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Ultrasonography |
1 From the Dept of Radiology and Nuclear Medicine, Universitätsklinikum Benjamin Franklin, Freie Universität Berlin, Hindenburgdamm 30, D-12200 Berlin, Germany (T.A., C.W.H.); Dept of Imaging, Hammersmith Hosp, Imperial College, London, England (M.J.K.B., C.J.H., D.O.C.); Sunnybrook Imaging Research, Univ of Toronto, Ontario, Canada (P.N.B.); Dept of Ultrasound, Toronto General Hosp-Univ Health Network, Ontario, Canada (S.W.); Dept of Radiology, Royal Infirmary, Glasgow, Scotland (E.L.); Dept of Radiology, CHU Nancy-Brabois, Nancy-Vandoeuvre, France (M.C., F.L.); Ospedale Maggiore di Lodi, Italy (F.C.); Dept of Adult Radiology, Centre Hosp Necker, Paris, France (J.M.C.); Hosp Saint-Luc, Montreal, Quebec, Canada (M.L.); and Dept of Radiology, IRCCS Policlinico S. Matteo, Univ of Pavia, Italy (R.C.). From the 1999 RSNA scientific assembly. Received Nov 15, 2001; revision requested Feb 1, 2002; revision received Jun 28; accepted Aug 27. Supported by a grant from Philips Ultrasound, Bothell, Wash. C.J.H. supported by a grant from the Medical Research Council, United Kingdom. M.J.K.B. supported by a grant from Schering, Berlin, Germany. P.N.B. supported by the National Cancer Institute of Canada. Address correspondence to T.A. (e-mail: thomas.albrecht@medizin.fu-berlin.de).
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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MATERIALS AND METHODS: One hundred twenty-three patients underwent conventional US, US in the liver-specific phase of SHU 508A, and single-section spiral CT. US and CT images were assessed by blinded readers. Differences in sensitivity, specificity, and the number and smallest size of metastases at conventional and contrast-enhanced US were compared by using CT as the standard of reference. Lesion conspicuity was assessed objectively (quantitatively) and subjectively by one reader before and after contrast material administration.
RESULTS: In 45 of 80 (56%) patients with metastases, more metastases were seen at contrast-enhanced US than at conventional US. In three of these patients, conventional US images appeared normal. The addition of contrast-enhanced US improved sensitivity for the detection of individual metastases from 71% to 87% (P < .001). On a patient basis, sensitivity improved from 94% to 98% (P = .44), and specificity improved from 60% to 88% (P < .01). Contrast enhancement improved the subjective conspicuity of metastases in 66 of 75 (88%) patients and the objective contrast by a mean of 10.8 dB (P < .001). Contrast-enhanced US showed more metastases than did CT in seven patients, and CT showed more than did contrast-enhanced US in one of 22 patients in whom an independent reference (magnetic resonance imaging, intraoperative US, or pathologic findings) was available.
CONCLUSION: Contrast-enhanced US improved sensitivity and specificity in the detection of hepatic metastases.
© RSNA, 2003
Index terms: Liver neoplasms, CT, 761.12115 • Liver neoplasms, metastases, 761.33 • Liver neoplasms, US, 761.1298, 761.12988 • Ultrasound (US), contrast media, 761.12988
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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The microbubble US contrast agent SHU 508A (Levovist; Schering, Berlin, Germany) is a widely used contrast agent for enhancement of Doppler signals during its vascular phase. It also has a late hepatosplenic-specific phase, and this selective uptake by normal liver highlights metastases as nonenhancing defects and can improve their detection (5–8). The liver-specific late-phase effect begins 2–3 minutes after bolus injection as the contrast agent clears from the blood pool and persists for up to 30 minutes, provided the microbubbles are not destroyed by earlier scanning (7). Although the precise mechanism of the late microbubble accumulation in normal liver is unknown, the temporal course and distribution suggest an interaction with the reticuloendothelial system.
