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1
Department of Radiology and Nuclear Medicine,
Universitätsklinikum Benjamin Franklin, Freie
Universität Berlin, Hindenburgdamm 30, D-12200
Berlin, Germany.
2
Department of Surgery, Universitätsklinikum
Benjamin Franklin, Freie Universität Berlin,
D-12200 Berlin, Germany.
Received April 10, 2000;
accepted after revision October 17, 2000.
Partially supported by a grant from Schering AG, Berlin, Germany, and by a
grant from Siemens Ultrasound Group, Issaquah, WA.
Abstract
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SUBJECTS AND METHODS. Sixty-two patients were studied with unenhanced B-mode sonography and phase-inversion sonography 2.5 min after the injection of Levovist. All patients underwent one reference examination (CT, MR imaging, or intraoperative sonography). The conspicuity, number, size, and distribution of metastases before and after contrast administration as judged by a sonographer (who was unaware of other imaging findings) were compared with each other and with reference imaging.
RESULTS. The conspicuity of metastases was improved by contrast-enhanced phase inversion in 94% of patients. Thirty-nine patients showed metastases on reference imaging; 36 of these were positive on baseline sonography and 38 on phase-inversion sonography. Phase-inversion sonography showed more reference imaging—confirmed metastases than baseline sonography in 28 patients (45%). The average number of confirmed metastases per patient was 3.06 for baseline sonography and 5.42 for contrast-enhanced phase-inversion sonography (p < 0.01). The average sensitivity for detecting individual metastases improved from 63% to 91%. Metastases of less than 1 cm were shown in 14 patients on baseline sonography, in 24 patients on phase-inversion sonography, and in 26 on reference imaging. Both sonographic techniques showed false-positive lesions in six patients.
CONCLUSION. Contrast-enhanced phase-inversion sonography in the liver-specific phase of contrast enhancement using Levovist provides a marked improvement in the detection of hepatic metastases relative to unenhanced conventional sonography, without loss of specificity. Phase-inversion sonography was particularly advantageous in detecting small metastases and may be a competitive alternative to CT and MR imaging.
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The microbubble sonographic contrast agent Levovist (SHU 508 A; Schering, Berlin, Germany), which was originally developed to enhance Doppler signals during an early vascular phase, accumulates in normal liver parenchyma during a late liver-specific phase. The late-phase contrast effect is specific to normal liver (and spleen) parenchyma and spares focal lesions such as metastases [5,6,7,8]. Although the precise mechanism of the late microbubble accumulation is unknown, the temporal course and the distribution mimic uptake of liver-specific MR contrast agents with an affinity to the reticuloendothelial system.
The late-phase parenchymal contrast effect cannot be detected using conventional (fundamental) B-mode sonography; highly sensitive microbubble-specific imaging techniques are required. These techniques use the non-linear (i.e., distorted) signals that are returned from microbubbles as a result of harmonic resonance and—most relevant in the case of Levovist—microbubble destruction with stimulated acoustic emission [9]. Until recently, stimulated acoustic emission was imaged mainly using conventional color Doppler sonography, on which it is displayed as a flow-independent characteristic color mosaic of "pseudo Doppler shifts." Although color-stimulated acoustic emission imaging during the late phase of contrast enhancement with Levovist can show hepatic metastases that are occult to conventional sonography [7, 8], color-stimulated acoustic emission imaging has several technical limitations, such as a relatively narrow and sometimes inhomogeneous zone of enhancement and limited spatial and temporal resolution.
Recently, a highly sensitive microbubble-specific sonography technique called phase or phase inversion has emerged; it displays nonlinear signals from microbubbles in B-mode [10,11,12,13]. The technique uses two sonographic pulses that are phase-shifted by 180° for one image frame. Linear signals from the two pulses will cancel each other, and the image is produced exclusively by nonlinear scattering (Fig. 1). Phase inversion produces considerable B-mode enhancement of liver parenchyma in the late phase of contrast enhancement with Levovist at excellent spatial and temporal resolution [13]. The purpose of this study was to assess if phase inversion during the late phase of contrast enhancement with Levovist improves the detection of hepatic metastases in comparison with conventional unenhanced B-mode sonography.
