DOI: 10.1148/rg.252045066
RadioGraphics 2005;25:333-349
© RSNA, 2005
Real-Time Harmonic Contrast Material–specific US of Focal Liver Lesions1
Orlando Catalano, MD,
Antonio Nunziata, MD,
Roberto Lobianco, MD and
Alfredo Siani, MD
1 From the Department of Radiology, S. Maria delle Grazie Hospital, Via Domitiana Località La Schiana, Pozzuoli, Italy (O.C., R.L., A.S.); and the Diagnostic Imaging Area, PSI Napoli Est, Naples, Italy (A.N.). Presented as an education exhibit at the 2003 RSNA Scientific Assembly. Received April 7, 2004; revision requested June 30; final revision received November 3; accepted November 3. All authors have no financial relationships to disclose.
Address correspondence to O.C., Via Crispi 92, Naples 80121, Italy (e-mail: orlandcat{at}tin.it).
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Abstract
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Recent advances in contrast material–enhanced ultrasonography (US) mainly include (a) development of low-acoustic-pressure (low-mechanical-index) harmonic software, capable of obtaining real-time images without disrupting contrast material microbubbles, and (b) commercialization of new contrast media ("second-generation" contrast media), capable of producing intense echo signals in this low-mechanical-index setting. With use of low-mechanical-index continuous-mode contrast-enhanced US, the circulatory kinetic models of various focal liver lesions can be displayed dynamically. Hepatic lesions usually have typical perfusion characteristics and enhancement patterns through the various phases of parenchymal enhancement, which helps characterize lesions and, in most cases, allows definitive diagnosis, even among lesions that exhibit very similar baseline appearances. Because of the use of harmonic technologies at low emission frequencies, there is some loss of spatial resolution and overall image quality, typically resulting in a grainy appearance. In addition, lesion depth affects the detectability of vascularity to some degree in that poor signal arises from deep-seated lesions. Moreover, liver attenuation (eg, in patients with steatosis or chronic liver disease) further reduces the sensitivity of contrast-enhanced US. Nevertheless, with its unique capacity to provide images in real time, low-mechanical-index contrast-enhanced US is the dynamic imaging modality of choice in the differential diagnosis of focal liver lesions.
© RSNA, 2005
Abbreviations: CCC = cholangiocellular carcinoma, FNH = focal nodular hyperplasia, HCC = hepatocellular carcinoma
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Introduction
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"Second-generation" blood pool ultrasonographic (US) contrast media are filled with gases other than air and allow continuous real-time assessment of liver lesions at low acoustic pressure (low mechanical index). Air-filled agents (first-generation US contrast media), on the other hand, can be used only with high-mechanical-index intermittent technologies because micro-bubble rupture is necessary to obtain an adequate echo signal.
With second-generation contrast media, real-time imaging is performed through all vascular phases: the arterial (early) phase (15–35 seconds after injection), the portal (venous) phase (35–90 seconds), and the sinusoidal (parenchymal or late vascular) phase (90–240 seconds) (1). On real-time images, contrast medium is seen arriving in the hepatic artery and rapidly spreading through its branches. Liver parenchymal echogenicity increases consistently from the arterial to the portal phase and then decreases slightly during the sinusoidal phase (2,3). Enhancement of the branches of the hepatic artery and portal vein is readily visualized, without flow signals "bleeding" outside the vessel lumina (as happens with Doppler US) (4). Cirrhotic liver may exhibit slightly delayed and less intense parenchymal enhancement during the portal phase (1,5).
Lesion echogenicity is defined with respect to the surrounding parenchymal echo levels at the same imaging time and depth. Lesions are either hyperechoic, isoechoic (undetectable), or hypo-echoic relative to the adjacent parenchyma. In addition, lesions can be compared with the blood pool, being hypervascular when demonstrating the same echogenicity as contrast material–enhanced vessels and hypovascular when demonstrating a lower echogenicity.
Knowledge of the hemodynamic behavior of liver lesions allows the formulation of a differential diagnosis (Fig 1). Several enhancement patterns have been identified (Fig 2) (6–10).
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Figure 1. Graph illustrates the hemodynamic behavior of liver lesions. Lesion conspicuity depends on the lesion-to-parenchyma echogenicity gradient; in this case, HCC has greater conspicuity during the arterial phase and appears hyperechoic. During the portal and sinusoidal phases, the lesion is first slightly and then clearly hypoechoic relative to the surrounding parenchyma.
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Figure 2. Drawings illustrate the most typical patterns of liver lesion enhancement. Enhancement may be absent (eg, cyst, small hemangioma, dysplastic nodule, or early HCC) or may be diffuse homogeneous or diffuse heterogeneous (eg, hypervascular metastasis or atypical CCC, lymphoma, FNH). Rim pattern manifests as peripheral, irregular but continuous arterial phase enhancement (eg, metastasis, CCC). The globular pattern consists of discontinuous peripheral arterial phase enhancement with discrete echoic globules (eg, cavernous hemangioma). The spokelike pattern seen during the arterial phase is due to discrete arteries radiating to the periphery (eg, FNH). The stippled pattern seen during this phase consists of discrete arteries with a chaotic distribution (eg, HCC). The arterial phase "basket" pattern, usually seen in combination with a stippled appearance, consists of a feeding artery branching around and then within a nodule (eg, HCC).
