Contrast-enhanced ultrasound Liver Imaging Reporting and Data System:Lights and shadows in hepatocellular carcinoma and cholangiocellular carcinoma diagnosis

BACKGROUND Contrast-enhanced ultrasound(CEUS)is considered a secondary examination compared to computed tomography(CT)and magnetic resonance imaging(MRI)in the diagnosis of hepatocellular carcinoma(HCC),due to the risk of misdiagnosing intrahepatic cholangiocarcinoma(ICC).The introduction of CEUS Liver Imaging Reporting and Data System(CEUS LI-RADS)might overcome this limitation.Even though data from the literature seems promising,its reliability in real-life context has not been well-established yet.AIM To test the accuracy of CEUS LI-RADS for correctly diagnosing HCC and ICC in cirrhosis.METHODS CEUS LI-RADS class was retrospectively assigned to 511 nodules identified in 269 patients suffering from liver cirrhosis.The diagnostic standard for all nodules was either biopsy(102 nodules)or CT/MRI(409 nodules).Common diagnostic accuracy indexes such as sensitivity,specificity,positive predictive value(PPV),and negative predictive value(NPV)were assessed for the following associations:CEUS LR-5 and HCC;CEUS LR-4 and 5 merged class and HCC;CEUS LR-M and ICC;and CEUS LR-3 and malignancy.The frequency of malignant lesions in CEUS LR-3 subgroups with different CEUS patterns was also determined.Inter-rater agreement for CEUS LI-RADS class assignment and for major CEUS pattern identification was evaluated.RESULTS CEUS LR-5 predicted HCC with a 67.6%sensitivity,97.7%specificity,and 99.3%PPV(P<0.001).The merging of LR-4 and 5 offered an improved 93.9%sensitivity in HCC diagnosis with a 94.3%specificity and 98.8%PPV(P<0.001).CEUS LR-M predicted ICC with a 91.3%sensitivity,96.7%specificity,and 99.6%NPV(P<0.001).CEUS LR-3 predominantly included benign lesions(only 28.8%of malignancies).In this class,the hypo-hypo pattern showed a much higher rate of malignant lesions(73.3%)than the iso-iso pattern(2.6%).Inter-rater agreement between internal raters for CEUS-LR class assignment was almost perfect(n=511,k=0.94,P<0.001),while the agreement among raters from separate centres was substantial(n=50,k=0.67,P<0.001).Agreement was stronger for arterial phase hyperenhancement(internal k=0.86,P<2.7×10-214;external k=0.8,P<0.001)than washout(internal k=0.79,P<1.6×10-202;external k=0.71,P<0.001).CONCLUSION CEUS LI-RADS is effective but can be improved by merging LR-4 and 5 to diagnose HCC and by splitting LR-3 into two subgroups to differentiate iso-iso nodules from other patterns.

Interobserver agreement for contrast-enhanced ultrasound of liver imaging reporting and data system:A systematic review and metaanalysis

BACKGROUND Hepatocellular carcinoma is the most common primary liver malignancy.From the results of previous studies,Liver Imaging Reporting and Data System(LIRADS)on contrast-enhanced ultrasound(CEUS)has shown satisfactory diagnostic value.However,a unified conclusion on the interobserver stability of this innovative ultrasound imaging has not been determined.The present metaanalysis examined the interobserver agreement of CEUS LI-RADS to provide some reference for subsequent related research.AIM To evaluate the interobserver agreement of LI-RADS on CEUS and analyze the sources of heterogeneity between studies.METHODS Relevant papers on the subject of interobserver agreement on CEUS LI-RADS published before March 1,2020 in China and other countries were analyzed.The studies were filtered,and the diagnostic criteria were evaluated.The selected references were analyzed using the“meta”and“metafor”packages of R software version 3.6.2.RESULTS Eight studies were ultimately included in the present analysis.Meta-analysis results revealed that the summary Kappa value of included studies was 0.76[95%confidence interval,0.67-0.83],which shows substantial agreement.Higgins I2 statistics also confirmed the substantial heterogeneity(I2=91.30%,95%confidence interval,85.3%-94.9%,P<0.01).Meta-regression identified the variables,including the method of patient enrollment,method of consistency testing,and patient race,which explained the substantial study heterogeneity.CONCLUSION CEUS LI-RADS demonstrated overall substantial interobserver agreement,but heterogeneous results between studies were also obvious.Further clinical investigations should consider a modified recommendation about the experimental design.

