Validated nomogram for the prediction of disease-free survival after hepatectomy for hepatocellular carcinoma within the Milan criteria: individualizing a surveillance strategy

  • Ka Wing Ma
  • Wong Hoi She
  • Tan To Cheung
  • Albert Chi Yan Chan
  • Wing Chiu Dai
  • James Yan Yue Fung
  • Chung Mau Lo
  • Kenneth Siu Ho ChokEmail author
Original Article



We sought to develop a nomogram for the prediction of tumor recurrence after resection of hepatocellular carcinoma (HCC) within the Milan criteria.


Consecutive HCC patients admitted for hepatectomy between 1994 and 2014 were enrolled in this study. Patients were excluded if they had recurrent HCC or tumors beyond the Milan criteria. Patients were randomized and assigned to the derivation and validation sets in a 1:1 ratio. Independent factors for disease-free survival were identified using the Cox regression model. A nomogram was derived and validated with the receiver-operating characteristic (ROC) and calibration curves.


There were 617 eligible patients included in the analysis. The median age was 59 years, 481 were male, and 87.8% of the patients were hepatitis B virus carriers. The median follow-up was 68.7 months. The 5-year overall survival rate was 73.3% and HCC recurrence was detected in 55% of the patients. In the derivation set, a nomogram was constructed based on the seven independent factors for disease-free survival: age, alpha-fetoprotein, preoperative prothrombin time, magnitude of hepatectomy, postoperative complication, number of tumor nodules, and presence of microvascular invasion. A satisfactory discrimination ability was observed in both the derivation and validation sets (c-stat 0.672 and 0.665, respectively). The calibration plot yielded agreement between the predicted and observed outcomes, using the derived nomogram.


A validated nomogram quantifies the risk of recurrence after hepatectomy for HCC within the Milan criteria, and assists with the planning of individual postoperative surveillance protocols.


Hepatocellullar carconoma Recurrence Prediction Nomogram 



Albumin–bilirubin index


Alpha-fetal protein


Natural log of AFP


Alanine transferase


Associating liver partition with portal vein ligation for staged hepatectomy


Aspartate transaminase


Area under curve




Clinical risk score


Cavitron ultrasonic surgical aspirator


Estimated standard liver volume


Hepatocellular carcinoma


The University of Hong Kong


Inflammation-based score


Indocyanine green


Intraoperative ultrasonography


International normalization ratio


Lymphovascular invasion


Protein-induced vitamin K antagonist II


Receiver-operating characteristic


Trans-arterial chemoembolization



We thank Mr. Yuen Ho Kam, Kim Bsc (Comp&stat) for data management and analysis.


This study received no support in the form of equipment, drugs, grants or funding.

Compliance with ethical standards

Conflict of interest

We have no conflicts of interest to declare in relation to this study.


