This article has Open Peer Review reports available.
Gd-EOB-DTPA-enhanced magnetic resonance imaging combined with T1 mapping predicts the degree of differentiation in hepatocellular carcinoma
- Zhenpeng Peng†1,
- Mengjie Jiang†1, 2,
- Huasong Cai†1,
- Tao Chan3,
- Zhi Dong1,
- Yanji Luo1,
- Zi-Ping Li1Email author and
- Shi-Ting Feng1Email author
© The Author(s). 2016
Received: 22 April 2016
Accepted: 25 July 2016
Published: 12 August 2016
Variable degrees of differentiation in hepatocellular carcinoma(HCC)under Edmondson-Steiner grading system has been proven to be an independent prognostic indicator for HCC. Up till now, there has been no effective radiological method that can reveal the degree of differentiation in HCC before surgery. This paper aims to evaluate the use of Gd-EOB-DTPA-Enhanced Magnetic Resonance Imaging combined with T1 mapping for the diagnosis of HCC and assessing its degree of differentiation.
Forty-four patients with 53 pathologically proven HCC had undergone Gd-EOB-DTPA enhanced MRI with T1 mapping before surgery. Out of the 53 lesions,13 were grade I, 27 were gradeII, and 13 were grade III. The T1 values of each lesion were measured before and at 20 min after Gd-EOB-DTPA administration (T1p and T1e). The absolute reduction in T1 value (T1d) and the percentage reduction (T1d %) were calculated. The one-way ANOVA and Pearson correlation were used for comparisons between the T1 mapping values.
The T1d and T1d % of grade I, II and III of HCC was 660.5 ± 422.8ms、295.0 ± 99.6ms、276.2 ± 95.0ms and 54.0 ± 12.2 %、31.5 ± 6.9 %、27.7 ± 6.7 % respectively. The differences between grade Iand II, grade Iand III were statistically significant (p < 0.05), but there was no statically significant difference between grade II and III. The T1d % was the best marker for grading of HCC, with a Spearman correlation coefficient of −0.676.
T1 mapping before and after Gd-EOB-DTPA administration can predict degree of differentiation in HCC.
Hepatocellular carcinoma (HCC) ranks as the sixth most common cancer worldwide and is responsible for about 9 % of the cancer-related deaths globally . Many new developments in medical imaging help to improve detection, characterization, and prognostication of HCC, eg contrast-enhanced ultrasonography (CEUS), multidetector computer tomography (MDCT), diffusion weighted magnetic resonance imaging (DW-MRI), and Gd-EOB-DTPA enhanced MRI [1–4]. Gadoxetic acid is a hepatocyte-specific contrast agent with a pendant ethoxybenzyl group covalently attached to the extracellular contrast agent gadopentetate dimeglumine, which can be taken up by functioning hepatocytes. It is eliminated in equal quantities by the urinary and biliary systems [5–8]. Therefore, it enables the assessment of tumor vascularity as well as other hepatocellular-specific properties within the tumor. Thus Gd-EOB-DTPA has been proven valuable in detection and differential diagnosis of focal liver lesions, especially between early HCC and dysplastic nodule(DN) [3, 9]. As HCCs in different degree of differentiation retain variable degree of normal liver function, they could potentially be classified using Gd-EOB-DTPA [10, 11].
Measurement of the T1 relaxation time in a lesion before and after Gd-EOB-DTPA administration allows quantitative evaluation of Gd-EOB-DTPA uptake, which potentially reveals related properties of the lesion . Unlike MR signal intensity, which is affected by many technical factors and variable MR imaging parameters, T1 relaxation time is a characteristic of the imaged tissue. T1 mapping can hence be used for quantitative measurements and characterization of tissues [4, 12, 13]. T1mapping on Gd-EOB-DTPA-enhanced MRI has been shown to be able to quantitatively distinguish hepatic hemangiomas from metastatic tumors . T1 mapping on Gd-EOB-DTPA-enhanced MRI also showed significant differences in T1 relaxation time in hepatobiliary phase and its rate of decrease (Δ %) between normal liver, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) . This method has also been successfully used to estimate liver function [12, 14].
