Contrast-Enhanced Ultrasound in Focal Liver Lesions

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Introduction

Contrast-enhanced ultrasound (CEUS) is now gaining popularity as a key a tool for demonstration and detection of focal liver lesions. It has replaced the normal medical ultrasound as an imaging technique. A normal medical ultrasound as an imaging technique has generally been the gold standard diagnostic imaging technique for the liver across the world.

Its pros lie in its affordability and availability. However, one of its major pitfalls is its reliability in demonstrating focal lesions despite the advent of Doppler. This has often been a major challenge because of the grey scale appearances of the sonograms causing blurring patterns. Small lesions with diameters >1cm and iso-echoic lesions too pose great difficulty in this diagnostic modality.

The sensitivity is poor with a false-negative rate of > 50 % (Wernecke et al 1991, p. 731). In addition, inaccessibility to the eighth of the liver is a major setback in detecting lesions in the segment.

With the advent of Doppler ultrasound, more insight in the diagnosis of liver lesions has been added by the use of the arterial patterns whose abnormality may be characteristic of certain pathology e.g. the spoke wheel pattern observed in focal nodular hyperplasia.

Contrast enhanced ultrasound involves intravenous injection of contrast media (microbubbles) prior to the ultrasound procedure. The microbubbles remain in the systemic circulation for a given duration of time during which ultrasonic waves are directed to the anatomic site of organ pathology. An echo is then reflected by the microbubbles which are then converted into contrast-enhanced image by the ultrasound system.

The operator needs to familiarize himself with the ultrasound equipment and its ‘contrast’ settings, which is dependant on the type of machine. The contrast agent is prepared according to instructions provided. 20 ml of normal saline should be given following the administration of the contrast. An intravenous cannula is placed away from the side of ultrasound examination.

A stop-watch in the machine is used for accurate interpretation of the phase of imaging (Arterial, venous and late phases). Scanning is then done for a period of at least 5 minutes. The examination may be video recorded for later review. Still images are also taken at points to help highlight the pathology.

Some focal lesions in the liver not demonstrable on ultrasound may not be suitable for demonstration with contrast agents. Small lesions <1 cm, may be difficult to characterize especially when deep within parenchyma, generally.However, liver metastases, even those < 0.5 cm, are normally demonstrated using slow infusions through the liver in the later portal-venous phase or the late phase.

The characterization of focal liver lesions forms a key element in the majority of radiological practices. Although the normal medical ultrasound imaging is useful for the identification of focal liver lesions, accurate demonstration and characterization of a lesion is often difficult even with the use of colour Doppler (Nino-Murcia et al., 1992, p. 1195).

Microbubble contrast enhanced ultrasound (CEUS) has proven diagnostic accuracy in focal liver lesions (Bleuzen et al., 2006, p. 40). It can also be used to augment other imaging modalities like plain abdominal X-ray, contrast enhanced ultrasound guided percutaneous biopsy and B-mode ultrasound. It does not use ionizing radiation and is non-invasive unlike angiography or biopsy. It is well tolerated, affordable and relatively time efficient.

Table 1: The quoted sensitivity and specificity for the detection and demonstration of some common liver lesions using microbubble contrast (Source: Berry & Sidhu 2004, p. 96).

The contrast agents used consist of gas-containing microbubbles in a shell. The shell is made of a carbohydrate or protein (albumin) and measures around 10 mm in diameter. Once injected, the microbubbles greatly increase the back scatter because of their resonant frequency which falls within the range of the medical ultrasound (Harvey et al., 2001, p. 675).

This literature review looks at the applications of contrast-enhanced ultrasound in the demonstration and characterization of focal liver lesions. Benign, malignant and traumatic focal lesions of the liver have been cited with specific characteristics that define their pathology in the contrast enhanced ultrasound.

It also describes the use of contrast enhanced ultrasound guided percutaneous biopsy that has improved the precision and accuracy in the histological diagnosis of focal liver lesions. In addition, the review points out the major gains made by the advent of CEUS, its demerits and their possible solutions.

Contrast‐Enhanced Ultrasound of Benign Focal Lesions

Focal liver benign lesions that can be detected by Contrast Enhanced Ultrasound include Hepatic cysts which occur in up to 18% of patients in a study by Bleuzen and Tranquart (2004). They are frequently due to a developmental anomaly of the bile ducts.

