Hepatobiliary MRI as novel selection criteria in liver transplantation for hepatocellular carcinoma

JOURNAL OF HEPATOLOGY

Research Article Transplantation

Hepatobiliary MRI as novel selection criteria in liver transplantation for hepatocellular carcinoma

Graphical abstract

Authors Ah Yeong Kim, Dong Hyun Sinn, Woo Kyoung Jeong, ..., Sin-Ho Jung, Seung Woon Paik, Won Jae Lee

Within the Milan criteria 100 80 60 40 20 0 0

12 24 36 48 60 72 84 96 Time (month)

Number at risk Group: None 62 57 54 50 35 21 13 10 Group: One or More 6

2

2

2

1

1

1

0

0 0

Survival probability (%)

Outside the Milan criteria 100

High-risk radiologic findings None One or More

80

[email protected] (W.K. Jeong)

60

Lay summary

40 20 0 0

High-risk radiologic finding suggestig recurrence after LT

Correspondence

12 24 36 48 60 72 84 96

Time (month) Number at risk Group: None 18 14 13 12 10 5 3 Group: One or More 14 6 3 3 2 0 0

1

0

0

0

Highlights
Satellite nodules and peritumoral hypointensity can be seen by hepatobiliary MRI.
These features were associated with tumor recurrence after liver transplantation.

High-risk radiological findings on preoperative hepatobiliary magnetic resonance imaging (either one of the following features: satellite nodule and peritumoural hypointensity on hepatobiliary phase) were associated with a higher tumour recurrence rate in patients transplanted either within or outside the Milan criteria.


This association has been applied to all patients within and out of Milan criteria.
Hepatobiliary MRI can be a useful tool to select candidates for transplantation.

http://dx.doi.org/10.1016/j.jhep.2018.01.024 Ó 2018 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. J. Hepatol. 2018, xxx, xxx–xxx

JOURNAL OF HEPATOLOGY

Research Article Transplantation

Hepatobiliary MRI as novel selection criteria in liver transplantation for hepatocellular carcinoma Ah Yeong Kim1,y, Dong Hyun Sinn2,y, Woo Kyoung Jeong1,⇑, Young Kon Kim1, Tae Wook Kang1, Sang Yun Ha3, Chul Keun Park3, Gyu Seong Choi4, Jong Man Kim4, Choon Hyuck David Kwon4, Jae-Won Joh4, Min-Ji Kim5, Insuk Sohn5, Sin-Ho Jung6, Seung Woon Paik2, Won Jae Lee1 1 Department of Radiology and Center for Imaging Sciences, Research Institute for Future Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea; 2Department of Internal Medicine, Research Institute for Future Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea; 3Department of Pathology, Research Institute for Future Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea; 4Department of Surgery, Research Institute for Future Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea; 5Statistics and Data Center, Research Institute for Future Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea; 6 Department of Biostatics and Bioinformatics, Duke University, USA

Background & Aims: Hepatobiliary magnetic resonance imaging (MRI) provides additional information beyond the size and number of tumours, and may have prognostic implications. We examined whether pretransplant radiological features on MRI could be used to stratify the risk of tumour recurrence after liver transplantation (LT) for hepatocellular carcinoma (HCC). Methods: A total of 100 patients who had received a liver transplant and who had undergone preoperative gadoxetic acidenhanced MRI, including the hepatobiliary phase (HBP), were reviewed for tumour size, number, and morphological type (e.g. nodular, nodular with perinodular extension, or confluent multinodular), satellite nodules, non-smooth tumour margins, peritumoural enhancement in arterial phase, peritumoural hypointensity on HBP, and apparent diffusion coefficients. The primary endpoint was time to recurrence. Results: In a multivariable adjusted model, the presence of satellite nodules [hazard ratio (HR) 3.07; 95% confidence interval (CI) 1.14–8.24] and peritumoural hypointensity on HBP (HR 4.53; 95% CI 1.52–13.4) were identified as independent factors associated with tumour recurrence. Having either of these radiological findings was associated with a higher tumour recurrence rate (72.5% vs. 15.4% at three years, p <0.001). When patients were stratified according to the Milan criteria, the presence of these two high-risk radiological findings was associated with a higher tumour recurrence rate in both patients transplanted within the Milan criteria (66.7% vs. 11.6% at three years, p <0.001, n = 68) and those who were transplanted outside the Milan criteria (75.5% vs. 28.6% at three years, p <0.001, n = 32).

