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

Deike Strobel; Abbas Agaimy; Daniel Jesper; Sebastian Zundler; Barbara Schellhaas

doi:10.1055/a-2034-1911

Ultraschall in der Medizin - European Journal of Ultrasound, Table of Contents

Ultraschall Med 2023; 44(06): 606-613
DOI: 10.1055/a-2034-1911

Original Article

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

Hepatozelluläre Karzinome (HCCs) ohne arterielles Hyperenhancement (APHE) in der Kontrastmittelsonografie (CEUS) – Erkenntnisse aus der prospektiven multizentrischen DEGUM-CEUS-HCC-Studie

Authors

Deike Strobel

¹Department of Medicine 1 Gastroenterology Endocrinology and Pneumology, Erlangen University Hospital, Erlangen, Germany (Ringgold ID: RIN72175)
Abbas Agaimy

²Institute of Pathoogy, Erlangen University Hospital, Erlangen, Germany (Ringgold ID: RIN27168)
Daniel Jesper

¹Department of Medicine 1 Gastroenterology Endocrinology and Pneumology, Erlangen University Hospital, Erlangen, Germany (Ringgold ID: RIN72175)
Sebastian Zundler

¹Department of Medicine 1 Gastroenterology Endocrinology and Pneumology, Erlangen University Hospital, Erlangen, Germany (Ringgold ID: RIN72175)
Barbara Schellhaas

¹Department of Medicine 1 Gastroenterology Endocrinology and Pneumology, Erlangen University Hospital, Erlangen, Germany (Ringgold ID: RIN72175)

Abstract

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.

Zusammenfassung

Ziele Hepatozelluläre Karzinome (HCCs) zeigen in der Kontrastmittelsonografie (CEUS) typischerweise ein arterielles Hyperenhancement (APHE) mit nachfolgend spätem (> 60 Sekunden), mildem Auswaschen (WO). Obwohl APHE das Hauptkriterium in der HCC-Diagnostik darstellt, fehlt dieses Merkmal bei einigen HCCs. Die vorliegende Arbeit sollte untersuchen, welche sonomorphologischen und histopathologischen Eigenschaften mit fehlendem APHE assoziiert sind.

Methoden Fokale Leberläsionen bei HCC-Hochrisikopatienten wurden nach einem standardisierten CEUS-Protokoll in einem prospektiven multizentrischen Ansatz untersucht. Die CEUS-Muster der HCCs wurden analysiert und Tumor- und Patientencharakteristika für HCCs mit und ohne APHE verglichen.

Ergebnisse 316 HCC-Patienten wurden eingeschlossen (76,9% Zirrhose). APHE fand sich bei 271/316 HCCs (85,8%). Fehlendes APHE war assoziiert mit Pfortaderthrombose, Tumorinfiltration in die Lebergefäße (p<0,001), größerem Tumordurchmesser, Multilokularität und größerer Tiefenlokalisation (p<0,01). Der histologische Differenzierungsgrad unterschied sich nicht zwischen HCCs mit und ohne APHE (p=0,39). Histologisch zeigten HCCs ohne APHE zirrhotische Stromareaktionen, ausgeprägte Tumorzellverfettung und ein Fehlen der typischen umgebenden erweiterten Sinusoide.

Schlussfolgerungen Die Korrelation mit histopathologischen Merkmalen belegt, dass HCCs mit fehlendem APHE im CEUS eine heterogene Gruppe darstellen. Der Untersucher sollte sich bewusst machen, dass APHE insbesondere bei HCCs mit Pfortaderthrombose oder Makrogefäßinvasion fehlen kann.