They pose little clinical significance and appear as well defined hypo-reflective regions on ultrasound. Differential diagnosis of such a lesion would be a small haemangioma. The use of contrast reveals hypo-enhancing throughout all phases in a simple cyst unlike what is seen in a haemangioma. All the Arterial, Venous and Late phases show iso-enhancing on CEUS.

Focal fatty infiltrations may occur primarily or may be secondary to Budd–Chiari syndrome, portal vein thrombosis or Porto-arterial shunts. They are demonstrated as focal areas of reduced reflectivity or discrete areas of hyper-reflectivity on ultrasound.

This could appear like malignant liver lesion. They however have a geometric pattern of appearance, normal vascularity and proximity to the portal vein. CEUS shows such lesions to be iso-enhancing with the surrounding parenchyma. All the phases (Arterial, Venous and Late phases) show iso-enhancing.

Haemangiomas are second to benign cysts as the most common benign liver neoplasm. They occur in up to 20% in an autopsy series described by Karhunen (1986). It appears on histology as vascular spaces and endothelial lines. On Contrast Enhanced Ultrasound, the Arterial phase shows peripheral hyper-enhancement and central non-enhancement.

The Venous phase has complete or increased peripheral hyper-enhancement depending on the size of lesion. The Late phase is iso-enhancing. Haemangiomas appear as homogeneous hyper-reflective lesions with well-defined borders on B-mode imaging.

It may occasionally show central heterogeneity. The early Arterial phase imaging shows a progressive peripheral nodular hyper enhancement pattern similar to that seen with contrast CT or MRI imaging. This is however in real time unlike in CT and MRI imaging.

Regenerative nodules occur equally in men and women. Histology shows normal appearing hepatocytes and Kupffer cells within the nodules. The nodules range in size with some too small to be detected with radiological techniques and others with diameters >10 cm. Contrast enhanced ultrasound reveals regenerative nodules as hypo- or isoreflective lesions.

They may have occasional hypo-reflective centres due to haemorrhage. Differential diagnoses for such lesions are hepatocellular carcinoma and metastasis from other sites (Dietrich et al., 2006, p. 1699). The arterial phase is hyper-enhancing whereas the venous phase and late phase are iso-enhancing.

Liver Abscesses are also among the frequent focal lesions on the liver. Individual liver abscesses differ in their appearances on B-mode ultrasound appearance. In contrast enhanced ultrasound, the arterial phase shows a hyper-enhancing rim with a low reflecting area centrally. The venous phase demonstrates hyper- or iso-enhancing rim that is also low reflective centrally.

The late phase shows an iso-reflective rim to surrounding parenchyma with a low reflective central area. Their appearance also changes with time as the contents mature. Solid contents have increased reflectivity and may be confused with a wide range of focal liver lesions.

Contrast enhanced ultrasound demonstrates peripheral rim enhancement and vascularity within septae whenever present. In the vicinity of the abscess, parenchymal hypo-perfusion is demonstrated in the venous phase (Catalano et al., 2004 p. 447).

Hepatocellular adenoma is much less common in men than women (ratio 9: 1). The risk factors to its occurrence include anabolic steroid and oral contraceptive use. Histology shows normal hepatocytes, bile duct elements and connective tissue. It is however devoid of portal vessels. Contrast Enhanced Ultrasound imaging reveals well-defined iso- or hyper-reflective single or multiple lesions with a capsule.

The arterial phase is hyper-enhancing whereas the venous and late phases are iso-enhancing. The main differential diagnosis is focal nodular hyperplasia (FNH). Differentiating between the two has been shown with the use of Contrast enhanced ultrasound (Dietrich et al., 2005, p. 705). Arterial phase imaging shows hyper enhancement of the capsule and central component.

Areas of necrosis or haemorrhage may show hypo-enhancement centrally. The same pattern persists in the venous phase. These differ from focal nodular hyperplasia, which appears hyper-enhanced through to the early venous phase with a central feeding artery, and lack a capsule.

Focal nodular hyperplasia (FNH) has a less aggressive course than hepatocellular adenoma, which may complicate with haemorrhage. Histology shows nodules of hepatocytes and Kupffer cells separated by fibrous tissue with vessels and bile ducts radiating from a central scar. In CEUS, the arterial and venous phases have rapid hyper-enhancement whereas the late phase could be hyper or iso-enhancing.

