Journal of Hepatology
Volume 38, Issue 2 , Pages 237-239, February 2003

Prognostic factors after resection of hepatocellular carcinoma: are there landmarks in the wild forest?

  • Jean-Nicolas Vauthey

      Affiliations

    • Department of Surgical Oncology, The University of Texas, M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Box 444, Houston, TX 77030-4095, USA
    • Corresponding Author InformationCorresponding author. Tel.: +1-713-792-2022; fax: +1-713-792-0722
    • ,
  • Gregory Y Lauwers

      Affiliations

    • Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

See Article, pages 200–207

Article Outline

 

Whether or not the prognostication of patients with hepatocellular carcinoma (HCC) can be accommodated by a single system has been debated and elevated to an art form [1]. Given recent improvement in detection, surgical technique and post operative management, there has been, an increase in the number of patients who undergo curative resection for HCC, over the past decade. In well-selected patients, the mortality rate after resection of HCC is now approaching zero at specialized centers. However, for this population whose prognostic determinants may differ from those observed in unresectable patients, the challenge is to define the landmarks in the wild forest of tumor and liver factors affecting prognosis after resection. In 1988, the American Joint Committee on Cancer and International Union Against Cancer (AJCC/UICC) adopted the tumor node metastasis (TNM) classification of the Liver Cancer Study Group of Japan for evaluation of the prognosis of HCC [2]. The main limitation of this classification was that it was based on the macroscopic evaluation of surgical specimens. Further drawbacks included a complex T classification including ten subcategories, a challenged 2-cm size cut-off, and overlap in prognosis between the T subcategories [3].

Recently, in an effort to improve the staging of HCC, the International Cooperative Study Group for Hepatocellular Carcinoma analyzed 591 patients who underwent curative resection at major hepatobiliary centers in Japan, France, and the United States [4]. This study included a detailed clinical and pathologic review of tumor and liver factors potentially influencing prognosis using uniform criteria. Five independent predictors of death were identified: major vascular invasion (defined as invasion of the major branch of the portal vein or the hepatic veins), microscopic vascular invasion, severe fibrosis or cirrhosis, multiple tumors, and tumor size greater than 5 cm. On the basis of these prognostic factors, a simplified T classification for the staging of HCC was proposed (Table 1) [4], [5]. The backbone of this classification is the presence or absence and extent of vascular invasion. Perhaps the most striking feature of this scheme is that solitary tumors without vascular invasion carry the same prognosis regardless of tumor size. In other words, large size does not necessarily imply a poor prognosis since the 5-year survival for T1 tumors (solitary without vascular invasion) including tumors greater than 10 cm was 55% (median survival time was 67 months) [4]. While this classification was derived from prognostic factors determined in patients undergoing hepatic resection, data from two recent studies in patients undergoing liver transplantation for treatment of HCC indicate a favorable outcome in the absence of vascular invasion [6], [7]. This new T classification has been adopted by the AJCC/UICC for the staging of HCC and will become effective for coding and classification purposes on January 1, 2003 [5].

Table 1. Prognosis of the main T categories of the new AJCC/UICC classificationc
GroupFibrosisa5-year survival (%)P value
T1 – Solitary without vascular invasionF0640.01
F149
T2 – Solitary with vascular invasion or multiple tumors ≤5 cmF0460.01
F130
T3 – Major vascular invasionb or multiple tumors >5 cmF0170.005
F19

a F0: fibrosis grade 0–4; and F1: fibrosis grade 5–6 according to Ishak [21].

b Defined as invasion of the major branch of the portal vein or the hepatic veins.

c Adapted from Vauthey et al. with permission [4].

In this issue of the Journal, Imamura et al. analyzed the risk factors contributing to early and late intrahepatic recurrence of HCC after hepatectomy [8]. Their study population consisted of 272 consecutive Japanese patients who had undergone initial curative resection for HCC smaller than 5 cm. The authors based their analysis on the hypothesis that recurrence of the index HCCs takes place in the early period after surgery (<2 years) whereas later recurrences mainly represent de novo HCC. The main limitation of this study is the authors’ assumption that most recurrences from the index HCC occur within 2 years after resection. This assumption is not supported by the results of a recent study of histopathologic prognostic factors after resection in 425 patients [9]. In that study, univariate and multivariate analysis indicated that the presence of vascular invasion in the index HCC affected prognosis not only at 2 years but also at 5 years following resection [9]. The assumption of Imamura et al. may be a reflection of the small tumors (<5 cm) included their study.

