Intrahepatic Cholangiocarcinoma Lesions Research Articles

Subtype prediction of intrahepatic cholangiocarcinoma using dynamic contrast-enhanced ultrasound

ObjectiveThe study aimed to investigate the predictive value of dynamic contrast-enhanced ultrasound (DCE-US) in differentiating small-duct (SD) and large-duct (LD) types of intrahepatic cholangiocarcinoma (ICC).MethodsThis study retrospectively enrolled 110 patients with pathologically confirmed ICC lesions who were subject to preoperative contrast-enhanced ultrasound (CEUS) examinations between January 2022 and February 2023. Patients were further classified according to the subtype: SD-type and LD-type, and an optimal predictive model was established and validated using the above pilot cohort. The test cohort, consisting of 48 patients prospectively enrolled from March 2023 to September 2023, was evaluated.ResultsIn the pilot cohort, compared with SD-type ICCs, more LD-type ICCs showed elevated carcinoembryonic antigen (p < 0.001), carbohydrate antigen 19-9 (p = 0.004), ill-defined margin (p = 0.018), intrahepatic bile duct dilation (p < 0.001). Among DCE-US quantitative parameters, the wash-out area under the curve (WoAUC), wash-in and wash-out area under the curve (WiWoAUC), and fall time (FT) at the margin of lesions were higher in the SD-type group (all p < 0.05). Meanwhile, the mean transit time (mTT) and wash-out rate (WoR) at the margin of the lesion were higher in the LD-type group (p = 0.041 and 0.007, respectively). Logistic regression analysis showed that intrahepatic bile duct dilation, mTT, and WoR were significant predictive factors for predicting ICC subtypes, and the AUC of the predictive model achieved 0.833 in the test cohort.ConclusionsPreoperative DCE-US has the potential to become a novel complementary method for predicting the pathological subtype of ICC.Critical relevance statementDCE-US has the potential to assess the subtypes of ICC lesions quantitatively and preoperatively, which allows for more accurate and objective differential diagnoses, and more appropriate treatments and follow-up or additional examination strategies for the two subtypes.Key PointsPreoperative determination of intrahepatic cholangiocarcinoma (ICC) subtype aids in surgical decision-making.Quantitative parameters from dynamic contrast-enhanced US (DCE-US) allow for the prediction of the ICC subtype.DCE-US-based imaging has the potential to become a novel complementary method for predicting ICC subtypes.Graphical

Patlak Reconstruction Using Dynamic 18 F-FDG PET Imaging for Evaluation of Malignant Liver Tumors : A Comparison of HCC, ICC, and Metastatic Liver Tumors.

The aim of this study was to explore the different patterns of dynamic whole-body (D-WB) FDG PET/CT parameters among liver malignancy types as potential diagnostic clues and investigate the association between static and dynamic PET/CT parameters for each tumor histology. Seventy-one patients with intrahepatic cholangiocarcinoma (ICC), metastatic liver tumor (MLT), or hepatocellular carcinoma (HCC) who underwent D-WB and static dual-time-point FDG PET/CT were enrolled. We obtained Pearson correlation coefficients between the metabolic rate of FDG (MR FDG ; mg/min/ 100ml) or distribution volume of free FDG (DV FDG , %) and static PET/CT parameters. We compared MR FDG and DV FDG values by tumor type and performed receiver operating characteristic analyses for MR FDG and static images. A total of 12 ICC, 116 MLT, and 36 HCC lesions were analyzed. MR FDG and DV FDG showed excellent correlation with early (SUV e ) and delayed SUV max (SUV d ) ( r = 0.71~0.97), but DV FDG in the HCC lesions did not ( r = 0.62 and 0.69 for SUV e and SUV d , respectively) ( P < 0.001 for all). HCC lesions showed significantly lower MR FDG (2.43 ± 1.98) and DV FDG (139.95 ± 62.58) than ICC (5.02 ± 3.56, 207.06 ± 97.13) and MLT lesions (4.51 ± 2.47, 180.13 ± 75.58) ( P < 0.01 for all). The optimal MR FDG could differentiate HCC from ICC and MLT with areas under the curve of 0.84 and 0.80, respectively. Metastatic liver tumor lesions showed the widest distribution of MR FDG and DV FDG values but with no significant difference among most primary sites. MR FDG was strongly correlated with SUV max in the 3 malignancies and showed utility for differentiating HCC from ICC and MLT. Each tumor type has a different glucose metabolism, and D-WB FDG PET/CT imaging has the potential to visualize those differences.

