Hypervascular Hepatocellular Carcinoma Research Articles

Liver Lesions at Risk of Transformation into Hepatocellular Carcinoma in Cirrhotic Patients: Hepatobiliary Phase Hypointense Nodules without Arterial Phase Hyperenhancement.

Recent technical advances in liver imaging and surveillance for patients at high risk for developing hepatocellular carcinoma (HCC) have led to an increase in the detection of borderline hepatic nodules in the gray area of multistep carcinogenesis, particularly in those that are hypointense at the hepatobiliary phase (HBP) and do not show arterial phase hyperenhancement. Given their potential to transform and advance into hypervascular HCC, these nodules have progressively attracted the interest of the scientific community. To date, however, no shared guidelines have been established for the decision management of these borderline hepatic nodules. It is therefore extremely important to identify features that indicate the malignant potential of these nodules and the likelihood of vascularization. In fact, a more complete knowledge of their history and evolution would allow outlining shared guidelines for their clinical-surgical management, to implement early treatment programs and decide between a preventive curative treatment or a watchful follow-up. This review aims to summarize the current knowledge on hepatic borderline nodules, particularly focusing on those imaging features which are hypothetically correlated with their malignant evolution, and to discuss current guidelines and ongoing management in clinical practice.

Objective Tumor Response of Hepatocellular Carcinoma Obtained by Transarterial Radioembolization with Iodine-131-Lipiodol Versus Transarterial Chemoembolization for Patients with and without Portal Venous Thrombosis: A Controlled Interventional Trial

Hepatocellular carcinoma (HCC) treatment often requires transarterial chemoembolization (TACE). However, TACE efficacy is controversial in the presence of portal vein thrombosis (PVT). Although transarterial radioembolization (TARE) benefit was previously documented in PVT, neither the objective tumor response (OTR) after TARE with Iodine-131-lipiodol (131I-lipiodol) nor the PVT effect on the results of locoregional therapies was accurately measured in prospective clinical trials. The aim of this study was to compare OTR and survival obtained by TARE with 131I-lipiodol versus TACE in patients with cirrhosis and HCC, as well as between those with and without PVT. 33 patients were included, from whom 38 tumors were assessed. OTR was quantified by a special algorithm to measure hypervascular HCC tissue. 19 tumors received each therapy. Nine subjects (27%) had PVT, most of them in the TARE group (p=0.026). Mean OTR according to the tumor volumes was 24.2%±56% after TARE and 32.8%±48.9% after TACE, with no difference between the treatments (p=0.616). Similar values were also observed between those with and without PVT (p=0.704). Mean survival was 340 days and did not differ between the two treatments (p=0.596), but was 194 days in PVT cases (p=0.007). This is the first study in which OTR obtained by TARE with 131I-lipiodol is accurately measured. Additionally, PVT impact on survival after TARE and TACE was precisely documented. Although the TARE group had more PVT subjects (who had shorter survival), TARE and TACE achieved similar OTR and OS rates.

Early detection of hypervascularization in hepatocellular carcinoma (≤2 cm) on hepatic arterial phase with virtual monochromatic imaging: Comparison with low-tube voltage CT.

This study aims to assess the diagnostic value of virtual monochromatic image (VMI) at low keV energy for early detection of small hepatocellular carcinoma (HCC) in hepatic arterial phase compared with low-tube voltage (80 kVp) CT generated from dual-energy CT (DE-CT). A total of 107 patients with 114 hypervascular HCCs (≤2 cm) underwent DE-CT, 140 kVp, blended 120 kVp, and 80 kVp images were generated, as well as 40 and 50 keV. CT numbers of HCCs and the standard deviation as image noise on psoas muscle were measured. The contrast-to-noise ratios (CNR) of HCC were compared among all techniques. Overall image quality and sensitivity for detecting HCC hypervascularity were qualitatively assessed by three readers. The mean CT numbers, CNR, and image noise were highest at 40 keV followed by 50 keV, 80 kVp, blended 120 kVp, and 140 kVp. Significant differences were found in all evaluating endpoints except for mean image noise of 50 keV and 80 kVp. Image quality of 40 keV was the lowest, but still it was considered acceptable for diagnostic purposes. The mean sensitivity for detecting lesion hypervascularity with 40 keV (92%) and 50 keV (84%) was higher than those with 80 kVp (56%). Low keV energy images were superior to 80 kVp in detecting hypervascularization of early HCC.