Hepatocellular carcinoma Liver Imaging Reporting and Data Systems treatment response assessment: Lessons learned and future directions

Hepatocellular carcinoma(HCC)is a leading cause of morbidity and mortality worldwide,with rising clinical and economic burden as incidence increases.There are a multitude of evolving treatment options,including locoregional therapies which can be used alone,in combination with each other,or in combination with systemic therapy.These treatment options have shown to be effective in achieving remission,controlling tumor progression,improving disease free and overall survival in patients who cannot undergo resection and providing a bridge to transplant by debulking tumor burden to downstage patients.Following locoregional therapy(LRT),it is crucial to provide treatment response assessment to guide management and liver transplant candidacy.Therefore,Liver Imaging Reporting and Data Systems(LI-RADS)Treatment Response Algorithm(TRA)was created to provide a standardized assessment of HCC following LRT.LIRADS TRA provides a step by step approach to evaluate each lesion independently for accurate tumor assessment.In this review,we provide an overview of different locoregional therapies for HCC,describe the expected post treatment imaging appearance following treatment,and review the LI-RADS TRA with guidance for its application in clinical practice.Unique to other publications,we will also review emerging literature supporting the use of LI-RADS for assessment of HCC treatment response after LRT.

Liver Imaging Reporting and Data System criteria for the diagnosis of hepatocellular carcinoma in clinical practice: A pictorial minireview

Hepatocellular carcinoma(HCC)is the sixth most common cancer.The main risk factors associated with HCC development include hepatitis B virus,hepatitis C virus,alcohol consumption,aflatoxin B1,and nonalcoholic fatty liver disease.However,hepatocarcinogenesis is a complex multistep process.Various factors lead to hepatocyte malignant transformation and HCC development.Diagnosis and surveillance of HCC can be made with the use of liver ultrasound(US)every 6 mo.However,the sensitivity of this imaging method to detect HCC in a cirrhotic liver is limited,due to the abnormal liver parenchyma.Computed tomography(CT)and magnetic resonance imaging(MRI)are considered to be most useful tools for at-risk patients or patients with inadequate US.Liver biopsy is still used for diagnosis and prognosis of HCC in specific nodules that cannot be definitely characterized as HCC by imaging.Recently the American College of Radiology designed the Liver Imaging Reporting and Data System(LI-RADS),which is a comprehensive system for standardized interpretation of CT and MRI liver examinations that was first proposed in 2011.In 2018,it was integrated into the American Association for the Study of Liver Diseases guidance statement for HCC.LI-RADS is designed to ensure high sensitivity,precise categorization,and high positive predictive value for the diagnosis of HCC and is applied to“highrisk populations”according to specific criteria.Most importantly LI-RADS criteria achieved international collaboration and consensus among liver experts around the world on the best practices for caring for patients with or at risk for HCC.

Differentiating malignant and benign focal liver lesions in children using CEUS LI-RADS combined with serum alpha-fetoprotein

