Intraoperative contrast-enhanced ultrasound (CEUS) with time intensity curve (TIC) analysis for better assessment of liver tumor margins

• Abstract
• Zusammenfassung
• Introduction
• Materials and Methods
• Ethics
• Patient Collective
• Performing intraoperative examination techniques using ultrasound and CEUS
• Characterization and quantitative perfusion analysis with IO-CEUS
• TIC analysis and verification of the final diagnosis
• Statistical analysis
• Results
• Discussion
• Conclusion
• References

Abstract

Purpose

The purpose of this study was to conduct an intraoperative evaluation of focal liver lesions using time intensity curve (TIC) analysis of contrast-enhanced ultrasound (CEUS) to better assess liver tumor margins.

Materials and Methods

This study included 28 patients (21 men 75%, 7 women 25%) with malignant liver lesions (cholangiocellular carcinoma (CCC), n = 9; hepatocellular carcinoma (HCC), n = 6; hepatic metastases (HepMET), n = 13). A B-mode scan, color-coded Doppler sonography, and CEUS were performed intraoperatively to analyze the focal lesions. The generated parametric images were based on continuous cine loops, acquired with a multifrequency T-probe (6–9 MHz), from the early arterial phase (0–15 seconds) to the portal venous phase (1 minute), generated by integrated perfusion software. Analyses of the CEUS loops were performed using TICs with respect to time-to-peak (TTP) and area under the curve (AUC). Perfusion analysis was performed in the center and periphery of the tumor as well as in healthy liver tissue. All tumor lesions were evaluated histopathologically to verify the diagnosis.

Results

Sufficient image quality was achieved in all cases using CEUS for TIC analysis. A comparison of all groups showed a clear difference compared with the center, margin, and healthy liver tissue in the measured parameters of TTP and AUC (p = 0.035 and p = 0.045, respectively). In detail, differences were observed in the CCC group (TTP: p = 0.025) and in the HepMET group (TTP: p = 0.009), particularly in the peripheral areas (strong arterial flooding with a rapid increase in the flooding curve), with equally clear tumor edge representation compared with healthy liver tissue, as shown by the AUC analysis (CCC AUC: p = 0.032 and HepMET AUC: p = 0.029). In patients with HCC, the perfusion pattern (starting from the center) showed the center to be more clearly distinguishable from the edge with significant TTP and AUC (p = 0.035 and p = 0.038).

Conclusion

Intraoperative TIC analysis of malignant liver tumors is an important diagnostic tool for better highlighting liver tumor margins during surgery.

Key Points

• CEUS with dynamic vascularization. Analysis of liver malignancies and tumor margins. Intraoperative time intensity curve analysis.

Citation Format

• Dropco I, Kaiser U, Jung F et al. Intraoperative contrast-enhanced ultrasound (CEUS) with time intensity curve (TIC) analysis for better assessment of liver tumor margins. Rofo 2025; DOI 10.1055/a-2600-7229

Zusammenfassung

Ziel

Ziel dieser Studie war es, eine intraoperative Bewertung fokaler Leberläsionen mit Hilfe der Zeit-Intensitäts-Kurven-Analyse (TIC) des kontrastverstärkten Ultraschalls (CEUS) durchzuführen, um Lebertumorränder besser beurteilen zu können.

Material und Methoden

Diese Studie umfasste 28 Patienten (21 Männer 75%, 7 Frauen 25%) mit bösartigen Leberläsionen (cholangiozelluläres Karzinom CCC, n = 9; hepatozelluläres Karzinom HCC, n = 6; Lebermetastasen HepMET, n = 13). Zur Analyse der fokalen Läsionen wurden intraoperativ ein B-Scan, eine farbkodierte Dopplersonografie und ein CEUS durchgeführt. Die erzeugten parametrischen Bilder basierten auf kontinuierlichen Cine-Loops, die mit einer Multifrequenz-T-Sonde (6–9 MHz) von der frühen arteriellen Phase (0–15 Sekunden) bis zur portalvenösen Phase (1 Minute) aufgenommen und von einer integrierten Perfusionssoftware generiert wurden. Die Analyse der CEUS-Schleifen erfolgte mithilfe von TICs in Bezug auf die Zeit bis zum Spitzenwert (TTP) und die Fläche unter der Kurve (AUC). Die Perfusionsanalyse wurde sowohl im Zentrum und in der Peripherie des Tumors als auch im gesunden Lebergewebe durchgeführt. Alle Tumorläsionen wurden histopathologisch untersucht, um die Diagnose zu bestätigen.

Ergebnisse

In allen Fällen wurde mit CEUS eine ausreichende Bildqualität für die TIC-Analyse erreicht. Ein Vergleich aller Gruppen zeigte einen deutlichen Unterschied in den gemessenen Parametern TTP und AUC gegenüber dem Zentrum, dem Rand und dem gesunden Lebergewebe (p = 0,035 bzw. p = 0,045). Im Einzelnen wurden Unterschiede in der CCC-Gruppe (TTP: p = 0,025) und in der HepMET-Gruppe (TTP: p = 0,009) vor allem in den peripheren Bereichen (starke arterielle Anflutung mit schnellem Anstieg der Anflutungskurve) bei ebenso deutlicher Tumorranddarstellung im Vergleich zum gesunden Lebergewebe beobachtet, wie die AUC-Analyse zeigte (CCC AUC: p = 0,032 und HepMET AUC: p = 0,029). Bei Patienten mit HCC zeigte das Perfusionsmuster (ausgehend vom Zentrum), dass das Zentrum deutlicher vom Rand zu unterscheiden war, mit signifikanter TTP und AUC (p = 0,035 und p = 0,038).

Schlussfolgerung

Die intraoperative TIC-Analyse bösartiger Lebertumore ist ein wichtiges diagnostisches Instrument zur besseren Hervorhebung der Lebertumorränder während der Operation.

