Is there an ideal prognostic classification for hepatocellular carcinoma? The quest for the Holy Grail
Authors: Jean-Claude Trinchet, Michel Beaugrand
Journal: Journal of Hepatology (2010)

A new prognostic model for hepatocellular carcinoma based on total tumor volume: The Taipei Integrated Scoring systemJournal of HepatologyVol. 53Issue 1PreviewThe currently used staging systems for hepatocellular carcinoma (HCC) are not satisfactory. The optimal prognostic model for HCC is still under intense debate. This study aimed to propose a new staging system for HCC based on total tumor volume (TTV) and to compare it with the currently used systems. Full-Text PDF To predict the future has always been a major concern of humanity. To identify prognostic factors of death and survival is one facet of this concern. A prognostic model is a combination of various factors related to survival in a given disease which allows for the prediction of outcome. Such prognostic models can help to determine the best route for treatment, help to inform patients and their relatives of the prognosis, and to stratify patients in clinical studies. An ideal classification should use simple and easily reproducible clinical variables, clearly sort out patients into several groups with different survival outcomes, and be usable in all populations of patients whatever their origin and the cause of their underlying liver disease. Is there such an ideal classification for hepatocellular carcinoma (HCC)?HCC almost always occurs in patients with chronic liver disease, usually cirrhosis [[1]Bruix J. Sherman M. Management of hepatocellular carcinoma.Hepatology. 2005; 42: 1208-1236Crossref PubMed Scopus (5052) Google Scholar]. Accordingly, survival is strongly influenced by factors related both to tumour extension and liver impairment as well as the occurrence of new tumours. The classifications, including variables only related either to tumour burden or liver function, such as Tumour Node Metastasis (TNM) and Child-Pugh classifications, have obviously insufficient performance in patients with HCC [2Minagawa M. Ikai I. Matsuyama Y. Yamaoka Y. Makuuchi M. Staging of hepatocellular carcinoma: assessment of the Japanese TNM and AJCC/UICC TNM systems in a cohort of 13,772 patients in Japan.Ann Surg. 2007; 245: 909-922Crossref PubMed Scopus (254) Google Scholar, 3Pascual S. Zapater P. Such J. Garcia-Herola A. Sempere L. Irurzun J. et al.Comparison of staging systems to predict survival in hepatocellular carcinoma.Liver Int. 2006; 26: 673-679Crossref PubMed Scopus (26) Google Scholar]. From the first popular classification proposed by Okuda et al. [[4]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: 918-928Crossref PubMed Scopus (1773) Google Scholar] in 1985 to more recent models such as BCLC (Barcelona Clinic Liver Cancer) [[5]Llovet J.M. Bru C. Bruix J. Prognosis of hepatocellular carcinoma. The BCLC staging classification.Semin Liver Dis. 1999; 19: 329-338Crossref PubMed Scopus (2877) Google Scholar], GRETCH (Groupe d’Etude et de Traitement du Carcinome Hépatocellulaire) [[6]Chevret S. Trinchet J.C. Mathieu D. Rached A.A. Beaugrand M. Chastang C. A new prognostic classification for predicting survival in patients with hepatocellular carcinoma. Groupe d’Etude et de Traitement du Carcinome Hepatocellulaire.J Hepatol. 1999; 31: 133-141Abstract Full Text Full Text PDF PubMed Scopus (432) Google Scholar], CLIP (Cancer of Liver Italian Program) [[7]Perrone F. Daniele B. Gaeta G.B. Pignata S. Gallo C. Izzo F. et al.Prospective validation of the CLIP score: a new prognostic system for patients with cirrhosis and hepatocellular carcinoma.Hepatology. 2000; 31: 840-845Crossref PubMed Scopus (490) Google Scholar], CUPI (Chinese University Prognostic Index) [[8]Leung T. Tang A. Zee B. Lau W. Lai P. Leung K. et al.Construction of the Chinese University Prognostic Index for hepatocellular carcinoma and comparison with the TNM staging system, the Okuda staging system, and the Cancer of the Liver Italian Program staging system: a study based on 926 patients.Cancer. 