Dynamic contrast enhanced ultrasound in differential diagnosis of hepatocellular carcinoma: A systematic review and meta-analysis

BACKGROUND Non-invasive differential diagnosis between hepatocellular carcinoma(HCC)and other liver cancer(i.e.cholangiocarcinoma or metastasis)is highly challenging and definitive diagnosis still relies on histological exam.The patterns of enhancement and wash-out of liver nodules can be used to stratify the risk of malignancy only in cirrhotic patients and HCC frequently shows atypical features.Dynamic contrast-enhanced ultrasound(DCEUS)with standardized software could help to overcome these obstacles,providing functional and quantitative parameters and potentially improving accuracy in the evaluation of tumor perfusion.AIM To explore clinical evidence regarding the application of DCEUS in the differential diagnosis of liver nodules.METHODS A comprehensive literature search of clinical studies was performed to identify the parameters of DCEUS that could relate to histological diagnosis.In accordance with the study protocol,a qualitative and quantitative analysis of the evidence was planned.RESULTS Rise time was significantly higher in HCC patients with a standardized mean difference(SMD)of 0.83(95%CI:0.48-1.18).Similarly,other statistically significant parameters were mean transit time local with a SMD of 0.73(95%CI:0.20-1.27),peak enhancement with a SMD of 0.37(95%CI:0.03-0.70),area wash-in area under the curve with a SMD of 0.47(95%CI:0.13-0.81),wash-out area under the curve with a SMD of 0.55(95%CI:0.21-0.89)and wash-in and wash-out area under the curve with SMD of 0.51(95%CI:0.17-0.85).SMD resulted not significant in fall time and wash-in rate,but the latter presented a trend towards greater values in HCC compared to intrahepatic cholangiocarcinoma.CONCLUSION DCEUS could improve non-invasive diagnosis of HCC,leading to less liver biopsy and early treatment.This quantitative analysis needs to be applied on larger cohorts to confirm these preliminary results.

Gastrointestinal contrast-enhanced ultrasonography for diagnosis and treatment of peptic ulcer in children

BACKGROUND The detection rate of peptic ulcer in children is improving,with development of diagnostic procedures.Gastroscopy is the gold standard for the diagnosis of peptic ulcer,but it is an invasive procedure.Gastrointestinal contrast-enhanced ultrasonography(CEUS)has the advantages of being painless,noninvasive,nonradioactive,easy to use,and safe.AIM To investigate the clinical value of CEUS for diagnosis and treatment of peptic ulcer in children.METHODS We investigated 43 children with digestive tract symptoms in our hospital from January 2021 to June 2022.All children were examined by routine ultrasound,gastrointestinal CEUS,and gastroscopy.The pathological results of gastroscopy were taken as the gold standard.Routine ultrasonography was performed before gastrointestinal CEUS.Conventional ultrasound showed the thickness of the gastroduodenal wall,gastric peristalsis,and the adjacent organs and tissues around the abdominal cavity.Gastrointestinal CEUS recorded the thickness of the gastroduodenal wall;the size,location and shape of the ulcer;gastric peristalsis;and adjacent organs and tissues around the abdominal cavity.The results of routine ultrasound and gastrointestinal ultrasound were compared with those of gastroscopy to evaluate the diagnostic results and coincidence rate of routine ultrasound and gastrointestinal CEUS.All children received informed consent from their guardians for CEUS.This study was reviewed and approved by the hospital medical ethics committee.RESULTS Among the 43 children,17(15 male,2 female)were diagnosed with peptic ulcer by gastroscopy.There were 26 children with nonpeptic ulcer.There were eight cases of peptic ulcer and 35 of nonpeptic ulcer diagnosed by conventional ultrasound.The diagnostic coincidence rate of peptic ulcer in children diagnosed by conventional ultrasound was 79.1%(34/43),which was significantly different from that of gastroscopy(P=0.033).It indicates that the coincidence rate of gastrointestinal contrast-enhanced ultrasound and gastroscope is low.Fifteen cases of peptic ulcer and 28 of nonpeptic ulcer were diagnosed by CEUS.The diagnostic coincidence rate of peptic ulcer in children was 95.3%(41/43).There was no significant difference between CEUS and gastroscopy(P=0.655).It indicates that the coincidence rate of gastrointestinal contrast-enhanced ultrasound and gastroscope is high.CONCLUSION Gastrointestinal CEUS has a high coincidence rate in the diagnosis of peptic ulcer in children,and can be used as a preliminary examination method.

