Liver Cancer
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Primary liver cancer is a disease in which the cells of liver become cancerous (malignant). Primary liver cancer is different from cancer that has spread from another place in the body to the liver. The liver is found in the upper right side of the abdomen. It is an an important organ which is involved in digesting food and converting it to energy and it also filters and stores blood. Liver cancer is relatively rare, known risk factors for liver cancer are prior hepatitis B or C infections or cirrhosis of the liver. There are two main types of liver cancer in adults: hepatocellular carcinoma and cholangiocarcinoma. Hepatoblastoma is another type of liver cancer which mostly occurs in children. Some types of liver cancer produce abnormaly high levels of alpha-fetoprotein (AFP) which can aid diagnosis.

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Latest Research Publications
Childhood Liver Cancer

Information Patients and the Public (12 links)


Information for Health Professionals / Researchers (12 links)

Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Piccirillo M, Granata V, Albino V, et al.
Can hepatocellular carcinoma (HCC) produce unconventional metastases? Four cases of extrahepatic HCC.
Tumori. 2013 Jan-Feb; 99(1):e19-23 [PubMed]
AIMS AND BACKGROUND: Extrahepatic spread of hepatocellular carcinoma (HCC) diagnosed during the clinical course of the disease is not frequent; however, with the prolonged survival of HCC patients, the incidence of extrahepatic metastases seems to be increasing.
METHODS AND STUDY DESIGN: We present four unusual cases of extrahepatic metastasis from HCC: the first concerns a patient who underwent a liver transplantation for HCC with cirrhosis and three years later developed metastases in the lung and the left orbit; the second is that of a patient who developed an extraperitoneal pararectal metastasis; in the third case a large osteolytic lesion developed on the left iliac bone, and in the fourth case we found an isolated metastasis in the left mandible.
RESULTS AND CONCLUSIONS: These cases offer important information related to the unusual biology of isolated metastases from HCC after successful treatment of the primary cancer.


Khalil A, Elgedawy J, Faramawi MF, et al.
Plasma osteopontin level as a diagnostic marker of hepatocellular carcinoma in patients with radiological evidence of focal hepatic lesions.
Tumori. 2013 Jan-Feb; 99(1):100-7 [PubMed]
AIMS: Hepatocellular carcinoma is one of the most aggressive malignant tumors and has limited treatment options. Needle-guided biopsies have been utilized as a tool to diagnose malignant focal hepatic lesions. These techniques are discouraged because of their complications. Nowadays, alpha fetoprotein is the most widely used tumor marker for screening and diagnosis of hepatocellular carcinoma. Nevertheless, this marker has limitations. The diagnostic role of plasma osteopontin as an adjuvant or alternative marker to alpha fetoprotein to detect hepatocellular carcinoma in Egyptian patients with focal hepatic lesions was evaluated in this study.
SUBJECT AND METHODS: Eighty participants were recruited from the Egyptian National Liver Institute and were self-assigned to three groups, namely, focal hepatic lesions (n = 40), liver cirrhosis (n = 20), and controls (n = 20). Participants' plasma osteopontin and serum alpha fetoprotein levels were determined and were compared across the three groups.
RESULTS: The discriminatory ability of plasma osteopontin for hepatocellular carcinoma was lower than that of alpha fetoprotein. Osteopontin and alpha fetoprotein were not correlated with each other. Neither the gender nor the age of the patients showed a significant association with plasma osteopontin level.
CONCLUSION: Measuring plasma osteopontin level alone has no advantage over serum alpha fetoprotein in patients with focal hepatic lesions due to chronic liver disease.


Yilmaz Y, Colak Y, Kurt R, et al.
Linking nonalcoholic fatty liver disease to hepatocellular carcinoma: from bedside to bench and back.
Tumori. 2013 Jan-Feb; 99(1):10-6 [PubMed]
AIMS AND BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) and hepatocellular carcinoma (HCC) are two major causes of liver disease worldwide. Epidemiological and clinical data have clearly demonstrated that NAFLD and its associated metabolic abnormalities are a risk factor for HCC. Traditionally, the mechanisms whereby NAFLD acts as a risk for HCC are believed to include replicative senescence of steatotic hepatocytes and compensatory hyperplasia of progenitor cells as a reaction to chronic hepatic injury. Recent years have witnessed significant advances in our understanding of the mechanisms underlying the link between NAFLD and HCC.
METHODS: In the present review, we provide an update on the pathophysiological pathways linking NAFLD and its associated metabolic derangements to malignant hepatic transformation, with a special focus on insulin resistance, adipokines, inflammation, and angiogenesis. We will also discuss the potential therapeutic implications that such molecular links carry.
RESULTS: Although treating NAFLD could reduce the risk of malignant hepatic transformation, no long-term studies focusing on this issue have been conducted thus far. Insulin resistance, inflammation as well as derangements in adipokines and angiogenic factors associated with NAFLD are closely intertwined with the risk of developing HCC.
CONCLUSIONS: Traditional therapeutic approaches in NAFLD including metformin and statins may theoretically reduce the risk of HCC by acting on common pathophysiological pathways shared by NAFLD and HCC.


