Washout-parametric imaging with Sonazoid for enhanced differentiation of focal liver lesions
Article information
Abstract
Purpose
The study aimed to compare the diagnostic performance of washout-parametric imaging (WOPI) with that of conventional contrast-enhanced ultrasound (cCEUS) in differentiating focal liver lesions (FLLs).
Methods
A total of 181 FLLs were imaged with contrast-enhanced ultrasound using Sonazoid, and the recordings were captured for 10 minutes in a prospective setting. WOPI was constructed from three images, depicting the arterial phase (peak enhancement), the early portal venous phase (1-minute post-injection), and the vasculo-Kupffer phase (5 or 10 minutes post-injection). The intensity variations in these images were color-coded and superimposed to produce a single image representing the washout timing across the lesions. From the 181 FLLs, 30 hepatocellular carcinomas (HCCs), 30 non-HCC malignancies, and 30 benign lesions were randomly selected for an observer study. Both techniques (cCEUS and WOPI) were evaluated by four off-site readers. They classified each lesion as benign or malignant using a continuous rating scale, with the endpoints representing "definitely benign" and "definitely malignant." The diagnostic performance of cCEUS and WOPI was compared using the area under the receiver operating characteristic curve (AUC) with the DeLong test. Interobserver agreement was assessed using the intraclass correlation coefficient (ICC).
Results
The difference in average AUC values between WOPI and cCEUS was 0.0062 (95% confidence interval, -0.0161 to 0.0285), indicating no significant difference between techniques. The interobserver agreement was higher for WOPI (ICC, 0.77) than cCEUS (ICC, 0.67).
Conclusion
The diagnostic performance of WOPI is comparable to that of cCEUS in differentiating FLLs, with superior interobserver agreement.
Introduction
Contrast-enhanced ultrasound (CEUS) has been shown to be effective in characterizing focal liver lesions (FLLs), with diagnostic performance comparable to contrast-enhanced computed tomography (CT) and contrast-enhanced magnetic resonance imaging (MRI) [1]. Among these imaging modalities, CEUS has distinct advantages, including generation of pure vascular images, real-time dynamic imaging, and an excellent safety profile for patients with renal impairment or allergies to iodine or gadolinium [2].
Currently, two types of ultrasound (US) contrast agents are available for liver imaging [3]. The first category comprises pure blood pool contrast agents, such as Lumason (Bracco Diagnostics, Monroe Township, NJ, USA) and Definity (Lantheus Medical Imaging, Billerica, MA, USA). The second consists agents that target both the blood pool and Kupffer cells, exemplified by Sonazoid (GE HealthCare, Amersham, UK). Malignancy of a lesion may be indicated by washout relative to the surrounding liver parenchyma during the portal phase (from 30-45 to 120 seconds) or late phase (>120 seconds) with pure blood pool contrast agents [2] and during the portal phase, vasculo-Kupffer phase (from 2 to 10 minutes), or Kupffer phase (≥10 minutes) with Kupffer cell contrast agents [4]. In contrast, persistent enhancement beyond these phases often suggests a benign lesion. Consequently, the presence or absence of washout represents a key imaging finding for differentiating between malignant and benign liver lesions.
Washout is a relative phenomenon influenced by the hemodynamics and echogenicity of both the lesion and the surrounding liver tissue. Thus, the visual assessment of washout is particularly challenging in patients with liver function compromised by conditions such as severe liver cirrhosis or significant steatosis. These challenges can lead to indeterminate assessments, especially when evaluations are not conducted by highly experienced radiologists [5]. To address these issues, the present authors have developed washout-parametric imaging (WOPI), a technique that represents washout characteristics with a distinctive color-coded map. This approach aims to improve objectivity and thus increase the diagnostic accuracy in differentiating FLLs. Parametric imaging involves the creation of a two-dimensional map that uses color to represent the value of a parameter of interest. Previous studies have reported on the utility of parametric imaging for visualizing the arrival time of contrast agents, among other applications [6–8]. Accordingly, this study was performed to compare the diagnostic performance of WOPI against conventional CEUS (cCEUS) in the differential diagnosis of FLLs.
