Contrast-enhanced ultrasound of focal liver masses

Ultrasound contrast agents: what are they and how do they work?

Ultrasound contrast agents are comprised of tiny encapsulated bubbles of a perfluoropropane gas within a variable, usually lipid, shell. They are on the same order of size as a red blood cell, and their distribution in the circulation is sparse. They are purely intravascular as their size does not allow them to pass into the interstitial tissues. After their venous injection, they are quickly exhaled by the lungs. They are very safe in clinical practise for adults and for children, they have no nephrotoxicity, and their imaging requires no ionizing radiation^[5-7].

Specialized imaging techniques

The successful imaging of microbubble contrast agents is facilitated by their oscillation when they are viewed in a low-power US field. To detect the signal from the oscillating microbubbles in the circulation, CEUS is performed with contrast specific software^[8]. This generally includes pulse inversion imaging, whereby two pulses are sent down each scan line with subtraction of the returning echoes^[9]. The background tissue, a linear reflector, sends back a wave which is a reflection of the insonating wave. Their subtraction, therefore, equals zero, totally removing the background signal. The result is a relatively black image at the beginning of an imaging sequence for CEUS. The returning echoes from the oscillating microbubble contrast agents, by comparison, will produce additive signals so that there is great augmentation of the Doppler signal from blood. The result of these sequences is the creation of an incredibly sensitive microbubble only image, with removal of the signals from the background tissues. The intensity of the signal on the image occurs in direct proportion to the volume of microbubbles within the region of view. Today, all high-end US systems offer a contrast specific software package with low mechanical index (MI) imaging and also a bubble tracking technique. This bubble tracking may involve a transient brief high MI insonation which destroys bubbles within the field of view, following which the refilling of the vessels may be tracked, improving their visualization.

Contrast-enhanced imaging diagnosis of all liver masses on all modalities focuses on their enhancement following contrast injection. Although CEUS follows the very same principles as CT and MR scan for diagnoses, with similar result, CEUS shows, in addition, unique capabilities that give it a special place for this application^[10].

Unique capabilities of CEUS

Importance of the clinical scenario

Additionally, for all contrast-enhanced liver imaging, interpretations must be made with knowledge of demographic and clinical information. Age and sex are helpful as are relevant health events with the greatest importance given to a history of cancer and also risk factors for development of HCC. The clinical indication for a scan, whether it be for surveillance for metastatic tumor or HCC or related to symptoms may also be directive. The algorithmic interpretation of CEUS should always be guided by what is a reasonable answer for the patient under study.

Principle 1. The intensity in a CEUS image reflects the number of microbubbles in the field of view

As these are exclusively in blood vessels, echo-enhancement is therefore indicative of the volume of blood and its change with time indicative of the rate of perfusion in the region of interest. All interpretations compare nodule enhancement levels with the adjacent and enhancing liver parenchyma.

Principle 2. Determination of malignancy: importance of washout

Most malignant masses are identified by washout of the mass in the portal venous or late phase^[14,15]. Washout refers to the decline in the enhancement of a mass relative to that of the adjacent liver parenchyma, following initial AP enhancement. Therefore, if washout is present, malignancy should be considered likely [Figures 1 and 2]. Conversely, if washout is not present and if the mass shows sustained enhancement, there is a high likelihood that it is benign^[16]. These rules are guidelines and there are, of course, exceptions. These exceptions to this important rule are very important, since occasionally, benign tumors, focal nodular hyperplasia (FNH), hemangioma, and most often adenoma, may show washout, and some malignant tumors, especially precursor nodules for HCC and well-differentiated HCC, may show no washout. Nonetheless, the fundamental rule is invaluable.