Mahtab MA, Akbar SM, Rahman S
Hepatitis B surface antigen-negative, but HBV DNA-positive patients in Bangladesh.
Bangladesh Med Res Counc Bull. 2012; 38(3):104-7 [PubMed]
Hepatitis B surface antigen (HBsAg) is regarded as sole marker of hepatitis B virus (HBV) infection in Bangladesh and most other developing countries. However, some HBV-negative subjects may harbor HBV DNA and transfusion of their blood may cause HBV infection in recipients. HBV DNA was checked in 20 patients with cryptogenic liver cirrhosis, 10 patients with hepatocellular carcinoma without any known etiology, and 10 apparently healthy subjects with elevated levels of serum alanine aminotransferase (ALT). HBV DNA was detected in 8 of 20 patients with cryptogenic liver cirrhosis, 1 of 10 patients with hepatocellular carcinoma, and 2 of 10 apparent healthy subjects with elevated ALT. However, all of them were negative for HBsAg in the sera. This study indicates that some additional mechanisms should be developed for detection of HBsAg-negative HBV-infected subjects for efficient control and management of HBV infection in Bangladesh.


Mao H, Gao W, Lu G, et al.
Clinicopathological and prognostic implications of arginase expression in hepatocellular carcinoma.
Clin Lab. 2013; 59(1-2):37-43 [PubMed]
BACKGROUND: To investigate the correlation of Arg-1 expression with clinicopathologic factors and prognosis of HCC patients, including recurrence and survival rate.
METHODS: We examined the expression of Arg-1 in HCC by immunohistochemistry and studied its correlation with a series of clinicopathologic features and prognositic parameters of patients with HCC.
RESULTS: We found patients with higher Arg-1 expression showed less aggressive features based on less portal vein invasion (chi2 = 10.794, df = 1, p = 0.001), less microvessel invasion (chi2 = 4.247, df = 1, p = 0.039), lower TNM stage (chi2 = 4.992, df = 1, p = 0.025), and better differentiated histology (chi2 = 24.155, df= 1, p < 0.001). Among them, portal vein invasion (p = 0.024, 95% CI 1.010 - 2.321), microvessel invasion (p = 0.043, 95% CI 1.014 - 3.225), histology (p = 0.001, 95% CI 2.230 - 5.934), and TNM stage (p = 0.001, 95% CI 1.364 - 3.401) have been suggested as prognostic factors in HCC patients. Furthermore, the enhanced expression of Arg-1 in HCC appears to be associated with a lower recurrence rate and prolonged overall survival.
CONCLUSIONS: These results suggest that Arg-1 may play a tumor suppressive role in HCC and could be a new, promising prognostic biomarker for HCC patients.


Kidoh M, Nakaura T, Oda S, et al.
Contrast enhancement during hepatic computed tomography: effect of total body weight, height, body mass index, blood volume, lean body weight, and body surface area.
J Comput Assist Tomogr. 2013 Mar-Apr; 37(2):159-64 [PubMed]
OBJECTIVE: The objective of this study was to evaluate the effect of total body weight, height, body mass index, blood volume, lean body weight, and body surface area (BSA) on aortic and hepatic contrast enhancement during hepatic computed tomography (CT).
METHODS: We calculated the changes in the CT number per gram of iodine ((Δ Hounsfield units/g [ΔHU/g])) for the aorta and the liver during portal venous phase. We performed linear regression analyses between ΔHU/g and each of the body parameters.
RESULTS: ΔHU/g and BSA showed the strongest inverse correlation. The correlation coefficients for the aorta and liver were 0.70 and 0.68 for ΔHU/g and total body weight, 0.41 and 0.37 for height, 0.54 and 0.55 for body mass index, 0.68 and 0.59 for blood volume, 0.70 and 0.62 for lean body weight, and 0.71 and 0.68 for BSA, respectively (P < 0.001 for all).
CONCLUSION: Our study supports the use of a protocol with iodine dose adjusted for the patient BSA.


Yacob M, Raju RS, Vyas FL, et al.
Management of colorectal cancer liver metastasis in a patient with immune thrombocytopaenia.
Ann R Coll Surg Engl. 2013; 95(2):e50-1 [PubMed]
Immune thrombocytopaenia (ITP) was referred to previously as idiopathic thrombocytopaenic purpura and is usually of autoimmune or viral aetiology. Colorectal cancer liver metastasis with concomitant ITP is rare and only three cases have been reported in the English literature. Adverse effects of adjuvant chemotherapy may aggravate ITP. The sequencing of chemotherapy, operation for the primary and liver metastasis, and a decision on splenectomy is important. We present our experience in the management of a 52-year-old man who, having undergone anterior resection one year earlier for carcinoma of the rectum, presented with liver metastasis and ITP. He underwent splenectomy with hepatectomy prior to chemotherapy.


Poggi G, Montagna B, DI Cesare P, et al.
Microwave ablation of hepatocellular carcinoma using a new percutaneous device: preliminary results.
Anticancer Res. 2013; 33(3):1221-7 [PubMed]
BACKGROUND: Thermal ablative techniques have gained increasing popularity as safe and effective options for patients with unresectable solid malignancies. Microwave ablation has emerged as a relatively new technique with the promise of larger and faster ablation areas without some of the limitations of radiofrequency thermal ablation. Herein, we report our preliminary results on the feasibility and efficacy of thermal ablation for hepatocellular carcinoma (HCC) with a new 2.45-MHz microwave generator.
PATIENTS AND METHODS: Under ultrasound guidance 194 HCCs in 144 patients were treated through a percutaneous approach. The median diameter of lesions was 2.7 cm (range=2.0-11.0 cm); 68 lesions had a diameter greater than 30 mm. We used a microwave generator (AMICA-GEM, Apparatus for MICrowave Ablation) connected to a 14- or 16-gauge coaxial antenna endowed with a miniaturized sleeve choke to reduce back heating effects and increase the sphericity of the ablated area. Contrast-enhanced computed tomography scan was carried out one month after treatment, and then every three months to assess efficacy.
RESULTS: Complete ablation was achieved in 94.3% of the lesions after a mean of 1.03 percutaneous sessions. For small HCCs (diameter <3 cm) complete necrosis was obtained in 100%. Local tumor progressions were found in 10 treated lesions (5.1%) a median of 19.5 months after ablation. Minor complications occurred in 5.1% procedures. No deaths, or other major complications occurred.
CONCLUSION: In our experience, the new device for microwave ablation proved to provide an effective and safe percutaneous ablative method, capable of producing large areas of necrosis.