value of contrast-enhanced ultrasound in the differential diagnosis of gallbladder lesion

AIM To describe contrast-enhanced ultrasound(CEUS) features and evaluate differential diagnosis value of CEUS and conventional ultrasound for patients with benign and malignant gallbladder lesions. METHODS This study included 105 gallbladder lesions. Before surgical resection and pathological examination, conventional ultrasound and CEUS were performed to examine for lesions. Then, all the lesions were diagnosed as(1) benign,(2) probably benign,(3) probably malignant or(4) malignant using both conventional ultrasound and CEUS. The CEUS features of these gallbladder lesions were analyzed and diagnostic efficiency between conventional ultrasound and CEUS was compared.RESULTS There were total 17 cases of gallbladder cancer and 88 cases of benign lesion. Some gallbladder lesions had typical characteristics on CEUS(e.g., gallbladder adenomyomatosis had typical characteristics of small nonenhanced areas on CEUS). The sensitivity, specificity, positive predictive value, negative predictive value and accuracy of CEUS were 94.1%, 95.5%, 80.0%, 98.8%and 95.2%, respectively. These were significantly higher than conventional ultrasound(82.4%, 89.8%, 60.9%, 96.3% and 88.6%, respectively). CEUS had an accuracy of 100% for gallbladder sludge and CEUS helped in differential diagnosis among gallbladder polyps, gallbladder adenoma and gallbladder cancer.CONCLUSION CEUS may provide more useful information and improve the diagnosis efficiency for the diagnosis of gallbladder lesions than conventional ultrasound.

Contrast-enhanced ultrasound of histologically proven hepatic epithelioid hemangioendothelioma

AIM: To analyze contrast-enhanced ultrasound(CEUS) features of histologically proven hepatic epithelioid hemangioendothelioma(HEHE) in comparison to other multilocular benign focal liver lesions(FLL).METHODS: Twenty-five patients with histologically proven HEHE and 45 patients with histologically proven multilocular benign FLL were retrospectively reviewed. Four radiologists assessed the CEUS enhancement pattern in consensus.RESULTS: HEHE manifested as a single(n = 3) or multinodular(n = 22) FLL. On CEUS, HEHE showed rim-like(18/25, 72%) or heterogeneous hyperenhancement(7/25, 28%) in the arterial phase and hypoenhancement(25/25, 100%) in the portal venous and late phases(PVLP), a sign of malignancy. Eighteen patients showed central unenhanced areas(18/25, 72%); in seven patients(7/25, 28%), more lesions were detected in the PVLP. In contrast, all patients with hemangioma and focal nodular hyperplasia showed hyperenhancement as the most distinctive feature(P < 0.01).CONCLUSION: CEUS allows for characterization of unequivocal FLL. By analyzing the hypoenhancement in the PVLP, CEUS can determine the malignant nature of HEHE.

Liver metastases:Contrast-enhanced ultrasound compared with computed tomography and magnetic resonance

The development of ultrasound contrast agents with excellent tolerance and safety profiles has notably improved liver evaluation with ultrasound(US)for several applications,especially for the detection of metastases.In particular,contrast enhanced ultrasonography(CEUS)allows the display of the parenchymal microvasculature,enabling the study and visualization of the enhancement patterns of liver lesions in real time and in a continuous manner in all vascular phases,which is similar to contrast-enhanced computed tomography(CT)and contrast-enhanced magnetic resonance imaging.Clinical studies have reported that the use of a contrast agent enables the visualization of more metastases with significantly improved sensitivity and specificity compared to baseline-US.Furthermore,studies have shown that CEUS yields sensitivities comparable to CT.In this review,we describe the state of the art of CEUS for detecting colorectal liver metastases,the imaging features,the literature reports of metastases in CEUS as well as its technique,its clinical role and its potential applications.Additionally,the updated international consensus panel guidelines are reported in this review with the inherent limitations of this technique and best practice experiences.