Keywords: Magnetic resonance imaging; Gadoxetic acid; Liver transplantation; Recurrence; Microvascular invasion. Received 9 August 2017; received in revised form 18 December 2017; accepted 24 January 2018 ⇑ Corresponding author. Address: Department of Radiology and Center for Imaging Science, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Republic of Korea. Tel.: +82 2 3410 1923; fax: +82 2 3410 0049. E-mail address: [email protected] (W.K. Jeong). y Contributed equally in this paper.

Conclusions: Radiological features on preoperative hepatobiliary MRI can stratify the risk of tumour recurrence in patients who were transplanted either within or outside the Milan criteria. Therefore, hepatobiliary MRI can be a useful way to select potential candidates for LT. Lay summary: High-risk radiological findings on preoperative hepatobiliary magnetic resonance imaging (either one of the following features: satellite nodule and peritumoural hypointensity on hepatobiliary phase) were associated with a higher tumour recurrence rate in patients transplanted either within or outside the Milan criteria. Ó 2018 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Introduction Liver transplantation (LT) is regarded as the best option for radical treatment in patients with very early (stage 0) or early (stage A) hepatocellular carcinoma (HCC), according to the Barcelona Clinic Liver Cancer guideline.1–3 Careful patient selection is important in reducing the tumour recurrence rate and maximising the effectiveness of LT for HCC because the availability of deceased and living donor organs is limited. Thus, the Milan criteria are used as the gold standard to increase the posttransplant survival rate of patients with HCC, with a five-year survival rate of 70% after LT and a recurrence rate of <20%.1,2,4 However, as experience using LT to treat HCC has grown and recent developments in imaging techniques have enabled the identification of very small lesions (even <1 cm in diameter) that were undetectable a decade ago,5 physicians have raised concerns that the Milan criteria are too restrictive and fail to satisfy the increasing candidate list.6,7 Several expansions of the Milan criteria, including larger and more numerous tumours, have been proposed and claim comparable post-transplant survival rates.6–9 Outside the size-and-number category, biological profiles reflecting tumour behaviour were recently incorporated into selection criteria for waiting lists.10 Tumour markers, such as alpha-fetoprotein (AFP) and protein induced by vitamin K absence or antagonist-II (PIVKA-II), are widely used in biological profiles, and pathological and genomic markers that suggest the

Journal of Hepatology 2018 vol. xxx j xxx–xxx Please cite this article in press as: Kim AY et al. Hepatobiliary MRI as novel selection criteria in liver transplantation for hepatocellular carcinoma. J Hepatol (2018), https://doi.org/ 10.1016/j.jhep.2018.01.024

Research Article

Transplantation

LT for HCC + preoperative Gd-EOB-DTPA MRI (n = 128) Exclusion criteria (n = 28) • No viable tumor on radiologic evaluation (n = 22) • Perioperative mortality (within one month): Hepatic failure (n = 3), acute myocardial infarction (n = 1), pulmonary edema (n = 1), and disseminated intravascular coagulation (n = 1)

Final enrollment (n = 100; M : F = 87 : 13) Fig. 1. Enrolment of subjects. HCC, hepatocellular carcinoma; LT, liver transplantation.