Nishikawa H, Arimoto A, Wakasa T, et al.
Pre-treatment C-reactive protein as a prognostic factor for recurrence after surgical resection of hepatocellular carcinoma.
Anticancer Res. 2013; 33(3):1181-8 [PubMed]
BACKGROUND AND AIMS: We examined the prognostic value of pre-treatment C-reactive protein (CRP) after surgical resection (SR) for hepatocellular carcinoma (HCC).
PATIENTS AND METHODS: A total of 298 patients with HCC who underwent SR were analyzed. They were categorized into a CRP-positive group (group A: CRP >0.2 mg/dl, n=130) and a CRP-negative group (group B: CRP <0.2 mg/dl, n=168). Overall survival (OS) and recurrence-free survival (RFS) were compared.
RESULTS: The 1- and 3-year cumulative OS rates were 87.0% and 68.3% in group A and 95.9% and 81.1% in group B (p=0.194). The corresponding RFS rates were 61.6% and 30.3% in group A and 77.2% and 44.9% in group B (p=0.004). In multivariate analysis, the pre-treatment CRP level was a significant prognostic factor linked to RFS (p=0.046).
CONCLUSION: Pre-treatment CRP levels may be a useful predictor of recurrence after SR for HCC.


Mukozu T, Nagai H, Matsui D, et al.
Serum VEGF as a tumor marker in patients with HCV-related liver cirrhosis and hepatocellular carcinoma.
Anticancer Res. 2013; 33(3):1013-21 [PubMed]
AIM: Vascular endothelial growth factor (VEGF) is a primary driving force for both physiological and pathological angiogenesis, and its overexpression has been found in hepatocellular carcinoma (HCC). The aim of this study was to retrospectively clarify the usefulness of serum VEGF levels as a tumor marker in patients with hepatitis C virus (HCV)-related liver cirrhosis (CLC) and HCC.
MATERIALS AND METHODS: The patients with CLC were divided into three groups: 28 patients without HCC (CLC group), 11 patients with HCC (HCC group), and 48 patients with advanced HCC (aHCC group). The control group consisted of 37 patients with chronic HCV.
RESULTS: When the relation of serum VEGF to liver function was assessed, there was no significant difference of VEGF levels between the control group and the CLC group. When serum VEGF levels were assessed in relation to the presence of HCC, the VEGF levels of the HCC group and aHCC group were found to be significantly higher than that of the control group, while there was no significant difference between the control group and the CLC group. For the detection of cancer, serum VEGF had the largest area under the curve (AUC) and the highest accuracy when we employed the cut-off value obtained by receiver operating characteristic (ROC) analysis using the Youden index. Evaluation of various tumor markers in the aHCC group showed that the serum levels of α-fetoprotein (AFP) were higher in patients with infiltrating tumors than in patients with multiple discrete nodules or confluent multinodular tumors, while there were no significant differences in the serum levels of VEGF, Lens culinaris agglutinin-reactive fraction of AFP (AFP-L3), and des-γ-carboxy prothrombin. There were no significant differences on the serum levels of all four markers between tumor stages, but serum VEGF was higher in patients with vascular invasion than in those without vascular invasion.
CONCLUSION: The present findings suggest that the serum levels of VEGF might be a useful predictor of the presence of HCC in patients with CLC, while serum levels of AFP and VEGF can predict the tumor type and vascular invasion, respectively.


Moriya S, Morimoto M, Numata K, et al.
Fucosylated fraction of alpha-fetoprotein as a serological marker of early hepatocellular carcinoma.
Anticancer Res. 2013; 33(3):997-1001 [PubMed]
AIM: This study aimed to evaluate the fucosylated fraction of alpha-fetoprotein (AFP-L3) as a marker of early hepatocellular carcinoma (HCC).
PATIENTS AND METHODS: We diagnosed early HCC in 15 patients (15 tumors) by gadolinium-ethoxybenzyl-diethylenetriamine-pentaacetic acid-enhanced magnetic resonance imaging and confirmed the diagnoses using new criteria of the International Consensus Group for Hepatocellular Neoplasia. We measured the AFP-L3%, simultaneously, using a liquid-phase binding assay-electrokinetic analyte transport assay. We compared the AFP-L3% levels between patients with early HCC and a control cohort with benign liver disease.
RESULTS: The AFP-L3% levels were higher in patients with early HCC than in the controls (4.1%±4.0% vs. 2.0%±3.5%, p=0.024). The sensitivity and specificity with AFP-L3% were 33.3% and 78.7% at a cut-off value of 5%, and 20.0% and 88.0% at a cut-off value of 7%, respectively.
CONCLUSION: AFP-L3% is a suitable serological marker for evaluating early HCC.


