Contrast enhanced ultrasound for the diagnosis of hepatocellular carcinoma (HCC): Comments on AASLD guidelines

Abstract

Contrast enhanced ultrasound (CEUS) has been introduced 10 years ago for liver imaging in many European and Asian countries, but FDA approval in the US is still lacking [[1]Wilson S.R. Greenbaum L.D. Goldberg B.B. Contrast-enhanced ultrasound: what is the evidence and what are the obstacles?.AJR Am J Roentgenol. 2009; 193: 55-60Crossref PubMed Scopus (163) Google Scholar]. The excellent value of CEUS has been established by numerous prospective studies including the German DEGUM-Study with over 1000 patients [[2]Strobel D. Seitz K. Blank W. Schuler A. Dietrich C. von Herbay A. et al.Contrast-enhanced ultrasound for the characterization of focal liver lesions – diagnostic accuracy in clinical practice (DEGUM multicenter trial).Ultraschall Med. 2008; 29: 499-505Crossref PubMed Scopus (265) Google Scholar] and the respective French multicentric study [[3]Trillaud H. Bruel J.M. Valette P.J. Vilgrain V. Schmutz G. Oyen R. et al.Characterization of focal liver lesions with SonoVue-enhanced sonography: international multicenter-study in comparison to CT and MRI.World J Gastroenterol. 2009; 15: 3748-3756Crossref PubMed Scopus (154) Google Scholar]. CEUS was proven able to detect and characterize liver tumours in clinical routine within at least the same accuracy range as contrast enhanced computed tomography (CECT) and contrast enhanced magnetic resonance imaging (CEMRI) [4Dietrich C.F. Kratzer W. Strobe D. Danse E. Fessl R. Bunk A. et al.Assessment of metastatic liver disease in patients with primary extrahepatic tumors by contrast-enhanced sonography versus CT and MRI.World J Gastroenterol. 2006; 12: 1699-1705Crossref PubMed Scopus (200) Google Scholar, 5Dietrich C.F. Ignee A. Trojan J. Fellbaum C. Schuessler G. Improved characterisation of histologically proven liver tumours by contrast enhanced ultrasonography during the portal venous and specific late phase of SHU 508A.Gut. 2004; 53: 401-405Crossref PubMed Scopus (125) Google Scholar]. Therefore, CEUS has been introduced into important guidelines and recommendations, like those from the American Association for the Study of Liver Diseases (AASLD) 2005 [[6]Bruix J. Sherman M. Management of hepatocellular carcinoma.Hepatology. 2005; 42: 1208-1236Crossref PubMed Scopus (5065) Google Scholar], the Asian Pacific Association for the Study of the Liver (APASL) [[7]Omata M. Lesmana L.A. Tateishi R. Chen P.J. Lin S.M. Yoshida H. et al.Asian Pacific Association for the Study of the Liver consensus recommendations on hepatocellular carcinoma.Hepatol Int. 2010; 4: 439-474Crossref Scopus (830) Google Scholar], the Japanese Society of Hepatology [[8]Kudo M. Izumi N. Kokudo N. Matsui O. Sakamoto M. Nakashima O. et al.Management of hepatocellular carcinoma in Japan: consensus-based Clinical Practice Guidelines proposed by the Japan Society of Hepatology (JSH) 2010 updated version.Dig Dis. 2011; 29: 339-364Crossref PubMed Scopus (627) Google Scholar] and the European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB) guidelines 2004 [[9]Albrecht T. Blomley M. Bolondi L. Claudon M. Correas J.M. Cosgrove D. et al.Guidelines for the use of contrast agents in ultrasound. January 2004.Ultraschall Med. 2004; 25: 249-256Crossref PubMed Scopus (421) Google Scholar], 2008 [[10]Claudon M. Cosgrove D. Albrecht T. Bolondi L. Bosio M. Calliada F. et al.Guidelines and good clinical practice recommendations for contrast enhanced ultrasound (CEUS) – update 2008.Ultraschall Med. 2008; 29: 28-44Crossref PubMed Scopus (697) Google Scholar], and WFUMB-EFSUMB guidelines 2012 (in preparation). However, CEUS has been eliminated from the diagnostic flow chart of nodules in cirrhosis in the updated AASLD guidelines 2011 [[11]Bruix J. Sherman M. Management of hepatocellular carcinoma: an update.Hepatology. 