biological behaviour of HCC could also be included. Microvascular invasion (MVI) can predict patient outcomes after hepatectomy and LT7,11–13 and is associated with low survival rates in patients with HCC after LT.14–16 According to a recent international consensus meeting report, an MVI assessment should be used to determine prognosis after LT for HCC.4 However, MVI assessment also has its limitations, because it cannot be readily evaluated preoperatively. The identification and reliable organisation of liver lesions have been made possible by the latest magnetic resonance imaging (MRI) techniques for the abdomen and by structured reporting systems, such as Liver Imaging Reporting and Data System (LI-RADS), especially hepatobiliary MRI using a hepatocyte-specific contrast agent and diffusion-weighted imaging (DWI).16,17 The use of LI-RADS provides a systematic approach to HCC diagnosis, providing images of both major and ancillary features of HCC, thus facilitating the treatment decision-making process (e.g. transplantation vs. locoregional treatment). Although LI-RADS was developed for conventional CT and MRI, it was also shown that hepatobiliary MRI was useful to diagnose definitive HCC, with excellent positive predictive values.18 Recently, studies have suggested that some MRI findings reflect biological features of tumours,19–22 and that such features can be helpful in selecting patients who are appropriate for LT. However, to the best of our knowledge, there are no published studies that have assessed whether preoperative MRI features can help predict tumour recurrence after LT. Therefore, our aim in this study was to assess the prognostic power of preoperative gadoxetic acid-enhanced MRI and DWI in predicting tumour recurrence after LT for HCC.

Materials and methods Subjects and source of data This retrospective study was approved by the Institutional Review Board of our institution (2015-09-016) and was performed after obtaining a waiver for informed patient consent. We reviewed information from our LT database relating to 550 patients who had undergone LT from January 2009 to December 2013 in our institution. We retrieved 128 consecutive patients who had undergone LT for HCC and who had also undergone gadoxetic acid-enhanced MRI during their preoperative evaluation. The period between MRI and LT did not exceed three months (mean, 46.4 ± 21.4 days; range, 12–90 days). Patients were excluded from LT if extrahepatic metastasis was detected before the operation. We excluded 28 patients from this study for several reasons (Fig. 1), resulting in a study 2

sample of 100 patients (87 men and 13 women with an age range of 34–68 years and a mean age of 52.5 ± 6.4 years). All patients had undergone living-donor LT. Blood tests (including serum AFP and PIVKA-II) and dynamic liver computed tomography (CT) were performed every three to six months during the first two years after LT. Patients were then clinically assessed every three months, and imaging studies were performed once or twice per year for routine follow-up. If the clinical assessment or diagnostic studies showed an abnormal finding, including increased AFP, imaging studies [liver MRI, chest CT, and 18F-FDG positron emission tomography (PET)] were performed to detect any tumour recurrence. MRI methodology All MR images were acquired using a 3.0-T whole-body MRI system (Intera Achieva 3.0-T, Philips Healthcare, Best, The Netherlands) with a 32-channel phased-array receiver coil. For gadoxetic acid-enhanced imaging (Primovist; Bayer Schering Pharma, Berlin, Germany), unenhanced, arterial phase (20–35 s), portal venous phase (60 s), delayed phase (3 min), and 20-min HBP images were obtained using a T1-weighted 3D turbo-field-echo sequence (THRIVE, Philips Healthcare). The contrast agent was administered intravenously at a rate of 2 ml/s for a total dose of 0.025 mmol/kg body weight, followed by a 20-ml saline flush. DWI with b-values of 0, 100, and 800 s/mm2 were acquired simultaneously. An apparent diffusion coefficient (ADC) map was generated from b values of 0 and 800 s/mm2. Detailed MRI sequences and parameters are provided in Table S1. Image interpretation Two abdominal radiologists (A.Y.K. and W.K.J. with 12 and 5 years of experience interpreting liver MRI, respectively) reviewed all MR images in consensus. All images were evaluated using a picture archiving and communication system (PACS; Centricity Radiology RA 1000; GE Healthcare, Chicago, IL, USA). To compare imaging findings with pathological findings, information on tumour size and location from the pathological reports was provided to radiologists before imaging interpretation. However, to minimise bias, any further information (e.g. clinical information on tumour recurrence after LT or detailed pathological data on the presence of microvascular invasion) was blinded to the reviewers. First, the reviewers examined the observations categorised as LR-5 (definitive HCC) according to the LI-RADS.18 In brief, LR-5 means a lesion 20 mm or larger in diameter with arterial hyperenhancement and one or two additional major features, including hypoenhancement on portal venous phase (‘washout’), tumour capsules, and threshold growth of the lesion, or a lesion 10 mm or larger in diameter with arterial hyperenhancement and the presence of two different major features. The number and size of LR-5 lesions were collected and used to define the Milan criteria. A representative tumour was then selected based on size of the largest viable tumour, and the following detailed information was collected: morphological type; tumour margin (distinct vs. vague); presence or absence of a satellite nodule (defined as a smaller nodule attached to or within 2 cm of the main tumour);23 and a non-smooth tumour margin (defined as a non-nodular tumours in all imaging planes, including focal or crescent extranodular extension, multinodular confluence appearance, and focal infiltrative margin).24,25 Morphological types was classified as: (1) vaguely nodular; (2)

