Using Contrast‐Enhanced Ultrasound to Characterize Focal Liver Lesions

Answer questions and earn CME

Abbreviations

CEUS

contrast‐enhanced ultrasound

CT

computed tomography

FLL

focal liver lesion

FNH

focal nodular hyperplasia

HCC

hepatocellular carcinoma

iCCA

intrahepatic cholangiocarcinoma

MRI

magnetic resonance imaging

UCA

ultrasound‐specific contrast agent

US

ultrasound

Ultrasound (US) of the liver is often the primary screening imaging tool for a range of indications, including: (1) elevated liver function tests, (2) screening for chronic liver disease, and (3) screening for hepatocellular carcinoma (HCC). In the past, if a focal liver lesion (FLL) was detected on liver US, multiphasic contrast‐enhanced computed tomography (CT) or magnetic resonance imaging (MRI) was often required. However, the recent availability of US‐specific contrast agents (UCAs) in the United States allows definitive characterization of FLL by contrast‐enhanced US (CEUS). This enables US to function as both a screening tool and a definitive diagnostic test for a wide range of pathologies. This review highlights the use of UCAs in the evaluation of FLLs in adults.

UCAs

UCAs consist of small particles of poorly dissolvable fluorocarbon gas encased by a lipid or protein shell (also known as microbubbles). These agents are injected intravenously, similar to iodinated and gadolinium‐based agents for CT and MRI, respectively. UCAs are quickly cleared by the body, with a half‐life of only a few minutes; the gas core is cleared by the lungs, and the biocompatible shell processed by the reticuloendothelial system. There are three US Food and Drug Administration–approved agents in the United States, one with specific indication for characterization of FLLs. Billing codes are also now available.

Technical Considerations

Microbubbles are fragile. Once injected, they can be destroyed by a normal US pulse. Contrast‐specific imaging mode facilitates low‐power imaging that minimizes microbubble destruction and helps differentiate signal from UCA and signal from background tissues. This allows for real‐time “contrast‐only” imaging (also known as tissue subtraction). Therefore, enhancement patterns and the differentiation of enhancing from nonenhancing tissues is straightforward. ¹

Benefits and Challenges

CEUS takes advantage of inherent benefits of US: low‐cost, wide availability, tolerability, and portability. ¹ In addition, the safety profile of UCA allows for imaging of patients with contraindications or aversions to CT or MRI. UCAs are extremely safe: reactions are rare, and there are few contraindications. There is no associated nephrotoxicity. In addition, given their rapid clearance from the body, there is no absolute dose limit, and multiple doses can be administered during a single examination.

A few challenges limit the use of CEUS in all patients. A poorly visualized targeted lesion on grayscale US due to depth or obscuration by bowel gas or ribs is unlikely to be well seen on CEUS. CEUS is generally used for the characterization of a small number of target lesions. Therefore, although highly accurate, it is not appropriate for disease staging.

CEUS in Liver Imaging

Similar to CT and MRI, liver CEUS can be divided into precontrast (appearance on grayscale image), arterial, portal‐venous, and delayed (or late) phases. A target can be imaged continuously during the arterial phase, allowing for capture of the entire “wash‐in.” Therefore, contrast mistiming is rarely an issue, and the patterns of rapidly filling lesions can be precisely captured and analyzed.

A key discriminating feature is the absence or presence of washout: malignant lesions tend to show washout relative to liver, whereas benign lesions remain hyperenhancing to isoenhancing. ² , ³

FLLs

CEUS may be used to accurately characterize many FLLs, ² , ³ , ⁴ , ⁵ with the most common discussed later. CEUS is particularly helpful in the setting of an incidental lesion seen by grayscale US, or an inconclusive CT or MRI. ⁶ , ⁷

Cysts and Abscesses

Simple cysts are rarely a diagnostic dilemma. On US, a typical simple cyst is unilocular and anechoic with well‐defined walls. In some cases, cysts may have atypical features and contain debris or septations. This may simulate a solid lesion, warranting further evaluation.

On CEUS, simple cysts appear devoid of enhancement. Benign cysts can show thin septal enhancement and nonenhancing debris, requiring no further workup. Abscesses are associated with thick enhancing septations or a thickened enhancing wall, although this feature can overlap with malignancy (clinical presentation is helpful). Enhancing mural nodules may indicate other etiologies, such as mucinous cystic neoplasm.

Hemangiomas

Hemangioma, the most common neoplasm of liver, classically appears as a homogeneous, circumscribed, and hyperechoic mass by grayscale US. Atypical features or underlying risk factors for malignancy may warrant definitive imaging. Similar to multiphase contrast‐enhanced CT and MRI, hemangiomas at CEUS show peripheral, discontinuous nodular enhancement with puddles of contrast that slowly fill to the center (Fig. 1). Although not all hemangiomas completely fill in at CEUS, this pattern of peripheral enhancement is both sensitive and specific. One of the benefits of CEUS is the real‐time viewing and continuous imaging of the arterial phase; therefore, the classic enhancement pattern can often be demonstrated even if reported as “flash‐filling” at CT or MRI. Generally, no further workup is needed.

FIG 1.

Hemangioma. A 35‐year‐old man with chronic hepatitis B with liver nodule identified at surveillance US. Image from the US (A) shows a hyperechoic nodule in the superior right lobe (white arrows). CEUS images show peripheral, discontinuous nodular enhancement (B, 11 seconds), peripheral puddling, and progressive centripetal fill‐in (C, 14 seconds; D, 25 seconds). No washout was identified (not shown). This pattern of enhancement is both sensitive and specific for hemangioma.