Predicting Progression to Hypervascular HCC in Hypovascular Hypointense Nodules in Gadoxetic Acid-enhanced MR Images in Patients with Chronic Liver Disease

Objective: To identify patient characteristics and MR imaging features of hypovascular hypointense nodules in the hepatobiliary phase (HBP) of gadoxetic acid-enhanced MR imaging in patients with chronic liver disease associated with progression to hypervascular hepatocellular carcinoma (HCC). Materials and Methods: The institutional review board approved this retrospective review of 40 patients with 60 hypovascular hypointense nodules in the HBP of gadoxetic acid-enhanced MR imaging. Univariate and multivariate Cox regression analyses for hypervascular HCC development were used to define variables, including initial nodule size, cause of cirrhosis, history of locoregional therapy of HCC, fat-containing, signal intensity on T1W, T2W, portal and equilibrium phases of dynamic phase, and DW images. The cumulative percentage incidence of hypervascularity and growth rate were calculated using the receiver operating characteristic (ROC) curve. Results: The prevalence of progression to hypervascular HCC was 45% (27 out of 60). The Multivariable Cox analysis of developing hypervascularization was an initial nodule diameter more than 1 cm. (P=0.027; HR 2.52; 95% CI: 1.11,5.74) The mean growth rate was significantly higher in subsequent hypervascular nodules than in those without hypervascularization (P < 0.001). The cumulative risk incidence of hypervascularization at 3, 6, 12, 24 months was 5%, 20%, 35%, 44 %, respectively. Conclusion: An initial nodule diameter of more than 1 cm and nodules with higher growth rates are significant predictive factors for hypervascular transformation of hypovascular hypointense nodules in the HBP of gadoxetic acid-enhanced MR imaging.

Supramolecular Polymer-Nanomedicine Hydrogel Loaded with Tumor Associated Macrophage-Reprogramming polyTLR7/8a Nanoregulator for Enhanced Anti-Angiogenesis Therapy of Orthotopic Hepatocellular Carcinoma.

Anti-angiogenic therapies targeting inhibition of vascular endothelial growth factor (VEGF) pathway show clinical benefit in hypervascular hepatocellular carcinoma (HCC) tumors. However, HCC expresses massive pro-angiogenic factors in the tumor microenvironment (TME) in response to anti-angiogenic therapy, recruiting tumor-associated macrophages (TAMs), leading to revascularization and tumor progression. To regulate cell types in TME and promote the therapeutic efficiency of anti-angiogenic therapy, a supramolecular hydrogel drug delivery system (PLDX-PMI) co-assembled by anti-angiogenic nanomedicines (PCN-Len nanoparticles (NPs)) and oxidized dextran (DX), and loaded with TAMs-reprogramming polyTLR7/8a nanoregulators (p(Man-IMDQ) NRs) is developed for orthotopic liver cancer therapy. PCN-Len NPs target tyrosine kinases of vascular endothelial cells and blocked VEGFR signaling pathway. p(Man-IMDQ) NRs repolarize pro-angiogenic M2-type TAMs into anti-angiogenic M1-type TAMs via mannose-binding receptors, reducing the secretion of VEGF, which further compromised the migration and proliferation of vascular endothelial cells. On highly malignant orthotopic liver cancer Hepa1-6 model, it is found that a single administration of the hydrogel formulation significantly decreases tumor microvessel density, promotes tumor vascular network maturation, and reduces M2-subtype TAMs, thereby effectively inhibiting tumor progression. Collectively, findings in this work highlight the great significance of TAMs reprogramming in enhancing anti-angiogenesis treatment for orthotopic HCC, and provides an advanced hydrogel delivery system-based synergistic approach for tumor therapy.

Gadoxetic Acid-Enhanced Liver MRI: Everything You Need to Know.

