Hypovascular Hepatocellular Carcinoma Research Articles

Imaging Findings in Cirrhotic Liver: Pearls and Pitfalls for Diagnosis of Focal Benign and Malignant Lesions.

Cirrhosis is the end stage of chronic liver disease and causes architectural distortion and perfusional anomalies. It is a major risk factor for developing hepatocellular carcinoma (HCC). Common disease entities in noncirrhotic livers, such as hemangiomas, can be rare in cirrhotic livers, and benign entities such as confluent hepatic fibrosis and focal nodular hyperplasia-like lesions may mimic the appearance of malignancies,. HCC usually has typical imaging characteristics, such as the major features established by the Liver Imaging Reporting and Data System. However, HCC can also have a spectrum of atypical or uncommon appearances, such as cystic HCC, hypovascular HCC, or macroscopic fat-containing HCC. HCCs with certain genetic mutations such as CTNNB-1-mutated HCC can harbor unique imaging features not seen in other types of HCC. In addition, malignancies that are less common than HCC, such as cholangiocarcinoma and metastases, which can be difficult to differentiate, can still occur in cirrhotic livers. Atypical imaging features of benign and malignant lesions can be challenging to accurately diagnose. Therefore, familiarity with these features and an understanding of the prevalence of disease entities in cirrhotic livers are key in the daily practice of radiologists for evaluation of cirrhotic livers. The authors illustrate the typical and atypical features of benign and malignant lesions in cirrhosis and discuss the technical pitfalls and unique advantages associated with various imaging modalities in assessing cirrhotic livers, including noncontrast and contrast-enhanced US, CT, and MRI. Work of the U.S. Government published under an exclusive license with the RSNA. Quiz questions for this article are available in the supplemental material.

Clinical effectiveness oftranscatheter arterial chemoembolization sequential microwave ablation for lack of blood supply in hepatocellular carcinoma.

Aims: To determine the effectiveness and safety of sequential computed tomography-guided percutaneous microwave ablation (MWA) after transcatheter arterial chemoembolization(TACE) for hypovascular liver lesions <5cm in size. Methods: The clinical data of 69 hypovascular hepatocellular carcinoma lesions <5cm in 60 patients treated with TACE followed by MWA were retrospectively analyzed. Results: There was no significant difference in AFP levels among AFP-positive patients before and after TACE (p=0.515), but levels were significantly lower 1 month after MWA than before MWA (p=0.039). Compared with 1 month after TACE, the objective response rate (p<0.001) and disease control rate (p=0.004) were increased 1 month after MWA. Any adverse events were well tolerated, and the albumin bilirubin score did not deteriorate within 4 weeks. Conclusion: Sequential MWA after TACE was found to be safe and effective for treating hypovascular hepatocellular carcinoma for lesions <5cm in size.

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.

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.

Drug-Eluting Beads versus Lipiodol Transarterial Chemoembolization for the Treatment of Hypovascular Hepatocellular Carcinoma: A Single-Center Retrospective Study.

PurposeTo evaluate the efficacy and safety of drug-eluting beads transarterial chemoembolization (DEB-TACE) and conventional TACE (C-TACE) in treating hypovascular hepatocellular carcinoma (HCC).Materials and MethodsThe medical records based on HCC patients who underwent TACE from January 2016 to June 2019 were reviewed in the study. The diagnosis of hypovascular HCC was conducted by two senior radiologists according to imaging. We evaluated the adverse events (AEs), objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS) in the study.ResultsA total of 98 patients with hypovascular HCC were included in the study. 46 patients underwent DEB-TACE treatment, and 52 patients underwent C-TACE treatment. The PFS of DEB-TACE group and C-TACE group was 12.0 months and 7.0 months (P < 0.001), and OS was 21.0 months and 14.0 months (P = 0.035), respectively. In addition, DEB-TACE group had better ORR (76.1% vs 40.4%, P < 0.001) and DCR (91.3% vs 75.0%, P = 0.033) compared to C-TACE group. The occurrence rate of AEs showed no difference between the two groups (67.3% vs 57.7%, P = 0.323). Furthermore, we found that DEB-TACE can be identified as a positive independent prognostic factor for improved PFS and OS.ConclusionDEB-TACE, as an effective treatment, can yield better objective response rate, similar safety profile and improved survival for hypovascular HCC patients compared to C-TACE.

