Serum PIVKA-II as a Preoperative Predictor of Microvascular Invasion and Tumor Proliferation in HBV-Related Hepatocellular Carcinoma
DOI:
https://doi.org/10.59784/glosains.v7i1.658Keywords:
hepatocellular carcinoma, serum PIVKA-II, microvascular invasion, tumor proliferation, hepatitis B virusAbstract
Background: Hepatocellular carcinoma (HCC) contributes significantly to cancer-related mortality worldwide, particularly in hepatitis B–endemic regions such as Indonesia. The need for reliable preoperative biomarkers remains a major gap, especially to predict microvascular invasion (MVI) and tumor proliferation. PIVKA-II was specifically selected over AFP because of its superior ability to reflect tumor-invasive biology through MET and JAK/STAT pathway activation.
Objective: This study aimed to assess whether serum PIVKA-II levels can predict MVI and Ki-67 proliferation index.
Methods: A retrospective study was conducted on 20 patients with HBV-related HCC who underwent liver resection at Cipto Mangunkusumo Hospital (2017–2025). Serum PIVKA-II was categorized as high (>40 mAU/mL) or low (≤40 mAU/mL). MVI was identified histologically; Ki-67 expression was categorized as high (>20%) or low (≤20%) using immunohistochemistry.
Results: PIVKA-II levels showed a significant relationship with AFP (p = 0.033) and BCLC stage (p = 0.038). ROC analysis showed that PIVKA-II had fair discriminative ability (AUC = 0.703) in predicting vascular invasion, with a sensitivity of 87.5% and specificity of 75%. There was a significant relationship between high PIVKA-II levels and the occurrence of vascular invasion (p = 0.032; RR = 2.33). However, PIVKA-II did not show good predictive ability for tumor cell proliferation (Ki-67) (AUC = 0.484), and no significant relationship was found between them (p = 0.530).
Conclusion: PIVKA-II is a useful preoperative biomarker for predicting microvascular invasion in HBV-related HCC. Its lack of association with Ki-67 indicates that additional markers are needed to assess tumor proliferative behavior. These findings support the integration of PIVKA-II into preoperative risk assessment.
References
Adams, A. M., Kaseb, A. O., & Tran Cao, H. S. (2024). Hepatocellular carcinoma. In Transplant Oncology: A Frontier in Multidisciplinary Cancer Care. https://doi.org/10.1016/B978-0-443-21901-6.00003-3
Alawyia, B., & Constantinou, C. (2023). Hepatocellular Carcinoma: a Narrative Review on Current Knowledge and Future Prospects. In Current Treatment Options in Oncology (Vol. 24, Number 7). https://doi.org/10.1007/s11864-023-01098-9
Alqahtani, S. A., & Colombo, M. (2020). Viral hepatitis as a risk factor for the development of hepatocellular carcinoma. In Hepatoma Research (Vol. 6). https://doi.org/10.20517/2394-5079.2020.49
Cardoso, M. F., & Machado, M. V. (2024). The Changing Face of Hepatitis Delta Virus Associated Hepatocellular Carcinoma. In Cancers (Vol. 16, Number 22). https://doi.org/10.3390/cancers16223723
Feng, L. H., Dong, H., Lau, W. Y., Yu, H., Zhu, Y. Y., Zhao, Y., Lin, Y. X., Chen, J., Wu, M. C., & Cong, W. M. (2017). Novel microvascular invasion-based prognostic nomograms to predict survival outcomes in patients after R0 resection for hepatocellular carcinoma. Journal of Cancer Research and Clinical Oncology, 143(2). https://doi.org/10.1007/s00432-016-2286-1
Hotta, M., Kashiwabara, M., Arai, M., Takasaki, H., Yamahatsu, K., Ueda, J., Yoshida, H., Makino, H., Naitoh, Z., & Uchida, E. (2016). A Case of Alpha-fetoprotein and Des-gamma-carboxy Prothrombin-Producing Gastric Carcinoma Mimicking Hepatocellular Carcinoma. International Journal of Gastroenterology Disorders & Therapy, 3(1). https://doi.org/10.15344/2393-8498/2016/121
Hu, S. S. (2024). Epidemiology and current management of cardiovascular disease in China. Journal of Geriatric Cardiology, 21(4). https://doi.org/10.26599/1671-5411.2024.04.001
Jasirwan, C. O. M., Fahira, A., Siregar, L., & Loho, I. (2020). The alpha-fetoprotein serum is still reliable as a biomarker for the surveillance of hepatocellular carcinoma in Indonesia. BMC Gastroenterology, 20(1). https://doi.org/10.1186/s12876-020-01365-1
Kim, M. N., Kim, B. K., Kim, S. U., Park, J. Y., Ahn, S. H., Han, K. H., & Kim, D. Y. (2019). Longitudinal assessment of alpha-fetoprotein for early detection of hepatocellular carcinoma in patients with cirrhosis. Scandinavian Journal of Gastroenterology, 54(10). https://doi.org/10.1080/00365521.2019.1673478
King, K. L., Hwang, J. J., Chau, G. Y., Tsay, S. H., Chi, C. W., Lee, T. G., Wu, L. H., Wu, C. W., & Lui, W. Y. (1998). Ki-67 expression as a prognostic marker in patients with hepatocellular carcinoma. Journal of Gastroenterology and Hepatology (Australia), 13(3). https://doi.org/10.1111/j.1440-1746.1998.01555.x
Lai, Y. W., & Chung, C. H. (2024). Epidemiology of Hepatocellular Carcinoma in Taiwan. Clinics and Practice, 14(2). https://doi.org/10.3390/clinpract14020044
Lim, J., & Singal, A. G. (2019). An Official Learning Resource of AASLD surveillance and Diagnosis of Hepatocellular Carcinoma. Clinical Liver Disease, 13(1).