FNH lacks a capsule, commonly isolated and difficult to distinguish from the normal surrounding liver parenchyma on B-mode imaging. Highly vascular FNH is demonstrable on colour Doppler imaging. Quantitative analysis of contrast-enhanced images has shown a feeding artery that is a useful indicator when differentiating focal nodular hyperplasia from other hypervascular lesions (Huang-Wei et al., 2006, p. 363).

Contrast‐Enhanced Ultrasound of Malignant Lesions

In a prospective study to investigate the ability of contrast-enhanced sonography (CEUS) to differentiate between benign and malignant focal liver lesions, 317 patients (204 males, 113 females, aged 12- 59 years) with focal liver lesions detected by B-mode grey-scale sonography were identified. After intravenous injection of contrast, the liver was examined by CEUS.

The final diagnosis was then established by histopathology, CT, MRI, or HIDA-scintigraphy. Results showed that the CEUS diagnosis had a sensitivity of 90%, a specificity of 99%, and an accuracy of 89% in the diagnosis of malignant liver lesions. It was therefore concluded that CEUS is helpful in the differentiation between benign and malignant focal liver lesions (VonHerbay, et al., 2010, p. 1).

Liver metastases are the most common liver malignancies. According to Wernecke (1991) up to 25-50% of patients with a non-haematological malignancy have liver metastases.

The sensitivity of normal ultrasound for liver metastases is relatively low (53%–77%)) which is inferior to other imaging techniques like computer tomography (CT) and magnetic resonance (MR) imaging ( Dietrich et al., 2006, p. 1699). Early detection of liver metastases is paramount for establishing management plan that determines the prognosis. This is made possible by the use of CUES.

Hypo-vascular metastases are from primary tumours the Gastrointestinal tract, pancreas and lung. The lesions are hypo-reflective on CEUS with internal heterogeneity whenever they have foci of calcification. CEUS has been shown to improve the demonstration of these lesions (Albrecht et al., 2004 p. 25).

As a result, some suggest that CEUS should be a routine assessment in patients with suspected hepatic metastases. CEUS demonstrates arterial phase peripheral rim hyper-enhancement with central hypo-enhancement. The arterial phase shows rim enhancement or iso-enhancement with possible non-enhancing in areas of necrosis. The venous and late phases demonstrate hypo-enhancement.

Hyper-vascular metastases include metastasis from melanoma, neuro-endocrine, tumours, breast carcinoma and renal cell carcinoma. On CEUS, the arterial phase shows hyper-enhancing. The venous phase has hypo-enhancing whereas the late phase may be hypo enhancing or non-enhancing.

Vascularity is best appreciated in the arterial phase where it shows hyper-enhancement of the lesion with focal areas of necrosis that appear as areas of hypo-enhancement (Albrecht et al., 2004, p. 25).

Hepatocellular carcinoma (HCC) is associated with hepatitis C with its incidence rising across the world. Early detection is the key to its management that include resection or liver transplantation. According to Patel (2005) an attempt to use of CEUS as part of HCC screening programmes has been problematic. The arterial phase shows hyper-enhancing with focal areas of non-enhancement in necrotic areas.

The venous phase has iso-enhancing or slight-enhancement whereas the late phase is hypo-enhancing. Small lesions appear as well-defined hypo-reflective lesions while larger lesions may be either hypo- or hyper-reflective. There has been difficulty in differentiating HCC from the surrounding liver parenchyma and regenerative nodules within an attenuating cirrhotic liver (Berry et al., 2004, p.96).

CEUS assists by showing intense arterial enhancement in up to 90% of the cases (Nicolau et al., 2004, p. 63). Subsequent phases of imaging demonstrate iso- or hypo-enhancing with the surrounding parenchyma. According to Nicolau (2004) the degree of cellular differentiation of the tumour is related to the variability in the later phases of imaging with the iso-enhancing lesions being more highly differentiated.

Cholangiocarcinoma may either be intra- or extra-hepatic. Majority arise at the bifurcation of the hepatic ducts. In CEUS, the arterial phase shows rim enhancement or non-enhancement. The venous and late phases are non-enhancing. The tumour secondary effects which include intra-hepatic bile duct dilatation and enlarged regional lymph nodes are appreciated. Identification is often challenging.

This is a factor in its low survival rate which is 5% at 5 years. Available data suggests that up to 44.4% of peripheral cholangiocarcinomas show rim hyper-enhancement in the arterial phase and demonstrate hypo-enhancement in subsequent phases (Xu et al., 2006, p. 23).