Kernaussagen

• CEUS mit dynamischer Vaskularisierung. Analyse von Lebermalignomen und Tumorrändern. Intraoperative Zeit-Intensitätskurven-Analyse.

Introduction

In recent years, there has been significant advancement in the field of intraoperative imaging with the introduction of intraoperative contrast-enhanced ultrasound sonography (IO-CEUS) [1]. This technique involves the use of a specialized ultrasound contrast agent, consisting of microbubbles, to enhance the visualization of vascular anatomy down to the microcirculation and tumor perfusion in real time [2]. Liver-specific contrast agents are already being tested worldwide but are not approved in the European Union. Contrast agent-based ultrasound analysis, therefore, offers improved characterization of wash-in and washout kinetics. For the first time, the tumor margins and their vascular infiltration can be measured and highlighted more clearly, as was previously only possible with MRI perfusion diffusion using liver-specific contrast agents [3].

CEUS has revolutionized conventional B-mode and Doppler sonography by increasing the intensity of the blood echo signal and allowing for microvascular perfusion [4]. This has created new opportunities for improved detection of tissue perfusion as well as the identification of organ and vascular lesions. By injecting the contrast agent intravenously, ultrasound imaging can provide enhanced visualization of blood flow and tissue perfusion. Furthermore, CEUS offers the advantage of being able to detect blood vessels as small as 100 μm in diameter, thus providing more detailed information about microvascular perfusion than conventional color Doppler imaging [5]. If there are several hypervascularized lesions on CT or MRI without a correlate on the B-mode scan, it is possible to achieve early arterial reflooding of the microbubbles using flash-kinetics. Alternatively, the CEUS examination can also be repeated, as there is no limit to the amount of contrast medium itself, as the microbubbles are well exhaled. In flash-kinetics, the transmission power is briefly increased to 100%, which leads to shattering of the local microbubbles. A subsequent reduction to an MI <0.2 then allows re-flooding – for the detection of early arterial microvascularization of further tumor foci and their characterization. The evaluation of this reflooding is also referred to as FLASH replenishment. Time intensity curves, known as TIC analyses, can be helpful for this purpose [6].

One of the key advantages of CEUS is its ability to provide detailed information about the rate of tumor perfusion. By analyzing the time intensity curve (TIC) of the contrast agent, using algorithms to determine the peak of maximum enhancement, clinicians can gain valuable insight into the vascular dynamics within the tumor [7]. This parameter is closely linked to tumor angiogenesis; it can help guide treatment decisions and involves tracking the intensity of the contrast agent over time and generating a curve that represents its enhancement pattern [8]. Especially in conventional intraoperative decision-making strategies using CEUS techniques, this curve can provide more valuable information about the vascular characteristics of the tumor, within neo-angiogenesis, such as the time-to-peak (TTP) enhancement, wash-in and washout rates, and the area under the curve (AUC). This detailed analysis can provide insight into tumor vascularization and treatment response. Moreover, the use of IO-CEUS with perfusion analysis has proven to be particularly valuable in surgical procedures. By providing real-time visualization of tumor perfusion, CEUS allows surgeons to assess the vascular status of the tumor during surgery [1].

In conclusion, the use of conventional intraoperative CEUS in the setting of a long-term strategy is certainly a contributor to good patient outcomes [9]. Nevertheless, this information can help guide surgical decisions, such as determining the extent of resection or providing more reliable identification of areas and boundaries of residual tumor that may require further intervention. In addition, performing perfusion analysis with TIC analysis during intraoperative procedures adds an additional level of precision and accuracy to surgical interventions.

Materials and Methods

Ethics

The university approved this study and the retrospective analysis of CEUS and its intraoperative perfusion images.

Patient Collective

A total of 28 patients [n = 21 men (75%), n = 7 women (25%)] with malignant liver lesions [cholangiocellular carcinoma (CCC), n = 9; hepatocellular carcinoma (HCC), n = 6; and hepatic metastases of a colorectal carcinoma (HepMET), n = 13] were examined retrospectively over a period of 1 year using IO-CEUS. As a requirement for performing surgery for malignant liver tumors, all patients underwent contrast-enhanced magnetic resonance imaging (MRI) and computed tomography (CT) or, in individual cases, preoperative histopathological examination of the existing liver lesions ([Table 1]). The IO-CEUS examination was performed by an interdisciplinary radiological and surgical examiner using a high-resolution multifrequency convex T-probe transducer (6–9 MHz). The procedure chosen in the present study was a CEUS examination, which was subsequently analyzed using device-integrated perfusion software by means of perfusion curves. Written informed consent was obtained from the participants for all examinations. Surgical informed consent and a tumor board decision were present for all patients. These documents are maintained in the patient’s medical record in an internal computer system. However, written information about applications and surgical procedures is subject to internal hospital documentation requirements and may not be shared. The preoperative information discussion includes the surgery and the use of CEUS up to and including the procedure according to the findings.

A contrast agent allergy was considered a contraindication but was not an issue. Additionally, all methods were performed in accordance with the relevant guidelines and regulations. The guidelines refer to the European Federation for Ultrasound in Medicine (EFSUMB) guidelines.

Performing intraoperative examination techniques using ultrasound and CEUS

An examiner at the operating table (surgeon) and a radiologist operating the ultrasound device performed the intraoperative examination in an interdisciplinary manner. The ultrasound examination was performed by an experienced examiner (more than 20 years of experience, more than 3000 examinations per year), the operation was performed by an experienced surgeon (more than 10 years of experience in liver surgery, head of hepatobiliary surgery). Only one sonographer and one surgeon were involved. Only the primary tumor for research was analyzed, thus only tumor lesions clearly detected on CT and MRI were correlated with intraoperative CEUS. In detail, no other satellite or more than one intrahepatic metastases were included in this study. Only solid unifocal tumors were analyzed.

