Signal Processing

Harnessing the power of fast digital computers to US has resulted in a number of important improvements in imaging and in convenience and reproducibility (3).

Harmonics

The discovery that sound propagates through the tissue in a nonlinear fashion to produce overtones of the transmitted signal (harmonics) has improved contrast resolution and reduced artifacts that result from beam imperfections (4). The principle is simple: tissue is slightly compressed during the positive pressure phase of the ultrasonic wave (and vice versa); sound travels faster in a denser medium and so the compression part of the cycle travels faster so that the wave looses its original symmetry. Such an asymmetric wave contains harmonics, which can be selected from the returning echoes either by applying a frequency filter or by comparing the echoes from a pair of pulses transmitted with opposite phase; the linear signals cancel, leaving the harmonics for image formation. Because these tissue harmonics are more strongly elicited by higher power US, artifacts caused by the side lobes and reverberations are relatively reduced, resulting in a cleaner, less noisy image (Fig. 1). In effect, the imaging beam is generated from within the tissue itself.

Compounding

Compounding is a technique in which two or more images acquired simultaneously from the same tissue are superimposed; this reduces the speckle content, which has a random distribution and gives a smoother, more anatomically correct image (Fig. 2) (5). An obvious way is to collect two images from different angles, a method that was widely used with the original articulated arm static scanners. Using the electronic beam steering of an array transducer, overlapping scans (varying from three to nine frames) from different angles can be acquired in real time with only a modest loss of frame rate. Alternatively, the same effect can be achieved by collecting data at different frequencies and the two methods can be combined. The scans are then averaged to produce real-time compound images.

437865H, JWB

ABDOMEN GENERAL

437865H,JWB

ABDOMEM

GENERAL

Figure 1 Tissue harmonics. The echo-poor region in segment 4 (arrowheads in A) has the appearances of focal fatty sparing but its outlines are more clearly seen when imaged with tissue harmonics (B) using the same settings. Tissue harmonics improves contrast by reducing side lobe and reverberation artifacts. The patient was being staged for breast cancer; the typical benign appearances made further investigation unnecessary.

Map 3 170dBiC 4 Persist Med 2D Opt: Res Fr Rale:High

R T THYROID

MapS 170dB/C 4 Persist Off 2D Opt:FSCT Fr Ra!e:Suru SonoCT™

RT THYROID

Figure 2 Compound scan. Compared with the conventional image of this thyroid cancer (A), the compounded image (B) shows more detail because the information from beams at three different angles has been combined, and also there is more contrast because the speckle noise has been reduced.

Display

Extended Field of View (EFOV)

When US was introduced into clinical practice in the 1970s, the transducer was mounted on an articulated arm and swept to produce extended field of view images but this was sacrificed when real-time US was developed. Advances in computing

Figure 3 Extended field-of-view. In this patient with extensive polycystic liver disease, the liver was too large to fit on a single scan. However, using the extended field of view technique (Sciescape, Siemens, Germany) the entire liver could be measured.

that track the speckle pattern of the images as the transducer is swept across extended anatomical regions now allow high-resolution EFOV images to be created in gray-scale or color Doppler (Fig. 3). Large lesions can be included in a single image and also provides a better display of their anatomical relationships. It is an excellent teaching aid; it allows measurements of large structures to be performed and serves as a useful record for follow-up.

3D Imaging

Until comparatively recently US has lagged behind both CT and MR in three-dimensional (3D) imaging. The 3D US is based on reconstruction algorithms and is therefore dependent on high quality 2D data, which has been limited by speckle, side lobes, clutter, and other artifacts. Recent improvements in imaging (harmonic imaging, nonlinear signal processing, and 2D matrix array transducers) have reduced these problems and paved the way for useful 3D imaging, while fast computing has allowed the production of real-time 3D scans (so-called 4D US imaging) (Voluson® 730, GE-Kretz). A position sensor attached to the transducer or an arrangement whereby the transducer is swept across the volume by a motor provides the necessary positional data. Volumes can be displayed as either series of multipla-nar reformats or rendered 3D images, which improve appreciation of the relative position of structures, including flowing blood. Currently, the main clinical application is in obstetrics but the approach shows promise in breast and prostate cancer, and reveals the complexity of tumor vascularity in an elegant way (Fig. 4) (6). In interventional procedures, 4D US is promising for needle biopsy guidance while 3D US is used to guide radioactive seed implants in the prostate and for breast

