K. Seitz

Contrast-enhanced Ultrasound for the Characterization of Focal Liver Lesions – Diagnostic Accuracy in Clinical Practice (DEGUM multicenter trial)

PURPOSE To evaluate the diagnostic benefit of contrast-enhanced ultrasound for the differential diagnosis of liver tumors in clinical practice. MATERIALS AND METHODS From May 2004 to December 2006 1349 patients (male 677, female 672) with a hepatic tumor lacking a definite diagnosis based on B-mode ultrasound and power Doppler ultrasound were examined at 14 hospitals by contrast-enhanced ultrasound using a standardized protocol (pulse/phase inversion imaging, mechanical index < 0.4). The Tumor status was assessed based on the vascularity pattern and contrast enhancement seen in focal lesions during the arterial, portal, and late phase. The diagnosis established after contrast-enhanced ultrasound was compared to histology (> 75% cases) or in some cases to CT or MRI. RESULTS The final diagnosis of hepatic tumors included 573 benign hepatic tumors (hemangiomas n = 242, focal nodular hyperplasia n = 170, hepatocellular adenoma n = 19, other benign lesions n = 142) and 755 malignant hepatic tumors (metastases n = 383, hepatocellular carcinoma n = 279, other malignant lesions n= 93). The overall diagnostic accuracy of contrast-enhanced ultrasound in comparison to the correct final diagnosis based on the combined gold standard was 90.3%. Contrast-enhanced ultrasound was able to correctly assess 723/755 malignant lesions (sensitivity 95.8%) and 476/573 benign lesions (specificity 83.1%). The positive predictive value of contrast-enhanced ultrasound for the diagnosis of a malignant tumor was 95.4% and the negative predictive value of contrast-enhanced ultrasound was 95.7%. CONCLUSION Contrast-enhanced ultrasound clearly improves the differential diagnosis of hepatic tumors and is very helpful in clinical practice when B-scan or power Doppler morphological criteria are missing.

Tumor-Specific Vascularization Pattern of Liver Metastasis, Hepatocellular Carcinoma, Hemangioma and Focal Nodular Hyperplasia in the Differential Diagnosis of 1349 Liver Lesions in Contrast-Enhanced Ultrasound (CEUS)

AIM To evaluate the incidence and diagnostic accuracy of tumor-specific vascularization pattern in contrast-enhanced ultrasound (CEUS) in the differential diagnosis of liver tumors in clinical practice. MATERIALS AND METHODS From May 2004 to December 2006 1349 patients (male 677, female 672) with a hepatic tumor lacking a definite diagnosis based on B-mode ultrasound and power Doppler ultrasound were examined at 14 hospitals by CEUS using a standardized protocol (pulse/phase inversion imaging, mechanical index < 0.4). Vascularity pattern and contrast enhancement pattern were analyzed in focal lesions during the arterial, portal, and late phase. The tumor-specific diagnosis established after CEUS was compared to histology (> 75 % cases) or in some cases to CT or MRI. RESULTS The final diagnosis of 573 benign hepatic tumors included hemangiomas (n = 242) and focal nodular hyperplasia (n = 170), other benign lesions (n = 161). Tumor-specific vascularization pattern such as a wheel-spoke pattern and arterial hyperenhancement followed by isoenhancement in the late phase in FNH or a nodular peripheral enhancement and partial or complete fill-in pattern in hemangiomas could be assessed in the majority, but not all lesions. The diagnostic accuracy of CEUS was 83.1 % for all benign lesions and 82.2 % for hemangioma and 87.1 % for FNH. The final diagnosis of 755 malignant hepatic tumors included metastases n = 383, hepatocellular carcinoma n = 279 and other malignant lesions n = 93. Late phase hypoenhancement was seen in almost all liver metastases (94.7 %) The diagnostic accuracy of CEUS was 95.8 % for all malignant lesions and 91.4 % for liver metastases and 84.9 % for hepatocellular carcinomas. CONCLUSION Tumor-specific vascularization pattern in CEUS have a high diagnostic impact on the overall high diagnostic accuracy of CEUS for the differential diagnosis of hepatic tumors in clinical practice.

Contrast-Enhanced Ultrasound (CEUS) for the characterization of focal liver lesions - prospective comparison in clinical practice: CEUS vs. CT (DEGUM multicenter trial). Parts of this manuscript were presented at the Ultrasound Dreiländertreffen 2008, Davos.

