Combined hepatocellular cholangiocarcinoma: Controversies to be addressed

Combined hepatocellular cholangiocarcinoma(CHC) accounts for 0.4%-14.2% of primary liver cancer cases and possesses pathological features of both hepatocellular carcinoma and cholangiocarcinoma. Since this disease was first described and classified in 1949, the classification of CHC has continuously evolved. The latest definition and classification of CHC by the World Health Organization is based on the speculation that CHC arises from hepatic progenitor cells. However, there is no evidence demonstrating the common origin of different components of CHC. Furthermore, the definition of CHC subtypes is still ambiguous and the identification of CHC subtype when a single tumor contains many components has remained unresolved. In addition, there is no summary on the newly recognized histopathology features or the contribution of CHC components to prognosis and outcome of this disease. Here we provide a review of the current literature to address these questions.

Combined hepatocellular and cholangiocarcinoma originating from the same clone:a pathomolecular evidence-based study

Background:Combined hepatocellular and cholangiocarcinoma(CHC) is a unique subtype of liver cancer comprising both hepatocellular carcinoma(HCC) and intrahepatic cholangiocarcinoma(ICC);however,its cellular origin remains unclear.The purpose of this study was to investigate the clinicopathologic features and the clonal relationship between HCC and ICC in 34 patients with CHC.Methods:The clinicopathologic features and prognosis of the 34 CHC patients were compared with those of 29 patients with separated HCC and ICC(5HC).Loss of heterozygosity(LOH) at 10 highly polymorphic microsatellite markers was detected in 16 CHC and 10 SHC tissues for determination of the clonal origin of CHC.Expression of hepatocyte markers[hepatocyte paraffin 1(Hep Par 1) and glypican 3(GPC3)]and cholangiocyte markers[cytokeratin(CK)7 and 19]in tumor tissues was examined by immuno histochemical analysis.Results:In the 16 CHC specimens,the difference in LOH patterns between HCC and ICC was less than 30%,suggesting the same clonal origin of HCC and ICC.Consistent with this finding,immunohistochemical analysis revealed that hepatocyte markers(Hep Par 1 and GPC3) and cholangiocyte markers(CK7 and CK19) were simultaneously expressed in both the HCC and ICC components in 52.9%of CHC specimens,suggesting that the two components shared a similar phenotype with hepatic progenitor cells(HPCs).On the contrary,in all 10 SHC cases,the difference in LOH patterns between the HCC and ICC components was greater than 30%,suggesting different clonal origins of HCC and ICC.Overall survival and disease-free survival were shorter for patients with CHC than for patients with SHC(P < 0.05).Conclusions:Our results suggest that the HCC and ICC components of CHC may originate from the same clone,having the potential for dual-directional differentiation similar to HPCs.CHC tended to exhibit the biological behaviors of both HCC and ICC,which may enhance the infiltrative capacity of tumor cells,leading to poor clinical outcomes for patients with CHC.

Long-term outcomes of combined hepatocellular-cholangiocarcinoma after hepatectomy or liver transplantation: A systematic review and meta-analysis

Background: Combined hepatocellular-cholangiocarcinoma(cHCC-CC) is a rare primary liver malignancy. We conducted a systematic review and meta-analysis to assess the evidence available on the long-term outcomes of cHCC-CC patients after either hepatectomy or liver transplantation(LT). Data Sources: Relevant studies published between January 2000 and January 2018 were identified by searching Pub Med and Embase and reviewed systematically. Data were pooled using a random-effects model. Results: A total of 42 observational studies involving 1691 patients(1390 for partial hepatectomy and 301 for LT) were included in the analysis. The median tumor recurrence and 5-year overall survival(OS) rates were 65%(range 38%–100%) and 29%(range 0–63%) after hepatectomy versus 54%(range 14%–93%) and 41%(range 16%–73%) after LT, respectively. Meta-analysis found no significant difference in OS and tumor recurrence between LT and hepatectomy groups. Conclusion: Hepatectomy rather than LT should be considered as the prior treatment option for cHCC-CC.

