CEUS in Hepatocellular Carcinoma and Intrahepatic Cholangiocellular Carcinoma in 320 Patients – Early or Late Washout Matters: A Subanalysis of the DEGUM Multicenter Trial

Abstract

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.

Zusammenfassung

Ziel: Ziel dieser Arbeit war es, die Vaskularisationsmuster von hepatozellulären (HCC) und intrahepatischen cholangiozellulären Karzinomen (ICC) in der Kontrastmittelsonografie (CEUS) zu vergleichen. Es handelt sich um eine Subanalyse der DEGUM – Multizenterstudie zum Stellenwert der Kontrastmittelsonografie von B-Bild-morphologisch unklaren Leberläsionen.

Material und Methoden: Aus der Datenbank der DEGUM Multizenterstudie (1349 Patienten) wurden alle histologisch gesicherten HCC (n = 278) und ICC (n = 42) analysiert. Dazu wurden die Vaskularisationsmuster und das Kontrastmittelenhancement der hämodynamisch relevanten Perfusionsphasen (arteriell, portal-venös, Spätphase) verglichen.

Ergebnisse: Bei 214/278 Patienten mit HCC (76.9 %) und bei 7/42 Patienten mit ICC (16.7 %) lag eine Leberzirrhose vor. In CEUS zeigten HCC im Vergleich zu ICC häufiger eine arterielle Hypervaskularisation (HCC: Tumorzentrum: 60.3 %; Tumorperipherie: 75 %. ICC: Tumorzentrum 16.7 %; Tumorperipherie 40.5 %). ICC zeigten in der portalvenösen Phase häufiger ein Hypoenhancement (Zentrum der Läsion: ICC: 85.8 % vs. HCC: 49.8 %. Peripherie: ICC 66.7 % vs. HCC 32.6 %). In der Spätphase zeigten die Mehrzahl der HCC (75 %) und nahezu alle ICC (92.9 %) ein Auswaschen des Kontrastmittels.

Schlussfolgerung: Die Differentialdiagnose eines ICC bei Leberzirrhose ist selten. In der CEUS zeigen HCC und ICC unterschiedliche Vaskularisationsmuster. Charakteristisch für ein HCC sind die globale arterielle KM-Aufnahme und ein langsames Auswaschen des Kontrastmittels in der Spätphase. Charakteristisch für ICC ist die initiale Kontrastmittelanflutung vorwiegend in der Tumorperipherie mit Auswaschen des Kontrastmittels ab der frühen portalvenösen Phase.

Key words

contrast-enhanced ultrasound - hepatocellular carcinoma - intrahepatic cholangiocellular carcinoma - enhancement pattern - characterization

Introduction

The presentation of an intrahepatic mass in patients with known liver cirrhosis is highly suggestive for the diagnosis of hepatocellular carcinoma (HCC). Conventional ultrasound is recommended for surveillance of patients at risk. The noninvasive diagnosis of HCC is based on arterial hypervascularization followed by portal-venous or delayed contrast washout in contrast-enhanced imaging using extracellular contrast agents in CT and MRI [1] [2]. While the EASL–EORTC clinical practice guidelines on the management of HCC require CT or MRI for nodules greater than 2 cm in diameter, a more conservative approach with CT and MRI is recommended in nodules between 1 and 2 cm or in suboptimal settings.

Contrast-enhanced ultrasound (CEUS) was introduced in the AASLD and EASL guidelines as an equivalent modality to CT and MRI to demonstrate arterial hypervascularization in HCC, but was removed again in the 2010 update due to the non-availability of CEUS in the USA and concerns regarding the ability to discriminate HCC from ICC with CEUS in cirrhotic livers. Thus, latest generation CT and MRI following reported protocols were recommended for noninvasive diagnosis of HCC [1]. The exclusion of CEUS was scientifically based on a small (21 patients), retrospective, monocentric study showing that intrahepatic cholangiocarcinoma (ICC) in cirrhosis patients may display a vascular pattern similar to HCC in CEUS [3]. Furthermore, an additional analysis suggested that the absence of contrast washout in delayed phases by MRI avoids misdiagnosis of ICC as HCC [4]. However, these studies offer only limited information as they just include patients with already diagnosed ICC with a retrospective analysis of CEUS and MRI images.

