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.

Contrast-enhanced ultrasound with SonoVue: differentiation between benign and malignant focal liver lesions in 317 patients.

PURPOSE: The aim of the study was to investigate the ability of contrast-enhanced sonography (CEUS) with the contrast agent SonoVue to differentiate between benign and malignant focal liver lesions. METHODS: In a prospective study, we examined 317 patients (204 males, 113 females, aged 59 +/- 12 years) with focal liver lesions detected by B-mode gray-scale sonography. After intravenous injection of 1.2 mL SonoVue, the liver was examined continuously for 3 minutes using low-MI sonography with contrast-specific software. Final diagnosis was established by histopathology, CT, MRI, or HIDA-scintigraphy. RESULTS: Two hundred nine patients had malignant focal lesions, including 107 hepatocellular carcinomas, 70 metastases, 26 cholangiocellular carcinomas, and 6 other types of malignancy. One hundred eight patients had benign focal lesions, including 30 regenerative nodules, 30 hemangiomas, 13 cases of focal nodular hyperplasia, 12 abscesses, 8 cases of necrosis, 7 cases of focal steatosis areas, and 8 other benign lesions. Hypoenhancement or no enhancement in the late phase was found in 91% of the malignant lesions but in only 37% of the benign lesions (p < 0.001, sensitivity = 64%, specificity = 93%). Hyperenhancement in the late phase was found in 20% of the benign lesions but in none of the malignant lesions (p < 0.001, sensitivity = 21%, specificity = 100%). Hyperenhancement in the early phase with diffuse complete enhancement was found in 30% of the patients with malignant lesions but in only 2% of the patients with benign lesions (p < 0.001, sensitivity = 30%, specificity = 98%). CEUS had a sensitivity of 90%, a specificity of 99%, and an accuracy of 89% in the diagnosis of malignant liver lesions. CONCLUSION: CEUS is helpful in the differentiation between benign and malignant focal liver lesions.

Contrast-enhanced ultrasonography with SonoVue: differentiation between benign and malignant lesions of the spleen.

OBJECTIVE: We investigated the ability of contrast-enhanced ultrasonography with SonoVue (Bracco SpA, Milan, Italy), a sulfur hexafluoride microbubble contrast agent, to reveal differences between benign and malignant focal splenic lesions. METHODS: In a prospective study we investigated 35 lesions in 35 patients (24 male and 11 female; mean age +/- SD, 54 +/- 15 years) with focal splenic lesions detected by B-mode ultrasonography. After intravenous injection of 1.2 to 2.4 mL of SonoVue, the spleen was examined continuously for 3 minutes using low-mechanical index ultrasonography with contrast-specific software. The final diagnosis was established by histologic examination, computed tomography, or magnetic resonance imaging. RESULTS: In 14 patients, the splenic lesions were malignant (metastasis, n = 6; non-Hodgkin lymphoma, n = 6; and Hodgkin lymphoma, n = 2). In 21 patients, the focal splenic lesions were benign (ischemic lesion, n = 6; echogenic cyst, n = 5; abscess, n = 4; hemangioma, n = 3; hematoma, n = 1; hemophagocytosis syndrome, n = 1; and splenoma, n = 1. Typical findings for benign lesions were 2 arrival patterns: no contrast enhancement (neither in the early nor in the parenchymal phase; P < .05) and the beginning of contrast enhancement in the early phase followed by contrast enhancement in the parenchymal phase 60 seconds after injection. In contrast, the combination of contrast enhancement in the early phase followed by rapid wash-out and demarcation of the lesion without contrast enhancement in the parenchymal phase (60 seconds after injection) was typical for malignant lesions (P < .001). CONCLUSIONS: Contrast-enhanced ultrasonography is helpful in the differentiation between benign and malignant lesions of the spleen.

[Contrast-enhanced sonography using Levovist is decisive for staging and therapeutic schedule in hepatocellular carcinoma]. / Kontrastmittelsonographie der Leber als wegweisende Untersuchung für die Therapieplanung des hepatozellulären Karzinoms.

In a 65-year-old female patient, B-mode sonography detected a single focal lesion in the right liver lobe with a diameter < 3 cm. Histopathologic examination revealed a low differentiated hepatocellular carcinoma (HCC; G3). Tumor staging was performed by CT (computed tomography) scan and Resovist MRI (magnetic resonance imaging). Both examinations found a single liver lesion without signs of additional focal hepatic lesions. In addition, phase-inversion sonography in the late phase was performed using the ultrasound contrast agent Levovist. This examination of late-phase Levovist uptake detected more than five additional focal hepatic lesions in the right liver lobe, which were invisible by CT scan and Resovist MRI. This finding of multiloculated HCC was very important to decide on the patient's correct therapy. While liver transplantation is the treatment of choice in single HCC < 3 cm, it is contraindicated in multicentric HCC. In the patient described here, hemihepatectomy of the right liver lobe was performed. The histopathologic examination of the resected liver confirmed the diagnosis of multicentric HCC, which was noninvasively diagnosed only by contrast-enhanced sonography, but not by CT scan or MRI.