2002; 94: 1760-1769Crossref PubMed Scopus (491) Google Scholar], and JIS (Japanese Integrated System) [[9]Kudo M. Chung H. Haji S. Osaki Y. Oka H. Seki T. et al.Validation of a new prognostic staging system for hepatocellular carcinoma: the JIS score compared with the CLIP score.Hepatology. 2004; 40: 1396-1405Crossref PubMed Scopus (314) Google Scholar], all classifications combine parameters reflecting tumour extension (number and size of nodules, vascular invasion, and serum alpha-fetoprotein level) and liver impairment (serum bilirubin, serum albumin, prothrombin activity, ascites, and degree of portal hypertension). Some models also incorporate variables related to patient performance status [5Llovet J.M. Bru C. Bruix J. Prognosis of hepatocellular carcinoma. The BCLC staging classification.Semin Liver Dis. 1999; 19: 329-338Crossref PubMed Scopus (2877) Google Scholar, 6Chevret S. Trinchet J.C. Mathieu D. Rached A.A. Beaugrand M. Chastang C. A new prognostic classification for predicting survival in patients with hepatocellular carcinoma. Groupe d’Etude et de Traitement du Carcinome Hepatocellulaire.J Hepatol. 1999; 31: 133-141Abstract Full Text Full Text PDF PubMed Scopus (432) Google Scholar]. In this issue of the Journal, Hsu et al. [[10]Hsu C.Y. Huang Y.H. Hsia C.Y. Su C.W. Lin H.C. Loong C.C. et al.A new prognostic model for hepatocellular carcinoma based on total tumor volume. The Taipei Integrated Scoring system.J Hepatol. 2010; 53: 108-117Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar] propose a new prognostic model based on total tumour volume calculated by adding up the volumes of all measurable tumours visible on imaging examinations. High total tumour volume was significantly correlated with decreased survival. The best model was the combination of this parameter with Child-Pugh classification and serum alpha-fetoprotein level.Which is currently the best (ideal) prognostic classification for HCC? There is no consensual answer [[11]Marrero J.A. Staging systems for hepatocellular carcinoma: should we all use the BCLC system?.J Hepatol. 2006; 44: 630-632Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar]. However, several clues can help to clarify this topic, coming from recent changes in HCC epidemiology and from clinical studies comparing classifications between them. Due to its great simplicity, Okuda’s score has been widely used for a long time, both in clinical practice and research. However, this score has been built empirically from a population of patients mainly with advanced HCC [[4]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: 918-928Crossref PubMed Scopus (1773) Google Scholar]. The variable reflecting tumour burden (more or less than 50% of total liver volume) is difficult to assess precisely by imaging and is not adapted to the increasing population of patients with small (early) HCC at diagnosis. Recent studies have clearly indicated that Okuda’s score has lower prognostic performance than more recent classifications [6Chevret S. Trinchet J.C. Mathieu D. Rached A.A. Beaugrand M. Chastang C. A new prognostic classification for predicting survival in patients with hepatocellular carcinoma. Groupe d’Etude et de Traitement du Carcinome Hepatocellulaire.J Hepatol. 1999; 31: 133-141Abstract Full Text Full Text PDF PubMed Scopus (432) Google Scholar, 7Perrone F. Daniele B. Gaeta G.B. Pignata S. Gallo C. Izzo F. et al.Prospective validation of the CLIP score: a new prognostic system for patients with cirrhosis and hepatocellular carcinoma.Hepatology. 2000; 31: 840-845Crossref PubMed Scopus (490) Google Scholar, 12Marrero J.A. Fontana R.J. Barrat A. Askari F. Conjeevaram H.S. Su G.L. et al.Prognosis of hepatocellular carcinoma: comparison of 7 staging systems in an American cohort.Hepatology. 