Super-resolution contrast-enhanced ultrasound (SR-CEUS) in solid organs

Abstract

It is becoming increasingly common for multimodal radiological imaging to use contrast-enhanced ultrasound (CEUS) because of its high-resolution ultrasound techniques. CEUS has several advantages. It can be used repeatedly without affecting renal function or the thyroid gland. It is also considered to be highly accurate with regard to the diagnosis and detection of small solid liver lesions. In addition, it can be used to characterize solid lesions in other abdominal organs. With additional perfusion imaging and its (semi)quantitative analysis using wash-in and wash-out kinetics, therapies can be monitored. It is also frequently used in the assessment of solid tumors in the near field, such as thyroid tumors and lymph nodes. Super-resolution CEUS (SR-CEUS) is a novel imaging method with dynamic evaluation of microflow changes to the level of capillary structures. SR-CEUS could also open up new possibilities regarding the dynamic assessment of the micro-vascularization of solid abdominal organs and interventional procedures.
Citation Format
▪ Jung EM, Weber M, Jung F. Super-resolution contrast-enhanced ultrasound (SR-CEUS) in solid organs. Rofo 2025; DOI 10.1055/a-2754-0219

Zusammenfassung

Kontrastverstärkter Ultraschall (CEUS) wird aufgrund seiner hochauflösenden Ultraschalltechnik zunehmend in der multimodalen radiologischen Bildgebung eingesetzt. CEUS bietet mehrere Vorteile. Er kann wiederholt eingesetzt werden, ohne die Nierenfunktion oder die Schilddrüse zu beeinträchtigen. Er gilt zudem als hochpräzise in der Diagnose und Erkennung kleiner solider Leberläsionen. Darüber hinaus kann er zur Charakterisierung solider Läsionen in anderen abdominellen Organen eingesetzt werden. Mit zusätzlicher Perfusionsbildgebung und deren (semi)quantitativer Analyse mittels Ein- und Auswaschkinetik können Therapien überwacht werden. Superhochauflösender CEUS (super resolution (SR) CEUS) ist eine neuartige Bildgebungsform zur Erfassung dynamischer Veränderungen bis auf kapillare SR-CEUS und könnte zudem neue Möglichkeiten zur dynamischen Beurteilung der Mikrovaskularisierung solider abdominaler Organe und interventioneller Verfahren eröffnen.

Keywords

CEUS - SR-CEUS - microcirculation - solid internal organs

Introduction

Contrast-enhanced ultrasound (CEUS) is a widely used technique for high-resolution, dynamic assessment of macro- and microvascularization [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11]. Currently the most frequently used technique is contrast harmonic imaging (CHI) with second-generation echo-signal enhancers and a low mechanical index (MI<0.2) with reduced transmission power. Sulphur hexafluoride microbubbles (SonoVue, Bracco, Italy) with a diameter of 2–10 µm are commonly used. Typically, 1.0–2.4 mL bolus injections are administered intravenously, followed by a 10 mL saline flush.

CEUS allows dynamic evaluation of microvascularization in solid lesions from the early arterial phase (10–15 s), the arterial phase (15–45 s), the portal venous phase (45–70 s) and the late venous phase up to 120 seconds after the injection. Late phase evaluation can extend to 5 minutes post-injection. Analyzing wash-in and washout kinetics is essential for detecting and characterizing solid lesions.

Super-resolution CEUS (SR-CEUS) is an innovative imaging modality that resolves the trade-off between penetration depth and resolution quality. It achieves high resolution (500 frames per second) while providing four different imaging maps: vascular density, flow density, flow direction, and vascular direction. SR-CEUS is based on the individual location and tracking of the injected microbubbles on high-frame-rate CEUS (HIFR-CEUS), producing maps of their density or velocity. This technique utilizes pattern fluctuations of contrast agents to enhance the visualization of the microvasculature in various organs, particularly the liver.

CEUS, SR-CEUS, parametric CEUS, and perfusion imaging allow dynamic evaluation of organ microvascularization to the capillary perfusion level ([Fig. 1]). This noninvasive visualization of microvasculature changes provides crucial information for diagnosing and assessing various pathologies. The recent introduction of SR-CEUS has expanded clinical imaging capabilities, particularly for the liver microvasculature at the capillary level [12] [13], and for primary dynamic evaluation of the arterial microvascular structures of abdominal organs for the characterization of solid lesions, reduced perfusion, malformations, and monitoring of interventional procedures.

