Assessment of Kupffer Cell–Specific Contrast-Enhanced Ultrasound for Characterization of Suspicious Malignant Focal Liver Lesions

Abstract

Background

This article aims to assess the diagnostic accuracy of Kupffer cell–specific contrast-enhanced ultrasound (Sonazoid) for characterization of suspicious malignant focal liver lesions and the diagnostic accuracy of Sonazoid in differentiating tumoral thrombosis of the portal vein from bland thrombosis.

Materials and Methods

This was a single-center, prospective, cross-sectional study conducted in the Department of Radiology. Baseline gray-scale ultrasound, along with contrast-enhanced imaging, was performed in patients who met the inclusion criteria. CEUS images were read by two radiologists with an experience of 3 and 15 years, respectively. Interobserver agreement between two observers was calculated. CECT and CEMRI images were read by a third radiologist with an experience of around 7 years; he was also blinded to the histopathology and CEUS results. CECT/CEMRI was taken as a gold standard for HCC (based on the evidence-based practice/AASLD guidelines); for non-HCC lesions, histopathology was taken as a gold standard. Diagnostic accuracy, sensitivity, and positive predictive value (PPV) of CEUS were then calculated with respect to the gold standard. In eight cases included in our study, portal vein thrombosis was present, and so the diagnostic accuracy of CEUS with Sonazoid for differentiating tumoral and bland thrombosis was also calculated.

Results

CEUS with Sonazoid has a sensitivity of 90%, an accuracy of 87%, and a PPV of 96% for characterizing focal liver lesions. CEUS with Sonazoid (with respect to histopathology) has a sensitivity of 87.5%, specificity of 87.5%, and diagnostic accuracy of 77.8% for the characterization of lesions. In a limited number of patients included in our study, CEUS had a sensitivity, specificity, negative predictive value, and PPV of 100% for differentiating between tumoral and bland thrombus.

Conclusion

CEUS is an excellent modality for differentiating tumoral from bland thrombus, and it can be safely used for lesion characterization in patients where CT/MRI contrast agent is contraindicated. In cases of diagnostic dilemma, CEUS can be used as an alternative modality. Since it is radiation free, it can be used in regular surveillance of high-risk patients.

 

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Keywords

Contrast-enhanced ultrasound - Kupffer cell specific - Sonazoid

Introduction

A focal liver lesion is a discrete abnormality arising within the liver. Hepatocellular carcinoma (HCC) is the most common primary malignant neoplasm of the liver and is the leading cause of death among patients with cirrhosis.[1] About 80% of the HCC arises in a cirrhotic liver. Besides HCC, there is an increased risk of developing cholangiocarcinoma in cirrhotic liver. Characterization of the multitude of lesions is important for timely and effective management of malignant lesions and alleviating patients' anxiety in case of benign lesions. There is a marked increase in neovascularity during carcinogenesis and arterial blood flow becomes dominant, thus producing the characteristic imaging features of HCC.[2] Arterial enhancement (hypervascularity) and neovascularity are considered the essential characteristics of HCC and are used as radiologic features on contrast-enhanced ultrasound (CEUS), contrast-enhanced computed tomography (CECT), or contrast-enhanced magnetic resonance (CEMR) images for the noninvasive diagnosis of HCC. Advances in imaging technology have led to the increased detection of focal liver lesions in a range of millimeters.

As the pathological features of liver lesions are closely related to the perfusion characteristics of the lesions, a contrast study is necessary for the characterization of liver lesions that are detected incidentally and/or during the screening procedure. Advances in contrast-enhanced imaging have improved the sensitivity and spatial resolution of CT, MRI, and US and have enabled one to visualize dynamic perfusion characteristics of lesions. Based on the different hemodynamics of various focal liver lesions, CECT and CEUS, which depict dynamic perfusion characteristics, are used to characterize focal liver lesions.