Since its introduction in the worldwide medical market, gadoxetic acid has attracted considerable interest. The year 2023 marks the 15th anniversary of the introduction of gadoxetic acid in Japan. Gadoxetic acid-enhanced magnetic resonance imaging (GA-MRI) is the predominantly performed contrast MRI examination for the liver. Its most essential characteristic, namely, the hepatobiliary phase, revolutionized the clinical management of liver disease. Gadoxetic acid-enhanced MRI is currently the most efficient method for focal liver lesion detection and analysis. Meta-analyses demonstrated its excellent effectiveness for the diagnosis of hepatocellular carcinoma and liver metastases. Owing to the extensive usage of gadoxetic acid, a hepatobiliary phase hypointense nodule without arterial phase hyperenhancement is well documented. The existence of such nodules may be a sign of hypervascular hepatocellular carcinoma in nodules and other areas in the liver. Apart from its role in tumor identification and characterization, GA-MRI can help assess response to therapy and liver fibrosis. Therefore, it is proposed to use gadoxetic acid as the first option for MRI of the liver in the majority of patients. The efficacy of gadoxetic acid surpasses its disadvantages, rendering this contrast agent the preferred choice for routine MRI of the liver. The clinical use of GA-MRI is discussed in this review article.

Imaging and Pathologic Evaluation of Cryoablation of Woodchuck (Marmota monax) Hepatocellular Carcinoma.

We characterized cryoablation as a mode of clinical intervention in adult woodchucks with hepatocellular carcinoma (HCC). Woodchucks (n = 4) were infected with woodchuck hepatitis virus at birth and developed LI-RADS-5 hypervascular HCC. At 21 mo of age, they underwent ultrasound (US), contrast-enhanced CT (CECT) imaging, and US-guided subtotal cryoablation (IcePearl 2.1 CX, Galil, BTG) of their largest tumor (Mean HCC volume of 49 ± 9 cm³). Cryoablation was performed using two 10-min freeze cycles, each followed by an 8-min thaw cycle. The first woodchuck developed significant hemorrhage after the procedure and was euthanized. In the other 3 woodchucks, the probe track was cauterized and all 3 completed the study. Fourteen days after ablation, CECT was performed, and woodchucks were euthanized. Explanted tumors were sectioned using subject-specific, 3D-printed cutting molds. Initial tumor volume, the size of the cryoablation ice ball, gross pathology and hematoxylin and eosin-stained tissue sections were evaluated. On US, the edges of the solid ice balls were echogenic with dense acoustic shadowing and average dimensions of 3.1 ± 0.5 × 2.1 ± 0.4 cm and cross-sectional area of 4.7 ± 1.0 cm². On day 14 after cryoablation, CECT of the 3 woodchucks showed devascularized hypo-attenuating cryolesions with dimensions of 2.8 ± 0.3 × 2.6 ± 0.4 × 2.93 ± 0.7 cm and a cross sectional area of 5.8 ± 1.2 cm². Histopathologic evaluation showed hemorrhagic necrosis with a central amorphous region of coagulative necrosis surrounded by a rim of karyorrhectic debris. A rim of approximately 2.5 mm of coagulative necrosis and fibrous connective tissue clearly demarcated the cryolesion from adjacent HCC. Partial cryoablation of tumors produced coagulative necrosis with well-defined ablation margins at 14 d. Cauterization appeared to prevent hemorrhage after cryoablation of hypervascular tumors. Our findings indicate that woodchucks with HCC may provide a predictive preclinical model for investigating ablative modalities and developing new combination therapies.

Iodine maps derived from sparse-view kV-switching dual-energy CT equipped with a deep learning reconstruction for diagnosis of hepatocellular carcinoma