The lesions were first examined using a B-scan with a high-end device (LOGIQ E9, GE, Milwaukee, WI, USA) and a T-probe (6–9 MHz). Macrovascularization was then recorded using power Doppler and color-coded Doppler sonography. For the subsequent examination with CEUS, 2.4–5 ml of intravenous contrast medium (SonoVue, Bracco, Milan, Italy) were used with subsequent bolus administration of 5–10 ml of 0.9% saline solution. SonoVue is a second-generation contrast agent. The sulfur hexafluoride microbubbles have a phospholipid coating, which accumulates in the blood and remains strictly intravascular. The microbubbles have a diameter of 2–10 μm and can pass through the capillaries. The interface between the sulfur hexafluoride gas and blood reflects the ultrasound waves and thus enhances the contrast between tissue and blood. Finally, 1-minute digital DICOM loops were stored in the picture archiving and communication system from the time of inflow to the beginning of arterial outflow of the contrast medium.

Characterization and quantitative perfusion analysis with IO-CEUS

Malignant lesions typically show irregular arterial contrast in metastases starting from the edge (especially colorectal tumor lesions) and in HCC and CCC in the center with increasing washout toward the late phase. Images that were recorded without relevant movement artifacts were required for perfusion analysis using CEUS. Stored DICOM loops longer than 1 minute were processed after the IO-CEUS examination. Since the examinations take more than one minute, artifact-free work is important for the result of the examination in order to be able to better analyze the perfusion curves. It is important to keep the probe steady on the liver surface. Minor artifacts can be ignored in the examiner’s manually selected ROI. Quantitative curves were generated using device-integrated perfusion software. In this regard, the TIC analysis indicated the dynamics of the microbubbles in the corresponding regions of interest (ROIs) over time. A total of eight ROIs (5–7 mm) were distributed over the focal liver lesions (FLLs) and healthy liver tissue (two in the center, four at the edge of the lesion, and 2 in healthy liver tissue). The ROIs were not selected by the device automatically. The experienced examiner had to select the ROIs manually. Within each ROI, we thus dynamically calculated and mapped the changes in perfusion behavior and intensity of the contrast agent using TIC, describing the dynamic microvascularization with the wash-in and washout phenomenon. This allowed the device-integrated software to generate an autonomous image sequence with perfusion patterns and TIC analyses already in the early arterial phase after administration of the contrast agent. To generate reproducible results, the software algorithm for the interpretation of dynamic vascularization required manual adjustments of the ROIs. We defined the TTP as the time interval (in seconds) between the bolus injection of the contrast agent and the peak of contrast agent accumulation (point of peak). The AUC described the integral and thus the quantitative area calculated under the TIC curve with relative units of measurements (rU). In this respect, TIC evaluation allowed a machine-assisted perfusion analysis with regard to changes in microvascularization in the wash-in and early washout phases in the tumor center and margins compared with surrounding healthy liver tissue in order to better highlight the resection margins ([Table 2]).

TIC analysis and verification of the final diagnosis

The evaluation of the TIC analyses using TTP and AUC was interpreted and analyzed based on the underlying tumor entity (CCC/HCC/HepMET) with their associated ROIs. By evaluating TTP, the dynamic perfusion of liver tissue and tumors can be assessed. After arterial stenosis, TTP is prolonged. Thrombosis and sclerosis of the V-port lead to the formation of arterial collaterals with rapid onset of flow and shortened TTP, as is the case with tumor shunts. It is important to use more objective findings and also perform statistical analysis. Numerical, metric data are generated via TTP and AUC.

Malignant tumors show early washout and, therefore, often a centrally low AUC, which characterizes the flow volume. At the edge, in the area of neovascularization in the arterial phase, the AUC may be significantly higher than in liver tissue. Benign tumors have the same AUC and therefore the same flow volume as the liver. We verified the diagnoses using histopathological examination.

Statistical analysis

Data are presented as mean values and range. In order to compare all groups, analysis was performed using two-factorial analysis of variance. The groups were tested for normal distribution. Individual groups within a collective were compared using a t-test. A p-value <0.05 was considered significant. We performed the statistical analysis using SPSS 25.0 (SPSS Inc., Chicago, IL, USA).

Results

We examined 28 patients in this study. Seven of the patients were women, and 21 were men. The average age was 63.5 years, with the youngest patient being 38 years old and the oldest being 79 years. All patients had preoperative CT and MRI scans. All patients underwent correlating histopathologic examination postoperatively. A total of 9 CCCs, 6 HCCs, and 13 HepMETs of a colorectal carcinoma were examined using IO-CEUS. The average diameter of the malignant FLLs was 6.2 cm (0.5–13.5 cm) in the case of CCC, 6.9 cm (4.4–9.2 cm) in the case of HCC, and 3.6 cm (0.4–8.1 cm) in the case of HepMET. Three liver operations were stopped because of unexpected intraoperative findings (e.g., peritoneal carcinomatosis, significant size progression, or vascular invasion of the tumor). In these cases, a histological specimen was also obtained ([Table 1]).

Among the malignant liver tumors studied, HepMET was the largest group with 13 analyses, followed by CCC with 9 patients and HCC with 6 patients. In the comparative analysis of the summary statistics, the groups of the respective tumor entities showed significant differences (TTP: p = 0.035; AUC: p = 0.045), taking into account the TTPs and AUCs in the central and peripheral areas as well as in the liver parenchyma ([Fig. 1]). However, these can be subdivided as follows.