As of to date, there has been no attempt to assess the degree of differentiation of HCC by medical imaging methods.
It has been established that Edmondson-Steiner grade was an independent predictor for early recurrence in HCC. Furthermore, Edmondson-Steiner grade has been shown to be related to other markers of poor prognosis, including microvascular invasion [15–19], expression of Nemo-like kinase (NLK), Protein disulfide isomerase (PDI), p21-activated protein kinase (PAK) 6, chemokine receptor CCR9 [20–23].
Previous studies have shown that different grades of HCCs appear differently on both dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) and hepatobiliary-phase MR images. Well-differentiated HCC tends to show signals closer to that of liver parenchyma and less conspicuous hypointensity Gd-EOB-DTPA on hepatobiliary-phase images [10, 11, 24]. One study also indicated that maximum sensitivity of Gd-EOB-DTPA enhanced MRI was only 69 % even when diagnostic criteria including all previously reported pattern of HCC were adopted, missing some well-differentiated and moderately differentiated HCC . It is noteworthy that the above studies were based on qualitative assessment. We propose the use of T1 mapping index on Gd-EOB-DTPA enhanced MRI that might predict Edmondson-Steiner grade of HCC, and hence improve the prognostication of HCC prior to surgery.
This is a retrospective study conducted in accordance with ethical guidelines for human research and was compliant with the Health Insurance Portability and Accountability Act (HIPAA). As such, the study received IRB or ethical committee approval, and the requirement for informed consent was waived.
Cells with abundant cytoplasm and minimal nuclear irregularity
Greater nuclear irregularity and prominent nucleoli
Increased nuclear pleomorphism and angulation of the nuclei; Tumour giant cells were also more commonly seen
Poorly differentiated with marked nuclear pleomorphism, hyperchromatism and anaplasia
MR imaging protocol
MRI sequences used in the study
Scan time (s)
Slice thickness (mm)
200 × 320
258 × 330
410 × 512
350 × 350
154 × 256
248 × 330
96 × 256
248 × 330
200 × 320
258 × 330
154 × 256
248 × 330
All patients received a body weight adjusted dose of Gd-EOB-DTPA (Primovist ®, 0.1ml/kg body weight) administered as bolus injection with a flow rate of 1ml/s, flushed with 30 ml of normal saline at the same rate. The T1 relaxation times were measured on both non-contrast images and images obtained at 20mins after injection of the Gd-EOB-DTPA.
T1 maps were also color-coded using a visualization tool of the open source OsiriX imaging software.
All statistical analyses were done using SPSS (version 19.0, Statistical Package for Social Science,Chicago,USA). A one-way analysis of variance (ANOVA) was used to analyze differences of these values between different Edmondson-Steiner grades. Spearman correlation was also done between T1 mapping characteristics and different Edmondson-Steiner grades.
All statistical tests were two-sided and p value < 0.05 indicated significant difference.
The median age of patients was 54.9 (range 37–77). Altogether, 53 lesions in 44 patients confirmed and graded by pathology were analyzed in the study.
Size of lesions for different Edmondson-Steiner grade
Diameters (mean, mm)a
31.3 ± 23.7
25.4 ± 23.5
38.8 ± 35.6
30.1 ± 28.5
Comparison of T1mapping for HCC in different Edmondson-Steiner grade
Correlation analysis between T1p, T1e, T1d, T1d % and Edmondson-Steiner grade
This study showed that HCC of Edmondson-Steiner grade I could be distinguished from grade II and III lesions using T1d and T1d %. The higher the grade, the lower the T1d and T1d %. From the above, it was suggested that uptake of Gd-EOB-DTPA decreases with increase in Edmondson-Steiner grade. Generally, 5–10 % of HCC are Edmondson-Steiner grade I lesions. But in this study, grade I HCC accounted for 24.5 % (13/53) of the samples, which could be due to the higher proportion of small HCC in the sample .