Figure 1. Hepatocellular carcinoma (HCC). 64-year-old male with a history of cirrhosis related to alcohol and fatty liver. Mass found on regular US surveillance. A greyscale image shows a small hypoechoic liver nodule in a very heterogeneous liver (A); at the peak of arterial phase (AP) enhancement, 20 s, the mass is brightly enhanced (B); at one minute, there is isoenhancement. The nodule is now invisible but marked by the arrow (C); there is late and weak washout at 3 min. Weak washout shows less enhancement than the immediately adjacent liver parenchyma but retains bubble signals within the nodule as here. AP hyperenhancement and late weak washout comprise the diagnostic features of HCC (D)

Figure 2. Metastasis. 70-year-old female with abdominal ultrasound performed for right upper quadrant pain, query gallstones. Greyscale ultrasound shows a focal hypoechoic mass in the right lobe of the liver (A); at 20 s, the mass is hypoenhanced, appearing very slightly less bright than the liver (B); at 30 s, there is already washout of the mass, so that it is now much less enhanced than the adjacent liver. It is also less enhanced than it was at 20 s (C); at 2 min, the mass appears as a black hole due to marked washout. This rapid transition from enhancement to washout is typical of metastatic disease. Biopsy showed adenocarcinoma, of unknown origin (D)

Principle 3. Differentiation of malignancy: importance of timing and intensity of washout

Although CT and MR scan also determine the presence of washout, CEUS additionally evaluates the intensity and timing of washout, further differentiating hepatocellular from nonhepatocellular malignancy^[17]. HCC tends to show late (later than 1 min) and weak washout (so that some bubbles remain in the washout zone) [Figure 1, Video 1], whereas all nonhepatocellular malignancies, including intrahepatic cholangiocarcinoma (ICC), lymphoma and metastasis are characterized by rapid (earlier than 1 min) and marked washout, so that all bubbles are absent from the nodule, making it appear as a black, punched out hole [Figure 2, Video 2]^[18,19]. This rapid washout may even occur so early as to be within the traditionally defined AP, prior to 30 s.

Principle 4. Detection of malignancy

A natural consequence of the two previous principles is that the portal venous phase is the optimal time to detect metastases, when their conspicuity will be increased relative to the enhanced background parenchyma^[20]. This increased conspicuity makes sweeping of the entire liver at this time the ideal technique and timing for improved detection of metastatic liver masses on CEUS. Although CEUS is not generally involved in the protocolled search for metastases which are developed for follow-up of common tumors of the colon, lung and breast, in particular, it has been shown that CEUS is comparable to CT scan in tumor detection and exceeds CT in some instances^[21]. Additionally, CEUS plays an important role in the oncology patient, resolving many indeterminate CT and MR scans and generally problem-solving in this population. In our department, CEUS is invaluable to resolve the low-attenuation small indeterminate masses shown regularly on portal venous phase CT scans, easily differentiating small cysts from solid tumors with CEUS features of metastatic disease^[22].

Principle 5. Diagnosis of benign tumors

Benign tumors commonly encountered on CEUS examinations include hemangioma, focal nodular hyperplasia and, much less often, hepatic adenoma. It is recognized that CEUS has a unique capability for their diagnosis in that all may demonstrate highly suggestive enhancement patterns in the AP^[23]. Optimally shown by the real-time dynamic scanning afforded by CEUS. Recognizing the significance of washout as an indicator of malignancy, it follows that sustained enhancement, such that the lesion will remain as enhanced as the adjacent liver to 4 or even 5 min following injection, is highly associated with benign outcome. Hemangiomas are characterized by peripheral nodular enhancement with centripetal progression of this enhancement over time [Figure 3, Video 3]. If these enhancement patterns are rapidly changing, they may not be appreciated on CT and MR scans, both of which obtain snapshots in time. This is especially important for the recognition of rapid, or “flash”, filling hemangiomas on CEUS which may show only as a zone of APHE on CT/MRI scan.