To participate in the current discussion on the role of CEUS for the differential diagnosis of HCC and ICC, we want to share our data on the vascularization pattern of 278 patients with HCC and 42 patients with ICC included in the DEGUM multicenter study. It has to be stated that the DEGUM multicenter study was not intended to compare HCC and ICC specifically. The study was designed as a prospective study to evaluate the diagnostic accuracy of CEUS on a large nonselective patient cohort with focal liver lesions that were discovered by fundamental ultrasound but could not be classified by conventional B-mode ultrasound and color Doppler. Several articles from this DEGUM study covering topics such as overall diagnostic accuracy, tumor vascularity and comparison to CT and MRI have already been published in this journal [5] [6] [7] [8] and have underlined the high diagnostic value of CEUS in clinical practice. In this paper we present detailed data on tumor vascularization and contrast enhancement pattern in CEUS of HCC and ICC documented in the DEGUM multicenter data set.

Materials and Methods

Study design

Detailed information on the study design and patient characteristics of the DEGUM multicenter study of the role of CEUS in the differential diagnosis of focal liver lesions were published earlier [5]. The study was approved by the local ethics committee. Consecutive patients with a solid liver tumor visible at routine ultrasound (US) were recruited for CEUS at the time of their US examination, after contraindications for US contrast agent were ruled out. All patients gave written informed consent before inclusion in the study. Patients with liver lesions diagnosed from characteristic B-mode echomorphology, such as patients with cysts and typical hemangiomas (in a non-steatotic liver), as well as lesions with clear signs of malignancy (e. g. large vessel infiltration) were not included. All patients were examined according to EFSUMB guidelines [9] according to a standardized protocol using low MI imaging with SonoVue^® bolus injection (BR1; Bracco, Milan, Italy) as described previously [5]. The contrast enhancement in the lesion was described in comparison to the surrounding liver parenchyma (hypo-, iso-, hyperenhanced) during the arterial phase (5 – 25 s), portal-venous phase (25 – 60 s) and late phase (> 120 s after bolus injection). The location and distribution of the contrast agent in the lesion (center, periphery) and the specific vascular pattern in the arterial phase (wheel spoke sign, chaotic or irregular arteries, nodular enhancement, rim sign), as well as the portal venous phase (fill-in, washout pattern) were documented and described. Contrast enhancement in the late phase was decisive for distinguishing between malignant (hypoenhanced) and benign (iso- or hyperenhanced) lesions. According to the predefined criteria of the DEGUM study, tumor-specific diagnosis of HCC was based on the following criteria in CEUS: An irregular chaotic intratumoral vascularity and hyperenhancement in the arterial phase, followed by iso- or hypoenhancement in the late phase, were considered suspicious for HCC in a cirrhotic liver. There were no predefined tumor specific criteria in CEUS for the diagnosis of ICC. Therefore, ICCs represent a subgroup of malignant liver lesions included in the DEGUM multicenter trial. The CEUS based diagnosis was made at the time of US exam. As a reference standard, the final diagnosis was based on all available imaging and clinical data, including histology and additional follow-up information. Final diagnosis without histological/cytological confirmation was only made in patients with a clear diagnosis of hemangioma or FNH at CEUS, in whom a biopsy was not ethically justified. In these cases imaging modalities (CT and/or MRI) and follow-up were judged as the reference standard. Detailed information on the standardized CT and MRI protocols used in this trial has been previously described [5] [7].

For this manuscript 320 patients with the final histological diagnosis of HCC or ICC from the DEGUM multicenter database were analyzed. The contrast enhancement of HCC and ICC in relation to the surrounding liver parenchyma (hypo-, iso-, hyperenhanced during the arterial, portal and late phase) was compared. In addition, the location and distribution of the contrast agent in the lesion (center, periphery) were analyzed.

Statistical analysis

Statistical analysis was performed using the software R (Version 2.15.3. The R Project for Statistical Computing. www.r-project.org). Values were expressed as median and range or count and proportion in percent as appropriate. Students’ t-test was used for the comparison of means. Categorical data was calculated using Chi-square test and Fisher’s exact test. A p-value of less than 0.05 was regarded as significant for each statistical test.

