CEUS and HCC: Are the 2008 EFSUMB Guidelines Still Valid or Has Their Wash-Out Already Started?

Dear Sir,

The 2008 EFSUMB guidelines and recommendations for contrast-enhanced ultrasound (CEUS) [1] stated that a noninvasive diagnosis of hepatocellular carcinoma (HCC) could be established without further radiological workup for a focal lesion > 2 cm, newly emerged in a cirrhotic liver during surveillance, showing complete enhancement in the arterial phase followed by wash-out during the portal-venous and delayed phases, while confirmation of this typical pattern by contrast-enhanced CT or MRI was needed in the case of lesions with a diameter of 1–2 cm. These statements were in line with the AASLD practice guidelines on the management of hepatocellular carcinoma that were published in 2005 and were widely used until a few months ago [2].

In July 2010, an update of the AASLD practice guidelines published online removed CEUS from the diagnostic algorithm of HCC for lesions of any size and, thus, EFSUMB statements have been called into serious question [3]. Since many European practitioners refer to AASLD guidelines in their clinical practice, we believe that a debate on whether and how EFSUMB recommendations need to be revised in light of the new AASLD guidelines is legitimate as well as necessary, considering the great importance of CEUS for scientific societies of ultrasonography.

Bruix and Sherman, the authors of the AASLD guidelines, justified the dismissal of CEUS with two reasons. The first is that ultrasound contrast agents are not available in the United States and therefore results obtained in other countries are not entirely applicable to a North American population. This statement is rather surprising to us. Many modern diagnostic facilities are still unavailable in most under-resourced countries. However, this does not mean that the newest protocols are invalid because those countries do not share them! In order to provide a wider view of currently available resources in a worldwide scenario, the writers of the AASLD guidelines, should have simply indicated the unavailability of CEUS in United States, without ignoring the evidence regarding this tool collected in several international studies [4]. Moreover, it should be noted that contrast agents were not licensed in the United States in 2005 when the first AASLD guidelines stated that CEUS is a reliable diagnostic option for HCC. This makes it difficult to explain why the commercial unavailability of CEUS has only recently been used to justify its exclusion from the diagnostic algorithm.

The second reason, which is the actual scientific one, is that CEUS when used alone could misdiagnose some cases of intrahepatic cholangiocarcinoma (ICC) as HCC arising in cirrhotic livers. Recent changes to the AASLD guidelines received strong support from the study of Vilana et al. [5]. However, their conclusions are not shared by other relevant studies. In the largest published ICC series to our knowledge, Chen et al. reported the occurrence of homogeneous enhancement in the arterial phase resembling that of HCC in only 3 % of cases of ICC, far lower than the 52.4 % claimed by Vilana [6]. In any case, there is currently significant consensus that CEUS should always be followed by contrast-enhanced CT, or even better, by contrast-enhanced MRI, in order to obtain a more panoramic view on the whole liver and the upper abdomen and, thereby, to stage the HCC before planning the suitable therapeutic strategy. Vilana et al. performed MRI in all patients for staging purposes, as they repeatedly emphasize. Moreover, in our experience, MRI and CEUS are strongly concordant with respect to the final diagnosis in lesions with a diameter between 11–30 mm [7].

From our point of view, the rim-like enhancement cannot be considered typical of ICC since it is observed in about half of the cases and less frequently in smaller lesions, which are the ones more commonly encountered in cirrhotic patients undergoing surveillance [5] [6] [8]. In contrast, the two tumors are best differentiated by wash-out features, rather than arterial phase enhancement (or non-enhancement) patterns. In fact, ICC tends to wash-out more thoroughly than HCC in the portal venous and delayed phases, thus almost invariably becoming hypoechoic to the surrounding liver parenchyma [6] ([Fig. 1]). On the other hand, after wash-out, HCC usually remains isoechoic throughout the portal and delayed phases [9] ([Fig. 2]). This behavior may be the result of the entrapment of blood pool contrast agent microbubbles in the abnormal arteriovenous shunts that are characteristic of tumor neoangiogenesis of HCC [6].