Fig. 1 The right liver lobe and kidney were enhanced with contrast on SR-CEUS (right), parametric CEUS with false colors (mid-right), and CEUS perfusion imaging with time intensity curve (TIC) (left).

For the evaluation of wash-in kinetics, it is important to observe regular or irregular microvascularization from the center to the margins of solid lesions. With CEUS perfusion, a quantification of these wash-in patterns can be achieved using digitally stored Cine loops. Homogeneous arterial perfusion from the center to the margins or from the margins to the center of a solid liver lesion mostly indicate a benign lesion. However, to accurately determine whether a lesion is benign or malignant, it is essential to assess the wash-out kinetics, time course, extent, and amount of washout. The most reliable diagnostic criterion for malignant liver lesions is the loss of contrast enhancement or washout starting in the portal venous phase and increasing in the late phase. Benign lesions typically show late or limited washout, while malignant lesions exhibit distinct washout patterns. Fast washout suggests cholangiocellular carcinoma, whereas hepatocellular carcinoma shows prolonged washout. CEUS perfusion allows detailed assessment of washout kinetics, which is crucial for chemotherapy follow-up and for evaluating ablation therapy success. Early local nodular hyper-enhancement with late-phase washout indicates tumor recurrence. While CEUS is primarily used for liver lesions [3], it is increasingly applied in non-hepatic dynamic examinations, particularly for evaluating early therapy success in GI tumors [4] [5] [6] [7].

Adverse events after SonoVue injection occurred in 0.13% of cases, with severe adverse events in 0.04% [8] [9]. The microbubbles neither decrease kidney function, even after repeated application, nor affect thyroid gland function, which is a key advantage over other contrast media used for CT and MRI. The following article will address the use of SR-CEUS and CEUS perfusion for detecting and characterizing microvascular changes in primary abdominal organs, such as liver tissue, and tumor changes, as well as soft-tissue changes such as in the breast, lymph nodes, and thyroid gland.

CEUS equipment

High-resolution multifrequency convex probes from 1–6 MHz are standard for abdominal imaging. Linear probes are used for near-field and non-abdominal examinations, most frequently between 6–9 MHz, with new probes being from 6 to 18 MHz. Virtual convex scanning increases the depth of the scanning field. Lower frequencies allow deeper penetration but reduce resolution. Alternatively, higher frequencies increase the local resolution but decrease the scanning depth. Lesions that are close to the liver surface or to the liver capsule (depth less than 4 cm), can be detected using high-frequency probes (at least 6–24 MHz), especially intraoperatively.

Dynamic CEUS with SonoVue requires significantly reduced transmission power and mechanical index (MI<0.2). It uses a split-screen mode to display B-mode and CEUS simultaneously, necessitating high-end ultrasound machines for adequate resolution at low transmission energy in B-mode.

Normally, it is not necessary to use a second contrast injection as with SR-CEUS, since the acquisition time is less than 10 seconds (3–10s) for a complete SR-CEUS cine loop acquisition. Future developments will include parallel imaging of CEUS and SR-CEUS. In addition, FLASH kinetics of CEUS replenishment can be used for a new evaluation of early enhancement.

For PACS transfer, DICOM videos of up to three minutes should be stored. It is recommended to store DICOM raw data on ultrasound machines for potential retrospective imaging optimization and perfusion analysis. Using integrated software, it is possible to perform measurements by diameter or adapted areas to evaluate changes in vascular density or lumen changes in different regions from the center to capsular structures. SR-CEUS allows subtraction of background information for only vascular visualization like DSA technology.

Select the distance and region of interest on the saved frame of SR-CEUS. All vascular vessels in the trajectory of the line of distance defined on the image will be shown on the vessel diagram. The parameters including vessel diameter, vessel distance, vessel density, and vessel density ratio can be acquired and quantified.

Contrast media application and evaluation

After written informed consent is obtained, SonoVue is administered via a cubital vein using a large cannula (18–20G). Patients should be informed of the rare risk of allergic reactions (<1:10,000). Risk factors include history of allergic reaction to contrast media, cardiac insufficiency, and pulmonary hypertension. For severe cardiac insufficiency and pulmonary hypertension, the administration of oxygen seems to minimize the risk of allergic reaction. The standard dose is 1–2.4 mL, adjusted for examination circumstances and patient weight. For children, the dose is up to 0.5 mL, adapted to weight. The injection should be performed using a three-way stopcock, with contrast media injected via the straight arm to reduce destruction of the bubbles. Sodium chloride (10 ml) can then be administered via a side arm. Continuous application with a special contrast medium pump is rare and is mostly used for perfusion kinetics in tumor research. SR-CEUS could be used for the evaluation of capillary flow changes. It is recommended to store DICOM data for the evaluation of CEUS loops with perfusion and to store raw DICOM data as a backup for SR-CEUS vascular diameter measurements using integrated software on ultrasound machines for potential retrospective independent analysis. Up to 2TB are possible but a multicore system with 64 GB RAM and a 64 GB GPU is usually used.