Focal Nodular Hyperplasia

Focal nodular hyperplasia (FNH) is the second most common neoplasm of the liver and is often isoechoic to liver on grayscale US. At CEUS, FNH often exhibits a characteristic spoke‐wheel pattern of enhancement, filling from a central nidus toward the periphery (Fig. 2); this pattern is quite specific. Similar to CT and MRI, these lesions are often hyperenhancing relative to liver and do not show washout, which is further supportive of benignity.

FIG 2.

FNH. A 40‐year‐old woman with incidental liver lesions seen on US performed for right upper quadrant pain. Image from US (A) shows a hypoechoic nodule in hepatic segment 6 (calipers). (B‐D) CEUS images show arterial phase hyperenhancement with spoke‐wheel pattern with fill‐in to the periphery (white arrows), isoenhancement in the portal venous phase (E, 1 minute), and lack of washout in the late phase (F, 3 minutes). This pattern of enhancement is particularly specific for FNH.

Hepatocellular Adenomas

Hepatocellular adenomas are more challenging to definitively diagnose because these lesions show a more heterogenous enhancement pattern. ⁸ Most adenomas are arterially hyperenhancing relative to liver and remain isoenhancing in the later phases, supportive of benignity (Fig. 3). However, about half of adenomas may show washout, likely representative of the various adenoma subtypes. Correlation with risk factors, imaging follow‐up, and/or biopsy may be needed.

FIG 3.

Hepatocellular adenoma. A 70‐year‐old woman with incidental liver lesion seen on US performed for elevated liver function tests. Image from the US (A) shows an isoechoic to hyperechoic nodule in the anterior right lobe (white arrows). CEUS images show heterogeneous hyperenhancement in the arterial phase (B, 3 seconds), isoenhancement in the portal‐venous phase (C, 1 minute 9 seconds), and late phase (D, 3 minutes 34 seconds), supportive of a benign hepatocellular lesion. Subsequent hepatobiliary contrast‐enhanced MRI (not shown) demonstrated intracellular lipid and lack of contrast uptake in the delayed phase, further suggesting adenoma.

HCC

CEUS is a powerful tool for diagnosis of HCC, particularly in at‐risk patients. ⁷ Similar to CT and MRI, typical HCC shows arterial phase hyperenhancement and washout (Fig. 4). However, recent literature indicates that timing and degree of washout are both important in the differentiation of HCC from intrahepatic cholangiocarcinoma (iCCA). HCC typically shows washout that is late (>60 seconds) and mild (less enhancing than liver, but not completely devoid of contrast). Details for qualifying risk for HCC and providing a definitive diagnosis for treatment planning were recently published by the American College of Radiology Liver Imaging, Reporting and Data System (CEUS LI‐RADS). ⁹ CEUS may be considered to further characterize an FLL in at‐risk patients for which CT or MRI were not definitive for HCC. ⁷

FIG 4.

HCC. A 69‐year‐old man with cirrhosis and prior history of HCC treated with ablation several years prior. Image from a surveillance US (A) shows an isoechoic to hypoechoic nodule (white arrows). CEUS images show hyperenhancement in the arterial phase (B, 12 seconds), isoenhancement in the portal‐venous phase (C, 24 seconds), remained isoenhancing at 1 minute (not shown), and late, mild washout (D, 3 minutes 18 seconds), diagnostic for HCC.

Cholangiocarcinoma

iCCAs can appear circumscribed, ill‐defined, heterogeneous, or infiltrative on US. At CEUS, iCCAs can show heterogeneous peripheral arterial hyperenhancement (rim enhancement), rapid washout (<60 seconds), and/or marked (becomes nearly black or “punched out”) within 2 minutes (Fig. 5). These features help distinguish this malignancy from HCC. ⁶

FIG 5.

Cholangiocarcinoma. A 59‐year‐old man with hyperbilirubinemia and intrahepatic ductal dilatation. Endoscopic duct brushings were noncontributory, and biopsy was requested. During a US‐guided biopsy, a fusion/navigation system was used. The preceding contrast‐enhanced CT was fused to the US for real‐time guidance. (A) The contrast‐only image is shown, revealing a rounded hilar mass demonstrating marked, rapid washout at 1 minute 43 seconds after contrast injection, characteristic of malignancy. The corresponding US image (B) shows this mass to be relatively hypoechoic to liver. The reformatted CT image (C) fails to show this mass. (D) A fused CT and US image. Note is made of intrahepatic ductal dilatation (open arrowheads) and a biliary stent (black arrowheads). Biopsy was successful, and pathology was consistent with adenocarcinoma of pancreaticobiliary primary, supportive of hilar cholangiocarcinoma.

Metastases

Metastases can present as an FLL or as multiple masses. Metastases show either arterial phase hyperenhancement or hypoenhancement; however, they show universally marked, early washout. This appearance is similar to iCCA. ³

Other Indications

CEUS has other applications in liver imaging, such as for interventional procedures, including guiding biopsy of an occult FLL, guiding biopsy of the viable components of an FLL, and confirming active extravasation from the liver from trauma or spontaneous hemorrhage. ¹⁰ Recent research also supports CEUS as a tool to assess for response to liver‐directed therapy.

Conclusion

CEUS is a useful tool to characterize an FLL and is highly accurate at differentiating benign from malignant lesions. Specific enhancement patterns help differentiate benign hemangiomas and FNH from iCCA and metastasis. With the introduction of CEUS LI‐RADS, US can now be used to definitively diagnose suspected HCC in at‐risk individuals.