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The patients' underlying malignancies were colorectal (n = 24), breast (n = 12), dermal (n = 5), renal (n = 4), pancreatic (n = 4), and other (n = 15); two patients had a history of two primary tumors.
Reference imaging examinations were performed within 0-26 days (mean, 6 days) of the sonography. These reference examinations were contrast-enhanced helical CT (n = 23), contrast-enhanced dynamic CT (n = 8), intraoperative sonography (n = 13), gadolinium-enhanced MR imaging (n = 12), and superparamagnetic iron oxide-enhanced MR imaging (n = 6). CT and MR imaging were performed as part of the clinical workup of the patients—in several cases outside our institution—and not for the purpose of this study. The imaging protocols were therefore not standardized. Minimum requirements for CT were portal venous phase images at 8-mm slice thickness with sufficient contrast enhancement as judged by a blinded observer, and for gadolinium-enhanced MR imaging were unenhanced T1- and T2-weighted sequences and dynamic T1-weighted contrast-enhanced sequences at 8-mm slices. Superparamagnetic iron oxide-enhanced MR imaging consisted of unenhanced T1- and T2-weighted sequences and contrast-enhanced T2-weighted imaging (five 8-mm slices).
For patients who underwent more than one imaging technique within 4 weeks of sonography, we choose the "best" available as reference imaging. Intraoperative sonography was considered to be the most reliable imaging technique, followed by superparamagnetic iron oxide—enhanced MR imaging, gadolinium-enhanced MR imaging, helical CT, and dynamic CT.
Twenty-three patients were judged to have no metastases on reference imaging (in two patients, combined with biopsy and follow-up imaging for lesions that subsequently proved benign) and 39 patients showed focal lesions typical of metastasis (prevalence, 63%). The metastatic nature of the liver lesions seen was determined on the basis of biopsy of at least one of the lesions (n = 16), progression on imaging during an observation period of 1-24 months (mean, 6 months) (n = 15), remission after chemotherapy during an observation period of 5-7 months (n = 2), or reference imaging and clinical judgement alone (n = 6; five of these have since died of metastatic disease). One patient had biopsy-proven hepatic cirrhosis with no evidence of hepatocellular carcinoma, and nine had imaging features of hepatic steatosis.
Sonography Technique
Scanning was performed by one of two experienced radiologists using a
Sonoline Elegra scanner (Siemens, Issaquah, WA) with a curved 3.5-MHz center
frequency transducer. All patients underwent conventional sonography of the
liver in fundamental B-mode in longitudinal and transverse sections with
individually optimized scanner settings.
After completion of the baseline scanning, Levovist (400 mg/mL) was injected IV as a bolus at 1 mL/sec followed by a 10-mL normal saline flush. Fifty-one patients obtained one injection, and two injections were required in the remaining 11 patients. The Levovist dose per injection was 2.5 g in 56 injections and 4 g in 17.
Delayed contrast-enhanced phase-inversion scanning was started 2.5 min after contrast injection and was terminated within 10 min. For the phase-inversion scanning "ensemble contrast imaging" software (Siemens) was used with the following settings: insonating frequency, 2.0-2.5 MHz; mechanical index, 0.7 or more; frame rate, more than 10 per second; parallel processing; and single focus with depth adapted to the area of interest (important because the enhancement was focal-zone dependent [13]). A single focal zone was used because we previously found it provided considerably stronger enhancement than multiple focal zones. Because of the marked transience of the contrast effect on phase-inversion sonography [13], the scanning technique was adapted as follows: During deep inspiration, two fast but controlled transverse sweeps of the entire right lobe of the liver from the diaphragm to the lower pole were performed over approximately 3-4 sec (one with a superficial and one with a deep focal zone). This was done so that a new and undestroyed microbubble population would be imaged with each new frame. When an individual sweep was completed, the image was frozen and the individual frames of the sweep were reviewed on the cine loop without time constraints. This was followed by a single longitudinal or transverse sweep of the left lobe with an appropriate focal zone position. After these standardized sweeps, additional scanning in phase inversion was performed when required to visualize areas of the liver that may not have been visualized sufficiently by the sweeps.