Hepatic lymphoma is of two causes: primary and secondary. Secondary lymphomas are more common occurring in up to 50% of patients with systemic lymphoma. They can also be diffuse infiltrating masses, single or multiple masses. The imaging findings are often non-contributory in the diffuse infiltrating type.

The arterial phase shows both iso-enhancement and hypo-enhancement whereas the venous phase and the late phase demonstrate hypo-enhancement. Multiple and focal lymphoma nodules are hypo-reflective on B-mode imaging. There is a great improvement in the appearance of these lesions in CEUS in the venous and late phases.

Contrast‐Enhanced Ultrasound of Traumatic Lesions

The usefulness of CEUS in trauma management has been proven recently in several studies. CEUS has proved useful in detecting and demonstration of different kinds of solid organ injuries including the liver. Several studies show that it is superior to the normal ultrasound in liver trauma cases because parenchymal lacerations, hematomas and infractions have no enhancement because of lack blood supply.

On CEUS, they appear as dark areas with no echogenicity. Active hemorrhage can be also be visualized by CEUS. This is vital to ensure hemodynamic stability is achieved by identifying and arresting the site in unstable patients. The accuracy of CEUS in trauma has sensitivities ranging from 69%‐100% and specificities ranging from 84%‐100% (Miele, et al., 2004).

According to trauma guidelines, the ideal patients in the trauma are patients with isolated parenchymal trauma, those not able to undergo CT for injury evaluation for several reasons and those in follow‐up after trauma.

Contrast Enhanced Ultrasound Guided Percutaneous Biopsy

In this case, CEUS is being used as an augmentative investigation to achieve more accuracy and precision in percutaneous biopsy of focal liver lesions. Tumour histology may at times be necessary in patients suffering from advanced focal liver lesions. This is also a necessary procedure before initiating proper treatment like chemotherapy.

In such scenario, histological data is the basis of the diagnosis and is obtained through percutaneous needle biopsy. With contrast enhanced ultrasound guidance, the accuracy of diagnosis of these lesions has been increased.

In a study published in 2006 it was shown that when using CEUS the diagnostic accuracy of percutaneous biopsy in the diagnosis of benign and malignant liver tumours, the diagnostic accuracy increased from 87% to 95.3%. The accuracy was even greater in lesions < 2 cm 97.1% compared to 78.8% (Wu et al., 2006, p. 752).

The potential added value of CEUS as an aid in percutaneous liver biopsy may also be related to:

1. Directing the needle in the tumour-affected areas with precision in cases of patchy involvement.
2. The target lesions could be hardly visible for example, small nodules of Hepatocellular carcinoma on cirrhosis.
3. Avoiding iatrogenic injury to surrounding organs and structures e.g. the hepatic artery and inferior vena cava that may lead to massive haemorrhage.

Merits of Contrast Enhanced Ultrasound

The advent of Contrast-enhanced ultrasound (CEUS) has led to a revolution in the detection of malignant lesions against the enhanced normal liver. It has also enabled the visualization of the circulation in larger vessels, capillary and sinusoids as they are imaged in real-time. This has helped overcome the limitations that earlier disadvantaged the ultrasonography thereby improving the ability to demonstrate focal liver lesions.

The sensitivity and specificity of Contrast-enhanced ultrasound (CEUS) now almost equals that of contrast computed tomography (CT) and magnetic resonance imaging (Catala et al., 2007, p. 1066).

According to a report by David Cosgrove of the Imperial College School of Medicine and Hammersmith Hospital, London in 2007, “CEUS has similar sensitivity to contrast-enhanced CT for liver metastases and for HCC, and the same applies in the differential diagnosis of benign focal lesions.”

The total body water makes the body acoustically homogeneous with respect to the conventional ultrasound waves. The body too has similar echogenicity between blood and surrounding tissues making it difficult to clearly demonstrate and determine the rate and degree of blood flow using the normal medical ultrasound.

CEUS imaging allows real-time evaluation of blood flow thus helping to differentiate between blood and the surrounding tissues.

Ultrasonic molecular imaging does not involve the use of radiation exposure making it safer than modalities like radionuclide imaging and X-rays. It is also not nephrotoxic which has been described in other contrast media.

Other molecular imaging modalities like Magnetic resonance imaging (MRI), Positron emission tomography (PET), and Single photon emission computed tomography (SPECT) are costly. This is relatively cheaper in the case in CEUS when compared to MRI, PET and SPECT. The conventional ultrasound, on the other hand, is very cost-efficient and widely available

CEUS uses a lower intravenous contrast dosage. This is because microbubbles generate strong signals. Only micrograms are needed as compared to milligrams that are needed for other molecular imaging modalities e.g. contrast MRI. This minimizes toxicity as the exposure dose is low.