SR-CEUS in hepatocellular carcinoma (HCC)

SR-CEUS enables dynamic assessment of wash-in and washout kinetics over a period of three minutes. Typical HCC lesions >1.5 cm show early, irregular hyper-vascularization centrally. Lesions <10 mm often have incomplete or no washout. Lesions <3 cm may display central hypo-perfused necrosis. Poorly differentiated HCC lesions <1.5 cm might show late washout after four minutes. CEUS LI-RADS classification aligns with MRI and CT standards [10]. SR-CEUS can detect irregular arterial tumor microvascularization.

HCCs typically exhibit delayed washout kinetics, starting 3 minutes post-contrast injection, unlike CCCs. Successful resection should result in an avascular scar. Follow-up after ablation therapies (MWA, RFA, IRE) should show a complete avascular defect. Post-TACE, clear devascularization should be visible.

Differentiating small, hyper-vascularized lesions (≤10 mm), such as regenerative/dysplastic nodules or early HCCs, can be challenging with SonoVue, an intravascular contrast agent. While not yet approved, tumor-specific (BR 55) and liver-specific ultrasound contrast agents are being investigated [10] [11] [12] [13] [14].

SR-CEUS of liver metastases

SR-CEUS outperforms B-mode ultrasound with regard to detecting and characterizing small solid nodules (< 10 mm) in colorectal carcinoma metastasis. These typically show early arterial rim hyperenhancement followed by washout in the portal venous phase. Similar patterns occur in breast, thyroid, and kidney cancer metastasis. Neuroendocrine tumors display irregular arterial hypervascularization but may not show washout, especially when small. Intraoperative CEUS with linear probes is effective for solid tumors often diagnosed by CT or MRI. Under ideal conditions, SR-CEUS demonstrates wash-out after arterial enhancement for metastases.

CEUS perfusion effectively monitors metastasis treatment, aiming for de-vascularization or complete resection. Systemic and local therapies should significantly reduce capillary enhancement [6] [14] [15]. Post-ablation, complete tumor devascularization with a margin of at least 5 mm around the lesions indicates success ([Fig. 2]).

Fig. 2 Post-treatment imaging of a malignant liver lesion (arrow) using CEUS (upper left), SR-CEUS (upper right and right), and CEUS perfusion imaging with time intensity curve analysis (TIC) (lower left) with vascularization of the tumor lesion after ablation therapy.

SR-CEUS for benign liver lesions

The most frequent benign solid liver lesions are hemangiomas, focal nodular hyperplasia (FNH), and adenomas. The most important characteristic of benign lesions is regular enhancement beginning in the arterial phase, which can be observed as nodular enhancement in hemangioma, a wheel-like pattern from the center to the margins in FNH, and regular enhancement from the margins to the center in adenomas. These patterns can be assessed using parametric imaging. Benign lesions do not show washout. However, in cases of FNH, a hypo-enhancing central scar may be visible ([Fig. 3]).

Fig. 3 Focal nodular hyperplasia (FNH) centrally located in the liver as a lower echogenic lesion on B-mode with local fat changes (upper left), with early central enhancement on CEUS (middle and upper right), UMA as microflow detection (lower left), and SR-CEUS (lower middle) up to micro-vascularization (arrows).

The diagnosis of an atypical or partially necrotic adenoma is challenging due to incomplete arterial enhancement and partial washout, complicating differentiation from malignant lesions, even with SR-CEUS perfusion. If CT or MRI imaging does not indicate benign features, histologic specimen collection, potentially guided by CEUS, may be necessary [15].

SR-CEUS perfusion of kidney and spleen lesions

Dynamic CEUS/SR-CEUS is the preferred imaging method for characterizing complicated cystic kidney (Bosniak IIF and III) and cystic spleen lesions, especially when combined with CT or MRI [16]. Its high resolution allows early detection of complicated cystic lesions or small intra-cystic tumors like papillomas. Malignant kidney and spleen lesions typically show irregular hypervascularization. Not all malignant lesions show portal-venous washout in the late phase (3 to 5 minutes), particularly small ones. Kidney angiomyolipomas show partial early enhancement. SR-CEUS can also characterize small perfused cystic lesions ([Fig. 4]).

