Introduction
Hepatocellular carcinoma (HCC) is the most common primary malignant tumor of the liver and a
leading cause of cancer-related mortality worldwide, especially in patients with chronic liver
disease and cirrhosis. [1] Early and accurate diagnosis is crucial, as prognosis and therapeutical
options such as resection, transplantation or local ablation, largely depend on tumor stage at the
time of detection. [2]
Multiphase computed tomography (CT) and magnetic resonance imaging (MRI) are established
first-line imaging modalities for HCC diagnosis. [3] Characteristic vascular patterns such as
arterial phase hyperenhancement (APHE) followed by portal venous or delayed phase washout,
are widely accepted in international guidelines and classification systems, including LI-RADS.
[4]
However, a substantial proportion of focal liver lesions remain indeterminate after CT or MRI,
resulting in diagnostic uncertainty, additional imaging, biopsy, or postponing the decision on
therapy. [5]
Contrast-enhanced ultrasound (CEUS) has proven to be a valuable complementary method in the
characterization of focal liver lesions. [6] Due to the ability to display vascular dynamics in real
time and high temporal resolution, CEUS can detect enhancement patterns such as non-marginal
APHE and late mild washout, which are highly suggestive of HCC. [7]
Compared to CT and MRI, CEUS has several advantages: it does not use ionizing radiation, it is
relatively inexpensive, it is easy to repeat and it is safe even in patients with renal failure. [8]
The latest studies and guidelines increasingly emphasize its role as the method of choice when
CT or MRI findings are indeterminate. [9]
However, the incremental diagnostic value of CEUS in resolving indeterminate findings on CT
or MRI has not been fully established in all clinical settings. Data on its application in the real
conditions of tertiary centers are still limited, especially in populations with a high prevalence of
HCC and various etiologies of chronic liver disease.
The aim of this study was to assess the diagnostic performance of CEUS compared with CT and
MRI and to determine the incremental diagnostic value of CEUS in lesions that remained
indeterminate on CT or MRI, using histopathology as the reference standard.
Materials and Methods
Patients
This retrospective study included 50 patients with focal liver lesions who underwent CEUS, with
CT and/or MRI available in the majority of cases, and with histopathological diagnosis as the
reference standard
Thirteen patients without definitive histopathological diagnosis were excluded, resulting in a
final cohort of 37 patients. Basic clinical variables included age, gender, lesion size, and presence
of chronic liver disease (hepatitis B, hepatitis C, MASLD, alcohol-related liver disease, and
cirrhosis).
Protocols
CEUS examinations were performed using a high-end ultrasound system (Canon Aplio i700)
with intravenous administration of 0.2–0.5 mL of sulphur hexafluoride microbubble contrast
agent (SonoVue). Lesions were evaluated for enhancement patterns, including arterial phase
hyperenhancement and timing and intensity of washout. Results obtained through CEUS were
categorized as direct diagnosis (HCC, ICC, hemangioma) or by CEUS LI-RADS classification.
CT and/or MRI examinations, done within a previous period of 3 months, were reviewed
according to standard diagnostic criteria for HCC, and the lesions were classified as HCC and
non-HCC lesions. In cases where the diagnosis could not be declared, they were marked as
"indeterminate" or were classified based on the LI-RADS classification as stage 3 or 4.
Histopathology served as the definitive reference standard in cases where it was available. In
selected cases, imaging diagnosis was considered definitive in accordance with accepted clinical
guidelines.
Statistical analysis
Diagnostic performance metrics (sensitivity, specificity, and overall accuracy) were calculated
for CEUS, CT, and MRI in patients with histopathological confirmation. Only cases with definite
results (HCC or non-HCC) for each modality were included in the analysis. Exact 95%
confidence intervals were calculated using the Clopper–Pearson method.
For cases classified as indeterminate on CT or MRI, the incremental value of CEUS was
estimated by comparing the proportion of definitively and correctly classified cases before and
after CEUS. Re-classification tables were constructed, and paired improvements were tested
using the exact McNemar test. All statistical tests were two-way, and p<0.05 was considered
statistically significant.
The analyzes were carried out in the statistical processing program IBM SPSS version XX, and
the results are presented in accordance with the STARD guidelines.
