Updates in Surgery

, Volume 71, Issue 1, pp 57–66 | Cite as

Dissecting the multinodular hepatocellular carcinoma subset: is there a survival benefit after hepatectomy?

  • Matteo Donadon
  • Andrea Fontana
  • Fabio Procopio
  • Daniele Del Fabbro
  • Matteo Cimino
  • Luca Viganò
  • Angela Palmisano
  • Guido TorzilliEmail author
Original Article


Whether hepatic resection for multinodular hepatocellular carcinoma (HCC) is indicated remains to be demonstrated. We investigated the prognostic factors in a large series of patients treated with hepatic resection at a reference cancer center. All consecutive patients resected for multinodular HCC from January 2004 to April 2015 were reviewed. The study endpoints were the survival analysis and the definition of resection criteria. Among 380 patients resected for HCC, 116 (31%) were affected by multinodular HCC without macrovascular invasion. The median tumor number was 2 (range 2–30), while the median tumor size was 3.5 cm (range 1.1–28). The 90-day mortality was 2.6%. Morbidity was 31%. After a median follow-up of 31 months (range 3.1–149.7), the 1-, 3-, and 5-year overall survival rates were 85, 52, and 35%, respectively. At the multivariate analysis, tumor number more than 4 (HR = 2.15; 95% CI 1.8–4.18; P = 0.001), tumor size more than 6 cm (HR = 2.78; 95% CI 2.08–4.91; P = 0.001), esophageal varices (HR = 3.01; 95% CI 1.98–5.61; P = 0.002), and major hepatectomy (HR = 2.91; 95% CI 1.97–4.54; P = 0.001) were independently significant for survival. Median survival shifted from 20 to 52 months based on these factors. Hepatic resection for multinodular HCC may result in survival benefit for patients up to four tumors, none more than 6 cm, without varices, and eventually treated by conservative surgery.


Multinodular hepatocellular carcinoma Multiple hepatocellular carcinoma Hepatectomy Survival for multiple hepatocellular carcinoma 


Compliance with ethical standards

Conflict of interest

The authors declare no conflicts of interest.

Research involving human participants and/or animals

The study was conducted according with the Helsinki declaration about ethical standards. Moreover, it was approved by the local ethical committee of our institution.

Informed consent

Informed consent was obtained by each patient included in the study.