Results

A total of 1349 liver lesions were studied in the prospective DEGUM multicenter study. Based on the final gold standard histology, 278 HCCs and 42 ICCs could be analyzed. Two patients with a mixed hepatocellular-cholangiocarcinoma were excluded in this analysis. The characteristics of the HCC and ICC patients are given in [Table 1]. Whereas the majority of HCCs were associated with liver cirrhosis (n = 214; 76.9 %), only a few ICCs (n = 7; 16.7 %) were associated with liver cirrhosis.

Table 1 Patient characteristics.

patients	HCCs (n = 278)	ICCs (n = 42)	p-value
age in years (median, range)	66.6 (38 – 89)	67.9 (39 – 84)	0.4483
male female	229 (82.4 %) 49 (17.6 %)	22 (52.4 %) 20 (47.6 %)	< 0.001
weight in kg (median, range)	75.2 (50 – 139)	75.4 (51 – 108)	0.9252
liver cirrhosis present	214 (76.9 %) [1n. a.]	7 (16.7 %)	< 0.001
tumor size < 2 cm tumor size ≥ 2 cm	17 (6.1 %) 261(93.9 %)	1 (2.4 %) 41 (97.6 %)	0.4857
solitary multiple	188 (67.6 %) 90 (32.4 %)	26 (62 %) 13 (31 %) [3 n. a.]	< 0.001

Liver tumor characterization of HCC and ICC

Based on the predefined diagnostic criteria, CEUS correctly identified 247/278 HCCs (88.8 %) and 723/755 malignant lesions (95.8 %), including 40/42 ICCs (95.2 %). The contrast enhancement patterns of HCC and ICC in comparison to the surrounding liver parenchyma during the arterial phase, portal-venous phase and late phase are given in [Table 2]. Intratumoral arterial hyperenhancement was more frequently seen in HCC compared to ICC. ICC showed an initial contrast enhancement primarily at the tumor periphery (ICC 85.7 % vs. HCC 61 %; p = 0.0017) followed by early portal-venous contrast washout in the tumor center (ICC 85.8 % vs. HCC 49.8 %; p < 0.001) and tumor periphery (ICC 66.7 % vs. HCC 32.6 %; p < 0.001). Contrast hypoenhancement during the portal-venous phase was more frequently observed in ICC (tumor center 85.8 %; tumor periphery 66.7 %) than in HCC (tumor center 49.8 %; tumor periphery 32.6 %), and appeared more rapidly (washout in the late phase seen in 92.9 % of ICCs but only 75 % of HCCs 2 min after bolus injection).

Table 2 Contrast enhancement of 278 HCCs and 42 ICCs in comparison to the surrounding liver parenchyma.

↗ hyperenhanced  = isoenhanced ↘ hypoenhanced	HCC࢕	ICC	p-value
arterial phase
lesion center	↗ 60.3 %  = 21.3 % ↘ 18.4 %	↗ 16.7 %  = 19.0 % ↘ 64.3 %	< 0.001
lesion periphery	↗ 75.0 %  = 20.7 % ↘ 4.3 %	↗ 40.5 %  = 42.9 % ↘ 16.6 %	< 0.001
portal-venous phase
lesion center	↗ 6.5 %  = 43.7 % ↘ 49.8 %	↗ 7.1 %  = 7.1 % ↘ 85.8 %	< 0.001
lesion periphery	↗ 11.6 %  = 55.8 % ↘ 32.6 %	↗ 7.1 %  = 26.2 % ↘ 66.7 %	< 0.001
late phase
total lesion	↗ 0 %  = 25.0 % ↘ 75.0 %	↗ 0 %  = 7.1 % ↘ 92.9 %	0.022

Combined vascular pattern in dynamic CEUS examinations of HCC and ICC

The typical dynamic vascular pattern between HCC and ICC was compared according to the abovementioned criteria and current definitions for each tumor entity [9]. For HCC lesions these are marked arterial hyperenhancement with isoenhancement or weak hypoenhancement in the portal and late phase. The dynamic vascular pattern of ICC lesions was defined by peripheral enhancement in the arterial phase with early hypoenhancement in the portal and late phase. [Fig. 1], [2] show the contrast enhancement of HCC and ICC during the arterial, (early) portal-venous and late phase. The distribution of combined CEUS vascularity patterns according to the typical HCC and ICC criteria show statistically significant differences and are described in [Table 3].