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The liver-enhancing effect of the blood pool contrast agent SonoVue (Bracco, Milan, Italy) used at our institution lasts 3–5 minutes; more than 5 minutes after contrast material injection, most lesions become undetectable or have the same echogenicity as on baseline images (1). Other contrast media—for example, the commercially available agent Levovist (Schering, Berlin, Germany)—have greater persistence, with a liver-specific late phase. Imaging during this postvascular phase may also be helpful in the detection and characterization of focal liver lesions (11,12), but we do not address this issue. Instead, we briefly describe our contrast-enhanced US technique and review in detail the contrast-enhanced US findings and patterns encountered in the assessment of various solid liver lesions, including hemangioma, hepatocellular adenoma, focal nodular hyperplasia (FNH), dysplastic nodules, hepatocellular carcinoma (HCC), cholangiocellular carcinoma (CCC), metastasis, lymphoma, abscess, peliosis hepatis, focal steatosis, and skip area in fatty liver. Although most of the references cited in this article relate to first-generation contrast-enhanced intermittent US, the findings that we illustrate were seen with the more recently developed real-time US used at our institution.
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Imaging Technique
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Manufacturers have developed a variety of gray-scale technologies that are specific for imaging with US contrast media. These technologies, most of which make use of harmonic imaging, can be divided into two main groups: (a) high-mechanical-index modalities, which allow static, intermittent imaging, and (b) low-mechanical-index modalities, which allow dynamic, continuous acquisition and require second-generation contrast media. At our institution, we have access to both techniques but prefer continuous-mode imaging, since real-time imaging is one of the main strengths of US. More specifically, we use the harmonic, contrast material–specific technology known as Contrast Tuned Imaging (Esaote, Genoa, Italy). Contrast Tuned Imaging is available on two scanners: the contrast material–devoted unit EsaTune and the multimodality unit Technos MPX.
We use a 3.5-MHz convex transducer with multiple tight bands (CA430) and a very low acoustic power setting (40–50 kPa derated pressure, expressing a mechanical index of 0.05–0.08). The US beam is focused at the deeper aspect of the region of interest. A high-power flash can be arbitrarily added to continuous acquisition (usually 4–5 times per examination), briefly breaking some microbubbles within the insonated volume and thereby allowing a kind of transient enhancement resetting (reperfusion evaluation). The entire examination is stored on the scanner as a video clip and subsequently sent to a personal computer for conversion into an AVI (audio-video interleave)–format video file.
We use the sulfur hexafluoride–based contrast medium SonoVue, which is currently being evaluated by the U.S. Food and Drug Administration. This agent comes as a sterile, nonpyrogenic, lyophilized powder. A white milky suspension is obtained by adding 5 mL of 0.9% normal saline solution with an aseptic technique and vigorously shaking the mixture for 10 seconds. The reconstituted product provides 8 µL/mL of SF6 micro-bubbles, which is then administered either in its entirety (4.8 mL) or as a half dose (2.4 mL). The half dose is usually sufficient, but injecting the entire volume may be desirable in cases of liver steatosis or chronic hepatitis (13,14).
The contrast medium is usually administered as a single rapid bolus injection into an antecubital vein via a 20-gauge catheter, followed by 5–10 mL of 0.9% saline solution to flush the line (three-way stopcock). US is started immediately and lasts 4–5 minutes (13,14).
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Lesion Appearances at US
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Hemangioma
Liver hemangioma is a hypervascular lesion consisting of a network of vascular spaces with slow or, less commonly, rapid flow. The distribution of small arterial branches, venous lakes, and fibrosis varies. Arterial inflow is present, whereas portal afference is absent or minimal, and there is no arteriovenous fistula.
Small (<1-cm) hemangiomas are usually iso-vascular relative to the surrounding parenchyma during the arterial phase (Fig 3 ). Less commonly, a subtle, diffuse enhancement (homogeneous or heterogeneous) is seen (2,15). Larger hemangiomas (>1 cm) usually demonstrate peripheral globular pooling of contrast medium, with hyperechoic globules (nodules) becoming progressively larger and more numerous (puddle enhancement) (Fig 4) (5,8,15–17). Contrast material uptake can be fast or slow depending on intralesional circulation speed. Uncommonly, contrast material enhancement is rapid and homogeneous, simulating that of hypervascular metastases (5,8). Rarely, peripheral rimlike enhancement or diffuse homogeneous enhancement is seen (small, hypervascular hemangioma) (17). Discrete intralesional arteries are usually not seen in hemangiomas (7,9).
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Figure 3a. Small hemangiomas discovered incidentally in a 45-year-old woman. (a) Baseline US image shows two homogeneously hyperechoic lesions (arrowheads) contiguous with a portal branch (arrow). (b) Early portal phase US image obtained 35 seconds after contrast material injection demonstrates lesion isoechogenicity. Arrow indicates an enhanced vein. (c) Parenchymal phase US image obtained 121 seconds after injection demonstrates persistent lesion isoechogenicity.
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Figure 3b. Small hemangiomas discovered incidentally in a 45-year-old woman. (a) Baseline US image shows two homogeneously hyperechoic lesions (arrowheads) contiguous with a portal branch (arrow). (b) Early portal phase US image obtained 35 seconds after contrast material injection demonstrates lesion isoechogenicity. Arrow indicates an enhanced vein. (c) Parenchymal phase US image obtained 121 seconds after injection demonstrates persistent lesion isoechogenicity.
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Figure 3c. Small hemangiomas discovered incidentally in a 45-year-old woman. (a) Baseline US image shows two homogeneously hyperechoic lesions (arrowheads) contiguous with a portal branch (arrow). (b) Early portal phase US image obtained 35 seconds after contrast material injection demonstrates lesion isoechogenicity. Arrow indicates an enhanced vein. (c) Parenchymal phase US image obtained 121 seconds after injection demonstrates persistent lesion isoechogenicity.