Gd-EOB-DTPA has been widely used in the HCC evaluation and proved to be helpful for its diagnosis, differential diagnosis and grading. Some previous studies found that hypointensity on gadoxetic acid–enhanced hepatobiliary phase images and hyperintensity on high-b-value DWI suggest well-differentiated HCCs rather than benign hepatocellular nodules, and might predict worse histological grades of HCC [27, 28]. Schelhorn et al.  also reported that the enhancement patterns changed with different grades of HCC. On the other hand, it has been shown that 50 % of well-differentiated HCCs exhibit isointensity or hyperintensity in the hepatobiliary-phase, causing difficulty in imaging diagnosis, especially in patients with worse Child-Pugh class [10, 11, 24, 25, 30]. It is known that cell morphology of well-differentiated HCC is similar to that of normal liver cell. The ultra microstructures of well-differentiated HCC cells as revealed by electron microscope also exhibit similarities in cell nucleus, organelle, contact of cell, etc. to that normal liver cell. It is therefore believed that well-differentiated HCC could have preserved liver cell functions , which has also been suggested in an imaging study on animal HCC model . Uptake of Gd-EOB-DTPA in hepatobiliary phase in HCC is determined by expression of OATP1B3, which expression varies in HCC of different grades . However, the minor difference between HCC of different grades, as well as between well-differentiated HCC and normal liver tissue, could be difficult to appreciate by qualitative assessment.
This study confirmed that quantitative analysis based on T1 mapping allowed differentiation between different grades of HCC. Of the different quantitative measurements studied, T1d % had the best correlation with histological grades. The results showed that T1d % for grade I lesions was 54.0 ± 12.2 %, and that for grade II and III lesions were 31.5 ± 6.9 and 27.7 ± 6.7 % respectively. Therefore T1d % of higher than 50 % would suggest that an HCC is likely to be of Edmondson-Steiner grade I. Theoretically, T1p and T1e, could also be different in different Edmondson-Steiner grades; however, this was not supported by the results. It is suspected that this could in part be related to abnormal blood perfusion due to artery-to-vein or artery-to-portal vein shunting , which would reduce the T1 shortening effect of Gd-EOB-DTPA.
Previous studies have suggested that Edmondson-Steiner grade is an independent factor affecting prognosis/recurrence of HCC [15–20], which should be taken into account when considering therapeutic strategy [16, 19]. In addition, liver cells take up Gd-EOB-DTPA via the receptors OATP1B1, OATP1B3 and NTCP. OATP1B3 is also the transport for some anti-cancer drugs [32, 35–39]. Therefore, tumor behavior in terms of Gd-EOB-DTPA uptake might also predict effect of therapy. The results obtained by this study held promise to predict tumor grading patients prior to surgery, which might also help to choose between treatment options.
There are limitations in the current study. Firstly, the retrospective nature of the study could not avoid sampling bias. Secondly, due to the relatively small number of lesions, a model that describes the relations between the best indicator of T1d % and the individual Edmondson-Steiner grades could not be formulated.
T1 mapping before and after Gd-EOB-DTPA administration can help to classify the HCC in terms of Edmondson-Steiner grade. The percentage reduction of T1 value after contrast in hepatobiliary phase was the best indication for such classification of HCC.
CEUS, contrast-enhanced ultrasonography; DCE-MRI, dynamic contrast-enhanced magnetic resonance imaging; DW-MRI, diffusion weighted magnetic resonance imaging; HCC, hepatocellular carcinoma; MDCT, multidetector computer tomography; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis; NLK, Nemo-like kinase; PAK6, p21-activated protein kinase6; PDI, protein disulfide isomerase
This work was funded by National Natural Science Foundation of China (81571750), Natural Science Foundation of Guangdong Province (2014A030311018, 2014A030310484, 2015A030313043), S&T Programs (2014A020212125) of Guangdong Province, Medical Scientific Research Foundation of Guangdong Province (A2013196).