US of the stationary microbubbles in the liver in the late phase requires bubble-specific imaging techniques that take advantage of the nonlinear signals returned from microbubbles or the strong nonlinear decorrelation of echoes following their disruption (9–11). A gray-scale microbubble-specific US technique, called pulse- or phase-inversion harmonic contrast-enhanced US, has been developed to display nonlinear signals from microbubbles with high spatial resolution (12–16). In pulse-inversion US, pairs of US pulses are transmitted in the same direction, the second having an inverse phase from the first. The resulting echoes are summed to form one image line. Linear signals from tissue cancel so that the image is produced mainly from nonlinear scattering from microbubbles. Pulse-inversion US is used to highlight or enhance normal liver parenchyma in the liver-specific phase of SHU 508A. Since metastases do not enhance, they become more conspicuous, and detection can be improved (17–20).
Experience has shown that benign lesions such as focal nodular hyperplasia, focal fatty sparing, and hemangiomas enhance in the liver-specific phase of SHU 508A (19,21–23). Therefore, a contrast-enhanced examination with SHU 508A includes a thorough baseline scan, as well as high-power sweeps through the liver with pulse-inversion US following contrast material injection in the postvascular liver-specific phase. The baseline images are used to document all masses, including benign cysts, typical hemangiomas, and any solid masses that might be metastases. Contrast-enhanced and baseline images are correlated to evaluate the number of lesions and their enhancement. Lesions that enhance after contrast material administration are interpreted as benign, and solid lesions that do not enhance are interpreted as metastases. For the purpose of this article, we refer to the combination of baseline US with contrast-enhanced pulse-inversion US as simply "contrast-enhanced US".
Until now, published studies on the use of this technique have originated from single centers with particular expertise in microbubble US. It is not clear how useful the technique would be with more general use. The purpose of our study, therefore, was to conduct a multicenter trial to compare conventional B-mode US with the combination of conventional B-mode US and contrast-enhanced (SHU 508A) late-phase pulse-inversion US for the detection of hepatic metastases by using dual-phase spiral CT as the standard of reference.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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Referral to the radiology department for CT and/or US of the liver for suspected or known hepatic metastases.—The suspicion of metastases was based on clinical data in patients who were considered to have a primary malignancy at the time of examination. In the patients with known hepatic metastases, metastases had been diagnosed on the basis of characteristic features in at least one previous imaging examination (US, CT, or MR imaging).
CT performed up to 28 days prior to contrast-enhanced US or scheduled up to 28 days after contrast-enhanced US.—The maximum intervals allowed between contrast-enhanced US and CT were reduced to up to 14 days in patients who received chemotherapy (n = 19) to avoid substantial discrepancies between US and CT as a result of remission of lesions. Exclusion criteria were cirrhosis (determined on the basis of biopsy or imaging findings), in case it might alter the liver uptake of SHU 508A, and contraindications to the use of SHU 508A (galactosemia and severe heart failure). Patients were recruited prior to undergoing baseline US, and, once recruited, a patient could not be excluded on the basis of poor technical quality of the US examination. This was done to avoid selection bias in favor of patients who were "easy to scan."
Of 146 patients recruited within 6 months between March and October 1999, 23 were excluded from analysis because of violations to the CT protocol. Data from the remaining 123 patients (57 female and 66 male patients; mean age, 61.8 years ± 12 [SD]; age range, 15–83 years) were analyzed. Of these patients, 114 had malignancies, while the initial clinical diagnosis of a primary cancer with or without metastases was not confirmed in nine (ie, these nine did not have cancer). The primary tumor sites were colorectal (n = 41), breast (n = 11), neuroendocrine (n = 11), gastric (n = 7), bronchial (n = 6), pancreatic (n = 6), and other primary sites with less than five patients each (n = 32).
All patients underwent conventional US, pulse- inversion US after contrast enhancement, and dual-phase spiral CT. The primary comparisons were made between conventional and contrast-enhanced US findings by using dual-phase spiral CT as the standard of reference. In most patients, follow-up data—including US, CT, MR imaging, intraoperative US (available in 65 patients), and histologic findings (available in 31 patients)—were available 2 months after the end of the study period (average follow-up time was 5 months). No follow-up data were available in the remaining 27 patients. For eight patients in the group with follow-up data, the data indicated that the original CT interpretation was incorrect. The reference count of metastases in these cases was corrected retrospectively before comparison with the US findings. For example, one patient had three hypervascular lesions at CT that were interpreted as metastases from a known carcinoma of the thyroid, but the lesions subsequently showed characteristic features of focal nodular hyperplasia at MR imaging. The patient’s reference metastases count was thus corrected from three to zero. In the 27 patients without follow-up data, the CT interpretation could not be checked for correctness and was thus used as interpreted by the blinded readers.