2005; 41: 707-716Crossref PubMed Scopus (524) Google Scholar] and that its use is no longer justified. On the other hand, several studies have found a better performance of the BCLC staging system when compared to other recent classifications [3Pascual S. Zapater P. Such J. Garcia-Herola A. Sempere L. Irurzun J. et al.Comparison of staging systems to predict survival in hepatocellular carcinoma.Liver Int. 2006; 26: 673-679Crossref PubMed Scopus (26) Google Scholar, 12Marrero J.A. Fontana R.J. Barrat A. Askari F. Conjeevaram H.S. Su G.L. et al.Prognosis of hepatocellular carcinoma: comparison of 7 staging systems in an American cohort.Hepatology. 2005; 41: 707-716Crossref PubMed Scopus (524) Google Scholar, 13Cillo U. Bassanello M. Vitale A. Grigoletto F. Burra P. Fagiuoli S. et al.The critical issue of hepatocellular carcinoma prognostic classification: which is the best tool available?.J Hepatol. 2004; 40: 124-131Abstract Full Text Full Text PDF PubMed Scopus (155) Google Scholar]. In the study by Marrero et al. [[12]Marrero J.A. Fontana R.J. Barrat A. Askari F. Conjeevaram H.S. Su G.L. et al.Prognosis of hepatocellular carcinoma: comparison of 7 staging systems in an American cohort.Hepatology. 2005; 41: 707-716Crossref PubMed Scopus (524) Google Scholar] performed in 239 patients with cirrhosis and HCC, BCLC classification had the best predictive power for survival when compared to six other prognostic models (Okuda, TNM, CLIP, GRETCH, CUPI, and JIS classifications). Such a performance is likely due to the fact that it takes into account several important factors such as liver function, portal hypertension, general status, and tumour characteristics with special attention focused on small tumours. The BCLC classification has at least two major advantages. Firstly, it is the most widely accepted classification and the most likely to become the international standard: whatever classification used, it must utilize only one language. Secondly, it is a staging system as well as a prognostic classification, which helps clinicians make more rational decisions for treatment and define proper selection criteria for randomized and non-randomized trials. Accordingly, recent international guidelines recommend the BCLC classification to assess prognosis and to guide decision making process with regards to therapeutic options in patients with HCC [[1]Bruix J. Sherman M. Management of hepatocellular carcinoma.Hepatology. 2005; 42: 1208-1236Crossref PubMed Scopus (5052) Google Scholar].Is this recommendation the end of the story and should we all definitively use the BCLC classification? Have we found the Holy Grail of prognostic models for HCC? The reply is probably negative. As previously emphasized, epidemiological characteristics and the treatment of patients with HCC have been markedly modified and hopefully improvements are yet to come. A better identification of patients with chronic liver diseases and cirrhosis would allow to include them in a periodic surveillance program [[14]Sherman M. Hepatocellular carcinoma: epidemiology, risk factors, and screening.Semin Liver Dis. 2005; 25: 143-154Crossref PubMed Scopus (375) Google Scholar]. Recent studies have shown important increases in the rate of patients with small HCC at diagnosis, up to 70% [[15]Leykum L.K. El-Serag H.B. Cornell J. Papadopoulos K.P. Screening for hepatocellular carcinoma among veterans with hepatitis C on disease stage, treatment received, and survival.Clin Gastroenterol Hepatol. 2007; 5: 508-512Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar]. This fact clearly accounts for currently low performance of prognostic classifications such as Okuda’s score, established a long time ago when patients primarily had advanced HCC at diagnosis. Future classifications will have to identify new, more relevant variables that discriminate between patients with small, early HCC without any vascular or extra-hepatic extension. It is likely that molecular tools, that allow for better characterization of the biological properties of tumours, will be useful for reaching this goal [[16]Boyault S. Rickman D.S. de Reynies A. Balabaud C. Rebouissou S. Jeannot E. et al.Transcriptome classification of HCC is related to gene alterations and to new therapeutic targets.Hepatology. 