Materials and Methods
Compliance with Ethical Standards
This study was reviewed and approved by the Ethics Review Board of Tokyo Medical University, and written informed consent was obtained from all participants. The diagnostic US scanner used in this study, the LOGIQ E10 (GE Healthcare, Wauwatosa, WI, USA), was supplied by the manufacturer. Authors with no conflicts of interest had full control over the inclusion of data and information.
Study Population
Between June 2020 and January 2023, 219 patients with treatment-naïve hepatic lesions measuring 1 cm or larger were consecutively recruited in a prospective study at Tokyo Medical University Hospital. The inclusion criteria were as follows: (1) an age of at least 20 years, (2) at least one treatment-naïve hepatic lesion measuring 1 cm or larger, and (3) all lesions visible on baseline US. When multiple eligible lesions were detected in a patient, only one representative lesion was analyzed. Initially, 219 participants met the inclusion criteria. However, 38 participants were subsequently excluded for various reasons: 20 due to poor-quality images unsuitable for analysis, which were attributed to severe liver steatosis or lesions located deep within the liver; 10 due to deviation from the examination protocol; and eight due to incomplete diagnosis with CT/MRI. Thus, the study ultimately included 181 patients (108 male and 73 female), each with a single liver lesion. The median patient age was 68 years (interquartile range, 27 to 92 years), and the median size of the observed lesions was 25.0 mm (interquartile range, 17.0 to 38.5 mm). Of these lesions, 43.1% (78 of 181) were diagnosed as hepatocellular carcinomas (HCCs), 30.4% (55 of 181) as non-HCC malignancies, and 26.5% (48 of 181) as benign lesions. The non-HCC malignancies comprised 38 metastases, 15 intrahepatic cholangiocarcinomas, and two malignant lymphomas. The benign lesions included 25 hemangiomas, 18 focal nodular hyperplasias (FNHs), and five angiomyolipomas (AMLs).
Reference Standard of the Targeted Lesions
Among the included lesions, 100% of non-HCC malignancies (55 of 181, 30.4%) were diagnosed histopathologically through surgery (n=5) or biopsy (n=50). Regarding HCCs, 76.9% (60 of 78) were diagnosed histopathologically (surgery, n=4; biopsy, n=56). The remaining 23.1% of HCCs (18/78) were non-invasively diagnosed, as they met the criteria for categorization as LR-5 according to the CT/MRI Liver Imaging Reporting and Data System version 2018 [9]. All FNHs and AMLs (23 of 181, 12.3%) were diagnosed histopathologically though biopsy (n=23). The authors’ institution routinely includes information on hepatic tumor pathology and immunohistochemistry in the pathological reports. All hemangiomas (25 of 181, 13.8%) exhibited typical MRI features, such as peripheral globular and centripetal enhancement or high signal intensity on T2-weighted images, which facilitated their identification as hemangiomas without pathological confirmation.
US Examination
Conventional B-mode and CEUS examinations were performed by two hepatologists with 15 and 5 years of experience in abdominal US, respectively. The US scanner used was a LOGIQ E10 with a C1-6-D transducer (convex, 3.5-MHz center frequency). The CEUS imaging mode was configured to a fundamental/harmonic dual-display setting. For contrast harmonic imaging, the amplitude modulation method was employed with a low mechanical index, ranging from 0.16 to 0.2, and a dynamic range of 63 dB. The Sonazoid contrast agent was administered as a 0.5-mL bolus injection into the antecubital vein via a 21-gauge peripheral intravenous cannula, followed by a 10-mL saline flush. A timer was started at the moment of contrast agent injection. The targeted lesion was continuously recorded as a cine clip for 60 seconds after injection. During this time, patients were instructed to maintain gentle breathing. Subsequently, the same lesion was captured at 1-minute intervals as a 5-second cine clip during a breath-hold, from the 2-minute to the 10-minute mark post-injection. By examining the fundamental B-mode results, the target image with the maximum diameter was identified. The sequence of the CEUS protocol is depicted in Supplementary Fig. 1.