Management of hepatocellular carcinoma: The role of contrast-enhanced ultrasound

Hepatocellular carcinoma(HCC)is the sixth most common neoplasm and the third cause of cancer death worldwide.Contrast enhanced ultrasound(CEUS)has been applied for more than ten years and plays increasingly important roles in the management of HCC.On the basis of the Guideline and Good Clinical Practice Recommendations for CEUS in the liver-update 2012and related literature about the management of HCC,we summarize the main roles and applications of CEUS in the management of HCC,including HCC surveillance,diagnosis,CEUS-guided treatment,treatment response evaluation and follow-up.The diagnostic algorithm for HCC is also suggested.Meanwhile,the comparisons between CEUS and contrast enhanced computed tomography/magnetic resonance imaging(CECT/CEMRI)in these areas are made.Although CEUS is subject to the same limitation as ordinary US and is inferior to CECT/CEMRI in some aspects,CEUS has proved to be of great value in the management of HCC with inher-ent advantages,such as sufficient high safety profile making it suitable for patients with renal failure or allergic to iodine,absence of radiation,easy reproducibility and high temporal resolution.The tremendous application of CEUS to the diagnosis and treatment of HCC provides more opportunities for patients with HCC diagnosed at different stages.

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

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

Contrast-enhanced endoscopic ultrasound in discrimination between focal pancreatitis and pancreatic cancer

AIM： To evaluate the contrast-enhanced endosonography as a method of differentiating inflammation from pancreatic carcinoma based on perfusion characteristics of microvessels. METHODS： In 86 patients with suspected chronic pancreatitis （age： 62± 12 years; sex： f/m 38/48）, pancreatic lesions were examined by conventional endo- scopic B-mode, power Doppler ultrasound and contrastenhanced power mode （Hitachi EUB 525, SonoVue, 2.4 mL, Bracco） using the following criteria for malignant lesions： no detectable vascularisation using conventional power Doppler scanning, irregular appearance of arterial vessels over a short distance using SonoVue contrastenhanced technique and no detectable venous vessels inside the lesion. A malignant lesion was assumed if all criteria were detectable [gold standard endoscopic ultrasound （EUS）-guided fine needle aspiration cytology, operation]. The criteria of chronic pancreatitis without neoplasia were defined as no detectable vascularisation before injection of SonoVue, regular appearance of vessels over a distance of at least 20 mm after injection of SonoVue and detection of arterial and venous vessels. RESULTS： The sensitivity and specifidty of conventional EUS were 73.2% and 83.3% respectively for pancreatic cancer. The sensitivity of contrast-enhanced EUS increased to 91.1% in 51 of 56 patients with malignant pancreatic lesion and the specificity increased to 93.3% in 28 of 30 patients with chronic inflammatory pancreatic disease.CONCLUSION： Contrast-enhanced endoscopic ultrasound improves the differentiation between chronic pancreatitis and pancreatic carcinoma.

Contrast-enhanced ultrasound in diagnosis and characterization of focal hepatic lesions

The extensive use of imaging techniques in differential diagnosis of abdominal conditions and screening of hepatocellular carcinoma in patients with chronic hepatic diseases,has led to an important increase in identification of focal liver lesions.The development of contrastenhanced ultrasound(CEUS) opens a new window in the diagnosis and follow-up of these lesions.This technique offers obvious advantages over the computed tomography and magnetic resonance,without a decrease in its sensitivity and specificity.The new second generation contrast agents,due to their intravascular distribution,allow a continuous evaluation of the enhancement pattern,which is crucial in characterization of liver lesions.The dual blood supply in the liver shows three different phases,namely arterial,portal and late phases.The enhancement during portal and late phases can give important information about the lesion's behavior.Each liver lesion has a different enhancement pattern that makes possible an accurate approach to their diagnosis.The role of emerging techniques as a contrastenhanced three-dimensional US is also discussed.In this article,the advantages,indications and technique employed during CEUS and the different enhancement patterns of most benign and malignant focal liver lesions are discussed.