Deep learning-based spectral CT imaging (DL-SCTI) is a novel type of fast kilovolt-switching dual-energy CT equipped with a cascaded deep-learning reconstruction which completes the views missing in the sinogram space and improves the image quality in the image space because it uses deep convolutional neural networks trained on fully sampled dual-energy data acquired via dual kV rotations. We investigated the clinical utility of iodine maps generated from DL-SCTI scans for assessing hepatocellular carcinoma (HCC). In the clinical study, dynamic DL-SCTI scans (tube voltage 135 and 80 kV) were acquired in 52 patients with hypervascular HCCs whose vascularity was confirmed by CT during hepatic arteriography. Virtual monochromatic 70 keV images served as the reference images. Iodine maps were reconstructed using three-material decomposition (fat, healthy liver tissue, iodine). A radiologist calculated the contrast-to-noise ratio (CNR) during the hepatic arterial phase (CNRa) and the equilibrium phase (CNRe). In the phantom study, DL-SCTI scans (tube voltage 135 and 80 kV) were acquired to assess the accuracy of iodine maps; the iodine concentration was known. The CNRa was significantly higher on the iodine maps than on 70 keV images (p < 0.01). The CNRe was significantly higher on 70 keV images than on iodine maps (p < 0.01). The estimated iodine concentration derived from DL-SCTI scans in the phantom study was highly correlated with the known iodine concentration. It was underestimated in small-diameter modules and in large-diameter modules with an iodine concentration of less than 2.0 mgI/ml. Iodine maps generated from DL-SCTI scans can improve the CNR for HCCs during hepatic arterial phase but not during equilibrium phase in comparison with virtual monochromatic 70 keV images. Also, when the lesion is small or the iodine concentration is low, iodine quantification may result in underestimation.

Added value of contrast enhancement boost images in routine multiphasic contrast-enhanced CT for the diagnosis of small (

PurposeTo investigate the added value of contrast enhancement boost (CE-boost) images in multiphasic contrast-enhanced CT (CE-CT) for diagnosing small (<20 mm) hypervascular hepatocellular carcinoma (HCC). Materials and methodsThis retrospective study included 69 patients (age, 74 ± 8 years; 52 men) with 70 hypervascular HCCs (<20 mm) who underwent multiphasic CE-CT (pre-contrast, late arterial phase [LAP], portal venous phase [PVP], and equilibrium phase). Two types of CE-boost images were generated by subtracting PVP from LAP (LA-PV) images and LAP from PVP (PV-LA) images to enhance the contrast effect of hepatic arterial and portal venous perfusion more selectively. Tumor-to-liver contrast-to-noise ratios (CNRs) in CE-boost images were compared with those in CE-CT images using the Wilcoxon signed-rank test. Two independent readers reviewed the imaging datasets: CE-CT alone and CE-CT with CE-boost images. The diagnostic performance of each dataset was compared using jackknife alternative free-response receiver operating characteristics (JAFROC-1). ResultsThe tumor-to-liver CNRs in the LA-PV (6.4 ± 3.0) and PV-LA (−3.3 ± 2.1) images were greater than those in the LAP (3.2 ± 1.7) and PVP images (−1.1 ± 1.4) (p <.001 for both). The reader-averaged figures of merit were 0.751 for CE-CT alone and 0.807 for CE-CT with CE-boost images (p <.001). Sensitivities increased by adding CE-boost images for both readers (p <.001 and = 0.03), while positive predictive values were equivalent (p >.99). ConclusionAdding CE-boost images to multiphasic CE-CT can improve the diagnostic accuracy and sensitivity for small hypervascular HCC by increasing the tumor-to-liver CNR.

Multiarterial Phase Acquisition in Gadoxetic Acid-Enhanced Liver MRI for the Detection of Hypervascular Hepatocellular Carcinoma in High-Risk Patients: Comparison of Compressed Sensing Versus View Sharing Techniques.