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Figure 4a. Large hemangioma in a 56-year-old woman with rectal cancer. (a) Baseline US image shows a heterogeneously hypoechoic lesion (arrow). (b) Arterial phase US image obtained 22 seconds after contrast material injection demonstrates peripheral globular enhancement (large arrow) and a perilesional vessel (small arrow). (c) Portal phase US image obtained 93 seconds after injection demonstrates centripetal (albeit incomplete) lesion enhancement (large arrow), which is clearly hyperechoic relative to the surrounding parenchyma. Small arrow indicates the perilesional vessel. (d) Portal phase computed tomographic (CT) scan shows a hyperattenuating lesion with small central areas of poor enhancement (arrow).
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Figure 4b. Large hemangioma in a 56-year-old woman with rectal cancer. (a) Baseline US image shows a heterogeneously hypoechoic lesion (arrow). (b) Arterial phase US image obtained 22 seconds after contrast material injection demonstrates peripheral globular enhancement (large arrow) and a perilesional vessel (small arrow). (c) Portal phase US image obtained 93 seconds after injection demonstrates centripetal (albeit incomplete) lesion enhancement (large arrow), which is clearly hyperechoic relative to the surrounding parenchyma. Small arrow indicates the perilesional vessel. (d) Portal phase computed tomographic (CT) scan shows a hyperattenuating lesion with small central areas of poor enhancement (arrow).
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Figure 4c. Large hemangioma in a 56-year-old woman with rectal cancer. (a) Baseline US image shows a heterogeneously hypoechoic lesion (arrow). (b) Arterial phase US image obtained 22 seconds after contrast material injection demonstrates peripheral globular enhancement (large arrow) and a perilesional vessel (small arrow). (c) Portal phase US image obtained 93 seconds after injection demonstrates centripetal (albeit incomplete) lesion enhancement (large arrow), which is clearly hyperechoic relative to the surrounding parenchyma. Small arrow indicates the perilesional vessel. (d) Portal phase computed tomographic (CT) scan shows a hyperattenuating lesion with small central areas of poor enhancement (arrow).
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Figure 4d. Large hemangioma in a 56-year-old woman with rectal cancer. (a) Baseline US image shows a heterogeneously hypoechoic lesion (arrow). (b) Arterial phase US image obtained 22 seconds after contrast material injection demonstrates peripheral globular enhancement (large arrow) and a perilesional vessel (small arrow). (c) Portal phase US image obtained 93 seconds after injection demonstrates centripetal (albeit incomplete) lesion enhancement (large arrow), which is clearly hyperechoic relative to the surrounding parenchyma. Small arrow indicates the perilesional vessel. (d) Portal phase computed tomographic (CT) scan shows a hyperattenuating lesion with small central areas of poor enhancement (arrow).
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Isovascularity persists throughout the portal and sinusoidal phases in small hemangiomas (2,15). In contrast, larger hemangiomas show progressive centripetal enlargement of peripheral hyperechoic globules with progressive filling (5,8). As the globules enlarge, they create "bridges" to the opposite side of the lesion. Centripetal filling may be absent in smaller lesions, but real-time images usually allow identification of this finding even in small, rapidly enhancing hemangiomas. Persistent strong intralesional enhancement (hyperechogenicity) is typical, although a central area or sac of persistent poor enhancement due to fibrosis may be seen in larger hemangiomas (2); owing to the blood pool nature of US contrast media, incomplete centripetal filling is more common at US than at CT or magnetic resonance (MR) imaging (Fig 5). Rarely, hemangioma shows heterogeneous hypoechogenicity (thrombosis) (9).
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Figure 5. Large, atypical hemangioma discovered incidentally in a 33-year-old woman. Early portal phase US image obtained 43 seconds after contrast material injection shows multiple peripheral enhancing globules (large arrows) and thin enhancing septa centrally (small arrows). Although most of the lesion is hypoechoic, and was even on delayed images (not shown), the globular pattern allowed characterization.
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Hepatocellular Adenoma
Adenoma is a hypervascular lesion without portal tracts. Large, subcapsular tributary arteries are typical, whereas necrotic and hemorrhagic changes are frequently seen in larger masses.
Intense, rapid or slow contrast material enhancement is seen during the arterial phase. Discrete, perilesional feeding arteries manifest as enhancement around the tumor capsule; such enhancement is never seen in HCC. Heterogeneous enhancement with perfusion defects corresponding to hemorrhagic areas is present in larger masses (18).
More or less rapid washout is seen during the portal and sinusoidal phases, with initial hypervascularity followed by isovascularity; a hypoechoic appearance is never seen. A heterogeneous texture is seen in larger masses, with internal hypoechoic regions (Fig 6 ) (18).
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Figure 6a. Hepatocellular adenoma in a 40-year-old woman with a history of oral contraception who was being evaluated for blunt abdominal trauma. (a) Baseline US image shows a subtle hyperechoic area (arrow). Contrast-enhanced US was performed to rule out liver injury. (b) Arterial phase US image obtained 21 seconds after contrast material injection demonstrates early, marked lesion enhancement (arrow). K = kidney. (c) Portal phase US image obtained 55 seconds after injection demonstrates subtle but persistent enhancement (arrow). K = kidney.
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Figure 6b. Hepatocellular adenoma in a 40-year-old woman with a history of oral contraception who was being evaluated for blunt abdominal trauma. (a) Baseline US image shows a subtle hyperechoic area (arrow). Contrast-enhanced US was performed to rule out liver injury. (b) Arterial phase US image obtained 21 seconds after contrast material injection demonstrates early, marked lesion enhancement (arrow). K = kidney. (c) Portal phase US image obtained 55 seconds after injection demonstrates subtle but persistent enhancement (arrow). K = kidney.
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Figure 6c. Hepatocellular adenoma in a 40-year-old woman with a history of oral contraception who was being evaluated for blunt abdominal trauma. (a) Baseline US image shows a subtle hyperechoic area (arrow). Contrast-enhanced US was performed to rule out liver injury. (b) Arterial phase US image obtained 21 seconds after contrast material injection demonstrates early, marked lesion enhancement (arrow). K = kidney. (c) Portal phase US image obtained 55 seconds after injection demonstrates subtle but persistent enhancement (arrow). K = kidney.