To test the robustness of CT as the standard of reference—in particular, as a means of evaluating the nature of presumed metastases noted at contrast-enhanced US but not at CT, other diagnostic findings obtained at the time of the study were also correlated with the study results. These findings formed independent references and were available in 22 patients: MR imaging (n = 13), intraoperative US (n = 7), and pathologic examination of resected liver specimens (n = 2).
US Examination Technique
Both pre- and postcontrast US were performed by a senior radiologist (one or two per center) who was blinded to all other imaging findings. All scanning was performed by using an HDI 5000 scanner (ATL, Bothell, Wash) with a C5-2 curved-array transducer. Patients underwent thorough conventional baseline US in fundamental B-mode in at least two planes with individually optimized scanner settings. To optimize the quality of the baseline scan, the radiologists were free to use additional tissue harmonic imaging (106 patients) and higher frequency transducers (nine patients). A marker metastasis was identified when possible, and digital images of this lesion were stored for offline quantitative analysis. The criteria for marker lesion selection were that it was considered to represent a metastasis on the unenhanced scan, was less than 10 cm from the skin surface, was 1 cm or larger in diameter, and provided a good acoustic window for insonation of the whole lesion.
A bolus of 2.5 g of SHU 508A (400 mg/mL) was then injected by hand via a 22-gauge intravenous cannula at a rate of approximately 1 mL/sec, followed by a 10-mL normal saline flush. If the degree of contrast enhancement provided by this dose was judged by the radiologist to be sufficient but assessment of the liver was incomplete or the findings were equivocal, a second injection of 2.5 g was given. If the first injection produced insufficient enhancement (defined as no or only slight enhancement of the parenchyma), one or two additional 4-g SHU 508A bolus injections could be given. A minimum interval of 5 minutes and complete bubble destruction, which was achieved by scanning the entire liver at a high mechanical index, were required between each individual injection to avoid carryover effects.
Contrast-enhanced scanning was started 2 minutes after injection by using pulse-inversion harmonic US with persistence switched off, maximal acoustic power (mechanical index > 1), and a single focal zone. Because of the transience of the contrast material effect on pulse-inversion US (16), the scanning technique was optimized to image a fresh undestroyed microbubble population with each new frame. Scanning was performed in deep inspiration with a transverse sweep that covered the right lobe of the liver over approximately 4 seconds, with the focal zone in the deep third of the field of view. If this did not provide sufficient near-field enhancement (the enhancement was focal zone dependent [16]), a second sweep of the same area was performed immediately after the first (without further contrast material injection) with the focus placed more superficially. The cine loop of the sweep was reviewed to look for defects against the background of the fully enhanced liver parenchyma. Once cine loop review was complete, the left lobe was examined in the same way. All sweeps performed after one injection were usually completed within 5 minutes. The marker metastasis from the baseline scan was identified with the cine loop, and the relevant frame was stored digitally for offline analysis.
CT Technique
CT scanning was performed up to 27 days (mean, 3.4 days) before or after US. In the 19 patients who received chemotherapy, the mean interval between US and CT was 2 days (maximum, 10 days). All patients underwent contrast-enhanced arterial phase (with bolus-tracking software or a 25–30-second delay) and portal venous phase (65-second delay) single-section spiral CT with a collimation of 5 mm, a table speed adapted to image the entire liver within a single breath hold, and a reconstruction interval of 4 mm. Nonionic contrast material (300 mg of iodine per milliliter) was injected intravenously at 4 mL/sec with 2 mL per kilogram of body weight.
