Comparison of Gd-EOB-DTPA-enhanced MRI and Contrast-enhanced Ultrasound for measuring tumor size of solitary hepatocellular carcinoma ≤ 5cm: A real-world study

doi:10.21203/rs.3.rs-4801711/v1

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Comparison of Gd-EOB-DTPA-enhanced MRI and Contrast-enhanced Ultrasound for measuring tumor size of solitary hepatocellular carcinoma ≤ 5cm: A real-world study

https://doi.org/10.21203/rs.3.rs-4801711/v1

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Objective To retrospectively compare the performance of Gd-EOB-DTPA-enhanced MRI (CE-MRI) and Contrast-enhanced Ultrasound (CEUS) in measuring tumor size of solitary hepatocellular carcinoma (HCC) ≤5cm.

Methods A total of 194 patients who met the inclusion criteria from January 2019 through May 2024 were included. Taken pathological results as the reference standard, The paired T-test and Bland–Altman analysis were conducted to assess the correlation and mean absolute error between the measured maximum diameter of HCC obtained from CE-MRI/CEUS and pathological results.

Results The comparison of baseline characteristics showed that there was no significant difference between the two groups of patients undergoing MRI and CEUS (P > 0.05). Both CE-MRI and CEUS demonstrated good correlation (r > 0.7) with histological results. The paired T-test analysis revealed that CE-MRI exhibited a smaller mean absolute error (0.1 ± 6.3 mm, P = 0.224, 95%CI -0.099~0.123) compared to CEUS (4.8 ± 7.1 mm, P < 0.001, 95%CI 0.354~0.615). Furthermore, results from the subgroup of patients who underwent both CE-MRI (r = 0.896, mean absolute error 1.2 ± 4.8 mm, P = 0.094, 95%CI -0.021~0.258) and CEUS (r = 0.882, mean absolute error 3.9 ± 4.7 mm, P < 0.001, 95%CI 0.252~0.527) echoed the aforementioned conclusions. The Bland-Altman analysis indicated that both CE-MRI and CEUS consistently overestimated the size of HCC when compared to pathological results. CE-MRI (bias 0.12; 1.19 mm) demonstrated a smaller bias in both the overall patient population and the subgroup patients, as opposed to CEUS (bias 5.02; 3.90 mm).

Conclusion In the preoperative assessment of tumor sizes for solitary HCC measuring ≤5cm, Gd-EOB-DTPA-enhanced MRI exhibited superior measuring accuracy and can be more clinically useful compared to CEUS.

Magnetic resonance imaging

Gd-EOB-DTPA-enhanced

Ultrasound

Contrast media

Hepatocellular carcinoma

Tumor size

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and poses a significant health challenge globally¹. Accurate assessment of tumor size plays a crucial role in determining the appropriate treatment and predicting the prognosis of individuals diagnosed with HCC². Specifically in cases of early-stage HCC where tumor size is less than 5 cm, curative treatment options encompass a spectrum from local ablation and surgical resection to liver transplantation³. The HCC size frequently influences the final selection of treatment options to optimize prognosis^4,5. Even small differences in HCC size measurements preoperatively can impact patient’s management and outcomes. Therefore, it is essential to choose an imaging method that can accurately measure tumro size of HCC before treatment.

HCC can frequently be diagnosed solely through imaging techniques due to its distinctive features⁶. Two prevalent imaging methods, Gd-EOB-DTPA-enhanced MRI (CE-MRI) and contrast-enhanced ultrasound (CEUS), have shown good diagnostic performance especially for early stage HCC^7,8. However, while research on the diagnostic accuracy of HCC is extensive, studies focusing on the precision of HCC size measurement are limited. And it remains unclear which imaging methods is superior. This study aimed to assess the efficacy of CE-MRI and CEUS in measuring solitary HCC size ≤ 5cm, using histopathology as the reference standard, and thereby determine which imaging method most accurately corresponds with histological results.