2007; 45: 42-52Crossref PubMed Scopus (842) Google Scholar]. Moreover, we have to keep in mind that prognostic models generally do not assess spontaneous survival. Due to the high rate of patients with small tumours, many patients receive curative treatment such as surgery or local ablation, [[1]Bruix J. Sherman M. Management of hepatocellular carcinoma.Hepatology. 2005; 42: 1208-1236Crossref PubMed Scopus (5052) Google Scholar] and in this latter field particularly, techniques are improving rapidly. Therefore, the therapeutic options suggested by the BCLC staging have to be modified accordingly in the future. Even in patients with advanced tumours, palliative treatments such as arterial chemoembolization [[1]Bruix J. Sherman M. Management of hepatocellular carcinoma.Hepatology. 2005; 42: 1208-1236Crossref PubMed Scopus (5052) Google Scholar] or sorafenib [[17]Llovet J.M. Ricci S. Mazzaferro V. Hilgard P. Gane E. Blanc J.F. et al.Sorafenib in advanced hepatocellular carcinoma.N Engl J Med. 2008; 359: 378-390Crossref PubMed Scopus (8751) Google Scholar] are now increasingly used in patients who were receiving only conservative treatments in the past. In addition, a lot of advances have been made in the management of patients with chronic liver diseases and cirrhosis, such as the effective prevention and treatment of variceal haemorrhages, but also in antiviral treatment of chronic HCV and HBV infections. These parameters are never taken into account in prognostic studies even if they do modify the outcome of patient survival. Finally, it seems to be clear that a definitive universal prognostic classification for HCC survival does not exist (and likely will never exist). A more realistic way to approach this, is to build specific prognostic models adapted to well-defined subsets of patients that takes into account each therapeutic option. Some models developed in patients with only (or mostly) advanced HCC [[18]Yau T. Yao T.J. Chan P. Ng K. Fan S.T. Poon R.T. A new prognostic score system in patients with advanced hepatocellular carcinoma not amendable to locoregional therapy: implication for patient selection in systemic therapy trials.Cancer. 2008; 113: 2742-2751Crossref PubMed Scopus (54) Google Scholar], early-intermediate HCC undergoing non-surgical treatment [[19]Grieco A. Pompili M. Caminiti G. Miele L. Covino M. Alfei B. et al.Prognostic factors for survival in patients with early-intermediate hepatocellular carcinoma undergoing non-surgical therapy: comparison of Okuda, CLIP, and BCLC staging systems in a single Italian centre.Gut. 2005; 54: 411-418Crossref PubMed Scopus (205) Google Scholar], or resection [[20]Tateishi R. Yoshida H. Shiina S. Imamura H. Hasegawa K. Teratani T. et al.Proposal of a new prognostic model for hepatocellular carcinoma: an analysis of 403 patients.Gut. 2005; 54: 419-425Crossref PubMed Scopus (220) Google Scholar] have been recently published. In patients with small HCC and very well compensated liver disease, it is unlikely that the usual clinical and biological parameters could be useful for building a prognostic model. More sophisticated variables, based on liver histology or molecular analysis, should be tested [16Boyault S. Rickman D.S. de Reynies A. Balabaud C. Rebouissou S. Jeannot E. et al.Transcriptome classification of HCC is related to gene alterations and to new therapeutic targets.Hepatology. 2007; 45: 42-52Crossref PubMed Scopus (842) Google Scholar, 21Toyoda H. Kumada T. Osaki Y. Oka H. Urano F. Kudo M. et al.Staging hepatocellular carcinoma by a novel scoring system (BALAD score) based on serum markers.Clin Gastroenterol Hepatol. 2006; 4: 1528-1536Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar, 22Kong S.Y. Park J.W. Lee J.A. Park J.E. Park K.W. Hong E.K. et al.Association between vascular endothelial growth factor gene polymorphisms and survival in hepatocellular carcinoma patients.Hepatology. 