Subtype Of Primary Liver Cancer Research Articles

MiRNA-708 functions as a tumour suppressor in hepatocellular carcinoma by targeting SMAD3

Hepatocellular carcinoma (HCC) is the most frequent subtype of primary liver cancer and the third most common cause of cancer-associated mortality worldwide. Previous studies have reported that microRNAs (miRNAs) serve key roles in the carcinogenesis and progression of HCC by regulating gene expression. The present study investigated the expression patterns, biological roles and underlying mechanisms of miRNA-708 (miR-708) in HCC. The expression levels of miR-708 in HCC tissue samples and cell lines were examined. Cell proliferation, migration and invasion assays were used to evaluate the effect of miR-708 on HCC cells. In addition, bioinformatic and western blotting analyses, and dual luciferase reporter assays were performed to investigate the direct gene target of miR-708. The results of the present study demonstrated that miR-708 expression was significantly decreased in HCC tissue samples and cell lines. In addition, the expression level of miR-708 was associated with increased HCC tumour stage. Furthermore, ectopic expression of miR-708 suppressed HCC cell proliferation, migration and invasion. The results of the present study also indicated that miR-708 targets SMAD family member 3 directly in vitro. The results of the present study indicated that miR-708 may be a novel target for future HCC therapy.

Advanced Combined Hepatocellular Carcinoma and Cholangiocarcinoma (cHCC-CC) in a Patient With Alcoholism and Chronic Hepatitis C

Introduction: A combined hepatocellular and cholangiocarcinoma (cHCC-CC) is rare subtype of primary liver cancer accounting for 0.87% of primary liver tumors. It is a distinct type of primary liver cancer with aggressive behavior, which is morphologically and phenotypically intermediate between HCC and CC. Although few studies have shown the increased occurrence of cHCC-CC in chronic hepatitis B patients, there is a lack of association with chronic hepatitis reported in US studies. We present a patient with advanced cHCC-CC and history of alcoholism and chronic hepatitis C(CHC). Case: A 64-year-old man with history of alcohol abuse and CHC, treatment naive, was referred to hepatology for jaundice for 2 weeks (blood work in table 1). Ultrasound of the abdomen showed a 6.6cm mass in left hepatic lobe extending to the hilum causing intrahepatic ductal dilatation(IHD), a 5.5cm mass in right hepatic lobe and scattered small liver lesions. MRI of the abdomen with Eovist revealed an 8.6cm mass in segment 4 extending to the hilum resulting in right(RT) and left (LT) IHD dilation and a 6cm mass in posterior right hepatic lobe. There were also smaller satellite nodules in both lobes, occlusion of the main portal vein with extensive cavernous transformation, and thrombus within the RT and LT intrahepatic portal veins. Liver was non-nodular while enhancement suggested CC. Liver biopsy showed CK7 positive, poorly differentiated CC with rare glandular architecture(Image 1). It also showed poorly differentiated HCC with giant cell features consistent with cHCC-CC (Image 2,3). Jaundice worsened and total bilirubin(TB) trended up to 30. A biliary drain was placed and TB decreased to 18. After the drain was capped 5 days later, he developed acute renal failure, leukocytosis and encephalopathy. Antibiotics, rifaximin, and albumin were given and his renal function and mental status improved. Palliative care was consulted for advanced cHCC-CC and the patient was discharged to home hospice. Conclusion: The diagnosis and treatment of cHCC-CC can be challenging due to clinical, imaging and histological features that overlap with pure HCC and CC. Our patient, although did not have ascites, had advanced stage disease with satellite lesions, multiple tumors, biliary, vascular and regional lymph node involvement. Further studies are needed to evaluate the risk of CHC in development of cHCC-CC. This may ultimately help us to screen for early disease and to improve prognosis.Table 1: LabsFigure 1Figure 2Figure 3

Overexpression Of Hepatocyte Nuclear Factor-1beta Predicting Poor Prognosis Is Associated With Biliary Phenotype In Patients With Hepatocellular Carcinoma.