Hypo-vascular hepatocellular carcinoma and liver transplantation: Morphological characteristics and implications on outcomes.

The clinical importance of hypovascular liver lesions in cirrhotic patients awaiting liver transplantation (LT) has not been fully investigated. The objective of this study was to characterize the clinicopathologic features and management of these tumors and to assess their impact on post-LT outcomes. We performed a retrospective review of cirrhotic patients with lesions suspicious for hypovascular hepatocellular carcinoma (HCC) who underwent LT at a single institution from 2011- 2017. We identified 22 pre-LT patients with radiologic diagnosis of a lesion(s) suspicious for hypovascular HCC. There were 28 hypovascular lesions within the 22 patient cohort; 9 lesions (32%) converted to hypervascular HCC before LT and 19 lesions remained hypovascular at LT. 88% of hypovascular lesions were HCC on explant pathology. Compared to patients with hyper-vascular HCC lesions, hypovascular HCC lesions underwent less preoperative tumor ablation (58% vs 89%; P < .01). Hypovascular HCC were more likely to be well-differentiated (67% vs 11%; P < .01), but there were no differences in the microvascular invasion, tumor recurrence, or survival post-LT. Hypovascular HCC has similar clinical outcomes and needs for transplantation as hypervascular HCC. The high prevalence of HCC within suspicious hypovascular lesions supports a similar monitoring and locoregional therapy strategy as for hypervascular HCC.

Clinical Outcomes of Radiofrequency Ablation for Early Hypovascular HCC: A Multicenter Retrospective Study

Purpose To retrospectively evaluate the clinical outcomes of radiofrequency ablation (RFA) for early hypovascular hepatocellular carcinomas (HCCs) and to compare them with those of typical hypervascular HCCs. Materials and Methods This retrospective multicenter study received institutional review board approval, with a waiver of the need to obtain informed consent. A total of 56 patients (male-to-female ratio, 40:16; mean age, 61.8 years; age range, 33-87 years) with pathologically proven early HCCs that did not meet the noninvasive diagnosis criteria and who were initially treated with RFA at one of five university-affiliated hospitals between January 2009 and December 2013 comprised the study group. Thereafter, 240 patients with hypervascular HCCs initially treated with RFA in the same period in a historical cohort were selected as control patients. Overall survival (OS), progression-free survival (PFS), and cumulative incidence of local tumor progression (LTP) were estimated by using Kaplan-Meier analysis and were compared by using the Cox proportional hazard regression model. After the first analysis, propensity score analysis was performed to reduce potential bias. Results Complete ablation was achieved in all 56 patients with early hypovascular HCCs after RFA. The estimated 5-year cumulative incidence of LTP in the 56 patients with early hypovascular HCCs was significantly lower than in the 240 patients with hypervascular HCCs (5.4% for early hypovascular HCCs vs 20.8% for hypervascular HCCs; hazard ratio = 6.57 [95% confidence interval: 1.59, 27.2]; P = .009). After propensity matching, the estimated 5-year cumulative incidence of LTP in patients with early hypovascular HCCs was still significantly lower than that in patients with hypervascular HCCs (5.4% vs 23.0%; P = .025; hazard ratio = 5.71 [95% confidence interval: 1.27, 25.8]). OS was not significantly different between the groups (P = .100). One-year PFS in the 56 patients with early hypovascular HCCs, on the other hand, appeared to be favorable at 92.7%, compared with 79.4% in the 240 patients with hypervascular HCCs, but overall, PFS was not significantly different (P = .066). Conclusion RFA of early hypovascular HCCs provided similar OS and PFS compared with RFA of typical hypervascular HCCs, despite its significantly lower 5-year cumulative incidence of LTP. © RSNA, 2017 Online supplemental material is available for this article.