Risk factors for combined hepatocellular-cholangiocarcinoma:A hospital-based case-control study

AIM:To identify risk factors contributing to the development of combined hepatocellular-cholangiocarcinoma(CHC) in China.METHODS:One hundred and twenty-six patients with CHC and 4:1 matched healthy controls were interviewed during the period from February 2000 to October 2012.Logistic regression analysis was used to calculate odds ratios(OR)and 95%confidence intervals(CI)for each risk factor.RESULTS:Univariate analysis showed that the significant risk factors for CHC development were hepatitis B virus(HBV)infection,heavy alcohol consumption,a family history of liver cancer,and diabetes mellitus.Multivariate stepwise logistic regression analysis showed that HBV infection(OR=19.245,95%CI:13.260-27.931)and heavy alcohol consumption(OR=2.186,95%CI:1.070-4.466)were independent factors contributing to the development of CHC.CONCLUSION:HBV infection and heavy alcohol consumption may play a role in the development of CHC in China.

Liver transplantation in patients with incidental hepatocellular carcinoma/cholangiocarcinoma and intrahepatic cholangiocarcinoma： a single-center experience

BACKGROUND： Reports of fiver transplantation （LT） in patients with mixed hepatocellular carcinoma/cholangiocarcinoma （HCC/CC） and intrahepatic cholangiocarcinoma （ICC） are modest and have been mostly retrospective after pathological categorization in the setting of presumed HCC. Some studies suggest that patients undergoing LT with small and unifocal ICC or mixed HCC/CC can achieve about 40%-60% 5-year post-transplant survival. The study aimed to report our experience in patients undergoing LT with explant pathology revealing HCC/CC and ICC. METHODS： From a prospectively maintained database, we performed cohort analysis. We identified 13 patients who underwent LT with explant pathology revealing HCC/CC or ICC. RESULTS： The observed recurrence rate post-LT was 31% （4/13） and overall survival was 85%, 51%, and 51% at 1, 3 and 5 years, respectively. Disease-free survival was 68%, 51%, and 41% at 1, 3 and 5 years, respectively. In our cohort, four patients would have qualified for exception points based on updated HCC Organ Procurement and Transplantation Network imaging guidelines. CONCLUSIONS： Lesions which lack complete imaging characteristics of HCC may warrant pre-LT biopsy to fully elucidate their pathology. Identified patients with early HCC/CC or ICC may benefit from LT if unresectable. Additionally, incorporating adjunctive perioperative therapies such as in the case of patients undergoing LT with hilar cholangiocarcinoma may improve outcomes but this warrants further investigation.

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

BACKGROUND： 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. METHODS： The dinicopathological 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. RESULTS： Significant differences were observed in clinico- pathological 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. CONCLUSION： Patients with cHCC-CC showed similar dinico- pathological 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.

Differentiation of intrahepatic cholangiocarcinoma from hepatocellular carcinoma in high-risk patients: a predictive model using contrast-enhanced ultrasound

AIM To develop a contrast-enhanced ultrasound(CEUS)predictive model for distinguishing intrahepatic cholangiocarcinoma(ICC) from hepatocellular carcinoma(HCC) in high-risk patients.METHODS This retrospective study consisted of 88 consecutive high-risk patients with ICC and 88 high-risk patients with HCC selected by propensity score matching between May 2004 and July 2016. Patients were assigned to two groups, namely, a training set and validation set, at a 1:1 ratio. A CEUS score for diagnosing ICC was generated based on significant CEUS features. Then, a nomogram based on the CEUS score was developed, integrating the clinical data. The performance of the nomogram was then validated and compared with that of the LR-M of the CEUS Liver Imaging Reporting and Data System(LI-RADS).RESULTS The most useful CEUS features for ICC were as follows: rim enhancement(64.5%), early washout(91.9%), intratumoral vein(58.1%), obscure boundary of intratumoral non-enhanced area(64.5%), and marked washout(61.3%, all P < 0.05). In the validation set, the area under the curve(AUC) of the CEUS score(AUC = 0.953) for differentiation between ICC and HCC was improved compared to the LI-RADS(AUC = 0.742)(P < 0.001). When clinical data were added, the CEUS score nomogram was superior to the LI-RADS nomogram(AUC: 0.973 vs 0.916, P = 0.036, Net Reclassification Improvement: 0.077, Integrated Discrimination Index: 0.152). Subgroup analysis demonstrated that the CEUS score model was notably improved compared to the LIRADS in tumors smaller than 5.0 cm(P < 0.05) but not improved in tumors smaller than 3.0 cm(P > 0.05).CONCLUSION The CEUS predictive model for differentiation between ICC and HCC in high-risk patients had improved discrimination and clinical usefulness compared to the CEUS LIRADS.