Availability of data and materials
The ethics approval was provided by The First Affiliated Hospital, Sun Yat-Sen University, China. All the data and materials are available.
All authors meet the requirements for authorship and manuscript submission. ZP L and ST F conceived and carried out experiments. ZPP and MJ J carried out experiments. HS C performed the MR scan on each subject. TC, ZD and YJL collected and analysed data. All authors were involved in writing the paper and had final approval of the submitted and published versions.
The authors declare that they have no competing interests.
Consent for publication
Ethics approval and consent to participate
The study was conducted in accordance with ethical guidelines for human research and was compliant with the Health Insurance Portability and Accountability Act (HIPAA). As such, the study received IRB or ethical committee approval, and the requirement for informed consent was waived.
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
- Cancer research UK http://www.cancerresearchuk.org/health-professional/cancer-statistics/worldwide-cancer 2014;2:14
- Inoue T, Kudo M, Komuta M, et al. Assessment of Gd-EOB-DTPA-enhanced MRI for HCC and dysplastic nodules and comparison of detection sensitivity versus MDCT. J Gastroenterol. 2012;47(9):1036–47.View ArticlePubMedGoogle Scholar
- Ichikawa T, Sano K, Morisaka H. Diagnosis of pathologically early HCC with EOB-MRI: experiences and current consensus. Liver Cancer. 2014;3(2):97–107.View ArticlePubMedPubMed CentralGoogle Scholar
- Ding Y, Rao SX, Meng T, Chen C, Li R, Zeng MS. Usefulness of T1 mapping on Gd-EOB-DTPA-enhanced MR imaging in assessment of non-alcoholic fatty liver disease. Eur Radiol. 2014;24(4):959–66.View ArticlePubMedGoogle Scholar
- Yoshimura N, Saito K, Saguchi T, et al. Distinguishing hepatic hemangiomas from metastatic tumors using T1 mapping on gadoxetic-acid-enhanced MRI. Magn Reson Imaging. 2013;31(1):23–7.View ArticlePubMedGoogle Scholar
- Hamm B, Staks T, Muhler A, et al. Phase I clinical evaluation of Gd-EOB-DTPA as a hepatobiliary MR contrast agent: safety, pharmacokinetics, and MR imaging. Radiology. 1995;195(3):785–92.View ArticlePubMedGoogle Scholar
- Tanimoto A, Lee JM, Murakami T, Huppertz A, Kudo M, Grazioli L. Consensus report of the 2nd International Forum for Liver MRI. Eur Radiol. 2009;19 Suppl 5:S975–89.View ArticlePubMedGoogle Scholar
- Haimerl M, Verloh N, Zeman F, et al. Assessment of clinical signs of liver cirrhosis using T1 mapping on Gd-EOB-DTPA-enhanced 3T MRI. Plos One. 2013;8(12), e85658.View ArticlePubMedPubMed CentralGoogle Scholar
- Chou CT, Chou JM, Chang TA, et al. Differentiation between dysplastic nodule and early-stage hepatocellular carcinoma: the utility of conventional MR imaging. World J Gastroenterol. 2013;19(42):7433–9.View ArticlePubMedPubMed CentralGoogle Scholar
- Kim SH, Kim SH, Lee J, et al. Gadoxetic acid-enhanced MRI versus triple-phase MDCT for the preoperative detection of hepatocellular carcinoma. AJR Am J Roentgenol. 2009;192(6):1675–81.View ArticlePubMedGoogle Scholar