Journal of Hepatology 2018 vol. xxx j xxx–xxx

Please cite this article in press as: Kim AY et al. Hepatobiliary MRI as novel selection criteria in liver transplantation for hepatocellular carcinoma. J Hepatol (2018), https://doi.org/ 10.1016/j.jhep.2018.01.024

JOURNAL OF HEPATOLOGY

A

imaging, independently reviewed the MR images and interpreted the imaging features of each tumour as described above.

B

C

D

E

F

Pathological evaluation Two liver pathologists (S.Y.H. and C.K.P.) reviewed the histopathological features of HCC in the explanted livers, including: gross type, cellular type, presence or absence of fibrous capsule, MVI, intrahepatic metastasis, and multicentric occurrence. Microvascular invasion indicated microscopic vascular invasion near the tumour. Intrahepatic metastasis was considered if one or more of the following criteria was satisfied: (1) tumour thrombi in portal vein or nodules that had putatively grown from tumour thrombi; (2) the group of nodules that was most abundant near the largest tumour (main mass), and the number of nodules that decreased with distance from the largest nodule; and (3) small solitary nodules located adjacent to the largest nodule but whose histological type and differentiation grade did not differ from that of the largest nodule. Among these criteria, we investigated the presence of MVI and intrahepatic metastasis so that we were able to clarify the relationship between these and the radiological findings and HCC recurrence in this study (Fig. 2E and F). Definitions of the histopathological features were determined according to the criteria of the Liver Cancer Study Group of Japan.27

Fig. 2. Radiological and pathological features of hepatocellular carcinoma in a 41-year-old male patient. There is a lobular hypervascular mass (arrow) in liver S3 with abutment of the segment portal vein (A), and it is washed out in the portal venous phase (B). A wedge-shaped hypointense area around the mass is seen in the hepatobiliary phase (arrowhead, C). A diffusion-weighted image shows a bright nodule (D), and the gross specimen shows a perinodular extension type tumour with the surrounding adjacent portal vein (E). Microvascular invasion (open arrow) is also seen on microscopic examination (haematoxylin and eosin stain 100, F). After one month, extrahepatic recurrence developed at the pericaval lymph node at the infrarenal level, and the patient died four months later.