The image of an HCC is characterized by a clearly irregular hypervascularization in the arterial phase on CEUS. The hypervascularity is clearly demarcated in the arterial phase. In the portal venous phase, lesion enhancement is slightly more pronounced compared to the surrounding liver tissue. The values for TTP and AUC compared with healthy liver tissue were higher for TTP (28.5 ±15.1 seconds) and lower for AUC (577 ±329.7 rU) but were not statistically significant. Differences were observed only when comparing the center to the periphery (TTP: p = 0.035; AUC: p = 0.038) ([Fig. 2]).

In contrast to HCC, CCC in the arterial phase is characterized by rim enhancement (TTP from center to rim: 15.5 ± 9.1 seconds to 10.2 ± 5.4 seconds; p = 0.025) and reduced central microvascularization as hypoenhancement on CEUS. However, in the portal venous phase, we observed washout of the lesion compared to the surrounding tissue after approximately 1 minute. This phenomenon is reflected in the AUC (592.6 ± 343 rU to 444.1 ± 280.9 rU; p = 0.032) when the border area is delineated from the periphery ([Fig. 3] and [Fig. 6]).

Metastases with early accumulation in the arterial phase show special CEUS kinetics compared to the surrounding tissue on the CEUS image. This can be seen from the significantly higher TTP curve values in the comparison from the center to the liver tissue (23 ±14.4 seconds vs. 13.9 ±8.7 seconds; p = 0.033) as well as from the significant differences in the AUC curve values with a complete onset of washout after approximately 1 minute when comparing the boundaries from the peripheral area to the healthy liver tissue (569.8 ± 251 rU vs. 450 ± 226.1 rU; p = 0.029) ([Fig. 4] and [Fig. 5]).

As shown in [Fig. 6], another example of clearer characterization of tumor margins based on perfusion pattern and TIC analysis is the aforementioned CCC, highlighting better recognition of the capillary microcirculation of the tumor. Prior to surgery, a CT or MRI scan is needed for diagnosis and to determine vessel contribution.

Discussion

The current study underscores the value of integrating IO-CEUS in TIC analysis to highlight structure boundaries in solid tissues, in this case liver lesions. This integration has not only ushered in a new era of advances in diagnostic imaging [4] [10] [11] but can also be used intraoperatively to provide vivid real-time visualization of vascular anatomy, tumor perfusion, and the navigation of microvascular blood flow [1]. In this study, significant differences were shown, especially in the hepatic-metastasis group as well as in the CCC and HCC groups, by analyzing the two parameters, time-to-peak and area under the curve. More objective principles for data analysis could be presented to analyze the tumor margins with TIC, thereby the center and tumor margin could be highlighted specifically in comparison with healthy liver tissue.

CEUS of the liver has a high diagnostic value in the hands of experienced examiners [12]. In the DEGUM multicenter study, CEUS was able to achieve diagnostic reliability comparable with contrast-enhanced CT in terms of the detection and characterization of solid liver lesions under appropriate examination conditions [13] [14]. Contrast-enhanced MRI may have diagnostic advantages over CEUS in the detection and characterization of solid liver lesions due to the use of liver-specific MRI contrast agents [15] [16]. In contrast, second-generation ultrasound contrast agents are based on the principle of echo signal amplification by oscillating microbubbles using contrast harmonic imaging with a low mechanical index of <0.2. The EFSUMB guidelines describe a large number of applications relating to diagnostic imaging of the liver [4]. There is high diagnostic relevance for liver tumor diagnosis, as also reported by the Food and Drug Administration, including recommendations for applications related to pediatric issues [14] [17] [18].

Thus, CEUS represents a significant step beyond the limitations of conventional Doppler imaging [5] [19], particularly because of its novel ability to detect and diagnose the narrowing of even tiny blood vessels as small as 100 μm in diameter [10]. The ability to obtain detailed information regarding tumor perfusion rates using CEUS has been a significant revelation [20]. By interpreting the maximum enhancement intensity curve of the contrast agent, valuable insight into tumor-specific vascular dynamics has been obtained [7], facilitating informed clinical decision making [21]. Particularly in liver surgery, artifact-free examinations of liver lesions have conventionally been essential for good decision-making strategies [9]. Moreover, TIC analysis provides the clinician with a more valuable tool for understanding the vascular characteristics of the tumor by tracking the intensity pattern of the contrast agent over time, also adding individual information and perfusion characteristics of the lesions [10]. Neovascularization at the margins of lesions is particularly well visualized by the dynamic behavior of the contrast agent in the organ [22] [23]. This behavior can therefore also potentially serve as an important criterion for the analysis of margins in the TIC analysis. However, the original images obtained up to the late washout phase after 5 to 6 minutes must always be considered in the final characterization [24] [25].

The results of this study suggest that intraoperative CEUS, especially when used in conjunction with perfusion analysis, provides powerful insight into tumor vascularization and supports the monitoring of the response to therapy. A further advantage of intraoperative examination is the direct placement of the ultrasound probe on the organ without relevant artifacts and superpositions in the technique, which brings advantages both in both B-mode examination and in the CEUS diagnosis and characterization of solid liver tumors. This usually results in better and clearer visualization of the lesions based on intraoperative ultrasound, and examinations are first performed in the fundamental B-mode scan for quick orientation. The choice of probe and penetration depth can be adapted to the individual situation, although the use and advantages of T-probes have been proven intraoperatively [26].