Are any liver factors associated with an increased risk for the development of new HCCs? Among the liver factors studied for their potential influence on late recurrence (≥2 years), Imamura et al. found that hepatitis activity was the only contender, and even for this factor the evidence was weak (hazard ratio 1.39, P=0.11). In our opinion, the best clinical study to differentiate recurrence from de novo HCC should be based on long-term follow-up (analysis beyond 5 years rather than 2 years) and should include a ‘control’ group of patients with HCC without chronic liver disease. In the study by Imamura et al. only 18 patients had no or mild fibrosis. In a separate study, the International Cooperative Study Group for Hepatocellular Carcinoma evaluated 143 patients who survived 5 years or more after hepatic resection for HCC [10]. Interestingly, no tumor factor was found to influence survival beyond 5 years, and the only liver factor affecting survival beyond 5 years was the initial fibrosis stage. In this study, 58% of patients with moderate fibrosis or severe fibrosis/cirrhosis still died of HCC after having survived 5 years while only 7% of patients with minimal or no fibrosis died of HCC. While no clinical study will clearly determine whether patients die of primary tumor recurrence or of de novo HCC resulting from the field cancerization of chronic liver disease, in the absence of tumor factors affecting prognosis after 5 years, this study represents the best presumptive evidence linking chronic liver disease with the risk of metachronous de novo HCCs. In agreement, to take into account the effect of underlying liver disease on prognosis, the new AJCC/UICC staging recommends the coding of fibrosis/cirrhosis, similar to the coding of grade, in addition to stage grouping in the evaluation of HCC (Table 1) [5].

Where do we go from here? For patients undergoing hepatic resection, there is little doubt that if vascular invasion is found in the specimen, the patient should be considered for an investigational trial of adjuvant chemotherapy to prevent recurrence. For patients with fibrosis of the underlying liver the lifetime risk of HCC is high, and the patient should undergo hepatic transplantation. However, transplantation is not possible for most patients and is a risky undertaking in patients with vascular invasion or high-grade tumors. Another option could be the medical treatment of underlying liver disease, (preferably as part of a randomized study) with agents with the potential to alter the natural history of hepatocarcinogesis by modulating fibrosis and cirrhosis [11], [12].

The value of the new AJCC/UICC staging for HCC is that it better reflects the biology of HCC and the main prognostic factors (vascular invasion and fibrosis/cirrhosis) of resected patients. The new staging is not designed to support treatment algorithms; therapeutic methods evolve while biological factors remain. This is evidenced by the series reporting resection of HCC in patients with advanced-stage disease (invasion of adjacent organs or hepatic vein thrombosis) [13], and transplantation in patients with disease well beyond the three tumors up to 3 cm originally proposed as the upper limit of disease extent for which transplantation was possible [14]. The new AJCC/UICC staging is neither designed to evaluate prognosis in unresectable patients with advanced liver disease as primary tumor factors (T categories) become irrelevant when liver disease (cirrhosis) dominates the prognosis. In that respect it reaffirms the prediction of Johnson and Bruix that one single prognostic model will note accommodate all clinical situations [1]. In the instance of unresectable patients, other clinical stagings that combine the evaluation of liver disease and hepatocellular carcinoma (Okuda staging [15], Cancer of the Liver Italian Program score [16], or Barcelona Clinic Liver Cancer staging [17]) will be more appropriate.

The good news today is that efforts such as the study by Imamura et al. and the new staging go beyond the basic evaluation of tumor number and tumor size and the mere reporting of absence or presence of cirrhosis to encompass markers reflecting the biology and natural history of HCCs as well as of the disease leading to its development and prognosis. The bad news is that the determination of these histopathologic factors is prone to variability driven by the quality of sampling and interpretation and this means that we must evaluate promising molecular determinants of prognosis in the forthcoming decade [18], [19], [20].