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Focal Nodular Hyperplasia
FNH is a hypervascular, hyperplastic lesion caused by preexisting vascular malformation (19). Patients are typically women with a history of oral contraception. FNH is not seen in patients with cirrhosis. There is usually a peripheral pseudo-capsule and a central or eccentric fibrous scar radiating to the periphery and containing arteries.
During the arterial phase, FNH manifests as a tortuous feeding artery and a central artery with very early centrifugal stellate branching ("wheel spoke" or "central spider" pattern) (6,20,21). Immediately thereafter, during the full arterial phase, the lesion demonstrates homogeneous, intense, and very rapid contrast material enhancement (Fig 7). A hypoechoic central scar may be present (5,20).
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Figure 7a. FNH discovered incidentally in a 29-year-old woman with a history of oral contraception. (a) Baseline US image shows a slightly hypoechoic lesion (arrows). (b) Very early arterial phase US image obtained 15 seconds after contrast material injection demonstrates rapid lesion enhancement (arrows) with discrete intralesional and perilesional arteries. (c) Later arterial phase US image obtained 29 seconds after injection demonstrates marked homogeneous lesion enhancement (arrows). (d) Portal phase US image obtained 49 seconds after injection demonstrates lesion isoechogenicity (arrows). (e) Arterial phase CT scan show a homogeneously hyperattenuating lesion (arrow) (cf c).
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Figure 7b. FNH discovered incidentally in a 29-year-old woman with a history of oral contraception. (a) Baseline US image shows a slightly hypoechoic lesion (arrows). (b) Very early arterial phase US image obtained 15 seconds after contrast material injection demonstrates rapid lesion enhancement (arrows) with discrete intralesional and perilesional arteries. (c) Later arterial phase US image obtained 29 seconds after injection demonstrates marked homogeneous lesion enhancement (arrows). (d) Portal phase US image obtained 49 seconds after injection demonstrates lesion isoechogenicity (arrows). (e) Arterial phase CT scan show a homogeneously hyperattenuating lesion (arrow) (cf c).
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Figure 7c. FNH discovered incidentally in a 29-year-old woman with a history of oral contraception. (a) Baseline US image shows a slightly hypoechoic lesion (arrows). (b) Very early arterial phase US image obtained 15 seconds after contrast material injection demonstrates rapid lesion enhancement (arrows) with discrete intralesional and perilesional arteries. (c) Later arterial phase US image obtained 29 seconds after injection demonstrates marked homogeneous lesion enhancement (arrows). (d) Portal phase US image obtained 49 seconds after injection demonstrates lesion isoechogenicity (arrows). (e) Arterial phase CT scan show a homogeneously hyperattenuating lesion (arrow) (cf c).
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Figure 7d. FNH discovered incidentally in a 29-year-old woman with a history of oral contraception. (a) Baseline US image shows a slightly hypoechoic lesion (arrows). (b) Very early arterial phase US image obtained 15 seconds after contrast material injection demonstrates rapid lesion enhancement (arrows) with discrete intralesional and perilesional arteries. (c) Later arterial phase US image obtained 29 seconds after injection demonstrates marked homogeneous lesion enhancement (arrows). (d) Portal phase US image obtained 49 seconds after injection demonstrates lesion isoechogenicity (arrows). (e) Arterial phase CT scan show a homogeneously hyperattenuating lesion (arrow) (cf c).
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Figure 7e. FNH discovered incidentally in a 29-year-old woman with a history of oral contraception. (a) Baseline US image shows a slightly hypoechoic lesion (arrows). (b) Very early arterial phase US image obtained 15 seconds after contrast material injection demonstrates rapid lesion enhancement (arrows) with discrete intralesional and perilesional arteries. (c) Later arterial phase US image obtained 29 seconds after injection demonstrates marked homogeneous lesion enhancement (arrows). (d) Portal phase US image obtained 49 seconds after injection demonstrates lesion isoechogenicity (arrows). (e) Arterial phase CT scan show a homogeneously hyperattenuating lesion (arrow) (cf c).
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During the portal and sinusoidal phases, there is slow or, less commonly, rapid washout, with initial hypervascularity followed by isovascularity (isoechoic or hyperechoic appearance). A homogeneous texture with possible central stellate hypoechogenicity is characteristic (Fig 8) (5).
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Figure 8a. Large, pedunculated FNH in a 38-year-old woman with a palpable mass. The patient had no history of oral contraception. (a) Baseline US image shows a homogeneous, well-defined mass (arrows) depending from the right hepatic lobe. (b) Arterial phase US image obtained 22 seconds after contrast material injection demonstrates multiple radiating arteries within the mass (arrows). (c) Portal phase US image obtained 56 seconds after injection demonstrates marked enhancement of the mass (white arrows), with a hypoechoic central scar (black arrow). (d) Late arterial phase CT scan shows a markedly enhancing mass (white arrows) with central scarring (black arrow) (cf c).
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Figure 8b. Large, pedunculated FNH in a 38-year-old woman with a palpable mass. The patient had no history of oral contraception. (a) Baseline US image shows a homogeneous, well-defined mass (arrows) depending from the right hepatic lobe. (b) Arterial phase US image obtained 22 seconds after contrast material injection demonstrates multiple radiating arteries within the mass (arrows). (c) Portal phase US image obtained 56 seconds after injection demonstrates marked enhancement of the mass (white arrows), with a hypoechoic central scar (black arrow). (d) Late arterial phase CT scan shows a markedly enhancing mass (white arrows) with central scarring (black arrow) (cf c).