The aim of this study was to compare compressed sensing (CS) and view sharing (VS) techniques for single breath-hold multiarterial phase imaging with respect to image quality and focal liver observation detectability during gadoxetic acid-enhanced magnetic resonance imaging in patients at high risk for hepatocellular carcinoma (HCC). A total of 385 patients who underwent gadoxetic acid-enhanced magnetic resonance imaging, including triple arterial phases using either CS (n = 224) or VS (n = 161) techniques, were retrospectively included. Among them, 117 patients had 171 focal liver observations (median diameter, 1.3 cm), which were classified according to Liver Imaging Reporting and Data System version 2018. The acquisition rate of optimally timed late arterial phase (LAP) was assessed, and image quality, including respiratory motion artifact and observation conspicuity, was rated on a 4-point scale by 3 radiologists. The Mann-Whitney U test and nonparametric test for repeated measures data were used for image quality and observation conspicuity analysis. The jackknife alternative free-response receiver operating characteristics method was used to compare the observation detectability between the 2 techniques. The CS technique showed significantly higher acquisition rate of optimally timed LAP without transient severe motion (82.1% [184/224] vs 71.4% [115/161]; P = 0.013) than the VS technique. The CS technique also demonstrated significantly improved overall image quality (3.42 ± 0.70 vs 2.97 ± 0.61; P < 0.001) compared with the VS technique. Regarding the detection of hyperenhancing observations, there was no significant difference between the figure of merits of CS and VS techniques (0.660 vs 0.665; P = 0.890). However, the CS technique showed a higher detection rate in Liver Imaging Reporting and Data System M (LR-M, probably or definitely malignant but not HCC specific) observations than the VS technique (100.0% [9/9] vs 44.4% [8/18]; P = 0.009). The CS technique tended to provide optimally timed LAP without transient severe motion and demonstrated greater detection rate of LR-M observations than the VS technique in patients at high risk of HCC.

Dicer Enhances Bevacizumab-Related Inhibition of Hepatocellular Carcinoma via Blocking the Vascular Endothelial Growth Factor Pathway.

PurposeVascular endothelial growth factor (VEGF) family members contribute greatly to the development and angiogenesis of hypervascular hepatocellular carcinoma (HCC). We have previously shown that Dicer inhibited HCC growth. In this study, we aimed to determine the relationship between Dicer and VEGF in HCC.MethodsGain-of-function studies were performed to determine the effect of different treatments on the proliferation, migration, and invasion of HCC cells. Expression of VEGF-A in xenograft tumor tissues was analysed using Western blotting, and that of CD31 using immunohistochemical analysis.ResultsWe found that Dicer inhibited proliferation, migration and invasion of HCC cells by suppressing VEGF-A expression. Interestingly, VEGF-A165, which is the most prominent VEGF-A isoform, counteracted Dicer-induced inhibition of HCC cells. In addition, a monoclonal anti-VEGF antibody (bevacizumab) enhanced Dicer-induced inhibition of HCC in vitro and in vivo. Further, immunohistochemical analysis of CD31 indicated bevacizumab and Dicer synergized to reduce tumor microvessel density.ConclusionOur data demonstrated that Dicer enhanced bevacizumab-related inhibition of HCC cell via the VEGF pathway; therefore, Dicer in coordination with bevacizumab may provide another potential approach for HCC therapy.

Risk stratification of hepatocellular carcinoma in patients with chronic liver disease by combining gadolinium‐ethoxybenzyl diethylenetriamine‐pentaacetic acid–enhanced magnetic resonance imaging and magnetic resonance elastography

Background Liver stiffness (LS) as measured by magnetic resonance elastography (MRE) and the presence of intrahepatic nonhypervascular hypointense nodules (NHHNs) during the hepatobiliary phase of gadolinium-ethoxybenzyl diethylenetriamine-pentaacetic acid–enhanced magnetic resonance imaging are non-invasive MR-based biomarkers of hepatocarcinogenesis. Methods We retrospectively evaluated the ability of these two MR-based biomarkers to stratify the risk of hepatocellular carcinoma (HCC) development in patients with chronic liver disease. Between September 2013 and April 2020, 868 consecutive patients underwent MRE and gadolinium-ethoxybenzyl diethylenetriamine-pentaacetic acid–enhanced magnetic resonance imaging, among whom 487 were enrolled in this study. Factors associated with hepatocarcinogenesis were analysed by a Cox proportional hazard model. Results Thirty-two patients developed hypervascular HCC. According to the time-dependent receiver operating characteristic analysis, an LS value of 3.94 kPa was selected as the optimal cut-off value for predicting HCC development. Multivariate analyses identified high LS (≥3.94 kPa) and the presence of NHHN as independent predictive factors for HCC development. Patients were classified as follows: high LS/NHHN+ (Group 1), high LS/NHHN− (Group 2), low LS/NHHN+ (Group 3) and low LS/NHHN− (Group 4). The 5-year incidence rates of HCC in Groups 1, 2, 3 and 4 were 49.0%, 16.3%, 10.0% and 2.5% respectively. The HCC development rate was highest in Group 1 and lowest in Group 4 (P < 0.01). Conclusion MRE-based LS measurements and the presence of NHHN are useful biomarkers to stratify the risk of HCC development among chronic liver disease patients. Combining these biomarkers can provide a detailed classification of the risk of HCC development.

