Abstract
The main clinically recognized application of contrast-enhanced US (CEUS) with microbubble contrast agents is the characterization of incidental focal liver lesions. CEUS with low transmit power insonation allows the real-time assessment of contrast enhancement in a focal liver lesion after microbubble contrast agent injection, during the arterial (10–25 s), portal venous (from 35 s up to 2 min) and late phase (4–6 min after microbubble injection). During the portal venous and late phase benign lesions appear hyper or iso-enhancing in comparison to the adjacent liver parenchyma, while malignant lesions prevalently present contrast washout with hypo-enhancing appearance. CEUS may provide an added diagnostic value in those incidental focal liver lesions in which contrast-enhanced CT or MR imaging are not conclusive. In particular, CEUS may provide an added diagnostic value in those focal liver lesions appearing indeterminate on single-phase CT scan, or on CT scans performed by an incorrect delay time or also after injection of a low dose of iodinated contrast agent, or also in those focal liver lesions revealing equivocal enhancement patterns on contrast-enhanced CT or MR imaging. CEUS may have an added diagnostic value also in hepatocellular nodules in a cirrhotic liver and can be considered a complementary imaging technique to CT.
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Unenhanced gray-scale and color Doppler ultrasound (US) present limited accuracy in solid focal liver lesion characterization since benign and malignant lesions may reveal similar echopattern and vascular architecture [1, 2]. Even though tumoral vessels visibility may be improved by color and power Doppler after microbubble contrast agents injection, color signal saturation and motion and blooming artifacts represent important limitations [3, 4]. Contrast-enhanced US (CEUS) with microbubble contrast agents and dedicated US specific contrast modes were introduced to overcome the limitations of unenhanced gray-scale and color Doppler US [5–16].
Several papers have described the general capabilities of CEUS in improving focal liver lesion characterization compared to unenhanced US [1–15]. CEUS provides a reliable benign or malignant diagnosis based on focal liver lesion contrast enhancement [1–11, 16]. This is determined by the high spatial resolution of CEUS due to the high digital image matrix over a limited field of view, its high contrast resolution due to the high sensitivity to harmonic frequencies produced by microbubble insonation, and its high temporal resolution which allows the real-time assessment of contrast enhancement.
The European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB) guidelines recommends the use of CEUS to diagnose incidental focal liver lesions not characterized on unenhanced US, in lesions or suspected lesions identified in a background of chronic hepatitis or liver cirrhosis, or also in patients with a known history of malignancy [17]. Finally, EFSUMB suggests the use of CEUS also in those focal liver lesions with an inconclusive CT or MR imaging [17]. The uncertain lesion characterization after CT or MR imaging frequently leads to focal liver lesion biopsy or, alternatively, long-term imaging follow-up. The aim of this update article is to describe the added diagnostic value of CEUS in focal liver lesions remaining indeterminate after contrast-enhanced CT or MR imaging.
CEUS and focal liver lesion characterization
CEUS allows the real-time assessment of focal liver lesion perfusion during low transmit power insonation (mechanical index value, 0.1–0.25 according to the US equipment and the employed contrast-specific technique) and it is not limited by motion and blooming artifacts as color and power Doppler US. CEUS is easily performed. The operator has to identify the most suitable acoustic window to evaluate the lesion and simply observe tumoral contrast enhancement after microbubble injection without moving the transducer from the initial scanning position. CEUS is technically a simple imaging method and allows real-time acquisition after microbubble administration without any drawback due to incorrect scanning time in comparison to CT and MR which are limited by image acquisition time issues. Contrast-enhanced CT and MR imaging may be limited in scanning hypervascular tumors owing to difficulties in starting the acquisition at a suitable time point, and are penalized by costs, availability, and patient irradiation in the case of CT. The main limitation of CEUS in comparison to multiphase CT and MR imaging is the fact that only one liver tumor can be scanned at a time as the transducer has to be kept still during the examination, and further microbubble injections are often necessary to characterize additional liver tumors. On CEUS the image planes and different technical parameters (e.g., focal zones position, echo-signal amplification) must be individually optimized for each tumor examined in those cases in which tumors present a different segmental location and depth.