MR Imaging Technique
In 13 patients, MR imaging was performed as part of the clinical work-up up to 48 days (mean, 8.5 days) after US. The MR imaging technique was not standardized but had to fulfill the following minimum requirements for inclusion of the MR imaging data into the data analysis: unenhanced T1- and T2-weighted sequences and contrast-enhanced sequences performed with gadolinium-based contrast material (dynamic T1-weighted sequences) or liver-specific superparamagnetic iron oxide particles (T2-weighted sequences). The maximum section thickness was 8 mm, and the intersection gap was up to 20% of the section thickness. Both spin-echo and gradient-echo sequences were permitted.
Intraoperative US Technique
Intraoperative US was performed as part of the routine intraoperative work-up in seven patients up to 12 days (mean, 4.5 days) after US by a radiologist and/or surgeon who was aware of all preoperative imaging results, including CT and contrast-enhanced US. Dedicated high-frequency (7-MHz) transducers were used.
Image Interpretation
The number, size, and location of suspected metastases were documented on a segmental basis (Couinaud classification [24]) on schematic liver charts for each imaging modality. The US images were interpreted at the time of the examination by the sonographer, who was blinded to CT and other imaging data. Up to 20 metastases per patient were documented; when more than 20 were present, a precise count was not attempted, and a numeric value of 21 was used for analysis. For baseline US, established criteria were used to identify metastatic and nonmetastatic lesions (25,26). After contrast material administration, metastases were defined as sharply marginated round, oval, or lobulated hypoechoic defects within the enhanced parenchyma, with or without rim enhancement. Conversely, lesions that showed late-phase enhancement and were thus iso- or hyperechoic at contrast-enhanced US were documented as benign and were not counted as metastases. For cysts, standard criteria of minimal or no internal echoes, sharp border definition, and increased through transmission were used for diagnosis in both US examinations. Questionable lesions of unclear nature or suspicious areas of heterogeneity with no definite lesion could be documented as indeterminate both before and after contrast material administration.
The conspicuity of the marker metastasis at contrast-enhanced US was ranked subjectively by the radiologist as greater, unchanged, or less than that at conventional US. This was performed during the examination and without knowledge of the results of quantitative analysis, which was performed at a later date. Quantitative measurement of lesion-to-liver contrast was carried out centrally by using proprietary software (HDI Lab; ATL). This analysis was limited to the first 50 patients with a marker metastasis. A round or oval region of interest (mean maximum diameter, 3.0 cm ± 2.5) that covered the entire marker metastasis was placed over the lesion, and another of the same size and at the same depth was placed over the adjacent normal liver on pre- and postcontrast images. Differences in tissue contrast were calculated by dividing the signal intensity of the normal liver by that of the lesion and by expressing the results in decibels.
CT and MR images were interpreted locally at the study centers by senior radiologists (one reader per center and modality) who were blinded to the results of all other imaging examinations. Both soft and hard copies (soft-tissue window settings for CT) were used, depending on local practice. Established CT and MR imaging criteria were used to identify metastatic and nonmetastatic lesions (27).
Data Analysis
Primary comparisons were made between conventional and contrast-enhanced US findings. For all primary assessments of sensitivity and specificity, spiral CT was used as the reference modality. Among the 96 patients with follow-up data available 2 months after the end of the study period, there were eight patients in whom the data indicated that the original CT interpretation was incorrect. The reference count of metastases in these cases was corrected retrospectively before comparison with the US findings. For example, one patient had three hypervascular lesions at CT that were interpreted as metastases from a known carcinoma of the thyroid, but the lesions subsequently showed characteristic features of focal nodular hyperplasia at MR imaging. The patient’s reference metastases count was thus corrected from three to zero.
In the 22 patients who also underwent MR imaging, intraoperative US, or pathologic examination in resected specimens up to 48 days after US, these examinations were used as an independent reference for the comparison between contrast-enhanced US and CT (for this part of the analysis, the CT data per se were used without the corrections described above).