Morgan RL, Baack B, Smith BD, et al.
Eradication of hepatitis C virus infection and the development of hepatocellular carcinoma: a meta-analysis of observational studies.
Ann Intern Med. 2013; 158(5 Pt 1):329-37 [PubMed]
BACKGROUND: Hepatitis C virus (HCV) is a leading cause of hepatocellular carcinoma (HCC). In the United States, this form of cancer occurs in approximately 15 000 persons annually. A systematic review of the evidence is needed to assess the benefits of treatment of HCV-infected persons on development of HCC.
PURPOSE: To systematically review observational studies to determine the association between response to HCV therapy and development of HCC among persons at any stage of fibrosis and those with advanced liver disease.
DATA SOURCES: MEDLINE, EMBASE, CINAHL, the Cochrane Library, Web of Science, and the Database of Abstracts of Reviews and Effectiveness from inception through February 2012.
STUDY SELECTION: English-language observational studies that compared therapy-derived sustained virologic response (SVR) with no response to therapy among HCV-infected persons, targeted an adult population, and had an average follow-up of at least 2 years.
DATA EXTRACTION: Two investigators independently extracted data into uniform relative risk measures. The Grading of Recommendations Assessment, Development and Evaluation framework was used to determine the quality of the evidence.
DATA SYNTHESIS: Thirty studies fulfilled the inclusion criteria, and 18 provided adjusted effect estimates that were used to calculate pooled relative risks. Among HCV-infected persons, SVR was associated with reduced risk for HCC (relative risk for all persons, 0.24 [95% CI, 0.18 to 0.31], moderate-quality evidence; advanced liver disease hazard ratio, 0.23 [CI, 0.16 to 0.35], moderate-quality evidence).
LIMITATION: In the meta-analyses, some variables could not be controlled for because of the observational design of the included studies.
CONCLUSION: Sustained virologic response after treatment among HCV-infected persons at any stage of fibrosis is associated with reduced HCC. The evidence was determined to be of moderate quality.


Miyake T, Nimura S, Hamada Y, et al.
MK-1 expression in gastric carcinoma with liver metastasis.
Jpn J Clin Oncol. 2013; 43(4):377-82 [PubMed]
OBJECTIVE: The prognosis for gastric carcinoma patients with liver metastasis is very poor. This retrospective study investigated the prognostic significance of MK-1 expression in gastric carcinoma patients with liver metastasis.
METHODS: Immunohistochemical staining using monoclonal antibody FU-MK-1 against MK-1 antigen was performed on paraffin-embedded tissues from 64 gastric carcinoma patients with liver metastasis. We attempted to determine the presence of any relationship between pathological prognostic factors and the expression of MK-1 in 64 gastric carcinoma patients with liver metastasis.
RESULTS: MK-1 expression was found in 43 (67%) of 64 tumor samples. MK-1 expression was significantly higher in the intestinal type (73%) than in the diffuse type carcinoma (33%, P = 0.049). Multivariate analysis showed that MK-1 expression and lymph node metastasis were significant factors for overall survival. The difference between overall survival rates with positive or negative MK-1 expression was statistically significant as shown by Kaplan-Meier survival analysis (P < 0.0001; log-rank). In addition, the difference between cumulative disease-free survival rates with positive or negative MK-1 expression in gastric carcinoma patients with metachronous liver metastasis was statistically significant as well, as shown by Kaplan-Meier survival analysis (P = 0.0006; log-rank).
CONCLUSIONS: The prognostic significance of MK-1 expression as a biological tumor marker was demonstrated in a series of gastric carcinoma patients with liver metastasis. MK-1 positivity may be a reliable marker for predicting and taking measures to control liver metastasis after curative gastrectomy for gastric carcinoma.


Liu C, Billadeau DD, Abdelhakim H, et al.
IQGAP1 suppresses TβRII-mediated myofibroblastic activation and metastatic growth in liver.
J Clin Invest. 2013; 123(3):1138-56 [PubMed] Free Access to Full Article
In the tumor microenvironment, TGF-β induces transdifferentiation of quiescent pericytes and related stromal cells into myofibroblasts that promote tumor growth and metastasis. The mechanisms governing myofibroblastic activation remain poorly understood, and its role in the tumor microenvironment has not been explored. Here, we demonstrate that IQ motif containing GTPase activating protein 1 (IQGAP1) binds to TGF-β receptor II (TβRII) and suppresses TβRII-mediated signaling in pericytes to prevent myofibroblastic differentiation in the tumor microenvironment. We found that TGF-β1 recruited IQGAP1 to TβRII in hepatic stellate cells (HSCs), the resident liver pericytes. Iqgap1 knockdown inhibited the targeting of the E3 ubiquitin ligase SMAD ubiquitination regulatory factor 1 (SMURF1) to the plasma membrane and TβRII ubiquitination and degradation. Thus, Iqgap1 knockdown stabilized TβRII and potentiated TGF-β1 transdifferentiation of pericytes into myofibroblasts in vitro. Iqgap1 deficiency in HSCs promoted myofibroblast activation, tumor implantation, and metastatic growth in mice via upregulation of paracrine signaling molecules. Additionally, we found that IQGAP1 expression was downregulated in myofibroblasts associated with human colorectal liver metastases. Taken together, our studies demonstrate that IQGAP1 in the tumor microenvironment suppresses TβRII and TGF-β dependent myofibroblastic differentiation to constrain tumor growth.


