Treatment and outcomes of multinodular hepatocellular carcinoma: a systematic review and meta-analysis


  • Rajeev Adhikari Department of Liver Surgery and Transplantation Center, West China Hospital, Sichuan Chengdu, China
  • Tianfu Wen Department of Liver Surgery and Transplantation Center, West China Hospital, Sichuan Chengdu, China
  • Hare Ram Karn Department of Gastrointestinal Surgery, West China Hospital, Sichuan Chengdu, China
  • Parvani Shrestha Department of Acupuncture, China-Nepal Boda Hospital, Nepal



Hepatocellular carcinoma, HCC, Multinodular carcinoma, Prognosis, Meta-analysis


Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. Recent advances in surgical techniques and perioperative management have been suggested to have improved survival. However, full agreement about the overall survival ofpatient with multinodular HCC is still not reached yet. The aim of this meta-analysis is to evaluate the survival of patients with multinodular HCC undergoing recent treatment modalities.Weperformed the systematic computerized search for eligible articles fromfour databases (PubMed, Embase, Google Scholar and Web of Science) published before February 2018. Summary effect size (ES) and 95% confidence interval (CI) were calculated with the random-effects model and fixed-effects model. A total of 25 studies with 18954 multinodular hepatocellular carcinoma patients were included. Overall survival was shorter inpatient having multinodular carcinoma undergoing different treatment modalities (ES 1.12, 95 % CI 1.02 to 1.21; p=0.000) which was statistically significant. Those undergoing hepatectomy was shorter (ES 1.49, 95% CI 1.33 to 1.64; p=0.304) which was not statistically significantand patients undergoing RFA was shorter (ES 1.61, 95% CI 1.28 to 1.94; p=0.020) which was statistically significant. Begg’s funnel plot showed no publication bias exists.Our meta-analysis result showed that the overall survival of patients with multinodular carcinoma is shorter.


Forner A, Llovet JM, Bruix J. Hepatocellular carcinoma. Lancet (London, England). 2012;379(9822):1245-55.

Bruix J, Llovet JM. Major achievements in hepatocellular carcinoma. Lancet (London, England). 2009;373(9664):614-6.

Kim YS, Lim HK, Rhim H, Lee MW. Ablation of hepatocellular carcinoma. Best Practice Research Clin Gastroenterol. 2014;28(5):897-908.

Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, et al. Sorafenib in advanced hepatocellular carcinoma. New England J Med. 2008;359(4):378-90.

Chen W, Zheng R, Zhang S, Zhao P, Li G, Wu L, et al. Report of incidence and mortality in China cancer registries, 2009. Chinese J Cancer Res (Chung-kuo yen cheng yen chiu). 2013;25(1):10-21.

Shire AM, Roberts LR. Prevention of hepatocellular carcinoma: progress and challenges. Minerva gastroenterologica e dietologica. 2012;58(1):49-64.

El-Serag HB, Rudolph KL. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology. 2007;132(7):2557-76.

Llovet JM, Bustamante J, Castells A, Vilana R, Ayuso Mdel C, Sala M, et al. Natural history of untreated nonsurgical hepatocellular carcinoma: rationale for the design and evaluation of therapeutic trials. Hepatology (Baltimore, Md). 1999;29(1):62-7.

Yamashita Y, Taketomi A, Shirabe K, Aishima S, Tsuijita E, Morita K, et al. Outcomes of hepatic resection for huge hepatocellular carcinoma (>/= 10 cm in diameter). J Surg Oncol. 2011;104(3):292-8.

Portolani N, Coniglio A, Ghidoni S, Giovanelli M, Benetti A, Tiberio GA, et al. Early and late recurrence after liver resection for hepatocellular carcinoma: prognostic and therapeutic implications. Ann Surg. 2006;243(2):229-35.

Bruix J, Boix L, Sala M, Llovet JM. Focus on hepatocellular carcinoma. Cancer cell. 2004;5(3):215-9.

Poon RT, Fan ST, Lo CM, Liu CL, Wong J. Intrahepatic recurrence after curative resection of hepatocellular carcinoma: long-term results of treatment and prognostic factors. Ann Surg. 1999;229(2):216-22.

Chen CY, Lin XZ, Shin JS, Lin CY, Leow TC, Chen CY, et al. Spontaneous rupture of hepatocellular carcinoma. A review of 141 Taiwanese cases and comparison with nonrupture cases. J Clin Gastroenterol. 1995;21(3):238-42.