expanding nodular; (3) nodular with perinodular extensions; (4) multinodular confluence; (5) infiltrative; (6) pedunculated; and (7) cirrhotomimetic, according to their gross morphology, and based on the general rules for the study of primary liver cancer published by the Korean Liver Cancer Association.26 Given that there were no infiltrative, pedunculated, or cirrhotomimetic types recorded, the tumours were grouped into (1) simple nodular type (vaguely nodular and expanding nodular); (2) nodular with perinodular extension; and (3) multinodular confluent types. The reviewers also assessed the enhancement patterns of the tumours in contrast-enhanced dynamic MR images. They evaluated peritumoural enhancement in the arterial phase (AP), the presence of a capsule or pseudocapsule (identified as rim enhancement along the lesion margin) in the portal venous phase or delayed phase, and peritumoural hypointensity (defined as decreased signal intensity around the tumour compared with the adjacent liver parenchyma) in the 20-min HBP images (Fig. 2A–C). DWI of the tumour was also evaluated (Fig. 2D). For the quantitative analysis of ADC, a circular region of interest was manually placed to encompass as much of the tumour as possible in each patient. If the patient had multiple tumours, the ADC value of the largest viable tumour was measured. To perform inter-reader agreement analysis, another radiologist (T.W.K.), who had nine years of experience of abdominal

Statistical analysis To perform inter-reader agreement analysis, kappa values of categorised variables and an intraclass coefficient (ICC) of the ADC values were calculated. The primary endpoint was recurrence-free survival (RFS), which was defined as the time from surgery to the date of tumour recurrence. The censoring time was defined as the final documented date of no evidence of tumour recurrence by imaging or time to the date of death without recurrence. Survival curves were estimated by the Kaplan-Meier method. To explore the preoperative MRI features and tumour markers associated with RFS, we used univariate and multivariate Cox proportional hazards regression analyses to calculate the hazard ratio (HR). We tested: age (per year); sex (male vs. female); Milan criteria (yes vs. no); morphological type (simple nodular vs. nodular with perinodular extension or confluent multinodular); distinctive tumour margin (yes vs. no); satellite nodule (yes vs. no); peritumoural enhancement in arterial phase (AP) (yes vs. no); tumour capsule/pseudocapsule (yes vs. no); peritumoural hypointensity in HBP (yes vs. no); ADC value (per unit change); AFP (per log ng/ml); and PIVKA-II level (per log mAU/ml). All variables with p values <0.05 on univariate analysis were selected for multivariate analysis. The proportional hazard assumption was confirmed using Schoenfeld residuals. Based on the results of the multivariate analysis, we derived high-risk radiological findings that indicated a high probability of recurrence. The difference in RFS according to the presence of high-risk radiological findings was assessed in all patients, in patients transplanted either within or outside the Milan criteria, and in patients whose AFP level was less than 100 ng/ml and more than 100 ng/ml. Additionally, to explore which radiological variables correlated with MVI and intrahepatic metastasis, Chi-square, Fisher’s exact, and Mann-Whitney U tests were also performed. Statistical analysis was executed using SAS version 9.4 (SAS Institute, Cary, NC, USA) and MedCalc version 14.12.0 (MedCalc Software, Mariakerke, Belgium). A two-sided p value <0.05 indicated statistical significance.

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Please cite this article in press as: Kim AY et al. Hepatobiliary MRI as novel selection criteria in liver transplantation for hepatocellular carcinoma. J Hepatol (2018), https://doi.org/ 10.1016/j.jhep.2018.01.024

Research Article

Transplantation

Table 1. Baseline clinical characteristics (N = 100).* Variables

(N = 100)

Age (years) Male (n, %) Aetiology of underlying liver disease Hepatitis B Hepatitis C Alcoholic liver disease Autoimmune hepatitis Previous history of treatment Treatment naïve Treatment experiencedy Tumour characteristics at time of LT Tumour number Maximum tumour size Milan criteria Within Outside Morphological type Simple nodular Simple nodular with extranodular growth Confluent multinodular Tumour margin Distinct Vague Non-smooth tumour margin Satellite nodule Peritumoural enhancement in AP Capsule or pseudocapsule Peritumoural hypointensity in HBP Apparent diffusion coefficient Tumour markers AFP (ng/ml) PIVKA-II (mAU/ml) Histology at explanted liver Microvascular invasion Intrahepatic metastasis