Long-term persistence of hepatocarcinogenic potential of a non-hypervascular hypointense nodule on EOB-MRI after the eradication of hepatitis C virus.

Non-hypervascular hypointense nodules (NHHNs) on gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging (EOB-MRI) have a high likelihood of hypervascularization progressing to typical hypervascular hepatocellular carcinoma (HCC). NHHNs that were present before the start of anti-hepatitis C virus (HCV) therapy is a risk marker for HCC development after achieving sustained virologic response (SVR). In this report, we show a patient without a previous history of HCC in whom HCC developed by hypervascularization of NHHN after SVR. This patient achieved SVR more than 8years before NHHN developed into HCC, and during this time NHHN had been present but had remained unchanged in size and imaging features as shown by repeated EOB-MRI. Hepatocarcinogenic potential of NHHNs persist for a long time after SVR, despite the eradication of HCV.

Value of precontrast and portal venous phases for evaluating atypical hepatocellular carcinoma mimicking arterioportal shunt

PurposeTo evaluate the value of precontrast phase (PP) and portal venous phase (PVP) for differentiation of small hypervascular hepatocellular carcinomas (HCCs) without delayed washout from arterioportal (AP) shunts in high-risk patients of HCC. MethodsA total of 122 lesions (73 AP shunts and 49 HCCs) detected on quadriphasic CT in 101 patients with chronic liver disease were analyzed. All lesions (≤2 cm) showed arterial enhancement and isodensity on delayed phase (DP) with exclusion of typical features of AP shunts. Lesion morphologic features (size, location, shape, margin) on biphasic CT (arterial phase and DP), Alpha-fetoprotein (AFP) values and coexistent HCC were evaluated. The qualitative and quantitative analyses of lesion attenuation on quadriphasic CT were performed. Diagnostic performances for prediction of AP shunts over HCC were compared among the biphasic CT, triphasic CT (adding PP or PVP) and quadriphasic CT. ResultsIn multivariate analysis, the presence of concomitant HCC (p = 0.0005, odds ratio [OR] = 0.11), visual hypodensity on PP (p = 0.0004, OR = 17.72) and visual hyperdensity on PVP (p = 0.0003, OR = 0.051) were independent predictors for HCCs rather than AP shunts. Additional review of PP and PVP revealed significantly improved diagnostic performance yielding the highest diagnostic performance. ConclusionsHypodensity on PP and hyperdensity on PVP are significant predictive features in differentiating atypical small hypervascular HCC from AP shunts in patients with high-risk of HCC. Careful evaluation of the PP and PVP may reduce underdiagnosis and lead to earlier diagnosis of atypical small HCCs.

Diagnosis of Hepatocellular Carcinoma Using Gd-EOB-DTPA MR Imaging.

Gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA; Gadoxetic acid; Gadoxetate disodium) is a hepatocyte-specific MR contrast agent. It acts as an extracellular contrast agent in the early phase after intravenous injection, and then is taken up by hepatocytes later. Using this contrast agent, we can evaluate the hemodynamics of the liver and liver tumors, and can therefore improve the detection and characterization of hepatocellular carcinoma (HCC). Gd-EOB-DTPA helps in the more accurate detection of hypervascular HCC than by other agents. In addition, Gd-EOB-DTPA can detect hypovascular HCC, which is an early stage of the multi-stage carcinogenesis, with a low signal in the hepatobiliary phase. In addition to tumor detection and characterization, Gd-EOB-DTPA contrast-enhanced MR imaging can be applied for liver function evaluation and prognoses evaluation. Thus, Gd-EOB-DTPA plays an important role in the diagnosis of HCC. However, we have to employ optimal imaging techniques to improve the diagnostic ability. In this review, we aimed to discuss the characteristics of the contrast media, optimal imaging techniques, diagnosis, and applications.