Fig. 1 HCC: CEUS enhancement in the arterial, portal-venous and late phase after administration of SonoVue^®. a Global wash-in in the arterial phase with delayed washout in the late phase and explicitly after 4 minutes from bolus injection. b Lesion with global wash-in and isoenhancement up to the late phase.

Abb. 1 HCC: Kontrastmittelverstärkter Ultraschall während der arteriellen, portal-venösen und Spätphase nach Gabe von SonoVue^®. a Ausgedehnte intratumorale Kontrastmittelaufnahme in der arteriellen Phase, gefolgt von einem verzögerten Abfluten des Kontrastmittels in der portal-venösen und Spätphase. b HCC mit globaler Kontrastmittelaufnahme in der arteriellen Phase und lebergleicher Darstellung in der portal-venösen und Spätphase.

Fig. 2 ICC: a CEUS enhancement from the periphery in the arterial phase, followed by rapid washout as in the portal-venous phase with distinct hypoenhancement in the late phase in a small lesion. b “Rim-like enhancement” in the arterial phase, again followed by washout in the portal-venous and late phase. c Global hypoenhancement in all phases due to a slim area in the tumor periphery with vital tumor cells and a distinct desmoplastic area in the center of the tumor.

Abb. 2 ICC: a Kontrastmittelanflutung von der Tumorperipherie mit vorzeitigem Abfluten des Kontrastmittels ab der frühen portal-venösen Phase in einem kleinen ICC. b Randständige KM-Aufnahme („Rim-like-enhancement“) in der arteriellen Phase gefolgt von einem Intensitätsverlust ab der portal-venösen und Spätphase. c Nahezu avaskuläre Läsion in allen Perfusionsphasen. Lediglich ein schmaler Saum vitaler Tumorzellen erscheint am äußersten Tumorrand arteriell perfundiert mit raschem Auswaschen des Ultraschallkontrastmittels ab der frühen portal-venösen Phase.

Table 3 Combined vascular pattern in dynamic CEUS of HCC and ICC.

	HCC	ICC	p-value
dynamic vascular pattern consistent with HCC
AP center ↗ and  = AND LP center ↘	56.5 %	31 %	0.0035
AP center ↗ and  = AND PP center  =	39.9 %	4.8 %	< 0.0001
dynamic vascular pattern consistent with ICC
AP center ↘ AND PP center ↘	15.5 %	61.9 %	< 0.0001
AP periphery ↗ and  = AND PP periphery ↘	28.1 %	50 %	0.0072

↗ Hyperenhanced; = Isoenhanced; ↘Hypoenhanced; AP Arterial Phase; PP Portal Phase; LP Late Phase.

Discussion

HCC is the second most common cause of cancer death worldwide with an increasing incidence rate even in previously low-risk regions of the world [10]. In the past years guidelines for HCC have been published worldwide to define standard care for patients at risk [11]. Since the introduction of the new editions of the AASLD and EASL guidelines [1] [2] for the management of HCC, a controversy has emerged concerning the reliability of contrast-enhanced ultrasound in the diagnostic algorithm for HCC [12] [13] [14] [15] [16]. Until then, CEUS was accepted as an equivalent imaging technique with comparable results to CT and MRI [7] [17] [18] [19] [20] [21]. Based on the results of a small retrospective study [3] from the Barcelona Clinic Liver Cancer (BCLC) Group and another retrospective evaluation of MRI in ICC [4], CEUS was excluded from the diagnostic algorithm for suspected HCC. Vilana et al. [3] described the CEUS enhancement patterns of 21 biopsy-proven ICCs in cirrhosis patients. 11 out of 21 lesions were concordant with the EFSUMB recommendations of 2008 [22] for ICC in CEUS (arterial rim-like enhancement or non-enhancement followed by hypoenhancement during the portal and delayed phases), but 10 lesions (47.6 %) were undistinguishable from HCC criteria (homogeneous global enhancement followed by washout).