US contrast agents are microbubble stabilized by a shell that is made up of albumin, galactose, lipid, or polymers. CEUS has been used for a long time for studying the micro-perfusion and micro-vascularity of a lesion. Currently, we are using second-generation USG contrast agents that include SonoVue and Sonazoid. Performing CEUS requires low MI and real-time imaging scanner technology.[3] The lipid layer provides elasticity to the microbubbles and enables them to pass through the pulmonary circulation and withstand the pressure in the circulatory system.[4] Because of its stability, this contrast agent is long-lasting and enables imaging for longer than 10 minutes and repeat scanning. Additional benefits, such as the absence of radiation exposure, risk due to use of iodinated contrast, and easy and wide availability, make CEUS an ideal modality for regular surveillance of cirrhotic patients for the development of focal liver lesions and characterization of any incidentally detected liver lesion. CEUS is the only dynamic imaging modality available for a subset of patients with compromised renal function.

Sonazoid is a lipid-coated microbubble of perfluorobutane, stabilized by a membrane of hydrogenated egg phosphatidyl serine; thus, allergy to egg products forms one of the contraindications for use of CEUS. Sonazoid comes in powdered form and is reconstituted with 2 mL of sterile water and administered by IV route in a dose of 0.015 mL/kg.[5] Techniques for CEUS include continuous scanning and acquisition of cine loop starting from the earliest arrival of microbubbles till the peak of arterial enhancement lasting up to 60 seconds. Thereafter, intermittent scanning and storing of a single image as well as short loops at ∼30- to 60-second intervals is performed to look for washout. Scanning in the late Kupffer phase is also done intermittently. Sonazoid has an advantage over SonoVue because Kupffer cells in liver sinusoids take up Sonazoid, thus giving an additional Kupffer phase. A stable time window of the Kupffer phase allows evaluation of the whole liver. The only disadvantage with Sonazoid is that it is not yet available in some regions and is also less studied than SonoVue. Two contrast enhancement phases occur with Sonazoid, namely, the vascular phase and the Kupffer phase. Images obtained in the Kupffer phase have higher diagnostic sensitivity for hepatic malignancies because the majority of the malignancies do not contain Kupffer cells[6] and hence appear as Kupffer phase defect ([Fig. 1D]). Dynamic images obtained in the vascular phase along with Kupffer phase characteristics markedly narrow the differential diagnosis of focal liver lesions. The existence of the Kupffer phase can be utilized in a technique called defect reperfusion imaging.

Fig. 1 (A) B-mode ultrasound image showing a relatively well-defined iso- to hyperechoic mass lesion in segment V of the liver. On post-contrast imaging with Sonazoid, the lesion shows non-rim arterial phase hyperenhancement (B) with washout on venous phase (C) and well-defined Kupffer phase defect (D), suggestive of HCC. Diagnosis was subsequently confirmed on CECT.Note: Arrow points to the lesion.

Defect reperfusion imaging (dual-phase fusion imaging) involves two steps: in the first phase, we detect a defect in the Kupffer phase and in the second phase, we assess the presence of arterial blood flow in those defects after reinjection of Sonazoid. This is particularly useful in a situation where a nodule is not well visualized by B-mode US, either because of the coarse liver parenchyma or because of technical limitations. Defect reperfusion imaging markedly increases the diagnostic sensitivity of HCC, and it has wide possibilities for screening HCC in coarse liver parenchyma, localization of recurrence after treatment, and needle insertion in the guidance of CEUS.[7] [8] [9]

Sonazoid was first approved as a contrast agent in Japan in 2007, followed by Norway, Korea, Singapore, Taiwan, and China (2019).[10] CEUS-LIRADS, which is a standardized system for CEUS exams and allows for accurate characterization of lesions in cirrhosis, has been in use for long.[11] SonoVue and Definity have already been incorporated in the CEUS LIRADS; however, Sonazoid utilization has not been included in the LIRADS yet and is expected to be incorporated in the next version of CEUS-LIRAD. Mukund et al concluded that Sonazoid helps in improving the response rate for ablative procedures.[12] However, currently there is no study available in India demonstrating the utility of Sonazoid for the characterization of liver lesions and therefore we have performed this study for the assessment of diagnostic accuracy of Sonazoid with respect to CT/MRI/histopathology (gold standards) whichever is available, along with the assessment of the diagnostic accuracy of CEUS with Sonazoid in differentiating tumoral from bland thrombus.[5]

 

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Aim and Objectives

Primary Objective

• To assess the diagnostic accuracy of Kupffer cell–specific CEUS for characterization of suspicious malignant focal liver lesions.