Ma, X. L., Zhu, J., Wu, J., Tian, L., Gao, Y. Y., Zhang, C. Y., Zhou, Y., Dai, Q., Wang, B. L., Pan, B. S., Zhou, J., Fan, J., Yang, X. R., & Guo, W. (2018). Significance of PIVKA-II levels for predicting microvascular invasion and tumor cell proliferation in Chinese patients with hepatitis B virus-associated hepatocellular carcinoma. Oncology Letters, 15(6). https://doi.org/10.3892/ol.2018.8375
Poté, N., Cauchy, F., Albuquerque, M., Voitot, H., Belghiti, J., Castera, L., Puy, H., Bedossa, P., & Paradis, V. (2015). Performance of PIVKA-II for early hepatocellular carcinoma diagnosis and prediction of microvascular invasion. Journal of Hepatology, 62(4). https://doi.org/10.1016/j.jhep.2014.11.005
Roayaie, S., Blume, I. N., Thung, S. N., Guido, M., Fiel, M. I., Hiotis, S., Labow, D. M., Llovet, J. M., & Schwartz, M. E. (2009). A System of Classifying Microvascular Invasion to Predict Outcome After Resection in Patients With Hepatocellular Carcinoma. Gastroenterology, 137(3). https://doi.org/10.1053/j.gastro.2009.06.003
Saitta, C., Raffa, G., Casuscelli, F., Brancatelli, S., Alibrandi, A., Raimondo, G., & Pollicino, T. (2016). PIVKA-II is a useful tool for the diagnosis of early hepatocellular carcinoma. Digestive and Liver Disease, 48. https://doi.org/10.1016/j.dld.2015.12.076
Si, Y. Q., Wang, X. Q., Fan, G., Wang, C. Y., Zheng, Y. W., Song, X., Pan, C. C., Chu, F. L., Liu, Z. F., Lu, B. R., & Lu, Z. M. (2020). Value of AFP and PIVKA-II in diagnosis of HBV-related hepatocellular carcinoma and prediction of vascular invasion and tumor differentiation. Infectious Agents and Cancer, 15(1). https://doi.org/10.1186/s13027-020-00337-0
Toh, M. R., Wong, E. Y. T., Wong, S. H., Ng, A. W. T., Loo, L. H., Chow, P. K. H., & Ngeow, J. (2023). Global Epidemiology and Genetics of Hepatocellular Carcinoma. Gastroenterology, 164(5). https://doi.org/10.1053/j.gastro.2023.01.033
Tsukamoto, M., Nitta, H., Imai, K., Higashi, T., Nakagawa, S., Okabe, H., Arima, K., Kaida, T., Taki, K., Hashimoto, D., Chikamoto, A., Ishiko, T., Beppu, T., & Baba, H. (2018). Clinical significance of half-lives of tumor markers α-fetoprotein and des-γ-carboxy prothrombin after hepatectomy for hepatocellular carcinoma. Hepatology Research, 48(3). https://doi.org/10.1111/hepr.12942
Tzartzeva, K., Obi, J., Rich, N. E., Parikh, N. D., Marrero, J. A., Yopp, A., Waljee, A. K., & Singal, A. G. (2018). Surveillance Imaging and Alpha Fetoprotein for Early Detection of Hepatocellular Carcinoma in Patients With Cirrhosis: A Meta-analysis. Gastroenterology, 154(6). https://doi.org/10.1053/j.gastro.2018.01.064
Downloads
Published
Issue
Section
License
Copyright (c) 2026 Irfansyah Irfansyah, Wifanto S. Jeo, Nur Rahadiani
This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License.
This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International.
Authors who publish with this journal agree to the following terms:
- Authors retain copyright and grant the journal right of first publication with the work simultaneously licensed under a Creative Commons Attribution-ShareAlike 4.0 International (CC-BY-SA). that allows others to share the work with an acknowledgement of the work's authorship and initial publication in this journal.
- Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the journal's published version of the work (e.g., post it to an institutional repository or publish it in a book), with an acknowledgement of its initial publication in this journal.
- Authors are permitted and encouraged to post their work online (e.g., in institutional repositories or on their website) prior to and during the submission process, as it can lead to productive exchanges, as well as earlier and greater citation of published work.
