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Karademir. Hepatoma Res 2018;4:58 I http://dx.doi.org/10.20517/2394-5079.2018.40 Page 7 of 18

Table 5. Simplified staging system (Vauthey et al. [51] -TNM 6th edition)
sT1 Single tumur without vascular invasion
sT2 Single tumour with vascular invasion or multiple tumours, none > 5 cm
sT3 Multiple tumours, any > 5 cm or tumour(s) involving major branch of hepatic vein(s)
F0 Grade 0-4 fibrosis (no fibrosis to moderate fibrosis)
F1 Grade 5-6 (severe fibrosis or cirrhosis)
Stage I sT1 N0 M0
Stage II sT2 N0 M0
Stage IIIA sT3 N0 M0
Stage IIIB Any sT N1 M0
Stage IV Any sT any N M1
s: simplified; TNM: tumor-node-metastasis

system has been mostly tested in the surgical setting and showed poor prognostic prediction in early HCC
[50]
[49]
patients undergoing either resection or transplantation .
[51]
Vauthey et al. developed a simplified staging system for HCC in 2002 which was adopted as the TNM
staging system of AJCC/UICC after minor changes (6th Edition) [Table 5]. It was derived from the finding
of a cohort of 557 HCC patients who underwent surgical resection. The authors identified independent
predictors of mortality (major vascular invasion, microvascular invasion, severe fibrosis/cirrhosis, multiple
tumors and a tumor size greater than 5 cm) using a multivariate analysis. Based on these variables, the AJCC
T classification reclassified and a simplified stratification was proposed: sT1: single tumor with no vascular
invasion; sT2: single tumor with microvascular invasion or multiple tumors, none more than > 5 cm and sT3:
multiple tumors, any > 5 cm or tumor(s) with major vascular invasion. The simplified staging system divides
patients into 3 independent prognostic groups (5-year survival rates: stage I 55%, stage II 37% and stage III
16%). The new system may improve the stratification of resected tumors, even though it is controversial
whether they will apply to nonsurgical patients. As TNM staging relies on detailed histopathologic
[52]
examination which requires two fine-needle biopsies, this might be associated with risk of tumor seeding .
The current AJCC/UICC 7th edition is a modification of the simplified staging system and has become
[5]
widespread since 2010 . The major change between the 6th and the 7th AJCC staging system is that the
new system imposes heavier prognostic weight on major vascular invasion as a potential predictive factor
[53]
for poor prognosis . The main limitation of this staging system is that it fails to account for liver function
whereas it is well known that prognosis of HCC patients also relies on features related to liver cirrhosis [49,50] .

Japan Integrated Staging Score
[10]
The Japan Integrated Staging Score (JIS Score) was proposed by Kudo et al. in 2003. It is derived from
a cohort of 722 HCC patients treated at two Japanese institutions. The JIS score combines the Child-
Pugh grade with the Japanese TNM (Liver Cancer Study Group of Japan- LCSGJ) which is based on three
parameters (vascular invasion, single vs. multiple nodules, diameter ≤ vs. > 20 mm) to address the specific
deficiency of LCSGJ for not having included liver function evaluation. Patients with a Child-Pugh grades
A, B and C status are allocated a score of 0, 1, and 2, respectively. Patients with the TNM stage by LCSGJ of
[54]
stages I, II, III and IV are allocated to score of 0, 1, 2 and 3, respectively [Table 6]. Patients are subsequently
classified into six groups (0-5) based on the sum of these scores. Statistically significant differences are
observed between the survival curves for almost all JIS scores. The cumulative 10-year survival rates of the
best prognostic groups in the CLIP staging system (CLIP score 0) and JIS staging system (JIS score 0) were
23% and 65%, respectively. The authors concluded that the JIS score stratifies patients with early diagnosed
HCC better than the CLIP score. The same group externally validated the JIS score in 4525 HCC patients
[55]
treated at five Japanese institutions in 2004 . In a study of 1679 patient, the JIS score has been compared
[56]
with the BCLC and CLIP and found to be superior in prognostic determination . Since the JIS score was