Diagnostic performance of magnetic resonance imaging and contrast-enhanced ultrasound in differentiating intrahepatic cholangiocarcinoma from hepatocellular carcinoma: a meta-analysis.

To compare the diagnostic ability between magnetic resonance imaging (MRI) and contrast-enhanced ultrasound (CEUS) in distinguishing intrahepatic cholangiocarcinoma (ICC) from hepatocellular carcinoma (HCC). Original studies reporting the diagnostic accuracy of MRI and CEUS in differentiating ICC from HCC were identified in PubMed and EMBASE databases. Histopathological examination was used as the reference standard for tumor diagnosis. Study quality was assessed using QUADAS-2 scale. Data were extracted to calculate the pooled diagnostic sensitivity, specificity, and diagnostic odds ratio (DOR) using a bivariate random-effects model, as well as the area under the curve (AUC). Sensitivity analysis, subgroup analysis, meta-regression, and investigation of publication bias were also performed. A total of 26 studies with 28 data subsets (18 on MRI, 10 on CEUS) were included, consisting of 4169 patients with 1422 ICC lesions and 2747 HCC lesions. Most MRI studies were performed at 3T with hepatobiliary agents, and most CEUS studies used SonoVue as the contrast agent. In MRI, the pooled sensitivity, specificity, DOR, and AUC in distinguishing ICC from HCC were 0.81 (0.79, 0.84), 0.90 (0.88, 0.91), 41.47 (24.07, 71.44), and 0.93 (0.90, 0.96), respectively. The pooled sensitivity, specificity, DOR, and AUC of CEUS were 0.88 (0.84, 0.90), 0.80 (0.78, 0.83), 42.06 (12.38, 133.23), and 0.93 (0.87, 0.99), respectively. Subgroup analysis and meta-regression analysis demonstrated significant heterogeneity among the studies associated with the type of contrast agent in MRI studies. No publication bias was found. Both MRI and CEUS showed excellent diagnostic performance in differentiating ICC from HCC. CEUS showed higher pooled sensitivity and MRI showed higher pooled specificity.

Radiomics nomogram based on optimal VOI of multi-sequence MRI for predicting microvascular invasion in intrahepatic cholangiocarcinoma.

Microvascular invasion (MVI) is a significant adverse prognostic indicator of intrahepatic cholangiocarcinoma (ICC) and affects the selection of individualized treatment regimens. This study sought to establish a radiomics nomogram based on the optimal VOI of multi-sequence MRI for predicting MVI in ICC tumors. 160 single ICC lesions with MRI scanning confirmed by postoperative pathology were randomly separated into training and validation cohorts (TC and VC). Multivariate analysis identified independent clinical and imaging MVI predictors. Radiomics features were obtained from images of 6 MRI sequences at 4 different VOIs. The least absolute shrinkage and selection operator algorithm was performed to enable the derivation of robust and effective radiomics features. Then, the best three sequences and the optimal VOI were obtained through comparison. The MVI prediction nomogram combined the independent predictors and optimal radiomics features, and its performance was evaluated via the receiver operating characteristics, calibration, and decision curves. Tumor size and intrahepatic ductal dilatation are independent MVI predictors. Radiomics features extracted from the best three sequences (T1WI-D, T1WI, DWI) with VOI10mm (including tumor and 10mm peritumoral region) showed the best predictive performance, with AUCTC = 0.987 and AUCVC = 0.859. The MVI prediction nomogram obtained excellent prediction efficacy in both TC (AUC = 0.995, 95%CI 0.987-1.000) and VC (AUC = 0.867, 95%CI 0.798-0.921) and its clinical significance was further confirmed by the decision curves. A nomogram combining tumor size, intrahepatic ductal dilatation, and the radiomics model of MRI multi-sequence fusion at VOI10mm may be a predictor of preoperative MVI status in ICC patients.

Applications of Dynamic Contrast-Enhanced Ultrasound in Differential Diagnosis of Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma in Non-cirrhotic Liver.