Perfluorocarbon or sulphur hexafluoride—filled microbubbles covered by a phospholipid shell, including Definity (Lantheus Medical Imaging, MA, USA) and SonoVue (Bracco, Milan, Italy), present non-linear response with production of harmonic and sub-harmonic frequencies at low acoustic power insonation, allowing the employment of continuous non-destructive imaging and the real-time evaluation of lesion contrast enhancement. Microbubble contrast agents present a pure intravascular distribution and do not leak in the interstitial space but persist in the sinusoids and portal vessels without the evidence of any equilibrium phase. The enhancement resulting exclusively from the hepatic arterial supply is timed from 10 s after the start of the intravenous injection and lasts for 10–15 s [18]. The portal venous phase starts about 35 s from microbubble injection and then lasts for 2 min after the start of injection, whereas the subsequent late phase lasts for up to 4–6 min after injection, until microbubble clearance from the liver parenchyma [18]. After blood pool clearance perfluorocarbon—filled agents, such as Sonazoid (GE Healthcare, UK) and Levovist (Bayer Schering, Germany) were shown to have also a Kupffer cell-specific parenchymal affinity at late phase [19].
CEUS provides a benign or malignant diagnosis based on focal liver lesion enhancement at hepatic arterial, portal venous, and late phase in comparison to the adjacent liver parenchyma. Malignancies typically show a low echo-signal intensity at late phase [4, 5, 8], regardless of whether they are hyper- or hypo-enhancing in terms of their arterial supply, while benign lesions generally present a sustained enhancement with hyper or iso-enhancing appearance to the adjacent liver parenchyma [5–15]. CEUS is a reliable imaging technique in the characterization of liver lesions as benign or malignant with a sensitivity and specificity ranging, respectively, from 85% to 90% and 80% and 99% [8, 10, 20, 21]. Most often in routine clinical practice it is not possible to predict a histological diagnosis by CEUS since many benign lesions appear hyper-enhancing during the hepatic arterial phase and, even after microbubble injection, are often indistinguishable. A small hyper-enhancing hemangioma, a focal nodular hyperplasia, and a hepatocellular adenoma may all appear iso or hyper-enhancing at portal venous and/or late phase; the only exception is the hepatocellular adenomas which may appear hypo-enhancing on late phase [22]. Neither different malignant lesion histotypes can be differentiated since hepatocellular carcinomas, intrahepatic cholangiocarcinomas, and liver metastases prevalently appear hypo- or hyper-enhancing during the arterial phase and hypo-enhancing with contrast washout at portal venous and late phase [8, 23, 24], even though hepatocellular carcinoma may also appear iso-enhancing to the adjacent liver parenchyma during the portal venous-late phase in about 40% of cases [6–9].
In selected cases CEUS may also provide improved lesion histological differential diagnosis provided that a specific enhancement pattern is visualized, as in the case of typical liver hemangiomas showing peripheral nodular enhancement and focal nodular hyperplasia showing centrifugal filling with central spoke wheel-shaped enhancement during the hepatic arterial phase [9, 10]. Between 5% and 25% of focal liver lesions remain indeterminate even after CEUS [2, 3, 5, 8, 10] and need to be characterized by contrast-enhanced CT or MR imaging [25, 26].
CEUS presents a high level of concordance with CT and MR imaging [27] in depicting the contrast enhancement pattern of focal liver lesions during the arterial phase. Concordance in the portal venous phase is generally lower, and discordance in the portal venous phase occurs most often in malignancies reflecting the tendency of CT and MR contrast agents, unlike microbubbles, to diffuse into the tumoral interstitium in cases in which CEUS showed washout [27].
