Hepatocellular carcinoma: modern aspects of interdisciplinary management. Part 1. Epidemiology, risk factors, diagnosis

Background: Hepatocellular carcinoma (HCC) is the most common form of liver cancer and the third cause of cancer-related death worldwide. Its incidence is increasing mainly due to hepatitis C virus (HCV) infection. A molecular classification of HCC is still lacking. microRNAs (miRNAs) are small non-coding RNA involved in HCC pathogenesis. Their expression profiling represents a powerful tool to classify cancers. Objectives: (1) To provide a miRNA-based molecular classification of HCC and, (2) To investigate the function of potential oncogenic miRNAs in HCC models. Methods: Expression of 358 miRNAs was analyzed in 89 HCV-related HCCs using a bead-based miRNA expression profiling method. Integrative analysis including miRNA profiling, gene expression (Affymetrix U133 2.0®), DNA changes (Affymetrix STY Mapping Array®), IHC (p-Akt, p-IGF-IR, p-S6, p-EGFR, β-catenin) and mutation analysis (β-catenin) was performed. Expression of selected miRNA was validated in a validation set (n=167) by qRT-PCR. Methylation-specific PCR, FISH and SNP-array analyses were performed to identify mechanisms of miRNA deregulation. The function of miRNAs of interest was investigated in vitro by analyzing cell proliferation (thymidine incorporation), migration and invasion (trans-well migration and invasion assays, wound healing assay). Tumor development and growth following direct injection of luciferase-expressing cells stably transfected with specific miRNAs into the liver of nude mice were monitored to investigate their function in vivo. The bioluminescent signal emitted by luciferase-expressing cells was used as indicator of tumor growth. Results: Three classes of HCC patients were identified and defined by activation of different pathways: Wnt signalling (32/89, 36%), IFN-related genes (29/89, 33%) and proliferative cascades (IGF, Akt/mTOR) (28/89, 31%). A subgroup within the proliferative class (8/89, 9% overexpressed a cluster of miRNAs on 19q13.42 (median fold change: 8.8). Hypomethylation of CpG island upstream the miRNA cluster (2/8, 25%) and copy number gains (1/8, 12.5%) were detected. Their overexpression was confirmed in a validation set (17/167, 10.2%). Members of the cluster family significantly increased proliferation (p<0.05), migration (p<0.02) and invasive capability (p<0.05) in vitro and promoted tumor development in vivo (detectable liver tumor in 4/6 mice compared with 0/6 of the controls after 4 weeks following injection). One mouse of the active arm was sacrificed at week 5 showing large invasive HCC at pathological study, while the others are still alive. Conclusions: Overexpression of 19q miRNA family and activation of proliferative pathways defined a subclass of HCC. Members of 19q miRNA family increased cell proliferation, migration and invasion in vitro and promoted tumor development in vivo suggesting their role as novel potential oncogenic drivers in HCC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2996.