2.1 Patients recruitment

The patients with the first definitive diagnosis of single HCC underwent hepatectomy from January 2019 to June 2024 were included. The inclusion criteria were as follows: (1) had no anti-HCC therapy prior to imaging examinations. (2) at least had one examination of Gd-EOB-DTPA-enhanced MRI or CEUS within one week before surgery. (3) if the patients had both imaging tests, the time interval between two examinations was less than one week. (4) both radiological and pathological results recorded the maximum tumor diameter. (5) postoperative pathology confirmed the diagnostic of single HCC with a diameter of 5cm or less. Exclusion criteria were as follows: (1) systemic or regional anti-HCC treatment before imaging examinations; (2) patients with multiple lesions (n ≥ 2) or HCC size > 5cm; (3) had no maximum diameter of HCC recorded in pathological or imaging reports.

Finally, a total of 194 participants were enrolled. This retrospective study was approved by our institutional ethics committee and written informed consent was waived for its retrospective nature.

2.2 Examinations and Procedures

Two radiological examinations of CE-MRI and CEUS were implemented in accordance with standard protocols. MRI was performed by using a superconducting magnet scanner operated at 3.0 T (GE discovery MR750w, USA), and the liver-specific contrast agent was intravenous administration of 0.2-0.4ml per kg body weight of gadoxetic acid at a rate of 1.0–2.0 ml/s. The results of CE-MRI was remeasured on the hepatobiliary-phase (HBP) by one single radiologist as it has been reproted that HBP had the best measuring performance of the MRI squences^9,10. As for the CEUS examination (Mindray, China), ultrasound was performed first in B-mode to identify the suspicious lesions and then switched to contrast mode prior to the injection of the contrast medium. Second-generation US contrast agent (SonoVue, Bracco, Italy) was injected 1.5ml (SF6 45ug/ml) intravenously once. However, the measurments of CEUS were from clinical reports. The pathologists examined the gross liver specimens and recorded the location, size, and resection margin of hepatic mass. They aimed to choose the largest tumor section, typically in the center of the tumor mass, to obtain a three-dimensional measurement of width×length×height. And the results of this part were also from clinical reports.

2.3 Statistical Analysis

Using Anderson–Darling test to check the normality. Continuous variables were presented as mean±standard deviation (SD), and categorical variables were presented as number with percentage. Comparison of continuous and categorical variables were achieved by Mann–Whitney U test and Chi-square test, respectively. The paired T -tests and Bland–Altman plots were used to compare the absolute error and assess agreement between imaging and pathological results. Box-plot was used to identify outliers and reflect the data distribution. All statistical analyses were conducted with GraphPad Prism version 10.2.3. A 2-tailed P value less than 0.05 was considered statistically significant.

3.1 Patient characteristics

A total of 194 patients participated in the study, with 126 patients undergoing CE-MRI and 116 patients undergoing CEUS. Furthermore, 48 patients underwent both imaging examinations. There were no significant differences in terms of sex, age, hepatitis B positive, liver cirrhosis, diagnostic accuracy, and tumor size between the two groups (P > 0.05) (Table 1).

Table 1

Baseline demographic characteristics
Variables	CE-MRI(n = 126)	CEUS(n = 116)	P values
Sex, n(%)			0.075
Male	107 (84.9)	107 (92.2)
Female	19 (15.1)	9 (7.8)
Age ≥ 65years, n(%)			0.891
Yes	37 (29.4)	35 (30.2)
No	89 (70.6)	81 (69.8)
Hepatitis B positive, n(%)			0.802
Yes	85 (67.5)	80 (69.0)
No	41 (32.5)	36 (31.0)
Liver cirrhosis, n(%)			0.507
Yes	92 (73.0)	89 (76.7)
No	34 (27.0)	27 (23.3)
Diagnostic accuracy, n(%)			0.286
Yes	122 (96.8)	109 (94.0)
No	4 (3.2)	7 (6.0)
Tumor size, n(%)			0.302
≤ 2cm	32 (25.4)	23 (19.8)
> 2, ≤5cm	94 (74.6)	93 (80.2)