Clinicopathological analysis of 14 patients with combined hepatocellular carcinoma and cholangiocarcinoma

BACKGROUND:Combined hepatocellular carcinoma and cholangiocarcinoma (cHCC-CC) is an uncommon subtype of primary hepatic carcinoma,and its prognosis is poor.This study was undertaken to investigate the prognosis and the clinicopathological characteristics of cHCC-CC,including their possible cellular origin.METHODS:Among 852 patients with a primary hepatic carcinoma who underwent hepatectomy from January 1998 to April 2008 at our hospital,cHCC-CC was identified in 14 patients The clinicopathological characteristics of the 14 patients were analyzed retrospectively.The expression of the liver stem cell markers (c-kit,CD90,CD133 and CK19) in the tumor tissue was detected by immunohistochemistry,and the Kaplan-Meier method was used to evaluate survival.RESULTS:Among the 14 patients,9 presented with abdominal pain,3 with anorexia and debilitation,and the remaining two patients were asymptomatic.The mean age was 53.6±3.0 (range 38-74) years.Among the included patients,11 had an elevated serum alpha-fetoprotein level,13 were infected with hepatitis B virus,9 had vascular invasion and 1 had lymph node metastasis The average diameter of the tumors was 9.9±1.1 (range 5.0-16.0) cm.The median overall survival time was 7.9±1.0 months In addition,the presence of the liver stem cell markers,c-kit CD90,CD133 and CK19 was 71.4%,85.7%,92.9% and 78.6% respectively.All four markers were simultaneously expressed in eight cases.CONCLUSIONS:cHCC-CC has aggressive characteristics and the prognosis is extremely dismal.The high expression of liver stem cell markers in the tumor tissue suggests that these tumors may derive from liver stem cells.

Clinicopathological characteristics of 15 patients with combined hepatocellular carcinoma and cholangiocarcinoma

BACKGROUND: Combined hepatocellular carcinoma and cholangiocarcinoma (cHCC-CC) is a rare subtype of primary liver cancer, and clinicopathological features of cHCC-CC have seldom been reported in detail. This study was undertaken to explore the diagnosis and clinicopathological characteristics of cHCC-CC in comparison with hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC), respectively. METHODS: The clinical data from 15 patients with cHCC-CC, 132 patients with HCC and 44 patients with CC who had undergone hepatic resection were analyzed retrospectively. Clinicopathological characteristics of cHCC-CC, HCC and CC such as hepatitis B viral infection, serum hepatitis C virus (HCV) antibody, serum alpha-fetoprotein (AFP) level, cirrhosis, vascular invasion, lymph node metastasis, surgical procedure and adjuvant treatment were also analyzed. Follow up was carried out in the patients, and their 1-, 3-, and 5-year survival rates were calculated. RESULTS: Two patients with cHCC-CC were correctly diagnosed by enhanced CT before operation, the other 13 patients were diagnosed by histology and immunohistochemistry after operation. Radical (8/15) and conservative hepatectomy (7/15) for cHCC-CC was similar to that for HCC and CC (P > 0.05). Pathologically cHCC-CC showed more significantly vascular invasion and lymph node metastasis than HCC (P < 0.05), and a similarity to CC (P > 0.05). Hepatitis B viral infection, serum HCV antibody, cirrhosis, and serum AFP level of cHCC-CC patients were similar to those of HCC patients (P > 0.05) but different from CC patients (P < 0.05). The cumulative 1-, 3-, and 5-year survival rates in patients with cHCC-CC were poorer than in patients with HCC or CC (P < 0.05). CONCLUSIONS: Patients with cHCC-CC are seldom diagnosed before operation. The progression of cHCC-CC is more rapid than that of HCC or CC. Survival rate of patients with cHCC-CC after hepatic resection is poorer than that of patients with HCC or CC.