The sensitivity in detecting metastases with contrast-enhanced US versus conventional US was assessed by comparing the charts from the two US examinations. Each metastasis identified with one imaging mode (conventional US, contrast-enhanced US, or CT) was compared with the findings of the other modes. In selected cases, discrepancies in detection and localization of individual lesions were jointly reviewed by the sonographer and CT reader. This was performed for cases in which both observers agreed on the presence of a lesion of equal size in one area of the liver at equal distance from the surface but jointly decided that it was erroneously located in adjacent liver segments because of the different imaging planes in US and CT. In such cases, the lesion findings were recorded as being concordant for both modalities. The mean number of CT-confirmed metastases per patient at conventional US was compared with that at contrast-enhanced US by using the Wilcoxon signed rank test. The sensitivities of both types of US for metastases were calculated on a patient basis and compared by using the 
2 test. We also calculated the sensitivity for both types of US in the detection of individual metastases for each patient with metastases. The average of these values was used as the overall sensitivity in the detection of individual metastases. The sensitivities were compared by using the Wilcoxon signed rank test. The specificity (on a patient basis) of conventional US was compared with that of contrast-enhanced US by using the 2 test.
The quantitatively assessed liver-to-lesion contrast before and after SHU 508A was compared by using the Wilcoxon signed rank test. The mean sizes of the smallest metastases detected at conventional US, contrast-enhanced US, and CT were also compared in patients with additional metastases at contrast-enhanced US by using the Wilcoxon signed rank test.
Comparison of contrast-enhanced US and CT was addressed by comparing the number of CT-confirmed metastases, as well as the total number of lesions consistent with metastases shown at contrast-enhanced US with the number of metastases shown at CT (Wilcoxon signed rank test). In the subgroup of 22 patients with MR imaging, intraoperative US, or pathologic findings available as an independent reference, detailed lesion-by-lesion comparison (as described above) of contrast-enhanced US and CT findings was possible. The number of metastases per patient that was detected with contrast-enhanced US and CT and confirmed at the independent reference examination was compared by using the Wilcoxon signed rank test.
A P value of less than .05 was considered to indicate a statistically significant difference.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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Contrast-enhanced US showed more CT-confirmed metastases than did conventional US in 45 of the 88 (56%) patients with metastases (Figs 1–3); three of these patients had normal conventional US images. The mean number of CT-confirmed metastases increased from 3.9 ± 6.8 at conventional US to 5.1 ± 8.0 with contrast-enhanced US (P < .001). Additional metastases at contrast-enhanced US were most commonly seen in patients who had three or more metastases on baseline US images (Fig 4).
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Specificity
Seven of the 43 patients without metastases at CT had false-positive lesions at conventional US that were subsequently proven benign (hemangioma, focal fatty sparing, focal nodular hyperplasia), and in another 10 of these 43 patients, the findings were indeterminate before contrast material administration. At contrast-enhanced US, only one patient had a false-positive lesion (focal nodular hyperplasia misinterpreted as a metastasis), while the other benign lesions that were false-positive at conventional US showed marked late-phase enhancement and were interpreted correctly as benign. At contrast-enhanced US, four of the 43 patients without malignancies had indeterminate findings. The true-negative rate was thus 26 of 43 for conventional US (specificity, 60%; 95% CI: 44.4, 75.0) and 38 of 43 for contrast-enhanced US (specificity, 88%; 95% CI: 74.9, 96.1). The improvement in specificity was statistically significant (P < .01).
Lesion Conspicuity
In 75 patients with metastases, a marker lesion was identified before and after contrast enhancement. Subjective conspicuity was increased after contrast material administration in 66 patients (88%) (Figs 1–3), unchanged in six (8%), and decreased in three (4%). Measurement of the objective contrast before and after administration of SHU 508A in the first 50 patients showed a marked increase from 6.5 dB ± 11.1 at conventional US to 17.3 dB ± 16.8 at contrast-enhanced US (P < .001).
Lesion Size
The mean maximum diameter of the marker metastases was 3.6 cm ± 3.0. Metastases with a diameter of 1 cm or less were found in 28 patients at conventional US, in 46 at contrast-enhanced US, and in 49 at CT. In patients with additional metastases shown at contrast-enhanced US, the mean size of the smallest lesion detected in each patient was 1.2 cm ± 0.9 for conventional US and 0.6 cm ± 0.3 for contrast-enhanced US (P < .001). The smallest lesion size at CT in this subgroup was almost identical to that at contrast-enhanced US (0.6 cm ± 0.2).