Contrast enhanced ultrasound of renal masses

Contrast enhanced ultrasound(CEUS) has gained clinical importance over the last years for the characterization of hepatic masses.Its role in extrahepatic indications has been investigated repeatedly but has been less comprehensively studied.Currently more than 50% of renal masses are incidentally diagnosed,mostly by B-mode ultrasound.The method of choice for characterization of renal lesions is contrast enhanced computed tomography(CECT).In the case of cystic lesions CECT refers to the Bosniak classification for cystic lesions to assess the risk of malignant behavior.The majority of masses are renal cell carcinoma,but the exact proportion is controversial.Disadvantages of CECT are a significant risk for patients with impaired renal function,allergic reactions and hyperthyroidism due to iodinated contrast agents.Several studies concerning CEUS for the characterization of both solid and cystic renal lesions have been published,but prospective multicenter studies are missing,the presented data being mainly descriptive.The aim of the this manuscript is to review the current literature for CEUS in renal masses,to summarize the available data and focus on possible concepts for studies in the future.

Evaluation of contrast-enhanced ultrasound for diagnosis of dysplastic nodules with a focus of hepatocellular carcinoma in liver cirrhosis patients

Objective： To compare the enhancement features of dysplastic nodnles with a focus of hepatocellular carcinoma （DN-HCC） versus HCC and regenerative nodules （RN） in cirrhotic patients. Methods： One hundred and ninety-three cirrhotic patients were enrolled in this study; they had 215 focal liver lesions, 1.0-3.5 cm in size, which were examined using contrast-enhanced ultrasound （CEUS） with SonoVue and diagnosed as HCC, RN or DN-HCC by biopsy. Samples were obtained using 18-gauge needles in the different enhanced areas. The enhancement features of DN-HCC, HCC and RN were evaluated. Results： There were 86 HCC lesions, 102 RN lesions, and 27 DN-HCC lesions diagnosed by biopsy. Of 86 HCC lesions, 87.2% （75/86） showed complete enhancement during the arterial phase, and 12.8% （11/86） had inhomogeneous enhancement, with no enhancement in the central area during the arterial phase; 100% （86/86） exhibited washout during the late phase. Of 102 RN lesions, 95.1% （97/102） had delayed or simultaneous enhancement during the arterial phase, and 4.9% （5/102） displayed slight enhancement during the arterial phase; 26.5% （27/102） exhibited washout and 73.5% （75/102） exhibited no washout during the late phase. In 27 DN-HCC lesions, only part of the lesions enhanced during the arterial phase and washed out during the late phase; the other areas had delayed or simultaneous enhancement during the arterial phase, and 29.6% （8/27） exhibited slight washout in the late phase. In 86 HCCs, the pathological feature was HCC in the enhanced area of 75 lesions, hepatocellular fatty degeneration in the slightly enhanced area of 7 lesions, and hepatocellular necrosis in the unenhanced area and HCC in the enhanced area of 4 lesions. In 102 RNs, the pathological diagnosis was hepatocyte proliferation with or without fatty degeneration. In 27 DN-HCCs, the pathological feature was HCC in the enhanced area and hepatocye regeneration in the unenhanced area. Conclusions： CEUS is useful for the diagnosis of focal liver lesions in cirrhotic patients. CEUS can help determine the progression from RN to DN-HCC to HCC by analyzing the hemodynamics. CEUS can promote the diagnostic accuracy of a biopsy by providing more accurate information on the site of the biopsy.