BACKGROUND Contrast-enhanced ultrasound(CEUS)can be used to diagnose focal liver lesions(FLLs)in children.The America College of Radiology developed the CEUS liver imaging reporting and data system(LI-RADS)for standardizing CEUS diagnosis of FLLs in adult patients.Until now,no similar consensus or guidelines have existed for pediatric patients to improve imaging interpretation as adults.AIM To evaluate the performance of CEUS LI-RADS combined with alpha-fetoprotein(AFP)in differentiating benign and malignant FLLs in pediatric patients.METHODS Between January 2011 and January 2021,patients≤18 years old who underwent CEUS for FLLs were retrospectively evaluated.The following criteria for diagnosing malignancy were proposed:Criterion I considered LR-4,LR-5,or LRM lesions as malignancies;criterion II regarded LR-4,LR-5 or LR-M lesions with simultaneously elevated AFP(≥20 ng/mL)as malignancies;criterion III took LR-4 Lesions with elevated AFP or LR-5 or LR-M lesions as malignancies.The sensitivity,specificity,accuracy and area under the receiver operating characteristic curve(AUC)were calculated to determine the diagnostic value of the aforementioned criteria.RESULTS The study included 63 nodules in 60 patients(mean age,11.0±5.2 years;26 male).There were no statistically significant differences between the specificity,accuracy,or AUC of criterion II and criterion III(95.1%vs 80.5%,84.1%vs 87.3%,and 0.794 vs 0.902;all P>0.017).Notably,criterion III showed a higher diagnostic sensitivity than criterion II(100%vs 63.6%;P<0.017).However,both the specificity and accuracy of criterion I was inferior to those of criterion II and criterion III(all P<0.017).For pediatric patients more than 5 years old,the performance of the three criteria was overall similar when patients were subcategorized by age when compared to all patients in aggregate.CONCLUSION CEUS LI-RADS combined with AFP may be a powerful diagnostic tool in pediatric patients.LR-4 with elevated AFP,LR-5 or LR-M lesions is highly suggestive of malignant tumors.

Systematic Training of Liver Imaging Reporting and Data System Magnetic Resonance Imaging v2018 can Improve the Diagnosis of Hepatocellular Carcinoma for Different Radiologists

Background and Aims:Liver imaging reporting and data system(LI-RADS)provides standardized lexicon and categorization for diagnosing hepatocellular carcinoma(HCC).However,there is limited knowledge about the effect of LI-RADS training.We prospectively explored whether the systematic training of LI-RADS v2018 on magnetic resonance imaging(MRI)can effectively improve the diagnostic performances of different radiologists for HCC.Methods:A total of 20 visiting radiologists and the multiparametric MRI of 70 hepatic observations in 61 patients with high risk of HCC were included in this study.The LI-RADS v2018 training procedure included three times of thematic lectures(each lasting for 2.5 h)given by a professor specialized in imaging diagnosis of liver,with an interval of a month.After each seminar,the radiologists had a month to adopt the algorithm into their daily work.The diagnostic performances and interobserver agreements of these radiologists adopting the algorithm for HCC diagnosis before and after training were compared.Results:A total of 20 radiologists(male/female,12/8;with an average age of 36.75±4.99 years)were enrolled.After training,the interobserver agreements for the LI-RADS category for all radiologists(p=0.005)were increased.The sensitivity,specificity,positive predictive value,negative predictive value,and coincidence rate of all radiologists for HCC diagnosis before and after training were 43%vs.54%,86%vs.88%,74%vs.81%,62%vs.67%,and 65%vs.71%,respectively.The diagnostic performances of all radiologists(p<0.001)showed improvement after training.Conclusions:The systematic training of LI-RADS can effectively improve the diagnostic performances of radiologists with different experiences for HCC.

Liver imaging reporting and data system and CT/MRI diagnosis of hepatocellular carcinoma

The Liver Imaging Reporting and Data System(LI-RADS)is a comprehensive and robust system which provides an algorithmic approach to stratify the probability of hepatocellular carcinoma(HCC)for each observation found in patients at risk for HCC.LI-RADS uses a standardized terminology and approach to improve communication between the radiologist and clinicians.LI-RADS version 2018 is noteworthy for its adoption by the American Association for the Study of Liver Disease into its HCC practice guidance.This manuscript provides an overview of the history of LI-RADS,reviews the Computed tomography/magnetic resonance imaging diagnostic algorithm,highlights the key diagnostic criteria for each category,and discusses the advantage of incorporating LI-RADS in clinical practice.

Contrast-enhanced ultrasound in association with serum biomarkers for differentiating combined hepatocellular-cholangiocarcinoma from hepatocellular carcinoma and intrahepatic cholangiocarcinoma