2007; 46: 446-455Crossref PubMed Scopus (65) Google Scholar]. Such prognostic classifications, specific to each precise situation, will need to be periodically revised in order to follow both future changes in epidemiology, better knowledge of liver carcinogenesis, and improvement of therapy.Conflicts of interestThe authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. To predict the future has always been a major concern of humanity. To identify prognostic factors of death and survival is one facet of this concern. A prognostic model is a combination of various factors related to survival in a given disease which allows for the prediction of outcome. Such prognostic models can help to determine the best route for treatment, help to inform patients and their relatives of the prognosis, and to stratify patients in clinical studies. An ideal classification should use simple and easily reproducible clinical variables, clearly sort out patients into several groups with different survival outcomes, and be usable in all populations of patients whatever their origin and the cause of their underlying liver disease. Is there such an ideal classification for hepatocellular carcinoma (HCC)? HCC almost always occurs in patients with chronic liver disease, usually cirrhosis [[1]Bruix J. Sherman M. Management of hepatocellular carcinoma.Hepatology. 2005; 42: 1208-1236Crossref PubMed Scopus (5052) Google Scholar]. Accordingly, survival is strongly influenced by factors related both to tumour extension and liver impairment as well as the occurrence of new tumours. The classifications, including variables only related either to tumour burden or liver function, such as Tumour Node Metastasis (TNM) and Child-Pugh classifications, have obviously insufficient performance in patients with HCC [2Minagawa M. Ikai I. Matsuyama Y. Yamaoka Y. Makuuchi M. Staging of hepatocellular carcinoma: assessment of the Japanese TNM and AJCC/UICC TNM systems in a cohort of 13,772 patients in Japan.Ann Surg. 2007; 245: 909-922Crossref PubMed Scopus (254) Google Scholar, 3Pascual S. Zapater P. Such J. Garcia-Herola A. Sempere L. Irurzun J. et al.Comparison of staging systems to predict survival in hepatocellular carcinoma.Liver Int. 2006; 26: 673-679Crossref PubMed Scopus (26) Google Scholar]. From the first popular classification proposed by Okuda et al. [[4]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: 918-928Crossref PubMed Scopus (1773) Google Scholar] in 1985 to more recent models such as BCLC (Barcelona Clinic Liver Cancer) [[5]Llovet J.M. Bru C. Bruix J. Prognosis of hepatocellular carcinoma. The BCLC staging classification.Semin Liver Dis. 1999; 19: 329-338Crossref PubMed Scopus (2877) Google Scholar], GRETCH (Groupe d’Etude et de Traitement du Carcinome Hépatocellulaire) [[6]Chevret S. Trinchet J.C. Mathieu D. Rached A.A. Beaugrand M. Chastang C. A new prognostic classification for predicting survival in patients with hepatocellular carcinoma. Groupe d’Etude et de Traitement du Carcinome Hepatocellulaire.J Hepatol. 1999; 31: 133-141Abstract Full Text Full Text PDF PubMed Scopus (432) Google Scholar], CLIP (Cancer of Liver Italian Program) [[7]Perrone F. Daniele B. Gaeta G.B. Pignata S. Gallo C. Izzo F. et al.Prospective validation of the CLIP score: a new prognostic system for patients with cirrhosis and hepatocellular carcinoma.Hepatology. 2000; 31: 840-845Crossref PubMed Scopus (490) Google Scholar], CUPI (Chinese University Prognostic Index) [[8]Leung T. Tang A. Zee B. Lau W. Lai P. Leung K. et al.Construction of the Chinese University Prognostic Index for hepatocellular carcinoma and comparison with the TNM staging system, the Okuda staging system, and the Cancer of the Liver Italian Program staging system: a study based on 926 patients.Cancer. 2002; 94: 1760-1769Crossref PubMed Scopus (491) Google Scholar], and JIS (Japanese Integrated System) [[9]Kudo M. Chung H. Haji S. Osaki Y. Oka H. Seki T. et al.Validation of a new prognostic staging system for hepatocellular carcinoma: the JIS score compared with the CLIP score.Hepatology. 