For IO-CEUS, a double image display B-mode/CEUS scan has become established [27]. This allows possible tumor foci to be quickly identified on the B-mode scan, correlated with the palpation findings, differentiated from the surrounding structures, and marked more precisely in the diameter based on washout behavior. Often, the longitudinal and transverse extent of tumor foci cannot be detected precisely on the B-mode scan. Similarly, the depth of the tumor is often not clearly visible. In cases where it is not possible to reliably detect recognizable tumor foci on the B-mode scan from the CT or MRI examination and the palpation findings remain unclear, CEUS is important especially in the arterial phase to make it possible to determine the location in the suspicious area on the basis of the irregular tumor vascularization. Moreover, compared to CT as the diagnostic preoperative standard, MRI was more effective but also more expensive, including incremental cost effectiveness, while CEUS is cost-effective in some cases [28]. In the case of specific tumor entities, such as smaller foci in HCCs or neuroendocrine tumors with a maximum size of 10 mm, there is no need to detect washout in the late phase [14] [29]. For this reason, it is even more important to detect irregular early arterial tumor vascularization within 10–25 seconds after bolus administration of the ultrasound contrast agent on CEUS, which is also used in the TIC analysis described above. Postoperative outcomes, for example, in the patient group of hepatic metastases, improve prognosis in some cases in a study recently published by a Chinese group [30]. There are no future outcomes in the clinical follow-up such as disease-free survival considering the intraoperative TIC analysis.

TIC analysis, which can also bring intraoperative advantages for tissue differentiation, has only been used in neurosurgery [31]. Therefore, dynamic CEUS microvascularization is also an important basic issue for further TIC analysis and, in combination with these two methods, dynamic microvascularization detected by CEUS and TIC analysis can assist in tumor delineation and analysis of the entities. Nevertheless, more investigation is needed to analyze perfusion patterns in time between, e.g., MRI, CT, and CEUS-TIC analysis in liver diseases. Therefore, sometimes different contrast agent flow dynamics are seen in chronic liver diseases [32].

In conclusion, the real-time visualization and precise diagnosis of intraoperative CEUS with perfusion analysis can transform intraoperative procedures. As a result, it can have a more direct impact on surgical decisions and treatment planning, especially in critically ill patients, such as those who have received neoadjuvant treatment. In the literature, the change in intraoperative strategy and decision-making can be up to 20%. However, more clinical practice using TIC is needed to perform new clinical strategies [33].

Conclusion

In this study, TIC analysis shows significant differences between the tumor center, margin, and healthy liver tissue, thus an objective assessment to highlight the tumor margins can be used as an important diagnostic tool during liver surgery. More data and studies are needed to understand decision-making during liver resection. A high level of examination experience is required to display the characterized lesions without relevant artifacts in the arterial phase on CEUS and as stored DICOM loops as well as to evaluate these with TIC analysis [12]. Nevertheless, more data and multicentric cohorts are needed to verify broader examinations performing TIC analysis in the future combining the results with different software, most likely artificial intelligence-based, and future correlation in disease-free survival.

Conflict of Interest

The authors declare that they have no conflict of interest.