BACKGROUND Combined hepatocellular-cholangiocarcinoma(CHC)is a rare type of primary liver cancer.Due to its complex histopathological characteristics,the imaging features of CHC can overlap with those of hepatocellular carcinoma(HCC)and intrahepatic cholangiocarcinoma(ICC).AIM To investigate the possibility and efficacy of differentiating CHC from HCC and ICC by using contrast-enhanced ultrasound(CEUS)Liver Imaging Reporting and Data System(LI-RADS)and tumor biomarkers.METHODS Between January 2016 and December 2019,patients with histologically confirmed CHC,ICC and HCC with chronic liver disease were enrolled.The diagnostic formula for CHC was as follows:(1)LR-5 or LR-M with elevated alphafetoprotein(AFP)and carbohydrate antigen 19-9(CA19-9);(2)LR-M with elevated AFP and normal CA19-9;or(3)LR-5 with elevated CA19-9 and normal AFP.The sensitivity,specificity,accuracy and area under the receiver operating characteristic curve were calculated to determine the diagnostic value of the criteria.RESULTS After propensity score matching,134 patients(mean age of 51.4±9.4 years,108 men)were enrolled,including 35 CHC,29 ICC and 70 HCC patients.Based on CEUS LI-RADS classification,74.3%(26/35)and 25.7%(9/35)of CHC lesions were assessed as LR-M and LR-5,respectively.The rates of elevated AFP and CA19-9 in CHC patients were 51.4%and 11.4%,respectively,and simultaneous elevations of AFP and CA19-9 were found in 8.6%(3/35)of CHC patients.The sensitivity,specificity,positive predictive value,negative predictive value,accuracy and area under the receiver operating characteristic curve of the aforementioned diagnostic criteria for discriminating CHC from HCC and ICC were 40.0%,89.9%,58.3%,80.9%,76.9%and 0.649,respectively.When considering the reported prevalence of CHC(0.4%-14.2%),the positive predictive value and NPV were revised to 1.6%-39.6%and 90.1%-99.7%,respectively.CONCLUSION CHCs are more likely to be classified as LR-M than LR-5 by CEUS LI-RADS.The combination of the CEUS LI-RADS classification with serum tumor markers shows high specificity but low sensitivity for the diagnosis of CHC.Moreover,CHC could be confidently excluded with high NPV.

Can contrast enhanced ultrasound differentiate intrahepatic cholangiocarcinoma from hepatocellular carcinoma?

BACKGROUND Hepatocellular carcinoma(HCC)and intrahepatic cholangiocarcinoma(ICC)differ in treatment and prognosis,warranting an effective differential diagnosis between them.The LR-M category in the contrast-enhanced ultrasound(CEUS)liver imaging reporting and data system(LI-RADS)was set up for lesions that are malignant but not specific to HCC.However,a substantial number of HCC cases in this category elevated the diagnostic challenge.AIM To investigate the possibility and efficacy of differentiating ICC from HCC classified in the LR-M category according to the CEUS LI-RADS.METHODS Patients with complete CEUS records together with pathologically confirmed ICC and LR-M HCC(HCC classified in the CEUS LI-RADS LR-M category)between January 2015 and October 2018 were included in this retrospective study.Each ICC was assigned a category as per the CEUS LI-RADS.The enhancement pattern,washout timing,and washout degree between the ICC and LR-M HCC were compared using theχ2 test.Logistic regression analysis was used for prediction of ICC.Receiver operating characteristic(ROC)curve analysis was used to investigate the possibility of LR-M criteria and serum tumor markers in differentiating ICC from LR-M HCC.RESULTS A total of 228 nodules(99 ICCs and 129 LR-M HCCs)in 228 patients were included.The mean sizes of ICC and LR-M HCC were 6.3±2.8 cm and 5.5±3.5 cm,respectively(P=0.03).Peripheral rim-like arterial phase hyperenhancement(APHE)was detected in 50.5%(50/99)of ICCs vs 16.3%(21/129)of LR-M HCCs(P<0.001).Early washout was found in 93.4%(93/99)of ICCs vs 96.1%(124/129)of LR-M HCCs(P>0.05).Marked washout was observed in 23.2%(23/99)of ICCs and 7.8%(10/129)of LR-M HCCs(P=0.002),while this feature did not show up alone either in ICC or LR-M HCC.Homogeneous hyperenhancement was detected in 15.2%(15/99)of ICCs and 37.2%(48/129)of LR-M HCCs(P<0.001).The logistic regression showed that rim APHE,carbohydrate antigen 19-9(CA 19-9),and alpha fetoprotein(AFP)had significant correlations with ICC(r=1.251,3.074,and-2.767,respectively;P<0.01).Rim APHE presented the best enhancement pattern for diagnosing ICC,with an area under the ROC curve(AUC)of 0.70,sensitivity of 70.4%,and specificity of 68.8%.When rim hyperenhancement was coupled with elevated CA 19-9 and normal AFP,the AUC and sensitivity improved to 0.82 and 100%,respectively,with specificity decreasing to 63.9%.CONCLUSION Rim APHE is a key predictor for differentiating ICC from LR-M HCC.Rim APHE plus elevated CA 19-9 and normal AFP is a strong predictor of ICC rather than LR-M HCC.Early washout and marked washout have limited value for the differentiation between the two entities.