HCCs are typically hypervascular tumors. Therefore, diagnosis is based on arterial hyperenhancement followed by portal-venous or delayed contrast washout in multiphasic imaging [23] [24]. On the other hand, ICCs are inhomogeneous tumors with hypovascular desmoplastic and fibrotic parts surrounded by areas with well vascularized vital tumor cells. This tumor entity itself is very heterogeneous and even histology as the gold standard frequently demands a process of exclusion in clinical diagnostics (adenocarcinoma requiring the differentiation between lung, upper and lower GI tract in synopsis with endoscopy and imaging results). Additionally, the variety of results is complicated by the topographic heterogeneity (e. g. central cholangiocellular carcinoma originating from intrahepatic small ducts misinterpreted as hilar tumors) and secondary reactions (e. g. grade of desmoplastic/fibrotic reaction, focal inflammation) of cholangiocellular tumors. The appearance of ICC in medical imaging depends on size, portion and distribution of poor and well vascularized tumor tissue. In CT and MRI, ICCs show mild delayed progressive enhancement after injection related to the extravasation of CT and MRI contrast agents into the interstitial space. Komuta et al. [25] analyzed the clinicopathological features of 85 resected ICCs: hilar cholangiocarcinoma equivalent to Klatskin tumor; mucin-producing intrahepatic cholangiocarcinoma, mixed intrahepatic cholangiocarcinoma and cholangiocellular carcinoma. In this study all mucin-producing intrahepatic cholangiocarcinomas showed concentric filling on venous phase dynamic contrast-enhanced MRI, whereas the mixed intrahepatic cholangiocarcinoma and cholangiocellular carcinoma showed late phase washout in various patterns. These results contradict the statement of Rimola et al. [4] that the absence of washout is a key pattern for ICC in MRI. Various advances in MR imaging (e. g. diffusion-weighted imaging, three-dimensional sequence, phased-array coils or parallel imaging techniques) and liver-specific contrast agents (e. g. gadoxetic acid) could help to establish accurate imaging criteria for the exact differentiation of focal liver lesions in this field. Unfortunately, the availability of MRI is mostly insufficient and the need for alternative imaging like CT and CEUS might arise in general [23] [24] [26] [27].

The contrast agent SonoVue^® used in our study shows a purely intravascular circulation and doesn´t diffuse into the interstitial space. The vascularization pattern of HCC and ICC in CEUS is the result of this characteristic feature. Only a few studies have focused on the role of CEUS for the differentiation of HCC and ICC and compared dynamic patterns [3] [28] [29] [30] [31] [32] [33] [34] [35] [[Table 4]]. Xu et al. were one of the first to characterize ICC perfusion pattern in CEUS [28] and described 3 different enhancement types in the arterial phase (Type I in 11.2 %: global inhomogeneous hyperenhancement; Type II in 44.4 %: irregular rim-like hyperenhancement; and Type III in 44.4 %: global inhomogeneous hypoenhancement). All lesions showed hypoenhancement in the portal-venous and late phase. 17 of 18 lesions were correctly classified as ICC and only 1 Type I lesion was misinterpreted as HCC. This study served as the basis for ICC criteria in the 2008 update of the EFSUMB CEUS guidelines (arterial phase: rim or non-enhancement; portal venous and late phase: hypo- or non-enhancement) [22]. The same group published several papers concerning CEUS pattern in ICC (comparison of CEUS and CT in ICC, comparison of ICC and HCC pattern in CEUS and correlation between tumor cell density and semi-quantitative appearance of ICC in CEUS [29] [31] [33]). In the 2010 publication [31], 50 % of ICCs showed rim enhancement in the arterial phase compared to only 4 % of HCCs. Small tumors (< 3 cm) showed homogeneous enhancement without a rim sign. This was explained by the different tumor morphology of smaller lesions. 24 % of ICCs showed arterial hypoenhancement, but no HCC was hypoenhanced in the arterial phase. The morphology in the portal venous and late phase did not differ between ICC and HCC. Bohle et al. [32] confirmed the differences in the perfusion pattern, but also stated the eventuality of misdiagnosing ICC as HCC in a small and heterogeneous collective (HCC, ICC, Klatskin tumor and gallbladder carcinoma). A rim sign was observed only in ICC, but with very low frequency (3 ICCs out of 11). Moreover, complete or nearly complete filling in the arterial phase was seen more often in HCCs (53.9 %) compared to ICCs (27.3 %).