Demerits of Contrast Enhanced Ultrasound And Their Solutions

Contrast-enhanced ultrasound is considered to be costly and time consuming when compared to the conventional ultrasound. It is however more costly and time consuming in the case of contrast-enhanced MRI.

The costs for attached to the contrast used can be reduced by using a continuous infusion or by using one half of a vial. The software and examination costs associated with ultrasound are 30% to 50% lower than those of MRI. More costs are also incurred in the training of personnel required for their use.

Microbubbles have a short half-life. This is because they are taken up by immune system cells and the liver or spleen even when coated with Polyethylglycol.

Contrast enhanced ultrasound generates more heat as the frequency increases and therefore needs careful monitoring. Microbubbles also burst at high mechanical indices and low ultrasound frequencies. Microvasculature rupture and haemolysis could result from microbubble destruction (Klibanov, 2005). In view of this manufacturers are now developing low mechanical index ultrasound imaging techniques.

CEUS has some limitations that are similar to standard ultrasound. Obese and uncooperative patients present a poor acoustic window that affects the clarity with which organs are discerned. The method is also operator dependent which influences the accuracy of diagnosis.

Conclusion

In the management of suspected focal hepatic lesions, Contrast enhanced ultrasound should be employed as part of the necessary investigations to enhance the accuracy in detection and characterization of focal hepatic lesions. It is more sensitive and specific than the conventional ultrasound in the detection of focal liver lesions (Bleuzen et al., 2006, p. 40).

Despite CEUS examination having almost similar accuracy to contrast CT and MRI, it is a non-radiant method, non-nephrotoxic and less costly. The operator however needs to appreciate standard CEUS appearances and utilise them the best advantage to increase its accuracy.

In cases where histology is mandatory, contrast enhanced ultrasound guide percutaneous biopsy can be used to increase the precision and accuracy in sampling the focal lesions in the liver.

List of References

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Berry, D & Sidhu, S 2004, Microbubble contrast-enhanced ultrasound in liver transplantation, European Radiology Supplements, vol. 14, no. 1, pp.96-103.

Bleuzen, A, Huang, C, Olar, M, Tchuenbou, J & Tranquart, F 2006, Diagnostic accuracy of contrast-enhanced ultrasound in focal lesions of the liver using cadence contrast pulse sequencing, Ultraschall Med, vol.27 no. 1, pp. 40-48.

Bleuzen, A & Tranquart, F 2004, Incidental liver lesions: Diagnostic value of cadence contrast pulse sequencing (CPS) and SonoVue, European Radiology Supplements, vol. 14, no.3, pp.53-62.

Catala, V, Nicolau, C & Vilana, R 2007, Characterization of focal liver lesions: Comparative study of contrast-enhanced ultrasound versus spiral computed tomography, European Journal of Radiology, vol.17, pp.1066-1073.

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Dietrich, F, Kratzer, W & Strobe, D 2006, Assessment of metastatic liver disease in patients with primary extrahepatic tumours by contrast-enhanced sonography versus CT and MRI, World Journal of Gastroenterology, vol.12, no.1, pp.1699-1705.

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Hagspiel, D, Neidl, F & Eichenberger, C 1995, Detection of liver metastases: Comparison of super paramagnetic iron oxide enhanced and unenhanced MR imaging at 1.5 T with dynamic CT, intraoperative US, and percutaneous US, American Journal of Roentgenology, vol. 196, no. 16, pp.47-48.

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Von Herbay, A, Westendorff, J & Gregor, M, 2010, Contrast-enhanced ultrasound with SonoVue: Differentiation between benign and malignant focal liver lesions in 317 patients, Journal of clinical ultrasound, vol. 38, no.1, pp.1-9.

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Wu, W, Chen, H & Yin, S 2006, The role of contrast-enhanced sonography of focal liver lesions before percutaneous biopsy, American Journal of Roentgenology, vol. 187 no.1 pp. 752-776.

Xu, H, Lu, D & Li, J 2006, Imaging of peripheral cholangiocarcinoma with low-mechanical index contrast-enhanced sonography and SonoVue: Initial experience, Journal of clinical ultrasound, vol. 25, no.1, pp. 23-33.

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