Image Interpretation
The number, size, and location of focal lesions with metastases were
documented for all imaging modalities on a segmental basis (using the Couinaud
classification [14]) on
schematic liver charts. Up to 10 individual metastatic lesions per patient
were counted; when more than 10 such lesions were present, a semiquantitative
scale of 11-20 and more than 20 was used, because reliable numeric lesion
counts were not obtainable in these patients. Benign-appearing lesions were
also documented but were not included in the lesion count.
Baseline sonography.—Metastases were defined as round, oval, or lobulated solid focal lesions that were clearly discernible and that were neither simple cysts nor typical of hemangioma, focal nodular hyperplasia, focal fatty change, or focal fatty sparing [15, 16].
Contrast-enhanced phase-inversion sonography.—Metastases were defined as sharply marginated round, oval, or lobulated hypoechoic defects in enhancing parenchyma with or without a thin surrounding rim of accentuated enhancement. Conversely, lesions that showed late-phase enhancement and were thus iso- or hyperechoic on the phase-inversion scan were documented but were not included in the lesion count.
Both the baseline and the phase-inversion sonography studies were interpreted by the sonologist at the time of the examination. The sonologists were unaware of the findings of the reference examination and of the details of any other imaging, including previous sonography, in all cases. However, they were aware of the referral diagnosis as spelled out on the request form, which often included whether metastases were already known.
Reference imaging.—CT and MR images (n = 50) were interpreted by an observer who was unaware of the sonographic findings, who again counted lesions typical of metastasis but also noted benign lesions. The observer documented the size and location of each lesion on schematic liver charts. The results of this blinded interpretation were checked for consistency with biopsy results (n = 24), follow-up imaging (n = 46), and the sonography results; sonography was used to differentiate simple cysts from solid lesions in this respect. In 15 cases, obvious inconsistencies were revealed, and the overall clinical judgment of the liver status of all these patients after complete workup was different from the results of the initial blinded interpretation. In these 15 patients, a second interpretation was performed by the same observer and was used as the result of the reference imaging, this time with the relevant additional information available to the observer. This was done so that potential misinterpretations of the blinded interpretation could be rectified in view of the additional information, if thought appropriate by the observer (the lesion count was changed by the observer in all 15 cases). For example, a small cyst was misinterpreted on CT as metastatic but was clearly shown to be a cyst on sonography and was confirmed by stability on follow-up imaging; or focal nodular hyperplasia was misinterpreted as a hypervascular metastasis on CT but proven to be focal nodular hyperplasia on biopsy.
For intraoperative sonography (n = 13), which was performed as part of the routine intraoperative workup, the sonographer was aware of all preoperative imaging results, including the results from contrast-enhanced sonography; the intraoperative sonography results were based on sonographic features combined with inspection, palpation, biopsy results (n = 8), and resection pathology results (n = 1).
Data Analysis and Statistical Evaluation
The conspicuity of metastases seen on both the baseline and the
phase-inversion sonograms was subjectively compared and was judged by the
sonologist at the time of scanning as better, unchanged, or worse than on the
baseline sonography.
The detection of metastases with contrast-enhanced phase-inversion
sonography versus unenhanced sonography was addressed by comparing the charts
from the baseline sonography, the contrast-enhanced phase-inversion
sonography, and the reference examination. Each metastasis identified on one
imaging technique was compared with the other techniques; this comparison
included size and localization. (For practical reasons, this was possible only
in patients with 
10 individually counted lesions. When > 10 metastases
were seen on the reference examination, it was assumed that these were
identical to the ones seen on sonography unless obvious discrepancies were
noted.) In questionable cases, discrepancies of the exact segmental location
were jointly reviewed by the sonologist and the observer of the reference
examination. When both observers agreed on the presence of a lesion of similar
size in one area of the liver but decided it was erroneously located in
adjacent liver segments, the lesion was recorded as being concordant on both
techniques.