Figure 4 Three-dimensional scan with Doppler. In this three-dimensional reconstruction of a breast mass (arrows), the image has been duplicated and opposite halves of the gray scale portion removed from the opposing sides to reveal the arrangement of the blood vessels using power Doppler (shown in red). Corresponding portions of the vasculature are numbered. This form of display allows the vessels to be seen in their relationship to the mass. Source: Photos courtesy of Drs. W.E. Svensson, S. Kyriazi, and K. Humphries. (See color insert.)

biopsy and a stereotactic system has been developed for needle delivery using electromagnetic position sensors (7).

Coded Excitation

One of the limits to the sensitivity of US imaging is the amount of acoustic energy that can be deposited in the tissues. Rather than increasing the transmit power, one way to get around this limitation is to use longer pulses. Generally, longer pulses mean poorer spatial resolution along the beam but this can be overcome if the acoustic pulses are digitally encoded: the received signals are then processed to recover the spatial information. Examples of coding strategies include varying the frequency (e.g., as a chirp of rising frequency) or amplitude (complex shapes that are similar to those used in mobile phone technology to allow a band to carry multiple signals and retain their integrity). Using this approach the sensitivity of the US scanner to weaker echoes can be improved. Therefore, higher frequencies can be used and still separate it from noise to give better spatial resolution down to greater depths.

Automatic Optimization Systems

Automatic Gain Compensation Modes set the correct gain in 2D at any point across the image with a single switch. This is achieved by the processor analyzing the distribution of gray levels in each part of the image and adjusting the level of each pixel to optimize local contrast. This not only improves image quality rapidly but also offers better consistency between operators, thus reducing operator dependence. Automatic optimization systems are also available for color and spectral Doppler where they unwrap aliasing by shifting the baseline and optimizing the pulse repetition frequency (PRF). They can also automatically place the angle correction cursor by "looking at'' the walls of the vessel in which the sample volume has been placed and noting their position. Dhotopic Ultrasound Imaging (Elegra; Siemens, Germany) is a real-time post processing technology, which takes advantage of the eye's perception of light to optimize gray-scale tissue differentiation. X-res (Philips-ATL, U.S.A.) is a postprocessing system that seeks to display the image brightness in an optimal fashion; it derives from MRI display processing and reduces speckles.

Contrast Agents

US, unlike all other imaging modalities, has lacked effective contrast agents until comparatively recently. This was rectified with the introduction of microbubbles in the 1990s; they have revolutionized clinical and research applications in this field and provided the stimulus for the development of harmonic modes to improve conventional imaging as well as microbubble-specific modes that have proved useful for staging and for characterizing tumors among other applications (8,9). They also provide opportunities for unique functional studies (10,11). Their small size and short life in the blood as well as their inert composition has meant that they are very safe with no significant adverse effects; in particular, they are not nephrotoxic and do not cause cardiovascular changes. A large number of agents have been developed and several have been introduced into clinical practice (Table 1).

Principles

The microbubbles used as contrast agents for US are made to be smaller than 7 ^ in diameter so that they can cross capillary beds. When administered intravenously, these agents flood the blood pool and (usually) remain within the vascular compartment. They must survive passage through the cardiopulmonary circulation to produce useful systemic enhancement. An ingenious range of methods has been deployed to achieve the required stability and to provide a clinically useful duration of enhancement. Both the gas contain usually air or a perfluoro gas and the stabilizing shell (denatured albumin, phospholipids, surfactants, or cyanoacrylate) are critical in this respect. The first agent for cardiac use, Albunex, had an albumen shell and contained air. The first generally used agent, Levovist, consists of galactose microcrystals whose surfaces provide nidation sites on which air bubbles form when they are

Table 1 Classification of Ultrasound Microbubbles

Microbubble

Gas

Stabilization

Company

Air-based agents

Agitated saline

Air

None

N/A

Albunexa

Air

Sonicated albumin

Tyco

Echovistb

Air

None

Schering

Levovistb SHU 508A

Air

Palmitic acid

Schering

Quantisona

Air

Dried albumin

Andaris Ltd.