52.5 ± 6.4 87 (87%) 90 (90%) 5 (5%) 4 (4%) 1 (1%) 51 (51%) 49 (49%) 2 (1–8) 2.2 (0.4–7.8) 68 32 45 48 7 86 14 59 8 10 49 14 1.07 ± 0.24 29.95 (1.7–20,503.3) 48 (5–3,358) 55 28

* Values are expressed as mean ± standard deviation or median (range), as appropriate. AFP, alpha-fetoprotein; AP, arterial phase; HBP, hepatobiliary phase; LT, liver transplantation; PIVKA-II, protein induced by vitamin K absence or antagonist-II. y Patients received radiofrequency ablation (n = 5), percutaneous ethanol injection (n = 1), transcatheter arterial chemoembolisation (n = 22), resection (n = 4), or multiple combined treatment (n = 17) before liver transplantation.

Results Baseline characteristics of the study population The baseline clinical characteristics of the study population are provided in Table 1. Most of the patients had liver cirrhosis associated with viral infection (n = 95). Before LT, 49 patients had a history of treatment for HCC, including transarterial chemoembolisation (TACE), radiofrequency ablation (RFA), resection, or a combination thereof. The mean interval between MRI and LT was 46.9 days. The mean follow-up time was 49.6 ± 24.8 months (range, 4–95 months). During the follow-up period, HCC recurrence was observed in 33 of 100 patients: five patients with only intrahepatic recurrence, nine patients with only extrahepatic recurrence, and 19 patients with both intra- and extrahepatic metastases. Extrahepatic tumour recurrence occurred in the lung (n = 20), lymph node (n = 10), bone (n = 10), adrenal gland (n = 5), peritoneal seeding (n = 4), and brain (n = 3). The mean time between LT and tumour recurrence was 15.8 ± 15.1 mont hs (range, 1–53 months): 17 patients within the 1st year, nine patients in the 2nd year, and seven patients in the 3rd year or later after LT. In 11 patients with both intra- and extrahepatic