The aim of the work described here was to investigate the value of dynamic contrast enhanced ultrasound (DCE-US) and quantitative analysis in pre-operative differential diagnosis of intrahepatic cholangiocarcinoma (ICC) and hepatocellular carcinoma (HCC) in non-cirrhotic liver. In this retrospective study, patients with histopathologically proven ICC and HCC lesions in non-cirrhotic liver were included. All patients underwent contrast-enhanced ultrasound (CEUS) examinations with an Acuson Sequoia unit (Siemens Healthineers, Mountain View, CA, USA) unit or LOGIQ E20 (GE Healthcare, Milwaukee, WI, USA) within 1 wk before surgery. SonoVue (Bracco, Milan, Italy) was used as the contrast agent. B-mode ultrasound (BMUS) features and CEUS enhancement patterns were analyzed. DCE-US analysis was performed by VueBox software (Bracco). Two regions of interest (ROIs) were set in the center of the focal liver lesions and their surrounding liver parenchyma. Time-intensity curves (TICs) were generated, and quantitative perfusion parameters were obtained and compared between the ICC and HCC groups using the Student t-test or Mann-Whitney U-test. From November 2020 to February 2022, patients with histopathologically confirmed ICC (n=30) and HCC (n=24) lesions in non-cirrhotic liver were included. During the arterial phase (AP) of CEUS, ICC lesions exhibited heterogeneous hyperenhancement (13/30, 43.3%), heterogeneous hypo-enhancement (2/30, 6.7 %) and rim-like hyperenhancement (15/30, 50.0%), whereas all HCC lesions exhibited heterogeneous hyperenhancement (24/24, 100.0%) (p < 0.05). Subsequently, most of the ICC lesions exhibited AP wash-out (83.3%, 25/30), whereas a few cases exhibited wash-out in the portal venous phase (PVP) (15.7%, 5/30). In contrast, HCC lesions exhibited AP wash-out (41.7%, 10/24), PVP wash-out (41.7%, 10/24) and a small part of late phase wash-out (16.7%, 4/24) (p < 0.05). Compared with those of HCC lesions, TICs of ICCs revealed earlier and lower enhancement during the AP, faster decline during the PVP and reduced area under the curve. The combined area under the receiver operating characteristic curve (AUROC) of all significant parameters was 0.946, with 86.7% sensitivity, 95.8% specificity and 90.7% accuracy in differential diagnosis between ICC and HCC lesions in non-cirrhotic liver, which improved the diagnostic efficacy of CEUS (58.3% sensitivity, 90.0% specificity and 75.9% accuracy). ICC and HCC lesions in non-cirrhotic liver might exhibit some overlap of CEUS features in diagnosis. DCE-US with quantitative analysis would be helpful in pre-operative differential diagnosis.

Dynamic 18F-FDG PET imaging of liver lesions: evaluation of a two-tissue compartment model with dual blood input function

BackgroundDynamic PET with kinetic modeling was reported to be potentially helpful in the assessment of hepatic malignancy. In this study, a kinetic modeling analysis was performed on hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) from dynamic FDG positron emission tomography/computer tomography (PET/CT) scans.MethodsA reversible two-tissue compartment model with dual blood input function, which takes into consideration the blood supply from both hepatic artery and portal vein, was used for accurate kinetic modeling of liver dynamic 18F-FDG PET imaging. The blood input functions were directly measured as the mean values over the VOIs on descending aorta and portal vein respectively. And the contribution of hepatic artery to the blood input function was optimization-derived in the process of model fitting. The kinetic model was evaluated using dynamic PET data acquired on 24 patients with identified hepatobiliary malignancy. 38 HCC or ICC identified lesions and 24 healthy liver regions were analyzed.ResultsResults showed significant differences in kinetic parameters {K}_{1}-{k}_{4}, blood supplying fraction {f}_{A}, and metabolic rate constant {K}_{i} between malignant lesions and healthy liver tissue. And significant differences were also observed in {K}_{1}, {k}_{3}, {f}_{A} and {K}_{i} between HCC and ICC lesions. Further investigations of the effect of SUV measurements on the derived kinetic parameters were conducted. And results showed comparable effectiveness of the kinetic modeling using either SUVmean or SUVmax measurements.ConclusionsDynamic 18F-FDG PET imaging with optimization-derived hepatic artery blood supply fraction dual-blood input function kinetic modeling can effectively distinguish malignant lesions from healthy liver tissue, as well as HCC and ICC lesions.

Assessment of the Outcomes of Intrahepatic Cholangiocarcinoma After Ultrasound-Guided Percutaneous Microwave Ablation Based on Albumin-Bilirubin Grade.