2011; 53: 1020-1022Crossref PubMed Scopus (6549) Google Scholar]. This removal raised controversial discussion and was not well received in Europe and Asia. This is therefore the issue to which the present commentary refers. There are two reasons for which CEUS has been eliminated from the AASLD guidelines. 1. “Contrast-enhanced US may offer false positive HCC diagnosis in patients with cholangiocarcinoma and thus, has been dropped from the diagnostic techniques” Intrahepatic cholangiocellular carcinoma (ICC) is a rare tumour in liver cirrhosis (about 1–3% of newly developed tumors) [12Rimola J. Forner A. Tremosini S. Reig M. Vilana R. Bianchi L. et al.Non-invasive diagnosis of hepatocellular carcinoma 2 cm in cirrhosis. Diagnostic accuracy assessing fat, capsule and signal intensity at dynamic MRI.J Hepatol. 2012; 56: 1317-1323Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar, 13Serste T. Barrau V. Ozenne V. Vullierme M.P. Bedossa P. Farges O. et al.Accuracy and disagreement of computed tomography and magnetic resonance imaging for the diagnosis of small hepatocellular carcinoma and dysplastic nodules: role of biopsy.Hepatology. 2012; 55: 800-806Crossref PubMed Scopus (116) Google Scholar] but the incidence appears raising [[14]Shaib Y.H. El Serag H.B. Nooka A.K. Thomas M. Brown T.D. Patt Y.Z. et al.Risk factors for intrahepatic and extrahepatic cholangiocarcinoma: a hospital-based case-control study.Am J Gastroenterol. 2007; 102: 1016-1021Crossref PubMed Scopus (220) Google Scholar]. In a retrospective series of 21 patients with histologically confirmed ICC on cirrhosis collected between 2003 and 2009, the Barcelona Clinic Liver Cancer (BCLC) group found that ten ICC had the same CEUS enhancement pattern considered diagnostic for HCC, consisting in homogeneous arterial hyperenhancement followed by wash-out [[15]Vilana R. Forner A. Bianchi L. Garcia-Criado A. Rimola J. de Lope C.R. et al.Intrahepatic peripheral cholangiocarcinoma in cirrhosis patients may display a vascular pattern similar to hepatocellular carcinoma on contrast-enhanced ultrasound.Hepatology. 2010; 51: 2020-2029Crossref PubMed Scopus (237) Google Scholar]. At variance, these tumours showed hyperintense enhancement in the arterial phase but lacked wash-out at MRI, failing to show the typical HCC pattern, thus prompting biopsy. The difference in the enhancement patterns is probably related to the different pharmacokinetics of contrast agents used for US (strictly intravascular) and MRI (extravascular space diffusion of Gadolinium which transiently binds to fibrous tissue, explaining enhancement in ICC in the late phase) [16Harris M.A. Johnson T.R. Weinberg P.M. Fogel M.A. Delayed-enhancement cardiovascular magnetic resonance identifies fibrous tissue in children after surgery for congenital heart disease.J Thorac Cardiovasc Surg. 2007; 133: 676-681Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar, 17Murakami T. Nakamura H. Tsuda K. Ishida T. Tomoda K. Hori S. et al.Contrast-enhanced MR imaging of intrahepatic cholangiocarcinoma: pathologic correlation study.J Magn Reson Imaging. 