Combined hepatocellular carcinoma and cholangiocarcinoma:a case report and review of the literature

BACKGROUND: combined hepatocellular carcinoma and cholangiocarcinoma (cHCC-CC) is a rare histopathologic form of primary liver cancer. We report a case of cHCC-CC and review the literature. METHOD: The clinicopathological features of a 61-year-old male were retrospectively analyzed. RESULTS: Hepatocellular carcinoma (HCC) was preoperatively considered on the basis of clinical findings resembling those associated with HCC. Hepatectomy was therefore performed. Microscopically, the specimen displayed histological features of cHCC-CC. The patient has remained alive after follow-up for 3 months without evidence of recurrence and metastasis. CONCLUSION: It is difficult to make a correct preoperative diagnosis of cHCC-CC and hepatic resection is the treatment of choice.

Comprehensive radiomics nomogram for predicting survival of patients with combined hepatocellular carcinoma and cholangiocarcinoma

BACKGROUND Combined hepatocellular carcinoma(HCC)and cholangiocarcinoma(cHCCCCA)is defined as a single nodule showing differentiation into HCC and intrahepatic cholangiocarcinoma and has a poor prognosis.AIM To develop a radiomics nomogram for predicting post-resection survival of patients with cHCC-CCA.METHODS Patients with pathologically diagnosed cHCC-CCA were randomly divided into training and validation sets.Radiomics features were extracted from portal venous phase computed tomography(CT)images using the least absolute shrinkage and selection operator Cox regression and random forest analysis.A nomogram integrating the radiomics score and clinical factors was developed using univariate analysis and multivariate Cox regression.Nomogram performance was assessed in terms of the C-index as well as calibration,decision,and survival curves.RESULTS CT and clinical data of 118 patients were included in the study.The radiomics score,vascular invasion,anatomical resection,total bilirubin level,and satellite lesions were found to be independent predictors of overall survival(OS)and were therefore included in an integrative nomogram.The nomogram was more strongly associated with OS(hazard ratio:8.155,95%confidence interval:4.498-14.785,P<0.001)than a model based on the radiomics score or only clinical factors.The area under the curve values for 1-year and 3-year OS in the training set were 0.878 and 0.875,respectively.Patients stratified as being at high risk of poor prognosis showed a significantly shorter median OS than those stratified as being at low risk(6.1 vs 81.6 mo,P<0.001).CONCLUSION This nomogram may predict survival of cHCC-CCA patients after hepatectomy and therefore help identify those more likely to benefit from surgery.

Contrast-enhanced ultrasound manifestations of synchronous combined hepatocellular-cholangiocarcinoma and hepatocellular carcinoma:A case report

BACKGROUND Synchronous combined hepatocellular-cholangiocarcinoma(CHC)and hepatocellular carcinoma(HCC)is very rare,with few literature reports and poor clinical outcomes associated with the disorder.Surgical resection is the main treatment,which makes the preoperative diagnosis very important.However,due to imaging manifestations overlapping with HCC,diagnosis of this type of synchronous cancer is challenging and it tends to be misdiagnosed as multiple HCC.Herein,we report the contrast-enhanced ultrasound(CEUS)manifestations of a case of synchronous CHC and HCC,aiming at adding to the understanding of this disease.CEUS displayed exquisite vascularity and tissue perfusion in real time with good spatial and temporal resolution and more accurately reflect tumor washin and washout times than contrast-enhanced computed tomography(CT)in this case.CASE SUMMARY The patient was a 69-year-old female with a 20-year history of chronic hepatitis B.Due to months of epigastric pain and anorexia,she reffered to our hospital for treatment.Five days before hospitalization,abdominal magnetic resonance imaging performed at another hospital detected a space-occupying lesion in the liver.After her hospitalization,laboratory tests showed elevated alpha-fetoprotein and carbohydrate antigen 19-9 level.Two suspicious liver lesions located in S4 and S6,respectively,were identified in a cirrhotic background by abdominal contrast-enhanced CT(CECT).Furthermore,the lesion in S4 and S6 were detected by CEUS and assigned to CEUS LI-RADS 5 and M categories,respectively.The patient underwent tumor radical resections.Post-operative pathology confirmed the S4 and S6 lesions to be HCC and CHC,respectively.A newly-found suspicious liver nodule with potential malignancy was detected in liver S1 by both CEUS and CECT 7 mo after operation.CONCLUSION The CEUS characteristics of CHC and HCC are different.CEUS features in combination with clinical information could help in effective diagnosis,clinical decision-making and better prognosis.