The mean numbers of reference imaging—confirmed metastases seen by the two sonographic techniques were compared with each other and with the number seen on reference imaging using analysis of variance with the Bonferroni posttesting. If 11-20 or more than 20 lesions were seen, numeric values of 15 or 25, respectively, were used for calculations.
Furthermore, the sensitivity of both sonographic techniques for detecting individual metastases was calculated for each patient with metastases on the reference imaging examination (the gold standard). The overall sensitivity of both sonographic techniques for detecting individual metastases was calculated as the means of the individual results and was compared using Wilcoxon's signed rank test.
The size of the smallest metastasis detectable with each imaging technique in each patient with metastases was compared using analysis of variance with Bonferroni adjustment. A p value of less than 0.029 was considered statistically significant for Bonferroni posttesting, and a significance level of less than 0.05 was used for the other tests.
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The enhancement spared metastases that appeared as hypo- or nearly anechoic lesions with a sharp border (Figs. 2A,2B,3A,3B,3C,3D,4A,4B,4C,5A,5B,5C,5D,5E). This was also the case in all six patients who had hyperechoic metastases on the baseline scan. Often the metastases showed a thin rim of increased enhancement around their edges (Figs. 4A,4B,4C and 5A,5B,5C,5D,5E). Thirty-six patients showed one or more metastases both on the baseline and the phase-inversion scans. The conspicuity of these lesions was improved on phase inversion compared with baseline scans in 34 patients (Fig. 2A,2B), unchanged in one, and decreased in one patient; the latter two patients had hyperechoic metastases on the baseline scan.
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Thirty-six of the 39 patients with metastases on reference imaging showed metastases on the baseline scans. Contrast-enhanced phase-inversion sonography showed metastases in 38 of the 39 cases with positive findings. The sensitivity for the presence or absence of metastatic liver disease was thus changed from 92% to 97% (not significant). Two of the three patients with false-negative findings on baseline scans showed a heterogeneous liver but no definite focal lesions; these patients had multiple small disseminated lesions on phase-inversion sonography and reference imaging. The one patient whose findings were false-negative both on the baseline and the phase-inversion scans had a single subdiaphragmatic lesion that was not accessible to sonography.
Contrast-enhanced phase-inversion imaging showed more metastases confirmed on reference imaging than did baseline sonography in 28 (45%) of all 62 patients and in 26 (72%) of the 36 patients whose findings were positive on both sonographic techniques (Figs. 3A,3B,3C,3D,4A,4B,4C,5A,5B,5C,5D,5E). The average number of confirmed metastases per patient was 3.06 ± 5.77 for fundamental sonography and 5.42 ± 8.41 for contrast-enhanced phase-inversion sonography, whereas reference imaging showed a mean of 6.15 ± 9.26 metastases. Analysis of variance showed that the differences among the three techniques were highly significant (p < 0.0001). Posttesting for comparison of individual techniques revealed a significant difference between fundamental and phase-inversion sonography (p < 0.01), whereas the difference between phase-inversion sonography and reference imaging was not significant.
Sensitivity in the detection of individual metastases was improved from 63% (95% confidence interval, 50-75%) with fundamental sonography to 91% (95% confidence interval, 84-98%) with contrast-enhanced phase-inversion sonography (p < 0.001).
Contrast-enhanced phase-inversion sonography detected significantly smaller metastases than baseline sonography (p < 0.001), whereas no significant difference was seen in the size of the smallest lesions detected by phase-inversion sonography and reference imaging (Table 1).
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The false-positive rate of phase-inversion sonography showed little change in comparison with fundamental sonography. Of the 23 patients without metastases on reference imaging, four had false-positive findings on fundamental sonography. These were caused by biopsyproven benign lesions (multiple granulomata in one patient, focal nodular hyperplasia, and a regenerative nodule) that were interpreted as metastases in three patients, and by a 4-mm hypoechoic lesion that was not seen on superparamagnetic iron oxide—enhanced MR imaging, including follow-up, in one patient. On contrast-enhanced phase-inversion sonography, three patients had false-positive findings that were caused by multiple nonenhancing granulomata in one patient and by two nonenhancing lesions of less than 1 cm that were not confirmed on intraoperative sonography and follow-up imaging.