2004; 40: 1396-1405Crossref PubMed Scopus (314) Google Scholar], all classifications combine parameters reflecting tumour extension (number and size of nodules, vascular invasion, and serum alpha-fetoprotein level) and liver impairment (serum bilirubin, serum albumin, prothrombin activity, ascites, and degree of portal hypertension). Some models also incorporate variables related to patient performance status [5Llovet J.M. Bru C. Bruix J. Prognosis of hepatocellular carcinoma. The BCLC staging classification.Semin Liver Dis. 1999; 19: 329-338Crossref PubMed Scopus (2877) Google Scholar, 6Chevret S. Trinchet J.C. Mathieu D. Rached A.A. Beaugrand M. Chastang C. A new prognostic classification for predicting survival in patients with hepatocellular carcinoma. Groupe d’Etude et de Traitement du Carcinome Hepatocellulaire.J Hepatol. 1999; 31: 133-141Abstract Full Text Full Text PDF PubMed Scopus (432) Google Scholar]. In this issue of the Journal, Hsu et al. [[10]Hsu C.Y. Huang Y.H. Hsia C.Y. Su C.W. Lin H.C. Loong C.C. et al.A new prognostic model for hepatocellular carcinoma based on total tumor volume. The Taipei Integrated Scoring system.J Hepatol. 2010; 53: 108-117Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar] propose a new prognostic model based on total tumour volume calculated by adding up the volumes of all measurable tumours visible on imaging examinations. High total tumour volume was significantly correlated with decreased survival. The best model was the combination of this parameter with Child-Pugh classification and serum alpha-fetoprotein level. Which is currently the best (ideal) prognostic classification for HCC? There is no consensual answer [[11]Marrero J.A. Staging systems for hepatocellular carcinoma: should we all use the BCLC system?.J Hepatol. 2006; 44: 630-632Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar]. However, several clues can help to clarify this topic, coming from recent changes in HCC epidemiology and from clinical studies comparing classifications between them. Due to its great simplicity, Okuda’s score has been widely used for a long time, both in clinical practice and research. However, this score has been built empirically from a population of patients mainly with advanced HCC [[4]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: 918-928Crossref PubMed Scopus (1773) Google Scholar]. The variable reflecting tumour burden (more or less than 50% of total liver volume) is difficult to assess precisely by imaging and is not adapted to the increasing population of patients with small (early) HCC at diagnosis. Recent studies have clearly indicated that Okuda’s score has lower prognostic performance than more recent classifications [6Chevret S. Trinchet J.C. Mathieu D. Rached A.A. Beaugrand M. Chastang C. A new prognostic classification for predicting survival in patients with hepatocellular carcinoma. Groupe d’Etude et de Traitement du Carcinome Hepatocellulaire.J Hepatol. 1999; 31: 133-141Abstract Full Text Full Text PDF PubMed Scopus (432) Google Scholar, 7Perrone F. Daniele B. Gaeta G.B. Pignata S. Gallo C. Izzo F. et al.Prospective validation of the CLIP score: a new prognostic system for patients with cirrhosis and hepatocellular carcinoma.Hepatology. 2000; 31: 840-845Crossref PubMed Scopus (490) Google Scholar, 12Marrero J.A. Fontana R.J. Barrat A. Askari F. Conjeevaram H.S. Su G.L. et al.Prognosis of hepatocellular carcinoma: comparison of 7 staging systems in an American cohort.Hepatology. 2005; 41: 707-716Crossref PubMed Scopus (524) Google Scholar] and that its use is no longer justified. On the other hand, several studies have found a better performance of the BCLC staging system when compared to other recent classifications [3Pascual S. Zapater P. Such J. Garcia-Herola A. Sempere L. Irurzun J. et al.Comparison of staging systems to predict survival in hepatocellular carcinoma.Liver Int. 2006; 26: 673-679Crossref PubMed Scopus (26) Google Scholar, 12Marrero J.A. Fontana R.J. Barrat A. Askari F. Conjeevaram H.S. Su G.L. et al.Prognosis of hepatocellular carcinoma: comparison of 7 staging systems in an American cohort.Hepatology. 