Construction of WOPI
The WOPI technique utilizes a two-dimensional color map to illustrate the dynamics of washout timing within the CEUS protocol, as shown in Fig. 1. The color of each pixel on the map is derived from the intensity variation (in dB) observed during both the early portal venous phase and the vasculo-Kupffer phase of washout. These variations are mapped onto the x-axis (early portal venous phase) and y-axis (vasculo-Kupffer phase) of the color map. The resulting color scheme—with yellow indicating early portal venous washout, red signifying vasculo-Kupffer washout, and blue denoting minimal or no variation—provides a visual representation of washout timing across the lesion. For imaging analysis, three critical time frames were established: (1) the arterial phase, specifically the point of maximum lesion enhancement; (2) the early portal venous phase, occurring approximately 1-minute post-injection and marking the initial washout observation period; and (3) the vasculo-Kupffer phase, defined as occurring about 5 or 10 minutes after injection and enabling the visualization of any prolonged washout effects. This approach may facilitate a more nuanced analysis of washout characteristics, potentially improving the accuracy of FLL differentiation.
Two-dimensional color map of the washout (WO) parametric image.
Procedure for Calculating WOPI
For the calculation of WOPI, the software first loads the previously recorded cine clips. The operator then selects three image frames, corresponding to the arterial phase, early portal venous phase, and vasculo-Kupffer phase of enhancement. For each image, the operator manually selects the cross-section of the target lesion at its largest diameter. For images captured between 0 to 1 minute after injection, the desired cross-section can be consistently obtained due to the regularity of the breathing cycle. For subsequent images, since patients are instructed to hold their breath, the desired cross-section is captured when the image is saved.
Initially, for the arterial phase peak enhancement frame, the operator defines the first region of interest (ROI) on the targeted liver lesion and the second ROI on the adjacent liver parenchyma. ROIs of the same size are then automatically applied to subsequent frames in the same location. The operator must confirm that the ROI is properly positioned on the target or adjust its location to the correct position if displacement occurs due to motion.
Following ROI selection, the software calculates the WOPI by quantifying the differences in pixel intensity between the lesion and the average intensity within the parenchymal tissue ROI. This process mirrors the conventional analytical methods employed in CEUS assessments. The software then superimposes the calculated differences (expressed in dB) for the early portal venous and vasculo-Kupffer phases onto the contrast B-mode image, producing a visual representation of the washout characteristics. This facilitates not only the detection of washout presence or absence but also a semi-quantitative assessment of the washout degree through the brightness and hue of the color. The determination of ROI settings is made collaboratively by two physicians via consensus, thus promoting the reliability and accuracy of the analysis.
Observer Study
A receiver operating characteristic (ROC) observer study was independently conducted by four hepatologists (H.T, Y.Y, H.T, T.W, with 12, 10, 3, and 1 year of experience in liver CEUS, respectively) who were not involved in performing the CEUS examinations and were blinded to the final diagnoses and patient information. They used ROC software (ROCViewer-ForMethod 1 ver. 1.0.1) developed by the Japanese Society of Radiological Technology task group [10]. This software featured a rating bar that allowed the observers to indicate their confidence in differentiating between benign and malignant lesions by clicking on the bar, with the left and right ends representing "definitely benign" and "definitely malignant," respectively (Supplementary Fig. 2). The ratings were quantified on a continuous scale from 0.0 to 1.0, based on the distance from the left end of the bar to the selected point.
Four independent reading sessions were conducted, featuring the following image sets: (1) native CEUS images comprising B-mode, arterial phase (peak enhancement), 1-minute, and 5-minute images; (2) a B-mode image paired with a washout-parametric image derived from the peak, 1-minute, and 5-minute images; (3) native CEUS images including B-mode, arterial phase (peak enhancement), 1-minute, and 10-minute (Kupffer phase) images; and (4) a B-mode image alongside a washout-parametric image generated from the peak, 1-minute, and 10-minute images. Initially, the four readers independently evaluated sets 1 and 2 in sequence. Subsequently, after a 1-month interval to mitigate any potential learning effects, the same readers independently assessed sets 3 and 4 in sequence.