Factors associated with 5-year survival of combined hepatocellular and cholangiocarcinoma

BACKGROUND Combined hepatocellular and cholangiocarcinoma(HCC/CC)is a rare primary hepatic malignancy which carries a poor prognosis due to its aggressive nature.Few centers have enough cases to draw definitive conclusions and there is limited understanding of prognosis.Given the rarity of HCC/CC,an analysis of large national cancer database was needed to obtain larger number of HCC/CC cases.AIM To identify associated factors for 5-year survival of HCC/CC.METHODS We conducted a retrospective study of The Surveillance,Epidemiology,and End Results(SEER)database obtained from SEER*Stat 8.3.6 software.Previously defined histology code 8180 for the International Classification of Disease for Oncology,3rd edition was used to identify HCC/CC cases from 2004 to 2015.We collected demographics,American Joint Committee on Cancer(AJCC)stage,treatment,tumor size,and survival data.These data were converted to categorical variables.The Shapiro-Wilk normality test was used to assess normal distribution.Mann-Whitney U test was used to compare continuous variables without normal distribution,and t-test was used to compare continuous variables with a normal distribution.The Kaplan-Meier survival curve analyzed 5-year survival.Univariate and multivariate logistic regression model was used to analyze factors associated with 5-year survival.Multivariate Cox proportional hazard regression was done on 5-year survival.We defined P<0.05 was statistically significant.RESULTS We identified 497 patients with the following characteristics:Mean age 62.4 years(SD:11.3),149(30.0%)were female,racial distribution was:276(55.5%)white,53(10.7%)black,84(16.9%)Asian and Pacific Islander(API),77(15.5%)Hispanic,and 7(1.4%)others or unknown.Stage I/II disease occurred in 41.5%and tumor size<50 mm was seen in 35.6%of patients.Twenty-four(4.8%)received locoregional therapy(LRT),119(23.9%)underwent resection,and 50(10.1%)underwent liver transplantation.The overall median survival was 6 mo[Interquartile range(IQR):1-22].After multivariate logistic regression,tumor size<50 mm[Odds ratios(OR):2.415,P=0.05],resection(OR:12.849,P<0.01),and transplant(OR:27.129,P<0.01)showed significance for 5-year survival.Age>60,sex,race,AJCC stages,metastasis,and LRT were not significant.However,API vs white showed significant OR of 2.793(CI:1.120-6.967).Cox proportional hazard regression showed AJCC stages,tumor size<50 mm,LRT,resection,and transplant showed significant hazard ratio.CONCLUSION HCC/CC patients with tumor size<50 mm,resection,and transplant were associated with an increase in 5-year survival.API showed advantageous OR and hazard ratios over white,black.

Role of serum total sialic acid in differentiating cholangiocarcinoma from hepatocellular carcinoma

AIM:This study was designed to evaluate the clinical application of serum total sialic acid (TSA) in the diagnosis of cholangiocarcinoma (CCA).METHODS: Serum TSA was determined by periodateresorcinol microassay in 69 patients with CCA, 59 patients with hepatocellular carcinoma (HCC), 37 patients with cirrhosis, 61 patients with chronic hepatitis and 50 healthy blood donors.RESULTS: The mean serum TSA concentration in CCA (2.41±0.70 mmol/L) was significantly higher than those of HCC, cirrhosis, chronic hepatitis and healthy blood donors (1.41±0.37 mmol/L, 1.13±0.31 mmol/L, 1.16±0.26 mmol/L, and 1.10±0.14 mmol/L, respectively; P＜0.001). Based on ROC curve analysis, a cut-off point of 1.75 mmol/L discriminated between CCA and HCC with a sensitivity,specificity and accuracy of 82.6%, 83.1%, and 82.8%,respectively.CONCLUSION: Based on our results, serum TSA would be a useful marker for the differential diagnosis of CCA from HCC.