Hepatocyte nuclear factor-1beta (HNF-1B) is involved in the hepatobiliary specification of hepatoblasts to cholangiocytes during liver development, and is strongly expressed throughout adult biliary epithelium. The aim of this study was to examine the expression of HNF-1B in different pathologic subtypes of primary liver cancer, including hepatocellular carcinoma (HCC) and cholangiocarcinoma (ICC), and the relationship between HNF-1B expression, clinicopathological features and prognosis. We retrospectively investigated 2 cohorts of patients, including 183 HCCs and 69 ICCs. The expression of HNF-1B was examined by immunohistochemistry. We found that HNF-1B expression was associated with pathological subtype of primary tumor, and HNF-1B expression in HCC tissue may be associated with the change of phenotype on recurrence. The HNF-1B expression was positively correlated with biliary/HPC (hepatic progenitor cell) markers expression. Further, multivariable analysis showed that HNF-1B expression was an independent prognostic factor for both overall survival and disease-free survival of HCC patients. However, no correlation between HNF-1B expression and survival was found in ICC patients. In summary, HCC with high HNF-1B expression displayed biliary phenotype and tended to show poorer prognosis. HNF-1B-positive malignant cells could be bipotential cells and give rise to both hepatocytic and cholangiocytic lineages during tumorigenesis.

Ursolic acid inhibited growth of hepatocellular carcinoma HepG2 cells through AMPKα-mediated reduction of DNA methyltransferase 1.

Hepatocellular carcinoma (HCC), the major histological subtype of primary liver cancer, remains one of the most common malignancies worldwide. Due to the complicated pathogenesis of this malignancy, the outcome for comprehensive treatment is limited. Chineseherbalmedicine(CHM) is emerging as a promising choice for its multi-targets and coordinated intervention effects againstHCC. Ursolic acid (UA), a natural pentacyclic triterpenoid carboxylic acid found in CHM, exerts anti-tumor effects and is emerging as an effective compound for cancer prevention and therapy. However, the molecular mechanisms underlying the action of UA remain largely unknown. In this study, we showed that UA inhibited the growth of HCC cells and induced apoptosis in the dose- and time-dependent fashion. Furthermore, we found that UA induced phosphorylation of AMP-activated protein kinase alpha (AMPKα) and suppressed the protein expression of DNA methyltransferase 1 (DNMT1) in the dose-dependent manner. The inhibitor of AMPK, compound C blocked, while an activator of AMPK, metformin augmented the effect of UA on DNMT1 expression. In addition, UA suppressed the expression of transcription factor Sp1. Conversely, overexpression of Sp1 reversed the effect of UA on DNMT1 expression and cell growth. Collectively, our results show for the first time that UA inhibits growth of HCC through AMPKα-mediated inhibition of Sp1; this in turn results in inhibition of DNMT1. This study reveals a potential novel mechanism by which UA controls growth of HCC cells and suggests that DNMT1 could be novel target for HCCchemoprevention and treatment.

Clinicopathological features and prognosis of combined hepatocellular carcinoma and cholangiocarcinoma after surgery