For the observer study, 90 patients were randomly selected. These included 30 with HCCs, 30 with non-HCC malignancies (comprising 25 liver metastases and five intrahepatic cholangiocarcinomas), and 30 with benign lesions (18 hemangiomas and 12 FNHs). This group was selected from the imaging database, which included all 181 patients and 181 lesions. The decision to limit the number of cases for the observer study was based on two main considerations. First, a complete review of all lesions would have excessively burdened the observers, and reducing the number of cases helped maintain their concentration. Second, the lesion database was imbalanced, with 133 of 181 lesions (73.5%) malignant and only 48 benign, making it unsuitable to conduct the observer study with the entire set. Furthermore, malignant lymphomas and AMLs were excluded from the observer study due to their rarity. The details are presented in Table 1. Prior to the observer study, each reader was trained on how to use the software’s rating bar and interpret the WOPI, with the aid of some pretest cases. The diagnostic criteria for CEUS used by the readers to determine their confidence in differentiating benign from malignant lesions were based on established US criteria for hepatic tumors [11]. The WOPI was interpreted using specific reading rules: lesions were classified as malignant if they displayed red or yellow hues on the color map (indicative of a washout pattern) and as benign if they exhibited blue hues. One hepatologist (K.S.) who did not participate in the observer study reviewed all FLLs and documented the intensity and pattern of arterial phase enhancement, as well as the presence or absence of washout, up to 10 minutes post-injection.
Observer performance study regarding liver lesions
Statistical Analysis
To summarize the data, normally distributed continuous variables are expressed as means±standard deviations, while non-normally distributed continuous variables are presented as medians (interquartile ranges). Categorical variables are expressed as absolute numbers with percentages. The differences in background characteristics between malignant and benign lesions were assessed using the Student t-test or the chi-square test. The overall diagnostic performance of CEUS and WOPI for differentiating between benign and malignant FLLs was evaluated using the area under the receiver operating characteristic curve (AUC) and the 95% confidence interval (CI). Cutoff values for the two techniques were determined to maximize the Youden index, as sensitivity and specificity were equally important. Sensitivity, specificity, and accuracy, along with their 95% CIs, were reported for these cutoff values. The average AUC values were compared using the DeLong test, and pooled sensitivity, specificity, and accuracy values were compared using the McNemar test. The intraclass correlation coefficient (ICC) was used to evaluate interobserver agreement for both techniques, with ICC values greater than 0.75 considered indicative of good agreement [12]. All statistical analyses were performed using SAS version 9.4 (SAS Institute Inc., Cary, NC, USA) and JSRT-MRMC (multi-reader multi-case) software [13]. P-values of less than 0.05 were considered to indicate statistical significance.
Results
Differentiation between Malignant and Benign Lesions
The diagnostic performance of cCEUS and WOPI was evaluated based on the average AUC and pooled sensitivity, specificity, and accuracy metrics, as observed by four readers (Table 2). The data for each of the four readers are provided in Supplementary Table 1. For the 5-minute evaluation, cCEUS exhibited an average AUC of 0.87 and pooled sensitivity of 0.83 (95% CI, 0.78 to 0.88), specificity of 0.83 (95% CI, 0.75 to 0.89), and accuracy of 0.83 (95% CI, 0.79 to 0.87). WOPI showed similar performance, with an average AUC of 0.85 and pooled sensitivity of 0.80 (95% CI, 0.75 to 0.85), specificity of 0.78 (95% CI, 0.70 to 0.85), and accuracy of 0.80 (95% CI, 0.75 to 0.84). For the 10-minute evaluation, cCEUS metrics were slightly lower, with an average AUC of 0.84 and pooled sensitivity of 0.78 (95% CI, 0.73 to 0.83), specificity of 0.82 (95% CI, 0.74 to 0.88), and accuracy of 0.79 (95% CI, 0.75 to 0.84). The performance of WOPI was comparable to that of cCEUS, with an average AUC of 0.83 and pooled sensitivity of 0.82 (95% CI, 0.76 to 0.86), specificity of 0.77 (95% CI, 0.68 to 0.84), and accuracy of 0.80 (95% CI, 0.76 to 0.84).
