COMBINED DETECTION OF SERUM TUMOR MARKERS FOR EARLY DIAGNOSIS OF HEPATOCELLULAR CARCINOMA: A SYSTEMATIC REVIEW

Authors

  • Maida Jabeen Khawaja Fareed University of Engineering and Information Technology, Rahim Yar Khan, Pakistan Author
  • Aiman Saqib Khawaja Fareed University of Engineering and Information Technology, Rahim Yar Khan, Pakistan Author
  • Amna Shafique Khawaja Fareed University of Engineering and Information Technology, Rahim Yar Khan, Pakistan Author
  • Maryam Javed Khawaja Fareed University of Engineering and Information Technology, Rahim Yar Khan, Pakistan Author
  • Farwa Riaz Khawaja Fareed University of Engineering and Information Technology, Rahim Yar Khan, Pakistan Author
  • Zainab Ali Khawaja Fareed University of Engineering and Information Technology, Rahim Yar Khan, Pakistan Author
  • Muhammad Sulaiman Saeed Khawaja Fareed University of Engineering and Information Technology, Rahim Yar Khan, Pakistan Author

DOI:

https://doi.org/10.71000/93t4g094

Keywords:

Hepatocellular carcinoma, , Tumor Markers, Sensitivity and Specificity, ROC Curve, PIVKA-II, Biomarker, , AFP-L3

Abstract

Background: Hepatocellular carcinoma (HCC) is the most common primary liver cancer and ranks among the leading causes of cancer-related mortality worldwide. Early diagnosis remains a cornerstone in reducing its associated morbidity and mortality. Serum tumor markers such as alpha-fetoprotein (AFP), AFP-L3, Des-Gamma-Carboxy Prothrombin (DCP), and PIVKA-II are frequently used for screening and diagnostic purposes. However, their individual limitations in sensitivity and specificity, especially for early-stage disease, necessitate investigation into the diagnostic value of combined biomarker strategies.

Objective: To evaluate the diagnostic accuracy of combined serum tumor biomarkers for early detection of hepatocellular carcinoma.

Methods: A systematic review of literature published from January 2000 to March 2025 was conducted using PubMed and Google Scholar databases. A total of 20 peer-reviewed studies meeting inclusion criteria were analyzed. Data extraction focused on the diagnostic performance of serum biomarkers alone and in combination. Diagnostic accuracy was assessed using sensitivity, specificity, and area under the ROC curve (AUC).

Results: AFP alone demonstrated a sensitivity of 63.3% and specificity of 80.8%. PIVKA-II outperformed AFP with a sensitivity of 71% and specificity of 90%. AFP-L3 and GP73 showed higher diagnostic performance in small tumor detection, with GP73 achieving 72.0% sensitivity and 86.7% accuracy, and GPC3 offering 98.0% specificity. Combining AFP with AFU yielded the highest diagnostic values with 95% sensitivity and 100% specificity. The triplet panel of AFP, AFP-L3, and DCP achieved 88% sensitivity and 91% specificity. Biomarker combinations consistently outperformed individual tests in detecting early and all-stage HCC.

Conclusion: Single biomarkers like AFP are insufficient for early-stage HCC detection. Combining AFP with other markers such as PIVKA-II, AFP-L3, and DCP significantly enhances diagnostic accuracy. Adoption of multi-marker strategies may improve early detection and clinical outcomes in HCC.