After approval of imatinib for treatment of chronic myeloid leukemia,1 molecular-targeted therapies make change of the management strategies against cancers. Many target molecules have been revealed in several cancers such as lung cancer, breast cancer, colorectal cancer, and hematopoietic tumor. Representative molecular-targeted agents are trastuzumab for breast cancer, imatinib and rituximab for hematopoietic tumors, and gefitinib and erlotinib for lung cancer. These molecular-targeted agents improved patient’s survival and life quality. Hepatocellular carcinoma (HCC) is one of the popular cancers in the world. The prognosis is still poor even though we have tried to detect it at early stage and treat it properly with numerous treatment modalities such as transarterial chemoembolization (TACE), radiofrequency ablation (RFA), systemic cytotoxic chemotherapy, surgical resection and liver transplantation. Now, we have only one approved molecular-targeted agent against advanced HCC with limited efficacy, which is sorafenib as an inhibitor of tyrosine kinases such as the vascular endothelial growth factor receptor (VEGFR) and platelet derived growth factor receptor (PDGFR).2,3 Unfortunately, the carcinogenesis pathway of HCC is not clear compared to other cancers. Several targets such as VEGFR, PDGFR, epidermal growth factor receptor, fibroblast growth factor receptor, and mammalian target of rapamycin (mTOR) were investigated recently and several molecular-targeted agents such as brivanib, sunitinib, linifanib erlotinib and everolimus were clinically studied but, the results were disappointing.4 Some signaling pathways including growth factor pathway, Jak/Stat pathway, Akt/mTOR pathway, Hedgehog pathway, Wnt/β-catenin pathway can be molecular targets for treatment of HCC.5 Although great efforts have been made for looking out the unique target molecule of HCC, we don’t know the proper molecular targets of HCC which can be investigated for the development of new molecular-targeted agents. So, we need new effective molecular target of HCC, when it blocked, it improves patient’s survival and life quality, as other tumors were treated with their own molecular-targeted agents. Several international clinical guidelines recommend the diagnosis criteria of HCC without liver mass biopsy in selected conditions.6–8 Because of these diagnosis criteria, liver mass biopsies have been decreased dramatically compared to past decade. These diagnosis strategies of HCC without biopsy improve clinical convenience and we can avoid the complications of liver biopsy especially in patients with cirrhosis such as bleeding and tumor seeding. But, we lose the opportunity for getting HCC tissues. Without tissues, we could not progress in molecular classification of HCC. And we could not find the unique molecular targets for HCC. From these perspectives, the article titled “High expression of ribonucleotide reductase subunit M2 correlates with poor prognosis of hepatocellular carcinoma” by Lee et al.9 has several meaningful messages. First, Ribonucleotide reductase subunit M2 (RRM2) could be target molecule of HCC, which is another field of target molecule in HCC. It is essential for DNA synthesis therefore inhibition of RRM2 could stop DNA synthesis and cell proliferation.10 RRM2 could be considered a promising target for HCC therapy. Second, RRM2 overexpression could induce nuclear factor-κB activation and matrix metalloproteinase-9, which enhance invasiveness of HCC. So, RRM2 overexpression is reasonable marker of early recurrence of HCC. RRM2, as biomarker of invasiveness, is meaningful independent factor for prognosis after curative resection of HCC and similar with pathologic feature such as tumor size, micro-vascular invasion and intrahepatic metastasis. If we have more valuable biomarkers of HCC for prognosis, we could do better decision making for patients care. We need more prognostic biomarkers for improving patient’s survival and proper management of HCC. Third, tissue study is mandatory for improving molecular classification of HCC, which is the weak point of HCC compared to other cancers. We need more liver mass biopsies or tissue specimens for investigation of the proper and unique target molecules of HCC. The introduction of sorafenib was the start of paradigm shift of HCC treatment, but recent disappointing results of several molecular-targeted agents against HCC persuade us to find out new targets of HCC. We need to get liver biopsies or specimens for tissue studies and molecular classification of HCC, which could be the start of investigation for new targets and biomarkers of HCC. It will develop the management strategy of HCC in the era of molecular-targeted therapy.

We found that the occurrence of hepatocellular carcinoma (HCC) has increased significantly in non-cirrhotic individuals, with HCC being frequently overlooked or misdiagnosed. Contrast-enhanced ultrasound (CEUS) Liver Imaging Reporting and Data System (LI-RADS) is known to have a high diagnostic quality in high-risk HCC patients. Therefore, we aimed to compare the detection accuracy of CEUS LI-RADS for HCC between low- and high-risk individuals, to confirm its value in low-risk patients at increased risk of HCC, but not yet included in the high-risk groups of LI-RADS. In addition, since CEUS LR-4 and LR-M categories contain a relatively high proportion of HCC, and serum alpha-fetoprotein (AFP) is the most commonly used biomarker for HCC, and the clinically valid, we attempted to further improve the early diagnostic capability of CEUS LI-RADS for HCC in the low-risk and high-risk patients by combining CEUS LR-4 and LR-M categories with AFP. We defined high-risk groups (HR)-included in the high-risk patients of LI-RADS, low-risk groups (LR)-not included in the high-risk patients of LI-RADS and enrolled 189 HCC patients with LR and HR settings in a retrospective study. All lesions were confirmed histopathologically. The CEUS LI-RADS accuracy for detecting HCC in these two patients was compared. In addition, the diagnostic algorithm in our study was proposed (for CEUS LR-4 and LR-M patients with AFP>20 ng/ml). we analyzed the ability of CEUS LI-RADS as a valid method of establishing the early diagnosis of HCC in LR and HR patients by combining LR-4 and LR-M categories with AFP. Through comparative analysis, the specificity of the CEUS LR-5 category for HCC in the HR group was 78.4%, whereas in the LR group, it was 94.2%. Meanwhile, the sensitivity (63.2% vs. 63.0%) and positive predictive value (PPV) (75.0% vs. 88.7%) did not differ between the LR and HR groups ( P = 0.990, P = 0.299). It is noteworthy that there were the high proportion of HCC in CEUS LR-4 and LR-M categories in our cases and when we combined CEUS LR-4 and LR-M categories with AFP significantly improved the sensitivity by 21.0% (84.2%) in the LR group, and by 16.0% (79.0%) in the HR group, with statistically difference in sensitivity after combination in the HR group ( P = 0.014). The CEUS LR-5 category has real meaningful utility in the diagnosis of HCC in both LR and HR patients. The early detection power of the CEUS LI-RADS category for HCC patients was further increased when the CEUS LR-4 and LR-M categories were combined with elevated AFP.