Perfluoro agents

BR14

Perfluorobutane

Phospholipids

Bracco

Echogena QW3600

Dodecafluoropentane

Emulsion, surfactants

Sonus

Definity perflutren

Perfluoropropane

Phospholipids

Bristol-Myers Squibb

Imagent AFO150

Perfluorohexane

Surfactants

Schering

Optison

Perfluoropropane

Albumen

Amersham Health

Perfluorocarbon

Perfluorobutane

Sonicated albumin

University of

Exposed Sonicated

Nebraska

Dextrose Albumin

PESDA

Quanfuxian QFX

Perfluoro

Sonicated albumin

Nanfang Hospital,

Guangzhou, China

SonoVue BR1

Sulfur hexafluoride

Phospholipids

Bracco

Liver trophic agents

Levovist SHU 508A

Air

Palmitic acid

Schering

Sonavista SHU 563A

Air

Cyanoacrylate

Schering

Sonazoida NC100100

Perfluorocarbon

Not published

aNo longer under development or marketed. bLicensed for clinical use.

(Nycomed)

aNo longer under development or marketed. bLicensed for clinical use.

suspended in water; the resulting microbubbles are stabilized by a trace of a surfactant, palmitic acid. An improved version of Albunex, Optison, is filled with perfluoropropane while a family of perfluoro gas containing agents such as SonoVue and Definity use phospholipids as the membrane are becoming important in clinical practice.

Interactions of Microbubbles with US Waves

The interactions of microbubbles with an US beam are complex (12-14). Their gas content makes them much more compressible than soft tissue and so, when exposed to the compression-rarefaction wave of an ultrasonic pulse, they undergo alternate contractions and expansions. Like all oscillating systems, they vibrate most readily at a particular frequency, their resonance frequency. For microbubbles <10 ^m in diameter this turns out to correspond to the frequencies actually used in diagnostic US (2-10 MHz). It is this fortunate coincidence that underpins the extraordinary effectiveness of microbubbles as US contrast agents. When the ultrasound beam used is weak (power <0.1 MPa corresponding to a mechanical index (MI) of around 0.01), these oscillations are symmetrical (i.e., their behavior is "linear") and the frequency of the returned signal is unaltered. However, as the acoustic power is increased (MI, 0.1-1.0), the expansion and contraction phases become unequal because the microbubbles resist compression more strongly than expansion. This "nonlinear" behavior means that the signals they return contain multiples of the insonating frequency. These higher frequency components are known as harmonics as the phenomenon is identical to the overtones produced by a musical instrument. (It is to be noted that microbubble harmonics are produced when the ultrasound is reflected by the microbubbles, not during ultrasound propagation, as is the case with tissue harmonics.) At still higher powers (though within accepted limits for diagnostic imaging), highly nonlinear behavior occurs and the microbubbles are disrupted and disappear from the sound field.

Harmonics may be used to image US contrast agents by tuning the receiver to listen to a band of frequencies centered on a harmonic signal (usually the second harmonic at double the fundamental frequency) so that the harmonics can be separated from the fundamental signals from tissue. However, as noted above, tissues also produce harmonics, especially when higher acoustic powers are used and distinguishing between them is challenging. In practice, in many of the simple contrast modes available, the two are inextricably mixed together.

The goal of separating them completely can be achieved in two ways. In the first approach to be discovered, a high MI beam is used and the microbubbles are deliberately disrupted (15). When using a color Doppler mode, the sudden disappearance of a signal from its previous location (loss of correlation between sequential echoes) is seen as a major Doppler shift and registered as color signals, rather like aliasing. This method works well for the more fragile air-based agents such as Levovist and modified color Doppler software has been developed to optimize the display. This approach, often known a Stimulated Acoustic Emission (SAE), is particularly successful in the late phase of contrast agents that show liver/spleen tropism, which develops a few minutes after injection. Because it highlights the normal liver and spleen, lesions that do not contain functioning tissue, such as malignancies, appear as obvious voids in the color map. This method has the advantage of high sensitivity (it can probably detect a single microbubble being disrupted) and of showing the microbubble signature exclusively in the color layer of the registered image with the conventional gray scale image as an under layer for reference purposes. However, it does destroy the contrast agent rapidly, and this precludes the use of real time, so a sweep-and-review approach has to be adopted.

