Estrogen R eceptor C lassification f or H epatocellular Carcinoma: C omparison W ith C linical S taging S ystems

Purpose: Several scoring systems to evaluate patients with hepatocellular carcinoma (HCC) exist. A good scoring system should provide information on prognosis and guide therapeutic decisions. The presence of variant liver estrogen receptor (ER) transcripts in the tumor has been shown to be the strongest negative predictor of survival in HCC. The aim of this study was to compare the predictive value of the commonly applied clinical scoring systems for survival of patients with HCC with that of the evaluation of ER in patients with HCC (molecular scoring system). Materials and Methods: HCC was staged according to the Okuda classification, Barcelona Clinic Liver Cancer classification, Italian classification system (CLIP), French classification, and ER status in 96 patients. Analysis of survival was performed according to the Kaplan-Maier test and was made for each classification system and ER. A comparison between classifications was made by univariate and multivariate analysis. Results: Among the clinical classification systems, only the CLIP was able to identify patient populations with good, intermediate, and poor prognosis. On multivariate analysis, ER classification was shown to be the best predictive classification for survival of patients with HCC (P <.0001). This difference was the result of a better allocation of patients with ominous prognosis (variant ER) having nevertheless good clinical score. Conclusion: The evaluation of the presence of wild-type or variant ER transcripts in the tumor is the best predictor of survival in patients with HCC. Its accuracy in discriminating patients with good or unfavorable prognosis is significantly greater than that of the commonly used scoring systems for the staging of HCC. J Clin Oncol 21:441-446. © 2003 by American Society of Clinical Oncology. T HE SURVIVAL RATE of patients with cirrhosis and hepatocellular carcinomas (HCC) ranges from a few months to several years. This variability is related to both characteristics of the tumor and the severity of the underlying liver disease. 1,2 Therefore, the classification systems in use for the staging of HCC combine information on tumor size, extrahepatic spread, and/or vascular invasion with parameters of liver function. The clinical staging systems currently used for the classification of patients with cirrhosis and HCC are the Okuda classification, 3 Barcelona Clinic Liver Cancer (BCLC) classification, 4 Italian classification system (CLIP), 5 and French classification proposed by Chevret et al. 6 The tumor-node-metastasis classification of neoplasms is only rarely used in Europe in the hepatologic environment. 7 The parameters included in each scoring system are factors shown by univariate and multivariate analysis of series of patients with HCC to be predictive of survival. Although the simplicity of these scoring systems make them clinically attractive, a level of accuracy sufficient to predict survival in the individual patient cannot be reached. Therefore, the current prognostic systems are of value in predicting the average probability of survival in groups of patients but are much less accurate in predicting the probability of survival in the individual patient. To set the prognosis and to choose the most appropriate treatment strategy is extremely important in the management of patients with HCC. Therefore, the identification of the best system to predict patient survival represents a priority for investigators in oncology. The incidence of HCC has increased during the past decades in most of the developed countries as a consequence of the epidemic of infection by hepatitis C virus (HCV). 8 In fact, HCC is thought to represent the final step in the natural history of hepatitis B virus (HBV) and HCV chronic infection. 9 Our group investigated the presence of estrogen receptors (ERs) in HCC. Recently, a variant form of the wild-type ER (wtER) that maintains a constitutive transcriptional activity has been described. 10 The presence of this variant ER (vER) identifies HCC with a higher clinical aggressiveness, shorter doubling time as compared with the tumors characterized by wtER, and insensitivity to tamoxifen, the receptor being modified in the hormone-binding domain. 11 Moreover, the presence of vER transcripts in the tumor is the strongest negative predictor of survival in inoperable HCC, and their presence is associated with a worse survival rate than that of patients with HCC expressing the wtER. 12 When treated with antihormonal therapy chosen according to the presence of wtER (tamoxifen) or vER (megestrol acetate), tumor volume in all patients with wtERs halved after 9 months of tamoxifen treatment, whereas megestrol acetate was able to slow down tumor growth in patients with