• References

• 1 Jung EM, Moran VO, Engel M. et al. Modified contrast-enhanced ultrasonography with the new high-resolution examination technique of high frame rate contrast-enhanced ultrasound (HiFR-CEUS) for characterization of liver lesions: First results. Clin Hemorheol Microcirc 2023; 83: 31-46
  PubMedSearch in Google Scholar
• 2 Robbin ML. Ultrasound contrast agents: a promising future. Radiol Clin North Am 2001; 39: 399-414
  CrossrefPubMedSearch in Google Scholar
• 3 Dietrich CF, Correas JM, Cui XW. et al. EFSUMB Technical Review – Update 2023: Dynamic Contrast-Enhanced Ultrasound (DCE-CEUS) for the Quantification of Tumor Perfusion. Ultraschall Med 2024; 45: 36-46
  Thieme ConnectPubMedSearch in Google Scholar
• 4 Dietrich CF, Nolsøe CP, Barr RG. et al. Guidelines and Good Clinical Practice Recommendations for Contrast Enhanced Ultrasound (CEUS) in the Liver – Update 2020 – WFUMB in Cooperation with EFSUMB, AFSUMB, AIUM, and FLAUS. Ultraschall Med 2020; 41: 562-585
  Thieme ConnectPubMedSearch in Google Scholar
• 5 Jung EM, Weber MA, Wiesinger I. Contrast-enhanced ultrasound perfusion imaging of organs. Radiologe 2021; 61: 19-28
  CrossrefPubMedSearch in Google Scholar
• 6 Xie F, Wan WB, Fei X. et al. Repeatability of the “flash-replenishment” method in contrast-enhanced ultrasound for the quantitative assessment of hepatic microvascular perfusion. Braz J Med Biol Res 2018; 51: e7058
  CrossrefPubMedSearch in Google Scholar
• 7 Schaible J, Stroszczynski C, Beyer LP. et al. Quantitative perfusion analysis of hepatocellular carcinoma using dynamic contrast enhanced ultrasound (CEUS) to determine tumor microvascularization. Clin Hemorheol Microcirc 2019; 73: 95-104
  CrossrefPubMedSearch in Google Scholar
• 8 Vogl TJ, Martin SS, Gruber-Rouh T. et al. Comparison of Microwave and Radiofrequency Ablation for the Treatment of Small- and Medium-Sized Hepatocellular Carcinomas in a Prospective Randomized Trial. Rofo 2024; 196: 482-490
  Thieme ConnectPubMedSearch in Google Scholar
• 9 Kupke LS, Dropco I, Götz M. et al. Contrast-Enhanced Intraoperative Ultrasound Shows Excellent Performance in Improving Intraoperative Decision-Making. Life (Basel) 2024; 14: 1199
  PubMedSearch in Google Scholar
• 10 Schwarz S, Clevert DA, Ingrisch M. et al. Quantitative Analysis of the Time-Intensity Curve of Contrast-Enhanced Ultrasound of the Liver: Differentiation of Benign and Malignant Liver Lesions. Diagnostics (Basel) 2021; 11: 1244
  CrossrefPubMedSearch in Google Scholar
• 11 Strobel D, Bernatik T, Blank W. et al. Diagnostic accuracy of CEUS in the differential diagnosis of small (≤ 20  mm) and subcentimetric (≤ 10  mm) focal liver lesions in comparison with histology. Results of the DEGUM multicenter trial. Ultraschall Med 2011; 32: 593-597
  PubMedSearch in Google Scholar
• 12 Pausch AM, Kammerer S, Weber F. et al. Parametric Imaging of Contrast-Enhanced Ultrasound (CEUS) for the Evaluation of Acute Gastrointestinal Graft-Versus-Host Disease. Cells 2021; 10: 1092
  CrossrefPubMedSearch in Google Scholar
• 13 Strobel D, Seitz K, Blank W. et al. Contrast-enhanced ultrasound for the characterization of focal liver lesions--diagnostic accuracy in clinical practice (DEGUM multicenter trial). Ultraschall Med 2008; 29: 499-505
  Thieme ConnectPubMedSearch in Google Scholar
• 14 Schellhaas B, Bernatik T, Bohle W. et al. Contrast-Enhanced Ultrasound Algorithms (CEUS-LIRADS/ESCULAP) for the Noninvasive Diagnosis of Hepatocellular Carcinoma – A Prospective Multicenter DEGUM Study. Ultraschall Med 2021; 42: e20
  Thieme ConnectPubMedSearch in Google Scholar
• 15 Haimerl M, Poelsterl S, Beyer LP. et al. Chronic liver disease: Quantitative MRI vs CEUS-based microperfusion. Clin Hemorheol Microcirc 2016; 64: 435-446
  CrossrefPubMedSearch in Google Scholar
• 16 Tai CJ, Huang MT, Wu CH. et al. Contrast-Enhanced Ultrasound and Computed Tomography Assessment of Hepatocellular Carcinoma after Transcatheter Arterial Chemo-Embolization: A Systematic Review. J Gastrointestin Liver Dis 2016; 25: 499-507
  CrossrefPubMedSearch in Google Scholar
• 17 Franke D, Daugherty RJ, Ključevšek D. et al. Contrast-enhanced ultrasound of transplant organs – liver and kidney – in children. Pediatr Radiol 2021; 51: 2284-2302
  CrossrefPubMedSearch in Google Scholar
• 18 Safai Zadeh E, Prosch H, Ba-Ssalamah A. et al. Contrast-enhanced ultrasound of the liver: Vascular pathologies and interventions. Rofo 2024; 196: 1220-1227
  PubMedSearch in Google Scholar
• 19 Zuo D, Yang K, Wu S. Diagnostic performance of intravascular perfusion based contrast-enhanced ultrasound LI-RADS in the evaluation of hepatocellular carcinoma. Clin Hemorheol Microcirc 2021; 78: 429-437
  CrossrefPubMedSearch in Google Scholar
• 20 Dropco I, Kaiser U, Wagner L. et al. Color Mapping using Ultrasound System-integrated Perfusion Software for Evaluation of Focal Liver Lesions: A Possible First Step for More Independent Reading. J Gastrointestin Liver Dis 2023; 32: 479-487
  CrossrefPubMedSearch in Google Scholar
• 21 Platz Batista da Silva N, Engeßer M, Hackl C. et al. Intraoperative Characterization of Pancreatic Tumors Using Contrast-Enhanced Ultrasound and Shear Wave Elastography for Optimization of Surgical Strategies. J Ultrasound Med 2021; 40: 1613-1625
  CrossrefPubMedSearch in Google Scholar
• 22 Chang EH, Chong WK, Kasoji SK. et al. Diagnostic accuracy of contrast-enhanced ultrasound for characterization of kidney lesions in patients with and without chronic kidney disease. BMC Nephrol 2017; 18: 266
  PubMedSearch in Google Scholar
• 23 Pschierer K, Grothues D, Rennert J. et al. Evaluation of the diagnostic accuracy of CEUS in children with benign and malignant liver lesions and portal vein anomalies. Clin Hemorheol Microcirc 2015; 61: 333-345
  PubMedSearch in Google Scholar
• 24 Jung EM, Dong Y, Jung F. Current aspects of multimodal ultrasound liver diagnostics using contrast-enhanced ultrasonography (CEUS), fat evaluation, fibrosis assessment, and perfusion analysis – An update. Clin Hemorheol Microcirc 2023; 83: 181-193
  CrossrefPubMedSearch in Google Scholar
• 25 Giangregorio F. Contrast-Enhanced Ultrasound (CEUS) for Echographic Detection of Hepato Cellular Carcinoma in Cirrhotic Patients Previously Treated with Multiple Techniques: Comparison of Conventional US, Spiral CT and 3-Dimensional CEUS with Navigator Technique (3DNav CEUS). Cancers (Basel) 2011; 3: 1763-1776
  CrossrefPubMedSearch in Google Scholar
• 26 Dietrich CF, Averkiou M, Nielsen MB. et al. How to perform Contrast-Enhanced Ultrasound (CEUS). Ultrasound Int Open 2018; 4: E2-E15
  Thieme ConnectPubMedSearch in Google Scholar
• 27 Coco D, Leanza S. Routine Intraoperative Ultrasound for the Detection of Liver Metastases during Resection of Primary Colorectal Cancer – A Systematic Review. Maedica (Bucur) 2020; 15: 250-252
  CrossrefPubMedSearch in Google Scholar
• 28 Spiesecke P, Reinhold T, Wehrenberg Y. et al. Cost-effectiveness analysis of multiple imaging modalities in diagnosis and follow-up of intermediate complex cystic renal lesions. BJU Int 2021; 128: 575-585
  CrossrefPubMedSearch in Google Scholar
• 29 Chartampilas E, Rafailidis V, Georgopoulou V. et al. Current Imaging Diagnosis of Hepatocellular Carcinoma. Cancers (Basel) 2022; 14: 3997
  CrossrefPubMedSearch in Google Scholar
• 30 Li H, Shi M, Long X. et al. Contrast-enhanced intraoperative ultrasound improved hepatic recurrence-free survival in initially unresectable colorectal cancer liver metastases. Dig Liver Dis 2025; 57: 467-476
  CrossrefPubMedSearch in Google Scholar
• 31 Lekht I, Brauner N, Bakhsheshian J. et al. Versatile utilization of real-time intraoperative contrast-enhanced ultrasound in cranial neurosurgery: technical note and retrospective case series. Neurosurg Focus 2016; 40: E6
  CrossrefPubMedSearch in Google Scholar
• 32 Haimerl M, Poelsterl S, Beyer LP. et al. Chronic liver disease: Quantitative MRI vs CEUS-based microperfusion. Clin Hemorheol Microcirc 2016; 64: 435-446
  CrossrefPubMedSearch in Google Scholar
• 33 Bitterer F, Bauer A, Glehr G. et al. Intraoperative contrast-enhanced ultrasound has an outcome-relevant impact on surgery of primary and metastatic liver lesions. Ultraschall Med 2024;
  Thieme ConnectPubMedSearch in Google Scholar