Decreased expression of type Ⅱ tumor suppressor gene RARRES3 in tissues of hepatocellular carcinoma and cholangiocarcinoma

AIM: To analyze the expression of retinoic acid receptor responder 3 (RARRES3) protein in paraffin-embedded tissues of hepatocellular carcinoma (HCC) and cholangiocarcinoma(CC), and the correlation of RARRES3 production with tumor differentiation.METHODS: Expression of RARRES3 in tissues from 21CC (10 well-, 7 moderately- and 4 poorly-differentiated)and 32 HCC was determined by immunohistochemistry.RESULTS: Among 21 CC tissues, RARRES3 was detected in 8 (80%) of 10 well-differentiated tumors. Only 2 (18.2%)out of 11 tumors with moderate or poor differentiation showed positive RARRES3 expression. RARRES3 expression in well-differentiated CC was significantly higher than that in tumors with moderate or poor differentiation (Fisher exact test, P＜0.01). Expression of RARRES3 was not different between early (Ⅰ and Ⅱ) and late (Ⅲ and Ⅳ) stages of CC.Among 30 HCC tissues, 17 (56.7%) weakly expressed RARRES3 in HCC cells, and 25 (83.3%) normal tissues adjacent to HCC expressed the protein. RARRES3 expression was significantly decreased in HCC tissues compared to that in adjacent normal tissues (logistic regression analysis, OR = 0.27, 95% CI (0.11-0.62), P＜0.01).CONCLUSION: Expression of RARRES3 is positively correlated to well-differentiated CC, which supports the role of RARRES3 in malignant epithelial differentiation of the tumor. The decrease in RARRES3 expression in tissues of HCC and CC with moderate and poor differentiation suggests that altered RARRES3 expression may play a role in the carcinogenesis of the liver and biliary tract.

Histopathological characteristics of needle core biopsy and surgical specimens from patients with solitary hepatocellular carcinoma or intrahepatic cholangiocarcinoma

BACKGROUND Pathological manifestations of hepatic tumours are often associated with prognosis. Although surgical specimens(SS) can provide more information,currently, pre-treatment needle core biopsy(NCB) is increasingly showing important value in understanding the nature of liver tumors and even in diagnosis and treatment decisions. However, the concordance of the clinicopathological characteristics and immunohistochemical(IHC) staining between NCB and SS from patients with hepatic tumours were less concerned.AIM To introduce a more accurate method for interpreting the IHC staining results in order to improve the diagnostic value of hepatic malignancy in NCB samples.METHOD A total of 208 patients who underwent both preoperative NCB and surgical resection for hepatocellular carcinoma(HCC) or intrahepatic cholangiocarcinomaRESULTS Morphologically, the presence of compact tumour nests or a cord-like structure in NCB was considered the primary cause of misdiagnosis of HCC from ICC. The kappa statistic showed a moderate agreement in histomorphology(k = 0.504) and histological grade(k = 0.488) between NCB and SS of the tumours. A 4-tier(+++,++, +, and-) scoring scheme that emphasized the focal neoplastic cell immunoreactivity of tumour cells revealed perfect concordance of CK19, GPC3 and HepPar1 between NCB and SS(k = 0.717; k = 0.768; k = 0.633). Furthermore,with the aid of a binary classification derived from the 4-tier score, a high concordance was achieved in interpreting the IHC staining of the three markers between NCB and final SS(k = 0.931; k = 0.907; k = 0.803), increasing the accuracy of NCB diagnosis C(k = 0.987; area under the curve = 0.997, 95%CI: 0.990-1.000; P< 0.001).CONCLUSION These findings imply that reasonable interpretation of IHC results in NCB is vital for improving the accuracy of tumour diagnosis. The simplified binary classification provides an easy and applicable approach.

Recent advances of miRNA involvement in hepatocellular carcinoma and cholangiocarcinoma

MicroRNAs (miRNAs), which are a class of highly evolutionarily conserved non-coding RNAs, modulate gene expression and are regulated by specific genes. Several studies have shown that the expression of miRNAs is deregulated in Hepatitis C virus (HCV) & Hepatitis B virus (HBV) infection, liver cancer progression, tumor invasion and metastasis. There are a number of high-quality review articles relative to the general role of miRNA alterations in carcinogenesis and specific reviews dealing with the miRNA changes in hepatocellular carcinoma (HCC) and cholangio-carcinoma (CCA). Since primary liver cancer is predominantly comprised of HCC and intrahepatic cholangiocarcinoma (ICC), in the present review we specifically focus on recent advances of miRNAs related to tumorigenesis, invasion and metastasis of primary liver cancer, with special emphasis on their relationships to their target genes. HCV & HBV are major causes of liver disease, including acute and chronic hepatitis, liver cirrhosis, and HCC, while HCV infection is a risk factor for ICC. We also discuss the mi-RNA alterations involved in HCV & HBV infection. We briefly describe advances in molecular signaling of miRNAs in liver cancers and present insights into new therapeutic clues that target liver cancer.

