Staging for hepatocellular carcinoma in light of tumor heterogeneity: Time to change or update?
Authors: Do Young Kim, Kwang‐Hyub Han
Journal: Hepatology (2017)

Potential conflict of interest: Dr. Han advises and received grants from Eisai and Kowa. He received grants from Ceno. SEE ARTICLE ON PAGE 2215 Unlike other solid malignancies, the prognosis of hepatocellular carcinoma (HCC) is affected by liver function as well as by the tumor burden, making it difficult to establish an optimal staging system that can be applied in clinical practice. The most commonly used cancer staging system for solid cancers that considers only tumor–node–metastasis, that of the American Joint Committee on Cancer, is only selectively helpful for HCC amenable to resection or transplantation.1 Historically, the first staging system specific to HCC that incorporated tumor‐associated factors and liver function was the OKUDA score developed in 1985.2 Thereafter, the Cancer of the Liver Italian Program score, introduced in 1998, included serum alpha‐fetoprotein (AFP) in addition to the liver function indicated by the Child‐Pugh score, portal vein thrombosis, and tumor burden.3 Unfortunately, the disease extent parameter in both the OKUDA and Cancer of the Liver Italian Program scoring systems was poorly defined, such as hepatic spread of <50% versus ≥50%. The substantial progress in the management of HCC has decreased the usefulness of these staging systems. The heterogeneity of HCC was partly reflected in a novel staging system proposed in 1999, the Barcelona Clinic Liver Cancer (BCLC) algorithm.4 Using tumor number, size, Child‐Pugh score, and performance status, HCC was classified into five stages, from the very early to the terminal stage. Because of the uniqueness of assigning a treatment modality for a specific stage and the suggestion of an expected overall survival, the BCLC classification has become the most widely used staging system and has been endorsed by international liver societies such as the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver. However, this staging system has several limitations in terms of prognostication, particularly in inoperable patients with BCLC stage B or C, because this system did not consider tumor heterogeneity in these stages. Indeed, linking BCLC‐B HCC to a single modality of transarterial chemoembolization and BCLC‐C HCC to only sorafenib has been challenged by subsequent studies.5 Accordingly, the overall adherence to the BCLC algorithm was not so high in real practice. The Hong Kong Liver Cancer staging system, proposed in 2014 and internally validated, tried to address the weaknesses of the BCLC and extend the role of resection and transarterial chemoembolization in subsets of patients with intermediate and advanced stages. However, due to several limitations, this staging system cannot be generalized worldwide. The data were obtained retrospectively from a single institution, which might not allow us to recommend more aggressive treatment in unresectable HCC, such as resection for intermediate‐stage HCC or transarterial chemoembolization for advanced HCC. In addition, this system is too complicated to follow.7 In this regard, the article in this issue of hepatology by Borzio et al. presents the ITA.LI.CA system, a new staging that is similar to the BCLC system but has refined the BCLC‐B and C stages, adopting a scoring system instead of allocating specific therapies to solely predict prognosis of patients with HCC.8 The serum AFP level is a prognostic factor in the OKUDA and Cancer of the Liver Italian Program scoring systems, but it was omitted in the BCLC and Hong Kong Liver Cancer systems. It was also a prognostic factor in the ITA.LI.CA system. Actually, this new system, initially proposed in 2016, was validated in a large independent cohort consisting of 1,508 patients with HCC from multiple Italian institutions. The strength of the study was that the data were prospectively collected for the purpose of validating different HCC staging systems, although the analysis was performed retrospectively. Additionally, strict application of the statistical method to derive the scoring system made the results more reliable than other previous staging systems. If we look at each component of the ITA.LI.CA scoring system, the tumor staging is composed of diameter, number, and presence of vascular invasion or metastasis. Tumor stages 0 and A are the same as BCLC‐0 (very early) and BCLC‐A (early), respectively. A distinct difference between ITA.LI.CA and BCLC staging is in classifying multinodular HCC. While BCLC‐B stage did not take into account the heterogeneity of tumor size and number in the intermediate stage, the new scoring system subdivided B stage into B1, B2, and B3 according to size and number cutoffs of 5 cm and 3, respectively. Subdividing BCLC‐B stage was first proposed by Bolondi et al. based on the tumor size, number of tumors, and Child‐Pugh score, applying an "up to seven criteria" without a cutoff for each variable.9 Giving a specific size and number cutoff in B1‐B3 stages seems to be arbitrary, but a previous study showed that if the HCC is larger than 5 cm or the tumor number is more than 3, the prognosis will be poor.10 Thus, the presentation of size and number cutoffs might be reasonable but requires further validation in patients with hepatitis B–related HCC. ITA.LI.CA scoring resembles the Japan Integrated Staging system, which simply added Child‐Pugh score to tumor–node–metastasis–based staging11 but upgraded it by combining tumor staging with performance status and serum AFP as well as liver function. Although this integrated system seems to be more complicated, it might be meaningful to include key prognostic factors to better predict prognosis. Nonetheless, all these variables need to be validated by follow‐up studies. Particularly, the prognostic impact of performance status in HCC needs to be further validated using ITA.LI.CA staging. Furthermore, the assessment of residual liver function using different tools should be compared in the context of a staging system. The traditional Child‐Pugh score system is being challenged owing to a subjective parameter of hepatic encephalopathy and ascites and difficulty in discriminating between scores 6 and 7. It is an area of future research to evaluate simple and objective measurement of liver function such as the albumin–bilirubin grade and compare it with the Child‐Pugh system. AFP, included as an independent prognostic factor, was divided into ≤1,000 ng/mL and >1,000 ng/mL based on the results of a multivariate analysis in the development of the staging system. Another HCC biomarker, prothrombin induced by vitamin K absence‐II, was not tested during derivation of ITA.LI.CA staging. Because the serum level of this biomarker is also an important prognostic factor in HCC, further studies are necessary to evaluate the prognostic roles of AFP and prothrombin induced by vitamin K absence‐II in a staging system. Treatment allocation for a specific stage was abandoned because the restriction of treatment modality to the standard of care according to evidence‐based medicine resulted in a great discrepancy between recommendations and real clinical practice. Data on emerging therapies such as programmed cell death‐1 inhibitors, molecularly targeted agents, and radiation therapy are being accumulated. Hence, it might be better to postpone linking a specific therapy to a certain stage until new, solid data are obtained. It may be ideal to derive a staging system using both Eastern and Western cohorts. Unfortunately, the ITA.LI.CA system was constructed using an Italian HCC cohort with a hepatitis C virus–dominant etiology, although it was partially validated using a Taiwanese cohort. Because the underlying disease and treatment‐related practice patterns are substantially different between Eastern and Western countries, ITA.LI.CA staging should be validated independently in Asian patients. HCC staging systems are like a two‐edged sword. A finely tuned and complicated system has a high performance but is less practical. On the contrary, a simple system has a high applicability, but its clinical utility is low. Now it is time to use a more qualified HCC staging system according to recent remarkable advances in HCC management. Development and validation of the ITA.LI.CA system is estimated to achieve a one‐step progress on staging for HCC, in light of tumor heterogeneity. Author names in bold designate shared co‐first authorship.