Table 4 Relevant publications concerning the appearance of HCC and ICC on CEUS, CT and MRI.

author	year	patient no. HCC/ICC	imaging technique	mean lesion size (mm) HCC/ICC	cirrhotic patients HCC/ICC	quantification techniques	study design
Xu et al.[28]	2006	–/18	CEUS	–/76	n. a.	no	retrospective
Chen et al.[29]	2008	–/40	CEUS/CT	–/67	n.a.	no	retrospective
D´Onofrio et al.[30]	2008	–/23	CEUS/CT	–/59	n.a.	no	retrospective
Rimola et al.[4]	2009	–/25	MRI	–/25	–/13	no	retrospective
Chen et al.[31]	2010	50/50	CEUS/CT	61/72	26/5	yes	retrospective
Vilana et al.[3]	2010	–/21	CEUS/MRI	–/32	–/21	no	retrospective
Bohle et al.[32]	2012	39/11	CEUS	60/51	32/2	no	retrospective
Xu et al.[33]	2012	–/40	CEUS	–/67	n. a.	no	retrospective
Kang et al.[26]	2012	–/50	MRI	–/70	–/7	yes	retrospective
Galassi et al.[34]	2013	–/25	CEUS/CT/MRI	–/30	–/25	no	retrospective
Iavarone et al.[16]	2013	–/32	CT	–/30	–/32	no	retrospective
Li et al.[35]	2014	50/33	CEUS/CT	59/49.9	50/33	yes	retrospective
Wildner et al. [36]	2014	23/20	CEUS	52/59	16/6	yes	prospective

CEUS: contrast-enhanced ultrasound; CT: computed tomography; MRI: magnetic resonance imaging.

Due to the minor incidence rate of ICC in cirrhosis, most studies could not report on this special group of patients. Along with the Spanish report from 2010 [3], the Italian group of Galassi et al. [34] focused on this particular cohort. In their retrospective multicenter analysis, a total of 25 CEUS examinations of small ICCs were evaluated in comparison to contrast-enhanced CT and MRI. The authors report a higher rate of misdiagnosis of ICC as HCC by CEUS (52 %) compared to CT (4.2 %) or MRI (9.1 %), but 60 % of all lesions showed different heterogeneous patterns in all techniques. The imprecise CEUS vascular pattern for ICC was adopted according to the EFSUMB 2008 guidelines [22]. This might be one reason for the weakness of CEUS in this study. Due to the small lesion size, less desmoplasia might have been instant with a lower rate of rim signs (8 %). Interestingly only 4 out of 11 lesions examined with MRI showed the late enhancement of ICC described by Rimola et al. [4], perhaps related to the different MRI contrast agents used.

Based on these studies, detailed recommendations for the characterization of ICC have been defined (rim-like enhancement, heterogeneous/slight hyperenhancement with rapid washout as in the portal-venous phase) in the latest 2012 update of CEUS guidelines [9]. Present publications tend to achieve further improvement of the temporal ICC perfusion pattern in CEUS [35] [36]. A recently published report from Li et al. [35] confirms the marked early washout of SonoVue^® within 60 seconds after injection in ICC lesions. 78.8 % of the ICC lesions but only 12 % of the HCC lesions showed both early and marked washout during the late portal-venous phase (p < 0.001) as one superior criterion for ICC. In their analysis with improved CEUS criteria for ICC, no statistical difference between CEUS and contrast-enhanced CT could be found for the diagnostic performance.

In the current analysis we evaluated the perfusion pattern of all HCCs and ICCs included in the DEGUM multicenter study. Although we present data of a large cohort, our current paper has some limitations. We are presenting a retrospective analysis which was not designed for the specific comparison of HCC and ICC. Therefore, the results might have been influenced by different types of scanners and the fact that the examiner was informed about the clinical background of the patient. While the comparison of the vascular pattern was significantly different, there is still a relevant overlap between both entities.