Back to Article Outline

References 

  1. Johnson P, Bruix J. Hepatocellular carcinoma and the art of prognostication. J Hepatol. 2000;33:1006–1008
  2. Liver including intrahepatic bile ducts. In: Beahrs OH, Henson DE, Hulter RVP, Meyers MH, editors. Manual for staging of cancer, 3rd ed., Philadelphia, PA: JB Lippincott, 1988. pp. 87–92.
  3. Izumi R, Shimizu K, Ii T, Yagi M, Matsui O, Nonomura A, et al.  Prognostic factors of hepatocellular carcinoma in patients undergoing hepatic resection. Gastroenterology. 1994;106:720–727
  4. Vauthey JN, Lauwers GY, Esnaola NF, Do KA, Belghiti J, Mirza N, et al.  Simplified staging for hepatocellular carcinoma. J Clin Oncol. 2002;20:1527–1536
  5. Liver including intrahepatic bile ducts. In: Greene FL, Page DL, Fleming ID, Fritz AG, Balch CM, Haller DG, Morrow M, editors. American Joint Committee on Cancer Staging Manual, 6th ed., New York, NY: Springer, 2002. pp. 131–144.
  6. Roayaie S, Frischer JS, Emre SH, Fishbein TM, Sheiner PA, Sung M, et al.  Long-term results with multimodal adjuvant therapy and liver transplantation for the treatment of hepatocellular carcinomas larger than 5 centimeters. Ann Surg. 2002;235:533–539
  7. Hemming AW, Cattral MS, Reed AI, Van Der Werf WJ, Greig PD, Howard RJ. Liver transplantation for hepatocellular carcinoma. Ann Surg. 2001;233:652–659
  8. Imamura H, Matsuyama Y, Tanaka E, Ohkubo T, Hasegawa K, Miyagawa S, et al.  Risk factors contributing to early and late phase intrahepatic recurrence of hepatocellular carcinoma after hepatectomy. J Hepatol. 2003;38:200–207
  9. Lauwers GY, Terris B, Balis UJ, Batts KP, Regimbeau JM, Chang Y, et al.  Prognostic histologic indicators of curatively resected hepatocellular carcinomas: a multi-institutional analysis of 425 patients with definition of a histologic prognostic index. Am J Surg Pathol. 2002;26:25–34
  10. Bilimoria MM, Lauwers GY, Doherty DA, Nagorney DM, Belghiti J, Do KA, et al.  Underlying liver disease, not tumor factors, predicts long-term survival after resection of hepatocellular carcinoma. Arch Surg. 2001;136:528–535
  11. Nishiguchi S, Kuroki T, Nakatani S, Morimoto H, Takeda T, Nakajima S, et al.  Randomised trial of effects of interferon-alpha on incidence of hepatocellular carcinoma in chronic active hepatitis C with cirrhosis. Lancet. 1995;346:1051–1055
  12. Muto Y, Moriwaki H, Ninomiya M, Adachi S, Saito A, Takasaki KT, et al.  Prevention of second primary tumors by an acyclic retinoid, polyprenoic acid, in patients with hepatocellular carcinoma. Hepatoma Prevention Study Group. N Engl J Med. 1996;334:1561–1567
  13. Ikai I, Yamamoto Y, Yamamoto N, Terajima H, Hatano E, Shimahara Y, et al.  Results of hepatic resection for hepatocellular carcinoma invading major portal and/or hepatic veins. Surg Oncol Clin N Am. 2003;12:65–75
  14. Bismuth H, Chiche L, Adam R, Castaing D, Diamond T, Dennison A. Liver resection versus transplantation for hepatocellular carcinoma in cirrhotic patients. Ann Surg. 1993;218:145–151
  15. Okuda K, Ohtsuki T, Obata H, Tomimatsu M, Okazaki N, Hasegawa H, et al.  Natural history of hepatocellular carcinoma and prognosis in relation to treatment. Study of 850 patients. Cancer. 1985;56:918–928
  16. CLIP . Prospective validation of the CLIP score: a new prognostic system for patients with cirrhosis and hepatocellular carcinoma. Hepatology. 2000;31:840–845
  17. Llovet JM, Bru C, Bruix J. Prognosis of hepatocellular carcinoma: the BCLC staging classification. Semin Liver Dis. 1999;19:329–338
  18. Poon RT, Ng IO, Lau C, Zhu LX, Yu WC, Lo CM, et al.  Serum vascular endothelial growth factor predicts venous invasion in hepatocellular carcinoma: a prospective study. Ann Surg. 2001;233:227–235
  19. Yeh TS, Chen TC, Chen MF. Dedifferentiation of human hepatocellular carcinoma up-regulates telomerase and Ki-67 expression. Arch Surg. 2000;135:1334–1339
  20. Miyamoto A, Fujiwara Y, Sakon M, Nagano H, Sugita Y, Kondo M, et al.  Development of a multiple-marker RT-PCR assay for detection of micrometastases of hepatocellular carcinoma. Dig Dis Sci. 2000;45:1376–1382
  21. Ishak K, Baptista A, Bianchi L, Callea F, De Groote J, Gudat F, et al.  Histological grading and staging of chronic hepatitis. J Hepatol. 1995;22:696–699

PII: S0168-8278(02)00407-5

Journal of Hepatology
Volume 38, Issue 2 , Pages 237-239, February 2003

Article Tools