To determine whether albumin-bilirubin (ALBI) grade could be used to predict the outcomes of patients with intrahepatic cholangiocarcinoma (ICC) who underwent ultrasound-guided percutaneous microwave ablation (MWA). This retrospective study was approved by the institutional review board, and the requirement for informed consent was waived. We studied 52 treatment-naïve patients with 74 ICC lesions according to the Milan criteria who subsequently underwent MWA from April 2011 to March 2018. Overall survival (OS) and recurrence-free survival (RFS) were compared in groups classified by Child-Pugh score and ALBI grade, which were statistically analyzed with the log-rank test. Cox proportional hazard regression analyses were used to determine the prognostic factors for survival in patients with ICC. The median follow-up time was 21.2months (3.2-78.7months). Seventeen patients died during this period. After MWA, the cumulative 1-, 3-, and 5-year OS rates were 87.4%, 51.4%, and 35.2%, respectively, and the cumulative 1-, 3-, and 5-year RFS rates were 68.9%, 56.9%, and 56.9%, respectively. The major complication rate was 3.8% (2/52). Stratified according to ALBI grade, the cumulative 1-, 3-, and 5-year OS rates were 95.5%, 72.4%, and 72.4% for patients with ALBI grade 1 and 62.5%, 40.6%, and 36.3% for patients with ALBI grade 2, respectively, showing a significant difference (P = 0.006). Multivariate analysis results showed that older age (hazard ratio [HR]: 1.67, 95% confidence interval [CI]: 1.11-2.82; P = 0.002), tumor size ≥ 3cm in diameter (HR: 11.33, CI: 2.24-34.52; P = 0.021) and ALBI grade (HR: 8.23, CI: 1.58-58.00; P = 0.004) may be predictors of poor OS. ALBI grade was validated as a significant biomarker for predicting survival in ICC patients within the Milan criteria who underwent MWA.

Differential diagnosis between hepatic alveolar echinococcosis and intrahepatic cholangiocarcinoma with conventional ultrasound and contrast-enhanced ultrasound

BackgroundMisclassifications of hepatic alveolar echinococcosis (HAE) as intrahepatic cholangiocarcinoma (ICC) may lead to inappropriate treatment strategies. The aim of this study was to explore the differential diagnosis with conventional ultrasound and contrast-enhanced ultrasound (CEUS).MethodsSixty HAE lesions with 60 propensity score-matched ICC lesions were retrospectively collected. The 120 lesions were randomly divided into a training set (n = 80) and a testing set (n = 40). In the training set, the most useful independent conventional ultrasound and CEUS features was selected for differentiating between HAE and ICC. Then, a simplified US scoring system for diagnosing HAE was constructed based on selected features with weighted coefficients. The constructed US score for HAE was validated in both the training set and the testing set, and diagnostic performance was evaluated.ResultsCompared with ICC lesions, HAE lesions were mostly located in the right lobe and had mixed echogenicity, a pseudocystic appearance and foci calcifications on conventional ultrasound. On CEUS, HAE lesions showed more regular rim-like enhancement than ICC lesions and had late washout with a long enhancement duration. The simplified US score consisted of echogenicity, pseudocystic/calcification, bile duct dilatation, enhancement pattern, enhancement duration, and marked washout. In the testing set, the sensitivity, specificity, LR+, LR- and the area under the ROC curve for the score to differentiate HAE from ICC were 80.0, 81.3%, 4.27, 0.25 and 0.905, respectively.ConclusionsThe US score based on typical features from both conventional ultrasound and CEUS could accurately differentiate HAE from ICC.

A retrospective pilot study to examine the feasibility of real-time navigation for laparoscopic liver resections in intrahepatic cholangiocarcinoma using fusion indocyanine green fluorescence imaging.

Recently, PINPOINT, a novel laparoscopic fusion indocyanine green fluorescence imaging (IGFI) system has become available for laparoscopic liver resection. This study aims to characterize fluorescence patterns of intrahepatic cholangiocarcinoma (ICC) using the negative counterstaining method in laparoscopic anatomical hepatectomies of ICC. Eleven consecutive patients, diagnosed with intrahepatic cholangiocarcinoma and underwent laparoscopic liver resection between April 2017 and December 2018, were retrospectively reviewed. A laparoscopic IGFI navigation system was used to characterize fluorescence patterns of ICC with intraoperative liver segment demarcation by means of negative counterstaining. Fusion IGFI of ICC was successfully obtained from all 11 patients from the surgical specimens. The fluorescence patterns of ICC can be categorized into rim-type fluorescence and segmental fluorescence, depending on tumor growth. In eight patients, indocyanine green fluorescence imaging was used to identify the hepatic lobes or segments by negative counterstaining. In six cases, a valid and persistent demarcation was achieved intraoperatively. Laparoscopic IGFI system could identify different types of ICC lesions and may facilitate real-time navigation for laparoscopic anatomic liver resection of ICC.