1995; 5: 165-170Crossref PubMed Scopus (77) Google Scholar]. The valuable observation of the BCLC group on the potential risk of false positive diagnosis of HCC in cirrhosis by CEUS has to be fully acknowledged and kept in high consideration. However, the quality of the study and the clinical consequences of this possible risk do not seem to justify the complete removal of CEUS from the imaging armamentarium. The study included a relatively low number of patients recruited over a long time of six years (approximately only 1–2/year at risk of misdiagnosis by CEUS), which outlines the rarity of ICC, and had a non-prospective and non-controlled study design. This means that an incorporation bias could have occurred. In other words, it cannot be excluded that some ICC were erroneously diagnosed as HCC by MRI. MRI was, in fact, the diagnostic reference standard, at least for nodules >2 cm, with no possibility to detect false positive cases for HCC. Furthermore, no information was reported about the behaviour of ICC at CT [[15]Vilana R. Forner A. Bianchi L. Garcia-Criado A. Rimola J. de Lope C.R. et al.Intrahepatic peripheral cholangiocarcinoma in cirrhosis patients may display a vascular pattern similar to hepatocellular carcinoma on contrast-enhanced ultrasound.Hepatology. 2010; 51: 2020-2029Crossref PubMed Scopus (237) Google Scholar]. Nonetheless, CT was maintained as capable of establishing a diagnosis of HCC, despite it may show the typical pattern of HCC also in primary liver lymphoma [[18]Foschi F.G. Dall’aglio A.C. Marano G. Lanzi A. Savini P. Piscaglia F. et al.Role of contrast-enhanced ultrasonography in primary hepatic lymphoma.J Ultrasound Med. 2010; 29: 1353-1356PubMed Google Scholar], an entity which in some series of HCV-related cirrhosis was reported to occur even more frequently than cholangiocarcinoma [[19]Caturelli E. Bartolucci F. Biasini E. Vigliotti M.L. Andriulli A. Siena D.A. et al.Diagnosis of liver nodules observed in chronic liver disease patients during ultrasound screening for early detection of hepatocellular carcinoma.Am J Gastroenterol. 2002; 97: 397-405Crossref PubMed Google Scholar]. Consequently, applying a required positive predictive values (PPV) of 100% for accepting a technique as diagnostic for HCC (CEUS was eliminated despite estimated positive predictive value >95%) could make not only CEUS, but possibly also CT unacceptable, and a large prospective trial of histologically confirmed nodules would be required to demonstrate how accurate MRI is. It is worth reminding, however, that in one prospective trial with histology as reference standard for all patients, a total specificity of the arterial wash-in with venous wash-out pattern for HCC in cirrhosis was reported [[20]Sangiovanni A. Manini M.A. Iavarone M. Romeo R. Forzenigo L.V. Fraquelli M. et al.The diagnostic and economic impact of contrast imaging techniques in the diagnosis of small hepatocellular carcinoma in cirrhosis.Gut. 2010; 59: 638-644Crossref PubMed Scopus (312) Google Scholar], but the number of cases could have been too low to confirm 100% PPV. Furthermore, it is worth pointing out that, in ICC, the pattern of CEUS would anyway suggest a diagnosis of malignancy, for which it is approximately totally specific [[20]Sangiovanni A. Manini M.A. Iavarone M. Romeo R. Forzenigo L.V. Fraquelli M. et al.The diagnostic and economic impact of contrast imaging techniques in the diagnosis of small hepatocellular carcinoma in cirrhosis.Gut. 2010; 59: 638-644Crossref PubMed Scopus (312) Google Scholar], whereas the pattern of MRI in case of ICC would not be diagnostic for malignancy (wash-in not followed by wash-out). This is an important point, since biopsy is not always technically feasible and it shows only moderate sensitivity for malignancy in very small nodules (1–2 cm) [[21]Forner A. Vilana R. Ayuso C. Bianchi L. Sole M. Ayuso J.R. et al.Diagnosis of hepatic nodules 20 mm or smaller in cirrhosis: prospective validation of the noninvasive diagnostic criteria for hepatocellular carcinoma.Hepatology. 2008; 47: 97-104Crossref PubMed Scopus (794) Google Scholar]. Detailed analysis of the patterns reported in the study by which guidelines were modified [[15]Vilana R. Forner A. Bianchi L. Garcia-Criado A. Rimola J. de Lope C.R. et al.Intrahepatic peripheral cholangiocarcinoma in cirrhosis patients may display a vascular pattern similar to hepatocellular carcinoma on contrast-enhanced ultrasound.Hepatology. 