The alternative approach, and increasingly the mode of choice for contrast studies, relies on the fact that with newer microbubbles (particularly those with phospholipid shells), harmonics can be elicited at much lower acoustic powers than are necessary to generate tissue harmonics (16). Thus, if a very low acoustic power can be used without the image being lost in noise, the microbubble signals (harmonics) can be separated from the tissue signal (fundamental). An important step in the progress to this ideal was the development of phase inversion techniques, which evolved from the need to detect microbubble harmonics but to avoid frequency filtering because the narrow bandwidth that this method requires degrades spatial resolution. In the phase inversion mode (PIM), a pair of pulses is sent sequentially along each scan line, the second being inverted in phase from the first. The returning echoes from the pair are summed so that the linear echoes cancel because they are out of phase, leaving only non linear components, which are used for image formation. Because the transmitted pulses are the same as those used for conventional imaging (except for the phase inversion), spatial resolution is not impaired—in fact, this method is sometimes termed "wideband harmonics.'' PIM gives excellent quality images in both vascular and late phases and, like the high

MI approach, detects the presence of microbubble without relying on their motion. Thus, both these modes can detect contrast in the microcirculation (though, of course, vessels smaller than the resolution limit of ultrasound—some 200 ^ at best—cannot be resolved as discrete structures).

As initially implemented, PIM deployed a relatively high MI and therefore tissue harmonics contaminated the microbubble signal. Special approaches are required to operate PIM at the very low powers needed to avoid tissue harmonics without too much noise in the images. One solution is to send a stream of alternating phase pulses and use color Doppler circuitry to pick out the harmonics; essentially this method (known as Power Pulse Inversion, PPI) exploits the high sensitivity of Doppler to overcome the signal-to-noise limitation. Because the Doppler circuitry is used for the microbubble signature, PPI achieves the twin goals of complete separation of the contrast from the tissue information and of displaying each in a separate image layer (PPI in color, B-mode in gray), which can be viewed separately or as a mix. Another approach to solve the problem also uses a series of pulses, though usually only around three per line. Here, as well as inverting the phase, the amplitude of the pulses is also changed. This method preserves more of the nonlinear content of the received signals and, importantly nonlinear signals at the fundamental frequency, which are discarded in PIM, can be detected. Since these fall within the most sensitive band of the transducers, this can improve the sensitivity of this mode. Implemented as Contrast Pulse Sequences (CPS, Siemens), the harmonics are displayed in a color tint over the B-mode picture and, as with PPI, either one or both can be viewed as required.

In another approach, the direction of flow of the microbubbles (and therefore of blood) in larger vessels is detected with low MI velocity Doppler, while slow moving and stationary microbubbles are shown in green using power Doppler. This combined mode, known as vascular recognition imaging (VRI, Toshiba), also allows the microbubble signature to be displayed separately from or combined with the B-mode and has the advantage of providing additional information on the flow direction in larger vessels.

If the sequence of images obtained using a low MI mode is cumulated over a period of a minute or so after the injection, the tracks of individual microbubbles form lines representing the arrangement of the microvasculature (Fig. 5). This method, microvascular imaging (MVI, Philips) has been applied in the breast where it reveals the neovascularity of malignancies better than unenhanced Doppler. All of these modes operate at very low powers (MI < 0.2 and sometimes as low as 0.02) and as well as not eliciting tissue harmonics, this has the major advantage that bubble destruction is minimized. In practical terms, using a very low MI means that working in real time is possible and this makes contrast studies much easier to perform since no special scanning techniques are required.

