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.

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.

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.

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.

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.

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.