3.2 The paired T-test and Bland–Altman analysis

As seen in Fig. 1 and Fig. 2 and summarized in Table 2, both CE-MRI and CEUS demonstrated good correlation (r > 0.7) with histological results, indicating their potential for accurately measuring HCC size. The paired T-test analysis revealed that CE-MRI exhibited a smaller mean absolute error (0.1 ± 6.3 mm, P = 0.224, 95%CI -0.099 ~ 0.123) compared to CEUS (4.8 ± 7.1 mm, P < 0.001, 95%CI 0.354 ~ 0.615). Furthermore, results from the subgroup of patients who underwent both CE-MRI (r = 0.896, mean absolute error 1.2 ± 4.8 mm, P = 0.094, 95%CI -0.021 ~ 0.258) and CEUS (r = 0.882, mean absolute error 3.9 ± 4.7 mm, P < 0.001, 95%CI 0.252 ~ 0.527) echoed the aforementioned conclusions. The Bland-Altman analysis indicated that both CE-MRI and CEUS consistently overestimated the size of HCC when compared to pathological results. CE-MRI (bias 0.12; 1.19 mm) demonstrated a smaller bias in both the overall patient population and the subgroup patients, as opposed to CEUS (bias 5.02; 3.90 mm). Box Plots also illustrated that the median HCC size difference of CE-MRI was smaller than CEUS when compared with histological results(Fig. 3).

Table 2

The paired T-test and Bland–Altman analysis between CE-MRI/CEUS and pathological measurements
	CE-MRI, n = 126	CEUS, n = 116	CE-MRI, n = 48	CEUS, n = 48
Paired T-test
Mean ± SD (mm)	0.1 ± 6.3	4.8 ± 7.1	1.2 ± 4.8	3.9 ± 4.7
P	0.833	< 0.001	0.094	< 0.001
95%CI	-0.099 ~ 0.123	0.354 ~ 0.615	-0.021 ~ 0.258	0.252 ~ 0.527
r	0.858	0.770	0.896	0.882
Bland-Altman analysis
Bias (mm)	0.12	5.02	1.19	3.90
95%CI
From	-1.225	-0.929	-0.824	-0.539
To	1.248	1.932	1.061	1.318

Currently, the clinical management guidelines of hepatocellular carcinoma worldwide emphasize tumor size as the primary indicator for staging single HCC, significantly impacting treatment approaches and patient outcomes¹¹. For example, the Milan criteria, which serve as a crucial guideline for determining the eligibility for liver transplantation, stipulate that the diameter of a solitary tumor should not exceed 5cm¹². For very early HCC (single nodule < 2 cm), radiofrequency ablation (RFA) provided similar life-expectancy and quality-adjusted life-expectancy at a lower cost than hepatectomy, but it is opposite for single HCCs of 3–5 cm¹³. Although current guidelines recommend surgical resection as the preferred treatment for solitary HCC ≤ 5 cm and considered HCC > 5 cm as a high-risk for recurrence after surgery¹⁴. Tumor size is still an independent prognostic factor for resected small HCC, and patients with tumors of 0–35 mm diameter have a better 60-month overall survival rate than do those with larger tumors of 36–50 mm¹⁵. In conclusion, accurate assessment of HCC sizes is crucial prior to commencing treatment.