 

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Secondary Objective

• To assess the diagnostic accuracy of differentiating tumoral thrombosis of the portal vein from bland thrombosis wherever applicable.

• To compare the diagnostic accuracy of Kupffer cell–specific CEUS in comparison with histopathology/CT/MRI findings of liver lesions wherever available.

 

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Materials and Methods

This was a single-center, prospective, cross-sectional study conducted in the Department of Radiology. The study was approved by the Institutional Scientific Research Review Board and Ethical Committee of the institution.

Patient Selection: Patients meeting the inclusion criteria from September 2022 to March 2023 were included in the study.

Inclusion Criteria

• CEUS characterization of lesions detected on B-mode US.

• Focal lesion in patients with deranged renal function test.

• Suspicious malignant focal liver lesion.

• Tertiary care workup for previous insufficient imaging done outside.

 

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Exclusion Criteria

• Patients with a history of hypersensitivity/allergy to egg products.

• Congenital cardiac or pulmonary shunt.

• Pregnant patients (as per manufacturer specifications, not yet tested on pregnant females).

 

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Technique

Informed consent was taken from the patients. Baseline grayscale ultrasound, along with contrast-enhanced imaging, was performed using the Philips Affiniti 70 G. Broadband convex probe (1–5 mHz) and dedicated low-MI contrast-imaging software were used. Second-generation contrast agent (Sonazoid) was injected as a bolus of 2 mL followed by a flush of 10 mL normal saline solution intravenously, through an 18- or 20-gauge cannula placed in the antecubital vein. Digital cine clips/single images representing the dynamic contrast enhancement pattern of the lesion and the surrounding liver tissue were recorded, starting at the time of contrast injection and covering the arterial (at 10–30 seconds), portal (at 60s), and late phases (at 120–150 seconds) after the injection and in the Kupffer phase (10 minutes after the contrast injection). No complications were recorded during the procedure.

CEUS images were read by two radiologists with an experience of 3 and 15 years, respectively. Interobserver agreement between two observers was calculated which was near perfect with a kappa value of 1. CECT and CEMRI images were read by a third radiologist with an experience of around 7 years; he was also blinded to the histopathology and CEUS results. CECT/CEMRI was taken as a gold standard for HCC (based on the evidence-based practice/AASLD guidelines); for non-HCC lesions, histopathology was taken as the gold standard. Diagnostic accuracy, sensitivity, and positive predictive value (PPV) of CEUS were then calculated with respect to the gold standard. portal vein thrombosis (PVT) was present in eight cases included in our study; so, the diagnostic accuracy of CEUS with Sonazoid for differentiating tumoral and bland thrombosis was also calculated. The algorithm of our study has been summarized in [Flowchart 1].

Flowchart 1 Flowchart depicting study algorithm.

 

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Observation and Results

Of the 31 patients included in our study, 24 were male (77.4%) and 7 were female (22.6%); underlying chronic liver disease (CLD) was present in 23 patients (74.2%). Single lesions was present in 22 patients (71%), multiple lesions were present in 6 patients (19.4%), and infiltrative HCC was present in 3(9.7%) of the patients. The size of the lesion in our study ranges between 1.3 and 12 cm, with a mean size of 5.7 cm. Lesions were well defined in 19 patients (61.3%) and ill-defined/infiltrative in the rest of the patients. PIVKA II and AFP were raised in 22 and 16 patients, respectively ([Table 1]). Wherever multiple lesions were present, characterization of the largest one was performed.

Table 1 Baseline characteristics of the patients

N = 31
	Male: 24 (77.4%), female: 7 (22.6%)
Underlying CLD	Present: 23 (74.2%), absent: 8 (25.8%)
No. of lesion	Single: 22 (71%), multiple: 6 (19.4), infiltrative (9.7%)
Characteristic of lesions	Well defined: 19 (61.3%), ill defined (38%)
Size of lesions	Max: 12 cm, min: 1.3 cm, mean: 5.7 cm (SD: 3.2)
PIVKA II: normal (0–40 mAU/mL)	Raised: 22 (71%)
AFP level: normal (0–8.5 ng/mL)	Raised: 16 (51.6%)

Abbreviations: AFP, alpha fetoprotein; CLD, chronic liver disease.