Liver Biopsy and Microwave Ablation Complicated by Hemorrhagic Shock and Massive Hemoperitoneum: A Root Cause Analysis

Case Summary: A 47 year-old man with Child-Pugh class B alcoholic cirrhosis was found to have an indeterminate 2 cm right hepatic lobe lesion concerning for hypovascular hepatocellular carcinoma. The patient underwent CT-guided percutaneous liver biopsy followed by microwave ablation. Post-procedure blood loss was minimal, with no immediate complications; however, the patient presented < 48 hours later with hypotension and abdominal pain. CT angiography demonstrated large volume hemoperitoneum with active contrast extravasation from a branch of the right hepatic artery. Distal right hepatic artery branch embolization was performed. Within 24 hours, the patient developed refractory hypotension requiring repeat embolization of the right hepatic artery with no further contrast extravasation. Later that day, the patient developed elevated intra-abdominal pressure, worsening hypotension, and profound lactic acidosis with persistent coagulopathy. The patient was taken emergently to the operating room for exploratory laparotomy and evacuation of the hematoma. Despite these interventions, the patient developed cardiac arrest in the operating room and expired. Methods: A systematic root-cause analysis (RCA) was performed. Data was gathered and evidence collected from multiple hospital stakeholders (staff, nurses, advance practice providers, physicians, bed management, and hospital administrators). Causal factors, current practice paradigms, and root causes were investigated. Potential corrective actions were explored. Results: Detailed discussions were held with emergency, IR, hepatology, hematology, and medical and surgical ICU staffing. Cause and effect diagram was constructed - Figure. RCA revealed potential areas for institutional improvement including post-procedural follow-up (phone contact and lab monitoring), physician consultation methods (automatic consultations for high-risk patients), massive transfusion protocols (thromboelastrography correction of coagulopathy), and triage of patients to medical versus surgical intensive care units (ICU).Figure: Cause and Effect Fishbone Diagram.Discussion: This case highlights a fatal complication from liver biopsy and microwave ablation. Through this RCA, an institution-wide protocol through discussions with all stakeholders is needed to reduce future adverse events. Furthermore, this case emphasizes the need for early involvement of the hepatobiliary surgical service and appropriate triage of massive transfusion protocol patients to a surgical ICU.

Differential sensitivity of hepatocellular carcinoma cells to suppression of hepatocystin transcription under hypoxic conditions.

Mutations in the gene encoding hepatocystin/80K-H (PRKCSH) cause autosomal dominant polycystic liver disease. Hepatocystin deficiency impairs glucosidase II activity, which is critical for processing and folding glycoproteins in the endoplasmic reticulum (ER). Hypoxia is known as a strong stimulus for generating survival signals in hepatocellular carcinoma (HCC) cells. However, hypoxia may induce cell apoptosis under conditions of severe ER stress. Thus, we hypothesized that suppression of hepatocystin transcription induces HCC cell death under hypoxic conditions due to excessive ER stress. A new human HCC cell line, SNU-3058, was established following primary culture of tumor cells harvested from a Korean patient with rapidly growing hypovascular HCC. In cell culture, human HCC cells (Huh-7, SNU-761, and SNU-3058) were treated with control siRNA or hepatocystin siRNA with or without doxorubicin under hypoxic conditions. Cell viability, ER stress, unfolded protein response (UPR), and apoptosis were assessed using the MTS assay, immunoblot assay, and RT-PCR. Suppression of hepatocystin transcription attenuated proliferation in Huh-7 and SNU-761 cells, while proliferation was amplified in SNU-3058 cells. Similar results were observed following treatment with doxorubicin. Hepatocystin siRNA transfection increased cell death in Huh-7 and decreased cell death in SNU-3058. In SNU-3058, hepatocystin siRNA amplified GRP78, known as a pro-survival and cyto-protective signal, and attenuated the pro-apoptotic signal CHOP. These findings suggest that suppression of hepatocystin transcription induce the UPR, which alleviates damage associated with ER stress in SNU-3058. UPR had a limited role in protecting SNU-761 cells, resulting in cell death through apoptosis. In addition, blocking of pro-survival UPR signal by bacitracin or GRP78 knockdown, attenuated hepatocystin siRNA-induced proliferation in SNU-3058 cells under hypoxia. In this study, we demonstrated that different sensitivities to hepatocystin siRNA among human HCC cell lines are dependent on appropriate UPRs to hypoxia-induced ER stress following hepatocystin siRNA transfection. Because UPR is the main evasive mechanism for apoptosis induced by suppression of hepatocystin, targeting hepatocystin via UPR suppression could be a strategy for treating HCC.