CLINICOPATHOLOGIC FEATURES AND DIAGNOSISOF COMBINED HEPATOCELLULAR ANDCHOLANGIOCARCINOMA

Hepatoma cases(N=130) were analyzed through histochemical and immunohistochemical staining. There were 99 cases of hepatocellular carcinoma(HCC), 15 cholangiocarcinoma(CC), and 16 combined HCC and CC (HCC+CC). The clinical features and the cases accompanied with hepatitis and/or liver cirrhosis in the non-tumor liver tissue of HCC+CC Group were between HCC GrouP and CC Group. Histologically, there were 4 cases with trabecular, 4 with pseudoglandula, 3 with solid type in HCCWC Group. In these 11 cases, the CC area was less than 10% of the neoplasm- The cases were classified as HCCWC type I. There was no obvious stroma fibrosis. The rest 5 cases of HCC+CC showed tubular carcinoma. The CC area took up over 10% of the tumor. These cases were designed as HCC+CC type II. There was significant fibrosis in the stroma so that its CC area is indistinguishable from that of CC cases. The CC area of all HCC+CC cases was positive to mucin and EMA staining, the same to that of CC cases. Near 70% of the HCC+CC cases had intracytoplasmic glycogen in the HCC area. The HCC area was mucin and EMA negative, similar to that of HCC cases- We also observed transition areas between HCC and CC in both of the type I and type II HCC+CC cases. The areas were mucin negative but EMA positive. We concluded that HCC+CC bad HCC and CC area. with the characteristics of HCC of CC respectively. Histochemical mucin staining and immunohistochemical EMA staining were valuable in detection and diagnosis of the HCC+CC.

Combined Hepatocellular-Cholangiocarcinoma with Stem Cell Features—Case Report

Combined hepatocholangiocarcinoma is a rare and unique form of primary hepatic neoplasm, expressing histopathological and phenotypic aspects of hepatocellularcarcinoma and cholangiocarcinoma in the same tumor. Diagnosis may be performed by imaging, showing typical features of both components. We present a case of a 55-year-old woman presenting with abdominal pain and a hepatic mass. The patient underwent surgery and combined hepatocholangiocarcinoma with stem cells features was confirmed on pathological analysis. There are no signs of recurrence to date. Combined hepatocholangiocarcinoma requires a preoperative diagnosis, since it is a unique entity with higher rates of local and lymph node recurrence, compared to isolated forms.

超声造影各期增强特点在肝内胆管细胞癌与肝细胞癌、肝血管瘤鉴别诊断中的价值

目的 探讨超声造影(CEUS)在肝内胆管细胞癌、肝细胞癌、肝血管瘤鉴别诊断中的价值。方法 选取肝脏占位性病变患者157例,其中肝内胆管细胞癌患者41例,肝细胞癌患者50例,肝血管瘤患者66例,比较各组CEUS图像特征及定量参数差异。结果 肝内胆管细胞癌形态不规则、病灶边界模糊、动脉期非均匀增强和门静脉期低增强比例分别为65.85%、53.66%、90.24%和100.00%,明显高于肝细胞癌和肝血管瘤(P<0.05);肝内胆管细胞癌和肝细胞癌延迟期低增强比例分别为100.00%和94.00%,明显高于肝血管瘤(P<0.05);肝细胞癌病灶边界模糊、门静脉低增强比例分别为12.00%和68.00%,明显高于肝血管瘤(P<0.05);肝内肝管细胞癌始增时间和达峰时间分别为(8.89±1.95)s和(18.65±7.11)s,明显快于肝细胞癌和肝血管瘤(P<0.05);肝细胞癌始增时间和达峰时间分别为(10.82±2.21)s和(22.15±8.36)s,明显快于肝血管瘤(P<0.05);始增时间、达峰时间鉴别诊断肝内胆管细胞癌、肝血管瘤的ROC曲线下面积均高于0.800,P<0.05。结论 肝内胆管细胞癌、肝细胞癌和肝血管瘤CEUS图像特征有所差异,同时CEUS可为鉴别诊断提供定量参数。