Estrogen receptor classification for hepatocellular carcinoma: comparison with clinical staging systems.

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.

Variant estrogen receptors and their role in liver disease.

The liver presents estrogen receptors alpha and beta. As for breast cancer, a variant form of estrogen receptor alpha transcript (ER) has been described in hepatocellular carcinoma (HCC). It is derived by an exon 5-deleted transcript (vER), which lacks the hormone-binding domain of the receptor but, being intact in the DNA-binding domain, maintains constitutive transcriptional activity. HCCs presenting vER have an extremely aggressive clinical course and are unresponsive to the antiestrogen tamoxifen. On the other hand, megestrol, a drug able to block both the wild type and the variant form of ER, influence the clinical course of HCC presenting vER. The presence of vER is associated with elevated cancer cell proliferation rate.

Hepatocellular carcinoma: role of estrogen receptors in the liver.

Experimental and clinical evidence indicates that estrogens have a relevant role in the pathogenesis of cancer of hormone-sensitive organs. Estrogen receptors (ERs) are present in liver cells. Normal liver expresses almost exclusively wild-type ERs derived from the full-length transcript of the gene. During progression of liver disease to hepatocellular carcinoma, variant forms of ERs have been demonstrated that greatly influence the course of the disease and the possibility of palliative treatment. Peritumoral cirrhotic tissue of patients with hepatocellular carcinoma, especially males, expresses a variant form of ER (vER) with an exon 5 deletion. In hepatocellular carcinoma, vER largely predominates and sometimes becomes the only form expressed. That the occurrence of vER alone is limited almost exclusively to males suggests that it could be one of the molecular events that eventually lead to the preferential development of hepatocellular carcinoma in males. In addition, the presence of vER appears most frequently in patients infected with the hepatitis B virus. The growth rate of hepatocellular carcinoma in patients with vER is also significantly higher than that in patients with tumors expressing wtER.

Pretransplantation pre-S2 and S protein heterogeneity predisposes to hepatitis B virus recurrence after liver transplantation.

Liver transplantation (LT) in patients with hepatitis B virus (HBV) infection often is complicated by recurrence of infection despite immunoglobulin treatment. To evaluate whether variability in HBV genomic sequences and the target of antibody to hepatitis B surface antigen action in pre-LT samples may be associated with a high recurrence rate, HBV pre-S/S regions of 14 HBV-positive candidates for LT (in 9 of these patients, HBV infection subsequently recurred) were amplified and sequenced. Two hundred ninety-one mutations in 1,167 sequenced nucleotides (24.9%) were found. Of these, 120 mutations (10.2%) led to an amino-acid change. The only significant difference between patients with and without recurrent disease was in the number of mutations in the pre-S2 region (total mutations, P =.042; missense mutations, P =.012) of pre-LT HBV DNA. In addition, a difference in amino-acid level was present in the pre-S2 region (P =.030). The delay in HBV infection recurrence was proportional to the number of pre-LT HBV mutations in the pre-S2 and S genes: the higher the number, the longer the interval between LT and recurrence of infection (pre-S2, P =.0124; S, P =.0060; total number of mutations in S protein, P =.0421). In conclusion, pre-LT determination of pre-S/S gene sequence variability showed that heterogeneity of the pre-S2 and, to a lesser extent, S genes was associated with a greater chance for HBV recurrence. Modification of B-cell epitopes of S, but especially of pre-S2, protein leading to conformational changes and alterations in the viral encapsidation and secretion process may facilitate HBV recurrence and contribute to the failure of immune globulin therapy.