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Figure 8c. Large, pedunculated FNH in a 38-year-old woman with a palpable mass. The patient had no history of oral contraception. (a) Baseline US image shows a homogeneous, well-defined mass (arrows) depending from the right hepatic lobe. (b) Arterial phase US image obtained 22 seconds after contrast material injection demonstrates multiple radiating arteries within the mass (arrows). (c) Portal phase US image obtained 56 seconds after injection demonstrates marked enhancement of the mass (white arrows), with a hypoechoic central scar (black arrow). (d) Late arterial phase CT scan shows a markedly enhancing mass (white arrows) with central scarring (black arrow) (cf c).
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Figure 8d. Large, pedunculated FNH in a 38-year-old woman with a palpable mass. The patient had no history of oral contraception. (a) Baseline US image shows a homogeneous, well-defined mass (arrows) depending from the right hepatic lobe. (b) Arterial phase US image obtained 22 seconds after contrast material injection demonstrates multiple radiating arteries within the mass (arrows). (c) Portal phase US image obtained 56 seconds after injection demonstrates marked enhancement of the mass (white arrows), with a hypoechoic central scar (black arrow). (d) Late arterial phase CT scan shows a markedly enhancing mass (white arrows) with central scarring (black arrow) (cf c).
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The overall appearance of FNH usually allows differentiation from fibrolamellar HCC, an uncommon lesion that also contains a central scar (5). Fibrolamellar HCC is usually heterogeneous because of necrosis, shows internal calcification, and is hypoechoic on portal phase images.
Dysplastic Nodules and Early HCC
Dysplastic nodules are premalignant lesions within a cirrhotic liver that develop small arteries and exhibit portal tracts. Early HCC is usually a small, well-differentiated nodule with increased arterialization and gradual loss of portal vessels.
During the arterial phase, dysplastic nodules and early HCC are usually substantially isovascular with no arterial enhancement (21,22). Nevertheless, high-grade dysplastic nodules can sometimes demonstrate marked enhancement.
Dysplastic nodules and early HCC have an isoechoic or subtly hypoechogenic appearance throughout the portal and sinusoidal phases (Fig 9).
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Figure 9a. Dysplastic nodule in a 61-year-old man with chronic liver disease. (a) Baseline US image shows a small, hypoechoic nodule (arrow). (b) Arterial phase US image obtained 25 seconds after contrast material injection fails to depict any lesion.
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Figure 9b. Dysplastic nodule in a 61-year-old man with chronic liver disease. (a) Baseline US image shows a small, hypoechoic nodule (arrow). (b) Arterial phase US image obtained 25 seconds after contrast material injection fails to depict any lesion.
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Advanced HCC
Typically, small to medium-sized HCC (1–5 cm) is a hypervascular lesion with intense arterial flow (neoangiogenesis) and little or no portal supply.
During the arterial phase, advanced HCC demonstrates hyperperfusion relative to parenchymal enhancement; this hyperperfusion starts immediately after enhancement of the hepatic artery (Fig 10) (23–27). This arterial phase–dependent enhancement is rapid and intense, with a conspicuity level comparable to that seen at CT, and is typically transient (1). Smaller HCCs usually enhance slightly faster than larger ones (23).
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Figure 10a. Small HCC in a 54-year-old man with chronic liver disease. (a) Baseline US image shows a small, hypoechoic nodule (arrows) (cf Fig 9a). (b) Arterial phase US image obtained 26 seconds after contrast material injection demonstrates diffuse homogeneous enhancement of the nodule (arrows). (c) Portal phase US image obtained 41 seconds after injection shows isoechogenicity of the nodule (arrow).
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Figure 10b. Small HCC in a 54-year-old man with chronic liver disease. (a) Baseline US image shows a small, hypoechoic nodule (arrows) (cf Fig 9a). (b) Arterial phase US image obtained 26 seconds after contrast material injection demonstrates diffuse homogeneous enhancement of the nodule (arrows). (c) Portal phase US image obtained 41 seconds after injection shows isoechogenicity of the nodule (arrow).
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Figure 10c. Small HCC in a 54-year-old man with chronic liver disease. (a) Baseline US image shows a small, hypoechoic nodule (arrows) (cf Fig 9a). (b) Arterial phase US image obtained 26 seconds after contrast material injection demonstrates diffuse homogeneous enhancement of the nodule (arrows). (c) Portal phase US image obtained 41 seconds after injection shows isoechogenicity of the nodule (arrow).
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One or more hypertrophic feeding arteries are seen reaching lesion poles and branching intralesionally (basket pattern). These afferent arteries are seen in a minority of cases at CT and MR imaging, even on thin sections, whereas they are a frequent finding at contrast-enhanced US (22). Discrete peri- and intranodular vessels are also recognizable at US, usually being dysmorphic, chaotic, and randomly stippled and having a corkscrew-shaped distribution (1,4,5,8,20,25). Real-time imaging usually allows observation of a defined (although sometimes very rapid) sequence of enhancement, similar to that which has been seen for many years at selective angiography: enhancement of the hepatic artery, the main feeding vessels, and the intranodular vessels (first seen near the afferent arteries)—in that order—followed by global contrast agent pooling (tumor stain) (Fig 11) (1,4,22).
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Figure 11a. HCC in a 78-year-old man with chronic liver disease and an elevated serum  -fetoprotein level. (a) Very early arterial phase US image obtained 21 seconds after contrast material injection shows an enhancing mass, with a feeding artery (large arrow) and perinodular arteries (small arrows) nearby. (b) Delayed arterial phase US image obtained 31 seconds after injection shows a homogeneously enhancing mass (arrows).
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Figure 11b. HCC in a 78-year-old man with chronic liver disease and an elevated serum -fetoprotein level. (a) Very early arterial phase US image obtained 21 seconds after contrast material injection shows an enhancing mass, with a feeding artery (large arrow) and perinodular arteries (small arrows) nearby. (b) Delayed arterial phase US image obtained 31 seconds after injection shows a homogeneously enhancing mass (arrows).