AIM The aim of our study was to evaluate the diagnostic value of Contrast-Enhanced Ultrasound (CEUS) for the characterization of focal liver lesions in a prospective multi-center study in clinical practice. For this purpose CEUS was compared with the spiral-CT (SCT), the standard radiological method. MATERIAL AND METHODS 1349 patients with unclear liver lesions after fundamental ultrasound diagnostics including color doppler analysis were examined with standardized CEUS (pulse inversion method, mechanical index < 0.4) from May 2004 to December 2006 in 14 hospitals in a prospective study. The enhancement of contrast medium in the liver tumors was analyzed according to known tumor-specific vascular patterns, using standardized documentation and analysis methods for the differentiation of tumor differentiation (malign or benign) and tumor specification (entity). A subcollective of 267 patients was additionally examined by standardized SCT method. Final diagnosis was based on histology, SCT or MRI in typical findings of liver hemangioma and FNH and on proved clinical data and additional follow up. RESULTS The subcollective of 267 patients was divided in two subgroups. In 109 of these patients (subgroup A) there was no histological verification, diagnoses based on clear SCT-findings in 79 cases of hemangioma or FNH, as well as in 20 cases with a clear clinical diagnosis. 6 cases (5.5 %) remained unclear. In this subgroup the assessment of tumor differentiation was concordant with CEUS in 90 cases, discordant in 19 cases and the assessment of tumor specification was concordant in 82 and and discordant in 27 cases. In 158 patients (subgroup B) a histological finding was also present, only in 4 cases no definitive tumor diagnosis was achieved. In this subgroup assessment of tumor differentiation with CEUS and SCT was concordant in 124 cases and discordant in 30 cases (CEUS/SCT: sensitivity 94.0 / 90.7 %, specificity 83.0 / 81.5 %, PPV 91.6 / 91.5 %, NPV 87.5 / 80.0 %, accuracy 90.3 / 87.8 %). Tumor specification matched in 103cases and were different in 51 cases (CEUS/SCT: sensitivity 95.3 / 90.6 %, specificity 83.7 / 81.6 %, PPV 92.7 / 91.4 %, NPV 89.1 / 80.0 %, accuracy 91.6 / 87.7 %). A statistically significant difference could not be established. The analysis of particular tumor specification showed a statistically non significant slight advantage in tumor differentiation for CEUS in the case of hemangioma, FNH, HCC and metastases. CONCLUSION In a multi-center approach under routine clinical conditions, this prospective study demonstrates CEUS to be of equal rank to the CT-scan in regard to the assessment of tumor differentiation and specification. No statistically significant differences could be established. CEUS should be employed before computed tomography is performed for the differentiation of liver tumors, because radiation exposure and invasive biopsies can be avoided in veritable numbers of cases, when precise clinical evaluation of the findings is implemented.

Diagnostic accuracy of CEUS in the differential diagnosis of small (≤ 20 mm) and subcentimetric (≤ 10 mm) focal liver lesions in comparison with histology. Results of the DEGUM multicenter trial.

PURPOSE To evaluate the diagnostic accuracy of contrast-enhanced ultrasound (CEUS) in the differential diagnosis of small and subcentimetric liver tumors in clinical practice. MATERIALS AND METHODS 1349 patients with a hepatic tumor lacking a definite diagnosis based on B-mode ultrasound and power Doppler ultrasound were examined at 14 hospitals by CEUS using a standardized protocol (pulse/phase inversion imaging, mechanical index < 0.4). Differential diagnosis was based on the vascularity pattern and contrast enhancement pattern during the arterial, portal, and late phase according to the EFSUMB guidelines. 335 patients with focal liver lesions (FLL) ≤ 20  mm were analyzed. The tumor status established after CEUS was compared to histology (73.2 %) or in some cases to CT or MRI. RESULTS A definitive diagnosis based on the gold standard was possible in 329 FLLs, while 6 FLLs remained unclear even in the combined gold standard (histology and/or CT and/or MRI). The final diagnoses of ≤ 20  mm FLL with histological confirmation (n = 241) included 87 benign and 154 malignant entities. The overall diagnostic accuracy of CEUS in FLL ≤ 20  mm with histological confirmation was 83.8 %. CEUS correctly identified 144 /154 malignant FLLs (sensitivity 93.5 %) and 58 /87 benign FLLs (specificity 66.7 %). 24 /241 FLLs remained unclear after CEUS (9.9 %). CEUS misclassified 15 /241 FLLs (6.2 %; 12 benign and 3 malignant FLLs). The positive predictive value of CEUS for a malignant FLL was 92.3 % and the negative predictive value was 95.1 %. Out of 241 small FLLs with histological confirmation, 62  FLLs were ≤ 10  mm (diagnostic accuracy of CEUS 80.6 %) and 179 FLLs were > 10  mm and ≤ 20  mm (diagnostic accuracy of CEUS 84.9 %). CONCLUSION CEUS has a high diagnostic accuracy for the differential diagnosis of small and subcentimetric FLLs in clinical practice.