Author Biographies

  • Maida Jabeen, Khawaja Fareed University of Engineering and Information Technology, Rahim Yar Khan, Pakistan

    Institute of Health Sciences, Khawaja Fareed University of Engineering and Information Technology, Rahim Yar Khan, Pakistan

  • Aiman Saqib, Khawaja Fareed University of Engineering and Information Technology, Rahim Yar Khan, Pakistan

    Institute of Health Sciences, Khawaja Fareed University of Engineering and Information Technology, Rahim Yar Khan, Pakistan

  • Amna Shafique, Khawaja Fareed University of Engineering and Information Technology, Rahim Yar Khan, Pakistan

    Institute of Health Sciences, Khawaja Fareed University of Engineering and Information Technology, Rahim Yar Khan, Pakistan

  • Maryam Javed, Khawaja Fareed University of Engineering and Information Technology, Rahim Yar Khan, Pakistan

    Institute of Health Sciences, Khawaja Fareed University of Engineering and Information Technology, Rahim Yar Khan, Pakistan

  • Farwa Riaz, Khawaja Fareed University of Engineering and Information Technology, Rahim Yar Khan, Pakistan

    Institute of Health Sciences, Khawaja Fareed University of Engineering and Information Technology, Rahim Yar Khan, Pakistan

     

  • Zainab Ali, Khawaja Fareed University of Engineering and Information Technology, Rahim Yar Khan, Pakistan

    Institute of Health Sciences, Khawaja Fareed University of Engineering and Information Technology, Rahim Yar Khan, Pakistan

  • Muhammad Sulaiman Saeed, Khawaja Fareed University of Engineering and Information Technology, Rahim Yar Khan, Pakistan

    Institute of Health Sciences, Khawaja Fareed University of Engineering and Information Technology, Rahim Yar Khan, Pakistan

References

Ferlay, J., Colombet, M., Soerjomataram, I., Parkin, D. M., Piñeros, M., Znaor, A., & Bray, F. (2021). Cancer statistics for the year 2020: An overview. International Journal of Cancer, 149(4), 778–789.

Piña-Sánchez, P., Chávez-González, A., Ruiz-Tachiquín, M., Vadillo, E., Monroy-García, A., Montesinos, J., Grajales, R., Gutiérrez de la Barrera, M., & Mayani, H. (2021). Cancer biology, epidemiology, and treatment in the 21st century: Current status and future challenges from a biomedical perspective. Cancer Control, 28, 10732748211038735.

Patel, A. (2020). Benign vs malignant tumors. JAMA Oncology, 6(9), 1488.

Shah, P. A., Patil, R., & Harrison, S. A. (2023). NAFLD-related hepatocellular carcinoma: The growing challenge. Hepatology, 77(1), 323–338.

Ibrahim Alhadi EDOO M, Kumar Chutturghoon V, Kwabena WUSU-ANSAH G, Zhu H, Yang ZHEN T, Yang XIE H, et al. Serum Biomarkers AFP, CEA and CA19-9 Combined Detection for Early Diagnosis of Hepatocellular Carcinoma [Internet]. Vol. 48, Iran J Public Health. 2019.

Tufael, M., Rahman, M. M., Upadhye, V. J., Hossain, M. F., & Uddin, N. (2024, May 9). Combined biomarkers for early diagnosis of hepatocellular carcinoma. Journal of Angiotherapy, 8(5), 1–12.

Rana, M. S., Bashir, M. S., Das, S. S., Hossian, M., & Barua, S. (2024, April). Biomarkers for hepatocellular carcinoma: Diagnosis, prognosis, and treatment response assessment—A systematic review. PrimeAsia, 1–7.

Attia, A. M., Rezaee-Zavareh, M. S., Hwang, S. Y., Kim, N., Adetyan, H., Yalda, T., Chen, P., Koltsova, E. K., & Yang, J. D. (2024, October 13). Novel biomarkers for early detection of hepatocellular carcinoma. Diagnostics, 14(20), 2278.

Solhi, R., Pourhamzeh, M., Zarrabi, A., Hassan, M., Mirzaei, H., & Vosough, M. (2024, December 24). Novel biomarkers for monitoring and management of hepatocellular carcinoma. Cancer Cell International, 24(1), Article 428.

Lee, T. H., Kim, W. R., & Poterucha, J. J. (2012). Evaluation of elevated liver enzymes. Clinics in Liver Disease, 16(2), 183–198.

