Unraveling distinctions between contrast-enhanced ultrasound and CT/MRI for liver mass diagnosis

Arterial Phase Hyperenhancement

APHE is defined as increased enhancement within a lesion when compared to the background liver parenchyma during the arterial phase (approximately 10-20 to 30-45 seconds after the injection of contrast). This is indicative of increased hepatic arterial vascularity and is a key diagnostic feature in evaluating various focal liver lesions. Regardless of the imaging modality, APHE is a major feature for the diagnosis of HCC that must be present to categorize a nodule as LI-RAD 5. CEUS provides continuous real-time imaging, unlike CT or MRI, allowing for the dynamic assessment of lesions and improving the assessment of APHE [2,4,14-16].

This is of particular value for the characterization of indeterminate hypervascular lesions on CT or MRI, such as flash filling or small hemangiomas (Fig. 2), and pseudolesions such as arterioportal shunts [7,9]. For instance, small or rapidly filling hemangiomas may appear as arterial phase hyper or hypoenhancing nodules on CT and MRI without showing the typical discontinuous, peripheral, nodular enhancement, leading to their categorization as LR-3, LR-4, or, less frequently, LR-M. However, with real-time capability of CEUS, the pattern of enhancement can be evaluated in greater detail, confirming the diagnosis of hemangioma and allowing the lesion to be downgraded to LR-1. Similarly, arterioportal shunts, which are common in cirrhotic livers, may have nodular appearance on CT and MRI being potentially miscategorized as LR-3 or LR-4; these are usually not visualized on CEUS, along with the absence of true nodule on grayscale confidently excluding the presence of hypervascular nodules [17,18].

Fig. 2.

Flash filling hemangioma in a 51-year-old man with hepatitis B.

A. Arterial-phase contrast-enhanced computed tomography (CT) scan shows a 10-mm homogeneously hyperenhancing nodule (arrow) in the left lobe of the liver. B. The nodule is isoenhancing relative to the liver (arrow) in the delayed phase. The nodule can be categorized as LR-3 on CT. C-E. Three contrast-enhanced ultrasound images obtained at 22 (C), 24 (D), and 29 seconds (E). Arrows show how the nodule demonstrates discontinuous, peripheral, nodular enhancement with rapid central fillin, confirming the diagnosis of hemangioma (LR-1).

Furthermore, the presence of APHE alone on CEUS in a true nodule on grayscale has higher specificity for HCC compared with CT or MRI [19]. Consequently, the CEUS LR-3 category typically includes a higher rate of HCC compared to its CT/MRI counterpart since CEUS is predominantly performed on genuine nodules, often larger than 10 mm, which inherently pose a significant risk of HCC [20,21]. Jang et al. [22] described a sensitivity of 87% with a specificity of 100% of APHE alone without the imaging features of hemangioma, in their study including 59 nodules smaller than 2 cm in patients with high risk of HCC. Giorgio et al. [23] reported the same specificity (100%) for diagnosing HCC based on APHE alone, in 199/229 new hepatic nodules (measuring 7-20 mm) detected in patients with cirrhosis on surveillance [22,23].

CEUS may also act as a problem-solving tool for liver observations without APHE on CT and MRI categorized as LR-3 and LR-4 (Fig. 3) due to arterial phase mistiming on CT and MRI. Additionally, it may depict subtle APHE nodules not discernible on CT or MRI, allowing an early diagnosis. CEUS has an inherent superior sensitivity for the detection of arterial hypervascularity partly due to the subtraction effect, where contrast mode only reflects signals from microbubbles, suppressing the background tissue signal. In contrast, CT and MRI still reflect the attenuation or signal intensity of the background parenchyma [14,20]. Many studies have consistently supported this superior sensitivity of CEUS in the depiction of APHE. For example, a study by Kang et al. [24], including 43 observations without APHE on CT/MRI, found that 27.9% demonstrated APHE on CEUS, all subsequently confirmed HCC. A study by Bolondi et al. [25] showed that CEUS offers a higher sensitivity for the detection of APHE in HCC compared to CT (88% vs. 77%, respectively). Maruyama et al. [26] found that CEUS identified APHE in seven out of 27 indeterminate hepatic nodules not showing APHE on CT, all of which were later confirmed as HCC. Takahashi et al. [27] also reported higher sensitivity of APHE for well-defined HCC on CEUS (59.3%) versus MRI (46.3%). Quaia et al. [28] whose study compared the sensitivity of CT alone versus CT combined with CEUS for HCC detection, demonstrated a significant improvement from 71%-74% to 97%, respectively.