Contrast-enhanced Ultrasound Features of Intrahepatic Cholangiocarcinoma: A New Perspective

The objective of this study was to illustrate our specific findings for intrahepatic cholangiocarcinoma (ICC) lesions on contrast-enhanced ultrasound (CEUS). In this study, 21 patients at our hospitals with pathologically proven ICC and CEUS data were retrospectively enrolled. General clinical data of the patients, and features of lesions on conventional and contrast-enhanced ultrasound were recorded. Two experienced radiologists retrospectively reviewed all images by consensus. On gray-scale sonography, hypoechoic, isoechoic and hyperechoic lesions accounted for 85.7%, 9.5% and 4.8%, respectively, of all lesions. Hypovascular patterns were found for 95.2% of the lesions on color Doppler flow imaging. During the arterial phase of CEUS, heterogeneous hyperenhancement, homogeneous hyperenhancement, rim-like hyperenhancement, isoenhancement and hypoenhancement were observed for 61.9%, 19.0%, 9.5%, 4.8%, 4.8% of the lesions, respectively. During the portal venous and late phases, 85.7% and 95.2% of the lesions, respectively, exhibited hypoenhancement. In addition, 66.7% of the ICC lesions exhibited washed-out interiors but little decrease in enhancement at the periphery during the portal venous phase, resulting in the formation of a hyperenhanced peripheral rim. In conclusion, the rim sign in the portal venous phase of CEUS could help diagnose ICC. This trait could be related to the infiltrating growth pattern of ICC.

Nonanatomic resection is not inferior to anatomic resection for primary intrahepatic cholangiocarcinoma: A propensity score analysis

Whether anatomic resection (AR) achieves better outcomes than nonanatomic resection (NAR) in patients with primary intrahepatic cholangiocarcinoma (ICC) is unclear. Data were retrieved for all consecutive patients who underwent liver resection for primary ICC from January 2007 to July 2017. The prognoses of the patients without direct invasion to contiguous organs or extrahepatic metastasis who underwent AR or NAR were compared. 85 patients underwent AR, and 65 patients underwent NAR. operation time were slightly decreased in the NAR group. The risk of Clavien-Dindo classification (CDC) IV in the AR group was significant higher than that in the NAR group. Cox regression analysis showed lymph node metastasis and adjuvant therapy were significant prognostic factors for overall survival (OS) and disease-free survival (DFS), respectively. After 1:1 propensity score matching (PSM), 29 pairs of patients were compared. The survival curves showed the NAR group had slightly improved DFS and OS than the AR group before and after matching. Thus, we conclude NAR was not inferior to AR in improving the survival outcomes for patients with primary solitary ICC lesions without direct invasion to contiguous organs or extrahepatic metastasis. Furthermore, patients may benefit from NAR.

Kupffer Cell-Derived Tnf Triggers Cholangiocellular Tumorigenesis through JNK due to Chronic Mitochondrial Dysfunction and ROS

Intrahepatic cholangiocarcinoma (ICC) is a highly malignant, heterogeneous cancer with poor treatment options. We found that mitochondrial dysfunction and oxidative stress trigger a niche favoring cholangiocellular overgrowth and tumorigenesis. Liver damage, reactive oxygen species (ROS) and paracrine tumor necrosis factor (Tnf) from Kupffer cells caused JNK-mediated cholangiocellular proliferation and oncogenic transformation. Anti-oxidant treatment, Kupffer cell depletion, Tnfr1 deletion, or JNK inhibition reduced cholangiocellular pre-neoplastic lesions. Liver-specific JNK1/2 deletion led to tumor reduction and enhanced survival in Akt/Notch- or p53/Kras-induced ICC models. In human ICC, high Tnf expression near ICC lesions, cholangiocellular JNK-phosphorylation, and ROS accumulation in surrounding hepatocytes are present. Thus, Kupffer cell-derived Tnf favors cholangiocellular proliferation/differentiation and carcinogenesis. Targeting the ROS/Tnf/JNK axis may provide opportunities for ICC therapy.

Effect of contrast-enhanced ultrasound on differential diagnosis of intrahepatic cholangiocarcinoma and arterial phase enhanced hepatic inflammatory lesions.