Observation in the form of diagnosis was made on CEUS for each patient by observers 1 and 2; diagnosis was made by a third observer (who was blinded to the result of CEUS and histopathology) based on CECT, CEMRI for each lesion, and histopathology results (wherever available); and the presence or absence of PVT was recorded in an excel sheet ([Table 2]). Data were analyzed for the calculation of sensitivity, specificity, PPV, negative predictive value (NPV), and diagnostic accuracy of CEUS with respect to gold standard tests.

Table 2 Summary of cases included in the study (n = 31)

Sl. no.	CLD present/absent	Observer-I	Observer-II	Diagnosis on CECT	Diagnosis on MRI	PVT	Biopsy
1	Present	Infiltrative HCC	Infiltrative HCC	Infiltrative HCC		Tumoral PVT
2	Present	HCC	HCC	HCC
3	Present	Cholangiocarcinoma	Cholangiocarcinoma	Cholangiocarcinoma	hepaticocholangiocarcinoma (HCCA)	Bland PVT	HCC
4	Present	HCC	HCC	HCC
5	Absent	FNH	FNH	FNH	FNH		FNH
6	Present	HCC	HCC	HCC
7	Present	HCC	HCC	HCCA
8	Absent	Adenoma	Adenoma	Adenoma	Adenoma
9	Absent	FFH	FFH	FFH
10	Present	HCC	HCC	HCC	HCC		HCC
11	Present	HCC	HCC	HCC		Tumoral PVT
12	Present	HCC	HCC	HCC		Bland PVT
13	Present	HCC	HCC	HCC
14	Absent	Cholangiocarcinoma	Cholangiocarcinoma	Cholangiocarcinoma	Cholangiocarcinoma		Cholangiocarcinoma
15	Present	HCC	HCC	HCC
16	Present	HCC	HCC		HCC	Nontumoral
17	Present	HCC	HCC	HCC
18	Present	HCC	HCC	HCC
19	Present	HCC	HCC	HCC		Bland
20	Present	HCC	HCC	HCC	HCC
21	Present	HCC	HCC
22	Present	HCC	HCC	HCC
23	Absent	FNH	FNH	FNH			FNH
24	Absent	Multifocal HCC	Multifocal HCC	Multifocal HCC		PVT equivocal	Tumoral PVT
25	Absent	adenocarcinoma	adenocarcinoma	HCCA			Adenocarcinoma
26	Absent	FLH	FLH	FLH	FLH/Adenoma
27	Present	HCC	HCC	HCC	HCC		HCC
28	Present	HCC	HCC		HCC
29	Present	HCC	HCC	HCC	HCC
30	Present	HCC	HCC		HCC
31	Present	HCC	HCC		HCC with tumoral PVT	Tumoral

Abbreviations: CECT, contrast-enhanced computed tomography; CLD, chronic liver disease; FLH, fibrolamellar hepatocellular carcinoma; FNH, focal nodular hyperplasia; HCC, hepatocellular carcinoma; PVT, portal vein thrombosis; UHID, unique health identification.

Out of the 31 patients included in our study, there was agreement between the diagnosis made on CEUS and CEMRI/CET/histopathology in 30 patients ([Figs. 1] and [2]). In one patient, a diagnosis of mesenchymal tumor was given on CEUS, which turned out to be benign on histopathology ([Table 3]).

Fig. 2 (A) B-mode ultrasound image showing an ill-defined isoechoic mass lesion in segment VIII of the liver. On post-contrast imaging with Sonazoid, the lesion shows arterial phase hyperenhancement (B) with retention of contrast on venous phase (C) and delayed Kupffer phase (D), likely suggestive of FNH. Diagnosis was subsequently confirmed on histopathology (E, F).Note: Arrow points to the lesion.