- Frericks BB, Loddenkemper C, Huppertz A, et al. Qualitative and quantitative evaluation of hepatocellular carcinoma and cirrhotic liver enhancement using Gd-EOB-DTPA. AJR Am J Roentgenol. 2009;193(4):1053–60.View ArticlePubMedGoogle Scholar
- Katsube T, Okada M, Kumano S, et al. Estimation of liver function using T1 mapping on Gd-EOB-DTPA-enhanced magnetic resonance imaging. Invest Radiol. 2011;46(4):277–83.View ArticlePubMedGoogle Scholar
- Katsube T, Okada M, Kumano S, et al. Estimation of liver function using T2* mapping on gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid enhanced magnetic resonance imaging. Eur J Radiol. 2012;81(7):1460–4.View ArticlePubMedGoogle Scholar
- Ding Y, Rao SX, Chen C, Li R, Zeng MS. Assessing liver function in patients with HBV-related HCC: a comparison of T1 mapping on Gd-EOB-DTPA-enhanced MR imaging with DWI. Eur Radiol. 2015;25(5):1392–8.View ArticlePubMedGoogle Scholar
- Zhou L, Rui JA, Wang SB, Chen SG, Qu Q. Early recurrence in large hepatocellular carcinoma after curative hepatic resection: prognostic significance and risk factors. Hepatogastroenterology. 2014;61(135):2035–41.PubMedGoogle Scholar
- Zhou L, Rui JA, Wang SB, Chen SG, Qu Q. Risk factors of microvascular invasion, portal vein tumor thrombosis and poor post-resectional survival in HBV-related hepatocellular carcinoma. Hepatogastroenterology. 2014;61(134):1696–703.PubMedGoogle Scholar
- Chou CT, Chen RC, Lin WC, Ko CJ, Chen CB, Chen YL. Prediction of microvascular invasion of hepatocellular carcinoma: preoperative CT and histopathologic correlation. AJR Am J Roentgenol. 2014;203(3):W253–9.View ArticlePubMedGoogle Scholar
- Kwon SK, Yun SS, Kim HJ, Lee DS. The risk factors of early recurrence after hepatectomy in hepatocellular carcinoma. Ann Surg Treat Res. 2014;86(6):283–8.View ArticlePubMedPubMed CentralGoogle Scholar
- Wang K, Liu G, Li J, et al. Early intrahepatic recurrence of hepatocellular carcinoma after hepatectomy treated with re-hepatectomy, ablation or chemoembolization: a prospective cohort study. Eur J Surg Oncol. 2015;41(2):236–42.View ArticlePubMedGoogle Scholar
- Chen HW, Qiao HY, Li HC, et al. Prognostic significance of Nemo-like kinase expression in patients with hepatocellular carcinoma. Tumour Biol. 2015. doi:10.1007/s13277-015-3609-6.Google Scholar
- Yu SJ, Won JK, Ryu HS, et al. A novel prognostic factor for hepatocellular carcinoma: protein disulfide isomerase. Korean J Intern Med. 2014;29(5):580–7.View ArticlePubMedPubMed CentralGoogle Scholar
- Chen H, Miao J, Li H, et al. Expression and prognostic significance of p21-activated kinase 6 in hepatocellular carcinoma. J Surg Res. 2014;189(1):81–8.View ArticlePubMedGoogle Scholar
- Zhang Z, Qin C, Wu Y, Su Z, Xian G, Hu B. CCR9 as a prognostic marker and therapeutic target in hepatocellular carcinoma. Oncol Rep. 2014;31(4):1629–36.PubMedGoogle Scholar
- Vogl TJ, Stupavsky A, Pegios W, et al. Hepatocellular carcinoma: evaluation with dynamic and static gadobenate dimeglumine-enhanced MR imaging and histopathologic correlation. Radiology. 1997;205(3):721–8.View ArticlePubMedGoogle Scholar
- Nakamura Y, Tashiro H, Nambu J, et al. Detectability of hepatocellular carcinoma by gadoxetate disodium-enhanced hepatic MRI: tumor-by-tumor analysis in explant livers. J Magn Reson Imaging. 2013;37(3):684–91.View ArticlePubMedGoogle Scholar
