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

Abstract

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.

Zusammenfassung

Hintergrund Diese prospektive, multizentrische, DEGUM-geförderte Studie untersucht die diagnostische Genauigkeit standardisierter Algorithmen für die Kontrastmittelsonografie (CEUS-Algorithmen) in der nichtinvasiven Diagnostik des hepatozellulären Karzinoms (HCC) bei Hochrisikopatienten.

Methoden HCC-Hochrisikopatienten mit histologisch gesicherter Leberläsion im B-Bild-Ultraschall wurden prospektiv multizentrisch eingeschlossen. Klinische Daten und Bildgebungsbefunde wurden über Online-Eingabemasken erfasst. Es erfolgte ein direkter Vergleich der diagnostischen Genauigkeiten für die konventionelle CEUS-Befundung zum Untersuchungszeitpunkt (CEUS-on-site) und die CEUS-Algorithmen ESCULAP (Erlanger Synopsis for Contrast-enhanced Ultrasound for Liver lesion Assessment in Patients at risk) und CEUS LI-RADS (Contrast-Enhanced UltraSound Liver Imaging Reporting and Data System).

Ergebnisse 321 Patienten an 43 Zentren wurden eingeschlossen (93,1 % Leberzirrhose). Der histologische Befund ergab 256 HCCs und 23 intrahepatische cholangiozelluläre Karzinome (iCCA). Die höchste Sensitivität bei Zirrhose-Patienten (n = 299) erzielten der CEUS-Algorithmus ESCULAP (94,2 %) und CEUS-on-site (90,9 %), die geringste Sensitivität der CEUS LI-RADS-Algorithmus (64 %; p < 0,001). Die Spezifität war höher für CEUS LI-RADS (78,9 %) versus ESCULAP (50,9 %) und CEUS on-site (64,9 %; p < 0,001). Der negativ prädiktive Wert (NPW) war für CEUS LI-RADS niedriger als für ESCULAP (34,1 % vs. 67,4 %; p < 0,001) und CEUS-on-site (62,7 %; p < 0,001). Der positiv prädiktive Wert (PPW) war für alle Modalitäten hoch (rund 90 %).

Schlussfolgerungen Dies ist die erste prospektive, multizentrische Studie zum Vergleich der standardisierten Kontrastmittelsonografie mit den kürzlich entwickelten CEUS-Algorithmen in histologisch gesicherten Leberläsionen bei Zirrhose-Patienten. Unsere Ergebnisse bestätigen die exzellente diagnostische Genauigkeit der Kontrastmittelsonografie in der nichtinvasiven HCC-Diagnostik bei Hochrisikopatienten. Die On-site-Diagnose eines erfahrenen Untersuchers erzielt dabei eine beinahe ebenso gute diagnostische Genauigkeit wie die CEUS-basierten Diagnosealgorithmen

Key words

hepatocellular carcinoma - CEUS algorithms - ESCULAP - CEUS LI-RADS (Contrast-Enhanced UltraSound Liver Imaging Reporting and Data System) - contrast-enhanced ultrasound (CEUS)