Bose S, Tripathi DM, Sukriti, et al.
Genetic polymorphisms of CYP2E1 and DNA repair genes HOGG1 and XRCC1: association with hepatitis B related advanced liver disease and cancer.
Gene. 2013; 519(2):231-7 [PubMed]
A population based case-control study was designed to explore the genetic risk factors for hepatitis B virus (HBV) related liver disease susceptibility. A total of 424 subjects comprising 210 controls, 50 acute HBV (AVH), 84 chronic HBV (CHBV), 25 HBV related cirrhosis and 55 HBV related hepatocellular carcinoma (HCC) cases were included in the study. PCR-RFLP was used for the genotyping of Cyp2E1*5B, hOGG1 codon 326 and XRCC1 codon 399. Compared to controls, Cyp2E1 rsaI variant c2 genotype increased the risk of HBV related liver disease severity by 2.68 fold, the highest for HCC cases (3.981 folds, p=0.106); and was associated with higher histology activity index (HAI) (p<0.001) in CHBV patients. Cyp2E1 and hOGG1 variants were independently associated with a significantly higher fibrosis score in CHBV group. Analysis of gene-gene interaction studies showed an increased risk of HCC, cirrhosis and CHBV in a Cyp2E1 variant+XRCC1 variant combination (p<0.001); and hOGG1 variants+XRCC1 variants. A mutually independent heterozygous hOGG1 and XRCC1 combination resulted in a decreased risk of HBV related liver disease. On the other hand, a wild-type hOGG1 and XRCC1 combination was associated with a significantly higher risk of AVH (p=0.010) but a lower risk of CHBV (p=0.032) and HCC (p=0.006). The gene-gene interactions were also associated with a significant increase in HAI and fibrosis score in CHBV patients. Cyp2E1, hOGG1 and XRCC1 genotypes significantly alter the risk of HBV related liver disease susceptibility and severity, independently or through gene-gene interaction.


Hanson JA, Ason R, Weinreb J, et al.
Radiology estimates of viable tumor percentage in hepatocellular carcinoma ablation cavities correlate poorly with pathology assessment.
Arch Pathol Lab Med. 2013; 137(3):392-9 [PubMed]
CONTEXT: No study has evaluated radiology/pathology correlation of percentage viable tumor (PVT) estimates in ablated hepatocellular carcinoma (HCC) to examine the reliability of radiologic estimates.
OBJECTIVE: To determine how well interdisciplinary PVT estimates correlate and identify pathologic factors that influence this correlation.
DESIGN: Pathologists and radiologists established blinded PVT estimates in 22 HCC ablation cavities. Paired sample t tests examined the differences between the interdisciplinary estimates.
RESULTS: Fifteen cavities had pathologic viable tumor (VT) (68%) and 6 had radiographic VT (22%). Radiology's sensitivity for detecting VT was 40% and the specificity was 100%. Pathology detected significantly more VT than radiology (pathology mean = 22.3% versus radiology mean = 2.6%; P = .005). Five cavities had tumor growth in a discontinuous rim pattern, 7 in a nodular pattern, and 3 in a solid pattern. Radiology did not detect VT in cavities with a discontinuous rim pattern (sensitivity = 0%) but did detect VT in 3 cavities with a nodular pattern (sensitivity = 43%), and in all cavities with a solid pattern (sensitivity = 100%). There was no significant difference in PVT estimates in cavities 3.5 cm or larger (P = .07), but there was a significant difference in cavities smaller than 3.5 cm (P = .01).
CONCLUSION: This study clarifies that the risk of underestimation by imaging is greatest in small lesions (<3.5 cm), though the sensitivity of detection depends primarily on the tumor growth pattern within the cavity. This underestimation raises the question of whether basing treatment decisions on a radiologic impression of complete ablation is valid.


Nishida N, Kudo M
Recent advancements in comprehensive genetic analyses for human hepatocellular carcinoma.
Oncology. 2013; 84 Suppl 1:93-7 [PubMed]
Hepatocellular carcinoma (HCC) typically develops in the liver with chronic hepatitis and cirrhosis, and activation of oncogenes and inactivation of tumor suppressor genes occurs during carcinogenesis via genetic and epigenetic mechanisms. Recent advancements in the development of analyses for examining the cancer genome have revealed information regarding genetic alterations in HCC tissues. According to previous studies, the incidence of recurrent genetic alterations in individual genes was thought to be relatively rare and limited to a subset of a few cancer-specific genes such as tumor suppressor p53, RB genes and oncogenes such as CTNNB1. However, recent whole-genome analyses and exome sequencing of tumor DNA have revealed numerous novel alterations of cancer-related genes and pathways critical for HCC development. In addition, various risk factors for HCC, such as the presence or absence of hepatitis B and C virus, may affect the mutation profile of the corresponding cancer genome. On the other hand, genome-wide association studies have also identified important single-nucleotide polymorphisms involved in HCC development, which may allow detection of a group at high risk of HCC emergence. Such analyses will clarify how this malignancy can be treated, diagnosed and prevented more effectively.


Minata M, Kudo M, Harada KH, et al.
Expression of E-cadherin and vascular endothelial growth factor in noncancerous liver is associated with recurrence of hepatocellular carcinoma after curative resection.
Oncology. 2013; 84 Suppl 1:88-92 [PubMed]
OBJECTIVES: Hepatocellular carcinoma (HCC) frequently recurs even after curative resection. The purpose of this study was to examine how background liver affects postoperative recurrence of HCC that underwent curative resection using expression of cancer-related molecules in the adjacent noncancerous liver of HCC patients.
METHODS: We examined expression of E-cadherin and vascular endothelial growth factor in noncancerous liver tissues of 133 HCC patients who underwent curative resection of tumors using immunohistochemical analysis. Associations between expressions of these molecules and disease-free survival of HCC were analyzed using the Kaplan-Meier method.
RESULTS: The average period of follow-up of the patients was 6.7 years. Multivariate analyses revealed that low platelet count and negative expression of E-cadherin in adjacent noncancerous liver were significantly associated with metastatic recurrence [p = 0.017, hazard ratio (HR) = 1.31 for low platelet count, and p = 0.009, HR = 1.43 for negative expression of E-cadherin, respectively].
CONCLUSIONS: Expression levels of E-cadherin in adjacent noncancerous liver after surgical resection was associated with metastatic HCC recurrence later on. Analysis of E-cadherin expression should provide important information for predicting recurrence after curative resection of HCC.