Moher D, Shamseer L, Clarke M, Ghersi D, Liberati A, Petticrew M, et al. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Systematic reviews. 2015;4:1.

Buscemi N, Hartling L, Vandermeer B, Tjosvold L, Klassen TP. Single data extraction generated more errors than double data extraction in systematic reviews. J Clin Epidemiol. 2006;59(7):697-703.

Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327(7414):557-60.

Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics. 1994;50(4):1088-101.

Chang HC, Lin YM, Yen AM, Chen SL, Wu WY, Chiu SY, et al. Predictors of long-term survival in hepatocellular carcinomas: A longitudinal follow-up of 108 patients with small tumors. Anticancer Res. 2013;33(11):5171-8.

Dan J, Zhang Y, Peng Z, Huang J, Gao H, Xu L, et al. Postoperative neutrophil-to-lymphocyte ratio change predicts survival of patients with small hepatocellular carcinoma undergoing radiofrequency ablation. PloS one. 2013;8(3):e58184.

Fan ST, Yang ZF, Ho DW, Ng MN, Yu WC, Wong J. Prediction of posthepatectomy recurrence of hepatocellular carcinoma by circulating cancer stem cells: a prospective study. Ann Surg. 2011;254(4):569-76.

Goh BKP, Chow PKH, Teo J-Y, Wong J-S, Chan C-Y, Cheow P-C, et al. Number of Nodules, Child-Pugh Status, Margin Positivity, and Microvascular Invasion, but not Tumor Size, are Prognostic Factors of Survival after Liver Resection for Multifocal Hepatocellular Carcinoma. J Gastrointes Sur. 2014;18(8):1477-85.

Hoffmann K, Mueller-Buetow V, Franz C, Hinz U, Longerich T, Buechler MW, et al. Factors Predictive of Survival After Stapler Hepatectomy of Hepatocellular Carcinoma: A Multivariate, Single-center Analysis. Anticancer Res. 2014;34(2):767-76.

Jianyong L, Jinjing Z, Lunan Y, Jingqiang Z, Wentao W, Yong Z, et al. Preoperative adjuvant transarterial chemoembolization cannot improve the long term outcome of radical therapies for hepatocellular carcinoma. Scientific Reports. 2017;7:41624.

Jun CH, Sim DW, Kim SH, Hong HJ, Chung MW, Myoung E, et al. Predictive factors for recurrence and survival in hepatocellular carcinoma in South Korea. Anticancer Res. 2013;33(9):4129-34.

Li T, Wang SK, Zhi XT, Zhou J, Dong ZR, Zhang ZL, et al. Cholecystectomy is associated with higher risk of early recurrence and poorer survival after curative resection for early stage hepatocellular carcinoma. Scientific reports. 2016;6:28229.

Li T, Wang SK, Zhou J, Sun HC, Qiu SJ, Ye QH, et al. Positive HBcAb is associated with higher risk of early recurrence and poorer survival after curative resection of HBV-related HCC. Liver international: official journal of the International Association for the Study of the Liver. 2016;36(2):284-92.

Liu J, Liu JF, Wang K, Yan ZL, Wan XY, Huang AM, et al. Loss of function of Notch1 identifies a poor prognosis group of early stage hepatocellular carcinoma following hepatectomy. Oncol Rep. 2015;34(6):3174-86.

Liu XY, Xu JF. Liver resection for young patients with large hepatocellular carcinoma: a single center experience from China. World J Surg Oncol. 2014;12:175.

Ng KK, Vauthey J-N, Pawlik TM, Lauwers GY, Regimbeau J-M, Belghiti J, et al. Is hepatic resection for large or multinodular hepatocellular carcinoma justified? Results from a multi-institutional database. Ann Surg Oncol. 2005;12(5):364-73.

Ochiai T, Ikoma H, Murayama Y, Shiozaki A, Komatsu S, Kuriu Y, et al. Factors resulting in 5-year disease-free survival after resection of hepatocellular carcinoma. Anticancer Res. 2012;32(4):1417-22.

Pawlik TM, Poon RT, Abdalla EK, Zorzi D, Ikai I, Curley SA, et al. Critical appraisal of the clinical and pathologic predictors of survival after resection of large hepatocellular carcinoma. Archives of Surg. 2005;140(5):450-7.

Shiina S, Tateishi R, Arano T, Uchino K, Enooku K, Nakagawa H, et al. Radiofrequency ablation for hepatocellular carcinoma: 10-year outcome and prognostic factors. Am J Gastroenterol. 2012;107(4):569-77.