  1. 1.
    Venook AP, Papandreou C, Furuse J et al (2010) The incidence and epidemiology of hepatocellular carcinoma: a global and regional perspective. Oncologist 15(Suppl 4):5–13CrossRefGoogle Scholar
  2. 2.
    Mazzaferro V, Llovet JM, Miceli R et al (2009) Predicting survival after liver transplantation in patients with hepatocellular carcinoma beyond the Milan criteria: a retrospective, exploratory analysis. Lancet Oncol 10:35–43CrossRefGoogle Scholar
  3. 3.
    European Association for the Study of the Liver, European Organisation for Research and Treatment of Cancer (2012) EASL-EORTC Clinical Practice Guidelines: Management of hepatocellular carcinoma. J Hepatol 56:908–943CrossRefGoogle Scholar
  4. 4.
    Torzilli G, Belghiti J, Kokudo N et al (2013) A snapshot of the effective indications and results of surgery for hepatocellular carcinoma in tertiary referral centers: is it adherent to the EASL/AASLD recommendations?: an observational study of the HCC East-West study group. Ann Surg 257:929–937CrossRefGoogle Scholar
  5. 5.
    Roayaie S, Jibara G, Tabrizian P et al (2015) The role of hepatic resection in the treatment of hepatocellular cancer. Hepatology 62:440–451CrossRefGoogle Scholar
  6. 6.
    Ciria R, Lopez-Cillero P, Gallardo AB et al (2015) Optimizing the management of patients with BCLC stage-B hepatocellular carcinoma: modern surgical resection as a feasible alternative to transarterial chemoemolization. Eur J Surg Oncol 41:1153–1161CrossRefGoogle Scholar
  7. 7.
    Torzilli G, Donadon M, Belghiti J et al (2016) Predicting individual survival after hepatectomy for hepatocellular carcinoma: a novel nomogram from the “HCC East & West Study Group”. J Gastrointest Surg 20:1154–1162CrossRefGoogle Scholar
  8. 8.
    Belghiti J, Clavien P, Gadzijev E (2000) The Brisbane 2000 terminology of liver anatomy and resections. HPB (Oxford) 2:333–339CrossRefGoogle Scholar
  9. 9.
    Dindo D, Demartines N, Clavien P-A (2004) Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg 240:205–213CrossRefGoogle Scholar
  10. 10.
    Donadon M, Costa G, Cimino M et al (2014) Safe hepatectomy selection criteria for hepatocellular carcinoma patients: a validation of 336 consecutive hepatectomies. The BILCHE score. World J Surg 39:237–243CrossRefGoogle Scholar
  11. 11.
    Pugh RNH, Murray-Lyon IM, Dawson JL et al (1973) Transection of the oesophagus for bleeding oesophageal varices. Br J Surg 60:646–649CrossRefGoogle Scholar
  12. 12.
    Torzilli G, Donadon M, Marconi M et al (2008) Hepatectomy for stage b and stage c hepatocellular carcinoma in the barcelona clinic liver cancer classification: results of a prospective analysis. Arch Surg 143:1082–1090CrossRefGoogle Scholar
  13. 13.
    Kinoshita H, Sakai K, Hirohashi K et al (1986) Preoperative portal vein embolization for hepatocellular carcinoma. World J Surg 10:803–808CrossRefGoogle Scholar
  14. 14.
    Torzilli G, Montorsi M, Donadon M et al (2005) “Radical but conservative” is the main goal for ultrasonography-guided liver resection: prospective validation of this approach. J Am Coll Surg 201:517–528CrossRefGoogle Scholar
  15. 15.
    Torzilli G, Procopio F, Cimino M et al (2010) Anatomical segmental and subsegmental resection of the liver for hepatocellular carcinoma: a new approach by means of ultrasound-guided vessel compression. Ann Surg 251:229–235CrossRefGoogle Scholar
  16. 16.
    Torzilli G (2014) Ultrasound-guided liver surgery: an atlas. Springer, BerlinCrossRefGoogle Scholar
  17. 17.
    Donadon M, Costa G, Cimino M et al (2016) Diagnosis and management of bile leaks after hepatectomy: results of a prospective analysis of 475 hepatectomies. World J Surg 40:172–181CrossRefGoogle Scholar
  18. 18.
    Groenwold RH, Hak E, Hoes AW (2009) Quantitative assessment of unobserved confounding is mandatory in nonrandomized intervention studies. J Clin Epidemiol 62:22–28CrossRefGoogle Scholar
  19. 19.
    Copas JB (1983) Regression, prediction and shrinkage. J R Stat Soc 45:311–354Google Scholar
  20. 20.
    Peduzzi P, Concato J, Feinstein AR et al (1995) Importance of events per independent variable in proportional hazards regression analysis. II. Accuracy and precision of regression estimates. J Clin Epidemiol 48:1503–1510CrossRefGoogle Scholar
  21. 21.
    Malinchoc M, Kamath PS, Gordon FD et al (2000) A model to predict poor survival in patients undergoing transjugular intrahepatic portosystemic shunts. Hepatology 31:864–871CrossRefGoogle Scholar
  22. 22.
    Yin L, Li H, Li AJ et al (2014) Partial hepatectomy vs. transcatheter arterial chemoembolization for resectable multiple hepatocellular carcinoma beyond Milan Criteria: a RCT. J Hepatol 61:82–88CrossRefGoogle Scholar
  23. 23.
    Zhong JH, Xiang BD, Gong WF et al (2013) Comparison of long-term survival of patients with BCLC stage B hepatocellular carcinoma after liver resection or transarterial chemoembolization. PLoS One 8:e68193CrossRefGoogle Scholar
  24. 24.