Novel model combining contrast-enhanced ultrasound with serology predicts hepatocellular carcinoma recurrence after hepatectomy

BACKGROUND Surgery is the primary curative option in patients with hepatocellular carcinoma(HCC).However,recurrence within 2 years is observed in 30%–50%of patients,being a major cause of mortality.AIM To construct and verify a non-invasive prediction model combining contrastenhanced ultrasound(CEUS)with serology biomarkers to predict the early recurrence of HCC.METHODS Records of 744 consecutive patients undergoing first-line curative surgery for HCC in one institution from 2016–2018 were reviewed,and 292 local patients were selected for analysis.General characteristics including gender and age,CEUS liver imaging reporting and data system(LIRADS)parameters including wash-in time,wash-in type,wash-out time,and wash-out type,and serology biomarkers including alanine aminotransferase,aspartate aminotransferase,platelets,and alpha-fetoprotein(AFP)were collected.Univariate analysis and multivariate Cox proportional hazards regression model were used to evaluate the independent prognostic factors for tumor recurrence.Then a nomogram called CEUS model was constructed.The CEUS model was then used to predict recurrence at 6 mo,12 mo,and 24 mo,the cut-off value was calculate by X-tile,and each C-index was calculated.Then Kaplan-Meier curve was compared by logrank test.The calibration curves of each time were depicted.RESULTS A nomogram predicting early recurrence(ER),named CEUS model,was formulated based on the results of the multivariate Cox regression analysis.This nomogram incorporated tumor diameter,preoperative AFP level,and LIRADS,and the hazard ratio was 1.123(95%confidence interval[CI]:1.041-1.211),1.547(95%CI:1.245-1.922),and 1.428(95%CI:1.059-1.925),respectively.The cut-off value at 6 mo,12 mo,and 24 mo was 100,80,and 50,and the C-index was 0.748(95%CI:0.683-0.813),0.762(95%CI:0.704-0.820),and 0.762(95%CI:0.706-0.819),respectively.The model showed satisfactory results,and the calibration at 6 mo was desirable;however,the calibration at 12 and 24 mo should be improved.CONCLUSION The CEUS model enables the well-calibrated individualized prediction of ER before surgery and may represent a novel tool for biomarker research and individual counseling.

CT and MRI of the liver for hepatocellular carcinoma

Computed tomography(CT)and magnetic resonance imaging(MRI)are commonly used modalities for the imaging based diagnosis and staging of hepatocellular carcinoma(HCC).The Liver Imaging Reporting and Data System(LI-RADS)was initially released in 2011 in an effort to standardize the interpretation and reporting of these studies in patients at increased risk for the development of HCC.With the release of LI-RADS v2018,LI-RADS has reached two important milestones-10 years since the formation of the American College of Radiology supported LI-RADS committee and integration of LI-RADS into the 2018 American Association for the Study of Liver Disease practice guidance for HCC.In this article,we will discuss recent changes to LI-RADS with v2018,technical recommendations for the performance of CT and MRI in patients at risk for HCC,and critical imaging features in the LI-RADS algorithm.