Of the 50 patients included in the study, the majority were men (60%), with an average age of 68
years. The average size of the lesions was 50.9 mm. Most lesions were hypoechoic (70%), with
arterial phase hyperenhancement (APHE) noted in 92% and late washout in 88% of cases on
CEUS. Etiology of chronic liver disease included hepatitis B (20%), hepatitis C (10%), MASLD
(20%) and cirrhosis (12%). According to the CEUS LI-RADS classification, 46% of lesions were
classified as LR-5, while 40% remained unclassified (table 1).
Table 1. Demographics and lesion characteristics
Numbe
r % Min Mean Max
Male 30 60%
Gender
Female 20 40%
Age 28 68 101
50.88m
Size
11mm m 170mm
Hypoechoic 35 70%
Echogenicity Isoechogenic 10 20%
Hyperechoic 5 10%
No 1 2%
APHE Yes 46 92%
Peripheral 3 6%
Early 1 2%
Washout Late 44 88% 20sec 4min 6min
No 5 10%
No 5 10%
Hepatitis B 10 20%
Hepatitis C 5 10%
MASLD 10 20%
CLD AH 3 6%
ALD 7 14%
MASH
cirrhosis 3 6%
Cirrhosis 6 12%
Missing 1 2%
4 5 10%
5 23 46%
CEUS LI-RADS
M 2 4%
Without 20 40%
CEUS diagnosed almost all lesions as HCC (98%), with one case of ICC. CT identified HCC in
42% of patients, while 32% remained indeterminate. MRI classified 36% of lesions as HCC,
with additional diagnoses of hemangioma (6%), ICC (4%), metastases (4%) and 4% as LR-5.
Pathohistology confirmed HCC in 64% of patients, while the remaining cases included
hemangiomas, ICC, hematomas, inflammatory pseudotumors and benign changes (Table 2).
Table 2. Diagnosis by modality
Number %
HCC 49 98%
CEUS diagnosis
ICC 1 2%
HCC 21 42%
ICC 1 2%
CT diagnosis Indeterminate 16 32%
Normal 2 4%
CT not done 10 20%
HCA 1 2%
HCC 18 36%
Hemangioma 3 6%
ICC 2 4%
LIRADS M 1 2%
MRI diagnosis
LIRADS 5 2 4%
Metastasis 2 4%
Indeterminate 4 8%
Normal 1 2%
MRI not done 16 32%
HCC 32 64%
Hemangioma 1 2%
Hematoma 1 2%
PHD diagnosis ICC 2 4%
Inflammatory pseudotumor 1 2%
Failed 2 4%
Not done 11 22%
In the evaluation of the diagnostic accuracy of each imaging modality, a total of 37 patients with
a histopathology confirmation of HCC were included. CEUS had the highest sensitivity (96.9%),
but with low specificity due to almost universal classification of lesions as HCC (table 3).
Table 3. Sensitivity, specificity and precision of each modality with a histopathology confirmation
Sensitivity (95% CI) Specificity (95% CI) Precision (95% CI)
92.3% 33.3% 81.2%
CT
(64.0–99.8) (0.8–90.6) (54.4–96.0)
81.2% 60.0% 76.2%
MRI
(54.4–96.0) (14.7–94.7) (52.8–91.8)
96.9% 0.0% 83.8%
CEUS
(83.8–99.9) (0.0–52.2) (68.0–93.8)
With CT-indeterminate lesions, CEUS correctly resolved 85.7% of cases, while with MRI-
indeterminate lesions, 93.8% of cases were correctly resolved, with a statistically significant
improvement compared to independent CT and MRI findings (table 4).
Table 4. Indeterminate cases by CT and MRI that were corrected after contrast ultrasound
To
Correctly
Inorrectly To HCC non-HCC
Total solved McNemar p
solved (Correctly) (Correctl
(95% CI)
y)
18/21
20 (18 1 (0
CT- Indeterminate 21 (85.7%, 3 0.00149
tačno) tačno)
63.7–97.0)
15/16
15 (15 1 (0
MRI- Indeterminate 16 (93.8%, 1 0.00052
tačno) tačno)
69.8–99.8)
Conclusion
CEUS provides significant incremental diagnostic value in the assessment of focal liver lesions
that remain indeterminate after CT or MRI. While CT and MRI remain indispensable first-line
modalities, CEUS serves as an effective problem-solving tool, capable of resolving diagnostic
uncertainty in a large proportion of cases. Its high sensitivity and real-time assessment of
vascular patterns allow rapid and clinically meaningful reclassification of indeterminate lesions,
supporting its integration into diagnostic algorithms for suspected HCC.
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