The added diagnostic value provided by CEUS in incidental focal liver lesions
There are some evidences in the recent literature showing that CEUS may provide an added diagnostic value in the characterization of incidental focal liver lesions remaining indeterminate after contrast-enhanced CT due to different causes. This may be due to: (a) single-phase CT (usually during the arterial phase on CT angiography or during the portal venous phase for an overall evaluation of the abdomen and pelvis) revealing one or more hypo- or hyper-attenuating incidental focal liver lesions; (b) the small lesion diameter (below 3 mm) which does not allow a reliable density analysis on the different dynamic phases; (c) the incorrect delay time (e.g., too early scanning during the hepatic arterial or portal venous phase); (d) the low injected dose of iodinated contrast agent (low injected volume of iodinated contrast, or low iodine concentration per mL, or low amount of volume of iodinated contrast injected per minute) compared to the patient body weight. Moreover, focal liver lesions may present an equivocal enhancement pattern on contrast-enhanced CT or MR imaging, e.g., those lesions appearing persistently hypo-enhancing after contrast material injection during the different dynamic phases. According to the results of a recent study from our group [28] including fifty-five incidental solid focal liver lesions (1–5 cm in diameter; 40 hemangiomas, 2 hepatic angiomyolipomas, 1 hepatocellular adenoma, and 12 metastases) in 43 non-cirrhotic patients (24 female, 19 male; age ± SD, 55±10 years), CEUS provides improvement in the diagnosis in those focal liver lesions appearing equivocal or uncharacterized on contrast-enhanced CT or MR imaging avoiding biopsy or further contrast-enhanced CT examinations or long-term imaging follow-up in the vast majority of these lesions. In particular, the additional review of CEUS after CT/MR images allows to improve the diagnostic accuracy (before vs. after CEUS review = 48% vs. 85% -reader 1- and 51% vs. 87% -reader 2-) and diagnostic confidence (area under ROC curve before vs after CEUS review = 0.854 vs. 0.974 -reader 1- and 0.868 vs. 0.978 -reader 2-) in focal liver lesion characterization [28].
CEUS improves the characterization of these focal liver lesions by identifying some specific enhancement patterns, namely the peripheral nodular enhancement (Fig. 1) or the focal peripheral dot-like enhancement (Fig. 2) in those liver hemangiomas appearing hypo-attenuating on single-phase CT scan. The focal peripheral dot-like enhancement which may be evident on CEUS resembles the “bright-dot” sign previously described on contrast-enhanced CT in liver hemangiomas and defined as a tiny enhancing dot that did not progress to the globular peripheral enhancement [29]. Small fibrosclerotic hepatic hemangiomas with a persistent hypo-attenuating appearance on contrast-enhanced CT cannot be characterized either by dual-phase CT or by CEUS which confirms the persistent hypo-enhancing pattern (Fig. 3). Solid focal liver lesions appearing hyper-attenuating on single-phase contrast-enhanced CT may be characterized by CEUS which may visualize the complete enhancement pattern during the different dynamic phases (Fig. 4). Another field of application of CEUS, as an imaging technique providing an additional diagnostic value to CT, corresponds to those solid focal liver lesions appearing slightly hypo-attenuating on contrast-enhanced CT during the portal-venous or late equilibrium phase, with a low conspicuity due to the reduced liver-lesion attenuation difference related to the insufficient injected dose of iodinated contrast agent in relation to the large patient habitus or body weight (Fig. 5). Finally, some other solid focal liver lesions appearing indeterminate on contrast-enhanced MR imaging due to the atypical lesion enhancement pattern during the dynamic or hepatobiliary phase may be effectively characterized by CEUS as benign or malignant (Fig. 6). In all these frequent clinical situations CEUS may close the patient diagnostic work-up if a diagnosis of benignancy is achieved.
The added diagnostic value provided by CEUS in the cirrhotic liver
One of the key pathological factors for the differential diagnosis between hepatocellular carcinoma and non-malignant hepatocellular lesions in cirrhotic patients is the vascular supply to the nodule. According to the 2001 Barcelona criteria [30] and EASL and AASLD 2005 guidelines [31], the evidence of coincidental arterial hyper-vascularity during arterial phase with contrast washout during the portal venous or late phase on CEUS and CT or MR imaging in nodules ≤2 cm in patients with liver cirrhosis is considered diagnostic of hepatocellular carcinoma and no bioptic procedure is required. If a nodule >2 cm shows arterial hyper-vascularity and washes out in the portal venous or late phase, only a single imaging investigation (CEUS, CT, or MR) is required for HCC diagnosis. If an equivocal pattern is identified (e.g., iso- or hyper-vascularity not followed by hypo-vascularity, or persistent hypo-vascularity) in hepatocellular nodules of any size biopsy should be performed. In patients with cirrhosis with a nodule ≤2 cm detected during surveillance, CEUS showing a typical contrast pattern confidently permits the diagnosis of hepatocellular carcinoma [32].