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Well-differentiated HCC may show fewer peri- and intratumoral vessels and a lower degree of enhancement (9).
Uncommon hypovascular HCC demonstrates isoperfusion or even hypoperfusion relative to the surrounding parenchyma and hence is difficult to characterize (26). HCC with fatty degeneration shows baseline hyperechoic areas that do not enhance on contrast-enhanced images, whereas the isoechoic and hypoechoic portions show the typical intense but transient postinjection enhancement.
Large lesions ("big" HCC) demonstrate peripheral enhancement, central hypovascular necrotic areas, and vascular lakes with hyperechoic contrast agent pooling (Fig 12) (22).
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Figure 12a. Large liver dome HCC in an 81-year-old man with uncompensated liver cirrhosis. (a) Arterial phase US image obtained 27 seconds after contrast material injection shows a peripherally enhancing mass (large arrows) with discrete arteries (small arrows) and a necrotic center. (b) Arterial phase CT scan demonstrates a peripherally enhancing mass (arrows) with small internal arteries, findings that correlate well with those seen at US. F = peritoneal fluid.
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Figure 12b. Large liver dome HCC in an 81-year-old man with uncompensated liver cirrhosis. (a) Arterial phase US image obtained 27 seconds after contrast material injection shows a peripherally enhancing mass (large arrows) with discrete arteries (small arrows) and a necrotic center. (b) Arterial phase CT scan demonstrates a peripherally enhancing mass (arrows) with small internal arteries, findings that correlate well with those seen at US. F = peritoneal fluid.
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During the portal and sinusoidal phases, advanced HCC demonstrates rapid washout (faster than with FNH or adenoma) and has an isovascular or, less commonly, hypovascular appearance. Transient isoechogenicity is seen on full portal phase images, eventually followed by moderate hypoechogenicity on delayed images (26).
On low-mechanical-index images, most non-necrotic HCCs are isoechoic (ie, undetectable) during the sinusoidal phase (1,22). The remaining tumors show slight hypoechogenicity, unlike the marked hypoechoic defect encountered in cases of metastasis.
Most lesions are heterogeneous (mosaic-like) during the portal phase, but lesions that are markedly homogeneous on arterial phase images are usually homogeneous on portal phase images as well (7,8,19,26). Big HCC demonstrates heterogeneous echogenicity with central hypovascular areas and venous lakes (22).
Cholangiocellular Carcinoma
CCC can be hypovascular or, less commonly, hypervascular on arterial phase images, with portal phase vascularity usually being limited.
CCC demonstrates peripheral rimlike enhancement or heterogeneous enhancement during the arterial phase. Poor heterogeneous enhancement is possible, with an overall isoechoic or hypoechoic appearance (2,10).
CCC usually has a hypoechoic appearance on portal and sinusoidal phase images. Persistent subtle rim enhancement is possible. Conspicuity increases progressively, and necrotic areas with more marked hypoechogenicity may be seen. Satellite lesions may also be encountered (2,10).
Metastasis
Liver metastasis can be hypo- or, less commonly, hypervascular on arterial phase images depending on the organ of origin. All metastases show some degree of arterial neoangiogenesis (peripheral macrovessels and central microvessels) and lack at least a portion of the portal supply.
During the arterial phase, liver metastasis shows peripheral rimlike enhancement of varying thickness and uniformity, with an eventual target-like appearance (Fig 13) (28). Less commonly, there is intense, rapid, diffuse, more or less homogeneous enhancement (Fig 14) (1,5,29). There is always some kind of arterial inflow peripherally, even if subtle and heterogeneous, whereas most of the lesion is isoechoic relative to the surrounding parenchyma. Perilesional hyperemia with arterial phase–dependent enhancement of normal tissue is possible, and few discrete perilesional arteries can be found (5). Macroscopic arteries are usually not seen within the lesion (7).
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Figure 13a. Liver metastasis in a 59-year-old man with pancreatic cancer. (a) Arterial phase US image obtained 24 seconds after contrast material injection shows a thick, continuous collar of enhancement (arrows). (b) Portal phase US image obtained 114 seconds after injection shows a heterogeneously hypoechoic lesion (arrows).
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Figure 13b. Liver metastasis in a 59-year-old man with pancreatic cancer. (a) Arterial phase US image obtained 24 seconds after contrast material injection shows a thick, continuous collar of enhancement (arrows). (b) Portal phase US image obtained 114 seconds after injection shows a heterogeneously hypoechoic lesion (arrows).
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Figure 14a. Hypervascular liver metastases in a 60-year-old man with previously resected retroperitoneal sarcoma. (a) Early arterial phase US image obtained 20 seconds after contrast material injection shows a large lesion with heterogeneous and mostly peripheral (nonglobular) enhancement (large arrows). Two small lesions remain hypoechoic (small arrows). (b) Delayed arterial phase US image obtained 34 seconds after injection shows homogeneous enhancement of the large lesion and one of the small lesions (large arrows) and rim enhancement of the other small lesion (small arrow). Note that, in this case, lesion enhancement is variable and asynchronous.
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Figure 14b. Hypervascular liver metastases in a 60-year-old man with previously resected retroperitoneal sarcoma. (a) Early arterial phase US image obtained 20 seconds after contrast material injection shows a large lesion with heterogeneous and mostly peripheral (nonglobular) enhancement (large arrows). Two small lesions remain hypoechoic (small arrows). (b) Delayed arterial phase US image obtained 34 seconds after injection shows homogeneous enhancement of the large lesion and one of the small lesions (large arrows) and rim enhancement of the other small lesion (small arrow). Note that, in this case, lesion enhancement is variable and asynchronous.