Figure 3. Hemangioma. 39-year-old asymptomatic female with an incidentally discovered liver mass during an US examination for unrelated reasons. A greyscale image shows a focal slightly hypoechoic mass with a thin echogenic rim. It is suggestive of an atypical hemangioma (A); an early AP image, at 35 s, shows a rim of peripheral enhancement with tiny peripheral puddles (B); there is centripetal progression by 45 s with no linear vascularity (C); by 1 min, there is further centripetal progression with eccentric growth of the peripheral puddles of enhancement (D); by 2 min, there is virtually complete fill in with non-uniform enhancement (E); there is sustained enhancement to 4 min. Peripheral nodular enhancement with sustained enhancement is the classic description of an insignificant hemangioma. Hemangiomas may fill very rapidly, within seconds, or very slowly as here, over several minutes (F)

FNH is a highly vascular tumor and is characterized by stellate vessel morphology with filling of the lesion from its center to the periphery^[24] [Figure 4, Video 4].

Figure 4. Focal nodular hyperplasia. 25-year-old woman with an incidentally discovered liver mass found during ultrasound performed for examination of her bowel. An incidentally discovered superficial focal hypoechoic liver mass (A); an early arterial phase (AP) image shows a stellate pattern of linear vessels in the center of the mass (B); at the peak of AP enhancement, the mass is brightly and uniformly enhanced (C); at 3 min, the mass continues to show sustained enhancement greater than the adjacent liver (D)

Hepatic adenoma, a fairly rare liver tumor, is an exception to these general rules and may show diffuse enhancement or a more specific filling from the periphery to the center of the lesion [Figure 5, Video 5]. Additionally, adenoma is shown to have the possibility for washout, occurring in up to 50% of cases^[25].

Figure 5. Adenoma. 34-year-old woman with a long continuous history of oral contraceptive use. a greyscale image shows a superficial focal hypoechoic mass (arrows) in a fatty liver (A); an early arterial phase (AP) image at 12 s shows peripheral irregular vessels (B); at the peak of AP enhancement, 20 s, the mass is uniformly hyperenhanced (C); at 3 min, the mass shows sustained enhancement such that it is still slightly brighter than the adjacent enhanced liver parenchyma (D)

The above described benign tumors, FNH and adenoma, are most often detected incidentally, often on imaging performed for a totally unrelated reason. Adenoma has the additional association of long history of use of oral contraceptives. Both of these tumors have a propensity to occur in asymptomatic young females, and CEUS ranks with MRI performed with a liver specific agent with a dual elimination pathway for accurate differentiation of the two.

Principle 6. Precise diagnosis of malignant tumors

Unlike benign lesions, malignant tumors are not generally characterized as reliably by their AP enhancement pattern, which may be highly variable, but instead by the identification of washout in the portal venous and late phases^[26]. Nonetheless, HCC most often shows a globular pattern of APHE [Figure 1, Video 1]. Nonhepatocellular malignancies may show a similar pattern but also frequently show highly suggestive rim enhancement in the AP^[27].

Principle 7. Discordance of imaging between CEUS and CT/MRI scan

Discordance of imaging between CEUS and CT/MRI scan in the portal venous phase is often related to differences in the mechanism of action of the contrast agents for each modality^[11]. Microbubble contrast agents for ultrasound are purely intravascular agents and they do not have any interstitial phase. This is unlike contrast agents for CT and MR scanning where there is a well-recognized interstitial phase, especially evident in malignant tumors with permeable vascular endothelium and a fibrous stroma, such as ICC. Here, the contrast agent leaks into the interstitium, creating a type of pseudoenhancement in the late phase. Thereby, CEUS will show APHE and rapid washout for ICC whereas CT and MR scan may show instead sustained enhancement. This sustained enhancement is in fact pseudoenhancement related to the presence of interstitial contrast agent. This produces a valuable discordance with MR scan of these tumors where washout is appropriately recognized in association with malignant tumors on CEUS only^[28]. In our own unpublished data, this is most important for diagnosis of cholangiocarcinoma in any liver, either cirrhotic or normal.