Table 3 Accuracy of CEUS for lesion characterization (n = 31)

	Disease positive on the gold standard	Disease negative on the gold standard	Total	Sensitivity	90%	(74.38–96.54)
Positive on CEUS	27	1	28	PPV	96.4%	(82.3–99.3)
Negative on CEUS	3	0	3	Diagnostic accuracy	87.1%	(71.1–94.87)

Abbreviations: CEUS, contrast-enhanced ultrasound; PPV, positive predictive value.

Limitations: As there was no true negative in the study group, specificity and NPV could not be calculated.

Reason: Our study subgroup included only patients with suspected malignant lesions, and a majority of the patients were of CLD with suspected HCC.

Out of 31 patients included in our study, histopathology was available for 9 patients, and there was disagreement between CEUS and biopsy in 2 of them ([Table 4]). In one patient, a diagnosis of malignant mesenchymal tumor was made on CEUS, which turned out to be benign on histopathology; no atypical cells were noted. In another patient, a diagnosis of cholangiocarcinoma was made on CEUS and it turned out to be HCC on histopathology. Thus, we concluded that CEUS with Sonazoid (with respect to histopathology) has a sensitivity of 87.5%, specificity of 87.5%, and diagnostic accuracy of 77.8% for the characterization of each lesion.

Table 4 CEUS vs. histopathology for lesion characterization (n = 9)

Sl. no.	Observer 1 on CEUS	Observer 2 on CEUS	Histopathology
1	HCC (malignant)	HCC (malignant)	HCC (malignant)
2	Tumoral (malignant)	Tumoral (malignant)	Tumoral PVT (malignant)
3	Cholangioca (malignant)	Cholangio (malignant)	Cholangioca (malignant)
4	Cholangio (malignant)	Cholangio (malignant)	Cholangio (malignant)
5	HCC (malignant)	HCC (malignant)	HCC
6	Mesenchymal tumor (malignant)	Mesenchymal tumor (malignant)	Benign/no atypical cell
7	FNH (benign)	FNH (benign)	FNH (benign)
8	Cholangio	Cholangio	HCC (malignant)
9	FNH (benign)	FNH (benign)	FNH (benign)

Abbreviations: CEUS, contrast-enhanced ultrasound; FNH, focal nodular hyperplasia; HCC, hepatocellular carcinoma; PVT, portal vein thrombosis.

One case in which CT was negative for tumoral thrombus finally turned out to be tumoral on histopathology ([Fig. 3]).

Fig. 3 (A, B) Axial NCCT and CECT image in a patient with multifocal HCC with TIV (S/P chemotherapy) shows no obvious enhancement in the tumor vein thrombus. (C, D) CEUS and B-mode USG show eccentric enhancement (arrow) of the thrombus in the left portal vein, suggestive of tumoral thrombus, which was subsequently proved on biopsy from the left portal vein (E and F).Note: Arrow points to the eccentric enhancement of thrombus in the portal vein.

Out of the eight patients with PVT included in our study, diagnosis of tumoral and bland PVT was made on CEUS for four patients each ([Table 5]). On CT, five patients were characterized as having bland thrombus and three patients as having tumoral thrombus. In one patient, there was disagreement between the CECT and CEUS; so, a biopsy from the LPV thrombus was taken, which came out to be malignant. Thus, in a limited number of patients included in our study, CEUS had sensitivity, specificity, NPV, and PPV of 100% for differentiating between tumoral and bland thrombus ([Figs. 3] and [4]).

Table 5 Characterization of portal vein thrombus (bland vs. tumoral)

On CEUS	Tumoral	Bland
Tumoral	4	0
Bland	0	4
Sensitivity	100%
Specificity	100%
PPV	100%
NPV	100%

Abbreviations: CEUS, contrast-enhanced ultrasound; NPV, negative predictive value; PPV, positive predictive value.

Fig. 4 (A) B-mode ultrasound image showing the main portal vein filled with echogenic content with an ill-defined, mildly hyperechoic lesion in the adjacent liver segment. On post-contrast imaging with Sonazoid, thrombus in MPV shows hyperenhancement (B) with washout of the focal lesion in the adjacent liver segment in the venous phase (C) and delayed Kupffer phase (D), likely suggestive of HCC with tumoral PVT. Diagnosis was subsequently confirmed on CECT.