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There is no centripetal filling during the portal and sinusoidal phases. Subtle rim enhancement may persist. Washout is rapid; lesions are seen as filling defects that progressively increase in conspicuity relative to normal parenchymal enhancement (black holes on a bright background) (1,3). Metastases have a heterogeneously hypoechoic appearance with internal echo pollution due to microbubbles and haphazard movement within abnormal small tumor vessels (microcirculation) (Fig 15) (5,30). Markedly hypoechoic areas within larger lesions are due to necrosis. Less commonly, hypervascular metastases may become isoechoic (undetectable) during this phase.
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Figure 15a. Liver metastasis in a 48-year-old woman with colon cancer. (a) Baseline US image shows a barely appreciable hypoechoic lesion (arrow). (b) Portal phase US image obtained 54 seconds after contrast material injection demonstrates an enhancement defect (arrow) with parenchymal enhancement. Small intralesional echoic dots appear on real-time images as fine internal echo pollution (microcirculation).
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Figure 15b. Liver metastasis in a 48-year-old woman with colon cancer. (a) Baseline US image shows a barely appreciable hypoechoic lesion (arrow). (b) Portal phase US image obtained 54 seconds after contrast material injection demonstrates an enhancement defect (arrow) with parenchymal enhancement. Small intralesional echoic dots appear on real-time images as fine internal echo pollution (microcirculation).
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Lymphoma
Primary and secondary liver lymphomas are hypercellular lesions with some degree of arterial neoangiogenesis and a poor portal supply.
Like metastasis, lymphoma demonstrates peripheral rimlike enhancement of varying thickness and uniformity during the arterial phase, with an eventual targetlike appearance. Intense, diffuse heterogeneous enhancement is rarely noted.
Like metastasis, lymphoma demonstrates no centripetal filling during the portal and sinusoidal phase. Washout is rapid, and lymphoma has a heterogeneous hypoechoic appearance with internal echo pollution (microcirculation) that progressively increases in conspicuity.
Abscess
Pyogenic and amoebic liver abscesses have a variable degree of liquefaction and loculation. Their vascularity depends on the evolution stage.
Liver abscesses, especially pyogenic abscesses, have an overall coalescent appearance with a sharply defined necrotic cavity (31,32). Rim enhancement is typical. Discrete arteries are noted running along lesion margins and internal septa, with persistent enhancement of the septa. Internal enhancement is absent, and there is no microcirculation within fluid or necrotic components. Perilesional hyperemia with arterial phase–dependent enhancement of normal tissue can be seen (28,31,32).
During the portal and sinusoidal phases, abscesses demonstrate rapid (or sometimes slower) washout, an overall hypoechoic appearance, and marked necrotic and fluid areas internally (28, 31,32).
Peliosis Hepatis
Peliosis hepatis is characterized by multiple blood-filled spaces ranging from 1 mm to 4–5 cm within the hepatic parenchyma (33).
During the arterial phase, peliosis hepatis shows a transient "fast surge" central echo enhancement that is synchronous with vessel enhancement.
During the portal and sinusoidal phases, peliosis hepatis demonstrates isoechogenicity or hypoechogenicity with no contrast material pooling or centripetal filling, allowing differentiation of this entity from hemangiomatosis.
Focal Steatosis
Focal areas of fatty infiltration may have a round, lesionlike appearance and are hyperechoic on conventional US images. Vascularity is normal (10,34).
During the arterial phase, focal steatosis demonstrates substantial isovascularity but no arterial enhancement, with normal vessels traversing the pseudolesion without mass effect.
Isovascularity persists during the portal and sinusoidal phases, with normal vessels still traversing the pseudolesion without mass effect (Fig 16).
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Figure 16a. Focal steatosis in a 62-year-old woman with previous breast cancer. (a) Baseline US image shows a hyperechoic area within the dorsal aspect of liver segment IV (arrows). Although the appearance and location of the lesion were typical for a focal area of steatosis, the referring clinician requested contrast-enhanced US. (b) Arterial phase US image obtained 40 seconds after contrast material injection demonstrates lesion isoechogenicity.
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Figure 16b. Focal steatosis in a 62-year-old woman with previous breast cancer. (a) Baseline US image shows a hyperechoic area within the dorsal aspect of liver segment IV (arrows). Although the appearance and location of the lesion were typical for a focal area of steatosis, the referring clinician requested contrast-enhanced US. (b) Arterial phase US image obtained 40 seconds after contrast material injection demonstrates lesion isoechogenicity.
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Skip Area in Fatty Liver
Focal regions of spared normal parenchyma within a heterogeneously distributed steatosis may have a round, pseudolesional appearance and are hypoechoic at baseline US. The vascularity of these spared areas is normal (10,34).
Substantial isovascularity with no arterial enhancement is noted during the arterial phase, and normal vessels traverse the pseudolesion without mass effect.
During the portal and sinusoidal phases, there is substantial isovascularity with possible slight hypoechogenicity. As in the arterial phase, normal vessels traverse the pseudolesion without mass effect.
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Effectiveness of Contrast-enhanced US
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Comparing published series is difficult because of the use of different contrast media and contrast-specific technologies and the different classification systems for enhancement patterns. Nevertheless, some quantitative data can and should be analyzed.
Contrast-enhanced US provides more information for lesion characterization than does either conventional or color Doppler US (21).