Hypoxia Enhances Tumor-Stroma Crosstalk that Drives the Progression of Hepatocellular Carcinoma.

Crosstalk between tumor cells and their microenvironment plays a crucial role in the progression of hepatocellular carcinoma (HCC). Hypoxia, a common feature of advanced HCC, has been shown to modulate the evolution of the tumor microenvironment. In this study, we investigated the effect of hypoxia on tumor-stroma crosstalk in HCC. Human HCC cell lines (Huh-BAT, SNU-475) were cocultured with an activated human hepatic stellate cell line (HSCs; LX-2) under either normoxic or hypoxic conditions. Cell growth was evaluated with the MTS assay. Apoptotic signaling cascades were assessed by immunoblot analysis. Expression of CD31 and phosphorylated (p-) Akt in HCC tissues was detected by immunohistochemistry. Coculturing HCC cells with HSCs under hypoxic conditions enhanced their proliferation, migration, and resistance to bile acid (BA)-induced apoptosis compared to coculturing under normoxic conditions. Under hypoxia, of various HSC-derived growth factors, PDGF-BB was the most up-regulated, leading to the activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway in HCC cells. Immunohistochemical study also revealed that p-Akt was highly expressed in hypoxic, hypovascular HCC as compared to hypervascular HCC. Neutralizing antisera to PDGF-BB or a PI3K inhibitor attenuated the proliferation of HCC cells cocultured with HSCs, and sensitized HCC cells to BA-induced apoptosis, especially under hypoxic conditions. In conclusion, hypoxic HSC-derived PDGF-BB stimulates the proliferation of HCC cells through activation of the PI3K/Akt pathway, while the inhibition of PDGF-BB or PI3K/Akt pathways enhances apoptotic cell death. Targeting tumor-stroma crosstalk might be a novel therapy in the management of human HCCs.

Usefulness of early vascular phase images from contrast-enhanced ultrasonography using Sonazoid for the diagnosis of hypovascular hepatocellular carcinoma.

This study aimed to evaluate the usefulness of early vascular phase images produced by contrast-enhanced ultrasonography (CE-US) with Sonazoid for the diagnosis of hypovascular hepatocellular carcinoma (HCC). Four hundred and seventeen patients with 674 hepatic nodules were evaluated using CE-US with Sonazoid between January 2007 and March 2010. Retrospective analysis was conducted on 49 histologically confirmed nodules showing hypovascularity relative to the surrounding liver tissue in the early vascular phase and no enhancement defect in the Kupffer phase of CE-US with Sonazoid. These nodules were classified according to early vascular phase image enhancement patterns as types I (largest avascular; avascular as a whole), II (second avascular; partially avascular), III (smallest avascular; not avascular, but faintly hypovascular relative to the surrounding liver) and IV (hypovascular as a whole with vessel-like structures passing inside nodules). Among the 49 nodules, types I, II, III and IV were identified in 19 (38.8%), nine (18.4%), 15 (30.6%) and six (12.2%) cases, respectively. The proportion of tumorous nodules (well-differentiated HCC and high-grade dysplastic nodules) significantly decreased with a reduction of the avascular area (68.4% in the type I, 55.6% in the type II and 33.3% in the type III nodules; P <0.05). All nodules demonstrating the type IV enhancement pattern were non-tumorous. Based on the size of avascular area in the early vascular phase of CE-US with Sonazoid, we can predict the malignant potential of the nodules. CE-US with Sonazoid is very useful for evaluation of hypovascular hepatic nodules.

Hepatobiliary MR contrast agents in hypovascular hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) develops via multistep hepatocarcinogenesis, during which hypovascular/early HCC precedes the typical hypervascular HCC. The hypovascular HCC lacks the typical hallmark imaging features of HCC, such as late arterial phase enhancement and portal venous washout, limiting early detection using conventional extracellular contrast agents for dynamic magnetic resonance imaging (MRI) or computed tomography (CT) imaging. In recent years, gadolinium-based contrast agents with hepatobiliary uptake have garnered interest from radiologists and hepatologists due to their potential for improved detection of HCC during hepatobiliary phase MRI. Lesions with reduced or absent hepatocyte function appear hypointense in the hepatobiliary phase of gadoxetic acid-enhanced MRI. This behavior can be exploited for earlier detection of hypovascular HCC. This review describes the general characteristics and advantages of gadoxetic acid for the diagnosis of HCC with a particular focus on hypovascular/early HCC.