In eight patients with metastases on reference imaging, phase-inversion sonography showed more lesions consistent with metastases than did reference imaging. Three of these lesions (in three patients) were false-positive interpretations: two lesions were not confirmed by intraoperative sonography and resection pathology, and the third was a biopsy-proven hemangioma (baseline sonography produced two false-positive lesions in patients with metastases). In two patients with more lesions on phase-inversion sonography than on reference imaging, phase-inversion sonography was more sensitive than reference imaging. In one patient, two metastases seen on phase-inversion sonography were not seen on helical CT but were confirmed on intraoperative sonography 5 weeks after the examination; in another patient, two metastases were not seen on MR imaging but were seen on helical CT follow-up after 2 months. In the remaining three patients with more lesions on phase-inversion sonography than on reference imaging, multiple lesions were seen on both imaging techniques, but a greater number of clearly discernible lesions as small as 2-4 mm consistent with metastases were seen on phase-inversion sonography (Fig. 5A,5B,5C,5D,5E). No follow-up information was available for these three patients, but we suspect that the lesions seen on phase-inversion sonography were metastases missed by reference imaging (helical CT in all three cases).
False-Positive Results and Benign Lesions
We found 38 benign lesions (11 simple cysts, 12 hemangiomata, five areas of
focal fatty sparing, four cases of focal nodular hyperplasia, three areas of
focal fatty change, two regenerative nodules, and one scar) in 19 patients;
three additional patients had multiple cysts, multiple granulomata, and
multiple hemangiomata. Eight of the solid benign lesions were biopsy-proven,
and the nature of the remaining lesions was determined on the basis of
characteristic imaging features. As on conventional sonography, the cysts
appeared as echo-free and sharply marginated lesions with through-transmission
on contrast-enhanced phase-inversion sonography. With the exception of one
hemangioma and the multiple granulomata (which were wrongly interpreted as
metastases as described), all noncystic benign lesions showed appreciable
uptake of contrast material similar to normal liver on contrast-enhanced
phase-inversion imaging, and they were thus readily distinguishable from
metastases. This allowed one case of focal nodular hyperplasia and a
regenerative nodule, which were wrongly interpreted as metastases on baseline
sonography, to be recognized as benign lesions after contrast
administration.
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The false-positive rate of phase-inversion sonography was unchanged compared with fundamental sonography (three vs. four of the 23 patients without metastases and three vs. two lesions in patients with metastases). The initial blinded interpretation of the reference examination without further information available also resulted in two patients with false-positive findings: one with sarcoidosis and multiple histologically proven granulomata that were interpreted as metastases with all three imaging techniques, and the other with a small cyst that was confirmed on sonography and follow-up but was interpreted as metastasis on helical CT.
The reason for the relatively low false-positive rate of phase-inversion sonography is that metastases and benign lesions showed a different behavior after the administration of contrast material. Although all metastases showed no or little late-phase uptake of contrast material, almost all solid benign lesions showed late-phase enhancement that was similar to that of normal liver. Focal fatty change or sparing consists of essentially normal parenchyma and is therefore expected to behave like it. Focal nodular hyperplasia and regenerative nodules contain all elements of normal parenchyma, only in a deranged architecture, and it is therefore not surprising that they show contrast uptake. Hemangiomata are characterized by a gradual filling-in with contrast material over a few minutes on dynamic CT or MR imaging, which explains why 11 of 12 hemangiomata showed late-phase enhancement on phase-inversion sonography. Blomley et al. [17] found similar late-phase enhancement characteristics of benign liver lesions using color-stimulated acoustic emission imaging, and their and our results suggest that late-phase imaging with Levovist not only detects liver lesions but is also suitable for lesion characterization.