Correspondence

Publication History

Received: 02 January 2025

Accepted after revision: 05 May 2025

Article published online:
26 May 2025

© 2025. Thieme. All rights reserved.

Georg Thieme Verlag KG
Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany

• References

• 1 Jung EM, Moran VO, Engel M. et al. Modified contrast-enhanced ultrasonography with the new high-resolution examination technique of high frame rate contrast-enhanced ultrasound (HiFR-CEUS) for characterization of liver lesions: First results. Clin Hemorheol Microcirc 2023; 83: 31-46
  PubMedSearch in Google Scholar
• 2 Robbin ML. Ultrasound contrast agents: a promising future. Radiol Clin North Am 2001; 39: 399-414
  CrossrefPubMedSearch in Google Scholar
• 3 Dietrich CF, Correas JM, Cui XW. et al. EFSUMB Technical Review – Update 2023: Dynamic Contrast-Enhanced Ultrasound (DCE-CEUS) for the Quantification of Tumor Perfusion. Ultraschall Med 2024; 45: 36-46
  Thieme ConnectPubMedSearch in Google Scholar
• 4 Dietrich CF, Nolsøe CP, Barr RG. et al. Guidelines and Good Clinical Practice Recommendations for Contrast Enhanced Ultrasound (CEUS) in the Liver – Update 2020 – WFUMB in Cooperation with EFSUMB, AFSUMB, AIUM, and FLAUS. Ultraschall Med 2020; 41: 562-585
  Thieme ConnectPubMedSearch in Google Scholar
• 5 Jung EM, Weber MA, Wiesinger I. Contrast-enhanced ultrasound perfusion imaging of organs. Radiologe 2021; 61: 19-28
  CrossrefPubMedSearch in Google Scholar
• 6 Xie F, Wan WB, Fei X. et al. Repeatability of the “flash-replenishment” method in contrast-enhanced ultrasound for the quantitative assessment of hepatic microvascular perfusion. Braz J Med Biol Res 2018; 51: e7058
  CrossrefPubMedSearch in Google Scholar
• 7 Schaible J, Stroszczynski C, Beyer LP. et al. Quantitative perfusion analysis of hepatocellular carcinoma using dynamic contrast enhanced ultrasound (CEUS) to determine tumor microvascularization. Clin Hemorheol Microcirc 2019; 73: 95-104
  CrossrefPubMedSearch in Google Scholar
• 8 Vogl TJ, Martin SS, Gruber-Rouh T. et al. Comparison of Microwave and Radiofrequency Ablation for the Treatment of Small- and Medium-Sized Hepatocellular Carcinomas in a Prospective Randomized Trial. Rofo 2024; 196: 482-490
  Thieme ConnectPubMedSearch in Google Scholar
• 9 Kupke LS, Dropco I, Götz M. et al. Contrast-Enhanced Intraoperative Ultrasound Shows Excellent Performance in Improving Intraoperative Decision-Making. Life (Basel) 2024; 14: 1199
  PubMedSearch in Google Scholar
• 10 Schwarz S, Clevert DA, Ingrisch M. et al. Quantitative Analysis of the Time-Intensity Curve of Contrast-Enhanced Ultrasound of the Liver: Differentiation of Benign and Malignant Liver Lesions. Diagnostics (Basel) 2021; 11: 1244
  CrossrefPubMedSearch in Google Scholar
• 11 Strobel D, Bernatik T, Blank W. et al. Diagnostic accuracy of CEUS in the differential diagnosis of small (≤ 20  mm) and subcentimetric (≤ 10  mm) focal liver lesions in comparison with histology. Results of the DEGUM multicenter trial. Ultraschall Med 2011; 32: 593-597
  PubMedSearch in Google Scholar
• 12 Pausch AM, Kammerer S, Weber F. et al. Parametric Imaging of Contrast-Enhanced Ultrasound (CEUS) for the Evaluation of Acute Gastrointestinal Graft-Versus-Host Disease. Cells 2021; 10: 1092
  CrossrefPubMedSearch in Google Scholar
• 13 Strobel D, Seitz K, Blank W. et al. Contrast-enhanced ultrasound for the characterization of focal liver lesions--diagnostic accuracy in clinical practice (DEGUM multicenter trial). Ultraschall Med 2008; 29: 499-505
  Thieme ConnectPubMedSearch in Google Scholar
• 14 Schellhaas B, Bernatik T, Bohle W. et al. Contrast-Enhanced Ultrasound Algorithms (CEUS-LIRADS/ESCULAP) for the Noninvasive Diagnosis of Hepatocellular Carcinoma – A Prospective Multicenter DEGUM Study. Ultraschall Med 2021; 42: e20
  Thieme ConnectPubMedSearch in Google Scholar
• 15 Haimerl M, Poelsterl S, Beyer LP. et al. Chronic liver disease: Quantitative MRI vs CEUS-based microperfusion. Clin Hemorheol Microcirc 2016; 64: 435-446
  CrossrefPubMedSearch in Google Scholar
• 16 Tai CJ, Huang MT, Wu CH. et al. Contrast-Enhanced Ultrasound and Computed Tomography Assessment of Hepatocellular Carcinoma after Transcatheter Arterial Chemo-Embolization: A Systematic Review. J Gastrointestin Liver Dis 2016; 25: 499-507