Keywords

Hepatocellular carcinoma (HCC) - Contrast-enhanced ultrasound (CEUS) - Arterial phase hyperenhancement (APHE) - Histology - Prospective multicenter study

Full Text

References

References
1 van der Pol CB, McInnes MDF, Salameh JP. et al. CT/MRI and CEUS LI-RADS Major Features Association with Hepatocellular Carcinoma: Individual Patient Data Meta-Analysis. Radiology 2022; 302 (02) 326-335
2 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
3 Strobel D, Jung EM, Ziesch M. et al. Real-life assessment of standardized contrast-enhanced ultrasound (CEUS) and CEUS algorithms (CEUS LI-RADS/ESCULAP) in hepatic nodules in cirrhotic patients-a prospective multicenter study. Eur Radiol 2021; 31 (10) 7614-7625
4 Schellhaas B, Bernatik T, Dirks K. et al. Contrast-Enhanced Ultrasound Patterns for the Non-invasive Diagnosis of Hepatocellular Carcinoma: A Prospective Multicenter Study in Histologically Proven Liver Lesions in a Real-Life Setting Demonstrating the Benefit of Extended Late Phase Observation. Ultrasound Med Biol 2021; 47 (11) 3170-3180
5 European Association for the Study of the Liver. EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma. J Hepatol 2018; 69 (01) 182-236
6 Schellhaas B, Strobel D. Tips and Tricks in Contrast-Enhanced Ultrasound (CEUS) for the Characterization and Detection of Liver Malignancies. Ultraschall in Med 2019; 40 (04) 404-424
7 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
8 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: 484-490
9 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 in Med 2013; 34 (03) 280-287
10 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 1,006 nodules. J Hepatol 2018; 68 (03) 485-492
11 Oken MM, Creech RH, Tormey DC. et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982; 5 (06) 649-655
12 Fraquelli M, Nadarevic T, Colli A. et al. Contrast-enhanced ultrasound for the diagnosis of hepatocellular carcinoma in adults with chronic liver disease. Cochrane Database Syst Rev 2022; 9 (09) CD013483
13 Shin SK, Kim YS, Choi SJ. et al. Contrast-enhanced ultrasound for the differentiation of small atypical hepatocellular carcinomas from dysplastic nodules in cirrhosis. Dig Liver Dis 2015; 47 (09) 775-782
14 Forner A, Vilana R, Bianchi ER. et al. Lack of arterial hypervascularity at contrast-enhanced ultrasound should not define the priority for diagnostic work-up of nodules <2 cm. J Hepatol 2015; 62 (01) 150-155
15 Strobel D, Seitz K, Blank W. et al. Tumor-specific vascularization pattern of liver metastasis, hepatocellular carcinoma, hemangioma and focal nodular hyperplasia in the differential diagnosis of 1,349 liver lesions in contrast-enhanced ultrasound (CEUS). Ultraschall in Med 2009; 30 (04) 376-382
16 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 in Med 2018; 39 (06) 667-674
17 Schellhaas B, Bernatik T, Bohle W. et al. DEGUM CEUS HCC Study Group. Contrast-Enhanced Ultrasound Algorithms (CEUS-LIRADS/ESCULAP) for the Noninvasive Diagnosis of Hepatocellular Carcinoma – A Prospective Multicenter DEGUM Study. Ultraschall in Med 2021; 42 (02) e20
18 Ehman EC, Behr SC, Umetsu SE. et al. Rate of observation and inter-observer agreement for LI-RADS major features at CT and MRI in 184 pathology proven hepatocellular carcinomas. Abdom Radiol (NY) 2016; 41 (05) 963-969
19 Ludwig DR, Fraum TJ, Cannella R. et al. Hepatocellular carcinoma (HCC) versus non-HCC: accuracy and reliability of Liver Imaging Reporting and Data System v2018. Abdom Radiol (NY) 2019; 44 (06) 2116-2132
20 Chang J, Dumitrache A, Böhling N. et al. Alteration of contrast enhanced ultrasound (CEUS) of hepatocellular carcinoma in patients with cirrhosis and transjugular intrahepatic portosystemic shunt (TIPS). Sci Rep 2020; 10 (01) 20682
21 Jang HJ, Kim TK, Burns PN. et al. Enhancement patterns of hepatocellular carcinoma at contrast-enhanced US: comparison with histologic differentiation. Radiology 2007; 244 (03) 898-906
22 Fan PL, Ding H, Mao F. et al. Enhancement patterns of small hepatocellular carcinoma (≤ 30 mm) on contrast-enhanced ultrasound: Correlation with clinicopathologic characteristics. Eur J Radiol 2020; 132: 109341
23 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 in Med 2009; 30 (06) 544-550

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