The significance of prothrombin induced by vitamin K absence-Ⅱ in predicting the biological characteristics of hepatitis B virus-associated hepatocellular carcinoma_West China Medical Journal

Authors：

LUO Limei , SU Zhenzhen , ZHAO Wenling , MENG Liye , LI Lixin , CAI Bei , BAI Yangjuan ,  HUANG Zhuochun

Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China;

Corresponding?author：

HUANG Zhuochun, Email: huangzcscu@163.com

Keywords：

Hepatitis B viral; Hepatocellular carcinoma; Prothrombin induced by vitamin K absence-Ⅱ; Microvascular invasion

DOI：

10.7507/1002-0179.202007057

Video：

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Objective To explore the predictive value of serum prothrombin induced by vitamin K absence-Ⅱ (PIVKA-Ⅱ) detection for the biological characteristics of hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC).Methods This retrospective study included 394 patients with HBV-related HCC who were newly diagnosed and treated with surgical resection in West China Hospital of Sichuan University between June 2017 and December 2018. Their clinical information such as tumor size, tumor number, tumor cell differentiation, presence of microvascular invasion (MVI), distant metastasis, and portal vein tumor thrombus was collected from the medical record. The laboratory test results of patients during diagnosis and before surgery were collected, including alpha-fetoprotein (AFP), PIVKA-Ⅱ, alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (γ-GGT), etc., and the relationships between PIVKA-Ⅱ levels and tumor biological characteristics were analyzed. Non-normal continuous variables were presented as medium (lower quartile, upper quartile).Results Compared with the patients with low HCC serum PIVKA-Ⅱ levels (≤40 mAU/mL), patients with high serum PIVKA-Ⅱ levels (>40 mAU/mL) had larger tumor diameters [5.00 (3.00, 9.00) vs. 2.50 (1.63, 4.95) cm, P<0.001], more severe Barcelona Clinic Liver Cancer (BCLC) stage (P<0.001), and higher AFP [186.05 (6.86, 1 210.00) vs. 17.83 (4.33, 231.95) ng/mL, P<0.001], ALT [38.00 (26.00, 66.25) vs. 32.00 (22.00, 51.00) U/L, P=0.018], AST [42.00 (30.00, 76.00) vs. 34.00 (25.50, 48.25) U/L, P<0.001], and γ-GGT [71.00 (39.00, 165.50) vs. 55.50 (25.00, 93.00) U/L, P=0.005], and were more likely to form portal vein tumor thrombi (16.61% vs. 3.75%, P=0.003) and MVI (43.67% vs. 11.11%, P<0.001). In BCLC stage 0 HCC patients, the positive rate of PIVKA-Ⅱ was only 51.35%. Multivariate logistic regression analysis showed that PIVKA-Ⅱ>40 mAU/mL was an independent predictor of MVI [odds ratio=6.588, 95% confidence interval (CI) (1.645, 26.383), P=0.008]. The area under receiver operating characteristic curve of PIVKA-Ⅱ level predicting MVI was 0.761 [95%CI (0.693, 0.830)], with a sensitivity of 66.22% and a specificity of 79.06%.Conclusion In HBV-related HCC patients, high PIVKA-Ⅱ is associated with the poor biological characteristics of tumor, and is an independent risk factor for tumor MVI.

Citation： LUO Limei, SU Zhenzhen, ZHAO Wenling, MENG Liye, LI Lixin, CAI Bei, BAI Yangjuan, HUANG Zhuochun. The significance of prothrombin induced by vitamin K absence-Ⅱ in predicting the biological characteristics of hepatitis B virus-associated hepatocellular carcinoma. West China Medical Journal, 2020, 35(12): 1471-1477. doi: 10.7507/1002-0179.202007057 Copy