Combined hepatocellular carcinoma and cholangiocarcinoma (cHCC-CC) is a rare subtype of primary liver cancer consisting of both hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC). Because of the rarity of this tumor, its feature is poorly understood. The present study aimed to evaluate the clinicopathological features and long-term prognosis of patients with cHCC-CC after surgery and to compare with those of the patients with stage-matched HCC and CC. The clinicopathological features of the patients who underwent surgery for cHCC-CC at our center during the period of 2001-2010 were retrospectively analyzed and compared with those of stage-matched HCC and CC patients. Cancer staging was performed according to the AJCC Cancer Staging Manual (6th ed.). Overall survival and disease-free survival were compared among the groups and prognostic factors of cHCC-CC were evaluated. Significant differences were observed in clinicopathological features among 42 patients with cHCC-CC, 90 patients with HCC and 45 patients with CC. Similar to HCC patients, cHCC-CC patients had frequent hepatitis B virus antigen positivity, microscopic vessel invasion, cirrhosis and high level of serum alpha-fetoprotein. Similar to CC patients, cHCC-CC patients showed increased bile duct invasion and decreased capsule. The 1-, 3-, and 5-year overall survival and disease-free survival of patients with cHCC-CC were not significantly different from those with stage-matched patients with CC; but significantly poorer than those with HCC. In subanalysis of patients with stage II, the overall survival in patients with cHCC-CC or CC was significantly poorer than that in patients with HCC. We did not find the difference in patients with other stages. Univariate analysis of overall and disease-free survival of patients with cHCC-CC showed that the vascular invasion and intrahepatic metastasis were the significant predictive factors. Patients with cHCC-CC showed similar clinicopathological features as those with HCC or CC, and patients with cHCC-CC or CC had a poorer prognosis compared with those with HCC, especially at matched stage II.

Time and deprivation trends in incidence of primary liver cancer subtypes in England.

Primary liver cancer consists of distinct subtypes with differing aetiology so it is valuable to study the incidence of these subtypes separately. This study aims to investigate time and socio-economic deprivation trends in the incidence of primary liver cancer subtypes in England, identifying the burden in the population. Data were extracted from the population-based National Cancer Data Repository (NCDR) for patients diagnosed with primary liver cancer between 1990 and 2009. Subtypes were defined by the 10th edition of the International Classification of Diseases (ICD-10) codes: liver cell carcinoma (C22.0), intrahepatic bile duct carcinoma (C22.1), other (C22.2-C22.4, C22.7) and unspecified (C22.9). A sensitivity analysis was carried out on the main histological subtypes of liver cell carcinoma and intrahepatic bile duct using the 2nd edition of the International Classification of Diseases for Oncology (ICD-O-2). Male and female age-standardized incidence rates per 100 000 World standard population were calculated for each year and for the period 1999-2009 by socio-economic deprivation quintile. A total of 40 945 patients were diagnosed with primary liver cancer between 1990 and 2009. Liver cell carcinoma incidence increased in men from 0.63 in 1990 to 2.48 per 100 000 in 2009. While incidence was low in women, rates increased from 0.18 to 0.59, respectively. Intrahepatic bile duct carcinoma incidence increased between 1990 and 2009 from 0.40 to 1.25 per 100 000 in men, and from 0.28 to 1.08 in women. Incidence of the other liver cancer subtype remained low throughout the study period at less than 0.3 per 100 000 in each year in both men and women. The highest rate of liver cell carcinoma and intrahepatic bile duct carcinoma was generally in men and women resident in the most deprived areas between 1999 and 2009. The largest difference by deprivation quintile was observed for liver cell carcinoma in men, where the incidence was more than double in the most deprived quintile with an average rate of 3.56 per 100 000 compared to the least deprived quintile at 1.43. Liver cell carcinoma and intrahepatic bile duct carcinoma incidence increased between 1990 and 2009 in both sexes. This pattern was largely driven by patients living in the most deprived areas. Differences observed may be due to the variation in the prevalence of known risk factors such as chronic hepatitis B and C viral infections and excessive alcohol consumption.

New Routes to Targeted Therapy of Intrahepatic Cholangiocarcinomas Revealed by Next-Generation Sequencing