Fig. 4 Complex kidney cyst (Bosniak IIF) detected by B-mode, CEUS (both upper left), and dynamic SR-CEUS (upper right) with small intra-cystic septations and enhancement at the margin (see arrows).

Dynamic SR-CEUS can detect early enhancement, hypoperfusion, and infarcts in the kidneys or spleen ([Fig. 5]). It can also quantify rejection after kidney transplantation [17] [18] [19] [20]. In solid spleen lesions, SR helps to identify irregular neovascularization in malignant cases.

Fig. 5 Microvascularization of the spleen after bolus injection of 1 ml of ultrasound contrast agent post-echinococcosis infection with local reduced perfusion (arrow). B-mode (left), CEUS (middle), and SR-CEUS (right).

Endoluminal and special 3D CEUS probes (1–7 MHz) are used for prostate lesion diagnosis. CEUS perfusion aids in identifying aggressive tumors, enabling targeted or MRI fusion biopsies with higher success rates. Aggressive tumors typically show rapid, irregular hyperenhancement with partial washout. In parametric imaging, malignant tumors display red and yellow margins compared to healthy tissue. CEUS perfusion enhances post-interventional monitoring. Prostatitis typically exhibits prolonged, widespread contrast enhancement without early washout. Aggressive prostate cancer lesions display rapid nodular enhancement and venous washout [21] [22] [23]. Prior to prostate embolization (PAE) or in cases of uterus myomas, dynamic CEUS and SR-CEUS can be valuable for capillary microvascularization assessment and for follow-up.

CEUS perfusion for thyroid lesions

For CEUS, multifrequency linear probes with frequencies between 6 and 9 MHz should be used. The TI-RADS (Thyroid Imaging Reporting and Data System) classification includes B-mode criteria and color-coded duplex sonography (CCDS) to classify benign and malignant thyroid lesions and to assess the need for histological sampling. CEUS is used in TI-RADS III and IV lesions to identify early stage malignancy. In adenomas, there is hypervascularization at the margins and the typical washout in the late phase is absent. In contrast, thyroid carcinomas showed reduced or irregular vascularization with typical washout. SR-CEUS perfusion with assessment of dynamic capillary microvascularization can better differentiate between benign and malignant lesions when comparing the center with the margins and surrounding tissue ([Fig. 6]). This allows focused ultrasound-guided biopsy [24] [25] [26].

Fig. 6 Thyroid lesions with cystic and solid changes on B-mode (upper left), enhancement at the margin evaluated by CEUS (middle), and four different modalities of SR-CEUS (upper right and lower row) with color-coded kinetic detection of early enhancement at the margin.

CEUS perfusion in breast lesions and lymph nodes

CEUS perfusion shows promise with respect to monitoring neoadjuvant therapy and diagnosing small tumors with partial neovascularization, such as invasive cancer ([Fig. 7]). Peak enhancement and area under the curve parameters help visualize irregular dynamic microvasculature in breast cancer margins using SR-CEUS. Experimental studies are exploring tumor-specific ultrasound contrast agents with CEUS perfusion for improved early-stage breast cancer diagnosis [27] [28] [29]. For peripheral lymph nodes, multi-frequency linear probes are used for B-mode detection, while CEUS/SR-CEUS with perfusion is increasingly applied in pre-selected cases, such as monitoring targeted therapy for lymphoma or melanoma metastases ([Fig. 8]).

Fig. 7 Case of histopathologically proven breast tumor with inhomogeneous high stiffness on strain and shear wave elastography (black arrow), irregular neovascularization on SR-CEUS (red arrow), and irregular hyperenhancement at the margin with central washout on CEUS (white arrow).

Fig. 8 Lymph node metastasis (arrow) with irregular lower echogenicity on B-mode (left), irregular enhancement on CEUS (middle), and irregular neovascularization detected on SR-CEUS (right).

The aim is to reduce irregular tumor microvasculature, particularly at the margins of lymph node metastases. Efforts are ongoing to improve detection of sentinel lymph nodes in breast cancer using CEUS and of cervical lymph node metastases in tumors before surgery. Fast wash-in and early washout are typical of malignant lymph nodes [30].