Applications in Oncology

The earliest oncological applications of microbubbles used conventional Doppler ultrasound in which the signal enhancement merely served to boost the Doppler signal intensity so that slower flow in smaller vessels could be detected. The limitations of Doppler remained, particularly the fact that bulk tissue movement is faster than blood flow in the microcirculation, precluding its detection. Thus, conventional Doppler with or without microbubble enhancement can only detect vessels down to arteriolar level. Nevertheless, studies in cancer of the breast, liver, and prostate showed that the neovascularization of malignancies was better detected after enhancement and that

Map 3 liOdB/C 4 Persist Med 2D Opt:Res CPA 85% Map 1 WF Max PRF500 Hz Flow Opi: Res

Map 3 liOdB/C 4 Persist Med 2D Opt:Res CPA 85% Map 1 WF Max PRF500 Hz Flow Opi: Res

Fr RaferMed " :

Map 3

170dB/C 1 l0

Fr RaferMed " :

-1 MO SAVE

Figure 5 Microvascular imaging. In this mode, a low MI time sequence is cumulated over a period of time (in this example, 60 seconds) to display the motion tracks of microbubbles (Optison was used here) as they flow through the small vessels (B). The improved display of the neovasculature in this breast carcinoma compared with power Doppler (A) is striking. Source: MVI software, Philips Medical. (See color insert for Fig. 5A.)

this could improve both detection and differentiation of these tumors. Some of these early claims have not proved to be repeatable, perhaps because most of the early reports included only small numbers of patients. One application that seems to have stood the test of time is the value of enhanced Doppler in differentiating scar tissue from tumor recurrence (17). This is especially important in the breast where this important distinction may be very difficult to make clinically or with imaging methods. The demonstration that a suspicious mass is vascularized suggests that it is malignant and a biopsy should be performed, directed to the vascular portion of the lesion.

An analogous situation is the monitoring of residual tumor during interstitial ablation therapy (18). The liver is the very common target organ: ultrasound is generally used to guide placement of the probe (for RF, laser, or cryotherapy) and ablation is continued until no Doppler signals remain. Then enhancement with microbubbles may reveal persistent hypervascular regions that can be ablated immediately in the same session and the sensitivity of this approach is similar to that of enhanced CT (Fig. 6). Microbubbles allows the ablation session to be continued to completion without moving the patient to the CT scanner. This approach is particularly successful for hepatocellular carcinomas because they are usually hyper-vascular but is also effective for colo-rectal metastases.

For the most part however, simple Doppler techniques have been replaced by the nonlinear methods described above, and the assessment of the characterization of liver masses has proved to be a particularly useful application. Using SAE in the liver-specific phase, malignant tumors appear as defects surrounded by a colored mosaic pattern when the liver is scanned some five minutes after IV injection of a liver trophic agent such as Levovist. SAE has been shown to improve the conspicuity of liver metastases as well as to demonstrate new lesions not seen on conventional B-mode (19). It reveals subtle or isoechoic metastases and increases the sensitivity of ultrasound to the detection of metastatic disease. In a study of the specificity of SAE, a spectrum of benign and malignant focal liver lesions were assessed for SAE activity in the late phase after injection of Levovist. Metastases and hepatocel-lular carcinoma (HCC) showed no or low SAE signals while hemangiomas and focal nodular hyperplasia (FNH) had significantly higher scores.

In a multicenter prospective study using one of the tuned SAE modes (Agent Detection Imaging, ADI, Siemens), data from 142 patients was analyzed by blinded review (20). The reviewer's ability to distinguish benign from malignant masses improved significantly from about 80% on conventional scanning (using B-mode plus color Doppler) to around 90% with ADI. The contrast between the lesion and the surrounding liver was markedly higher for malignancies, which stood out as color defects, than for benign lesions (cysts excluded) (Fig. 7). All FNHs showed strong uptake, as did regions of irregular fatty deposition. Haemangiomas were variable: most showed at least moderate uptake but there were exceptions. On the other hand, while all cholangiocarcinomas and almost all metastases showed color negative regions (one each of melanoma, neuroendocrine and testicular tumor metastases showed some signals), a few HCCs did show moderate uptake and thus could not be distinguished from regenerating nodules which did show uptake. Surprisingly, the "hot" HCCs were not exclusively those that were well differentiated on histology, though the sampling error problem of percutaneous biopsies needs to be borne in mind in interpreting this finding.