Uptake of gadoxetic acid in hepatobiliary phase magnetic resonance imaging and transporter expression in hypovascular hepatocellular nodules

AimsTo evaluate the association between contrast patterns on gadoxetic acid-enhanced hepatobiliary phase (HBP) MR images and transporter expression in surgically resected hypovascular hepatocellular nodules including early hepatocellular carcinomas (HCCs). MethodsForty-two hypovascular hepatic nodules and 43 hypervascular HCCs as a control were included in this retrospective study. Contrast of the nodules on HBP images was graded as hypo-, iso-, or hyperintense. Histopathological assessment was performed in the context of multistep hepatocarcinogenesis. Immunohistochemical staining of organic anion transporter 1B3 (OATP1B3) and multidrug resistance protein 2 (MRP2) was performed. Cramer’s coefficient was used to determine the linear relationship between contrast grades and transporter expression, and the Cochran-Armitage trend test was used to determine the relationship between transporter expression and progression of multistep hepatocarcinogenesis. ResultsModerate linear relationships between contrast grades and OATP1B3 expression were observed for both hypo- and hypervascular nodules. OATP1B3 expression was negatively correlated with the progression of multistep hepatocarcinogenesis. MRP2 expression was not associated with the contrast grades or histopathological results. ConclusionOATP1B3 expression was associated with contrast grades of hepatocellular nodules observed in HBP image of gadoxetic acid-enhanced MRI in the hypovascular hepatocellular nodules and was negatively correlated with hepatocarcinogenesis.

Comparison of low kVp CT and dual-energy CT for the evaluation of hypervascular hepatocellular carcinoma.

To compare lesion conspicuity and image quality of arterial phase images obtained from low kVp (90-kVp) and dual-energy (DE) scans for the evaluation of hypervascular hepatocellular carcinoma (HCC). This retrospective study included 229 patients with HCC who underwent either 90kVp (n = 106) or DE scan (80- and 150-kVp with a tin filter) (n = 123) during the arterial phase. DE scans were reconstructed into a linearly blended image with a mixed ratio of 0.6 (60% 80kVp and 40% 150kVp) and post-processed for 40keV and 50keV images. The contrast-to-noise ratio (CNR) of HCC to the liver and image noise was measured. Lesion conspicuity, liver parenchymal image quality, and overall image preference were assessed qualitatively by three independent radiologists. DE 40keV images had the highest CNR of HCC, and DE blended images had the lowest image noise among four image sets (p = 0.01 and p < 0.001, respectively). There was no significant difference in mean volume CT dose index and dose-length product between DE and low kVp scan (ps > 0.05). For qualitative analyses, DE blended images had the highest scores for image quality and overall image preference (ps < 0.001). At an equal radiation dose, DE 40keV showed higher CNR of HCC and DE blended image showed higher image quality and image preference compared with low kVp CT.

Feeding artery ablation before radiofrequency ablation for hepatocellular carcinoma may reduce critical recurrence.

Background and AimPercutaneous radiofrequency ablation (RFA) is a minimally invasive and curative local treatment for hepatocellular carcinoma (HCC). However, serious concerns remain regarding critical recurrences such as metastasis, dissemination, and/or seeding due to RFA. In August 2006, we introduced selective feeding artery ablation before tumor ablation to reduce the risk of critical recurrence by blocking tumor blood flow. The aim of the present study was to clarify whether feeding artery ablation before tumor ablation can reduce the risk of critical recurrence after RFA.MethodsThis study retrospectively analyzed 279 patients with primary, solitary, and hypervascular HCC ≤5 cm in diameter who were treated with RFA alone between April 2001 and August 2013. Critical recurrence was defined as intra‐ or extrahepatic metastasis, dissemination, or seeding that was difficult to treat radically.ResultsOf the 279 HCC patients, 157 patients were treated with conventional RFA alone, and 122 patients underwent RFA with prior feeding artery ablation. Although no significant differences were seen in the rates of local tumor progression‐free survival, overall recurrence‐free survival, or overall survival between a conventional RFA group and a prior feeding artery ablation group, significant differences were seen in rates of critical recurrence‐free survival and cancer‐specific survival (5‐year, 69 vs 81%, P = 0.01 and 76 vs 88%, P = 0.03, respectively). On multivariate analysis, prior feeding artery ablation, tumor diameter, and alpha‐fetoprotein were independent factors related to critical recurrence.ConclusionsFeeding artery ablation before tumor ablation may reduce the risk of critical recurrence.