2005; 41: 707-716Crossref PubMed Scopus (524) Google Scholar, 13Cillo U. Bassanello M. Vitale A. Grigoletto F. Burra P. Fagiuoli S. et al.The critical issue of hepatocellular carcinoma prognostic classification: which is the best tool available?.J Hepatol. 2004; 40: 124-131Abstract Full Text Full Text PDF PubMed Scopus (155) Google Scholar]. In the study by Marrero et al. [[12]Marrero J.A. Fontana R.J. Barrat A. Askari F. Conjeevaram H.S. Su G.L. et al.Prognosis of hepatocellular carcinoma: comparison of 7 staging systems in an American cohort.Hepatology. 2005; 41: 707-716Crossref PubMed Scopus (524) Google Scholar] performed in 239 patients with cirrhosis and HCC, BCLC classification had the best predictive power for survival when compared to six other prognostic models (Okuda, TNM, CLIP, GRETCH, CUPI, and JIS classifications). Such a performance is likely due to the fact that it takes into account several important factors such as liver function, portal hypertension, general status, and tumour characteristics with special attention focused on small tumours. The BCLC classification has at least two major advantages. Firstly, it is the most widely accepted classification and the most likely to become the international standard: whatever classification used, it must utilize only one language. Secondly, it is a staging system as well as a prognostic classification, which helps clinicians make more rational decisions for treatment and define proper selection criteria for randomized and non-randomized trials. Accordingly, recent international guidelines recommend the BCLC classification to assess prognosis and to guide decision making process with regards to therapeutic options in patients with HCC [[1]Bruix J. Sherman M. Management of hepatocellular carcinoma.Hepatology. 2005; 42: 1208-1236Crossref PubMed Scopus (5052) Google Scholar]. Is this recommendation the end of the story and should we all definitively use the BCLC classification? Have we found the Holy Grail of prognostic models for HCC? The reply is probably negative. As previously emphasized, epidemiological characteristics and the treatment of patients with HCC have been markedly modified and hopefully improvements are yet to come. A better identification of patients with chronic liver diseases and cirrhosis would allow to include them in a periodic surveillance program [[14]Sherman M. Hepatocellular carcinoma: epidemiology, risk factors, and screening.Semin Liver Dis. 2005; 25: 143-154Crossref PubMed Scopus (375) Google Scholar]. Recent studies have shown important increases in the rate of patients with small HCC at diagnosis, up to 70% [[15]Leykum L.K. El-Serag H.B. Cornell J. Papadopoulos K.P. Screening for hepatocellular carcinoma among veterans with hepatitis C on disease stage, treatment received, and survival.Clin Gastroenterol Hepatol. 2007; 5: 508-512Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar]. This fact clearly accounts for currently low performance of prognostic classifications such as Okuda’s score, established a long time ago when patients primarily had advanced HCC at diagnosis. Future classifications will have to identify new, more relevant variables that discriminate between patients with small, early HCC without any vascular or extra-hepatic extension. It is likely that molecular tools, that allow for better characterization of the biological properties of tumours, will be useful for reaching this goal [[16]Boyault S. Rickman D.S. de Reynies A. Balabaud C. Rebouissou S. Jeannot E. et al.Transcriptome classification of HCC is related to gene alterations and to new therapeutic targets.Hepatology. 2007; 45: 42-52Crossref PubMed Scopus (842) Google Scholar]. Moreover, we have to keep in mind that prognostic models generally do not assess spontaneous survival. Due to the high rate of patients with small tumours, many patients receive curative treatment such as surgery or local ablation, [[1]Bruix J. Sherman M. Management of hepatocellular carcinoma.Hepatology. 