Comparison of diagnostic performance between cCEUS and WOPI as interpreted by four readers
Statistical analysis revealed no significant difference in diagnostic performance between cCEUS and WOPI at either 5 or 10 minutes. The differences in the AUC were 0.0183 (95% CI, -0.0533 to 0.0898) at 5 minutes and 0.0062 (95% CI, -0.0161 to 0.0285) at 10 minutes. Furthermore, extending the observation period from 5 to 10 minutes did not significantly affect the diagnostic outcomes for either technique, with the difference in AUC with being 0.0238 (95% CI, -0.0240 to 0.0716) for cCEUS and 0.0117 (95% CI, -0.0623 to 0.0858) for WOPI.
Inter-reader Agreement of cCEUS Images and Washout Parametric Images
The interobserver agreement for both cCEUS and WOPI was analyzed, with results reported for the initial 5-minute and extended 10-minute evaluation periods. For the 5-minute evaluation, cCEUS images exhibited an ICC of 0.71 (95% CI, 0.64 to 0.79), indicating moderate agreement among readers. WOPI images showed an ICC of 0.77 (95% CI, 0.70 to 0.83), reflecting good agreement (Table 3). For the 10-minute evaluation, cCEUS images maintained moderate agreement with an ICC of 0.67 (95% CI, 0.58 to 0.75). WOPI images again demonstrated good agreement with an ICC of 0.77 (95% CI, 0.70 to 0.90) (Table 3). This analysis suggests that WOPI yielded higher inter-reader agreement than cCEUS at both the 5-minute and 10-minute marks, indicating that WOPI may offer a more reliable basis for the differential diagnosis of FLLs.
Interobserver agreement
Patterns of Enhancement in cCEUS
The arterial phase and washout characteristics are detailed in Tables 4 and 5, respectively. Of the 18 hemangiomas studied, 16 lesions (88.9%) exhibited the typical peripheral globular enhancement pattern with centripetal filling. Conversely, two lesions (11.1%) displayed diffuse hyperenhancement during the arterial phase. Regarding washout characteristics, six lesions (33.3%) exhibited hypoenhancement and 12 lesions (66.7%) displayed isoenhancement in the Kupffer phase. Notably, one lesion that presented with diffuse hyperenhancement in the arterial phase also showed early washout, occurring within 60 seconds.
Arterial phase characteristics
Washout characteristics
Among the 12 FNHs, all nodules showed diffuse and homogeneous enhancement in the arterial phase. Among them, one lesion (8.3%) exhibited early washout (<60 seconds). In the Kupffer phase, eight lesions (66.7%) showed isoenhancement, three (25.0%) showed hyperenhancement, and one (8.3%) showed hypoenhancement.
Among the 30 HCCs, 18 lesions (60.0%) exhibited typical arterial phase hyperenhancement followed by mild washout during the vasculo-Kupffer phase (including the Kupffer phase). Four lesions (13.3%) demonstrated arterial phase hyperenhancement with persistent isoenhancement up to the Kupffer phase. Three lesions (10.0%) displayed arterial phase hyperenhancement with early washout (<60 s). Four lesions (13.3%) showed isoenhancement in the arterial phase; of these, two showed mild washout in the vasculo-Kupffer phase (including the Kupffer phase), while the other two exhibited early washout. One lesion (3.3%) presented with rim enhancement during the arterial phase and washout during the vasculo-Kupffer phase, including the Kupffer phase.