  CrossrefPubMedSearch in Google Scholar
• 17 Franke D, Daugherty RJ, Ključevšek D. et al. Contrast-enhanced ultrasound of transplant organs – liver and kidney – in children. Pediatr Radiol 2021; 51: 2284-2302
  CrossrefPubMedSearch in Google Scholar
• 18 Safai Zadeh E, Prosch H, Ba-Ssalamah A. et al. Contrast-enhanced ultrasound of the liver: Vascular pathologies and interventions. Rofo 2024; 196: 1220-1227
  PubMedSearch in Google Scholar
• 19 Zuo D, Yang K, Wu S. Diagnostic performance of intravascular perfusion based contrast-enhanced ultrasound LI-RADS in the evaluation of hepatocellular carcinoma. Clin Hemorheol Microcirc 2021; 78: 429-437
  CrossrefPubMedSearch in Google Scholar
• 20 Dropco I, Kaiser U, Wagner L. et al. Color Mapping using Ultrasound System-integrated Perfusion Software for Evaluation of Focal Liver Lesions: A Possible First Step for More Independent Reading. J Gastrointestin Liver Dis 2023; 32: 479-487
  CrossrefPubMedSearch in Google Scholar
• 21 Platz Batista da Silva N, Engeßer M, Hackl C. et al. Intraoperative Characterization of Pancreatic Tumors Using Contrast-Enhanced Ultrasound and Shear Wave Elastography for Optimization of Surgical Strategies. J Ultrasound Med 2021; 40: 1613-1625
  CrossrefPubMedSearch in Google Scholar
• 22 Chang EH, Chong WK, Kasoji SK. et al. Diagnostic accuracy of contrast-enhanced ultrasound for characterization of kidney lesions in patients with and without chronic kidney disease. BMC Nephrol 2017; 18: 266
  PubMedSearch in Google Scholar
• 23 Pschierer K, Grothues D, Rennert J. et al. Evaluation of the diagnostic accuracy of CEUS in children with benign and malignant liver lesions and portal vein anomalies. Clin Hemorheol Microcirc 2015; 61: 333-345
  PubMedSearch in Google Scholar
• 24 Jung EM, Dong Y, Jung F. Current aspects of multimodal ultrasound liver diagnostics using contrast-enhanced ultrasonography (CEUS), fat evaluation, fibrosis assessment, and perfusion analysis – An update. Clin Hemorheol Microcirc 2023; 83: 181-193
  CrossrefPubMedSearch in Google Scholar
• 25 Giangregorio F. Contrast-Enhanced Ultrasound (CEUS) for Echographic Detection of Hepato Cellular Carcinoma in Cirrhotic Patients Previously Treated with Multiple Techniques: Comparison of Conventional US, Spiral CT and 3-Dimensional CEUS with Navigator Technique (3DNav CEUS). Cancers (Basel) 2011; 3: 1763-1776
  CrossrefPubMedSearch in Google Scholar
• 26 Dietrich CF, Averkiou M, Nielsen MB. et al. How to perform Contrast-Enhanced Ultrasound (CEUS). Ultrasound Int Open 2018; 4: E2-E15
  Thieme ConnectPubMedSearch in Google Scholar
• 27 Coco D, Leanza S. Routine Intraoperative Ultrasound for the Detection of Liver Metastases during Resection of Primary Colorectal Cancer – A Systematic Review. Maedica (Bucur) 2020; 15: 250-252
  CrossrefPubMedSearch in Google Scholar
• 28 Spiesecke P, Reinhold T, Wehrenberg Y. et al. Cost-effectiveness analysis of multiple imaging modalities in diagnosis and follow-up of intermediate complex cystic renal lesions. BJU Int 2021; 128: 575-585
  CrossrefPubMedSearch in Google Scholar
• 29 Chartampilas E, Rafailidis V, Georgopoulou V. et al. Current Imaging Diagnosis of Hepatocellular Carcinoma. Cancers (Basel) 2022; 14: 3997
  CrossrefPubMedSearch in Google Scholar
• 30 Li H, Shi M, Long X. et al. Contrast-enhanced intraoperative ultrasound improved hepatic recurrence-free survival in initially unresectable colorectal cancer liver metastases. Dig Liver Dis 2025; 57: 467-476
  CrossrefPubMedSearch in Google Scholar
• 31 Lekht I, Brauner N, Bakhsheshian J. et al. Versatile utilization of real-time intraoperative contrast-enhanced ultrasound in cranial neurosurgery: technical note and retrospective case series. Neurosurg Focus 2016; 40: E6
  CrossrefPubMedSearch in Google Scholar
• 32 Haimerl M, Poelsterl S, Beyer LP. et al. Chronic liver disease: Quantitative MRI vs CEUS-based microperfusion. Clin Hemorheol Microcirc 2016; 64: 435-446
  CrossrefPubMedSearch in Google Scholar
• 33 Bitterer F, Bauer A, Glehr G. et al. Intraoperative contrast-enhanced ultrasound has an outcome-relevant impact on surgery of primary and metastatic liver lesions. Ultraschall Med 2024;
  Thieme ConnectPubMedSearch in Google Scholar