Publication History

Received: 12 December 2019

Accepted: 04 June 2020

Article published online:
14 July 2020

• References

• 1 Greten TF, Malek NP, Schmidt S. et al. Diagnosis of and therapy for hepatocellular carcinoma. Z Gastroenterol 2013; 51 (11) 1269-1326
• 2 Galle PR, Forner A, Llovet JM. et al. EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma. J Hepatol 2018; 69 (01) 182-236
• 3 Leoni S, Piscaglia F, Granito A. et al. Characterization of Primary and Recurrent Nodules in Liver Cirrhosis Using Contrast-Enhanced Ultrasound: Which Vascular Criteria Should be Adopted?. Ultraschall Med 2013; 34 (03) 280-287
• 4 Boozari B, Soudah B, Rifai K. et al. Grading of hypervascular hepatocellular carcinoma using late phase of contrast enhanced sonography – a prospective study. Dig Liver Dis 2011; 43 (06) 484-490
• 5 Giorgio A, Montesarchio L, Gatti P. et al. Contrast-Enhanced Ultrasound: a Simple and Effective Tool in Defining a Rapid Diagnostic Work-up for Small Nodules Detected in Cirrhotic Patients during Surveillance. J Gastrointestin Liver Dis 2016; 25 (02) 205-211
• 6 Von Herbay A, Vogt C, Westendorff J. et al. Correlation between SonoVue enhancement in CEUS, HCC differentiation and HCC diameter: analysis of 130 patients with hepatocellular carcinoma (HCC). Ultraschall Med 2009; 30 (06) 544-550
• 7 Claudon M, Dietrich CF, Choi BI. et al. Guidelines and good clinical practice recommendations for contrast enhanced ultrasound (CEUS) in the liver--update 2012: a WFUMB-EFSUMB initiative in cooperation with representatives of AFSUMB, AIUM, ASUM, FLAUS and ICUS. Ultraschall Med 2013; 34 (01) 11-29
• 8 Schellhaas B, Goertz RS, Pfeifer L. et al. Diagnostic accuracy of contrast-enhanced ultrasound for the differential diagnosis of hepatocellular carcinoma: ESCULAP versus CEUS-LI-RADS. Eur J Gastroenterol Hepatol 2017; 29 (09) 1036-1044
• 9 Schellhaas B, Hammon M, Strobel D. et al. 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. Eur Radiol 2018; 28 (10) 4254-4264
• 10 Schellhaas B, Pfeifer L, Kielisch C. et al. Interobserver Agreement for Contrast-Enhanced Ultrasound (CEUS)-Based Standardized Algorithms for the Diagnosis of Hepatocellular Carcinoma in High-Risk Patients. Ultraschall Med 2018; 39 (06) 667-674
• 11 Schellhaas B, Wildner D, Pfeifer L. et al. LI-RADS-CEUS – Proposal for a Contrast-Enhanced Ultrasound Algorithm for the Diagnosis of Hepatocellular Carcinoma in High-Risk Populations. Ultraschall Med 2016; 37 (06) 627-634
• 12 Terzi E, Iavarone M, Pompili M. et al. Contrast ultrasound LI-RADS LR-5 identifies hepatocellular carcinoma in cirrhosis in a multicenter restropective study of 1006 nodules. J Hepatol 2018; 68 (03) 485-492
• 13 Schellhaas B, Strobel D. Tips and Tricks in Contrast-Enhanced Ultrasound (CEUS) for the Characterization and Detection of Liver Malignancies. Ultraschall Med 2019; 40 (04) 404-424
• 14 Mazzaferro V, Regalia E, Doci R. et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 1996; 334 (11) 693-699
• 15 Leisenring W, Alonzo T, Pepe MS. Comparisons of predictive values of binary medical diagnostic tests for paired designs. Biometrics 2000; 56 (02) 345-351
• 16 R Core Team. A language and environment for statistical computing. 2018 Vienna, Austria : R Foundation for Statistical Computing.
• 17 Seitz K, Greis C, Schuler A. et al. 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. Ultraschall Med 2011; 32 (06) 598-603
• 18 D’Onofrio M, Crosara S, De Robertis R. et al. Contrast-Enhanced Ultrasound of Focal Liver Lesions. AJR Am J Roentgenol 2015; 205 (01) W56-W66
• 19 Durot I, Wilson SR, Willmann JK. Contrast-enhanced ultrasound of malignant liver lesions. Abdom Radiol (NY) 2018; 43 (04) 819-847
• 20 Ling W, Wang M, Ma X. et al. The preliminary application of liver imaging reporting and data system (LI-RADS) with contrast-enhanced ultrasound (CEUS) on small hepatic nodules (≤ 2cm). J Cancer 2018; 9 (16) 2946-2952