  1. 1.
    El-Serag HB. Hepatocellular carcinoma: an epidemiologic view. J Clin Gastroenterol. 2002;35(5):72-S8.Google Scholar
  2. 2.
    Fan ST, Lo CM, Liu CL, Lam CM, Yuen WK, Yeung C, et al. Hepatectomy for hepatocellular carcinoma: toward zero hospital deaths. Ann Surg. 1999;229(3):322–30.CrossRefGoogle Scholar
  3. 3.
    Fong Y, Sun RL, Jarnagin W, Blumgart LH. An analysis of 412 cases of hepatocellular carcinoma at a Western center. Ann Surg. 1999;229(6):790–9 (discussion 9-800).CrossRefGoogle Scholar
  4. 4.
    Ma KW, Cheung TT. Surgical resection of localized hepatocellular carcinoma: patient selection and special consideration. J Hepatocell Carcinoma. 2017;4:1–9.CrossRefGoogle Scholar
  5. 5.
    Llovet JM, Ducreux M, Lencioni R, Di Bisceglie AM, Galle PR, Dufour JF, Greten TF, Raymond E, Roskams T, De Baere T, Ducreux M, Mazzaferro V, Bernardi M. EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol. 2012;56(4):908–43.CrossRefGoogle Scholar
  6. 6.
    Yau T, Tang VY, Yao T-J, Fan S-T, Lo C-M, Poon RT. Development of Hong Kong liver cancer staging system with treatment stratification for patients with hepatocellular carcinoma. Gastroenterology. 2014;146(7):1691–700.e3.CrossRefGoogle Scholar
  7. 7.
    Poon RT, Fan ST, Lo CM, Liu CL, Wong J. Long-term survival and pattern of recurrence after resection of small hepatocellular carcinoma in patients with preserved liver function: implications for a strategy of salvage transplantation. Ann Surg. 2002;235(3):373–82.CrossRefGoogle Scholar
  8. 8.
    Bhangui P, Allard MA, Vibert E, Cherqui D, Pelletier G, Cunha AS, et al. Salvage versus primary liver transplantation for early hepatocellular carcinoma: do both strategies yield similar outcomes? Ann Surg. 2016;264(1):155–63.CrossRefGoogle Scholar
  9. 9.
    Furlow B. Radiation dose in computed tomography. Radiol Technol. 2010;81(5):437–50.PubMedGoogle Scholar
  10. 10.
    Umeda Y, Matsuda H, Sadamori H, Matsukawa H, Yagi T, Fujiwara T. A prognostic model and treatment strategy for intrahepatic recurrence of hepatocellular carcinoma after curative resection. World J Surg. 2011;35(1):170–7.CrossRefGoogle Scholar
  11. 11.
    Li Y, Ruan DY, Yi HM, Wang GY, Yang Y, Jiang N. A three-factor preoperative scoring model predicts risk of recurrence after liver resection or transplantation in hepatocellular carcinoma patients with preserved liver function. Hepatobiliary Pancreat Dis Int. 2015;14(5):477–84.CrossRefGoogle Scholar
  12. 12.
    Nakagawa S, Hayashi H, Nitta H, Okabe H, Sakamoto K, Higashi T, et al. Scoring system based on tumor markers and Child-Pugh classification for HCC patients who underwent liver resection. Anticancer Res. 2015;35(4):2157–63.PubMedGoogle Scholar
  13. 13.
    Lam CM, Fan ST, Lo CM, Wong J. Major hepatectomy for hepatocellular carcinoma in patients with an unsatisfactory indocyanine green clearance test. Br J Surg. 1999;86(8):1012–7.CrossRefGoogle Scholar
  14. 14.
    Poon RT, Fan ST, Lo CM, Liu CL, Lam CM, Yuen WK, et al. Improving perioperative outcome expands the role of hepatectomy in management of benign and malignant hepatobiliary diseases: analysis of 1222 consecutive patients from a prospective database. Ann Surg. 2004;240(4):698–708 (discussion—10).PubMedPubMedCentralGoogle Scholar
  15. 15.
    Cheung TT, Chan SC, Chok KS, Chan AC, Yu WC, Poon RT, et al. Rapid measurement of indocyanine green retention by pulse spectrophotometry: a validation study in 70 patients with Child-Pugh A cirrhosis before hepatectomy for hepatocellular carcinoma. Hepatobiliary Pancreat Dis Int. 2012;11(3):267–71.CrossRefGoogle Scholar
  16. 16.
    Chan SC, Liu CL, Lo CM, Lam BK, Lee EW, Wong Y, et al. Estimating liver weight of adults by body weight and gender. World J Gastroenterol. 2006;12(14):2217–22.CrossRefGoogle Scholar
  17. 17.
    Fan ST, Mau Lo C, Poon RT, Yeung C, Leung Liu C, Yuen WK, et al. Continuous improvement of survival outcomes of resection of hepatocellular carcinoma: a 20-year experience. Ann Surg. 2011;253(4):745–58.CrossRefGoogle Scholar
  18. 18.
    Liu CL, Fan ST, Cheung ST, Lo CM, Ng IO, Wong J. Anterior approach versus conventional approach right hepatic resection for large hepatocellular carcinoma: a prospective randomized controlled study. Ann Surg. 2006;244(2):194–203.CrossRefGoogle Scholar
  19. 19.
    Mazzaferro V, Regalia E, Doci R, Andreola S, Pulvirenti A, Bozzetti F, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med. 1996;334(11):693–700.CrossRefGoogle Scholar
  20. 20.
    Steyerberg EW, Harrell FE Jr, Borsboom GJ, Eijkemans MJ, Vergouwe Y, Habbema JD. Internal validation of predictive models: efficiency of some procedures for logistic regression analysis. J Clin Epidemiol. 2001;54(8):774–81.CrossRefGoogle Scholar
