Liver Resection Is Justified in Patients with BCLC Intermediate Stage Hepatocellular Carcinoma without Microvascular Invasion

  • Han Wang
  • You-Wen Qian
  • Meng-Chao Wu
  • Wen-Ming CongEmail author
Original Article



Large, multinodular (> 3 nodules and/or > 3 cm) hepatocellular carcinoma (HCC) is not an indication for liver resection based on the Barcelona Clinic Liver Cancer (BCLC) staging classification. We hypothesize that microvascular invasion (MVI) is a strong indication for surgery in these patients.


Between December 2009 and December 2010, a retrospective cohort of the patients with BCLC intermediate stage HCC undergoing surgical resection at Eastern Hepatobiliary Surgery Hospital was analyzed. Propensity score matching (PSM) was conducted to balance the patients with regard to their baseline characteristics. Survival analysis was performed according to the Kaplan–Meier method. Logistic regression was conducted to identify the predictors of MVI. Risk factors were evaluated using the Cox proportional hazards model.


Among 323 patients, the MVI-negative group (26.0%) had a more favorable prognosis than did the MVI-positive group (5-year recurrence-free survival: 25.2% vs. 7.8%; 5-year overall survival: 49.5% vs. 24.0%). Similar results were identified after PSM. Compared with MVI-negative patients, MVI-positive patients experienced more early recurrence (< 2 years, P = 0.006), multinodular recurrence (P = 0.004), and extrahepatic recurrence (P = 0.026). Total bilirubin levels > 17.1 μmol/L, alpha fetal protein levels > 400 ng/mL, the presence of > 2 nodules, and the lack of a capsule were independent predictors of MVI.


In BCLC intermediate stage HCC, MVI predicted an adverse recurrence pattern and poor prognosis and has the potential to be used as a reference index when deciding whether to operate. Factors predictive of MVI could assist in choosing preoperative treatment and postoperative surveillance.


Hepatocellular carcinoma Barcelona clinic liver cancer Intermediate stage Microvascular invasion Propensity score matching 



Hepatocellular carcinoma


Barcelona Clinic Liver Cancer


Microvascular invasion


Propensity score matching


American Association for the Study of Liver Diseases


European Association for the Study of the Liver


Multiple nodular HCC


Transarterial chemoembolization


Intrahepatic metastasis


Multicentric occurrence


Eastern Cooperative Oncology Group


Alpha fetal protein


Recurrence-free survival


Overall survival


Total bilirubin




Red blood cell


Hazard ratio


Confidence interval


Odds ratio



We thank Hua Yu and Zhen-Ying Cao (Department of Pathology, Eastern Hepatobiliary Surgery Hospital, Shanghai) for their advice regarding the pathological techniques used in this study.

Authors’ contributions

Conception: Wen-Ming Cong; study design: Wen-Ming Cong, Han Wang; administrative support: Meng-Chao Wu; data collection and acquisition: Han Wang, You-Wen Qian; data analysis: Han Wang; manuscript preparation: Han Wang, You-Wen Qian, Wen-Ming Cong; critical revision: Wen-Ming Cong; final approval of manuscript: all authors.


We received funding from the National Natural Science Foundation of China (Grant No. 81472278 and No. 8150101732), the Funds for Creative Research Groups of the National Natural Science Foundation of China (Grant No. 81521091), and the Scientific Research Foundation of the Shanghai Municipal Commission of Health and Family Planning (Grant No. 20154Y0140) for this study.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Supplementary material

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Supplementary Fig. 1

Cumulative overall survival after the first recurrence in patients with and without microvascular invasion (PNG 230 kb)

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High resolution image (TIF 1210 kb)
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Supplementary Fig. 2

Cumulative early recurrence-free survival (2A) and late recurrence-free survival (2B) in patients with and without microvascular invasion (PNG 293 kb)

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High resolution image (TIF 1504 kb)
11605_2019_4251_Fig6_ESM.png (494 kb)
Supplementary Fig. 3

Cumulative recurrence-free survival (3A) and overall survival (3B) in patients with different degrees of risk for microvascular invasion (PNG 493 kb)

11605_2019_4251_MOESM3_ESM.tif (1.6 mb)
High resolution image (TIF 1616 kb)