2010; 51: 2020-2029Crossref PubMed Scopus (237) Google Scholar] could be of help in better understanding the role of CEUS. Eleven patients showed rim enhancement in the arterial phase, a pattern which is not typical for HCC and tends to suggest ICC (or metastasis), whatever contrast imaging technique is used [22Chen L.D. Xu H.X. Xie X.Y. Lu M.D. Xu Z.F. Liu G.J. et al.Enhancement patterns of intrahepatic cholangiocarcinoma: comparison between contrast-enhanced ultrasound and contrast-enhanced CT.Br J Radiol. 2008; 81: 881-889Crossref PubMed Scopus (84) Google Scholar, 23Chen L.D. Xu H.X. Xie X.Y. Xie X.H. Xu Z.F. Liu G.J. et al.Intrahepatic cholangiocarcinoma and hepatocellular carcinoma: differential diagnosis with contrast-enhanced ultrasound.Eur Radiol. 2010; 20: 743-753Crossref PubMed Scopus (131) Google Scholar, 24D’Onofrio M. Vecchiato F. Cantisani V. Barbi E. Passamonti M. Ricci P. et al.Intrahepatic peripheral cholangiocarcinoma (IPCC): comparison between perfusion ultrasound and CT imaging.Radiol Med. 2008; 113: 76-86Crossref Scopus (38) Google Scholar, 25Xu H.X. Liu G.J. Lu M.D. Xie X.Y. Xu Z.F. Zheng Y.L. et al.Characterization of focal liver lesions using contrast-enhanced sonography with a low mechanical index mode and a sulfur hexafluoride-filled microbubble contrast agent.J Clin Ultrasound. 2006; 34: 261-272Crossref PubMed Scopus (74) Google Scholar], whereas 10 showed homogeneous enhancement, consistent with HCC. However, half of the latter (5 out of 10) showed early wash-out at CEUS (namely before 60 s) [[15]Vilana R. Forner A. Bianchi L. Garcia-Criado A. Rimola J. de Lope C.R. et al.Intrahepatic peripheral cholangiocarcinoma in cirrhosis patients may display a vascular pattern similar to hepatocellular carcinoma on contrast-enhanced ultrasound.Hepatology. 2010; 51: 2020-2029Crossref PubMed Scopus (237) Google Scholar], which is no longer totally typical of HCC. Even in poorly differentiated HCC, median time of onset of wash-out was reported to be 2 min and it is longer in well differentiated HCC [[26]Boozari B. Soudah B. Rifai K. Schneidewind S. Vogel A. Hecker H. et al.Grading of hypervascular hepatocellular carcinoma using late phase of contrast enhanced sonography – a prospective study.Dig Liver Dis. 2011; 43: 484-490Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar]. It is worth pointing out that the possibility to grade the intensity of the wash-out in the late venous phase applies to all contrast imaging techniques, whereas the possibility to establish an accurate temporal pattern of enhancement belongs to CEUS only, due to its real time modality [10Claudon M. Cosgrove D. Albrecht T. Bolondi L. Bosio M. Calliada F. et al.Guidelines and good clinical practice recommendations for contrast enhanced ultrasound (CEUS) – update 2008.Ultraschall Med. 2008; 29: 28-44Crossref PubMed Scopus (697) Google Scholar, 27Bolondi L. Correas J.M. Lencioni R. Weskott H.P. Piscaglia F. New perspectives for the use of contrast-enhanced liver ultrasound in clinical practice.Dig Liver Dis. 2007; 39: 187-195Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar, 28Lencioni R. Piscaglia F. Bolondi L. Contrast-enhanced ultrasound in the diagnosis of hepatocellular carcinoma.J Hepatol. 2008; 48: 848-857Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar]. To summarize, a true false positive diagnosis of HCC instead of ICC would have been established in only 5 cases in expert hands, out of the hundreds probably seen in the 6-year study period at BCLC. Briefly, the strength of the BCLC study on ICC is not so convincing to completely remove CEUS from the recall strategy, as it instead happened [[11]Bruix J. Sherman M. Management of hepatocellular carcinoma: an update.Hepatology. 