Unclear Focal Liver Lesions in Contrast-Enhanced Ultrasonography – Lessons to be Learned from the DEGUM Multicenter Study for the Characterization of Liver Tumors

PURPOSE To discuss the difficulties of contrast-enhanced ultrasound (CEUS) in a large multi-center trial. MATERIALS AND METHODS CEUS was performed on 1349 liver lesions with an unclear diagnosis after native ultrasound using a standardized protocol (phase inversion; low MI < 0.4; Sonovue Bolus 1.2 - 4.8 ml). The early arterial, arterial, portal venous and late phase > 2 min. were documented. The diagnosis based on CEUS results was compared to the final diagnosis (histology: n = 1006; MRI: n = 269; CT: n = 269 - multiple examinations possible). RESULTS Of the 1349 enclosed liver lesions, 20 could not be definitively diagnosed even using all diagnostic steps including histology (the others were proven to be benign n = 573 or malignant n = 756). Of the 1349 unclear liver lesions, 1257 could be differentiated with an accuracy of 90.3% using CEUS. The sensitivity, specificity, and positive and negative predictive value for malignant liver lesions was 95.8%, 83.1%, 88.2% and 93.7% respectively. 92 liver lesions (6.8%) could not be definitively diagnosed using CEUS. Most of them were benign (n = 67) on final diagnosis. The CEUS diagnosis was wrong for 39 lesions. However, only 8 lesions classified as benign by CEUS turned out to be malignant. In 3 cases HCC proven by histology was incorrectly diagnosed by CEUS as adenoma and 2 lesions incorrectly diagnosed by CEUS as FNH turned out to be an HCC and a metastasis. Two lesions diagnosed by CEUS as hemangiomas turned out to be an HCC and a metastasis. One lesion classified as benign by CEUS was ultimately diagnosed as a lymphoma. CONCLUSION Even in this multi-center trial, CEUS proved to be an excellent method for clarifying liver lesions remaining unclear after native ultrasound. The CEUS diagnosis of benign was only incorrect in a few cases.

Frequency of tumor entities among liver tumors of unclear etiology initially detected by sonography in the noncirrhotic or cirrhotic livers of 1349 patients. Results of the DEGUM multicenter study.

AIM Investigation of the frequency of various solid focal liver lesions (SFLL) in noncirrhotic and cirrhotic livers with focus on the frequency of metastasis in cirrhotic livers. MATERIAL AND METHODS The patient collective in the DEGUM multicenter study (n = 1349) was reevaluated and divided in subcollective A without (n = 1067) and B with cirrhosis (n = 282). 74.6 % of the various tumor entities were confirmed histologically (n = 1006). RESULTS In subcollective A there were 385 patients with metastases (36.4 %) and 65 with HCC (6.1 %), whereas the most common benign lesions were hemangioma, with 237 cases (22.4 %) and FNH, with 170 cases (16.1 %). In subcollective B there were 216 cases of HCC (76.6 %) and 12 metastases (4.3 %), as well as 42 benign lesions (14.9 %). CCC was rare in both subcollective A (3.3 %) and subcollective B (2.5 %). A positive oncological history increased the probability of a malignant SFLL in subcollective A by 1.8 times, but did not do so in subcollective B. CONCLUSION The frequency of various tumor entities is different in patients with and without cirrhosis of the liver. In noncirrhotic livers, malignant and benign SFLL are equally common. The most common forms are metastases, hemangiomas and FNH, CCC is rare. A positive history of extrahepatic malignancy increases the probability of a malignant SFLL. In cirrhosis, HCC dominates, HCC is 18 times as common as metastases. Benign SFLL and CCC are rare.

CEUS in hepatocellular carcinoma and intrahepatic cholangiocellular carcinoma in 320 patients - early or late washout matters: a subanalysis of the DEGUM multicenter trial.

PURPOSE The aim of the study was the comparison of tumor vascularization and contrast enhancement in contrast-enhanced ultrasound (CEUS) for the characterization of hepatocellular carcinoma (HCC) and intrahepatic cholangiocellular carcinoma (ICC). We present data of the subpopulations HCC and ICC examined in the DEGUM multicenter trial for the characterization of focal liver lesions in clinical practice. MATERIALS AND METHODS Based on the data of the DEGUM multicenter trial (1349 patients), all patients with histologically proven HCC (n = 278) and ICC (n = 42) were analyzed. The vascularity pattern and contrast enhancement pattern during the arterial, portal-venous and late phase were compared. RESULTS An underlying liver cirrhosis was found in 214/278 patients with HCC (76.9 %) and 7/42 patients with ICC (16.7 %). In CEUS, HCC showed a global arterial hyperenhancement compared to ICC (HCC: tumor center: 60.3 %; tumor periphery: 75 %; ICC: tumor center: 16.7 %; tumor periphery: 40.5 %). ICC showed an initial contrast enhancement primarily at the tumor periphery (ICC: 85.7 % vs. HCC: 61 %) followed by an early portal-venous contrast washout in the tumor center (ICC: 85.8 % vs. HCC: 49.8 %) and tumor periphery (ICC: 66.7 % vs. HCC: 32.6 %). HCC showed a delayed contrast washout (late phase hypoenhancement: HCC: 75 % vs. ICC: 92.9 %). CONCLUSION ICCs are rare in cirrhotic livers. CEUS can demonstrate differences in the vascularization patterns between HCC and ICC. HCC showed an arterial global hyperenhancement and delayed contrast washout in the late phase. ICCs are characterized by an arterial contrast enhancement at the tumor periphery with early contrast washout of the vascularized parts of the lesions in the portal-venous and late phase.