Fig. 3.

Recurrent hepatocellular carcinoma (HCC) in a 49-year-old man with a history of right hepatectomy for HCC.

A. Arterial-phase contrast-enhanced computed tomography (CT) scan shows a slightly hypoenhancing mass (arrow) in the caudate lobe of the liver. B. The mass is hypoenhancing (arrow) in the delayed phase. The mass corresponds to LR-4 on CT. C, D. On contrast-enhanced ultrasound, the mass (arrows) is hyperenhancing in the arterial phase (C) followed by washout at 82 seconds (D), confirming the diagnosis of recurrent HCC (LR-5).

Washout Patterns

Washout refers to the echo intensity of contrast agent within a lesion becomes lower compared to the surrounding liver parenchyma, making it appear darker (hypoechoic). This is another major feature for HCC in both CEUS and CT/MR LI-RADS and mostly concordant across the modalities in HCC. However, its assessment significantly differs between CEUS and CT/MRI in non-HCC malignancy, and the reasons are twofold [18].

Firstly, the discrepancy in washout arises from the difference in properties of contrast agents [6,16,29]: Contrast agents in US remain intravascular, therefore nearly all malignant tumors consistently exhibit washout on CEUS, except for some cases of well-differentiated HCC. On the other hand, CT and MRI contrast agents can permeate through the vascular endothelium into the interstitial space, which may result in persistent/progressive enhancement, especially in non-HCC malignancies with high vascular permeability and large volume of interstitial space (Fig. 4).

Fig. 4.

Intrahepatic cholangiocarcinoma in a 58-year-old woman with liver cirrhosis secondary to primary sclerosing cholangitis.

A. T2-weighted magnetic resonance image shows a subtle slight hyperintense mass (arrows) in the left lobe of the liver. B. The mass (arrows) is slightly hypoenhancing on the arterial-phase contrast-enhanced T1-weighted image. C. The mass (arrows) shows mild hyperenhancement in the delayed phase. D, E. On contrast-enhanced ultrasound, the mass (arrows) is mildly hyperenhancing in the arterial phase (D) followed by early and marked washout (arrows) at 55 seconds (E). Contrast-enhanced ultrasound–guided biopsy revealed cholangiocarcinoma.

Secondly, as a real-time imaging modality with high sensitivity to detect vascularity, CEUS mostly depicts even brief or weak arterial hypervascularity of non-HCC malignancy including those categorized as "hypovascular" on CT and MRI. On CEUS, not the mere presence or absence of washout, but determining the timing (early or late) and degree (mild versus marked) of washout is essential for distinguishing between HCC and non-HCC malignancies, thereby defining CEUS LR-M category. In LI-RADS CEUS, washout starting before 60 seconds post-injection is defined as "early" as opposed to "late", and the distinction between "marked" and "mild" washout is based on how pronounced the intralesional decrease of enhancement is; In marked washout the lesion becomes virtually devoid of contrast before 2 minutes after injection, while in mild washout there is some degree of persistent contrast enhancement at least for 2 minutes [7,30-36].

It is worth highlighting that CEUS can also significantly enhance the visualization of small, subtle or isoechoic lesions, difficult to detect on conventional ultrasound. Hepatic malignancies almost always show washout in the late phase on CEUS, which can be targeted for percutaneous real-time CEUS-guided biopsy (Fig. 5). Therefore, CEUS-guided biopsy can be an excellent tool for sampling these small isoechoic lesions [21].

Fig. 5.

Small hepatic metastasis in a 44-year-old man with newly diagnosed pancreatic ductal adenocarcinoma.

A-C. On contrast-enhanced T1-weighted magnetic resonance images in the arterial (A), portal venous (B), and delayed (C) phases, there is a 5-mm hypoenhancing nodule (arrow in B) only visualized in the portal venous phase. D. The nodule (arrow) shows washout at 74 seconds on contrast-enhanced ultrasound. E. Percutaneous contrast-enhanced ultrasound–guided biopsy was performed targeting the washout lesion (arrow). Pathology revealed metastatic adenocarcinoma. Surgery was subsequently aborted.

It is important to keep in mind that hemangiomas may show slight washout in the late phase of CEUS (typically longer than 3 minutes after contrast injection) due to the uptake of microbubble contrast agents by RES in the normal liver parenchyma (Fig. 6), while washout is rare in hemangiomas on CT and MRI. Mild washout of hemangiomas on CEUS appears in the late phase because hemangiomas do not have RES activity [11]. In these cases, it is critical to assess characteristic arterial phase enhancement pattern for diagnosing hemangiomas.