Hepatocellular carcinoma (HCC) is one of the major causes of morbidity, mortality and healthcare expenditure in patients with chronic liver disease. There are no consensus guidelines on diagnosis and management of HCC in India. The Indian National Association for Study of the Liver (INASL) set up a Task-Force on HCC in 2011, with a mandate to develop consensus guidelines for diagnosis and management of HCC, relevant to disease patterns and clinical practices in India. The Task-Force first identified various contentious issues on various aspects of HCC and these issues were allotted to individual members of the Task-Force who reviewed them in detail. The Task-Force used the Oxford Center for Evidence Based Medicine-Levels of Evidence of 2009 for developing an evidence-based approach. A 2-day round table discussion was held on 9th and 10th February, 2013 at Puri, Odisha, to discuss, debate, and finalize the consensus statements. The members of the Task-Force reviewed and discussed the existing literature at this meeting and formulated the INASL consensus statements for each of the issues. We present here the INASL consensus guidelines (The Puri Recommendations) on prevention, diagnosis and management of HCC in India.

PurposeTo achieve a historical perspective, the chronological changes in primary liver cancer over a 20-year period were investigated at a single institution, focusing on shifts in etiology and the impact on imaging and pathological findings using The Liver Imaging Reporting and Data System.Materials and methodsA retrospective study of surgically resected primary liver cancer in 680 patients from 2001 to 2020 resulted in 434 patients with 482 nodules being analyzed. Dynamic contrast-enhanced computed tomography imaging and the Liver Imaging Reporting and Data System 2018 classification were employed. Two pathologists and two radiologists independently evaluated specimens and images.ResultsThis study highlighted a significant decline in cases of viral hepatitis and cirrhosis in primary liver cancer patients but an increase in intrahepatic cholangiocarcinoma and scirrhous hepatocellular carcinoma. Notably, there was a rise in non-viral hepatitis cases, potentially pointing toward an increase in steatohepatitic hepatocellular carcinoma cases in the future. Intrahepatic cholangiocarcinoma, scirrhous hepatocellular carcinoma and steatohepatitic hepatocellular carcinoma tumors exhibited slightly different distributions in the Liver Imaging Reporting and Data System classification compared with ordinary hepatocellular carcinoma, which may reflect the presence of fibrosis and lipid in tumor parenchyma.ConclusionsConsistent with past reports, this study demonstrated the emergence of primary liver cancer against a backdrop of non-viral and non-cirrhotic liver. Liver Imaging Reporting and Data System has been consistently useful in diagnosing primary liver cancer; however, among the histological subtypes of hepatocellular carcinoma, an increase is anticipated in scirrhous hepatocellular carcinoma and steatohepatitic hepatocellular carcinoma, which may present imaging findings different from those of ordinary hepatocellular carcinoma. This development may necessitate a reevaluation of the current approach for diagnosing and treating hepatocellular carcinoma based solely on imaging.