Nishida N, Arizumi T, Takita M, et al.
Quantification of tumor DNA in serum and vascular invasion of human hepatocellular carcinoma.
Oncology. 2013; 84 Suppl 1:82-7 [PubMed]
OBJECTIVES: Hepatocellular carcinoma (HCC) is one of the common cancers worldwide. Accurate diagnosis of tumor progression is critical for the appropriate management of HCC. Here, we established a sensitive assay to detect and quantify tumor-derived DNA in the serum of HCC patients.
METHODS: Aberrant methylation of the APC gene was quantified in 23 HCC patients and 8 healthy volunteers using 100 µl of serum. For sensitive detection and accurate quantification of tumor DNA, we combined seminested polymerase chain reaction (PCR) with TaqMan PCR, which could amplify the APC gene regardless of the methylation status and detect the methylated and unmethylated sequences separately. The ratio of methylated to unmethylated sequences was quantified.
RESULTS: The methylated APC gene was detected in all HCC patients examined, but no healthy volunteers showed amplification of methylated sequences in serum. HCC patients with portal vein thrombosis showed a significantly higher methylated to unmethylated APC gene ratio in serum than those without portal vein thrombosis (p = 0.0029).
CONCLUSIONS: Considering the strong association between the ratio of the methylated to unmethylated APC sequences in serum and the presence of portal vein thrombosis, methylation status of APC sequences could be a promising marker for improving HCC management.


Minata M, Harada KH, Kudo M, et al.
The prognostic value of vascular endothelial growth factor in hepatocellular carcinoma for predicting metastasis after curative resection.
Oncology. 2013; 84 Suppl 1:75-81 [PubMed]
OBJECTIVES: Hepatocellular carcinoma (HCC) frequently recurs even after curative resection. The purpose of this study was to identify factors predictive for postoperative recurrence of HCC in patients who underwent curative resection using immunohistochemistry.
METHODS: Expression of vascular endothelial growth factor (VEGF), E-cadherin and cyclin D1 in HCC tissue were analyzed for 133 HCC patients who underwent curative resection of tumors using immunohistochemical analysis. Relationships of expressions and disease-free survival of HCC were evaluated using univariate and multivariate analyses.
RESULTS: The average period of follow-up of the patients was 6.7 years. Multivariate analyses revealed that only strong expression of VEGF in HCC tissue was significantly associated with metastatic recurrence (p < 0.001, hazard ratio, HR, 3.32).
CONCLUSIONS: Evaluating VEGF in HCC tissue after surgical resection has predictive value for metastatic HCC recurrence. The ability to risk stratify should improve the treatment strategies after hepatectomy.


Jiang W, Zeng ZC
Is it time to adopt external beam radiotherapy in the NCCN guidelines as a therapeutic strategy for intermediate/advanced hepatocellular carcinoma?.
Oncology. 2013; 84 Suppl 1:69-74 [PubMed]
OBJECTIVE: External beam radiotherapy (EBRT) is recommended as a therapeutic strategy for stage III hepatocellular carcinoma (HCC) in national guidelines of the Chinese Society of Liver Disease and in Korea Liver Cancer Study Group practice guidelines, but has not been considered a therapeutic option for HCC in Western countries. In this study, we review evidence supporting EBRT as an option for HCC treatment.
METHODS: Retrospective investigation was made of 775 patient records of intermediate/advanced HCC treated in our hospital during the last 10 years, including 98 patients with confined intrahepatic tumor, 181 with portal vein (PV) or inferior vena cava (IVC) tumor thrombi, 191 with lymph node metastases, 55 with adrenal gland metastases, 205 with bone metastases, 13 with lung metastases and 32 with brain metastases.
RESULTS: Transcatheter arterial chemoembolization combined with radiotherapy was found to constitute an improved therapeutic strategy for unresectable but confined intrahepatic HCC with poor lipid accumulation. Survival of HCC patients with PV/IVC tumor thrombi was prolonged to 10.7 months by radiotherapy, and it was 8.0 months in patients with abdominal lymph node metastasis. Radiotherapy also shrinks adrenal and lung metastatic HCC lesions, resulting in median survival times of 13.6 and progression-free survival of 13.4 months, respectively. In bone metastatic HCC, radiotherapy significantly relieved symptoms, although median survival time was only 7.4 months. Radiotherapy is effective for treatment of intermediate/advanced stages of HCC. Although our finding is based only on retrospective analysis, no therapeutic option that provides better treatment than EBRT in this indication has thus far been identified. Because sorafenib has been recommended as a treatment strategy by the National Comprehensive Cancer Network (NCCN) for HCC, we compared the survival after EBRT with sorafenib treatment on the basis of published clinical data. From this comparison, we found that EBRT treatment was more effective than sorafenib for improving patient survival when tested on tumors of comparable metastatic size.
CONCLUSION: Based on the evidence reviewed, we propose that EBRT be included in the NCCN guideline as a treatment strategy for intermediate/advanced HCC.


Tsai CL, Koong AC, Hsu FM, et al.
Biomarker studies on radiotherapy to hepatocellular carcinoma.
Oncology. 2013; 84 Suppl 1:64-8 [PubMed]
Radiotherapy (RT) has been gradually integrated into the multimodality treatment for hepatocellular carcinoma (HCC). The various patterns of failure in HCC patients undergoing RT drive the need of effective biomarkers to guide treatment decisions. Limited numbers of biomarkers have been investigated in HCC, with even fewer of them for patients treated by RT. Serum or plasma biomarkers measured by enzyme-linked immunosorbent assay were the most common practice. Of particular interest are those biomarkers that are detectable early in the course of radiotherapy which correlated with ultimate clinical outcome. Functional magnetic resonance imaging (MRI) is increasingly used to evaluate the imaging pattern indicative of disease control following RT. Positron emission tomography shows that pre-RT standard uptake values associate with various types of recurrence after treatment. Proximity ligation assay (PLA) is evolving with the unique features of dual-probe identification, ligation and amplification to allow the small volume of serum/plasma samples for evaluating multiple biomarkers. We demonstrate the screening work of biomarkers by PLA with pre- and post-RT serum samples from HCC patients undergoing RT. Efforts are being made to search for the potential biomarkers for HCC patients treated by RT.


