Prognostic relevance of ARFI elastography in comparison to liver histology and the FIB-4 score.

PURPOSE: Liver histology has prognostic relevance and is used in surveillance and therapeutic strategies. This longitudinal study was designed to evaluate the prognostic relevance of ARFI elastography in comparison to liver histology and to the FIB-4 score in a 5-year observation interval. MATERIALS AND METHODS: Based on the hospital database, patients with an elastography examination of the liver between 2010-2012, a liver biopsy, and a follow-up of 5 years were included in the study. The AUROCs of the events liver-related death, HCC, and liver decompensation/variceal bleeding were calculated for ARFI elastography, liver histology, and FIB-4 and compared using the DeLong test. RESULTS: In the final analysis 113 patients were included with 30 (26.5 %) patients having high-grade fibrosis and 19 (16.8 %) having liver cirrhosis in histology. The AUROC for liver-related death in the 5-year interval (9.7 %, n=11) was 0.80 [0.68-0.92] for ARFI elastography, 0.79 [0.66-0.92] for liver histology, and 0.66 [0.53-0.79] for FIB-4 with a p-value of 0.83 comparing ARFI to histology and a p-value of 0.02 comparing ARFI to FIB-4. The AUROC for liver decompensation/variceal bleeding (13.3 %, n=15) was 0.86 [0.76-0.94] for ARFI, which is significantly higher than the AUROC of liver histology with 0.71 [0.56-0.86] (p=0.02) and FIB-4 with 0.67 [0.54-0.80] (p=0.003). There was no significant difference for the event HCC when comparing ARFI to histology (p=0.33) or FIB-4 (p=0.14). CONCLUSION: The prognostic value of ARFI elastography seems to not be inferior to liver histology regarding liver-related survival and might even outperform histology and the FIB-4 score for predicting some liver-related complications.

HCCs lacking arterial phase hyperenhancement (APHE) on contrast-enhanced ultrasound (CEUS) - a diagnostic challenge. Findings from the prospective multicenter DEGUM CEUS HCC trial.

OBJECTIVES: Hepatocellular carcinoma (HCC) upon contrast-enhanced ultrasound (CEUS) typically shows arterial phase hyperenhancement (APHE), followed by late (> 60 seconds) and mild contrast washout (WO). Although APHE is considered as the hallmark of HCC, it can be absent in some HCCs. Thus, we explored which sonomorphological and histopathological features of HCC are associated with a lack of APHE upon CEUS. METHODS: Focal liver lesions in high-risk patients for HCC were assessed with CEUS following a standardized protocol in a prospective multi-center real-life setting. CEUS patterns in HCC were assessed, and tumour and patient characteristics were compared for HCCs with and without APHE. RESULTS: 316 patients with HCC were recruited (cirrhosis, 76.9%). APHE occurred in 271/316 HCCs (85.8%). A lack of APHE was associated with portal vein thrombosis, tumour infiltration of the liver vessels (p<0.001), larger size, multilocularity, and higher depth location upon ultrasound (p<0.01). Histological grading did not differ between HCCs with and without APHE (p=0.39). Histopathological features of HCCs without APHE included cirrhotic stromal reaction, marked tumour cell steatosis and absence of the typical surrounding dilated sinusoidal vascular channels. CONCLUSION: Correlation with histopathological findings support the fact that HCCs with a lack of APHE in CEUS are a heterogeneous group. The examiner has to be aware that particularly HCCs with portal vein thrombosis or macro-invasion of the liver vessels may lack APHE.

Shear Wave Dispersion Imaging for the Characterization of Focal Liver Lesions - A Pilot study.

PURPOSE: Shear wave dispersion imaging is a novel ultrasound-based technique, which analyzes the speed of different shear wave components depending on their frequency. The dispersion of shear wave speed correlates with the viscosity of the liver parenchyma. The aim of this prospective study was to evaluate the use of shear wave dispersion imaging in focal liver lesions in the non-cirrhotic liver. METHODS: Patients with unclear focal liver lesions in B-mode ultrasound were prospectively assigned to shear wave dispersion imaging (m/s/kHz). Measurements were conducted within the lesion and in the liver parenchyma of the right liver lobe using an intercostal window. Histology and contrast-enhanced ultrasound served as the reference for the characterization of the lesions. RESULTS: Out of 46 patients included in this study, 24 had liver metastases and 22 had benign liver lesions. Benign lesions consisted mostly of hemangiomas (n=12) and focal nodular hyperplasia (n=8). Malignant lesions showed significantly lower shear wave dispersion (13.0±2.45 m/s/kHz) compared to benign tumors (15.2±2.74 m/s/kHz, p<0.01). In further subgroup analysis, the difference was significant for hemangiomas (15.32±2.42 m/s/kHz, p=0.04) but not for FNHs (14.98±3.36 m/s/kHz, p=0.38). The dispersion of reference liver parenchyma did not differ significantly between the groups (p=0.54). CONCLUSION: The quantification of viscosity by shear wave dispersion is a new parameter for the characterization of focal liver lesions with higher dispersion values in hemangiomas and lower dispersion values in metastases. However, it cannot differentiate reliably between benign and malignant lesions.