4

recurrences, extrahepatic recurrences preceded intrahepatic recurrences (mean, 10 months; range, 2–19 months). In the pathological findings of explanted specimens, MVI and intrahepatic metastasis appeared in 55 and 28 patients, respectively. These pathological features significantly correlated with RFS (HR 5.74; 95% CI 2.21–14.90 and HR 3.68; 95% CI 1.85– 7.33, respectively). Prognostic factors in preoperative MRI and lab findings and their predictive values in tumour recurrence The interobserver agreement of imaging evaluation for preoperative MRI is summarised in Supplementary Table 2. Milan criteria showed good agreement (j = 0.72) and other variables had moderate to good agreement, except for the tumour margin (j = 0.36). The kappa values of satellite nodule and peritumoural hypointensity in the HBP were 0.73 and 0.58, respectively. The one-, two-, and three-year RFS rates were 82.9%, 76.6%, and 73.4%, respectively. Among the MRI findings, being matched to the Milan criteria (HR, 3.21; 95% CI, 1.61–6.40), tumours of a nodular with perinodular extension or a confluent multinodular type (HR, 2.20; 95% CI, 1.05–4.63), a satellite nodule (HR, 5.90; 95% CI, 2.62–13.29), peritumoural enhancement in the arterial phase (HR, 5.37; 95% CI, 2.24–12.91), peritumoural hypointensity in the HBP (HR, 6.19; 95% CI, 2.92–13.11), and a lower ADC value (HR, 0.13; 95% CI, 0.03–0.57) were all significantly associated with recurrence after LT in univariate analyses. Among these features, the presence of a satellite nodule (HR, 3.07; 95% CI, 1.14–8.25) and peritumoural hypointensity in the HBP (HR, 4.53; 95% CI, 1.53–13.44) were independent factors associated with RFS in the multivariable-adjusted analysis (Table 2). Serum AFP (HR, 1.24; 95% CI, 1.07–1.44) and PIVKAII levels (HR, 1.35; 95% CI, 1.09–1.67) were associated with recurrence in the univariate analyses, but were not independent factors associated with recurrence in the multivariate analyses (Table 2). Subgroup analyses to compare risks estimated by imaging features and Milan criteria Using the results of prior analyses, we defined the presence of high-risk radiological findings as at least one of two significant MRI features: the presence of a satellite nodule or peritumoural hypointensity in the HBP. Having high-risk radiological findings had a significant association with tumour recurrence in the univariate analysis in the overall group (HR, 8.22; 95% CI, 4.07–16.58), in patients transplanted within the Milan criteria (HR, 8.55; 95% CI, 2.87–25.43), and in patients transplanted outside the Milan criteria (HR, 4.77; 95% CI, 1.74–13.06). Overall, RFS was significantly better for those without highrisk radiological findings (84.6% vs. 27.5% at three years, p <0.001, Fig. 3A). RFS was significantly better for patients transplanted within the Milan criteria (83.5% vs. 51.5% at three years, p <0.001). When patients were stratified according to the Milan criteria, RFS was significantly better for those without high-risk radiological findings and who were transplanted either within the Milan criteria (88.4% vs. 33.3% at three years, p <0.001, Fig. 3B) or outside the Milan criteria (71.4% vs. 24.5% at three years, p <0.001, Fig. 3C). RFS was also better for those with lower AFP levels (<100 ng/ml) than with higher AFP levels (≥100 ng/ml; 83.3% vs. 53.1% at three years, p = 0.019). When patients were stratified according to AFP levels, RFS was significantly better for those without high-risk radiological findings and with low AFP levels (<100 ng/ml) (92.5% vs. 38.9% at three years,

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Please cite this article in press as: Kim AY et al. Hepatobiliary MRI as novel selection criteria in liver transplantation for hepatocellular carcinoma. J Hepatol (2018), https://doi.org/ 10.1016/j.jhep.2018.01.024

JOURNAL OF HEPATOLOGY Table 2. Significant prognostic factors in preoperative data, including MRI and Lab findings, in predicting HCC recurrence.* Variables

Age (year) Male Beyond the Milan criteria Morphological typey Non-smooth tumour margin Distinctive tumour margin Satellite nodule Peritumoural enhancement in AP Tumour capsule/pseudocapsule Peritumoural hypointensity in HBP Apparent diffusion coefficient AFP (log ng/ml) PIVKA-II (log mAU/ml)

Univariate analysis HR

95% CI

0.99 2.83 3.21 2.20 1.84 0.48 5.90 5.37 0.72 6.19 0.13 1.24 1.35

0.94–1.05 0.68–11.82 1.61–6.40 1.05–4.63 0.87–3.87 0.20–1.11 2.62–13.29 2.24–12.91 0.36–1.43 2.92–13.11 0.03–0.57 1.07–1.44 1.09–1.67

Multivariate analysis p value 0.729 0.155 <0.001 0.038 0.108 0.085 <0.001 <0.001 0.344 <0.001 0.007 0.004 0.007

p value

HR

95% CI

1.12 0.92

0.40–3.11 0.34–2.45

0.828 0.859

3.97 1.36

1.41–11.17 0.36–5.15

0.009 0.655

4.24 0.29 1.17 1.06

1.40–12.82 0.04–1.97 0.97–1.42 0.81–1.40

0.011 0.203 0.095 0.676

* AFP, alpha-fetoprotein; AP, arterial phase; CI, confidence interval; HBP, hepatobiliary phase; HCC, hepatocellular carcinoma; HR, hazard ratio; PIVKA-II, protein induced by vitamin K absence or antagonist-II. Analyses were undertaken using Cox proportional hazards regression models. All variables in multivariate analysis were selected as p values <0.05 on the univariate analyses. y Hazard ratio of the tumour, shown as simple nodular type vs. nodular with perinodular extension or confluent multinodular type in morphologic type, was calculated.