The development of high-throughput technologies able to simultaneously investigate thousands of genes (e.g. single nucleotide polymorphism-array, gene expression microarray, etc.) has opened a new era in translational research. Obtaining a molecular classification of hepatocellular carcinoma, however, remains a striking challenge. This review summarizes the molecular classifications of hepatocellular carcinoma reported so far, analyzes the status of targeted therapies tested in clinical trials, and evaluates feasibility of personalized medicine approaches in hepatocellular carcinoma. Different investigators attempted to classify patients according to their liver cancer molecular background, a feature that will path the way for trial enrichment and personalized medicine. Currently, hepatocellular carcinoma can be classified in molecular classes according to Wnt-beta-catenin pathway activation, proliferation signature activation (associated with chromosomal instability), and other subgroups. In parallel, the first-time-ever positive results of a phase III trial in advanced hepatocellular carcinoma with the multikinase inhibitor sorafenib have encouraged this approach. Selection of patient candidates according to their tumor molecular background is a reality in human malignancies. Thus, a molecular classification is essential to allow the development of new targets, and to customize therapies in patients with hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a highly complex disease that is generally resistant to commonly used chemotherapy and radiotherapy. Consequently, there is an urgent need for the development of new treatment strategies for this devastating disease. In the past decade, tremendous progress has been achieved in the molecular stratification of HCCs for diagnosis, prognosis, and therapeutic decision-making. To date, the molecular classification of HCCs has been carried out through transcriptomic, genetic and epigenetic profiling of tumors. Such research has led to identification of several potential molecular targets in HCC, and subsequently, development of novel systemic agents for the treatment of HCC has begun in earnest. In this article, we review the current knowledge of the molecular pathogenesis of HCC and outline potential areas for application of this knowledge in a clinical setting. As a typical virus and inflammation-associated cancer, both host immune response and tumor microenvironment have crucial roles in HCC pathogenesis. In addition, we examine the potential of immunotherapy and strategies targeting various components of the tumor microenvironment, as well as novel molecular and cellular targets in HCC such as cancer stem cells.

Patients with indeterminate liver nodules, classified as LR-3 and LR-4 observations per the Liver Imaging Reporting and Data System, are at risk of developing hepatocellular carcinoma (HCC), but risk estimates remain imprecise. We conducted a systematic review of Ovid MEDLINE, EMBASE, and Cochrane databases from inception to December 2021 to identify cohort studies examining HCC incidence among patients with LR-3 or LR-4 observations on computed tomography (CT) or magnetic resonance imaging (MRI). Predictors of HCC were abstracted from each study, when available. Of 13 total studies, nine conducted LR-3 observation-level analyses, with the proportions of incident HCC ranging from 1.2% to 12.5% at 12 months and 4.2% to 44.4% during longer study follow-up. Among three studies with patient-level analyses, 8%-22.2% of patients with LR-3 lesions developed LR-4 observations and 11.1%-24.5% developed HCC. Among nine studies conducting LR-4 observation-level analyses, incident HCC ranged from 30.8% to 44.0% at 12 months and 30.9% to 71.0% during study follow-up; conversely, 6%-42% of observations were downgraded to LR-3 or lower. Patient-level factors associated with HCC included older age, male sex, higher alpha-fetoprotein levels, viral etiology, and prior history of HCC; observation-level factors included maximum diameter, threshold growth, T2 hyperintensity, and visibility on ultrasound. Studies were limited by small sample sizes, inclusion of patients with prior HCC, short follow-up duration, and failure to account for clustering of observations in patients or competing risks of transplantation and death. LR-3 and LR-4 observations have elevated but variable risks of HCC. Higher quality studies are necessary to identify high-risk patients who warrant close CT or MRI-based follow-up.

Hepatocellular carcinomas represent the third leading cause of cancer-related deaths worldwide. The vast majority of cases arise in the context of chronic liver injury due to hepatitis B virus or hepatitis C virus infection. To identify genetic mechanisms of hepatocarcinogenesis, we characterized copy number alterations and gene expression profiles from the same set of tumors associated with hepatitis C virus. Most tumors harbored 1q gain, 8q gain, or 8p loss, with occasional alterations in 13 additional chromosome arms. In addition to amplifications at 11q13 in 6 of 103 tumors, 4 tumors harbored focal gains at 6p21 incorporating vascular endothelial growth factor A (VEGFA). Fluorescence in situ hybridization on an independent validation set of 210 tumors found 6p21 high-level gains in 14 tumors, as well as 2 tumors with 6p21 amplifications. Strikingly, this locus overlapped with copy gains in 4 of 371 lung adenocarcinomas. Overexpression of VEGFA via 6p21 gain in hepatocellular carcinomas suggested a novel, non-cell-autonomous mechanism of oncogene activation. Hierarchical clustering of gene expression among 91 of these tumors identified five classes, including "CTNNB1", "proliferation", "IFN-related", a novel class defined by polysomy of chromosome 7, and an unannotated class. These class labels were further supported by molecular data; mutations in CTNNB1 were enriched in the "CTNNB1" class, whereas insulin-like growth factor I receptor and RPS6 phosphorylation were enriched in the "proliferation" class. The enrichment of signaling pathway alterations in gene expression classes provides insights on hepatocellular carcinoma pathogenesis. Furthermore, the prevalence of VEGFA high-level gains in multiple tumor types suggests indications for clinical trials of antiangiogenic therapies.