ObjectiveTo investigate differential diagnosis between intrahepatic cholangiocarcinoma (ICC) and arterial phase enhanced hepatic inflammatory lesions in patients without liver cirrhosis using contrast-enhanced ultrasound (CEUS).MethodsICC and hepatic inflammatory lesions cases with CEUS and pathological diagnosis between Sep 2013 and Oct 2016 were investigated retrospectively. Imaging features of conventional ultrasound and CEUS were analyzed. The parameters of time intensity curve (TIC), including the arrival time, peak intensity (PI) in the lesions, the starting time for washout, and the intensity difference at 3 min (ΔI3) after contrast agent infection between the lesion and the liver parenchyma, were compared between ICC and hepatic inflammatory lesions. ResultsTwenty-five ICC and fifteen inflammatory patients were included in this study. Seventeen ICC (68.0%) and two inflammatory cases (13.3%) showed bile duct dilatation on conventional ultrasound. Using CEUS, three ICC cases (12.0%) were misdiagnosed as inflammatory lesions and three inflammatory lesions (20.0%) as ICC; two ICC (8.0%) and one inflammatory case (6.7%) could not be made definite diagnosis. Washout started at 34.5±3.5 s and 61.5±12.9 s for ICC and inflammatory lesions respectively (P<0.001). The intensity difference between lesion and liver parenchyma at 3 min after contrast agent injection was 10.8±3.1 dB in ICC and 4.2±2.3 dB in inflammatory group (P<0.001). The sensitivity and specificity differentiating ICC and inflammatory lesions were 76% and 87% if the cut-off value of the intensity difference was 7.7 dB.ConclusionsCombined with TIC analysis, and particularly with the characteristic of the early-starting and obvious washout in ICC, CEUS can be useful in differential diagnosis between hepatic inflammatory lesions and ICC.

Abstract 652: Establishment of a novel mouse model of intrahepatic cholangiocarcinoma by liver-specific Kras activation and Pten deletion

Abstract The mitogen-activated protein kinase (MAPK) pathway and the phosphoinositide 3-kinase (PI3K) pathway are intracellular signaling pathways that are involved in carcinogenesis. Various studies suggest that these pathways are important for the development of liver tumors. To investigate the effect of coactivation of MAPK and PI3K pathways in liver tumorigenesis, we generated three types of mouse models by crossbreeding conditional KrasG12D knockin mice and/or conditional Pten knockout mice with Alb-Cre mice (Alb-Cre KrasG12D/+ Pten flox/flox mice, Alb-Cre KrasG12D/+ Pten flox/+ mice, and Alb-Cre KrasG12D/+ mice). Among the three models, mice carrying liver-specific oncogenic Kras knockin and homozygous Pten deletion (Alb-Cre KrasG12D/+ Pten flox/flox) frequently demonstrated weight loss, abdominal distension, and jaundice with median survival of eight weeks. Macroscopic analysis detected diffuse and firm tumorous lesions mainly in the hepatic hilum. Histological examination of the Alb-Cre KrasG12D/+ Pten flox/flox mice disclosed bile duct hyperplasia at four weeks of age, precancerous lesions of intrahepatic cholangiocarcinoma (ICC) at five weeks of age, and advanced ICC lesions that resemble human ICC at seven weeks of age. On the other hand, the Alb-Cre KrasG12D/+ Pten flox/+ mice, the second model, developed ICCs as well as hepatocellular carcinomas (HCCs), and their average survival was eight months. The third mice model, the Alb-Cre KrasG12D/+ mice, developed HCCs but not ICCs, and survived more than one year. Immunohistochemical analysis of the ICCs in the Alb-Cre KrasG12D/+ Pten flox/flox mice corroborated the activation of the Mapk and the Pi3k pathways in the tumor cells. These data suggest that activity of Pi3k pathway might dictate the fate determination of hepatotumorigenesis into biliary or hepatocyte cell lineage. In addition, oncogenic Kras expression and homozygous Pten deletion cooperate to induce exclusively ICCs. Since a limited number of mouse ICC models have been reported, the Alb-Cre KrasG12D/+ Pten flox/flox mouse model should be a useful tool for the analysis of molecular mechanism(s) underlying ICC. Citation Format: Yumi Terakado, Tsuneo Ikenoue, Kiyoshi Yamaguchi, Yoichi Furukawa. Establishment of a novel mouse model of intrahepatic cholangiocarcinoma by liver-specific Kras activation and Pten deletion. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 652.

Differential requirement for de novo lipogenesis in cholangiocarcinoma and hepatocellular carcinoma of mice and humans.

Hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) are the most prevalent types of primary liver cancer. These malignancies have limited treatment options, resulting in poor patient outcomes. Metabolism reprogramming, including increased de novo lipogenesis, is one of the hallmarks of cancer. Fatty acid synthase (FASN) catalyzes the de novo synthesis of long-chain fatty acids from acetyl-coenzyme A and malonyl-coenzyme A. Increased FASN expression has been reported in multiple tumor types, and inhibition of FASN expression has been shown to have tumor-suppressing activity. Intriguingly, we found that while FASN is up-regulated in human HCC samples, its expression is frequently low in human ICC specimens. Similar results were observed in mouse ICC models induced by different oncogenes. Ablating FASN in the mouse liver did not affect activated AKT and Notch (AKT/Notch intracellular domain 1) induced ICC formation in vivo. Furthermore, while both HCC and ICC lesions develop in mice following hydrodynamic injection of AKT and neuroblastoma Ras viral oncogene homolog oncogenes (AKT/Ras), deletion of FASN in AKT/Ras mice triggered the development almost exclusively of ICCs. In the absence of FASN, ICC cells might receive lipids for membrane synthesis through exogenous fatty acid uptake. In accordance with the latter hypothesis, ICC cells displayed high expression of fatty acid uptake-related proteins and robust long-chain fatty acid uptake. Our data demonstrate that FASN dependence is not a universal feature of liver tumors: while HCC development is highly dependent of FASN and its mediated lipogenesis, ICC tumorigenesis can be insensitive to FASN deprivation; our study supports novel therapeutic approaches to treat this pernicious tumor type with the inhibition of exogenous fatty acid uptake. (Hepatology 2016;63:1900-1913).

Impact of intravenous contrast enhancement phase on target definition for hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (IHC): Observations from patients enrolled on a prospective phase 2 trial

BackgroundThe safety and efficacy of radiation therapy for hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (IHC) depend on accurate definition of gross tumor volume (GTV), but GTV often varies between phases of multiphasic computed tomography (CT) imaging. MethodsWe contoured GTVs on arterial, portal venous, and delayed phases of multiphasic CT scans for 32 patients treated on an institutional review board–approved prospective trial of proton therapy for primary liver tumors and determined which phase provided optimal GTV visualization. We assessed agreement between individual phase GTVs to determine if GTV for each phase was encompassed in a 5-mm expansion of either the smallest or the best-visualized GTV. ResultsThere were 19 HCC lesions and 14 IHC lesions. HCC lesions were best identified on the arterial phase in 42% (n = 8), portal venous phase in 32% (n = 6), and delayed phase in 26% (n = 5). IHC lesions were best identified on portal venous phase in 64% (n = 9) and the arterial phase in 29% (n = 4), with 1 case equally visualized on arterial and portal venous phases. In all 33 lesions, a 5-mm expansion around the smallest GTV failed to cover GTVs defined on other available phases. A 5-mm expansion around the best-visualized GTV provided satisfactory coverage of all available phases’ GTVs in 6/18 HCC cases and 2/9 IHC cases. ConclusionsVariability between GTVs on multiphasic CT scans could not be overcome with a 5-mm expansion of either the smallest GTV or the best-visualized GTV. Assessment of all available intravenous contrast phases is essential to accurately define the GTV.

Retraction Note to: Contrast-enhanced ultrasound appearances of enhancement patterns of intrahepatic cholangiocarcinoma: correlation with pathological findings.

The aim of this study was to investigate the correlation between enhancement patterns of intrahepatic cholangiocarcinoma (ICC) on contrast-enhanced ultrasound (CEUS) and pathological findings. The CEUS enhancement patterns of 40 pathologically proven ICC lesions were retrospectively analysed. Pathologically, the degree of tumour cell and fibrosis distribution in the lesion was semi-quantitatively evaluated. Four enhancement patterns were observed in the arterial phase for 32 mass-forming ICCs: peripheral rim-like hyperenhancement (n = 19); heterogeneous hyperenhancement (n = 6); homogeneous hyperenhancement (n = 3); and heterogeneous hypo-enhancement (n = 4). Among the four enhancement patterns, the differences in tumour cell distribution were statistically significant (p < 0.05). The hyperenhancing area on CEUS corresponded to more tumour cells for mass-forming ICCs. Heterogeneous hyperenhancement (n = 2) and heterogeneous hypo-enhancement (n = 2) were observed in the arterial phase for four periductal-infiltrating ICCs. In this subtype, fibrosis was more commonly found in the lesions. Heterogeneous hyperenhancement (n = 1) and homogeneous hyperenhancement (n = 3) were observed in the arterial phase for four intraductal-growing ICCs. This subtype tended to have abundant tumour cells. The CEUS findings of ICC relate to the degree of carcinoma cell proliferation at pathological examination. Hyperenhancing areas in the tumour always indicated increased density of cancer cells.