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2.	Tang ZY, Ye SL, Liu YK, et al. A decade’s studies on metastasis of hepatocellular carcinoma. J Cancer Res Clin Oncol, 2004, 130: 187-196.
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4.	Rodriguez-Perálvarez M, Luong TV, Andreana L, et al. A systematic review of microvascular invasion in hepatocellular carcinoma: diagnostic and prognostic variability. Ann Surg Oncol, 2013, 20: 325-339.
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7.	Liebman HA, Furie BC, Tong MJ, et al. Des-gamma-carboxy (abnormal) prothrombin as a serum marker of primary hepatocellular carcinoma. N Engl J Med, 1984, 310(22): 1427-1431.
8.	Hirokawa F, Hayashi M, Miyamoto Y, et al. Outcomes and predictors of microvascular invasion of solitary hepatocellular carcinoma. Hepatol Res, 2014, 44(8): 846-853.
9.	Poté N, Cauchy F, Albuquerque M, et al. Performance of PIVKA-Ⅱfor early hepatocellular carcinoma diagnosis and prediction of microvascular invasion. J Hepatol, 2015, 62(4): 848-854.
10.	Svobodova S, Karlikova M, Topolcan O, et al. PIVKA-Ⅱ as a potential new biomarker for hepatocellular carcinoma - A pilot study. In Vivo, 2018, 32(6): 1551-1554.
11.	Wu J, Xiang Z, Bai L, et al. Diagnostic value of serum PIVKA-Ⅱ levels for BCLC early hepatocellular carcinoma and correlation with HBV DNA. Cancer Biomark, 2018, 23(2): 235-242.
12.	Ji J, Wang H, Li Y, et al. Diagnostic evaluation of des-gamma-carboxy prothrombin versus α-fetoprotein for hepatitis B virus-related hepatocellular carcinoma in China: a large-scale, multicentre study. PLoS One, 2016, 11(4): e0153227.
13.	Yan YP, Su HX, Ji ZH, et al. Epidemiology of hepatitis B virus infection in China: current status and challenges. J Clin Transl Hepatol, 2014, 2(1): 15-22.
14.	Wang FS, Fan JG, Zhang Z, et al. The global burden of liver disease: the major impact of China. Hepatology, 2014, 60(6): 2099-2108.
15.	Arzumanyan A, Reis HMGPV, Feitelson MA. Pathogenic mechanisms in HBV- and HCV-associated hepatocellular carcinoma. Nat Rev Cancer, 2013, 13: 123.
16.	Hu HT, Wang Z, Kuang M, et al. Need for normalization: the non-standard reference standard for microvascular invasion diagnosis in hepatocellular carcinoma. World J Surg Oncol, 2018, 16(1): 50.
17.	中華人民共和國衛生和計劃生育委員會醫政醫管局. 原發性肝癌診療規范(2017年版). 中華肝臟病雜志, 2017, 25(12): 886-895.
18.	中華醫學會感染病學分會, 中華醫學會肝病學分會. 慢性乙型肝炎防治指南(2019年版). 臨床肝膽病雜志, 2019, 35(12): 2648-2669.
19.	European Association for the Study of the Liver. EASL clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol, 2018, 69(1): 182-236.
20.	Edmondson HA, Steiner PE. Primary carcinoma of the liver: a study of 100 cases among 48, 900 necropsies. Cancer, 1954, 7(3): 462-503.
21.	國家衛生健康委員會. 2019中國衛生健康統計年鑒. 北京: 中國協和醫科大學出版社, 2019: 251-272.
22.	Llovet JM, Di Bisceglie AM, Bruix JA, et al. Design and endpoints of clinical trials in hepatocellular carcinoma. J Natl Cancer Inst, 2008, 100(10): 698-711.
23.	Wang Q, Chen Q, Zhang X, et al. Diagnostic value of gamma-glutamyltransferase/aspartate aminotransferase ratio, protein induced by vitamin K absence or antagonist Ⅱ, and alpha-fetoprotein in hepatitis B virus-related hepatocellular carcinoma. World J Gastroenterol, 2019, 25(36): 5515-5529.
24.	Wang SB, Cheng YN, Cui SX, et al. Des-gamma-carboxy prothrombin stimulates human vascular endothelial cell growth and migration. Clin Exp Metastasis, 2009, 26(5): 469-477.
25.	Fujikawa T, Shiraha H, Yamamoto K. Significance of des-gamma-carboxy prothrombin production in hepatocellular carcinoma. Acta Med Okayama, 2009, 63(6): 299-304.
26.	Shirabe K, Toshima T, Kimura K, et al. New scoring system for prediction of microvascular invasion in patients with hepatocellular carcinoma. Liver Int, 2014, 34(6): 937-941.
27.	Wu M, Liu Z, Li X, et al. Dynamic changes in serum markers and their utility in the early diagnosis of all stages of hepatitis B-associated hepatocellular carcinoma. Onco Targets Ther, 2020, 13: 827-840.
28.	Ma XL, Zhu J, Wu J, et al. Significance of PIVKA-Ⅱ levels for predicting microvascular invasion and tumor cell proliferation in Chinese patients with hepatitis B virus-associated hepatocellular carcinoma. Oncol Lett, 2018, 15(6): 8396-8404.