Phase inversion mode scanning at high MI with Levovist increases the sensitivity of ultrasound in the detection of focal liver malignancies by improving their conspicuity (19-22). In a multicentre study of 123 patients, the sensitivity to liver metastases increased from 71% to 88% and more subcentimeter lesions were detected. These results were comparable to the sensitivity of contrast enhanced CT, which was used as the reference imaging modality, and PIM ultrasound detected some lesions that were not seen on CT, particularly subcentimeter lesions. The

Figure 6 Contrast for interstitial ablation. In this patient with a liver metastasis from a colorectal primary that had previously been treated with radiofrequency ablation, the scan was requested because of rising markers. Beside the cavity there was an echogenic region, which was considered suspicious for tumor although it did not show signals on power Doppler (A) A contrast study (B) did not show any changes in this region but an echopoor region slightly deeper in the liver (arrowheads) that had not been noted on the baseline scan became increasingly obvious in the sinusoidal phase as the liver accumulated contrast (SonoVue was used with CCI, a pulse subtraction mode). This proved to be recurrent tumor on biopsy.

Figure 6 Contrast for interstitial ablation. In this patient with a liver metastasis from a colorectal primary that had previously been treated with radiofrequency ablation, the scan was requested because of rising markers. Beside the cavity there was an echogenic region, which was considered suspicious for tumor although it did not show signals on power Doppler (A) A contrast study (B) did not show any changes in this region but an echopoor region slightly deeper in the liver (arrowheads) that had not been noted on the baseline scan became increasingly obvious in the sinusoidal phase as the liver accumulated contrast (SonoVue was used with CCI, a pulse subtraction mode). This proved to be recurrent tumor on biopsy.

possibility that these were false positive for US was thought unlikely because in a subset of these patients, another reference investigation was available (MRI, intraoperative US, or laparotomy) and these showed yet more lesions than PIM US. Its role in hepatocellular carcinoma is unclear but in cholangiocarcinoma, a tumor that is notoriously difficult to define on ultrasound (presumably because of its infiltrating margins) stands out clearly against the enhancing liver (Fig. 8).

Figure 7 High MI detection of liver metastases. On this staging scan in a patient with a gastric carcinoma, the liver is suspiciously heterogeneous (A). In the late phase after administration of Levovist and using the ADI mode to detect the agent in healthy liver (B), large lesions are seen that were not obvious before. (See color insert for Fig. 7B.)

Figure 7 High MI detection of liver metastases. On this staging scan in a patient with a gastric carcinoma, the liver is suspiciously heterogeneous (A). In the late phase after administration of Levovist and using the ADI mode to detect the agent in healthy liver (B), large lesions are seen that were not obvious before. (See color insert for Fig. 7B.)

Low MI Modes in the Liver

The advantage of being able to work in real time using low MI modes with the phospholipid-perfluoro microbubble agents has enabled a three-phase approach to characterize liver masses. The same thinking is used in dynamic contrast CT and MRI but ultrasound has the added benefits of working in true real time and a study

Figure 8 Contrast reveals cholangiocarcinoma. The liver appears slightly heterogeneous in this patient with a cholangiocarcinoma but no well-defined lesion is seen on the conventional scan (A), a common finding with this infiltrating tumor. In ADI mode after administration of a liver-trophic microbubble (Levovist), the normal liver is highlighted in color and the tumor is clearly revealed as an extensive color void (B). The discrepancy between the conventional and the contrast-enhanced scan is striking. (See color insert for Fig. 8B.)

Figure 8 Contrast reveals cholangiocarcinoma. The liver appears slightly heterogeneous in this patient with a cholangiocarcinoma but no well-defined lesion is seen on the conventional scan (A), a common finding with this infiltrating tumor. In ADI mode after administration of a liver-trophic microbubble (Levovist), the normal liver is highlighted in color and the tumor is clearly revealed as an extensive color void (B). The discrepancy between the conventional and the contrast-enhanced scan is striking. (See color insert for Fig. 8B.)

can be repeated within a few minutes (because of the relatively short life of the agents) (Table 2) (23,24). In practice, the arterial and sinusoidal phases (at 15-30 seconds and 1-3 minutes, respectively) are the most useful (the times for US are earlier than for CT, perhaps because of the tight boluses achieved with the smaller volumes, typically a few mL, and the very high sensitivity to the microbubbles). The sinusoidal phase is a