Intrahepatic cholangiocarcinoma (ICC) is a subtype of primary liver cancer that is rarely curable by surgery and is rapidly increasing in incidence. Relapsed ICC has a poor prognosis, and current systemic nontargeted therapies are commonly extrapolated from those used in other gastrointestinal malignancies. We hypothesized that genomic profiling of clinical ICC samples would identify genomic alterations that are linked to targeted therapies and that could facilitate a personalized approach to therapy. DNA sequencing of hybridization-captured libraries was performed for 3,320 exons of 182 cancer-related genes and 36 introns of 14 genes frequently rearranged in cancer. Sample DNA was isolated from 40 μm of 28 formalin-fixed paraffin-embedded ICC specimens and sequenced to high coverage. The most commonly observed alterations were within ARID1A (36%), IDH1/2 (36%), and TP53 (36%) as well as amplification of MCL1 (21%). Twenty cases (71%) harbored at least one potentially actionable alteration, including FGFR2 (14%), KRAS (11%), PTEN (11%), CDKN2A (7%), CDK6 (7%), ERBB3 (7%), MET (7%), NRAS (7%), BRCA1 (4%), BRCA2 (4%), NF1 (4%), PIK3CA (4%), PTCH1 (4%), and TSC1 (4%). Four (14%) of the ICC cases featured novel gene fusions involving the tyrosine kinases FGFR2 and NTRK1 (FGFR2-KIAA1598, FGFR2-BICC1, FGFR2-TACC3, and RABGAP1L-NTRK1). Two thirds of patients in this study harbored genomic alterations that are associated with targeted therapies and that have the potential to personalize therapy selection for to individual patients.

Combined Hepatocellular Cholangiocarcinoma: A Case Report and Review of Literature

The two commonly seen subtypes of primary liver cancer are hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC). They both have a distinct clinico-pathologic profile. Combined hepatocellular cholangiocarcinoma (cHCC-CC) is a far more uncommon tumor with histologic evidence of both hepatocellular and biliary epithelial differentiation [1, 2]. It accounts for about 1.0–14.2 % of all primary liver cancers with incidence varying in different studies [3, 4]. The reported incidence of cHCC-CC ranges from 1.4 to 6.5 % and varies geographically [5]. In 1949, Allen and Lisa first described this entity in detail and morphologically classified into three subtypes [6]. Since then there have been a few case series and single case reports describing this malignancy. Owing to its rarity, the natural history, clinical characteristics and optimal management of cHCC-CC is not well understood. We report a case of cHCC-CC along with review of literature. Wherever necessary, data from the Surveillance, Epidemiology and End Results (SEER) cancer registry (http://seer.cancer.gov/) was used to supplement the literature review. The results of our review suggests that cHCC-CC is closer to CC than to HCC. Further, surgery appears to be the modality of choice and regional lymph node dissection is recommended, but radiation therapy adds little to the overall survival of these patients.

Clinicopathological characteristics and prognostic factors in combined hepatocellular carcinoma and cholangiocarcinoma.

Backgrounds/AimsCombined hepatocellular carcinoma and cholangiocarcinoma (cHCC-CC) is an uncommon subtype of primary liver cancer that has rarely been reported in detail. This study was performed in order to evaluate the clinicopathological characteristics and prognostic factors of cHCC-CC in single center.MethodsThe clinicopathological features of patients diagnosed and operated with cHCC-CC at Chonbuk National Hospital between July 1998 and July 2007 were retrospectively studied by comparing them with patients with only hepatocellular carcinoma (HCC) who had undergone a hepatic resection during the same period.ResultsTen out of 152 patients who had undergone a hepatic resection were diagnosed with cHCC-CC and thus included in this study (M : F=8 : 2, median age: 52±11.1 years). According to the parameters of the 7th American Joint Committee on Cancer T staging, there were 76 (50.0%), 44 (28.9%), 9 (5.9%), 18 (11.8%) and 5 (3.3%) patients with T stages 1, 2, 3a, 3b and 4, respectively. The overall survival period was longer in the HCC only group (68±40.4 months) than in the combined cHCC-CC group (23±40.1 months) (p<0.0001). The 5-year survival rate was 10% in the cHCC-CC group and 60% in the HCC group (p<0.0001). The disease free survival for patients with cHCC-HCC and HCC were 16±37.4 and 51±44.3 months, respectively (p<0.0001). Univariate analysis revealed that age, gender, transarterial chemoembolization (TACE), and T stage were statistically significant in terms of patient's overall survival. However, there were no significant clinicopathological factors identified by the multivariate analysis.ConclusionsEven after the hepatic resection in the HCC, the prognosis is poorer if the patient has cholangiocellular components compared to the usual HCC.