Role of Contrast Enhanced Ultrasound in Radiofrequency Ablation of Metastatic Liver Carcinoma

Objective： To investigate the application of contrast enhanced ultrasound （CEUS） in planning and guiding for radiofrequency ablation （RFA） for metastatic liver carcinoma （MLC）. Methods： One hundred and thirty-five patients with clinically and pathologically diagnosed MLC （from gastrointestinal tumors） were included in the present study, and 104 of them had received CEUS prior to RFA to assess the number, size, shape, infiltration, location and enhancing features of the lesions. Among the 204 patients, 21 （20.1%） were excluded from RFA treatment due to too many lesions or large infiltrative range based on CEUS. The remaining 83 patients with 147 lesions underwent RFA （group A）. During the same period, other 32 patients with 202 lesions serving as control group were treated based on findings of conventional ultrasound without contrast （group B）. The patients underwent follow-up enhanced CT at the 1st month, and then every 3-6 months after RFA. The tumor was considered as early necrosis if no contrast enhancement was detected in the treated area on the CT scan at the 2st month. Results： In group A, 72 of 147 MLC lesions （48.9%） showed increased sizes on CEUS. Among them, 48 lesions （66.6%） appeared enlarged in arterial phase, and 24 （33.3%） showed enlarged hypoechoic area in parenchymal phase. CEUS showed total 61 additional lesions in 35 patients （42.2%） （ranged from 8 to 15 mm） compared with conventional ultrasound （US）, and 42 （68.8%） of them were visualized in parenchymal phase only. There were total 208 lesions in group A underwent RFA with CEUS planning, and the tumor necrosis rate was 94.2% （196/208）. In this group, local recurrence was found in 26 lesions （7.7%） during 3-42 months＇ following up, and new metastases were seen in 30 cases （36.2%）. For group B, the tumor necrosis rate was 86.3% （88/202）, local recurrence in 27 lesions （16.7%）, and new metastases in 13 cases （41.9%）. Tumor early necrosis and recurrence rates were significantly different between the two groups （P=0.018, P=0.016, respectively）. Conclusion： CEUS played an important role in RFA for liver metastases by candidate selecting and therapy planning, which helped to improve the outcome of the treatment.

Contrast-enhanced 3D ultrasound in the radiofrequency ablation of liver tumors

Liver metastases and hepatocellular carcinomas are two of the most common causes of cancer deaths in the world.Radiofrequency ablation(RFA) is a well recognized,effective and minimally invasive means of treating malignant hepatic tumors.This article describes the use of contrast-enhanced 3D ultrasound(CE-3DUS) in the staging,targeting and follow-up of patients with liver tumors undergoing RFA.In particular,its value in the management of large hepatic lesions will be illustrated.Current limitations of CE-3DUS and future developments in the technique will also be discussed.In summary,CE-3DUS is useful in the RFA of liver tumors with improved detection and display of occult lesions and recurrence,in the assessment of lesional geometry and orientation for a more accurate planning and guidance of multiple RFA needle electrodes in large tumors and in the evaluation of residual or recurrent disease within the immediate and/or subsequent follow-up periods.

Differentiation of atypical hepatic hemangioma from liver metastases: Diagnostic performance of a novel type of color contrast enhanced ultrasound