  1. 1.
    Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. 2018;68(1):7–30. doi: Scholar
  2. 2.
    Islami F, Miller KD, Siegel RL, Fedewa SA, Ward EM, Jemal A. Disparities in liver cancer occurrence in the United States by race/ethnicity and state. CA: a cancer journal for clinicians. 2017;67(4):273–89. doi: Scholar
  3. 3.
    Lu LC, Cheng AL, Poon RT. Recent advances in the prevention of hepatocellular carcinoma recurrence. Semin Liver Dis. 2014;34(4):427–34. doi: Scholar
  4. 4.
    Colecchia A, Schiumerini R, Cucchetti A, Cescon M, Taddia M, Marasco G et al. Prognostic factors for hepatocellular carcinoma recurrence. World Journal of gastroenterology. 2014;20(20):5935–50. doi: Scholar
  5. 5.
    Llovet JM, Bru C, Bruix J. Prognosis of hepatocellular carcinoma: the BCLC staging classification. Semin Liver Dis. 1999;19(3):329–38. doi: Scholar
  6. 6.
    Heimbach JK, Kulik LM, Finn RS, Sirlin CB, Abecassis MM, Roberts LR et al. AASLD guidelines for the treatment of hepatocellular carcinoma. Hepatology (Baltimore, Md). 2018;67(1):358–80. doi: Scholar
  7. 7.
    EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma. Journal of hepatology. 2018;69(1):182–236. doi: Scholar
  8. 8.
    Forner A, Reig M, Bruix J. Hepatocellular carcinoma. Lancet (London, England). 2018;391(10127):1301–14. doi: Scholar
  9. 9.
    Yang B, Zheng B, Yang M, Zeng Z, Yang F, Pu J et al. Liver resection versus transarterial chemoembolization for the initial treatment of Barcelona Clinic Liver Cancer stage B hepatocellular carcinoma. 2018. doi: Scholar
  10. 10.
    Liang L, Xing H, Zhang H, Zhong J, Li C, Lau WY et al. Surgical resection versus transarterial chemoembolization for BCLC intermediate stage hepatocellular carcinoma: a systematic review and meta-analysis. HPB : the official journal of the International Hepato Pancreato Biliary Association. 2018;20(2):110–9. doi: Scholar
  11. 11.
    Gehrau R, Mas V, Archer KJ, Maluf D. Molecular classification and clonal differentiation of hepatocellular carcinoma: the step forward for patient selection for liver transplantation. Expert review of gastroenterology & hepatology. 2011;5(4):539–52. doi: Scholar
  12. 12.
    Cong WM, Wu MC. New insights into molecular diagnostic pathology of primary liver cancer: Advances and challenges. Cancer letters. 2015;368(1):14–9. doi: Scholar
  13. 13.
    Kim JM, Kwon CH, Joh JW, Park JB, Lee JH, Kim SJ et al. Intrahepatic metastasis is more risky than multiple occurrence in hepatocellular carcinoma patients after curative liver resection. Hepato-gastroenterology. 2015;62(138):399–404.PubMedGoogle Scholar
  14. 14.
    Cong WM, Bu H, Chen J, Dong H, Zhu YY, Feng LH et al. Practice guidelines for the pathological diagnosis of primary liver cancer: 2015 update. World journal of gastroenterology. 2016;22(42):9279–87. doi: Scholar
  15. 15.
    Wang H, Wu MC, Cong WM. Microvascular invasion predicts a poor prognosis of solitary hepatocellular carcinoma up to 2 cm based on propensity score matching analysis. Hepatology research. 2019;49:344–54. doi: Scholar
  16. 16.
    Rubin DB, Thomas N. Matching using estimated propensity scores: relating theory to practice. Biometrics. 1996;52(1):249–64.CrossRefGoogle Scholar
  17. 17.
    Hyun MH, Lee YS. Hepatic resection compared to chemoembolization in intermediate- to advanced-stage hepatocellular carcinoma: A meta-analysis of high-quality studies. 2018. doi: Scholar
  18. 18.
    Guo H, Wu T, Lu Q, Li M, Guo JY, Shen Y et al. Surgical resection improves long-term survival of patients with hepatocellular carcinoma across different Barcelona Clinic Liver Cancer stages. Cancer management and research. 2018;10:361–9. doi: Scholar
  19. 19.
    Zhang W, Liu C, Tan Y, Jiang L, Yan L, Yang J et al. Role of liver resection in treating intermediate and advanced stage adolescent and young adult hepatocellular carcinoma patients: A propensity-matching cohort study. International journal of surgery (London, England). 2018;54(Pt A):259–64. doi: Scholar
  20. 20.
    Forner A, Gilabert M, Bruix J, Raoul JL. Intermediate-stage HCC--upfront resection can be feasible. Nature reviews Clinical oncology. 2015;12(5). doi: Scholar
  21. 21.
    Zhong J-H, Lu S-D, Wang Y-Y, Ma L, Li L-Q. Intermediate-stage HCC—upfront resection can be feasible. Nature Reviews Clinical Oncology. 2015;12:295. doi: Scholar
  22. 22.