Contrast-Enhanced Ultrasound for the Characterization of Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma

Purpose and methods: The ability of contrast-enhanced ultrasound (CEUS) to differentiate between hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) is still controversial. We reviewed the CEUS imaging of 819 patients (HCC=546, ICC=273) with an established pathological diagnosis. The enhancement patterns of lesions and the diagnostic performance of CEUS were analyzed. Results: Arterial hyperenhancement followed by washout was observed in 92.3% (504/546) of the HCC lesions and 85.7% (234/273) of the ICC lesions on CEUS (p<0.05). Additionally, the ICCs presented contrast washout much earlier than the HCCs, with an average time of 27.5 seconds after injecting the contrast agent compared with 70.1 seconds for the HCCs (p<0.05). Peripheral rim-like enhancement was observed in 68.5% (187/273) of the ICCs, which was significantly more common than that in the HCCs (2.0%, 11/546) (p<0.05). When using arterial hyperenhancement with a washout phase later than 43 seconds after injecting the contrast agent and with no peripheral rim-like enhancement as the diagnostic criteria for HCC ≤5 cm in diameter, the area under the curve was 0.808, with 64.1% sensitivity, 97.4% specificity and 73.6% accuracy. Conclusions: Although ICC may show the typical enhancement pattern of HCC on CEUS, peripheral rim-like enhancement and quick contrast washout show high efficiency in the differentiation of HCC from ICC.

Delayed-Phase Cone-Beam CT Improves Detectability of Intrahepatic Cholangiocarcinoma During Conventional Transarterial Chemoembolization.

To evaluate the detectability of intrahepatic cholangiocarcinoma (ICC) on dual-phase cone-beam CT (DPCBCT) during conventional transarterial chemoembolization (cTACE) compared to that of digital subtraction angiography (DSA) with respect to pre-procedure contrast-enhanced magnetic resonance imaging (CE-MRI) of the liver. This retrospective study included 17 consecutive patients (10 male, mean age 64) with ICC who underwent pre-procedure CE-MRI of the liver, and DSA and DPCBCT (early-arterial phase (EAP) and delayed-arterial phase (DAP)) just before cTACE. The visibility of each ICC lesion was graded by two radiologists on a three-rank scale (complete, partial, and none) on DPCBCT and DSA images, and then compared to pre-procedure CE-MRI. Of 61 ICC lesions, only 45.9% were depicted by DSA, whereas EAP- and DAP-CBCT yielded a significantly higher detectability rate of 73.8% and 93.4%, respectively (p < 0.01). Out of the 33 lesions missed on DSA, 18 (54.5%) and 30 (90.9%) were revealed on EAP- and DAP-CBCT images, respectively. DSA depicted only one lesion that was missed by DPCBCT due to streak artifacts caused by a prosthetic mitral valve. DAP-CBCT identified significantly more lesions than EAP-CBCT (p < 0.01). Conversely, EAP-CBCT did not detect lesions missed by DAP-CBCT. For complete lesion visibility, DAP-CBCT yielded significantly higher detectability (78.7%) compared to EAP (31.1%) and DSA (21.3%) (p < 0.01). DPCBCT, and especially the DAP-CBCT, significantly improved the detectability of ICC lesions during cTACE compared to DSA. We recommend the routine use of DAP-CBCT in patients with ICC for per-procedure detectability and treatment planning in the setting of TACE.

Contrast-enhanced ultrasound appearances of enhancement patterns of intrahepatic cholangiocarcinoma: correlation with pathological findings.

The aim of this study was to investigate the correlation between enhancement patterns of intrahepatic cholangiocarcinoma (ICC) on contrast-enhanced ultrasound (CEUS) and pathological findings. The CEUS enhancement patterns of 40 pathologically proven ICC lesions were retrospectively analysed. Pathologically, the degree of tumour cell and fibrosis distribution in the lesion was semi-quantitatively evaluated. Four enhancement patterns were observed in the arterial phase for 32 mass-forming ICCs: peripheral rim-like hyperenhancement (n = 19); heterogeneous hyperenhancement (n = 6); homogeneous hyperenhancement (n = 3); and heterogeneous hypo-enhancement (n = 4). Among the four enhancement patterns, the differences in tumour cell distribution were statistically significant (p < 0.05). The hyperenhancing area on CEUS corresponded to more tumour cells for mass-forming ICCs. Heterogeneous hyperenhancement (n = 2) and heterogeneous hypo-enhancement (n = 2) were observed in the arterial phase for four periductal-infiltrating ICCs. In this subtype, fibrosis was more commonly found in the lesions. Heterogeneous hyperenhancement (n = 1) and homogeneous hyperenhancement (n = 3) were observed in the arterial phase for four intraductal-growing ICCs. This subtype tended to have abundant tumour cells. The CEUS findings of ICC relate to the degree of carcinoma cell proliferation at pathological examination. Hyperenhancing areas in the tumour always indicated increased density of cancer cells.