Combined Hepatocellular Carcinoma and Cholangiocarcinoma: Clinical Features, Treatment Modalities, and Prognosis

Combined hepatocellular carcinoma and cholangiocarcinoma (cHCC-CC) is an uncommon subtype of primary liver cancer that has rarely been reported in large-scale clinical studies. The aim of this study was to clarify the clinical features, treatment modalities, and prognosis of cHCC-CC. Included in this study were 113 patients who were histologically diagnosed as having Allen type C cHCC-CC, 103 of whom received liver resection, 6 transarterial chemoembolization treatment, 3 radiofrequency ablation, and 1 palliative supportive treatment. Clinicopathologic features and prognosis of 103 cHCC-CC patients after liver resection were compared with those of 6,679 patients with hepatocellular carcinoma (HCC) and 386 patients with intrahepatic cholangiocarcinoma (ICC) who underwent liver resection during the same period. The proportion of cHCC-CC in primary liver cancers was 1.5 %. The 103 cases of cHCC-CC were characterized by male predominance, infection with hepatitis virus or presence of liver cirrhosis, and elevated alfa-fetoprotein-findings similar to HCC. However, serum CA19-9 elevation, incomplete capsules, and lymph node involvement were similar to ICC. The 1-, 3-, and 5-year overall survival rates after liver resection were 73.9, 41.4, and 36.4 %, respectively, for patients with cHCC-CC versus 77.5, 53.3, and 41.4 % for HCC patients, and 58.0, 29.1, and 22.3 % for ICC patients (χ(2) = 137.5, P < 0.001). Tumor, node, metastasis system stage (hazard ratio 1.27, 95 % confidence interval 1.08-1.49, P = 0.003) and radical liver resection (hazard ratio 0.31, 95 % confidence interval 0.14-0.68, P = 0.004) were independent prognostic factors for overall survival. cHCC-CC has biological behavior and prognosis that are intermediate between HCC and ICC. Radical liver resection can provide a better outcome for this uncommon malignancy.

Clinicopathologic Study on Combined Hepatocellular Carcinoma and Cholangiocarcinoma: with Emphasis on the Intermediate Cell Morphology

Combined hepatocellular carcinoma and cholangiocarcinoma (combined HCC-CC) is a rare subtype of primary liver cancer. We investigated the histopathologic features of transitional or intermediate areas in 21 combined HCC-CCs and immunophenotypes using different hepatic progenitor cell markers (CK7, CK19, c-kit, NCAM, and EpCAM). Major histologic findings of transitional or intermediate areas of 21 combined HCC-CCs included strands/trabeculae of small, uniform, oval-shaped cells with scant cytoplasm and hyperchromatic nuclei embedded within an abundant stroma, small cells with an antler-like anastomosing pattern, and solid nests of intermediate hepatocyte-like cells surrounded by small cells in periphery, in order of frequency. The intermediate area of one tumor was composed predominantly of spindle cells arranged in short fascicles. Immunophenotype of tumor cells with intermediate morphology suggested a progenitor cell origin for this tumor. Clinical findings of combined HCC-CC showed a closer resemblance with those of HCC than those of CC. In univariate analysis, tumor size, TNM stage, and serum alpha-fetoprotein levels showed a significant association with poor patient survival. Serum alpha-fetoprotein level was an independent prognostic indicator in multivariate analysis. In conclusion, an awareness of the clinicopathologic features, specifically the various morphologic features of intermediate areas in this tumor, is essential for prevention of potential misdiagnosis as another tumor.