Contrast-enhanced US has an 89% sensitivity and a 100% specificity in the diagnosis of hemangioma (28). The capability of this modality to characterize hemangiomas is approximately equal to that of MR imaging, even in small lesions (16). Peripheral globular enhancement with centripetal filling indicates a hemangioma, even if central enhancement is subtle or absent on portal and sinusoidal phase images (15,17,28,34). Centripetal filling is not seen in malignancies (8). Peripheral enhancement followed by centripetal enhancement has a 100% specificity but only an 18% sensitivity for hemangioma (35). Globular peripheral enhancement is found in 70%–92% of hemangiomas, rimlike peripheral enhancement in 10%–25%, and diffuse homogeneous enhancement in 5% (8,15,16). Peripheral nodular enhancement with contrast material filling and absence of intralesional arteries has showed an 88% sensitivity and a 99% specificity for hemangioma (7). Peripheral or diffuse contrast material pooling is typical for hemangioma, with a 76.5% sensitivity and a 100% specificity (20).
Contrast-enhanced US has a 94% sensitivity and a 93% specificity in the diagnosis of HCC (28) and has proved sensitive in demonstrating HCC vascularity. In one series, contrast-enhanced US demonstrated vascularity in 91% of HCC nodules, CT in 93%, and angiography in 88% (27). Contrast-enhanced US is more sensitive than Doppler US in this setting. In one study, color Doppler US demonstrated blood flow in 87% of HCC nodules that were hypervascular at contrast-enhanced US (4); in another series, power Doppler US demonstrated vascularity in 69% of HCC nodules that were identified at angiography-assisted CT, whereas contrast-enhanced US showed vascularity in 96% (36).
HCC is typically hypervascular on arterial phase images but never exhibits rim or globular enhancement (8). Enhancement is homogeneous in 50% of cases and heterogeneous in 50% (8). Diffuse lesion enhancement on early arterial phase images indicates HCC, especially when followed by rapid washout. If a diffuse or mosaic-like arterial phase enhancement pattern or a reticular parenchymal phase enhancement pattern is regarded as indicating HCC, contrast-enhanced US has a 92% sensitivity and a 96% specificity for this entity (10). The presence of intratumoral vessels on arterial phase images combined with homogeneous or heterogeneous enhancement on portal phase images has a 95% sensitivity and a 94% specificity for HCC (7). The presence of arteries spreading into the lesion together with homogeneous hyperechoic tumor enhancement has an 83% sensitivity and a 94% specificity for HCC (20).
Arterial phase enhancement with slow deenhancement suggests adenoma or FNH instead of HCC. HCC and FNH can be distinguished on the basis of several distinctive morphologic features. FNH is homogeneous, even when large, whereas HCC tends to develop necrotic areas. Moreover, FNH is usually hyperechoic during the portal phase of enhancement, whereas HCC becomes iso- or hypoechoic. Central stellate enhancement has a specificity of 100% but a sensitivity of only 67% for FNH (35).
Contrast-enhanced US has a sensitivity of 77% and a specificity of 93% in the diagnosis of metastases (28). This modality is more sensitive than conventional US in detecting liver metastasis and almost as sensitive as CT or MR imaging. In one series, conventional US helped detect 59% of liver metastases seen at CT, whereas contrast-enhanced US helped detect 97% (30). In another study, the number of lesions detected rose from nine to 19 when contrast-enhanced US was used in addition to conventional US; contrast-enhanced US in particular allowed detection of small metastases (37). Contrast-enhanced US has been shown to help detect 90% of liver metastases that are visualized at ferumoxides-enhanced MR imaging (3).
Peripheral rim enhancement strongly suggests metastasis, especially if it is not followed by lesion filling and is not combined with a finding of intralesional vessels (7,8,10,28). Rim enhancement has been observed in 48%–70% of liver metastases (2,8). Rim enhancement, a clear parenchymal phase defect, or both can be used to diagnose metastasis or CCC with a 90% sensitivity and a 95% specificity (10). Of course, hypervascular metastases overlap with other benign and especially malignant hypervascular lesions, although general context and a clearly hypoechoic appearance during the portal phase generally allow differentiation.
Aside from its arterial phase appearance, a homogeneously hypoechoic lesion on portal or sinusoidal phase images should be considered malignant until proved otherwise, since benign lesions are iso- or hyperechoic during these phases (5). A clearly hypoechoic lesion on portal or sinusoidal phase images is usually considered to represent metastasis. The differential diagnosis of enhancement defects includes lesions such as lymphoma, CCC, HCC (very rarely in our country in the absence of chronic liver disease), dysplastic nodules in chronic liver disease (rarely), and abscess. The constellation of contrast-enhanced US findings in pyogenic abscess has been shown to be effective in differentiating this benign entity from metastasis (32).
In itself, the arrival time of contrast medium cannot be used to distinguish between benign and malignant lesions; early arrival is only 67% sensitive and 60% specific for malignancy (35).
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Use of Contrast-enhanced US at Our Institution
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At our hospital, contrast-enhanced US has penetrated deeply into clinical practice. In our country, as in most other European and Asian countries, US is widely used in imaging of the liver and of the abdomen in general. US is the first tool used for liver evaluation. Patients with chronic liver disease, a social problem in our area, periodically undergo US. Patients with current or previous extrahepatic cancer undergo hepatic US together with or instead of whole-body CT. Patients with other equivocal findings, including vague abdominal symptoms, also undergo US, which frequently shows incidental liver abnormalities.
When US findings are typical for hyperechoic hemangioma, focal steatosis, or skip area in fatty liver, we usually forgo further studies. However, when the US findings are atypical or the patient has an extrahepatic malignancy, we immediately perform contrast-enhanced US for definitive diagnosis. Contrast-enhanced US is also performed when any kind of focal liver lesion is found at conventional US; the patient undergoes CT or MR imaging only if contrast-enhanced US does not allow a definitive diagnosis.
In patients with chronic liver disease, we perform contrast-enhanced US when a clear nodule or an ill-defined, nodulelike area of heterogeneity is found. In cases of arterial phase hypervascularity, a diagnosis of HCC is made and the patient is scheduled for a staging CT or MR imaging examinatio
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Abstract
Introduction