So far, both Gd-EOB-DTPA-enhanced MRI and CEUS have been shown to be effective in diagnosing HCC. CE-MRI has been proven to have the best performance in diagnosing small HCC according to several recent studies^16,17. CEUS, on the other hand, offers the benefits of conventional ultrasound, such as no radiation, quick examinations, and portability, while also providing more detailed information about the characteristics and blood supply of a focal lesion¹⁸. Additionally, both of these two imaging modalities outperformed CECT in terms of accuracy in diagnosing small HCCs^16,19. This study compared the accuracy of Gd-EOB-DTPA enhanced MRI and CEUS in measuring HCC size, and aimed to determine which is the most accurate examination for measuring the diameter of HCCs.The results showed that Gd-EOB-DTPA-enhanced MRI had superior measuring performance compared to CEUS, with a better correlation coefficient and smaller absolute error.

In our study cohort, both CE-MRI and CEUS demonstrated good correlation (r > 0.7) with histological results, indicating their potential for accurately measuring HCC size.

The Bland-Altman analysis indicated that both CE-MRI and CEUS consistently overestimated the size of HCC when compared to pathological results. CE-MRI demonstrated a smaller bias in both the overall patient population and the subgroup patients, as opposed to CEUS. One possible explanation is that the formalin inclusion leads to tumor shrinkage. Meanwhile, the enhancement capsule exhibited by imaging signs may also contribute to larger measurements in CE-MRI and CEUS compared to actual HCC size^20–22. However, the paired T-test analysis revealed that only the absolute error of CEUS was statistically significant (p < 0.001), indicating that CE-MRI had less error and higher accuracy in measuring HCC size.

This study is subject to several limitations. First, lack of interrater reliability confirmation. All the imaging and pathological procedures were performed by only one physician respectively, which may introduce bias and limit the generalizability of the findings. It would have been beneficial to have multiple physicians independently assess the imaging and pathology results to ensure consistency and reliability. Second, small sample size for subgroups. Although the study included a relatively large number of participants, the sample size for subgroups who underwent both imaging examinations was still small. This may limit the statistical power and precision of the results for this specific subgroups. In addition, as a retrospective design, unlike CE-MRI, radiologists selected the phase of CEUS when measuring tumor size was unknown. This lack of standardization may introduce variability and potential measurement errors, affecting the accuracy of the examination methods. Therefore, prospective randomized controlled trials with larger sample sizes are needed to further validate the results of this study.

In conclusion, our study indicated that the measuring performance of Gd-EOB-DTPA-enhanced MRI is superior to that of CEUS. Additionally, it is important to note that Gd-EOB-DTPA-enhanced MRI may tend to overestimate the HCC size.

CE-MRI

Gd-EOB-DTPA-enhanced MRI

CEUS

Contrast-enhanced Ultrasound

HCC

Hepatocellular carcinoma

HBP Hepatobiliary phase

Ethics approval and consent to participate:

This retrospective study was approved by the Ethics Committee of the First Affiliated Hospital of the University of Science and Technology of China (ID 2023-RE-117) and and written informed consent was waived for its retrospective nature.

Consent for publication:

not applicable

Availability of data and materials:

Data is provided within the supplementary information files. The raw data supporting the conclusion of this article will be made available by the authors, without undue reservation.

Competing Interests:

not applicable

Funding:

not applicable

Authors' contributions:

L-LG wrote the main manuscript text and analysis the data. K-YJ acquisition and analysis the data for the work; Q-XC prepared figure 1-3 ; X Y revised the manuscript critically and final approval of the version to be published. All authors reviewed the manuscript.

Acknowledgements:

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

A data sharing statement

The raw data supporting the conclusion of this article will be made available by the authors, without undue reservation.

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You are reading this latest preprint version

Comparison of Gd-EOB-DTPA-enhanced MRI and Contrast-enhanced Ultrasound for measuring tumor size of solitary hepatocellular carcinoma ≤ 5cm: A real-world study

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Version 1

Abstract

Figures

1 Introduction

2 Methods

2.1 Patients recruitment

2.2 Examinations and Procedures

2.3 Statistical Analysis

3 Results

3.1 Patient characteristics

3.2 The paired T-test and Bland–Altman analysis

4 Discussion

Abbreviations

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References

Additional Declarations

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