Contrast-Enhanced Ultrasound Algorithms (CEUS-LIRADS/ESCULAP) for the Noninvasive Diagnosis of Hepatocellular Carcinoma - A Prospective Multicenter DEGUM Study.

BACKGROUND: This prospective multicenter study funded by the DEGUM assesses the diagnostic accuracy of standardized contrast-enhanced ultrasound (CEUS) for the noninvasive diagnosis of hepatocellular carcinoma (HCC) in high-risk patients. METHODS: Patients at high risk for HCC with a histologically proven focal liver lesion on B-mode ultrasound were recruited prospectively in a multicenter approach. Clinical and imaging data were entered via online entry forms. The diagnostic accuracies for the noninvasive diagnosis of HCC were compared for the conventional interpretation of standardized CEUS at the time of the examination (= CEUS on-site) and the two CEUS algorithms ESCULAP (Erlanger Synopsis for Contrast-enhanced Ultrasound for Liver lesion Assessment in Patients at risk) and CEUS LI-RADS (Contrast-Enhanced UltraSound Liver Imaging Reporting and Data System). RESULTS: 321 patients were recruited in 43 centers; 299 (93.1 %) had liver cirrhosis. The diagnosis according to histology was HCC in 256 cases, and intrahepatic cholangiocarcinoma (iCCA) in 23 cases. In the subgroup of cirrhotic patients (n = 299), the highest sensitivity for the diagnosis of HCC was achieved with the CEUS algorithm ESCULAP (94.2 %) and CEUS on-site (90.9 %). The lowest sensitivity was reached with the CEUS LI-RADS algorithm (64 %; p < 0.001). However, the specificity of CEUS LI-RADS (78.9 %) was superior to that of ESCULAP (50.9 %) and CEUS on-site (64.9 %; p < 0.001). At the same time, the negative predictive value (NPV) of CEUS LI-RADS was significantly inferior to that of ESCULAP (34.1 % vs. 67.4 %; p < 0.001) and CEUS on-site (62.7 %; p < 0.001). The positive predictive values of all modalities were high (around 90 %), with the best results seen for CEUS LI-RADS and CEUS on-site. CONCLUSION: This is the first multicenter, prospective comparison of standardized CEUS and the recently developed CEUS-based algorithms in histologically proven liver lesions in cirrhotic patients. Our results reaffirm the excellent diagnostic accuracy of CEUS for the noninvasive diagnosis of HCC in high-risk patients. However, on-site diagnosis by an experienced examiner achieves an almost equal diagnostic accuracy compared to CEUS-based diagnostic algorithms.

Acoustic Radiation Force Impulse (ARFI) Elastography in Autoimmune and Cholestatic Liver Diseases.

INTRODUCTION: Acoustic Radiation Force Impulse (ARFI) elastography evaluates hepatic fibrosis non-invasively and has been mainly validated in viral hepatitis. Data on rare liver diseases such as autoimmune hepatitis (AIH), overlap syndrome, primary biliary cholangitis (PBC) or primary sclerosing cholangitis (PSC) are sparse. MATERIAL AND METHODS: 85 patients (including 31 AIH, 26 PBC, 16 PSC and 3 PSC-and 9 PBC-AIH-overlap syndromes) were retrospectively analysed pointing at ARFI elastography of the liver and the correlation with histologic Ishak fibrosis score (F0-6). Results of shear wave velocities (m/s) were expressed as mean ± standard deviation. RESULTS: The mean shear wave velocity of all 85 patients showed 1.80 ± 0.84 m/s (0.74-3.98). The ARFI elastography values correlated with the degree of fibrosis in all patients overall and in patients with AIH, overlap syndrome and PSC, respectively. The subgroup of 26 patients with PBC (only with Ishak F > 3) revealed no correlation between ARFI and these early fibrosis stages (r = 0.019, p = 0.927). ARFI elastography correlated with bilirubin, AST, but not with patient age, body mass index or measurement depth. The cut-off of 2.04 m/s for detecting cirrhosis (Ishak F > 5) leads to a sensitivity of 90.0% and specificity of 74.7% (AUROC 87.2%). CONCLUSION: ARFI elastography can evaluate fibrosis in AIH, PSC and PSC-/PBC-AIH-overlap syndrome with good accuracy for the detection of hepatic cirrhosis. Shear wave velocities in PBC should be interpreted with caution in early stages of fibrosis.