Elevated serum levels of heat shock protein 70 can be detected after radiofrequency ablation.

Due to their adjuvant effect and their ability to chaperone tumor-associated peptides, heat shock proteins constitute a potent alarm signal for the immune system and can lead to activation of anti-tumor T-cell immunity. Radiofrequency ablation has been reported to induce heat shock protein expression especially that of heat shock protein 70 in sublethally damaged tumor cells. In this study, we evaluated the release of heat shock protein 70 into the serum of cancer-bearing patients directly after radiofrequency ablation. Sera of 22 patients undergoing radiofrequency ablation for the treatment of primary and secondary malignancies of the liver, kidney, and lung, as well as control sera of 20 patients undergoing diagnostic liver biopsy were analyzed using a manufactured heat shock protein 70 ELISA. A significant increase in serum levels of heat shock protein 70 was detectable in the patient cohort 1 day after radiofrequency ablation. More than a twofold increase was observed in nine out of 22 patients, which tended to correlate with favorable clinical outcome. No patient of the control group revealed a comparable increase. Radiofrequency ablation can lead to a release of heat shock protein 70 into the serum, which is transiently detectable 1 day after treatment. Elevated heat shock protein 70 serum levels may constitute a biomarker for favorable clinical outcome.

[The use of colour-coded duplex sonography increases diagnostic accuracy of abdominal ultrasound]. / Der Einsatz der farbkodierten Duplexsonographie (FKDS) erhöht die diagnostische Sicherheit in der Abdomensonographie.

UNLABELLED: Colour Doppler sonography (CDS) avoids misinterpretation of abdominal ultrasonography. Differential diagnosis of pathological structures found by grey-scale sonography can be difficult in many cases. AIM: The present study aimed to determine how often additional colour Doppler sonography could be of benefit to avoid misinterpretation of grey-scale ultrasound images. METHODS: 1350 abdominal sonograms were examined. The sonographic examination was performed using a Toshiba SSA-140 A-ultrasound machine (3.75 MHz and 2.5 MHz-transducer). Findings which could be misinterpreted in grey-scale images, e. g. structures suspicious of lymph nodes, small areas of ascites, hydronephrosis, cysts or cholestasis, were examined by additional colour Doppler sonography. RESULTS: 327 findings (= 24 % of the cases) were classified as requiring additional examination by colour Doppler sonography. In 73 of these cases (= 22 % of cases having additional CDS), CDS identified blood flow in the pathological structure, which avoided misinterpretation of the grey-scale imaging. CONCLUSION: Additional CDS avoids misinterpretation of grey-scale sonography especially in patients with portal hypertension.

Differentiation between benign and malignant hepatic lesions: utility of color stimulated acoustic emission with the microbubble contrast agent Levovist.

OBJECTIVE: This study was undertaken to determine whether the examination of color stimulated acoustic emission in the late phase of Levovist (SH U 508A; Schering AG, Berlin, Germany) enhancement is helpful in the discrimination between benign and malignant liver lesions. METHODS: Fifty-six patients with focal hepatic lesions were examined. Diagnosis of the lesions was confirmed by liver biopsy, computed tomography, or scintigraphy. Thirty-one patients had malignant liver lesions: hepatocellular carcinoma (n = 14), cholangiocellular carcinoma (n = 1), metastasis (n = 14), and lymphoma (n = 2). Twenty-five patients had benign lesions: focal nodular hyperplasia (n = 8), hepatic adenoma (n = 1), focal hyposteatosis or hypersteatosis (n = 6), hemangioma (n = 7), and regenerative cirrhotic nodules (n = 3). After a delay of 5 to 10 minutes without scanning, the liver was examined by color stimulated acoustic emission with a fast sweep of 1 to 3 seconds. RESULTS: All patients with homogeneous color stimulated acoustic emission in the late phase of Levovist enhancement had benign liver lesions (P < .001; specificity, 100%; sensitivity, 68%; positive predictive value, 100%; and negative predictive value, 79%). Eighty-one percent of the patients with nonenhancing lesions in the late phase surrounded by enhanced liver parenchyma had malignant liver lesions (P < .001; specificity, 72%; sensitivity, 94%; positive predictive value, 81%; and negative predictive value, 90%). Interobserver agreement (weighted kappa value) improved from 0.570 +/- 0.038 for baseline sonography to 0.918 +/- 0.028 for color stimulated acoustic emission sonography. The area under the receiver operating characteristic curves for color stimulated acoustic emission sonography (0.927) was significantly higher than for baseline sonography (0.739; P < .05). CONCLUSIONS: Color stimulated acoustic emission in the late phase of Levovist enhancement has a high specificity and sensitivity for differentiation between benign and malignant focal liver lesions.

Real-time imaging with the sonographic contrast agent SonoVue: differentiation between benign and malignant hepatic lesions.