    Choi SH, Choi GH, Kim SU et al (2013) Role of surgical resection for multiple hepatocellular carcinomas. World J Gastroenterol 19:366–374CrossRefGoogle Scholar
  25. 25.
    Farinati F, Vanin V, Giacomin A et al (2015) BCLC stage B hepatocellular carcinoma and transcatheter arterial chemoembolization: a 20-year survey by the Italian Liver Cancer group. Liver Int 35:223–231CrossRefGoogle Scholar
  26. 26.
    Yang XD, Pan LH, Wang L et al (2015) Systematic review of single large and/or multinodular hepatocellular carcinoma: surgical resection improves survival. Asian Pac J Cancer Prev 16:5541–5547CrossRefGoogle Scholar
  27. 27.
    Qi X, Wang D, Su C et al (2015) Hepatic resection versus transarterial chemoembolization for the initial treatment of hepatocellular carcinoma: a systematic review and meta-analysis. Oncotarget 6:18715–18733Google Scholar
  28. 28.
    Kapitanov T, Neumann UP, Schmeding M (2015) Hepatocellular carcinoma in liver cirrhosis: surgical resection versus transarterial chemoembolization—a meta-analysis. Gastroenterol Res Pract 2015:696120CrossRefGoogle Scholar
  29. 29.
    Vitale A, Burra P, Frigo AC et al (2015) Survival benefit of liver resection for patients with hepatocellular carcinoma across different Barcelona clinic liver cancer stages: a multicentre study. J Hepatol 62:617–624CrossRefGoogle Scholar
  30. 30.
    Jianyong L, Lunan Y, Wentao W et al (2014) Barcelona clinic liver cancer stage B hepatocellular carcinoma: transarterial chemoembolization or hepatic resection? Medicine (Baltimore) 93:e180CrossRefGoogle Scholar
  31. 31.
    Lo CM, Ngan H, Tso WK et al (2002) Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma. Hepatology 35:1164–1171CrossRefGoogle Scholar
  32. 32.
    Llovet JM, Real MI, Montana X et al (2002) Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial. Lancet 359:1734–1739CrossRefGoogle Scholar
  33. 33.
    Llovet JM, Bruix J (2003) Systematic review of randomized trials for unresectable hepatocellular carcinoma: chemoembolization improves survival. Hepatology 37:429–442CrossRefGoogle Scholar
  34. 34.
    Marelli L, Stigliano R, Triantos C et al (2007) Transarterial therapy for hepatocellular carcinoma: which technique is more effective? A systematic review of cohort and randomized studies. Cardiovasc Intervent Radiol 30:6–25CrossRefGoogle Scholar
  35. 35.
    Camma C, Schepis F, Orlando A et al (2002) Transarterial chemoembolization for unresectable hepatocellular carcinoma: meta-analysis of randomized controlled trials. Radiology 224:47–54CrossRefGoogle Scholar
  36. 36.
    Torzilli G, Makuuchi M, Inoue K et al (1999) No-mortality liver resection for hepatocellular carcinoma in cirrhotic and noncirrhotic patients: is there a way? A prospective analysis of our approach. Arch Surg 134:984–992CrossRefGoogle Scholar
  37. 37.
    Ng KK, Vauthey JN, Pawlik TM et al (2005) Is hepatic resection for large or multinodular hepatocellular carcinoma justified? Results from a multi-institutional database. Ann Surg Oncol 12:364–373CrossRefGoogle Scholar
  38. 38.
    Sangro B, Carpanese L, Cianni R et al (2011) Survival after yttrium-90 resin microsphere radioembolization of hepatocellular carcinoma across Barcelona clinic liver cancer stages: a European evaluation. Hepatology 54:868–878CrossRefGoogle Scholar
  39. 39.
    Mazzaferro V, Sposito C, Bhoori S et al (2013) Yttrium-90 radioembolization for intermediate-advanced hepatocellular carcinoma: a phase 2 study. Hepatology 57:1826–1837CrossRefGoogle Scholar
  40. 40.
    Cucchetti A, Mazzaferro V, Pinna AD et al (2017) Average treatment effect of hepatic resection versus locoregional therapies for hepatocellular carcinoma. Br J Surg 104:1704–1712CrossRefGoogle Scholar
  41. 41.
    Giuliante F, Ardito F, Pinna AD et al (2012) Liver resection for hepatocellular carcinoma ≤ 3 cm: results of an Italian Multicenter Study on 588 patients. J Am Coll Surg 215:244–254CrossRefGoogle Scholar
  42. 42.
    Bruix J, Takayama T, Mazzaferro V et al (2015) Adjuvant sorafenib for hepatocellular carcinoma after resection or ablation (STORM): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet Oncol 16:1344–1354CrossRefGoogle Scholar
  43. 43.
    Bolondi L, Burroughs A, Dufour JF et al (2012) Heterogeneity of patients with intermediate (BCLC B) hepatocellular carcinoma: proposal for a subclassification to facilitate treatment decisions. Semin Liver Dis 32:348–359Google Scholar
  44. 44.
    Weinmann A, Koch S, Sprinzl M et al (2015) Survival analysis of proposed BCLC-B subgroups in hepatocellular carcinoma patients. Liver Int 35:591–600CrossRefGoogle Scholar

Copyright information

© Italian Society of Surgery (SIC) 2019

Authors and Affiliations

  • Matteo Donadon
    • 1
  • Andrea Fontana
    • 1
  • Fabio Procopio
    • 1
  • Daniele Del Fabbro
    • 1
  • Matteo Cimino
    • 1
  • Luca Viganò
    • 1
  • Angela Palmisano
    • 1
  • Guido Torzilli
    • 1
    Email author
  1. 1.Department of Hepatobiliary and General Surgery, Humanitas Clinical and Research Center - IRCCSHumanitas UniversityMilanItaly

Personalised recommendations