Among the 30 non-HCC malignancies (25 liver metastases and five intrahepatic cholangiocarcinomas), a typical pattern of rim enhancement was observed in nine lesions (30.0%), while diffuse enhancement was observed in 21 (70.0%). Early washout (<60 seconds) was seen in 27 lesions (90.0%). The remaining three lesions (10.0%), all of which were metastases, exhibited washout by 5 minutes.
Discussion
The present study demonstrated that the diagnostic performance of WOPI was comparable to that of cCEUS in the evaluation of FLLs. Specifically, the difference in the AUC value between cCEUS and WOPI at 10 minutes was 0.0062 (95% CI, -0.0161 to 0.0285). Similarly, at the 5-minute mark, the difference in AUC values between methods was 0.0183 (95% CI, -0.0533 to 0.0898). Furthermore, superior interobserver agreement was observed with WOPI compared to cCEUS. This improvement is likely due to the color-coded maps employed by WOPI, which improve the visibility and objectivity of washout characteristics and thus support interpretation. This feature is particularly beneficial for readers with limited experience in CEUS, making WOPI a valuable tool in settings with diverse levels of reader expertise.
Research has underscored the importance of analyzing various phases—arterial, portal, vasculo-Kupffer, and post-vascular (Kupffer)—for comprehensive characterization of FLLs [4]. A key factor in differentiating malignant from benign FLLs is the detection of washout in the lesion relative to the surrounding liver tissue. The observer study indicated that the identification of washout in HCC lesions increased over time, with 76.7% (23 of 30 HCCs) showing washout at 5 minutes and 83.3% (25 of 30 HCCs) by 10 minutes (Fig. 2A, B). Additionally, a clear majority of non-HCC malignancies exhibited washout within the first minute (90%, 27 of 30 lesions), with all such lesions displaying washout by 5 minutes (Fig. 3A, B). These washout patterns facilitated the accurate diagnosis of most lesions by the four readers using both cCEUS and WOPI.
A 74-year-old man with hepatocellular carcinoma.
Ultrasound (US) images consistently demonstrate a true-positive diagnosis across all evaluators, using both conventional contrast-enhanced ultrasound and washout-parametric imaging (WOPI), with a high degree of confidence. A. The lesion, 2 cm in diameter, is situated in Couinaud segment 6 of the liver. On B-mode US, the lesion appears slightly hyperechoic. Dynamic contrast-enhanced ultrasound shows arterial phase hyperenhancement followed by mild washout in the Kupffer phase, observed 10 minutes after injection. From left to right, the images represent B-mode, arterial phase, 1 minute, and 10 minutes. B. In the WOPI analysis, the corresponding lesion is marked in red, indicating vasculo-Kupffer phase washout.
A 60-year-old man with liver metastasis from stomach cancer.
Ultrasound (US) images consistently demonstrate a true-positive finding across all evaluators, using both conventional contrast-enhanced ultrasound and washout-parametric imaging (WOPI), with a high level of confidence. A. The lesion, 2 cm in diameter, is situated in Couinaud segment 6 of the liver. On B-mode US, the lesion appears slightly hyperechoic. Dynamic contrast-enhanced ultrasound shows rim enhancement during the arterial phase as well as early washout. At the Kupffer phase (10 minutes), the lesion presents a distinct contrast defect. From left to right, the images represent B-mode, arterial phase, 1 minute, and 10 minutes. B. WOPI delineates the same lesion in yellow, signifying early washout.
However, the HCCs that did not exhibit washout within 10 minutes—representing five of 30 lesions (16.7%)—posed diagnostic challenges for both imaging modalities. Within this subset of indeterminate cases, 80.0% (four out of five) were classified as well-differentiated HCCs, while the pathology of one lesion remained undetermined. These findings align with those reported by Jang et al., who noted that most (78%) of HCCs lacking washout were well-differentiated [14]. This highlights the diagnostic complexities associated with well-differentiated HCCs in CEUS imaging, emphasizing the need for careful interpretation of washout patterns, particularly when differentiating HCC subtypes.