Fig. 1 A 72-year-old man with intrahepatic cholangiocarcinoma (2.8 cm) of the III segment showing rim-like enhancement during the arterial phase (25 sec) and becoming hypoechoic in comparison with the surrounding liver parenchyma during the portal (39 sec) and sinusoidal (61 sec) phases.

Abb. 1 Ein 72-jähriger Mann mit intrahepatischem Cholangiokarzinom (2,8 cm) des III. Segments zeigt eine randförmige Verstärkung während der arteriellen Phase (25 s) und wird hypoechogen im Vergleich zum umgebenden Leberparenchym während der portalen (39 s) und sinusförmigen (61 s) Phasen.

Fig. 2 A 61-year-old woman with hepatocellular carcinoma (3.5 cm) of the VIII segment and cirrhosis. The tumor shows intense and homogeneous hyperenhancement during the arterial phase (17 sec) and remains isoechoic in comparison with the surrounding liver parenchyma during the portal (53 sec) and delayed sinusoidal (240 sec) phases.

Abb. 2 Eine 61-jährige Frau mit Hepatozellulärem Karzinom (3,5 cm) des VIII. Segments und einer Zirrhose. Der Tumor zeigt eine intensive und homogene Kontrastverstärkung während der arteriellen Phase (17 s) und bleibt isoechogen im Vergleich zum umgebenden Leberparenchym während der portalen (53 s) und verspäteten sinusförmigen (240 s) Phasen.

In conclusion we believe that due to its high capacity to discriminate between benign and malignant lesions, its feasibility, its low cost and low toxicity of contrast agents, CEUS legitimately maintains a preeminent role as the first diagnostic step in characterizing focal liver lesions before moving to other radiological studies. Considering the risk of misdiagnosing ICC as HCC, we agree with the authors of the AASLD guidelines that it is not possible to rely on CEUS alone for the diagnosis of HCC, also in the case of lesions > 2 cm. However, given the fact that contrast-enhanced CT or MRI has to be done in any case for staging purposes, we find it difficult to understand why we should be completely denied such a useful technique.

References

• 1 Claudon M, Cosgrove D, Albrecht T et al. Guidelines and good clinical practice recommendations for contrast enhanced ultrasound (CEUS) – Update 2008.  Ultraschall in Med. 2008;  29 28-44
• 2 Bruix J, Sherman M. Management of hepatocellular carcinoma.  Hepatology. 2005;  42 1208-1236
• 3 Bruix J, Sherman M. Management of hepatocellular carcinoma: an update.  Hepatology. 2010;  e-published www.aasld.org/practiceguidelines/Documents/Bookmarked Practice Guidelines/HCCUpdate2010.pdf
• 4 Bartolotta T V, Taibbi A, Midiri M et al. Focal liver lesions: contrast-enhanced ultrasound.  Abdom Imaging. 2009;  34 193-209
• 5 Vilana R, Forner A, Bianchi L et al. Intrahepatic peripheral cholangiocarcinoma in cirrhosis patients may display a vascular pattern similar to hepatocellular carcinoma on contrast-enhanced ultrasound.  Hepatology. 2010;  51 2020-2029
• 6 Chen L D, Xu H X, Xie X Y et al. Intrahepatic cholangiocarcinoma and hepatocellular carcinoma: differential diagnosis with contrast-enhanced ultrasound.  Eur Radiol. 2010;  20 743-753
• 7 Giorgio A, Stefano de G, Coppola C et al. Contrast-enhanced sonography in the characterization of small hepatocellular carcinomas in cirrhotic patients: comparison with contrast-enhanced ultrafast magnetic resonance imaging.  Anticancer Res. 2007;  27 4263-4269
• 8 Chen L D, Xu H X, Xie X Y et al. Enhancement patterns of intrahepatic cholangiocarcinoma: comparison between contrast-enhanced ultrasound and contrast-enhanced CT.  Br J Radiol. 2008;  81 881-889
• 9 Giorgio A, Ferraioli G, Tarantino L et al. Contrast-enhanced sonographic appearance of hepatocellular carcinoma in patients with cirrhosis: comparison with contrast-enhanced helical CT appearance.  Am J Roentgenol. 2004;  183 1319-26