Added Value of Quantitative Apparent Diffusion Coefficients for Identifying Small Hepatocellular Carcinoma from Benign Nodule Categorized as LI-RADS 3 and 4 in Cirrhosis

Background and Aims:Correct identification of small hepa-tocellular carcinomas(HCCs)and benign nodules in cirrhosis remains challenging,quantitative apparent diffusion coeffi-cients(ADCs)have shown potential value in characterization of benign and malignant liver lesions.We aimed to explore the added value of ADCs in the identification of small(≤3 cm)HCCs and benign nodules categorized as Liver Imag-ing Reporting and Data System(LI-RADS)3(LR-3)and 4(LR-4)in cirrhosis.Methods:Ninety-seven cirrhosis patients with 109 small nodules(70 HCCs,39 benign nodules)of LR-3 and 4 LR-4 based on major and ancillary magnetic resonance imaging features were included.Multiparametric quantitative ADCs of the lesions,including the mean ADC(ADCmean),min-imum ADC(ADCmin),maximal ADC(ADCmax),ADC standard deviation(ADCstd),and mean ADC value ratio of lesion-to-liv-er parenchyma(ADCratio)were calculated.Regarding the joint diagnosis,a nomogram model was plotted using multivariate logistic regression analysis.The performance was assessed using the area under the receiver operating characteristic curve(AUC).Results:The ADCmean,ADCmin,ADCratio,and ADCstd were significantly associated with the identification of small HCC and benign nodules(p<0.001).For the joint diagnosis,the LI-RADS category(odds ratio[OR]=12.50),ADCmin(OR=0.14),and ADCratio(OR=0.12)were identified as independent factors for distinguishing HCCs from benign nodules.The joint nomogram model showed good calibration and discrimination,with a C-index of 0.947.Compared with the LI-RADS category alone,this nomogram model demon-strated a significant improvement in diagnostic performance,with AUC increasing from 0.820 to 0.967(p=0.001).Con-clusions:The addition of quantitative ADCs could improve the identification of small HCC and benign nodules catego-rized as LR-3 and 4 LR-4 in patients with cirrhosis.

Role of imaging in management of hepatocellular carcinoma: surveillance, diagnosis, and treatment response

Imaging plays a notable role in hepatocellular carcinoma(HCC)surveillance,diagnosis,and treatment response assessment.Whereas HCC surveillance among at-risk patients,including those with cirrhosis,has traditionally been ultrasound-based,there are increasing data showing that this strategy is operator-dependent and has insufficient sensitivity when used alone.Several novel blood-based and imaging modalities are currently being evaluated to increase sensitivity for early HCC detection.Multi-phase computed tomography(CT)or contrast-enhanced magnetic resonance imaging(MRI)should be performed in patients with positive surveillance tests to confirm a diagnosis of HCC and perform cancer staging,as needed.HCC is a unique cancer in that most cases can be diagnosed radiographically without histological confirmation when demonstrating characteristic features such as arterial phase hyperenhancement and delayed phase washout.The Liver Imaging Reporting and Data System offers a standardized nomenclature for reporting CT or MRI liver findings among at-risk patients.Finally,cross-sectional imaging plays a critical role for assessing response to any HCC therapy as well as monitoring for HCC recurrence in those who achieve complete response.

Diagnostic imaging for hepatocellular carcinoma

Hepatocellular carcinoma(HCC)occurs mostly in individuals with cirrhosis,which is why the guidelines of the most important scientific societies indicate that these patients are included in surveillance programs through the repetition of an ultrasound examination every 6 months.The aim is to achieve early identification of the neoplasia in order to increase the possibility of curative therapies(liver transplantation,surgery or local ablative therapies)and to increase patient survival.HCC nodules arising in cirrhotic livers show characteristic angiographic behavior that can be evaluated with dynamic multidetector computed tomography and dynamic magnetic resonance imaging(MRI).However,the use of these techniques in real life is often hindered by the lack of uniform terminology in reporting and in the interpretation of the exams reflected in the impossibility of comparing examinations performed in different centers and/or at different times.Liver Imaging Reporting and Data System?was created to standardize reporting and data collection of computed tomography and MRI for HCC.In some cases HCC arises in patients with healthy livers and,although there is evidence that angiographic behavior is not different from cirrhotic patients in this clinical situation,the guidelines still indicate the execution of a biopsy.Frequent use of palliative therapeutic techniques such as transarterial chemoembolization,transarterial radioembolization or administration of antiangiogenic drugs(sorafenib)poses problems of interpretation of the therapeutic response with repercussions on the subsequent choices that have been attempted to resolve with the use of stringent criteria such as Modified Response Evaluation Criteria In Solid Tumors.