- Chinese Ministry of Health. Guideline for management of primary HCC. Chin Clin Oncol. 2011;16(10):929–46.Google Scholar
- Lee MH, Kim SH, Parket MJ, et al. Gadoxetic acid-enhanced hepatobiliary phase MRI and high-b-value diffusion-weighted imaging to distinguish well-differentiated hepatocellular carcinomas from benign nodules in patients with chronic liver disease. AJR Am J Roentgenol. 2011;197(5):W868–75.View ArticlePubMedGoogle Scholar
- Chang WC, Chen RC, Chou CT, et al. Histological grade of hepatocellular carcinoma correlates with arterial enhancement on gadoxetic acid-enhanced and diffusion-weighted MR images. Abdom Imaging. 2014;39(6):1202–12.View ArticlePubMedGoogle Scholar
- Schelhorn J, Best J, Dechene A, et al. Evaluation of combined Gd-EOB-DTPA and gadobutrol magnetic resonance imaging for the prediction of hepatocellular carcinoma grading. Acta Radiol. 2015. doi:10.1177/0284185115616293.Google Scholar
- Choi JW, Lee JM, Kim SJ, et al. Hepatocellular carcinoma: imaging patterns on gadoxetic acid-enhanced MR Images and their value as an imaging biomarker. Radiology. 2013;267(3):776–86.View ArticlePubMedGoogle Scholar
- Yang GH, Wu ZB. Chinese surgical pathology volume 1. Beijing: People's Medical Publishing House; 2002.Google Scholar
- Tsuda N, Kato N, Murayama C, Narazaki M, Yokawa T. Potential for differential diagnosis with gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging in experimental hepatic tumors. Invest Radiol. 2004;39(2):80–8.View ArticlePubMedGoogle Scholar
- Narita M, Hatano E, Arizono S, et al. Expression of OATP1B3 determines uptake of Gd-EOB-DTPA in hepatocellular carcinoma. J Gastroenterol. 2009;44(7):793–8.View ArticlePubMedGoogle Scholar
- Motosugi U, Ichikawa T, Sou H, et al. Liver parenchymal enhancement of hepatocyte-phase images in Gd-EOB-DTPA-enhanced MR imaging: which biological markers of the liver function affect the enhancement? J Magn Reson Imaging. 2009;30(5):1042–6.View ArticlePubMedGoogle Scholar
- Leonhardt M, Keiser M, Oswald S, et al. Hepatic uptake of the magnetic resonance imaging contrast agent Gd-EOB-DTPA: role of human organic anion transporters. Drug Metab Dispos. 2010;38(7):1024–8.View ArticlePubMedGoogle Scholar
- Ikema S, Takumi S, Maeda Y, et al. Okadaic acid is taken-up into the cells mediated by human hepatocytes transporter OATP1B3. Food Chem Toxicol. 2015. doi:10.1016/j.fct.2015.06.006.PubMedGoogle Scholar
- Chen C, Wu ZT, Ma LL, et al. Organic anion-transporting polypeptides contribute to the hepatic uptake of berberine. Xenobiotica. 2015. doi:10.3109/00498254.2015.Google Scholar
- Ebner T, Ishiguro N, Taub ME. The use of transporter probe drug cocktails for the assessment of transporter-based drug-drug interactions in a clinical setting-proposal of a four component transporter cocktail. J Pharm Sci. 2015. doi:10.1002/jps.24489.PubMedGoogle Scholar
- Takumi S, Ikema S, Hanyu T, et al. Naringin attenuates the cytotoxicity of hepatotoxin microcystin-LR by the curious mechanisms to OATP1B1- and OATP1B3-expressing cells. Environ Toxicol Pharmacol. 2015;39(2):974–81.View ArticlePubMedGoogle Scholar