    Bolondi L, Burroughs A, Dufour JF, Galle PR, Mazzaferro V, Piscaglia F et al. Heterogeneity of patients with intermediate (BCLC B) Hepatocellular Carcinoma: proposal for a subclassification to facilitate treatment decisions. Semin Liver Dis. 2012;32(4):348–59. doi: Scholar
  23. 23.
    Hiraoka A, Kumada T, Nouso K, Tsuji K, Itobayashi E, Hirooka M et al. Proposed New Sub-Grouping for Intermediate-Stage Hepatocellular Carcinoma Using Albumin-Bilirubin Grade. Oncology. 2016;91(3):153–61. doi: Scholar
  24. 24.
    Kimura H, Ohkawa K, Miyazaki M, Sakakibara M, Imanaka K, Tamura T et al. Subclassification of patients with intermediate-stage (Barcelona Clinic Liver Cancer stage-B) hepatocellular carcinoma using the up-to-seven criteria and serum tumor markers. Hepatology international. 2017;11(1):105–14. doi: Scholar
  25. 25.
    Wei WX, Yang ZS, Lu LH, Li J, Lei ZQ, Wang K et al. Long-term survival after partial hepatectomy for sub-stage patients with intermediate stage hepatocellular carcinoma. International journal of surgery (London, England). 2018;56:256–63. doi: Scholar
  26. 26.
    Wada H, Eguchi H, Noda T, Ogawa H, Yamada D, Tomimaru Y et al. Selection criteria for hepatic resection in intermediate-stage (BCLC stage B) multiple hepatocellular carcinoma. Surgery. 2016;160(5):1227–35. doi: Scholar
  27. 27.
    Nomoto S, Hishida M, Inokawa Y, Sugimoto H, Kodera Y. Management of hepatocellular carcinoma should consider both tumor factors and background liver factors. Hepatobiliary surgery and nutrition. 2014;3(2):82–5. doi: Scholar
  28. 28.
    Gao Q, Wang XY, Zhou J, Fan J. Multiple carcinogenesis contributes to the heterogeneity of HCC. Nature reviews Gastroenterology & hepatology. 2015;12(1):13. doi: Scholar
  29. 29.
    Oikawa T, Ojima H, Yamasaki S, Takayama T, Hirohashi S, Sakamoto M. Multistep and multicentric development of hepatocellular carcinoma: histological analysis of 980 resected nodules. Journal of hepatology. 2005;42(2):225–9.CrossRefGoogle Scholar
  30. 30.
    Wang B, Xia CY, Lau WY, Lu XY, Dong H, Yu WL et al. Determination of clonal origin of recurrent hepatocellular carcinoma for personalized therapy and outcomes evaluation: a new strategy for hepatic surgery. Journal of the American College of Surgeons. 2013;217(6):1054–62. doi: Scholar
  31. 31.
    Wang Z, Gong W, Shou D, Zhang L, Gu X, Wang Y et al. Clonal Origin of Hepatocellular Carcinoma and Recurrence After Liver Transplantation. Annals of transplantation. 2016;21:484–90.CrossRefGoogle Scholar
  32. 32.
    Huang C, Zhu XD, Ji Y, Ding GY, Shi GM, Shen YH et al. Microvascular invasion has limited clinical values in hepatocellular carcinoma patients at Barcelona Clinic Liver Cancer (BCLC) stages 0 or B. BMC cancer. 2017;17(1):58. doi: Scholar
  33. 33.
    Shen J, Wen J, Li C, Wen T, Yan L, Li B et al. The prognostic value of microvascular invasion in early-intermediate stage hepatocelluar carcinoma: a propensity score matching analysis. BMC cancer. 2018;18(1):278. doi: Scholar
  34. 34.
    Lei Z, Li J, Wu D, Xia Y, Wang Q, Si A et al. Nomogram for Preoperative Estimation of Microvascular Invasion Risk in Hepatitis B Virus-Related Hepatocellular Carcinoma Within the Milan Criteria. JAMA surgery. 2016;151(4):356–63. doi: Scholar
  35. 35.
    Schlichtemeier SM, Pang TC, Williams NE, Gill AJ, Smith RC, Samra JS et al. A pre-operative clinical model to predict microvascular invasion and long-term outcome after resection of hepatocellular cancer: The Australian experience. European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology. 2016;42(10):1576–83. doi: Scholar
  36. 36.
    Li H, Zhang J, Zheng Z, Guo Y, Chen M, Xie C et al. Preoperative histogram analysis of intravoxel incoherent motion (IVIM) for predicting microvascular invasion in patients with single hepatocellular carcinoma. European journal of radiology. 2018;105:65–71. doi: Scholar

Copyright information

© The Society for Surgery of the Alimentary Tract 2019

Authors and Affiliations

  1. 1.Department of PathologyEastern Hepatobiliary Surgery Hospital, The Second Military Medical UniversityShanghaiChina
  2. 2.Key Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer, The Second Military Medical University, Ministry of EducationShanghaiChina
  3. 3.Shanghai Key Laboratory of Hepatobiliary Tumor Biology, Eastern Hepatobiliary Surgery HospitalShanghaiChina
  4. 4.Department of Hepatic SurgeryEastern Hepatobiliary Surgery Hospital, The Second Military Medical UniversityShanghaiChina

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