Comparison of Contrast-enhanced US and Spiral CT
In the study population as a whole, the mean number of metastases at CT was greater than the number of CT-confirmed metastases at contrast-enhanced US (5.84 vs 5.10, respectively; P < .001). However, the mean number of metastases at CT was not significantly different from the total number of lesions with an appearance consistent with that of metastases (including those that were not confirmed at CT) at contrast-enhanced US (5.84 vs 5.66, respectively; P = .62).
In the 22 patients with data from MR imaging, intraoperative US, and pathologic examination of resected specimens available as independent references, we found a mean of 3.82 confirmed metastases ± 5.68 with contrast-enhanced US and 3.09 ± 5.56 with CT (P < .05). The modalities used as independent references showed a mean of 4.91 metastases ± 7.20. Fourteen patients had the same number of confirmed metastases (with use of an independent reference) at contrast-enhanced US and CT. Seven patients had one to four more confirmed metastases at contrast-enhanced US (Fig 5), and one patient had one more confirmed metastasis at CT. Contrast-enhanced US showed six false-positive lesions in three patients, while CT showed five false-positive lesions in three patients. In one patient, three false-positive lesions were identical at contrast-enhanced US and CT. These lesions were all cases of focal nodular hyperplasia misinterpreted as metastases with both modalities and subsequently characterized at MR imaging. The remainder of the false-positive lesions occurred in different patients at US and CT.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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Some metastases show only minimal contrast (the so-called isoechoic metastases) and are subsequently often not visualized. CT and, to a lesser extent, MR imaging have similar limitations in lesion-to-liver contrast on unenhanced images. These techniques, therefore, are routinely performed with the use of contrast agents, and liver-specific MR imaging agents have proven particularly useful in this respect. Such agents are now also available for US. The use of SHU 508A in its postvascular liver-specific phase substantially increases the echogenicity of the liver at pulse-inversion US as the microbubbles accumulate within the normal parenchyma. The echogenicity of metastases, on the other hand, remains unaffected, since they do not accumulate the contrast agent in the postvascular phase. Our results show that the conspicuity of hepatic metastases, as assessed both subjectively and objectively, was improved with the additional use of contrast-enhanced US. In 88% of our patients with metastases, the conspicuity of a marker lesion was assessed as better on the contrast-enhanced image than on the baseline image. Objective confirmation showed a dramatic increase in liver-to-lesion contrast from 6.5 dB at baseline to 17.5 dB after administration of SHU 508A.
In our study, this increase in contrast led to a marked improvement in the detection of hepatic metastases. By using dual-phase spiral CT as the standard of reference, contrast-enhanced US significantly improved the sensitivity in the detection of individual metastases. The sensitivity of conventional unenhanced US was 71%, which is within the range of 53%–77% in earlier studies (1–3), indicating that conventional US remains limited despite recent advances in scanner technology, such as tissue harmonic imaging, which was used in most of our patients. The use of contrast-enhanced US had a considerable effect, however, by improving sensitivity of individual lesions to 87% and showing metastases in three patients whose livers were apparently normal at conventional US. More lesions were detected at contrast-enhanced US in 56% of patients with metastases compared with those detected at conventional US alone. Our findings are in keeping with those in two previous single-center studies. In one series (18), a significant number of extra lesions was reported at contrast-enhanced US compared with baseline in all 11 patients. In another series (19), additional metastases not seen at conventional US were detected with contrast-enhanced US in 28 of 62 patients, and sensitivity for individual metastases increased from 63% to 91%.
Contrast enhancement proved particularly useful in the detection of small metastases, which is the most important shortcoming of conventional US: The detection rate of lesions smaller than 1 cm nearly doubled with the use of contrast-enhanced US in comparison to conventional US. The ability of an imaging system to resolve small structures is determined by its spatial resolution and by the contrast of the structure relative to the surrounding medium. Lateral resolution of abdominal probes for state-of-the-art US equipment is in the range of 1 mm, and structures a few millimeters in size are thus readily resolved, provided there is enough inherent contrast. At conventional US, this is frequently not the case, and many metastases smaller than 1 cm may not be detected. In our study, we believe that improved detection was a result of increased liver-to-lesion-contrast.