Recently, only contrast-enhanced CT and MR imaging were included as reliable imaging techniques for depicting hepatocellular nodule vascularity in the non-invasive diagnosis of hepatocellular carcinoma in cirrhotic patients according to the revised AASLD guidelines for hepatocellular carcinoma diagnosis [33]. This is determined by a significant proportion of false positives for hepatocellular carcinomas described in patients with intrahepatic cholangiocarcinoma scanned by CEUS [23]. According to Vilana et al. [23], the homogeneous hyper-vascularity on arterial phase followed by hypo-vascularity on the late phase, resembling the hepatocarcinoma pattern, was observed in 10/21 (47.6%) intrahepatic cholangiocarcinomas detected in cirrhotic patients over an observational period of 6 years. Anyway, another paper [24] recently reported that the same pattern was observed only in 3/50 (6%) of intrahepatic cholangiocarcinomas. Moreover, we should consider that the real clinical impact of the occurrence of peripheral cholangiocarcinoma in patients with chronic liver disease on the false-positive-rate for hepatocarcinoma remains unknown [34]. According to these observations, the real impact of false positive rate for hepatocellular carcinoma in cirrhotic patients due to intrahepatic cholangiocarcinomas is probably very low and should not justify the exclusion of CEUS from diagnostic criteria.
CEUS may have an additional diagnostic value to CT even in cirrhotic patients. In a recent paper from our group [35] including 106 cirrhotic patients (68 male, 38 female; mean age ± SD, 70 ± 7 years) with 121 biopsy-proven hepatocellular nodules (72 hepatocellular carcinomas, 10 dysplastic and 15 regenerative nodules, 12 hemangiomas, and 12 other benignancies), it was shown that the combined assessment of hepatocellular nodule vascularity at CT and CEUS improved the diagnostic performance in the diagnosis of malignancy [35] based on the visualization of nodule contrast washing during the arterial phase and contrast washout during the portal venous or late phase [30–32]. The combined assessment of CEUS/CT provided higher sensitivity in the diagnosis of malignancy than did separate assessment of CEUS and CT due to the reduction of false negative findings [35]. Nodules displaying higher, similar or lower enhancement compared to the adjacent liver parenchyma were defined as hyper-, iso- or hypo-vascular, respectively. Concordant vascular profiles on CEUS and CT were not requested and the higher grade of vascularity observed during the arterial phase was considered decisive (e.g., nodules appearing hypervascular on CEUS and iso-vascular on CT were classified as hypervascular), while the lower grade of vascularity in the portal/late phase was considered decisive (e.g., hypervascular nodules appearing iso-vascular on CEUS and hypo-vascular on CT during the portal/late phase were classified as hypo-vascular). The combined CEUS/CT provided a higher diagnostic accuracy (91% -reader 1- and 87% -reader 2-) than did the separate assessment of CEUS (83% -reader 1- and 79% -reader 2-) and CT (83% -reader 1- and 78% -reader 2-; P < 0.05) in the diagnosis of malignancy in patients with liver cirrhosis. This means that contrast washin during the arterial phase and contrast washout during the portal venous phase is depicted in a higher percentage of nodules if CEUS and CT are considered as complementary imaging techniques. According to these data, CEUS should be considered a preliminary examination after unenhanced US to exclude malignancy and a reliable additional imaging technique to CT for characterizing those hepatocellular nodules detected during surveillance (Figs. 7, 8).
Conclusions
CEUS may improve the diagnostic confidence in the characterization of those incidental focal liver lesions remaining indeterminate after contrast-enhanced CT or MR imaging, and may have an added diagnostic value also in hepatocellular nodules detected during surveillance in the cirrhotic liver, being complementary to CT.
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Quaia, E. Solid focal liver lesions indeterminate by contrast-enhanced CT or MR imaging: the added diagnostic value of contrast-enhanced ultrasound. Abdom Imaging 37, 580–590 (2012). https://doi.org/10.1007/s00261-011-9788-8
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DOI: https://doi.org/10.1007/s00261-011-9788-8