Combined hepatocellular and cholangiocarcinoma: clinical features and prognostic study in a Thai population

Combined hepatocellular and cholangiocarcinoma (HCC-CC) is an uncommon subtype of primary liver cancer, the clinicopathological features of which have rarely been reported in detail. Some authors believe that HCC-CC behaves like HCC, but biliary differentiation may be associated with poorer prognosis. Moreover, CC has more frequent lymph node metastases. In this study, we aimed to determine the clinical course and survival outcome of HCC-CC patients in a Thai population by comparing them with patients with ordinary HCC. The clinicopathological features of patients who were diagnosed with HCC-CC at Ramathibodi Hospital during 2000-2004 were retrospectively studied by comparing them with the features of patients suffering from ordinary HCC. Twenty-five patients who were diagnosed with HCC-CC were included in this study, and subsequently 50 patients with HCC who had tissues taken during the same period were selected randomly from among 148 HCC patients. Statistical analysis was done by using SPSS version 10.0. The Kaplan-Meier method was used to assess the survival rate. Multiple logistic regression analysis was performed to assess correlations. A value of P < 0.05 was considered statistically significant. There were no significant differences in etiologic risk factors between HCC-CC and HCC patients: cirrhosis (50% vs 44%), chronic alcohol abuse (36% vs 43%), presence of hepatitis B surface antigen (HBsAg; 66% vs 78%) and presence of hepatitis C virus (HCV) antibody (13% vs 3%). The serum alpha-fetoprotein (AFP) value in the HCC-CC group was lower than that in the HCC group (5.87 vs 41.46 ng/ml). No differences in tumor characteristics or liver status (tumor size, presence of multinodular lesions, portal vein thrombosis, intrahepatic bile duct dilatation, intraabdominal lymphadenopathy, extrahepatic metastasis, liver cirrhosis, portal hypertension, and ascites) between these two groups were found. The overall median survival of HCC-CC patients was 38 weeks while that of HCC patients was 54 weeks. Multivariate analysis showed that elevated carbohydrate antigen (CA)19-9 (>/=80 U/ml) and the presence of intrahepatic bile duct dilatation were independent risk factors for worse survival. The demographic and clinical features of patients with combined HCC-CC were similar to those of patients with HCC. The presence of cholangiocellular differentiation appeared to worsen the prognosis when compared with pure HCC, although this difference did not reach statistical significance. An increased CA19-9 level and intrahepatic bile duct dilatation in patients with HCC-CC were considered to be independent factors that suggested poor prognosis.

Combined hepatocellular and cholangiocarcinoma: a clinicopathologic study of 26 resected cases.

Combined hepatocellular and cholangiocarcinoma (cHCC-CC) is an uncommon subtype of primary liver cancer, the clinicopathological features of which have rarely been reported in detail. The aim of this study was to clarify the characteristics of cHCC-CC in comparison with hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC). The clinicopathological features of 26 cHCC-CC patients, who were surgically treated, were reviewed by comparing them with the features of patients suffering from ordinary hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC). The cHCC-CC patients showed greater similarity with HCC patients than with CC patients with regard to male/female ratio, status of hepatitis viral infection, serum alpha-fetoprotein (AFP) level, and non-tumor liver histology. The disease stage of the cHCC-CC patients was more advanced than that of either the HCC or CC patients. The cHCC-CC tumors were significantly more invasive to the portal vein than the HCC tumors and were comparable to the CC tumors. The overall 3-, 5-, and 10-year survival rates and the median survival times (95% confidence interval) were 34.6%, 23.1%, 11.5% and 1.8 (0.7-3.0) years for cHCC-CC patients, 86.7%, 66.2%, 46.8% and 4.6 (4.3-5.0) years for HCC patients, and 68.5%, 32.3%, 23.9% and 1.9 (1.1-2.7) years for CC patients, respectively. Survival of patients with cHCC-CC was significantly poorer than that of HCC or CC patients. Among the 26 patients, six survived for >5 years. In most cases, cHCC-CC seems to be a variant of ordinary HCC with cholangiocellular features, rather than a true intermediate disease entity between HCC and CC. The surgical approach is recommended for selected patients with cHCC-CC.