Minami Y, Kudo M
Therapeutic response assessment of transcatheter arterial chemoembolization for hepatocellular carcinoma: ultrasonography, CT and MR imaging.
Oncology. 2013; 84 Suppl 1:58-63 [PubMed]
Two randomized controlled trials identified that transcatheter arterial chemoembolization (TACE) for hepatocellular carcinoma (HCC) shows a significant survival benefit compared with controls, after a long-term controversy. Thus, TACE is the current standard of care for patients presenting with multinodular HCC. Monitoring tumor response to TACE is part of the clinical management of HCC patients. Imaging, including ultrasonography, computed tomography and magnetic resonance imaging, has an important role in assessing therapeutic effects earlier and more objectively. Imaging assessment needs to detect not only a reduction in overall tumor load but also a reduction in viable tumor. Here, we give an overview of the current status of the imaging assessment of HCC response to TACE.


Inoue T, Kudo M, Hatanaka K, et al.
Usefulness of contrast-enhanced ultrasonography to evaluate the post-treatment responses of radiofrequency ablation for hepatocellular carcinoma: comparison with dynamic CT.
Oncology. 2013; 84 Suppl 1:51-7 [PubMed]
OBJECTIVE: Contrast-enhanced ultrasonography (CEUS) with Sonazoid® and dynamic computed tomography (CT) were used to evaluate radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC). Local recurrence rate was used as the gold standard of evaluation.
METHODS: From January 2007 to December 2011, 86 HCCs from 70 patients were treated with RFA. CEUS with Sonazoid and dynamic CT were then used to evaluate the effect of RFA. For CEUS and dynamic CT, effects were classified as follows: (1) complete ablated response with safety margin >5 mm (CRSM+); (2) complete ablated response but with safety margin <5 mm (CRSM-); (3) incomplete, residual tumor detected after treatment.
RESULTS: CEUS judged 33 cases as CRSM+, while dynamic CT identified 49 cases. None of these 33 cases from the CEUS group had local recurrences, while dynamic CT had 1 case. CEUS judged 49 cases as CRSM-, compared to 34 cases with dynamic CT. Of these, 9 cases of CEUS and 8 cases of dynamic CT showed local recurrences. Two cases diagnosed as 'incomplete' by CEUS and dynamic CT had recurrences within 1 year.
CONCLUSION: CEUS can be used to assess the efficacy of RFA for HCC, with the potential to reduce the number of CT scans required for confirmation.


Makino Y, Imai Y, Ohama H, et al.
Ultrasonography fusion imaging system increases the chance of radiofrequency ablation for hepatocellular carcinoma with poor conspicuity on conventional ultrasonography.
Oncology. 2013; 84 Suppl 1:44-50 [PubMed]
OBJECTIVES: To investigate the usefulness of the ultrasonography (US) fusion imaging system for radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC).
METHODS: Since the US fusion imaging system became available in 2010, we have conducted RFA with this system in all cases. The characteristics of 75 patients with 120 HCCs and 89 patients with 123 HCCs who underwent RFA before the introduction of this system (period A) and after it (period B), respectively, were retrospectively compared.
RESULTS: Significant difference in the characteristics of the patients and HCCs between the two periods was found only in the proportion of HCCs with poor conspicuity on grayscale US treated with RFA (1.7%, 2/120 for period A vs. 15.4%, 19/123 for period B, p < 0.01). Among the 19 HCCs with poor conspicuity on grayscale US for period B, 5 and 9 HCCs were identified on grayscale US and contrast-enhanced US, respectively, by the use of the US fusion imaging system, whereas the 5 remaining undetectable HCCs were treated by using the system in conjunction with reference images displayed side-by-side with grayscale US.
CONCLUSION: Since the introduction of the US fusion imaging system, it has become possible to perform RFA for HCCs with poor conspicuity on grayscale US.


Peng ZW, Chen MS
Transcatheter arterial chemoembolization combined with radiofrequency ablation for the treatment of hepatocellular carcinoma.
Oncology. 2013; 84 Suppl 1:40-3 [PubMed]
Radiofrequency ablation (RFA) has become an important treatment for hepatocellular carcinoma (HCC). Nowadays, RFA is generally recognized as an alternative treatment to partial hepatectomy for early HCC, especially for patients with impaired liver function and when liver transplantation is not indicated, although some authors consider that RFA can be used as a first-line treatment for early HCC. Transcatheter arterial chemoembolization (TACE) is most commonly classified as palliative rather than potentially curative; there is evidence that TACE prolongs survival in patients with well-compensated liver disease and intermediate-stage HCC. Alone, TACE and RFA have their limitations; in particular, neither can result in adequate control of medium or large HCC. Sequential application of TACE and RFA is, therefore, increasingly being used in the treatment of HCC in patients with well-compensated liver disease. In this study, we will introduce our experience of TACE combined with RFA in the treatment of HCC in a cancer center in China.