Liver cancer: Approaching a personalized care

Simple SummaryThis retrospective study focused on 23 patients diagnosed with Hepatocellular Carcinoma (HCC), utilizing the Liver Imaging Reporting and Data System (LI-RADS) for classification. This system aids in the non-invasive diagnosis of HCC, potentially eliminating the need for a diagnostic biopsy. Patients were selected based on their diagnosis, confirmed either via imaging methods that identified advanced liver nodules or via histopathological findings consistent with HCC, including specific protein markers. The study aimed to assess the histopathological changes resulting from prior local interventions, such as trans-arterial chemoembolization or radiofrequency ablation, and their impact on the tumor’s response to subsequent immune therapies. Key findings indicated variations in alpha-fetoprotein levels and increased expression of the immune marker PD-L1 in untreated patients, suggesting a more aggressive cancer progression in these individuals. The study’s conclusions support the use of liver biopsy in refining therapeutic approaches for HCC, particularly in recurrent cases post-intervention, to enhance personalized immune therapy strategies.Background: The Liver Imaging Reporting and Data System (LI-RADS) combines standardized terminology with a classification system for imaging findings in patients with HCC, therefore rendering diagnostic biopsy unnecessary in many cases. This retrospective study included 23 patients with a biopsy diagnosis of HCC, performed either before or after local interventional procedures, in order to evaluate the histopathologic changes induced by previous procedures and their potential influence on the response to immune therapy. Material and Methods: The study encompassed a cohort of patients diagnosed with Hepatocellular Carcinoma (HCC). Diagnosis was established via contrast-enhanced computer tomography or magnetic resonance imaging that identified LI-RADS-5 nodules in conjunction with historical liver disease and elevated alpha-fetoprotein (AFP) levels or via histological examination confirming positivity for glypican3, heat shock protein 70, and glutamine synthetase. The study detailed the liver disease etiology, LI-RADS scores, characteristics and dimensions of HCC nodules, serum AFP concentrations, Edmondson–Steiner grading, and the expression of programmed cell death ligand 1 (PD-L1) in the tumor cells. Results: Among the study’s cohort of Hepatocellular Carcinoma (HCC) patients, a portion had not received any prior treatments, while the remainder experienced local HCC recurrence following trans-arterial chemoembolization or radiofrequency ablation. Observations indicated elevated alpha-fetoprotein (AFP) levels in those who had not undergone any previous interventions, showing statistical significance. The Edmondson–Steiner classification predominantly identified grade III differentiation across patients, irrespective of their treatment history. Furthermore, an increase in intra-tumoral programmed cell death ligand 1 (PD-L1) expression was noted in patients who had not been subjected to previous therapies. Conclusion: Liver biopsy offers valuable insights for patients with Hepatocellular Carcinoma (HCC), assisting in the tailoring of immune therapy strategies, particularly in cases of recurrence following prior local interventions.

Surveillance for Hepatocellular Carcinoma: Current Best Practice and Future Direction.