Abduljabbar, A. H. (2023). Diagnostic accuracy of ultrasound and alpha-fetoprotein measurement for hepatocellular carcinoma surveillance: A retrospective comparative study. Egyptian Journal of Radiology and Nuclear Medicine, 54(1), Article 31.

Ibrahim Alhadi EDOO M, Kumar Chutturghoon V, Kwabena WUSU-ANSAH G, Zhu H, Yang ZHEN T, Yang XIE H, et al. Serum Biomarkers AFP, CEA and CA19-9 Combined Detection for Early Diagnosis of Hepatocellular Carcinoma [Internet]. Vol. 48, Iran J Public Health. 2019.

Li, Y., Li, D. J., Chen, J., Liu, W., Li, J. W., Jiang, P., Zhao, X., Guo, F., Li, X. W., & Wang, S. G. (2015). Application of joint detection of AFP, CA19-9, CA125 and CEA in identification and diagnosis of cholangiocarcinoma. Asian Pacific Journal of Cancer Prevention, 16(8), 3451–3455.

Zhu, J., Chen, G., Xu, J., & Zhou, X. (2017). Serum AFU, 5'-NT and AFP as biomarkers for primary hepatocellular carcinoma diagnosis. Open Medicine (Warsaw), 12(1), 354–358.

Kobeissy, A., Merza, N., Al-Hillan, A., Boujemaa, S., Ahmed, Z., Nawras, M., Albaaj, M., Dahiya, D. S., Alastal, Y., & Hassan, M. (2023). Protein Induced by Vitamin K Absence or Antagonist-II Versus Alpha-Fetoprotein in the Diagnosis of Hepatocellular Carcinoma: A Systematic Review with Meta- Analysis. Journal of Clinical Medicine Research, 15(7), 343–359.

Huang, X., Li, J., Wang, F., & Hao, M. (2018). CT combined with tumor markers in the diagnosis and prognosis of hepatocellular carcinoma. Journal of BUON, 23(4), 985–991.

Choi, J. Y., Jung, S. W., Kim, H. Y., Kim, M., Kim, Y., Kim, D. G., & Oh, E. J. (2013). Diagnostic value of AFP-L3 and PIVKA-II in hepatocellular carcinoma according to total-AFP. World journal of gastroenterology, 19(3), 339–346.

Piratvisuth T, Tanwandee T, Thongsawat S, Sukeepaisarnjaroen W, Esteban JI, Bes M, et al. Multimarker Panels for Detection of Early-stage Hepatocellular Carcinoma: A Prospective, Multicenter, Case-Control Study. Hepatol Commun [Internet]. 2021;6(4):2022.

Malov SI, Malov IV, Kuvshinov AG, Marche PN, Decaens T, Macek-Jilkova Z, et al. Search for Effective Serum Tumor Markers for Early Diagnosis of Hepatocellular Carcinoma Associated with Hepatitis C. Sovrem Tekhnologii Med. 2021;13(1):27-33.

Lin Y, Ma Y, Chen Y, Huang Y, Lin J, Xiao Z, et al. Diagnostic and prognostic performance of serum GPC3 and PIVKA-II in AFP-negative hepatocellular carcinoma and establishment of nomogram prediction models. BMC Cancer. 2025;25(1):721.

Song H, Wang J, Zhang H, Wu Y, Wang K, Wang X, et al. Combination of serum alpha-fetoprotein, PIVKA-Ⅱ and glypican-3 in diagnosis of hepatocellular carcinoma: a meta-analysis. Zhejiang Da Xue Xue Bao Yi Xue Ban. 2024;53(1):131-9.

Mohammed AF, Chen X, Li C. Clinical utility of biomarkers of hepatocellular carcinoma. Bratisl Lek Listy. 2024;125(2):102-6.

Yu B, Ma W. Biomarker discovery in hepatocellular carcinoma (HCC) for personalized treatment and enhanced prognosis. Cytokine Growth Factor Rev. 2024;79:29-38.

Downloads

Published

2025-06-08