Kim YH, Kim do Y
Yttrium-90 radioembolization for hepatocellular carcinoma: what we know and what we need to know.
Oncology. 2013; 84 Suppl 1:34-9 [PubMed]
In spite of substantial progress in the management of hepatocellular carcinoma (HCC), suboptimal treatment results are frequently seen in the intermediate and advanced stages of HCC. The current staging system indicates that multinodular HCC without vascular invasion needs to be treated by transarterial chemoembolization (TACE) and HCC with vascular nvasion or distant metastasis is linked to sorafenib, an an-tiangiogenic therapy. Radioembolization with yttrium-90 ((90)Y) is a recently introduced liver-directed therapy employing a catheter-based approach. Growing data suggest that (90)Y radioembolization has a potent anticancer effect with negligible adverse events if appropriate pretreatment evaluations including dosimetry, calculation of lung shunt fraction and assessment of vascular anatomy are performed. Retrospective and small prospective studies have shown response rates and survival after (90)Y therapy which are comparable to TACE and sorafenib in the intermediate and advanced stages, respectively. Although a large sample size is necessary to compare the outcome between TACE and radioembolization in intermediate-stage HCC, selected populations, for whom TACE would not be effective, are candidates for testing the role of (90)Y radioembolization. A multidisciplinary, combined approach in advanced HCC using loco-regional therapy such as radioembolization and systemic therapy including sorafenib also has to be investigated.


Takayasu K
Transcatheter arterial chemoembolization for unresectable hepatocellular carcinoma: recent progression and perspective.
Oncology. 2013; 84 Suppl 1:28-33 [PubMed]
Transcatheter arterial chemoembolization (TACE) is widely performed in 32% of patients with unresectable hepatocellular carcinoma (HCC) at initial diagnosis and in 58% of those with recurrent HCC in Japan. However, the patient population which undergoes TACE is heterogeneous, and thus the 3-year survival rate varies from 26 to 47%. The selection criteria for TACE is 2-3 tumors >3 cm or 4 or more tumors in patients with liver damage A/B (corresponding well to Child-Pugh class A/B) and absence of vascular invasion and extrahepatic spread, as proposed by Japanese guidelines. The 3-year survival rate of TACE for patients with 2-3 tumors >3 cm or 4 or more tumors was 55 and 46%, respectively, in Child-Pugh A and 30 and 22%, respectively, in class B. These outcomes could help in understanding the various results of TACE in different backgrounds in the East and West. Recently, TACE with calibrated drug-eluting beads loaded with doxorubicin showed a similar tumor response and radioembolization with yttrium-90 microspheres demonstrated a similar median survival compared with conventional TACE. Based on these results, the combination of TACE and novel molecular targeted agents can be used to elucidate the synergic effect on survival.


Kudo M, Matsui O, Sakamoto M, et al.
Role of gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging in the management of hepatocellular carcinoma: consensus at the Symposium of the 48th Annual Meeting of the Liver Cancer Study Group of Japan.
Oncology. 2013; 84 Suppl 1:21-7 [PubMed]
We summarize here the consensus reached at the Symposium of the 48th Annual Meeting of the Liver Cancer Study Group of Japan held in Kanazawa on July 20th and 21st, 2012, on the role of gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging (EOB-MRI) in the management of hepatocellular carcinoma (HCC). Currently, dynamic CT is the first choice of imaging modality when HCC is suspected. EOB-MRI is useful for differentiation and definitive diagnosis of HCC when dynamic CT/MRI does not show conclusive findings for HCC. In addition, contrast- enhanced ultrasound with Sonazoid is useful for making a decision on whether or not to treat a hypovascular lesion <1 cm when the nodules are shown with low intensity in the hepatocyte phase of EOB-MRI. Furthermore, EOB-MRI should be performed in selected cases of HCC ultrahigh-risk groups every 3-4 months, or EOB-MRI should be performed at least once at the first visit in all HCC ultrahigh-risk groups.


Takaki H, Yamakado K, Nakatsuka A, et al.
Frequency of and risk factors for complications after liver radiofrequency ablation under CT fluoroscopic guidance in 1500 sessions: single-center experience.
AJR Am J Roentgenol. 2013; 200(3):658-64 [PubMed]
OBJECTIVE: The purpose of this article is to retrospectively evaluate the frequency of and risk factors for complications after liver radiofrequency ablation (RFA).
MATERIALS AND METHODS: This was a retrospective study of 656 patients (with 1755 liver tumors) who underwent 1500 CT fluoroscopy-guided liver RFA sessions. Of those patients, 501 had primary liver tumor and 155 had liver metastases. Mortality and treatment-related complications were documented. Complications were evaluated according to the Common Terminology Criteria for Adverse Events (version 4.0). Major complications were defined as grade 3 or higher adverse events. Factors affecting frequent complications with a frequency of 1% or more were detected using multivariate analysis.
RESULTS: Two deaths (0.1% [2/1500]) occurred. One patient died of liver failure subsequent to hemorrhage, and the other died of liver failure. The major complication rate was 2.8% (42/1500). The most frequent major complication was hemorrhage (1.1% [16/1500]). The absence of arterial embolization before RFA (p < 0.01), low hemoglobin level (p < 0.04), and elevated serum creatinine level (p < 0.04) were identified as significant risk factors for major hemorrhage. The minor complication rate was 17.1% (257/1500). Pneumothorax (7.7% [116/1500]) was the most frequent minor complication, followed by hemorrhage (7.0% [105/1500]). A transthoracic approach (p < 0.01) and subphrenic tumor location (p < 0.01) were significant risk factors for pneumothorax, and the use of a cluster needle (p < 0.02) and multiple tumors (p < 0.01) were significant risk factors for minor hemorrhage.
CONCLUSION: CT fluoroscopy-guided RFA is a safe procedure with an acceptably low rate of major complications for liver tumor treatment. Factors identified in this study will help to stratify high-risk patients.


This page last updated: 22nd May 2013
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