Hepatocellular Tumors:Immunohistochemical Analyses for Classification and Prognostication

Following the classification of hepatocellular nodules by the International Working Party in 1995 and further elaboration by the International Consensus Group for Hepatocellular Neoplasia in 2009, entities under the spectrum of hepatocellular nodules have been better characterized. Research work hence has been done to answer questions such as distinguishing high-grade dysplastic nodules from early hepatocellular carcinoma (HCC), delineating the tumor cell origin of HCC, identifying its prognostic markers, and subtyping hepatocellular adenomas. As a result, a copious amount of data at immunohistochemical and molecular levels has emerged. A panel of immunohistochemical markers including glypican-3, heat shock protein 70 and glutamine synthetase has been found to be of use in the diagnosis of small, well differentiated hepatocellular tumors and particularly of HCC. The use of liver fatty acid binding protein (L-FABP), β-catenin, glutamine synthetase, serum amyloid protein and C-reactive protein is found to be helpful in the subtyping of hepatocellular adenomas. The role of tissue biomarkers for prognostication in HCC and the use of biomarkers in subclassifying HCC based on tumor cell origin are also discussed.

Ruptured hepatocellular carcinoma following chemoembolization:a western experience

BACKGROUND: Transcatheter arterial chemoembolization (TACE) is a recommended first line therapy for unresectable hepatocellular carcinoma (HCC). Serious complications such as neutropenic sepsis and hepatic decompensation are well known, but rupture of HCC following TACE is a rare and potentially fatal complication. The aim of this study was to identify the incidence of ruptured HCC following TACE and the associated risk factors. METHODS: A retrospective analysis was performed using our liver database with 'chemoembolization', 'ruptured HCC' covering the patients who received chemoembolization from January 1995 to December 2005. There were no exclusions. RESULTS: A total of 294 patients received chemoemboliza- tion in 530 sessions during the 10-year period. Of these, 2 ruptured following treatment (incidence 0.68%). The mean age was 65 years and the interval between the treatment and rupture was 2 and 24 days. The common factors were male sex, large tumor size (range 11-13 cm), and exophytic tumor growth. One patient died 2 days after rupture with hepatic decompensation while the second is alive after a 6-month follow up without tumor recurrence. CONCLUSIONS: Ruptured HCC following TACE is a rare but serious complication. Large tumor size, male sex, and exophytic growth of tumor may be predisposing factors for rupture.

Predictive value of tumor markers in patients with recurrent hepatocellular carcinoma in different vascular invasion pattern

BACKGROUND： Four tumor markers for hepatocellular carcinoma（HCC）, alpha-fetoprotein（AFP）, glypican-3（GPC3）, vascular endothelial growth factor（VEGF） and des-gammacarboxy prothrombin（DCP）, are closely associated with tumor invasion and patient＇s survival. This study estimated the predictability of preoperative tumor marker levels along with pathological parameters on HCC recurrence after hepatectomy.METHODS： A total of 140 patients with HCC who underwent hepatectomy between January 2012 and August 2012 were enrolled. The demographics, clinical and follow-up data were collected and analyzed. The patients were divided into two groups： patients with macroscopic vascular invasion（Ma VI ＋） and those without Ma VI（Ma VI-）. The predictive value of tumor markers and clinical parameters were evaluated by univariate and multivariate analysis.RESULTS： In all patients, tumor size（〉8 cm） and Ma VI were closely related to HCC recurrence after hepatectomy. For Ma VI＋ patients, VEGF（〉900 pg/m L） was a significant predictor for recurrence（RR=2.421; 95% CI： 1.272-4.606; P=0.007）. The 1- and 2-year tumor-free survival rates for Ma VI＋ patients with VEGF ≤900 pg/m L versus for those with VEGF 〉900 pg/m L were 51.5% and 17.6% versus 19.0% and 4.8%（P〈0.001）. For Ma VI- patients, DCP 〉445 m Au/m L and tumor size 〉8 cm were two independent risk factors for tumor recurrence（RR=2.307, 95% CI： 1.132-4.703, P=0.021; RR=3.150, 95% CI： 1.392-7.127, P=0.006; respectively）. The 1- and 2-year tumor-free survival rates for the patients with DCP ≤445 m Au/m L and those with DCP 〉445 m Au/m L were 90.4% and 70.7% versus 73.2% and 50.5% respectively（P=0.048）. The 1-and 2-year tumor-free survival rates for the patients with tumor size ≤8 cm and 〉8 cm were 83.2% and 62.1% versus 50.0% and 30.0%, respectively（P=0.003）.CONCLUSIONS： The Ma VI＋ patients with VEGF ≤900 pg/m L had a relatively high tumor-free survival than those with VEGF 〉900 pg/m L. In the Ma VI- patients, DCP 〉445 m Au/m L and tumor size 〉8 cm were predictive factors for postoperative recurrence.

A three-factor preoperative scoring model predicts risk of recurrence after liver resection or transplantation in hepatocellular carcinoma patients with preserved liver function

BACKGROUND： No staging systems of hepatocellular carcinoma（HCC） are tailored for assessing recurrence risk. We sought to establish a recurrence risk scoring system to predict recurrence of HCC patients receiving surgical curative treatment（liver resection or transplantation）.METHODS： We retrospectively studied 286 HCC patients with preserved liver function receiving liver resection（n=184） or transplantation（n=102）. Independent risk factors were identified to construct the recurrence risk scoring model. The recurrence free survival and discriminatory ability of the model were analyzed. RESULTS： Total tumor volume, HBs Ag status, plasma fibrinogen level were included as independent prognostic factors for recurrence-free survival and used for constructing a 3-factor recurrence risk scoring model. The scoring model was as follows： 0.758×HBs Ag status（negative： 0; positive： 1）＋0.387×plasma fibrinogen level（≤3.24 g/L： 0; 〉3.24 g/L： 1）＋0.633×total tumor volume（≤107.5 cm3： 0; 〉107.5 cm3： 1）. The cutoff value was set to 1.02, and we defined the patients with the score ≤1.02 as a low risk group and those with the score 〉1.02 as a high risk group. The 3-year recurrence-free survival rate was significantly higher in the low risk group compared with that in the high risk group（67.9% vs 41.3%, P〈0.001）. In the subgroup analysis, liver transplantation patients had a better3-year recurrence-free survival rate than the liver resection patients in the low risk group（80.0% vs 64.0%, P〈0.01）. Additionally for patients underwent liver transplantation, we compared the recurrence risk model with the Milan criteria in the prediction of recurrence, and the 3-year recurrence survival rates were similar（80.0% vs 79.3%, P=0.906）.CONCLUSION： Our recurrence risk scoring model is effective in categorizing recurrence risks and in predicting recurrencefree survival of HCC before potential surgical curative treatment.

FXYD6： a novel therapeutic target toward hepatocellular carcinoma

FXYD6, FXYD domain containing ion transport regulator 6, has been reported to affect the activity of Na＋/K＋-ATP- ase and be associated with mental diseases. Here, we demonstrate that FXYD6 is up-regulated in hepatocellular carcinoma （HCC） and enhances the migration and prolif- eration of HCC cells. Up-regulation of FXYD6 not only positively correlates with the increase of Na＋IK＋-ATPase but also coordinates with the activation of its downstream Src-ERK signaling pathway. More importantly, blocking FXYD6 by its functional antibody significantly inhibits the growth potential of the xenografted HCC tumors in mice, indicating that FXYD6 represents a potential therapeutic target toward HCC. Altogether, our results establish a critical role of FXYD6 in HCC progression and suggest that the therapy targeting FXYD6 can benefit the clinical treatment toward HCC patients.