BACKGROUND In clinical practice,the diagnosis is sometimes difficult with contrast-enhanced ultrasound(CEUS)when the case has an atypical perfusion pattern.Color parametric imaging(CPI)is an analysis software for CEUS with better detection of temporal differences in CEUS imaging using arbitrary colors.It measures the differences in arrival time of the contrast agent in lesions so that the perfusion features of atypical hemangioma and colorectal cancer(CRC)liver metastasis can be distinguished.AIM To evaluate the role of a novel type of CPI of CEUS in the differential diagnosis of atypical hemangioma from liver metastases in patients with a history of CRC.METHODS From January 2016 to July 2018,42 patients including 20 cases of atypical hemangioma and 22 cases of liver metastases from CRC were enrolled.These patients had a mean age of 60.5±9.3 years(range:39-75 years).All patients received ultrasound,CEUS and CPI examinations.Resident and staff radiologists independently and retrospectively reviewed CEUS and CPI images.Two sets of criteria were assigned:(1)Routine CEUS alone;and(2)CEUS and CPI.The diagnostic sensitivity,specificity,accuracy and receiver operating characteristic(ROC)curve of resident and staff radiologists were analyzed.RESULTS The following CPI features were significantly different between liver hemangioma and liver metastases analyzed by staff and resident radiologists:Peripheral nodular enhancement(65%-70.0%vs 4.5%-13.6%,P<0.001,P=0.001),mosaic/chaotic enhancement(5%-10%vs 68.2%-63.6%,P<0.001,P<0.001)and feeding artery(20%vs 59.1%-54.5%,P=0.010,P=0.021).CPI imaging offered significant improvements in detection rates compared with routine CEUS in both resident and staff groups.By resident radiologists,the specificity and accuracy of CEUS+CPI were significantly increased compared with that of CEUS(77.3%vs 45.5%,P=0.030;78.6%vs 50.0%,P=0.006).In addition,the area under the curve(AUC)of CEUS+CPI was significantly higher than that of CEUS(0.803 vs 0.757,P=0.036).By staff radiologists,accuracy was improved in CEUS+CPI(81.0%vs 54.8%,P=0.010),whereas no significant differences in specificity and sensitivity were found(P=0.144,P=0.112).The AUC of CEUS+CPI was significantly higher than that of CEUS(0.890 vs 0.825,P=0.013)by staff radiologists.CONCLUSION Compared with routine CEUS,CPI could provide specific information on the hemodynamic features of liver lesions and help to differentiate atypical hemangioma from liver metastases in patients with CRC,even for senior radiologists.

Contrast-enhanced ultrasound evaluation of hepatic microvascular changes in liver diseases

AIM： To assess if software assisted-contrast-enhanced ultrasonography （CEUS） provides reproducible perfu- sion parameters of hepatic parenchyma in patients af- fected by chronic liver disease. METHODS： Forty patients with chronic viral liver dis- ease, with （n = 20） or without （n = 20） cirrhosis, and 10 healthy subjects underwent CEUS and video re- cordings of each examination were then analysed with Esaote＇s Qontrast software. CEUS dedicated software Qontrast was used to determine peak （the maximum signal intensity）, time to peak （TTP）, region of blood value （RBV） proportional to the area under the time- intensity curve, mean transit time （MTT） measured in seconds and region of blood flow （RBF）. RESULTS： Qontrast-assisted CEUS parameters dis- played high inter-observer reproducibility （κ： coefficients of 0.87 for MTT and 0.90 TTP）. When the region of in-terest included a main hepatic vein, Qontrast-calculated TTP was significantly shorter in cirrhotic patients （vs non-cirrhotics and healthy subjects） （71.0 ± 11.3 s vs 82.4±15.6 s, 86.3±20.3 s, P 〈 0.05）. MTIs in the patients with liver cirrhosis were significantly shorter than those of controls （111.9±22.0 s vs 139.4±39.8 s, P 〈 0.05）, but there was no significant difference between the cirrhotic and non-cirrhotic groups （111.9± 22.0 s vs 110.3 ±14.6 s）. Peak enhancement in the patients with liver cirrhosis was also higher than that observed in controls （23.9± 5.9 vs 18.9±7.1, P = 0.05）. There were no significant intergroup differences in the RBVs and RBFs. CONCLUSION： Qontrast-assisted CEUS revealed re- producible differences in liver perfusion parameters during the development of hepatic fibrogenesis.

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 rimlike 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.