2005; 42: 1208-1236Crossref PubMed Scopus (5052) Google Scholar] and in this latter field particularly, techniques are improving rapidly. Therefore, the therapeutic options suggested by the BCLC staging have to be modified accordingly in the future. Even in patients with advanced tumours, palliative treatments such as arterial chemoembolization [[1]Bruix J. Sherman M. Management of hepatocellular carcinoma.Hepatology. 2005; 42: 1208-1236Crossref PubMed Scopus (5052) Google Scholar] or sorafenib [[17]Llovet J.M. Ricci S. Mazzaferro V. Hilgard P. Gane E. Blanc J.F. et al.Sorafenib in advanced hepatocellular carcinoma.N Engl J Med. 2008; 359: 378-390Crossref PubMed Scopus (8751) Google Scholar] are now increasingly used in patients who were receiving only conservative treatments in the past. In addition, a lot of advances have been made in the management of patients with chronic liver diseases and cirrhosis, such as the effective prevention and treatment of variceal haemorrhages, but also in antiviral treatment of chronic HCV and HBV infections. These parameters are never taken into account in prognostic studies even if they do modify the outcome of patient survival. Finally, it seems to be clear that a definitive universal prognostic classification for HCC survival does not exist (and likely will never exist). A more realistic way to approach this, is to build specific prognostic models adapted to well-defined subsets of patients that takes into account each therapeutic option. Some models developed in patients with only (or mostly) advanced HCC [[18]Yau T. Yao T.J. Chan P. Ng K. Fan S.T. Poon R.T. A new prognostic score system in patients with advanced hepatocellular carcinoma not amendable to locoregional therapy: implication for patient selection in systemic therapy trials.Cancer. 2008; 113: 2742-2751Crossref PubMed Scopus (54) Google Scholar], early-intermediate HCC undergoing non-surgical treatment [[19]Grieco A. Pompili M. Caminiti G. Miele L. Covino M. Alfei B. et al.Prognostic factors for survival in patients with early-intermediate hepatocellular carcinoma undergoing non-surgical therapy: comparison of Okuda, CLIP, and BCLC staging systems in a single Italian centre.Gut. 2005; 54: 411-418Crossref PubMed Scopus (205) Google Scholar], or resection [[20]Tateishi R. Yoshida H. Shiina S. Imamura H. Hasegawa K. Teratani T. et al.Proposal of a new prognostic model for hepatocellular carcinoma: an analysis of 403 patients.Gut. 2005; 54: 419-425Crossref PubMed Scopus (220) Google Scholar] have been recently published. In patients with small HCC and very well compensated liver disease, it is unlikely that the usual clinical and biological parameters could be useful for building a prognostic model. More sophisticated variables, based on liver histology or molecular analysis, should be tested [16Boyault S. Rickman D.S. de Reynies A. Balabaud C. Rebouissou S. Jeannot E. et al.Transcriptome classification of HCC is related to gene alterations and to new therapeutic targets.Hepatology. 2007; 45: 42-52Crossref PubMed Scopus (842) Google Scholar, 21Toyoda H. Kumada T. Osaki Y. Oka H. Urano F. Kudo M. et al.Staging hepatocellular carcinoma by a novel scoring system (BALAD score) based on serum markers.Clin Gastroenterol Hepatol. 2006; 4: 1528-1536Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar, 22Kong S.Y. Park J.W. Lee J.A. Park J.E. Park K.W. Hong E.K. et al.Association between vascular endothelial growth factor gene polymorphisms and survival in hepatocellular carcinoma patients.Hepatology. 2007; 46: 446-455Crossref PubMed Scopus (65) Google Scholar]. Such prognostic classifications, specific to each precise situation, will need to be periodically revised in order to follow both future changes in epidemiology, better knowledge of liver carcinogenesis, and improvement of therapy. Conflicts of interestThe authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.