Tips and Tricks in Contrast-Enhanced Ultrasound (CEUS) for the Characterization and Detection of Liver Malignancies.

Contrast-enhanced ultrasound (CEUS) has a high diagnostic accuracy in the assessment of focal liver lesions. Clinical context (presence of liver cirrhosis, history of other malignancy versus incidental finding) is crucial for the correct interpretation of CEUS findings. CEUS has to be preceded by structured anamnesis and clinical examination as well as accurate B-mode sonography. Metastases are the most common malignant liver lesions in a non-cirrhotic liver. According to their contrast enhancement in the arterial phase, metastases are categorized as hyper- and hypo-vascular metastases. A common feature of all metastatic lesions is washout of the contrast agent in the portal venous or late phase. In the context of liver cirrhosis, > 95 % of focal liver lesions are hepatocellular carcinomas (HCCs). HCCs typically show arterial phase hyperenhancement, followed by mild and gradual contrast washout occurring very late in the late phase. For intrahepatic cholangiocellular carcinoma (ICC), the pattern of contrast enhancement in the arterial phase can vary. However, all ICCs typically show early and pronounced washout. Other liver malignancies like lymphoma, angiosarcoma, epithelioid hemangioendothelioma and others are very rare. Except for the contrast washout seen in all liver malignancies, they do not display pathognomonic enhancement patterns upon CEUS. Thus, biopsy is indispensable for definite diagnosis of the tumor entity. Furthermore, CEUS is used for the detection of metastases and therapeutic monitoring after local ablative procedures. The examination procedure differs slightly depending on the specific indication (characterization, detection).

Interobserver and intermodality agreement of standardized algorithms for non-invasive diagnosis of hepatocellular carcinoma in high-risk patients: CEUS-LI-RADS versus MRI-LI-RADS.

OBJECTIVES: We compared the interobserver agreement for the recently introduced contrast-enhanced ultrasound (CEUS)-based algorithm CEUS-LI-RADS (Liver Imaging Reporting and Data System) versus the well-established magnetic resonance imaging (MRI)-LI-RADS for non-invasive diagnosis of hepatocellular carcinoma (HCC) in high-risk patients. METHODS: Focal liver lesions in 50 high-risk patients (mean age 66.2 ± 11.8 years; 39 male) were assessed retrospectively with CEUS and MRI. Two independent observers reviewed CEUS and MRI examinations, separately, classifying observations according to CEUS-LI-RADSv.2016 and MRI-LI-RADSv.2014. Interobserver agreement was assessed with Cohen's kappa. RESULTS: Forty-three lesions were HCCs; two were intrahepatic cholangiocarcinomas; five were benign lesions. Arterial phase hyperenhancement was perceived less frequently with CEUS than with MRI (37/50 / 38/50 lesions = 74%/78% [CEUS; observer 1/observer 2] versus 46/50 / 44/50 lesions = 92%/88% [MRI; observer 1/observer 2]). Washout appearance was observed in 34/50 / 20/50 lesions = 68%/40% with CEUS and 31/50 / 31/50 lesions = 62%/62%) with MRI. Interobserver agreement was moderate for arterial hyperenhancement (ĸ = 0.511/0.565 [CEUS/MRI]) and "washout" (ĸ = 0.490/0.582 [CEUS/MRI]), fair for CEUS-LI-RADS category (ĸ = 0.309) and substantial for MRI-LI-RADS category (ĸ = 0.609). Intermodality agreement was fair for arterial hyperenhancement (ĸ = 0.329), slight to fair for "washout" (ĸ = 0.202) and LI-RADS category (ĸ = 0.218) CONCLUSION: Interobserver agreement is substantial for MRI-LI-RADS and only fair for CEUS-LI-RADS. This is mostly because interobserver agreement in the perception of washout appearance is better in MRI than in CEUS. Further refinement of the LI-RADS algorithms and increasing education and practice may be necessary to improve the concordance between CEUS and MRI for the final LI-RADS categorization. KEY POINTS: • CEUS-LI-RADS and MRI-LIRADS enable standardized non-invasive diagnosis of HCC in high-risk patients. • With CEUS, interobserver agreement is better for arterial hyperenhancement than for "washout". • Interobserver agreement for major features is moderate for both CEUS and MRI. • Interobserver agreement for LI-RADS category is substantial for MRI, and fair for CEUS. • Interobserver-agreement for CEUS-LI-RADS will presumably improve with ongoing use of the algorithm.