Clinical utility of imaging for evaluation of hepatocellular carcinoma.

The hemodynamics of a hepatocellular nodule is the most important imaging parameter used to characterize various hepatocellular nodules in liver cirrhosis, because sequential changes occur in the feeding vessels and hemodynamic status during hepatocarcinogenesis. Therefore, the imaging criteria for hepatocellular carcinoma (HCC) are also usually based on vascular findings, eg, early arterial uptake followed by washout in the portal venous and equilibrium phases. Contrast-enhanced ultrasonography, dynamic multidetector-row computed tomography (MDCT), and dynamic magnetic resonance (MR) imaging with gadopentetate dimeglumine (Gd-DTPA) are useful for detecting hypervascular HCC on the basis of vascular criteria but are not as useful for hypovascular HCC. Contrast-enhanced MR imaging with gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA), a hepatocyte-specific MR contrast agent, is superior to dynamic MDCT and dynamic MR imaging with Gd-DTPA in detecting both hypervascular and hypovascular HCC. Moreover, Gd-EOB-DTPA-enhanced MR imaging can display each histologically differentiated HCC as hypointense relative to the liver parenchyma. 18F-fluorodeoxyglucose positron emission tomography imaging might not be suitable for the screening and detection of HCC, given its lower diagnostic performance. However, this technique plays an important role in determining whether HCC has spread beyond the liver.

Post-transplantation hepatocellular carcinoma recurrence: Patterns and relation between vascularity and differentiation degree.

To evaluate the relationship between hepatocellular carcinoma (HCC) vascularity and grade; to describe patterns and vascular/histopathological variations of post-transplantation recurrence. This retrospective study included 165 patients (143 men, 22 women; median age 56.8 years, range 28-70.4 years) transplanted for HCC who had a follow-up period longer than 2 mo. Pre-transplantation dynamic computed tomography or magnetic resonance examinations were retrospectively reviewed, classifying HCC imaging enhancement pattern into hypervascular and hypovascular based on presence of wash-in during arterial phase. All pathologic reports of the explanted livers were reviewed, collecting data about HCC differentiation degree. The association between imaging vascular pattern and pathological grade was estimated using the Fisher exact test. All follow-up clinical and imaging data were reviewed for evidence of recurrence. Recurrence rate was calculated and imaging features of recurrent tumor were collected, classifying early and late recurrences based on timing (< or ≥ 2 years after transplantation) and intrahepatic, extrahepatic and both intrahepatic and extrahepatic recurrences based on location. All intrahepatic recurrences were classified as hypervascular or hypovascular and the differentiation degree was collected where available. The presence of variations in imaging enhancement pattern and pathological grade between the primary tumor and the intrahepatic recurrence was evaluated and the association between imaging and histopatholgical variations was estimated by using the χ(2) test. Of the 163 patients with imaging evidence of viable tumor, 156 (95.7%) had hypervascular and 7 (4.3%) hypovascular HCC. Among the 125 patients with evidence of viable tumor in the explanted liver, 19 (15.2%) had grade 1, 56 (44.8%) grade 2, 40 (32%) grade 3 and 4 (3.2%) grade 4 HCC, while the differentiation degree was not assessable for 6 patients (4.8%). A significant association was found between imaging vascularity and pathological grade (P = 0.035). Post-transplantation recurrence rate was 14.55% (24/165). All recurrences occurred in patients who had a hypervascular primary tumor. Three patients (12.5%) experienced late recurrence; the location of the first recurrence was extrahepatic in 14 patients (58.3%), intrahepatic in 7 patients (29.2%) and both intrahepatic and extrahepatic in 3 patients (12.5%). Two patients had a variation in imaging characteristics between the primary HCC (hypervascular) and the intrahepatic recurrent HCC (hypovascular), while 1 patient had a variation of histopathological characteristics (from moderate to poor differentiation), however no association was found between imaging and histopathological variations. A correlation was found between HCC grade and vascularity; some degree of variability may exist between the primary and the recurrence imaging/histopathological characteristics, apparently not correlated.