An overview of hepatocellular carcinoma with atypical enhancement pattern: spectrum of magnetic resonance imaging findings with pathologic correlation.

BackgroundIn the setting of cirrhotic liver, the diagnosis of hepatocellular carcinoma (HCC) is straightforward when typical imaging findings consisting of arterial hypervascularity followed by portal-venous washout are present in nodules larger than 1 cm. However, due to the complexity of hepatocarcinogenesis, not all HCCs present with typical vascular behaviour. Atypical forms such as hypervascular HCC without washout, isovascular or even hypovascular HCC can pose diagnostic dilemmas. In such cases, it is important to consider also the appearance of the nodules on diffusion-weighted imaging and hepatobiliary phase. In this regard, diffusion restriction and hypointensity on hepatobiliary phase are suggestive of malignancy. If both findings are present in hypervascular lesion without washout, or even in iso- or hypovascular lesion in cirrhotic liver, HCC should be considered. Moreover, other ancillary imaging findings such as the presence of the capsule, fat content, signal intensity on T2-weighted image favour the diagnosis of HCC. Another form of atypical HCCs are lesions which show hyperintensity on hepatobiliary phase. Therefore, the aim of the present study was to provide an overview of HCCs with atypical enhancement pattern, and focus on their magnetic resonance imaging (MRI) features.ConclusionsIn order to correctly characterize atypical HCC lesions in cirrhotic liver it is important to consider not only vascular behaviour of the nodule, but also ancillary MRI features, such as diffusion restriction, hepatobiliary phase hypointensity, and T2-weighted hyperintensity. Fat content, corona enhancement, mosaic architecture are other MRI feautures which favour the diagnosis of HCC even in the absence of typical vascular profile.

Multiregional whole-genome sequencing of hepatocellular carcinoma with nodule-in-nodule appearance reveals stepwise cancer evolution.

Recent genetic analyses revealed genetic heterogeneity in hepatocellular carcinoma (HCC), although it remains unclear how genetic alterations contribute to the multistage progression of HCC, especially the early step from hypovascular liver nodules to hypervascular HCC. We conducted multiregional whole-genome sequencing on HCCs with a nodule-in-nodule appearance, consisting of inner hypervascular HCC surrounded by hypovascular HCC arising from a common origin, and identified point mutations, structural variations, and copy-number variations in each specimen. According to the genetic landscape of the inner and outer regions, together with the pathological and radiological findings, we examined the stepwise evolution of cancer cells from slow-growing HCC to rapid-growing HCC. We first demonstrated that most tumor cells consisting of hypovascular well-differentiated HCCs already harbored thousands of point mutations and even several structural variations, including chromosomal translocations and chromothripsis, as the trunk events. Telomerase reverse transcriptase (TERT)-associated aberrations, including promoter mutations, chromosomal translocation, and hepatitis B virus DNA integration, as well as abnormal methylation status, were commonly detected as the trunk aberrations, while various liver cancer-related genes, which differed in each case, had additionally accumulated in the inner dedifferentiated nodules. Further, differences in the trunk and branch mutational signatures suggested a multistep contribution to the mutagenesis in each case. In conclusion, genomic alterations associated with the TERT gene could be the key driver events to form the hypovascular HCC, and additional case-specific driver mutations accumulate during the progression phase, forming intra- and inter-tumoral heterogeneity, confirming the importance of genetic testing before targeting therapy. These data shed light on the process of multistep hepatocarcinogenesis and will be helpful toward investigating new therapeutic strategies for HCC. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.