Interobserver Agreement for Contrast-Enhanced Ultrasound (CEUS)-Based Standardized Algorithms for the Diagnosis of Hepatocellular Carcinoma in High-Risk Patients.

OBJECTIVES: This pilot study aimed at assessing interobserver agreement with two contrast-enhanced ultrasound (CEUS) algorithms for the diagnosis of hepatocellular carcinoma (HCC) in high-risk patients. METHODS: Focal liver lesions in 55 high-risk patients were assessed independently by three blinded observers with two standardized CEUS algorithms: ESCULAP (Erlanger Synopsis of Contrast-Enhanced Ultrasound for Liver Lesion Assessment in Patients at risk) and ACR-CEUS-LI-RADSv.2016 (American College of Radiology CEUS-Liver Imaging Reporting and Data System). Lesions were categorized according to size and ultrasound contrast enhancement in the arterial, portal-venous and late phase. Interobserver agreement for assessment of enhancement pattern and categorization was compared between both CEUS algorithms. Additionally, diagnostic accuracy for the definitive diagnosis of HCC was compared. Histology and/or CE-MRI and follow-up served as reference standards. RESULTS: 55 patients were included in the study (male/female, 44/ 11; mean age: 65.9 years). 90.9 % had cirrhosis. Histological findings were available in 39/55 lesions (70.9 %). Reference standard of the 55 lesions revealed 48 HCCs, 2 intrahepatic cholangiocellular carcinomas (ICCs), and 5 non-HCC-non-ICC lesions. Interobserver agreement was moderate to substantial for arterial phase hyperenhancement (ĸ = 0.53 - 0.67), and fair to moderate for contrast washout in the portal-venous or late phase (ĸ = 0.33 - 0.53). Concerning the CEUS-based algorithms, the interreader agreement was substantial for the ESCULAP category (ĸ = 0.64 - 0.68) and fair for the CEUS-LI-RADS® category (ĸ = 0.3 - 0.39). Disagreement between observers was mostly due to different perception of washout. CONCLUSION: Interobserver agreement is better for ESCULAP than for CEUS-LI-RADS®. This is mostly due to the fact that perception of contrast washout varies between different observers. However, interobserver agreement is good for arterial phase hyperenhancement, which is the key diagnostic feature for the diagnosis of HCC with CEUS in the cirrhotic liver.

Dynamics of Fukuoka Criteria and Patient Management in Pancreatic Intraductal Papillary Mucinous Neoplasms (IPMNs) During Follow-Up.

BACKGROUND Pancreatic intraductal papillary mucinous neoplasms (IPMNs) present a clinical challenge. Evidence-based guidelines are lacking. The so-called "Fukuoka criteria" were developed to assess the risk of malignancy in IPMNs upon imaging. However, little is known about their diagnostic value and the natural course of IPMNs. Thus, the aim of this study was the assessment of Fukuoka criteria and patient management in pancreatic IPMNs -during follow-up. MATERIAL AND METHODS IPMNs were identified via retrospective survey of endoscopic ultrasound (EUS) examinations. Fukuoka criteria were assessed on EUS findings and additional imaging (CT, MRI, ultrasound). Patients' symptoms and comorbidities were recorded. Dynamics of Fukuoka criteria and patient management were compared at first presentation and during follow-up. RESULTS We screened 1324 EUS examinations. Sixty-five patients (male/female, 14/37; mean age, 68.8 years; range, 48-85 years) with IPMNs were identified (57 branch duct (BD-)IPMNs, 3 main duct (MD-) IPMNs, 5 mixed-type (MT)-IPMNs). Seven patients received surgical resection (4 BD-IPMNs, 2 MD-IPMNs, 1 MT-IPMN). Nine BD-IPMNs had neither surgery nor follow-up. Fifty-one patients (44 BD-IPMNs, 2 MD-IPMNs, 5 MT-IPMNs) underwent follow-up (mean duration, 18.7 months; range, 3-139 months). There were 15/51 patients who were initially Fukuoka-positive. One MD-IPMN, 4/5 MT-IPMNs, and 13/44 BD-IPMNs showed progressive changes but were not resected due to patients' refusal or comorbidities. Four BD-IPMNs converted to Fukuoka-positive. CONCLUSIONS Evidence-based guidelines for non-invasive dignity assessment of IPMNs are lacking. In our study, MD-IPMNs displayed greater dynamics than BD-IPMNs and MT-IPMNs concerning Fukuoka criteria. Prospective long-term studies are needed to clarify prognostic significance of the single Fukuoka criteria and sensible duration of follow-up.