In the evaluation of benign liver lesions, the present findings highlight specific diagnostic challenges and insights. For FNH, a large majority—11 of 12 lesions, or 91.7%—exhibited no washout until 10 minutes, which is consistent with typical benign behavior. However, one FNH lesion with a prominent central scar deviated from this pattern and exhibited washout. This atypical characteristic led all four readers to incorrectly classify it as malignant with high confidence on both cCEUS and WOPI, underscoring the potential for misinterpretation of lesions with atypical features (Fig. 4A-C).
A 36-year-old woman with focal nodular hyperplasia.
Ultrasound (US) images were deemed indeterminate by all readers using both conventional contrast-enhanced ultrasound and washout-parametric imaging (WOPI), albeit with varying confidence levels. A. The lesion measures 2.2 cm in diameter and is situated in Couinaud segment 7 of the liver. On B-mode US, the lesion appears slightly hyperechoic. Dynamic contrast-enhanced ultrasound shows hyperenhancement during the arterial phase followed by early washout within 60 seconds. From left to right, the images represent B-mode, arterial phase, 1 minute, and 10 minutes. B. WOPI displays the same lesion with a combination of yellow and red hues, indicative of washout. C. An axial gadoxetate-enhanced magnetic resonance image depicts the lesion as hypointense with a subtle peripheral ring of uptake (indicated by an arrow).
The hemangiomas in this study exhibited a range of diagnostic appearances (Fig. 5A-D). Of the 18 hemangiomas evaluated, 16 (88.9%) displayed the anticipated peripheral globular enhancement and centripetal filling pattern. This pattern facilitated accurate, high-confidence diagnoses by most readers using cCEUS. In contrast, WOPI presented challenges in detecting this pattern. Specifically, six hemangiomas (33.3%) demonstrated mild washout at 10 minutes but not at 5 minutes, leading to incorrect diagnoses by all readers using WOPI until the 10-minute mark (Fig. 5C). This underscores a limitation of WOPI in capturing the subtle enhancement patterns characteristic of hemangiomas. Furthermore, a hemangioma that showed diffuse hyperenhancement in the arterial phase followed by washout within 1 minute—indicative of a high-flow hemangioma—was misdiagnosed by all readers using both cCEUS and WOPI.
Ultrasound images of a 40-year-old man with a hemangioma presented challenges for all readers.
A. A hemangioma measuring 2 cm in diameter is evident in Couinaud segment 3 of the liver. The B-mode image displays a peripheral hyperechoic lesion. Contrast-enhanced ultrasound reveals peripheral globular enhancement with centripetal filling, achieving isoenhancement by 5 minutes, indicative of a typical hemangioma. B. However, the image at 10 minutes shows peripheral globular enhancement with centripetal filling and slight hypoenhancement. From left to right, the images represent B-mode, arterial phase, 1 minute, and 5 minutes (A)/10 minutes (B). C. Washout-parametric imaging (WOPI), including the image taken at 5 minutes, shows the lesion in blue, indicating no washout and strongly suggesting a benign lesion. D. WOPI, including the 10-minute image, shows the lesion in red, indicating washout and falsely suggesting a malignant lesion.
Pharmacokinetic research indicates that Sonazoid is phagocytosed by reticuloendothelial cells, such as Kupffer cells [15]. This results in highly effective identification of target lesions through sustained parenchymal enhancement, termed the Kupffer phase, during percutaneous procedures like tumor biopsy or local ablation therapy. The present research revealed no significant difference in overall diagnostic performance; however, the diagnostic accuracy of imaging sets at 5 minutes for both cCEUS and WOPI was slightly better than at 10 minutes. This discrepancy could be due to several factors: first, in the case series, a subset of hemangiomas (six of 18, or 33.3%) exhibited washout during the Kupffer phase, while only one (5.6%) showed washout by 5 minutes, which may have negatively impacted the results for the 10-minute imaging sets for both cCEUS and WOPI. Second, patients with diminished liver function exhibited rapid Sonazoid washout from the liver parenchyma, likely due to a reduced number and functionality of Kupffer cells. This could hinder the readers’ ability to accurately determine the presence or absence of washout, particularly during the Kupffer phase. However, various retrospective studies have reported increased sensitivity in diagnosing HCC without a loss of specificity when including the Kupffer phase [16–18]. Consequently, it remains unclear whether incorporating Kupffer-phase imaging improves diagnostic accuracy. Future prospective studies with larger samples are necessary to understand the added value of this imaging.