 

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Discussion

Liver tumor is one of the common causes of cancer-related morbidity and mortality. Early-stage malignancies have a good prognosis, as they are eligible for various potentially curative therapies, including surgical treatment (resection, liver transplantation) and locoregional treatment (transarterial chemoembolization, radiofrequency ablation, microwave ablation, cryoablation, IRE, or ethanol injection). HCC patients with advanced tumor staging have a poor prognosis. Therefore, diagnosing and characterizing liver lesions at an early stage is important. Ultrasound is the first-line examination for the evaluation of the focal lesions of the liver. CEUS, in addition to providing morphological details of lesions, also provides details about the microvascularity and microperfusion characteristics. The information provided by CEUS is analogous to the information obtained by CECT and dynamic CEMR; CEUS also provides information in real time. As the imaging in CEUS is real time and dynamic, it provides information about microperfusion characteristics at par with CECT/CEMRI.

Cao et al in their meta-analysis (included 26 studies comprising 8,495 patients with 9,244 lesions) compared the diagnostic efficiency of the CEUS LI-RADS for SonoVue and the modified LI-RADS for Sonazoid and concluded that the Sonazoid-modified LR-5 algorithm had a higher sensitivity, lower specificity, and higher AUC than SonoVue LR-5.[13] Wu et al in their meta-analysis included 57 studies (which used SonoVue/Sonazoid/Levovist) that was conducted to evaluate the diagnostic accuracy of CEUS in differentiating malignant from benign liver lesions and they found CEUS to be an accurate tool for stratification of the risk of malignancy in focal liver lesions. Also, they concluded that among the three major contrast agents (SonoVue, Sonazoid, and Levovist), Sonazoid demonstrated the highest diagnostic accuracy.[14]

Luo et al in their study included (by retrospective identification) 139 patients with focal liver lesions—77 HCC, 33 metastasis, 23 hemangiomas, and 6 focal nodular hyperplasia (FNH)—who underwent 3D US enhanced with a perflubutane microbubble contrast agent as well as 3D contrast-enhanced multidetector CT. Two readers blindly reviewed the multiplanar images reconstructed with both modalities and classified the depicted lesions according to diagnostic criteria based on their experience. They concluded that there were no significant differences between the two modalities (CEUS and CECT): sensitivity was 83% or greater with both modalities, specificity was 87% or greater with contrast-enhanced US and 92% or greater with contrast-enhanced CT, the PPV was 71% or greater with both modalities, and the Az was at least 0.89 with US and at least 0.92 with CT. Inter-reader agreement was good to excellent (0.76) with both modalities.[15]

Hsiao et al in their prospective study included 66 patients suspected of having liver tumors smaller than 3 cm and underwent CEUS (with Sonazoid), dynamic CT, and MRI examinations independently.[16] Subsequently, biopsies were used to verify the diagnostic performance of the three imaging modalities. They concluded that the diagnostic performance of CEUS is superior to that of dynamic CT and MRI when dealing with small liver tumors (<3 cm). CEUS could be used as a standard diagnostic tool for monitoring liver tumor recurrence after treatment.[14] In our study, we concluded that CEUS with Sonazoid (with respect to histopathology) has a sensitivity of 87.5%, specificity of 87.5%, and diagnostic accuracy of 77.8% for the characterization of each lesion.[16]

Huang et al in their study retrospectively analyzed (as per KLCA-NCC 2O22) cirrhotic patients (400 patients and 432 lesions) who underwent Sonazoid CEUS for liver lesion evaluation and they concluded CEUS to be an effective diagnostic tool for HCC. There was excellent inter-reader consistency in detecting arterial phase hyperenhancement and Kupffer defects.[17] Jang et al in their study concluded that extending the portal phase observation by up to 5 minutes helps in making a confident diagnosis of HCC, by allowing the assessment of final washout, which occurred in the majority (91%) of HCCs in their study. Similar findings were observed in our study.[18]

In our study, we found agreement between CEUS and TPCT/CEMRI (accepted gold standard as per evidence-based practice) in demonstrating the enhancement characteristics of the lesions. The majority of the lesions showed arterial phase hyperenhancement on (15–25 seconds) CEUS. This is the major advantage of the dynamic real-time scanning of CEUS, which allows continuous assessment of the lesion as soon as the contrast reaches the vessels. TPCT, however, lacks this advantage as the scan is acquired at only a specific point in time. Moreover, the resolution of CECT and CEMRI is also dependent on the slice thickness.