  21. 21.
    Zhou YM, Zhang XF, Li B, Sui CJ, Yang JM. Postoperative complications affect early recurrence of hepatocellular carcinoma after curative resection. BMC Cancer. 2015;15:689.CrossRefGoogle Scholar
  22. 22.
    Shah SA, Cleary SP, Wei AC, Yang I, Taylor BR, Hemming AW, et al. Recurrence after liver resection for hepatocellular carcinoma: risk factors, treatment, and outcomes. Surgery. 2007;141(3):330–9.CrossRefGoogle Scholar
  23. 23.
    Cha C, Fong Y, Jarnagin WR, Blumgart LH, DeMatteo RP. Predictors and patterns of recurrence after resection of hepatocellular carcinoma. J Am Coll Surg. 2003;197(5):753–8.CrossRefGoogle Scholar
  24. 24.
    Cheng Z, Yang P, Qu S, Zhou J, Yang J, Yang X, et al. Risk factors and management for early and late intrahepatic recurrence of solitary hepatocellular carcinoma after curative resection. HPB. 2015;17(5):422–7.CrossRefGoogle Scholar
  25. 25.
    Li T, Fan J, Qin LX, Zhou J, Sun HC, Qiu SJ, et al. Risk factors, prognosis, and management of early and late intrahepatic recurrence after resection of primary clear cell carcinoma of the liver. Ann Surg Oncol. 2011;18(7):1955–63.CrossRefGoogle Scholar
  26. 26.
    Wong TCL, Cheung TT, Chok KSH, Chan ACY, Dai WC, Chan SC, et al. Treatment strategy to improve long-term survival for hepatocellular carcinoma smaller than 5 cm: major hepatectomy vs minor hepatectomy. World J Surg. 2014;38(9):2386–94.CrossRefGoogle Scholar
  27. 27.
    Zhao H, Chen C, Gu S, Yan X, Jia W, Mao L, et al. Anatomical versus non-anatomical resection for solitary hepatocellular carcinoma without macroscopic vascular invasion: a propensity score matching analysis. J Gastroenterol Hepatol. 2017;32(4):870–8.CrossRefGoogle Scholar
  28. 28.
    Zhou Y, Xu D, Wu L, Li B. Meta-analysis of anatomic resection versus nonanatomic resection for hepatocellular carcinoma. Langenbeck’s Arch Surg. 2011;396(7):1109–17.CrossRefGoogle Scholar
  29. 29.
    Motoyama H, Kobayashi A, Yokoyama T, Shimizu A, Sakai H, Furusawa N, et al. Impact of advanced age on the short-and long-term outcomes in patients undergoing hepatectomy for hepatocellular carcinoma: a single-center analysis over a 20-year period. Am J Surg. 2015;209(4):733–41.CrossRefGoogle Scholar
  30. 30.
    Kaibori M, Yoshii K, Yokota I, Hasegawa K, Nagashima F, Kubo S, et al. Impact of advanced age on survival in patients undergoing resection of hepatocellular carcinoma: report of a Japanese Nationwide Survey. Ann Surg. 2017. Scholar
  31. 31.
    Mirici-Cappa F, Gramenzi A, Santi V, Zambruni A, Di Micoli A, Frigerio M, et al. Treatments for hepatocellular carcinoma in elderly patients are as effective as in younger patients: a 20-year multicentre experience. Gut. 2010;59(3):387–96.CrossRefGoogle Scholar
  32. 32.
    Liu P-H, Hsu C-Y, Lee Y-H, Hsia C-Y, Huang Y-H, Su C-W, et al. Uncompromised treatment efficacy in elderly patients with hepatocellular carcinoma: a propensity score analysis. Medicine. 2014;93(28).Google Scholar
  33. 33.
    Fu YP, Ni XC, Yi Y, Cai XY, He HW, Wang JX, et al. A novel and validated inflammation-based score (IBS) predicts survival in patients with hepatocellular carcinoma following curative surgical resection: A STROBE-compliant article. Medicine. 2016;95(7):e2784.CrossRefGoogle Scholar
  34. 34.
    Shim JH, Jun MJ, Han S, Lee YJ, Lee SG, Kim KM, et al. Prognostic nomograms for prediction of recurrence and survival after curative liver resection for hepatocellular carcinoma. Ann Surg. 2015;261(5):939–46.CrossRefGoogle Scholar
  35. 35.
    Lee SY, Konstantinidis IT, Eaton AA, Gonen M, Kingham TP, D’Angelica MI, et al. Predicting recurrence patterns after resection of hepatocellular cancer. HPB. 2014;16(10):943–53.CrossRefGoogle Scholar
  36. 36.
    Zheng J, Chou JF, Gonen M, Vachharajani N, Chapman WC, Majella Doyle MB, et al. Prediction of hepatocellular carcinoma recurrence beyond milan criteria after resection: validation of a clinical risk score in an international cohort. Ann Surg. 2017;266(4):693–701.CrossRefGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  • Ka Wing Ma
    • 1
  • Wong Hoi She
    • 1
  • Tan To Cheung
    • 1
  • Albert Chi Yan Chan
    • 1
  • Wing Chiu Dai
    • 1
  • James Yan Yue Fung
    • 2
  • Chung Mau Lo
    • 1
  • Kenneth Siu Ho Chok
    • 1
    Email author
  1. 1.Divisions of Hepatobiliary and Pancreatic Surgery and Liver Transplantation, Department of Surgery, The University of Hong KongQueen Mary HospitalHong KongChina
  2. 2.Department of MedicineThe University of Hong KongHong KongChina

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