OBJECTIVE: We investigated the ability of contrast-enhanced sonography with SonoVue (Altana Pharma, Konstanz, Germany), a sulfur hexafluoride microbubble contrast agent, to reveal differences between benign and malignant focal hepatic lesions. METHODS: One hundred twenty-six lesions in 124 patients with focal hepatic lesions detected by B-mode sonography (hepatocellular carcinoma, n = 36; metastasis, n = 25; cholangiocellular carcinoma, n = 1; lymphoma, n = 2; focal nodular hyperplasia, n = 9; adenoma, n = 4; regenerative cirrhotic nodule, n = 13; hemangioma, n = 29; and focal hyposteatosis, n = 7) were examined in a prospective study. After intravenous injection of 2.4 mL of SonoVue, the liver was examined continuously for 3 minutes by low-mechanical index pulse inversion sonography. RESULTS: For the discrimination of malignant versus benign liver lesions, SonoVue-enhanced sonography improved sensitivity from 78% to 100% and specificity from 23% to 92% compared with baseline sonography. Receiver operating characteristic analysis revealed a significant improvement in this discrimination (area under the receiver operating characteristic curve, 0.510 +/- 0.054 [SD] at baseline sonography, 0.998 +/- 0.003 with SonoVue-enhanced sonography; P < .001). The following flow patterns in the early phase were diagnosis specific: early central starlike pattern for focal nodular hyperplasia, peripheral globular-nodular pattern for hemangioma, and diffuse arterial enhancement for malignant lesions. Homogeneous enhancement in the late phase was predictive for benign lesions (P < .001). Conversely, 93% of patients without contrast enhancement in the late phase had malignant lesions (P < .001). CONCLUSIONS: SonoVue-enhanced sonography has greater specificity and sensitivity than baseline sonography for the differentiation of benign and malignant liver lesions.

Pulse inversion sonography in the early phase of the sonographic contrast agent Levovist: differentiation between benign and malignant focal liver lesions.

OBJECTIVE: To determine whether examination of focal liver lesions by pulse inversion sonography in the early perfusion phase of the contrast agent Levovist (SH U 508A; Schering AG, Berlin, Germany) enables distinction between benign and malignant lesions. METHODS: Seventy-two patients were examined. The cause of the lesion was confirmed by liver biopsy, computed tomography, or both or by hepatic iminodiacetic acid-enhanced scintigraphy. Forty-two patients had malignant liver lesions, and 30 had benign liver lesions. After injection of 2 g of Levovist intravenously, analysis of Levovist arrival was performed by the interval delay imaging technique for 60 seconds. RESULTS: The early arrival of Levovist less than 30 seconds after injection was used as an indicator for malignancy and had specificity of 67% and sensitivity of 60% (P < .05). The central starlike fill-in as a sign for focal nodular hyperplasia had specificity of 100% and sensitivity of 67% (P < .001). The rimlike pattern followed by centripetal fill-in as a sign for hemangioma had specificity of 100% and sensitivity of 18% (P < .01). In contrast, the early diffuse stippled arrival pattern was found in 60% of malignant lesions and also in 33% of cases of focal nodular hyperplasia and in 1 patient with an adenoma. CONCLUSIONS: Analysis of Levovist arrival time cannot distinguish between a malignant or benign lesion in individual cases. However, the central starlike arrival pattern is characteristic of focal nodular hyperplasia.

Late-phase pulse-inversion sonography using the contrast agent levovist: differentiation between benign and malignant focal lesions of the liver.

OBJECTIVE: We assessed the ability of contrast-enhanced sonography to reveal differences between benign and malignant focal hepatic lesions. SUBJECTS AND METHODS: We examined 67 patients with focal hepatic lesions in a prospective study. The causes of the lesions were confirmed by histology, CT, MR imaging, or scintigraphy. The liver was screened for focal lesions using sonography. Thereafter, 2 g of Levovist (300 mg/mL; 1 mL/sec) was injected IV as a bolus. After a delay of at least 2.5 min without scanning, the liver was examined via three different scans using pulse-inversion sonography. RESULTS: For the discrimination of malignant versus benign liver lesions, contrast-enhanced sonography improved sensitivity from 85% to 100% and specificity from 30% to 63%, as compared with baseline sonography. Receiver operating characteristic analysis revealed a significant improvement in this discrimination (A(z) = 0.692 +/- 0.065 at baseline sonography, A(z) = 0.947 +/- 0.037 with contrast-enhanced sonography, p < 0.001). Furthermore, a lower interobserver variability was found for contrast-enhanced sonography (weighted kappa = 0.947), as compared with baseline sonography (weighted kappa = 0.469). All lesions that had homogeneous enhancement in the late phase of Levovist enhancement were benign. In distinction, 90% of lesions without contrast enhancement in the late phase were malignant. All lesions were malignant that were isoechoic (invisible) on baseline sonography but visible because of lack of enhancement after injection. CONCLUSION: Contrast-enhanced sonography has greater specificity and sensitivity than baseline sonography for the differentiation of benign and malignant liver lesions.