1. Villanueva A. Hepatocellular carcinoma. N Engl J Med, 2019, 380(15): 1450-1462.
2. Tang ZY, Ye SL, Liu YK, et al. A decade’s studies on metastasis of hepatocellular carcinoma. J Cancer Res Clin Oncol, 2004, 130: 187-196.
3. Yang Y, Nagano H, Ota H, et al. Patterns and clinicopathologic features of extrahepatic recurrence of hepatocellular carcinoma after curative resection. Surgery, 2007, 141: 196-202.
4. Rodriguez-Perálvarez M, Luong TV, Andreana L, et al. A systematic review of microvascular invasion in hepatocellular carcinoma: diagnostic and prognostic variability. Ann Surg Oncol, 2013, 20: 325-339.
5. Cucchetti A, Piscaglia F, Grigioni AD, et al. Preoperative prediction of hepatocellular carcinoma tumour grade and micro-vascular invasion by means of artificial neural network: a pilot study. J Hepatol, 2010, 52: 880-888.
6. Johnson PJ. The role of serum alpha-fetoprotein estimation in the diagnosis and management of hepatocellular carcinoma. Clin Liver Dis, 2001, 5(1): 145-159.
7. Liebman HA, Furie BC, Tong MJ, et al. Des-gamma-carboxy (abnormal) prothrombin as a serum marker of primary hepatocellular carcinoma. N Engl J Med, 1984, 310(22): 1427-1431.
8. Hirokawa F, Hayashi M, Miyamoto Y, et al. Outcomes and predictors of microvascular invasion of solitary hepatocellular carcinoma. Hepatol Res, 2014, 44(8): 846-853.
9. Poté N, Cauchy F, Albuquerque M, et al. Performance of PIVKA-Ⅱfor early hepatocellular carcinoma diagnosis and prediction of microvascular invasion. J Hepatol, 2015, 62(4): 848-854.
10. Svobodova S, Karlikova M, Topolcan O, et al. PIVKA-Ⅱ as a potential new biomarker for hepatocellular carcinoma - A pilot study. In Vivo, 2018, 32(6): 1551-1554.
11. Wu J, Xiang Z, Bai L, et al. Diagnostic value of serum PIVKA-Ⅱ levels for BCLC early hepatocellular carcinoma and correlation with HBV DNA. Cancer Biomark, 2018, 23(2): 235-242.
12. Ji J, Wang H, Li Y, et al. Diagnostic evaluation of des-gamma-carboxy prothrombin versus α-fetoprotein for hepatitis B virus-related hepatocellular carcinoma in China: a large-scale, multicentre study. PLoS One, 2016, 11(4): e0153227.
13. Yan YP, Su HX, Ji ZH, et al. Epidemiology of hepatitis B virus infection in China: current status and challenges. J Clin Transl Hepatol, 2014, 2(1): 15-22.
14. Wang FS, Fan JG, Zhang Z, et al. The global burden of liver disease: the major impact of China. Hepatology, 2014, 60(6): 2099-2108.
15. Arzumanyan A, Reis HMGPV, Feitelson MA. Pathogenic mechanisms in HBV- and HCV-associated hepatocellular carcinoma. Nat Rev Cancer, 2013, 13: 123.
16. Hu HT, Wang Z, Kuang M, et al. Need for normalization: the non-standard reference standard for microvascular invasion diagnosis in hepatocellular carcinoma. World J Surg Oncol, 2018, 16(1): 50.
17. 中華人民共和國衛生和計劃生育委員會醫政醫管局. 原發性肝癌診療規范(2017年版). 中華肝臟病雜志, 2017, 25(12): 886-895.
18. 中華醫學會感染病學分會, 中華醫學會肝病學分會. 慢性乙型肝炎防治指南(2019年版). 臨床肝膽病雜志, 2019, 35(12): 2648-2669.
19. European Association for the Study of the Liver. EASL clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol, 2018, 69(1): 182-236.
20. Edmondson HA, Steiner PE. Primary carcinoma of the liver: a study of 100 cases among 48, 900 necropsies. Cancer, 1954, 7(3): 462-503.
21. 國家衛生健康委員會. 2019中國衛生健康統計年鑒. 北京: 中國協和醫科大學出版社, 2019: 251-272.
22. Llovet JM, Di Bisceglie AM, Bruix JA, et al. Design and endpoints of clinical trials in hepatocellular carcinoma. J Natl Cancer Inst, 2008, 100(10): 698-711.
23. Wang Q, Chen Q, Zhang X, et al. Diagnostic value of gamma-glutamyltransferase/aspartate aminotransferase ratio, protein induced by vitamin K absence or antagonist Ⅱ, and alpha-fetoprotein in hepatitis B virus-related hepatocellular carcinoma. World J Gastroenterol, 2019, 25(36): 5515-5529.
24. Wang SB, Cheng YN, Cui SX, et al. Des-gamma-carboxy prothrombin stimulates human vascular endothelial cell growth and migration. Clin Exp Metastasis, 2009, 26(5): 469-477.
25. Fujikawa T, Shiraha H, Yamamoto K. Significance of des-gamma-carboxy prothrombin production in hepatocellular carcinoma. Acta Med Okayama, 2009, 63(6): 299-304.
26. Shirabe K, Toshima T, Kimura K, et al. New scoring system for prediction of microvascular invasion in patients with hepatocellular carcinoma. Liver Int, 2014, 34(6): 937-941.
27. Wu M, Liu Z, Li X, et al. Dynamic changes in serum markers and their utility in the early diagnosis of all stages of hepatitis B-associated hepatocellular carcinoma. Onco Targets Ther, 2020, 13: 827-840.
28. Ma XL, Zhu J, Wu J, et al. Significance of PIVKA-Ⅱ levels for predicting microvascular invasion and tumor cell proliferation in Chinese patients with hepatitis B virus-associated hepatocellular carcinoma. Oncol Lett, 2018, 15(6): 8396-8404.

West China Medical Journal

The significance of prothrombin induced by vitamin K absence-Ⅱ in predicting the biological characteristics of hepatitis B virus-associated hepatocellular carcinoma

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