google Scholar 

  32. Marrero JA, Feng Z, Wang Y, Nguyen MH, Befeler AS, Roberts LR, et al. Alpha-fetoprotein, des-gamma carboxyprothrombin, and lectin-bound alpha-fetoprotein in early hepatocellular carcinoma. Gastroenterology. 2009;137:110–8.

    Article  CAS  PubMed  Google Scholar 

  33. Kagebayashi C, Yamaguchi I, Akinaga A, et al. Automated immunoassay system for AFP-L3% using on-chip electrokinetic reaction and separation by affinity electrophoresis. Anal Biochem. 2009;388:306–11.

    Article  CAS  PubMed  Google Scholar 

  34. Imamura H, Matsuyama Y, Miyagawa Y, Ishida K, Shimada R, Miyagawa S, et al. Prognostic significance of anatomical resection and des-gamma-carboxy prothrombin in patients with hepatocellular carcinoma. Br J Surg. 1999;86:1032–8.

    Article  CAS  PubMed  Google Scholar 

  35. Oishi K, Itamoto T, Amano H, Fukuda S, Ohdan H, Tashiro H, et al. Clinicopathologic features of poorly differentiated hepatocellular carcinoma. J Surg Oncol. 2007;95:311–6.

    Article  PubMed  Google Scholar 

  36. Okuda H, Nakanishi T, Takatsu K, Saito A, Hayashi N, Yamamoto M, et al. Clinicopathologic features of patients with hepatocellular carcinoma seropositive for alpha-fetoprotein-L3 and seronegative for des-gamma-carboxy prothrombin in comparison with those seropositive for des-gamma-carboxy prothrombin alone. J Gastroenterol Hepatol. 2002;17:772–8.

    Article  CAS  PubMed  Google Scholar 

  37. Tada T, Kumada T, Toyoda H, Kiriyama S, Sone Y, Tanikawa M, et al. Relationship between Lens culinaris agglutinin-reactive alpha-fetoprotein and pathologic features of hepatocellular carcinoma. Liver Int. 2005;25:848–53.

    Article  CAS  PubMed  Google Scholar 

  38. Miyaaki H, Nakashima O, Kurogi M, Eguchi K, Kojiro M. Lens cullinaris agglutinin-reactive alpha-fetoprotein and protein induced by vitamin K absence II are potential indicators of a poor prognosis: a histopathological study of surgically resected hepatocellular carcinoma. J Gastroenterol. 2007;42:962–8.

    Article  CAS  PubMed  Google Scholar 

  39. Inoue S, Nakao A, Harada A, Nonami T, Takagi H. Clinical significance of abnormal prothrombin (DCP) in relation to postoperative survival and prognosis in patients with hepatocellular carcinoma. Am J Gastroenterol. 1994;89:2222–6.

    CAS  PubMed  Google Scholar 

  40. Suehiro T, Sugimachi K, Matsumata T, Itasaka H, Taketomi A, Maeda T. Protein induced by vitamin K absence or antagonist II as a prognostic marker in hepatocellular carcinoma. Comparison with alpha-fetoprotein. Cancer. 1994;73:2464–71.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by Grant-in-Aid for Scientific Research (B) (20390352) and Mitsui Life Social Welfare Foundation.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Hiroshi Imamura.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yamamoto, K., Imamura, H., Matsuyama, Y. et al. AFP, AFP-L3, DCP, and GP73 as markers for monitoring treatment response and recurrence and as surrogate markers of clinicopathological variables of HCC. J Gastroenterol 45, 1272–1282 (2010). https://doi.org/10.1007/s00535-010-0278-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00535-010-0278-5

Keywords

Navigation