The underlying mechanism of the selective late uptake of Levovist by hepatic and splenic parenchyma is not fully understood. One possible explanation is that the accumulation may be mediated by the reticuloendothelial system, as previously described for two other microbubble agents in clinical development [18, 19]. Alternatively, microbubbles may be entrapped in the liver sinusoids, although it would be difficult to explain why this should also happen in the spleen that also displays late-phase enhancement but has a different microvasculature.
A limitation of our study is the lack of a uniform gold standard. Resection pathology represents the true gold standard but could not be obtained in relevant numbers in our center because of the relatively low number of liver resections performed. Instead, we used the best imaging examination available combined with all other relevant information (mainly follow-up imaging and biopsy of uncertain lesions) in each patient as the reference method. At the time of the data analysis, all patients had a completed workup of their liver with an established clinical diagnosis with regard to the presence and nature of focal lesions. Importantly, the use of additional information made available to the blinded observer led to a change in the lesion count in 15 of the 49 patients who did not undergo intraoperative sonography, which shows that this combined-reference approach provided a considerably more accurate lesion count than imaging alone. Only those metastases that were confirmed by the combined-reference method were used for the average lesion counts of the baseline and the contrast-enhanced phase-inversion sonograms and for the calculation of sensitivity. However, we are aware that our reference approach is open to criticism and may have underestimated the number of metastases in our patients.
Another problem in this study was the recognition of individual lesions on sonography and on the reference imaging because of the different imaging planes used. This sometimes led to different segmental localizations of identical lesions. We therefore had to allow a degree of flexibility when correlating individual lesions. If the size and general location of a lesion correlated well but the lesion was placed in two adjacent segments, it was nonetheless interpreted as the same lesion. With a lesion count of 10 or more, it became increasingly difficult to match individual lesions, and if their size and distribution was similar on sonography and reference imaging, we assumed that they were identical. This approach is certainly susceptible to error, with no obvious remedy; on the other hand, showing a particular individual lesion in these patients has little clinical relevance so long as an imaging technique shows widespread metastatic disease.
This study was a pilot study that tested the hypothesis that phase-inversion sonography in the late phase of contrast enhancement with Levovist detects more hepatic metastases than conventional sonography. Given the substantial improvement in the detection of reference imaging—confirmed metastases provided by phase-inversion sonography, this hypothesis was confirmed despite the limitations we have discussed. Our results are confirmed by two recent preliminary reports. Dalla Palma et al. [20] found an increased number of liver lesions detected with Levovist-enhanced phase-inversion sonography in 20 of 36 patients. Harvey et al. [21] examined 20 patients with known hepatic metastases and found additional lesions as small as 3 mm that were not seen on conventional sonography. In three patients, Harvey et al. found more lesions than on dual-phase helical CT.
The transient nature of late-phase enhancement with Levovist represents a limitation of the presented technique. Our technique requires a modification of conventional scanning to sweeps of the liver interpreted with the help of the cine loop, which requires some additional skill but can easily be learned by experienced sonographers. With the current high-mechanical-index phase-inversion technique, a part of the liver can be visualized on only one or two sweeps because of rapid bubble depletion. In equivocal cases a second injection is required for further contrast-enhanced scanning, which adds time and cost to the examination. Potential solutions to this problem would be the use of recent low-mechanical-index techniques such as pulse-inversion Doppler sonography [10], allowing several sweeps to be performed using the same bubble population or slow infusions of the contrast agent with continuous bubble replenishment, although the latter may reduce lesion contrast because of blood-pool enhancement within a metastasis.
No conclusions can be drawn from our study with regard to the diagnostic performance of phase-inversion sonography in comparison with other imaging modalities. That will have to be the subject of future studies. However, we suspect that contrast-enhanced phase-inversion sonography for liver imaging may become a competitive and cost-effective alternative to other modalities such as CT and MR imaging.
Acknowledgments
We thank Werner Hopfenmüller from the
Department of Biostatistics of the
Universitätsklinikum Benjamin Franklin, Freie
Universität Berlin, Germany, for his advice on
the statistical analysis of the data, and Simon D. Taylor-Robinson from the
Department of Medicine at Hammersmith Hospital, Imperial College, London, UK,
for reviewing the manuscript.
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