2011; 53: 1020-1022Crossref PubMed Scopus (6549) Google Scholar]. We acknowledge, however, the great value of MRI (and CT), and their capacity of overview of the liver. Combining these properties and the new size threshold of only 1 cm of liver nodules to establish a diagnosis of HCC in case of typical pattern [[11]Bruix J. Sherman M. Management of hepatocellular carcinoma: an update.Hepatology. 2011; 53: 1020-1022Crossref PubMed Scopus (6549) Google Scholar], a cost-effective approach would recommend to start either with MRI or CT. However, in cases lacking arterial hyperenhancement, it would seem preferable to the authors to use CEUS before biopsy. Such approach would allow theoretically rescuing a few possible cases which show a typical malignant pattern to establish the diagnosis of HCC. Indeed, absence of arterial hyperenhancement at MRI was not found in any ICC of the 21 cases described in the BCLC study [[15]Vilana R. Forner A. Bianchi L. Garcia-Criado A. Rimola J. de Lope C.R. et al.Intrahepatic peripheral cholangiocarcinoma in cirrhosis patients may display a vascular pattern similar to hepatocellular carcinoma on contrast-enhanced ultrasound.Hepatology. 2010; 51: 2020-2029Crossref PubMed Scopus (237) Google Scholar]. This approach would probably rescue a small number of cases from biopsy. Moreover, the guidelines do not take into consideration the not negligible number of cases in which MRI or CT are contraindicated or are carried out suboptimally due to insufficient patient cooperation, especially in presence of motion artefacts. In these cases, even a bioptic sampling could be technically suboptimal. Thus, having a real time imaging modality, such as CEUS, at least in second line after MRI or CT, to establish a diagnosis of HCC, would provide great benefit for the patient management. In conclusion, ICC is a rare primary liver tumour in liver cirrhosis. CEUS depicts ICC with either a peripherally located rim sign or homogeneous hyperenhancement and with pronounced hypoenhancement in the portal venous phase, whereas MRI, after an arterial pattern similar to CEUS, does not often show tumour wash-out, especially along the periphery. The MRI findings have to be confirmed in larger and prospective studies as well. 2. “Contrast enhanced ultrasound is not available in the USA, so these results are not entirely applicable to a North American population” Finally, we want to highlight that CEUS had been removed from the latest AASLD guidelines also because UCA are not available in USA. This is a conclusive argument, but it conflicts with the ambition of AASLD guidelines to be applied in other continents, rather than in America only. In this case, the limiting factor is restricted to USA, where indeed phase III trials in liver CEUS are ongoing. Furthermore, the guidelines suggest MRI, but in many countries worldwide, with a high incidence of HCC, the availability of MRI is close to exceptional, making CEUS, which is cheaper and much easier to implement, a powerful tool for daily routine. AASLD guidelines are traditionally not only important for American medical professionals but have impact worldwide. Therefore, the consequences of the revised AASLD guidelines 2011 should be discussed in the light of their impact beyond the USA. CEUS proved to be of great values in several well conducted studies with specific advantages such as extremely high safety profile, being easy repeatable and high temporal resolution and should be, therefore, in the opinion of the authors, part not only of most, but all international HCC guidelines. The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.