Table 2 Vascularity of Liver Masses in Low MI Contrast Imaging

Metastases Arterial Portal Sinusoidal

Metastases Arterial Portal Sinusoidal

Table 2 Vascularity of Liver Masses in Low MI Contrast Imaging

Hypovascular

i

O

O

Marginal vessels

Hypervascular

++

O

O

Fill from margin

HCC

+++

O

O

Fill from margin

HA

+

O

+

Centripetal fill

FNH

+++

O

+

Central supply

RN

+

+

+

Normal liver

Fat

+

+

+

Normal liver

Abbreviations: HCC, hepato-cellular carcinoma; HA, hemangioma; FNH, focal nodular hyperplasia; RN, regenerating nodule in cirrhosis; fat, focal fatty change or sparing.

Abbreviations: HCC, hepato-cellular carcinoma; HA, hemangioma; FNH, focal nodular hyperplasia; RN, regenerating nodule in cirrhosis; fat, focal fatty change or sparing.

measure of the tissue's vascular volume, which is particularly high for the liver—since microbubbles are too large to cross the endothelium, there is no interstitial phase. The liver's arteries fill rapidly, at the same time as the adjacent kidney, and then the liver parenchyma, in general, progressively enhances over the next minute or so before gradually fading back to baseline. This pattern is shared by "lesions" that consist of normal liver such as focal fatty change and sparing and by regenerating nodules. The actual appearance on screen depends on the mode selected: In phase inversion modes, contrast shows as a brightening of the gray scale, while in CPS and VRI it shows as the appropriate tints (Figs. 9 and 10).

Vascular lesions have a variety of patterns of arterial supply, the peripheral arterial supply of vascular malignancies being typical (Fig. 11). Often these arteries are markedly tortuous and there may be several vascular poles. Hypovascular metastases are inconspicuous in this phase though circumferential vessels may be demonstrated in some cases. Vascular benign lesions may show a spectacular arterial supply, particularly FNH but here the supply is from a central artery (the changes may be so quick that they can be missed if the operator is not on the alert with the probe centered on the lesion). FNH then retains contrast and gradually disappears to blend with the liver except for the central scar, which may form a very obvious defect at this late stage, while malignancies, with their low vascular volume, remain echo-poor against the increasing signal from the liver sinusoids. This forms a general rule; lesions that are more prominent in the sinusoidal phase are suspicious of malignancy (cysts and abscesses exempted!) while those that disappear are likely to be benign.

Haemangiomas may show a pathognomonic pattern with early but subtle arterial filling that forms clumps at their periphery, followed by slow, centripetal fill-in, sometimes over several minutes. The fill-in may be complete, so that they eventually disappear, or may be partial, especially in larger lesions (presumably because of thrombotic or fibrotic regions). However many hemangiomas behave nonspecifically on these dynamic studies and in these cases the contrast study remains inconclusive.

While the necessary multicenter studies have not been completed, dynamic low MI contrast US shows strong promise in differentiating liver lesions. Whether the sinusoidal phase is equivalent to the liver-specific phase of agents like Levovist has not been studied in detail though many workers in the field suspect that this is lesions that were not apparent certainly on baseline and become obvious in the sinusoidal phase.

Figure 9 Low MI detection of liver metastases. A suspicious lesion in segment 2 (arrowhead in A) was found in this patient being staged for a gastric carcinoma. It was more clearly seen as a color defect after enhancement with SonoVue and using the low MI contrast pulse sequences mode (B). Scanning the remainder of the liver revealed three other lesions in segment 5 and 8 (arrowheads in C) that could not be detected on the simultaneous gray scale image (D). ( See color insert for Figs. 9B and C.) (Continued on facing page.)

Figure 9 Low MI detection of liver metastases. A suspicious lesion in segment 2 (arrowhead in A) was found in this patient being staged for a gastric carcinoma. It was more clearly seen as a color defect after enhancement with SonoVue and using the low MI contrast pulse sequences mode (B). Scanning the remainder of the liver revealed three other lesions in segment 5 and 8 (arrowheads in C) that could not be detected on the simultaneous gray scale image (D). ( See color insert for Figs. 9B and C.) (Continued on facing page.)

1144:13 am

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1 "^aHr Baseline/V

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