Contrast-enhanced ultrasound pattern of hepatocellular carcinoma in noncirrhotic liver - results from the prospective multicentre DEGUM CEUS HCC study.

OBJECTIVES: Contrast-enhanced ultrasound (CEUS) has a high diagnostic accuracy for the noninvasive diagnosis of hepatocellular carcinoma (HCC) in cirrhosis. However, as HCC in noncirrhosis becomes an emerging clinical concern, our study aimed to assess the diagnostic value of CEUS and the CEUS algorithms CEUS LI-RADS and ESCULAP in noncirrhotic liver in a prospective multicentre real-life setting. METHODS: High-risk patients for HCC with focal liver lesions upon B-mode ultrasound were recruited prospectively in a multicentre real-life approach to undergo standardized CEUS. Diagnostic accuracies of CEUS and the CEUS algorithms were assessed for the sub-collective of noncirrhotic patients. Histology, MRI and CT served as the reference standard. RESULTS: In total 47/517 patients were noncirrhotic. The reference standard of the lesions showed 30 HCCs (63.8%), four intrahepatic cholangiocellular carcinomas (iCCAs), two other malignancies and 11 benign lesions. HCCs in noncirrhosis showed a tendency towards larger tumor size and better differentiation. A typical CEUS pattern of arterial phase hyperenhancement and late-onset (>60 s), mild washout occurred in 22/30 HCCs (73.3%). Very late onset of washout > 4-6 min was not seen in noncirrhotic liver. The CEUS algorithm ESCULAP showed a perfect sensitivity (100 vs. 68% with CEUS LI-RADS), whereas CEUS LI-RADS had a superior specificity (83 vs. 53%). The positive predictive value was high with both algorithms. CONCLUSION: The CEUS patterns of HCCs in noncirrhotic liver resembled those in cirrhosis. Our findings suggest that although designed for the application in cirrhosis only, the diagnostic accuracies of the CEUS algorithms in noncirrhotic liver seem comparable to the findings in cirrhosis.

Washout appearance of hepatocellular carcinomas using standardized contrast-enhanced ultrasound (CEUS) including an extended late phase observation - Real-world data from the prospective multicentre DEGUM study.

BACKGROUND: Non-invasive diagnosis of hepatocellular carcinoma (HCC) in contrast-enhanced ultrasound (CEUS) is based on the combination of arterial phase hyperenhancement (APHE) and subsequent late (>60 seconds) and mild contrast washout (WO). Whereas APHE is seen in the majority of HCC, wash-out pattern may vary in onset and intensity. In some HCC lesions, even no washout is seen at all. OBJECTIVE: Our prospective multicentre DEGUM HCC CEUS study aimed at identifying typical and atypical washout appearance of HCC in a real-life setting. METHODS: High-risked patients for HCC with focal liver lesions upon B-mode ultrasound were recruited prospectively. In a multicentre real-life setting, a standardised CEUS examination including an extended late phase up to 6 minutes was performed. CEUS patterns of HCC were recorded, and onset and intensity of washout appearance were assessed with respect to patient and tumour characteristics. Histological findings served as reference standard. RESULTS: In 230/316 HCC (72.8%), a CEUS pattern of APHE followed by WO was observed. In 158 cases (68.7%), WO was typical (onset > 60 seconds, mild intensity). 72 cases (31.3%) showed marked and / or early WO, whereas in 41 HCCs (13%), APHE was followed by sustained isoenhancement.Atypical WO upon CEUS was associated with macroinvasion of the liver vessels, portal vein thrombosis and diffuse growth pattern, but not tumour size and histological grading. CONCLUSIONS: In a prospective multicentre real-life setting, APHE is followed by atypical washout appearance or no washout at all in almost half of the HCCs with APHE. The examiner has to bear in mind that in spite of a characteristic APHE in HCCs, washout appearance can be atypical in CEUS, especially in HCCs with macrovascular invasion or diffuse growth pattern.