In accordance with the criteria described in the updated EFSUMB guideline for the use of CEUS in the liver, we discovered HCC to have predominant hyperenhancement in the arterial phase, which in most cases covers the whole lesion, except for some necrotic areas. In comparison, ICC typically showed wash-in primarily from the tumor periphery (rim sign) followed by significantly earlier hypoenhancement in portal-venous and late phase ([Fig. 3]). The majority of ICCs were correctly classified as malignant lesions in CEUS. However, 5 HCCs were incorrectly classified as benign lesions [37]. This is important because the most frequent differential diagnoses of a focal lesion in liver cirrhosis are benign regenerative nodules and HCC, whereas other benign tumor entities (e. g. hemangiomas and FNH) are rare compared to non-cirrhotic patients [38]. Taking the low incidence of ICC in cirrhosis into account, the differential diagnosis of ICC in a cirrhotic liver is also a very rare problem. Depending on the patient’s clinical background and liver function, complete oncological resection would be necessary in both solitary HCC and ICC. In contrast, the therapeutic approach (e. g. tumor ablation and systemic therapy) of advanced cancer differs in HCC and ICC [1] [39] [40].

Fig. 3 Typical enhancement pattern and temporal presentation of HCC and ICC in the dynamic CEUS examination.

Abb. 3 Typische Vaskularisationsmuster von HCC und ICC sowie Unterschiede im zeitlichen Verlauf in der dynamischen CEUS Untersuchung.

Applied to the diagnostic setting for patients at risk for HCC, the main issue is early detection and characterization of a new suspicious lesion in a harmless and cost-effective way. Several studies have sufficiently proven the diagnostic accuracy [17] [38] [41] [42] [43] [44] [45] and economical effectiveness [46] [47] [48] of CEUS in comparison to other imaging modalities in this context. Therefore, a couple of national guidelines contain CEUS in their algorithm for HCC diagnostics in a non-competitive approach for the benefit of an accurate evaluation of patients with cirrhosis [39] [49] [50]. Our analysis of the data from the DEGUM multicenter study clearly support this algorithm, provided the specific imaging criteria defined in EFSUMB liver CEUS guidelines are used.

Conclusion

Tumor-specific vascularization patterns 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. ICC is a very rare differential diagnosis in cirrhotic patients. CEUS can demonstrate differences in the vascularization pattern in the comparison between HCC and ICC. The majority of HCCs showed intratumoral contrast hyperenhancement in the arterial phase, whereas contrast washout is delayed beginning in the portal-venous phase. Initial contrast enhancement at the tumor periphery with early hypoenhancement in the portal-venous and late phase is a characteristic pattern of ICC.

Abbreviations

AASLD:: American Association for the Study of Liver Diseases

BCLC:: Barcelona Clinic Liver Cancer

CEUS:: Contrast-enhanced ultrasound

CT:: Computed tomography

DEGUM:: Deutsche Gesellschaft für Ultraschall in der Medizin e. V. – German Society of Ultrasound in Medicine and Biology

EASL:: European Association for the Study of the Liver

EFSUMB:: European Federation of Societies for Ultrasound in Medicine and Biology

EORTC:: European Organization for Research and Treatment of Cancer

FNH:: Focal nodular hyperplasia

HCC:: Hepatocellular carcinoma

ICC:: Intrahepatic cholangiocellular carcinoma

MI:: Mechanical index

MRI:: Magnetic resonance imaging

WFUMB:: World Federation for Ultrasound in Medicine and Biology

Acknowledgment

The research was supported by the DEGUM. We thank all centers participating in the CEUS multicenter trial on the characterization of focal liver lesions [5]: University hospital Erlangen (Strobel D, Bernatik T), KKH Sigmaringen (Seitz K), Klinikum am Steinenberg Reutlingen (Blank W), Helfenstein Klinik Geislingen (Schuler A), Caritas-Krankenhaus Bad Mergentheim (Dietrich C), University hospital Tübingen (v. Herbay A), University Homburg/Saar (Friedrich-Rust M), KH Villingen-Schwenningen (Kunze G), KH Rendsburg-Eckernförde (Becker D), Klinikum Gera (Will U), KH Kaiserslautern (Albert FW), Israelitisches KH Hamburg (Pachmann C), Klinikum Bayreuth (Dirks K).

Judith Schwitulla (Institute for biometry and empidemiology, University Erlangen-Nürnberg, Waldstr. 6, 91 054 Erlangen) is acknowledged for supporting the statistical analysis.

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