Contrast-enhanced ultrasound in the diagnosis of nodules in liver cirrhosis

Contrast-enhanced ultrasound (CEUS) using microbubble contrast agents are useful for the diagnosis of the nodules in liver cirrhosis. CEUS can be used as a problem-solving method for indeterminate nodules on computed tomography (CT) or magnetic resonance imaging (MRI) or as an initial diagnostic test for small newly detected liver nodules. CEUS has unique advantages over CT and MRI including no renal excretion of contrast, real-time imaging capability, and purely intravascular contrast. Hepatocellular carcinoma (HCC) is characterized by arterial-phase hypervascularity and later washout (negative enhancement). Benign nodules such as regenerative nodules or dysplastic nodules are usually isoechoic or slightly hypoechoic in the arterial phase and isoechoic in the late phase. However, there are occasional HCC lesions with atypical enhancement including hypovascular HCC and hypervascular HCC without washout. Cholangiocarcinomas are infrequently detected during HCC surveillance and mostly show rim-like or diffuse hypervascularity followed by rapid washout. Hemangiomas are often found at HCC surveillance and are easily diagnosed by CEUS. CEUS can be effectively used in the diagnostic work-up of small nodules detected at HCC surveillance. CEUS is also useful to differentiate malignant and benign venous thrombosis and to guide and monitor the local ablation therapy for HCC.

Images of Sonazoid-enhanced ultrasonography in multistep hepatocarcinogenesis: comparison with Gd-EOB-DTPA-enhanced MRI

Little is known about the difference in enhancement patterns of hepatocellular carcinoma (HCC) during multistep hepatocarcinogenesis between the post-vascular phase of Sonazoid-enhanced ultrasonography (SEUS) and hepatobiliary phase of gadolinium ethoxybenzyl diethylenetriamine (Gd-EOB-DTPA)-enhanced MRI, as well as uptakes of Sonazoid and Gd-EOB-DTPA by HCC. Seventy patients with 73 histologically proven HCCs (33 hypovascular well-differentiated HCCs and 40 progressed HCCs) and 9 dysplastic nodules (DNs) were enrolled. Enhancement patterns of the lesions on the post-vascular phase of SEUS and hepatobiliary phase of Gd-EOB-DTPA-enhanced MRI were evaluated. Uptakes of Sonazoid and Gd-EOB-DTPA were assessed by Sonazoid enhancement index and EOB enhancement ratio in relation to immunohistochemistry of CD68 and organic anion transporting polypeptide 8 (OATP8), respectively. On the post-vascular phase of SEUS, none of the 9 DNs and 3 of 33 hypovascular well-differentiated HCCs (9 %) were hypoechoic, whereas 3 of 9 DNs (33 %) and 31 of 33 hypovascular well-differentiated HCCs (94 %) showed hypointensity on the hepatobiliary phase of Gd-EOB-DTPA-enhanced MRI. Of 31 progressed HCCs, 95 and 93 % were hypoechoic and hypointense on the post-vascular phase of SEUS and hepatobiliary phase of Gd-EOB-DTPA-enhanced MRI, respectively. Sonazoid enhancement indexes decreased in progressed HCCs, correlating with lower Kupffer cell numbers (P < 0.001). EOB enhancement ratios decreased in hypovascular well-differentiated and progressed HCCs, as OATP8 expression declined (P < 0.001). In stepwise hepatocarcinogenesis, uptake of Sonazoid starts decreasing later than that of Gd-EOB-DTPA. Although signal reductions on the post-vascular phase of SEUS or hepatobiliary phase of Gd-EOB-DTPA-enhanced MRI suggest HCC, hypoechoic appearance on the post-vascular phase of SEUS might be HCC-specific, particularly progressed HCC.