The present study faced several limitations. First, although WOPI was sensitive in detecting the presence or absence of washout with high objectivity, it was less effective at capturing wash-in features, particularly in identifying peripheral globular patterns. To exceed the diagnostic efficacy of cCEUS, further improvements are necessary. Second, the ROIs were determined by consensus between two physicians, which may have introduced bias, especially affecting the objectivity of WOPI. Future research must investigate how variations in ROI placement might influence diagnostic accuracy. Moreover, the establishment of appropriate ROIs was challenging, particularly in cases with reduced liver enhancement due to liver function issues or when tumors occupied large areas, making clear contrast differentiation difficult. This may have skewed the results, particularly for WOPI. In such cases, the authors compensated by measuring the decrease in tumor enhancement from peak to early and vasculo-Kupffer frames, rather than directly comparing tumor and tissue intensities. Lastly, a histologic reference standard was not available for a minority of patients, often in cases presumed to be benign, due to ethical considerations.
Considering the results of the ROC observer study, only the non-experts’ scores were higher with WOPI than with cCEUS; the experts were able to make adequate judgments using cCEUS as well. This indicates a need to refine WOPI into an algorithm that facilitates interpretation. Nevertheless, regarding the goals of condensing information into a single image and offering straightforward assistance to non-expert users, these findings appear to align with the initial hypothesis.
In conclusion, the present study demonstrated that the diagnostic performance of WOPI is comparable to that of cCEUS in differentiating FLLs, with the added benefit of superior interobserver agreement. Although further improvements are required, WOPI represents a promising alternative imaging modality for the visualization of FLLs in clinical practice.
Notes
Author Contributions
Conceptualization: Kakegawa T, Sugimoto K, Kamiyama N, Hashimoto H, Itoi T. Data acquisition: Kakegawa T, Sugimoto K, Kamiyama N, Hashimoto H, Takahashi H, Wada T, Yoshimasu Y, Takeuchi H. Data analysis or interpretation: Kakegawa T, Nakayama R, Sakamaki K. Drafting of the manuscript: Kakegawa T, Sugimoto K, Kamiyama N. Critical revision of the manuscript: Kakegawa T, Sugimoto K, Kamiyama N, Hashimoto H, Takahashi H, Wada T, Yoshimasu Y, Takeuchi H, Nakayama R, Sakamaki K, Itoi T. Approval of the final version of the manuscript: all authors.
All authors declare no conflict of interest except for Naohisa Kamiyama and Hiroshi Hashimoto, who are employees of GE HealthCare Corporation. Only authors with no conflicts of interest had full control over the inclusion of data and information. The diagnostic ultrasound scanner used in this study, the LOGIQ E10 (GE HealthCare, Wauwatosa, WI, USA), was supplied by the manufacturer.
Supplementary Material
Comparison of diagnostic performance between cCEUS and WOPI by each of the four readers (https://doi.org/10.14366/usg.24100).
Sonazoid contrast-enhanced ultrasonography protocol (https://doi.org/10.14366/usg.24100).
Appearance of the software interface for the receiver operating characteristic observer study: for conventional contrast-enhanced ultrasound (A) and for washout (WO) parametric imaging (B) (https://doi.org/10.14366/usg.24100).
References
Article information Continued
Notes
Key point
The diagnostic performance did not significantly differ between conventional contrast-enhanced ultrasound (cCEUS) and washout-parametric imaging (WOPI) at either 5 or 10 minutes. Extending the observation period from 5 to 10 minutes did not significantly alter the diagnostic outcomes for either technique. WOPI consistently exhibited higher inter-reader agreement than cCEUS.