SR-CEUS in the prostate and uterine myomas

Endoluminal and special 3D CEUS probes (1–7 MHz) are used for prostate lesion diagnosis. CEUS perfusion aids in identifying aggressive tumors, enabling targeted or MRI fusion biopsies with higher success rates. Aggressive tumors typically show rapid, irregular hyperenhancement with partial washout. In parametric imaging, malignant tumors display red and yellow margins compared to healthy tissue ([Fig. 9]). CEUS perfusion enhances post-interventional monitoring.

Fig. 9 SR-CEUS (upper left and lower right), CEUS (upper right together with B-mode image), and false color parametric CEUS showing the dynamic microvascularization of the prostate with partial hyperemia and early rim enhancement (lower row together with corresponding B-mode images).

Prostatitis typically exhibits prolonged, widespread contrast enhancement without early washout. Aggressive prostate cancer lesions display rapid nodular enhancement and venous washout [21] [22] [23]. Prior to prostate embolization (PAE) or in cases of uterine myomas, dynamic CEUS and SR-CEUS can be valuable for capillary microvascularization assessment and for follow-up ([Fig. 10]).

Fig. 10 Multiparametric ultrasound imaging of a uterine fibroid with B-mode (upper left), elastography with higher stiffness (upper middle), ultra-micro angio-flow (UMA) detection with hypercirculation at the margin (upper right), parametric CEUS with false colors (lower right), CEUS (lower middle), and SR-CEUS (lower right).

New aspects from SR-CEUS quantification

The analyzed quantitative microvascular parameters are: vessel diameter, indicated by the full width at half-maximum of the amplitude distribution of the Gaussian fit curve; density-relevant parameters, calculated from the labeled pixels; velocity-relevant parameters, calculated from the microbubble motion trajectory; perfusion-relevant parameters, calculated by mean velocity multiplied by density; fractal dimension of the tumor vasculature, calculated using the box-counting algorithm on the SR-CEUS density maps; and local flow direction entropy, defined as information entropy extraction of flow direction [31].

We analyzed liver lesions in our own research group based on SR-CEUS vascular quantifications. The highest number of lesion measurements was observed in the malignant lesion group. Significant differences in the measurements were found when comparing benign lesions with the capillary region (p < 0.001) and normal liver tissue (p < 0.01). The use of SR-CEUS opens up new possibilities for the quantification of neovascularization, the assessment of microvascular changes, and the evaluation of the follow-up of intrahepatic interventions [32].

Conclusion

Neovascularization significantly impacts tumor morphology and growth. SR-CEUS can measure capillary density and diameter. Necrosis occurs in tumor degeneration but also in inflammation. Scars occur after ablation, resection, trauma or are found centrally in an FNH [13] [33] [34] [35].

In addition, SR-CEUS measurements of the capillary density and vascular parameters in the lesion area, centrally, parenchymally, and sub-capsularly enable an improved dynamic assessment of tumor vessels. This also allows a more critical evaluation of the success of systemic or local tumor treatments and the definition of the wash-in or washout effect of CEUS to be defined at the capillary level.

CEUS perfusion adds excellent value to B-mode and CEUS examination of solid organs. During the pandemic, CEUS offered an excellent way to monitor critically ill patients [36] [37] [38] [39]. Using the new modalities of parametric, perfusion, and SR-CEUS, bedside diagnostic procedures are a very important diagnostic tool for evaluating early changes in dynamic microvascularization.

Christian Stroszczynski

1992 Staatsexamen Humanmedizin, Johannnes-Gutenberg-Universität Mainz. 1992–1994 AiP Ruprechts-Karl-Universität Heidelberg mit Schwerpunkt Hämatologie, Onkologieund Rheumatologie. 1994–2000 Weiterbildungzum Facharzt für Diagnostische Radiologie an der Charité, Berlin. 2000–2006 Leitender Oberarzt an der Klinik für Strahlenkunde an der Charité, Berlin. 2006–2010 Stellvertretender Direktor und Leitender Oberarzt am Institut und an der Poliklinik für Radiologische Diagnostik der Medizinischen Fakultät Carl-Gustav-Carus, Technische Universität Dresden. Seit 2010 Direktor des Instituts für Röntgendiagnostik am Universitätsklinikum Regensburg.

Conflict of Interest

The authors declare that they have no conflict of interest.

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Publication History

Received: 16 April 2025

Accepted after revision: 20 November 2025

Article published online:
12 January 2026