Fig. 6.

Hemangioma in a 36-year-old man with hepatitis B.

A. Contrast-enhanced ultrasound in the arterial phase demonstrates a liver nodule (arrows) with discontinuous, peripheral, nodular arterial phase hyperenhancement. B. The nodule (arrows) shows homogeneous hyperenhancement at 120 seconds. C. The nodule (arrows) demonstrates slight washout at 300 seconds. D. It is noted that the spleen (S) shows homogeneous hyperenhancement whereas the left kidney (K) shows almost no enhancement at 350 seconds, reflecting reticuloendothelial system activity.

LI-RADS M Category

The differentiation between mass-forming intrahepatic cholangiocarcinoma (ICC) and HCC holds significant clinical implications as treatment strategies greatly diverge [31-33]. LR-M category refers to a definite or probable malignancy, not specific for HCC, and its criteria are different according to the imaging modality. CEUS LR-M criteria include rim-APHE, early- (before 60 seconds), or marked washout (visible within the first 2 minutes after the injection). In CT/MRI LR-M, there are various features to consider including targetoid morphology, infiltrative appearance, the presence of necrosis or severe ischemia, and marked diffusion restriction (Table 1). When LR-M category is assigned, histologic diagnosis is always recommended [4,7,9].

Table 1.

Comparison of LI-RADS M category descriptors for CEUS and CT/MRI

On CEUS, late and mild washout is typically observed in HCC, while early and marked washout is more indicative of non-HCC malignancies such as metastases, ICC, or combined HCC-ICC [1,7,34]. In contrast, the washout pattern on CT/MRI can be altered by the high vascular permeability in some lesions with fibrosis and desmoplastic reaction such as ICC, where contrast agents tend to accumulate within the extracellular interstitial space, often resulting in progressive enhancement during the delayed phase rather than washout (Fig. 7).

Fig. 7.

Combined hepatocellular carcinoma/cholangiocarcinoma in a 42-year-old man with hepatitis B.

A. Arterial-phase contrast-enhanced T1-weighted magnetic resonance image shows a nodule (arrow) with rim (targetoid) arterial phase hyperenhancement in the left lobe of the liver. B. The nodule (arrow) persistently shows rim hyperenhancement in the delayed phase. C. On contrast-enhanced ultrasound, the nodule (arrow) demonstrates subtle rim hyperenhancement in the arterial phase. D. The nodule (arrow) shows early and marked washout at 50 seconds, LR-M imaging features. Contrast-enhanced ultrasound–guided biopsy revealed combined hepatocellular carcinoma/cholangiocarcinoma.

Li et al. [35] demonstrated that using a washout time cut-off of less than 43 seconds on CEUS for lesions smaller than 5 cm, achieved a sensitivity of 64% and specificity of 97% for diagnosing ICC, among 273 ICC and 546 HCC lesions. However, Han et al. [36] showcased an improved sensitivity of 100% with 85% specificity by applying current LR-M with cut-off washout time of less than 60 seconds in their study including 56 ICC and 184 HCC lesions. Later, Terzi et al. [37] validated these findings in a significantly larger study including 1,006 hepatic nodules, including 40 ICC lesions; They observed that 31 of 40 ICC lesions were classified as LR-M, with none classified as LR-5, indicating the robustness of current CEUS LR-M criteria aiming for high sensitivity and positive predictive value for non-HCC malignancy. On the other hand, it is worth noting that in 48% of the cases classified as LR-M the final diagnosis was HCC.

Final Considerations

CEUS is a valuable imaging modality for patients with contraindications to CT or MRI, such as allergies to iodinated or gadolinium-based contrast agents, renal dysfunction, or conditions like claustrophobia or immobility. CEUS is a safer option because it does not utilize ionizing radiation. Additionally, CEUS can be performed without the need for sedation or screening for metallic objects, which is required for MRI, thus offering a practical solution for patients who cannot undergo CT or MRI (Fig. 8) [14,20].

Fig. 8.

Focal hepatic infarct in a 78-year-old man with alcoholic liver cirrhosis and acute renal failure.

A. Unenhanced computed tomography scan shows a hypoattenuating mass (arrows) in the subcapsular portion of the right lobe of the liver. Intravenous contrast agent could not be used due to renal failure. B. The mass (arrows) is completely nonenhancing on contrast-enhanced ultrasound at 65 seconds. The mass did not demonstrate any enhancement in all phases of contrast-enhanced ultrasound (not shown), confirming the diagnosis of focal hepatic infarct.