Contrast-enhanced US also increased specificity significantly (from 60% to 88%), since many questionable or benign lesions could be differentiated from metastases on the basis of their contrast material uptake.
Dual-phase spiral CT is not a perfect method for imaging hepatic metastases, and discrepancies between contrast-enhanced US and CT may not always represent limitations of contrast-enhanced US. In our comparison of contrast-enhanced US and spiral CT with MR imaging, intraoperative US, and pathologic findings as independent references in a subgroup of 22 patients, contrast-enhanced US showed more confirmed lesions (with use of an independent reference) in seven patients than did CT, whereas CT depicted more confirmed lesions in only one patient. While conclusions from such a small and selected subgroup must be drawn with caution, our findings show that contrast-enhanced US can be more sensitive to hepatic metastases than can dual-phase CT in select cases. On the other hand, the overall number of lesions with an appearance consistent with that of metastases at contrast-enhanced US and CT was almost identical in the total patient population, and this suggests that the performance of the two modalities is similar overall.
The use of conventional US alone for liver staging in patients with malignancy is considered insufficient in most centers, and spiral CT is generally preferred or added, especially when US results are negative. Because of its accuracy, contrast-enhanced US may offer an alternative to CT and may provide several advantages, including lack of ionizing radiation and high patient acceptance. SHU 508A has an excellent safety profile (28), with no marked side effects, such as anaphylactoid reactions or toxicity to the kidneys. It is available in many countries worldwide, although not in the United States. However, at least one microbubble agent with liver-specific properties is currently undergoing clinical trials in the United States and should become available in the near future (29,30). The liver specificity of this agent is similar to that of SHU 508A, but it shows stronger and more prolonged liver enhancement, which has obvious advantages in terms of both longer scanning opportunity and performance of US-guided biopsy of detected lesions.
Cost-effectiveness has not been addressed in this trial, but it would be of value in future studies. Contrast agent costs and time are substantive factors. The additional time required for the contrast-enhanced part of the examination, including placement of the intravenous needle, was not recorded in this study.
There are several limitations of our study. The use of two sonographers to assess the conventional US and contrast-enhanced US images would have been desirable. However, the same sonographer compared the addition of contrast enhancement to conventional US to mirror the clinical situation, since postcontrast scanning would not be performed without first performing nonenhanced US. Since SHU 508A is a fragile microbubble agent with a transient enhancement effect in the postvascular phase, it is necessary to perform thorough baseline US prior to contrast-enhanced scanning to assess the individual liver anatomy for planning the contrast-enhanced sweeps and to determine the focal zone setting and the image depth to be used. Furthermore, an unenhanced scan is used to identify the location and features of lesions that are already visible without the addition of contrast material and to assess the appearance of these lesions after contrast material administration. This is particularly important for benign lesions, which may "disappear" after contrast material injection because of contrast material uptake similar to that of the normal liver.
There was also a lack of definitive pathologic diagnosis in 92 of the 123 patients; 29 patients underwent biopsy (of only one lesion), and two underwent resection. Lesions seen only after contrast material administration but not at baseline US would ideally require a true standard of reference to verify that they are metastases and not artifacts. Most of these enhancement defects were confirmed with the use of CT or additional imaging, however, and no such defects were seen in the nine patients who were subsequently shown not to have malignant disease. Investigators in other studies (6,17,18) have not found any false-positive lesions in healthy control subjects. Biopsy of lesions that appeared as enhancement defects at contrast-enhanced US would be difficult to perform because of the transient nature of liver enhancement, which only lasts for a few US frames, after which the microbubbles are disrupted.
