Staging of hepatocellular carcinoma: assessment of the Japanese TNM and AJCC/UICC TNM systems in a cohort of 13,772 patients in Japan

Abstract

Objective: The aims of this study were to present evidence to develop and validate the Japanese Tumor-Node-Metastasis (TNM) staging system for primary liver cancer and to compare its discriminatory ability and predictive power with those of Vauthey's simplified staging, which was adopted as the TNM staging system of the American Joint Committee on Cancer (AJCC)/International Union Against Cancer (UICC).

Summary background data: Among many staging systems for hepatocellular carcinoma, the Japanese TNM staging system and the AJCC/UICC staging system were developed based on a survival analysis of surgical patients. These 2 staging systems have not been compared in large series.

Methods: The Liver Cancer Study Group of Japan (LCSGJ) prospectively collected clinicopathologic data of 63,736 patients with primary liver cancer from 1995 to 2001. Among them, 13,772 patients received curative hepatic resection. Based on univariate and multivariate survival analyses, the Japanese TNM staging system was developed. The accuracy of the Japanese TNM staging system for predicting patient survival was compared with that of the AJCC/UICC staging system using the cross-validation method.

Results: The independent prognostic factors (relative risk; 95% confidence interval) were vascular or bile duct invasion (1.36;1.29-1.43), liver cirrhosis (1.26;1.20-1.32), diameter (< or =2 cm or >2 cm) (1.21;1.14-1.28), alpha-fetoprotein (1.20;1.15-1.25), single/multiple (1.18;1.12-1.23), liver damage (1.15;1.10-1.20), hepatic involvement (1.14;1.09-1.19), histologic differentiation (1.14;1.08-1.20), gross classification (1.13;1.08-1.18), and esophageal varices (1.07;1.02-1.13). Based on these results, 3 criteria (vascular or bile duct invasion, diameter, and single/multiple) were selected. Patients with none of these 3 factors were considered T1, and those with 1, 2, and 3 factors were T2, T3, and T4, respectively. The number of patients and 5-year survival rates for T1, T2, T3, and T4 were 2078, 70%; 6853, 58%; 3021, 41%; and 582, 24% (P < 0.0001), respectively, while those for the AJCC-T were 8457, 61% in T1, 2888, 46% in T2, and 1189, 30% in T3 (P < 0.0001). While both the LCSGJ-T and the AJCC-T had good discriminating ability, the former was significantly superior (P = 0.0007).

Conclusions: Our findings support the development of LCSG stage. While both staging systems allow for the clear stratification of patients into prognostic groups, the LCSGJ staging may be more appropriate for stratifying patients with early-stage HCC.

FIGURE 1. Comparison of the T classification in LCSGJ and AJCC/UICC.

FIGURE 2. The T category of LCSGJ is determined on the basis of the “number,” “size,” and “vascular or bile duct invasion.” All multiple tumors, including multicentric tumors and intrahepatic metastatic tumors, are equally counted.

FIGURE 3. Kaplan-Meier survival analysis (solid line) with 95% confidence interval (dotted line) for patients in the curative-hepatectomy-N0M0 cohort stratified according to the number of liver nodules (a), the maximum diameter of liver nodules (b), and the location of portal invasion (c). The number, median survival time (95% CI), and 5-year survival rate of patients are described in Table 4.

FIGURE 4. Kaplan-Meier survival analysis (solid line) with 95% confidence interval (dotted line) for patients in the curative-hepatectomy-N0M0 cohort stratified according to vascular or bile duct invasion, and growth pattern (single or multiple). The number, median survival time (95% CI), and 5-year survival rate of patients with vascular or bile duct invasion (−) and single, vascular or bile duct invasion (−) and multiple, vascular or bile duct invasion (+) and single, and vascular or bile duct invasion (+) and multiple were 8565, 6.41 years (6.08–6.71), 61%; 2461, 4.37 years (4.12–4.61), 45%; 1163, 2.90 years (2.48–3.23), 38%; and 615, 1.92 years (1.56–2.28), 25% (P < 0.0001) (a). Influence of tumor size in the 4 groups (b, c, d, e). Tumor size significantly influenced survival in all of the groups.

FIGURE 5. Kaplan-Meier survival analysis (solid line) with 95% confidence interval (dotted line) for patients in the curative-hepatectomy-N0M0 cohort stratified according to the T classification (a) and the stage (b) of LCSGJ.

FIGURE 6. Influence of liver cirrhosis, chronic hepatitis (a, b, c, d) and the degree of liver damage (e, f, g, h) in T1, T2, T3, and T4.

FIGURE 7. Comparison of the predictive survival curves (solid line) and the observed survival curves (broken line) in the validation sample. Prediction based on the LCSGJ-T classification (a), and AJCC T classification (b).