Su CW, Chau GY, Hung HH, Yeh YC, Lei HJ, Hsia CY, et al. Impact of Steatosis on Prognosis of Patients with Early-Stage Hepatocellular Carcinoma After Hepatic Resection. Ann Surg Oncol. 2015;22(7):2253-61.

Wang YY, Huang S, Zhong JH, Ke Y, Guo Z, Liu JQ, et al. Impact of diabetes mellitus on the prognosis of patients with hepatocellular carcinoma after curative hepatectomy. PloS one. 2014;9(12):e113858.

Xiao GQ, Liu C, Liu DL, Yang JY, Yan LN. Neutrophil-lymphocyte ratio predicts the prognosis of patients with hepatocellular carcinoma after liver transplantation. World J Gastroenterol. 2013;19(45):8398-407.

Xiao H, Zhang B, Mei B, Zuo C, Wei G, Wang R, et al. Hepatic resection for hepatocellular carcinoma in patients with portal hypertension: a long-term benefit compared with transarterial chemoembolization and thermal ablation. Medicine (Baltimore). 2015;94(7):e495.

Yang L, Xu J, Ou D, Wu W, Zeng Z. Hepatectomy for huge hepatocellular carcinoma: single institute's experience. World J Surg. 2013;37(9):2189-96.

Yuan BH, Yuan WP, Li RH, Xiang BD, Gong WF, Li LQ, et al. Propensity score-based comparison of hepatic resection and transarterial chemoembolization for patients with advanced hepatocellular carcinoma. Tumour biol. 2016;37(2):2435-41.

Zhang L, Ge NL, Chen Y, Xie XY, Yin X, Gan YH, et al. Long-term outcomes and prognostic analysis of radiofrequency ablation for small hepatocellular carcinoma: 10-year follow-up in Chinese patients. Medical Oncol (Northwood, London, England). 2015;32(3):77.

Zheng L, Li HL, Guo CY, Luo SX. Comparison of the Efficacy and Prognostic Factors of Transarterial Chemoembolization Plus Microwave Ablation versus Transarterial Chemoembolization Alone in Patients with a Large Solitary or Multinodular Hepatocellular Carcinomas. Korean J Radiol. 2018;19(2):237-46.

Zhong F, Cheng XS, He K, Sun SB, Zhou J, Chen HM. Treatment outcomes of spontaneous rupture of hepatocellular carcinoma with hemorrhagic shock: a multicenter study. Springer Plus. 2016;5(1):1101.

Zhong JH, You XM, Lu SD, Wang YY, Xiang BD, Ma L, et al. Historical Comparison of Overall Survival after Hepatic Resection for Patients With Large and/or Multinodular Hepatocellular Carcinoma. Medicine (Baltimore). 2015;94(35):e1426.

Lai EC, Fan ST, Lo CM, Chu KM, Liu CL, Wong J. Hepatic resection for hepatocellular carcinoma. An audit of 343 patients. Ann Surg. 1995;221(3):291-8.

Chen MF, Hwang TL, Jeng LB, Jan YY, Wang CS, Chou FF. Hepatic resection in 120 patients with hepatocellular carcinoma. Arch Surg (Chicago, Ill : 1960). 1989;124(9):1025-8.

Lau H, Fan ST, Ng IO, Wong J. Long term prognosis after hepatectomy for hepatocellular carcinoma: a survival analysis of 204 consecutive patients. Cancer. 1998;83(11):2302-11.

Chen MF, Tsai HP, Jeng LB, Lee WC, Yeh CN, Yu MC, et al. Prognostic factors after resection for hepatocellular carcinoma in noncirrhotic livers: univariate and multivariate analysis. World J Surg. 2003;27(4):443-7.

Bruix J, Gores GJ, Mazzaferro V. Hepatocellular carcinoma: clinical frontiers and perspectives. Gut. 2014;63(5):844-55.

He XX, Li Y, Ren HP, Tian DA, Lin JS. 2010 guideline for the management of hepatocellular carcinoma recommended by the American Association for the Study of Liver Diseases. Chinese J Hepatol. 2011;19(4):249-50.

Llovet JM, Burroughs A, Bruix J. Hepatocellular carcinoma. Lancet (London, England). 2003;362(9399):1907-17.

Llovet JM, Bruix J. Systematic review of randomized trials for unresectable hepatocellular carcinoma: Chemoembolization improves survival. Hepatology (Baltimore, Md). 2003;37(2):429-42.






Review Articles