Exact segmental localization of a lesion at US can be difficult, since even transverse scanning is generally performed with some caudocranial angulation, resulting in oblique imaging planes. For the same reason, tracking of an individual lesion between truly transverse CT and US scans may be problematic. We therefore allowed a degree of flexibility with regard to the segmental localization of an individual lesion at US and CT. Lesions of equal size and distance from the surface that were seen in the same area of the liver at US and CT could be called identical if both the CT and the US reader agreed that this was the case, even if the lesions were placed near the border of two adjacent segments. We believe that this is a realistic approach that we also use in clinical practice, but we recognize that this may have introduced bias in favor of the US results.
In conclusion, performance of contrast-enhanced US during the late liver-specific phase of the microbubble US contrast agent SHU 508A markedly improved both sensitivity and specificity in the detection of hepatic metastases because of improved contrast between the enhanced parenchyma and the nonenhanced metastatic lesions. The technique has the potential to show metastases that are occult at conventional US and dual-phase spiral CT and appears to represent a competitive alternative to CT for imaging of hepatic metastases.
Author contributions: Guarantor of integrity of entire study, T.A.; study concepts, T.A., M.J.K.B., P.N.B., S.W.; study design, all authors; literature research, T.A.; clinical studies, all authors; data acquisition, all authors; data analysis/interpretation, T.A., M.J.K.B., P.N.B.; statistical analysis, T.A., P.N.B.; manuscript preparation, T.A., M.J.K.B., S.W., C.J.H.; manuscript definition of intellectual content, T.A., M.J.K.B., S.W., P.N.B., C.J.H.; manuscript editing, all authors; manuscript revision/review, T.A., M.J.K.B., S.W., P.N.B., C.J.H., D.O.C.; manuscript final version approval, all authors.
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ACKNOWLEDGMENTS |
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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  P S SIDHU The EFSUMB guidelines for contrast-enhanced ultrasound are comprehensive and informative for good clinical practice: will radiologists take the lead? Br. J. Radiol., July 1, 2008; 81(967): 524 - 525. [Full Text] [PDF]
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L. Greenbaum, P. Burns, J. Copel, D. Cosgrove, J. B. Fowlkes, B. Goldberg, R. Mattrey, D. Merton, M. Robbin, and S. Wilson American Institute of Ultrasound in Medicine Recommendations for Contrast-Enhanced Liver Ultrasound Imaging Clinical Trials J. Ultrasound Med., June 1, 2007; 26(6): 705 - 716. [Full Text] [PDF]
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M. J. Dill-Macky, S. R. Wilson, Y. Sternbach, J. Kachura, and T. Lindsay Detecting Endoleaks in Aortic Endografts Using Contrast-Enhanced Sonography Am. J. Roentgenol., March 1, 2007; 188(3): W262 - W268. [Abstract] [Full Text] [PDF]
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E. Leen, P. Ceccotti, C. Kalogeropoulou, W. J. Angerson, S. J. Moug, and P. G. Horgan Prospective multicenter trial evaluating a novel method of characterizing focal liver lesions using contrast-enhanced sonography. Am. J. Roentgenol., June 1, 2006; 186(6): 1551 - 1559. [Abstract] [Full Text] [PDF]
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C. Nicolau, R. Vilana, V. Catala, L. Bianchi, R. Gilabert, A. Garcia, and C. Bru Importance of Evaluating All Vascular Phases on Contrast-Enhanced Sonography in the Differentiation of Benign from Malignant Focal Liver Lesions Am. J. Roentgenol., January 1, 2006; 186(1): 158 - 167. [Abstract] [Full Text] [PDF]
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 M. Okada, C. W. Hoffmann, K. J. Wolf, and T. Albrecht Bolus versus Continuous Infusion of Microbubble Contrast Agent for Liver US: Initial Experience Radiology, December 1, 2005; 237(3): 1063 - 1067. [Abstract] [Full Text] [PDF]
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S. Bipat, M. S. van Leeuwen, E. F. I. Comans, M. E. J. Pijl, P. M. M. Bossuyt, A. H. Zwinderman, and J. Stoker Colorectal Liver Metastases: CT, MR Imaging, and PET for Diagnosis--Meta-analysis Radiology, October 1, 2005; 237(1): 123 - 131. [Abstract] [Full Text] [PDF]
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