Contrast-enhanced ultrasound in the biliary system:Potential uses and indications

Conventional ultrasound(US)is the first-line imaging investigation for biliary diseases.However,it is lack of the ability to depict the microcirculation of some lesions which may lead to failure in diagnosis for some biliary diseases.The use of contrast-enhanced US(CEUS)has reached the field of bile duct disease in recent years and promising results have been achieved.In this review,the methodology,image interpretation,enhancement pattern,clinical usefulness,and indications for CEUS in the biliary system are summarized.CEUS may be indicated in the biliary system under the following circumstances:(1)Where there is a need to make a characterization of intrahepatic cholangiocarcinoma(ICC);(2)For differentiation diagnosis between ICC and other tumors(i.e.hepatocellular carcinoma or liver metastasis)or infectious diseases;(3)For differentiation diagnosis between biliary cystadenoma and biliary cystadenocarcinoma;(4)To detect malignant change in Caroli’s disease;(5)To depict the extent of Klatskin’s tumor with greater clarity;(6)To make a distinction between gallbladder cholesterol polyp,adenoma and polypoid cancer;(7)To make a distinction between chronic cholecystitis with thickened wall and gallbladder cancer;(8)For differentiation diagnosis between motionless sludge and gallbladder cancer;(9)For differentiation diagnosis between common bile duct cancer and sludge or stone without acoustic shadowing;and(10)In patients who are suspected of having a drop of their percutaneous transhepatic cholangiodrainage tube,US contrast agent can be administered to through the tube detect the site of the tube.

Contrast-enhanced harmonic endoscopic ultrasound imaging: Basic principles, present situation and future perspectives

Over the last decade, the development of stabilised microbubble contrast agents and improvements in available ultrasonic equipment, such as harmonic imaging, have enabled us to display microbubble enhancements on a greyscale with optimal contrast and spatial resolution. Recent technological advances made contrast harmonic technology available for endoscopic ultrasound(EUS) for the first time in 2008. Thus, the evaluation of microcirculation is now feasible with EUS, prompting the evolution of contrast-enhanced EUS from vascular imaging to images of the perfused tissue. Although the relevant experience is still preliminary, several reports have highlighted contrast-enhanced harmonic EUS(CHEUS) as a promising noninvasive method to visualise and characterise lesions and to differentiate benign from malignant focal lesions. Even if histology remains the gold standard, the combination of CH-EUS and EUS fine needle aspiration(EUS-FNA) can not only render EUS more accurate but may also assist physicians inmaking decisions when EUS-FNA is inconclusive,increasing the yield of EUS-FNA by guiding the puncture with simultaneous imaging of the vascularity.The development of CH-EUS has also opened up exciting possibilities in other research areas,including monitoring responses to anticancer chemotherapy or to ethanolinduced pancreatic tissue ablation,anticancer therapies based on ultrasound-triggered drug and gene delivery,and therapeutic adjuvants by contrast ultrasound-induced apoptosis.Contrast harmonic imaging is gaining popularity because of its efficacy,simplicity and noninvasive nature,and many expectations are currently resting on this technique.If its potential is confirmed in the near future,contrast harmonic imaging will become a standard practice in EUS.

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.

Contrast-enhanced and targeted ultrasound

Ultrasonic imaging is becoming the most popular medical imaging modality,owing to the low price per examination and its safety.However,blood is a poor scatterer of ultrasound waves at clinical diagnostic transmit frequencies.For perfusion imaging,markers have been designed to enhance the contrast in B-mode imaging.These so-called ultrasound contrast agents consist of microscopically small gas bubbles encapsulated in biodegradable shells.In this review,the physical principles of ultrasound contrast agent microbubble behavior and their adjustment for drug delivery including sonoporation are described.Furthermore,an outline of clinical imaging applications of contrast-enhanced ultrasound is given.It is a challenging task to quantify and predict which bubble phenomenon occurs under which acoustic condition,and how these phenomena may be utilized in ultrasonic imaging.Aided by high-speed photography,our improved understanding of encapsulated microbubble behavior will lead to more sophisticated detection and delivery techniques.More sophisticated methods use quantitative approaches to measure the amount and the time course of bolus or reperfusion curves,and have shown great promise in revealing effective tumor responses to anti-angiogenic drugs in humans before tumor shrinkage occurs.These are beginning to be accepted into clinical practice.In the long term,targeted microbubbles for molecular imaging and eventually for directed anti-tumor therapy are expected to be tested.