Validation of diagnostic criteria using gadoxetic acid-enhanced and diffusion-weighted MR imaging for small hepatocellular carcinoma (≤ 2.0 cm) in patients with hepatitis-induced liver cirrhosis

Gadoxetic acid and diffusion-weighted imaging (DWI) is increasingly used for the diagnosis of hepatocellular carcinoma (HCC). It is relevant to refine the diagnostic parameters for HCC, using state-of-the-art imaging techniques. To validate usefulness of magnetic resonance imaging (MRI) criteria with gadoxetic acid-enhanced MRI and DWI for diagnosis of small HCC by differentiation from dysplastic nodule (DN) or regenerative nodule (RN) in cirrhotic patients with strongly suspected small HCC. One hundred and eight patients with 102 HCCs and 29 benign nodules including 21 DNs and two large RNs (≤ 2.0 cm), and 40 patients with no HCC underwent gadoxetic acid-enhanced MRI and DWI. All patients also underwent MDCT. Index MR criteria for HCC were: (i) arterial hyperenhancement and hypointensity on hepatobiliary phase (HBP) with hyperintensity on DWI; (ii) hypovascular nodule with hyperintensity on DWI; (iii) arterial hyperenhancement and hypointensity on HBP without hyperintensity on DWI; (iv) arterial hyperenhancement and either iso- or hyperintensity on HBP, with hyperintensity on DWI; and (v) hyperintensity only on DWI. According to these criteria, MRI findings for HCCs and benign nodules were independently classified by two reviewers. On multidetector-row computed tomography, 64 HCCs (62.7%) showed typical features for HCC while 13 (12.8%) were not identified. On MRI, 84 HCCs (82.4%) showed arterial hyperenhancement and hypointensity on HBP, and hyperintensity on DWI. Eight HCCs were regarded as hypovascular HCCs with hyperintensity DWI (category 2). One HCC (0.6 cm in diameter) was demonstrated only by DWI. For each observer, 101 (99.0%) and 100 HCCs (98.0%) were discernible when applying all MRI criteria for HCC, respectively. Three DNs also fit the HCC criteria, thus the specificity was 90.9% for both observers. With the HCC criteria based on combined gadoxetic acid-enhanced MRI and DWI, it is possible to reliably diagnose small HCC including hypovascular HCCs.

Clinical implication of hypovascular hepatocellular carcinoma studied in 4,474 patients with solitary tumour equal or less than 3 cm

To clarify the biological behaviour of small hypovascular hepatocellular carcinoma (HCC) because of insufficient evidence even though frequently encountered. The study covered naïve 4,474 patients who met solitary HCC ≤ 3 cm (mean, 2.1 cm), histopathologically proven and Child Pugh A or B. Macroscopic vascular invasion and distant metastasis were excluded. The hypovascularity of tumour was defined as hypo- or iso-enhancement in arterial phase of multiple dynamic imaging techniques. Of them, 802 (18%) were hypovascular. The ratio of hypovascular HCC decreased as tumour size increased (P < 0.001) and most of them developed to hypervascular type when they grew over 1.5 cm. Hypovascular group showed a significantly higher ratio of well differentiated grade (P < 0.001) and marginally less incidence of microvascular invasion and metastases compared with hypervascular group. The histologic dedifferentiation (less differentiation) developed step-by-step as tumour size increased in hyper- and even hypovascular group. The des-γ-carboxy prothrombin (DCP) value ≥ 300 mAU/ml was closely correlated with increase of tumour size in both groups. Logistic regression analysis revealed five variables were independent predictors for hypovascular HCC; tumour size ≤ 1.5 cm, alpha-fetoprotein < 200 ng/ml, DCP < 40 mAU/ml, well differentiated grade, and positivity for hepatitis C virus antibody. Hypovascular HCC was biologically less aggressive and developed with stepwise dedifferentiation and transformation to hypervascular appearance along with tumour growth. These results will help in leading correct diagnosis of small hypovascular tumour and assessing optimal treatment for hypovascular HCC ≤ 3 cm.

Early Hepatocellular Carcinomas Showing Isointensity or Hyperintensity in Gadoxetic Acid–Enhanced, Hepatocyte-Phase Magnetic Resonance Images

Hypointensity in the hepatocyte phase is believed to be a key feature of hypovascular early hepatocellular carcinoma, which indicates malignancy. The 3 cases we present suggest that the converse is not true. Three small hepatocellular lesions showed isointensity/hyperintensity on gadoxetic acid-enhanced, hepatocyte-phase magnetic resonance images and were pathologically confirmed as early hepatocellular carcinomas. We conclude that isointensity or hyperintensity in the hepatocyte phase does not always represent benignity of hepatocellular lesions in the cirrhotic liver.