Background American College of Radiology contrast agent-enhanced US Liver Imaging Reporting and Data System (CEUS LI-RADS) was developed to improve the accuracy of hepatocellular carcinoma (HCC) diagnosis at contrast agent-enhanced US. However, to the knowledge of the authors, the diagnostic accuracy of the system in characterization of liver nodules 20 mm or smaller has not been fully evaluated. Purpose To evaluate the diagnostic accuracy of CEUS LI-RADS in diagnosing HCC in liver nodules 20 mm or smaller in patients at risk for HCC. Materials and Methods Between January 2015 and February 2018, consecutive patients at risk for HCC presenting with untreated liver nodules 20 mm or less were enrolled in this retrospective double-reader study. Each nodule was categorized according to the CEUS LI-RADS and World Federation for Ultrasound in Medicine and Biology (WFUMB)-European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB) criteria. Diagnostic performance of CEUS LI-RADS and WFUMB-EFSUMB characterization was evaluated by using tissue histologic analysis, multiphase contrast-enhanced CT and MRI, and imaging follow-up as reference standard and compared by using McNemar test. Results The study included 175 nodules (mean diameter, 16.1 mm ± 3.4) in 172 patients (mean age, 51.8 years ± 10.6; 136 men). The sensitivity of CEUS LR-5 versus WFUMB-EFSUMB criteria in diagnosing HCC was 73.3% (95% confidence interval [CI]: 63.8%, 81.5%) versus 88.6% (95% CI: 80.9%, 94%), respectively (P < .001). The specificity of CEUS LR-5 versus WFUMB-EFSUMB criteria was 97.1% (95% CI: 90.1%, 99.7%) versus 87.1% (95% CI: 77%, 94%), respectively (P = .02). No malignant lesions were found in CEUS LR-1 and LR-2 categories. Only two nodules (of 41; 5%, both HCC) were malignant in CEUS LR-3 category. The incidences of HCC in CEUS LR-4, LR-5, and LR-M were 48% (11 of 23), 98% (77 of 79), and 75% (15 of 20), respectively. Two of 175 (1.1%) histologic analysis-confirmed intrahepatic cholangiocarcinomas were categorized as CEUS LR-M by CEUS LI-RADS and misdiagnosed as HCC by WFUMB-EFSUMB criteria. Conclusion The contrast-enhanced US Liver Imaging Reporting and Data System (CEUS LI-RADS) algorithm was an effective tool for characterization of small (≤20 mm) liver nodules in patients at risk for hepatocellular carcinoma (HCC). Compared with World Federation for Ultrasound in Medicine and Biology-European Federation of Societies for Ultrasound in Medicine and Biology criteria, CEUS LR-5 demonstrated higher specificity for diagnosing small HCCs with lower sensitivity. Published under a CC BY 4.0 license. See also the editorial by Crocetti in this issue.

To determine the strength of association with hepatocellular carcinoma (HCC) of each ancillary feature (AF) in LI-RADS version 2018, and to develop an appropriate strategy for applying AFs to improve the diagnosis of HCC ≤ 3cm on gadoxetate-enhanced MRI. A total of 385 nodules (283 HCCs, 18 non-HCC malignancies, 84 benign nodules) of ≤ 3cm in 266 patients at risk for HCC who underwent gadoxetate-enhanced MRI in 2016 were retrospectively evaluated. Two radiologists independently evaluated the presence/absence of AFs, and assigned a LI-RADS category to each nodule. Diagnostic odds ratio (DOR) of each AF was assessed. To improve the diagnostic performance for HCC, various criteria were developed based on the number of AFs favoring malignancy in general or HCC in particular. Generalized estimating equation models were used to compare the diagnostic performance of each criterion with that of the major features (MFs) only. All AFs favoring HCC in particular and malignancy in general were more common in the HCC group than in the non-HCC group. Of these AFs, hepatobiliary-phase hypointensity had the strongest association with HCC (DOR, 21.82; 95% confidence interval, 5.59-85.20). When we applied AFs in addition to MFs, the new criterion (with a number of AFs ≥ 4) had significantly higher sensitivity (80.6% vs. 70.0%; p < 0.001) than MFs only, without significant lower specificity (85.3% vs. 90.2%; p = 0.060). The AFs varied in the strengths of association with HCC. More strict application of AFs (AFs ≥ 4) in LR-3 may improve the diagnostic performance for probable HCC ≤ 3cm. • The ancillary features (AFs) in the Liver Imaging Reporting and Data System version 2018 showed variable frequencies of occurrence and strengths of association with hepatocellular carcinoma (HCC). • Of the various AFs, hepatobiliary-phase hypointensity had the highest frequency and strongest association with HCC on gadoxetate disodium-enhanced MRI. • When applying AFs in addition to major features, a criterion of four or more AFs significantly increased the sensitivity for diagnosing HCC, without a significantly decreased specificity, especially in LR-3 observations.

Prognostic biomarkers in and selection of surgical patients with hepatocellular carcinoma.