In the HCC cases included in our study, we observed arterial phase hypervascularity as early as 13 seconds, with a mean time of enhancement being 28 seconds. Washout was seen as early as 37 seconds, with mean time of washout being 49 seconds. Out of the two FNH cases included in our study, arterial phase enhancement was observed in one case in 7 seconds. Both the cases showed retention of contrast for more than 25 minutes. In our study, we also concluded that there was statistically significant agreement between CEUS and CECT in demonstrating the peripheral capsule as opposed to the study by Moudgil et al in which they concluded that CEUS (with SonoVue) is a better modality for demonstrating pseudocapsule.[19]

In our study, we concluded that there was no significant difference between nodule enhancement in the HPB phase and the Kupffer phase. This was in line with the findings noted by Hwang et al in their study, in which they characterized 203 nodules on CEUS using Sonazoid and concluded that the Kupffer phase best shows hypoenhancing changes in LR5 lesions. In our study, we observed that the Kupffer phase started as early as 10 minutes.[20]

Chen et al in their meta-analysis (which included seven studies that used either SonoVue or Levovist as contrast agent) published in European Radiology found CEUS to be highly efficient in differentiating TIV from PVT and is an alternative or substitute for CT/MRI.[21] Tarantino et al in their study concluded CEUS (SonoVue) to be a reliable technique with sensitivity higher than CT in detection as well as characterization of portal vein thrombus.[22] In the limited number of patients with PVT (n = 8) included in our study, we also found CEUS to have sensitivity, specificity, PPV, and NPV of 100%.

 

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Conclusion

CEUS with Sonazoid has a sensitivity of 90%, accuracy of 87%, and PPV of 96% for characterizing focal liver lesions. CEUS seems to be an excellent modality for differentiating tumoral from bland thrombus; however, to increase the confidence limit, larger studies need to be performed. Hepatobiliary phase defect on CEMRI corresponds to the Kupffer phase defect. As CEUS can be safely used for lesion characterization in patients where CT/MRI contrast agents are contraindicated, it can be used as an alternative modality in cases of diagnostic dilemma. As it is radiation-free, it can be used in regular surveillance of high-risk patients. Some of the potential barriers to the adoption of Sonazoid in India or any developing countries are a lack of training, a lack of equipment, and the high cost of Sonazoid, which increases further if the analysis of the lesion is to be performed by defect reperfusion imaging, as it requires the injection of contrast twice.

 

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Limitations

Our study had many shortcomings: first of all, the sample size was small with the presence of inherent selection bias, as most of the patients were of CLD with suspected HCC. The mean size of the lesions included in our study was large (5.2 cm); so, the efficacy of CEUS in the evaluation of small lesions needs further evaluation. Histopathology was not available for all the cases, and CECT/CEMRI was considered the gold standard. Sometimes, for example, in lesions near the dome of the diaphragm, lesions obscured by rib shadow, or in the presence of gaseous abdomen/obesity, it is difficult to obtain a good sonographic window. The arterial phase lasts for ∼30 seconds, and with a single injection of contrast, it is difficult to scan the whole liver for characterization of multiple lesions. Also, the correlation of Kupffer phase defects with quantitative CEUS metrics (e.g., time-intensity curves) would have improved objectivity. CECT/CEMR provides additional information about the comorbidities, metastasis. Further study needs to be performed by removing selection bias, that is, by including a control group (noncirrhotic patients) and smaller lesions equally. A multicentric, large cohort study with stratification by lesion type would further solidify CEUS's utility.

 

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Conflict of Interest

None declared.

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Artikel online veröffentlicht:
08. September 2025