p <0.001, Fig. 3D) and for patients who had high AFP levels (≥100 ng/ml) (66.7% vs. 12.5% at three years, p = 0.005, Fig. 3E). Comparison of MRI findings to histological findings In our analysis, morphology showing perinodular extensions or confluent multinodular types (p <0.001), beyond the Milan criteria (p <0.001), presence of a satellite nodule (p = 0.008), and peritumoural hypointensity in the HBP (p = 0.002) on preoperative MRI were associated with the presence of MVI on histology. Intrahepatic metastasis on histology was associated with the same two morphological types (p = 0.001), beyond the Milan criteria (p <0.001), indistinctive tumour margin (p = 0.020), and the presence of a satellite nodule (p <0.001) on preoperative MRI (Fig. 4). In particular, 28% (7/28) of patients with intrahepatic metastasis on histology showed satellite nodules on contrast-enhanced, DWI, and HBP of preoperative MRI, but almost all patients (71/72, 99%) without intrahepatic metastasis on histology did not show any satellite nodules on preoperative MRI. High-risk radiological findings were also associated with these two important pathological features (both p <0.001). Most of the patients with high-risk radiological findings had MVI on histology (95%, 19/20) and most of the patients without MVI on histology showed negative high-risk radiological findings (98%, 44/45); these positive predictive values and specificity to discriminate MVI were significantly higher than those of the Milan criteria [84% (27/32) and 89% (40/45), respectively] (Table 3 and Table S3).

Discussion Based on our results, we suggest that preoperative hepatobiliary MRI findings can predict tumour recurrence after LT for HCC. Perinodular extensions or confluent multinodular types in morphology, satellite nodules, peritumoural enhancement in arterial phase, peritumoural hypointensity in HBP, and decreased apparent diffusion coefficients were associated with tumour recurrence. Apart from these radiological features, the Milan criteria comprising tumour size and number, AFP levels, and PIVKA-II levels were also associated with tumour recurrence. Notably, in the multivariable-adjusted model including these potential factors, only two MRI features (satellite nodule and peritumoural hypointensity in HBP) were independently

associated with tumour recurrence, while the Milan criteria, AFP level, and PIVKA-II level lost their significant association. The difference in RFS was large according to the presence of high-risk radiological findings (84.6% vs. 27.5% at three years) and, more importantly, these high-risk features could classify tumour recurrence both in patients transplanted within the Milan criteria (88.4% vs. 33.3% at three years), and in patients transplanted outside the Milan criteria (71.4% vs. 24.5% at three years). In addition, high-risk features could classify tumour recurrence in both patients who had low AFP levels (<100 ng/ml) (92.5% vs. 38.9% at three years) and those who had high AFP levels (≥100 ng/ml) (66.7% vs. 12.5% at three years). LT is an accepted treatment modality for HCC, and the Milan criteria are considered as the gold standard for selecting patients with HCC for LT.28 However, there has been an ongoing debate over whether the Milan criteria are imperfect criteria and that, as a result, a significant number of patients who would and would not benefit from LT might have been selected.29 In response, many centres worldwide have developed refined criteria of their own to select patients suitable for LT.29 In this study, the Milan criteria were associated with RFS in a univariate analysis, but were not independent factors in a multivariate analysis. RFS was significantly better for patients transplanted within the Milan criteria (83.5% vs. 51.5% at three years, p <0.001); however, when radiological findings were added to the Milan criteria, those patients with high-risk radiological findings also had a high risk of tumour recurrence despite being transplanted within the Milan criteria (RFS of 33.3% at three years); by contrast, the risk of tumour recurrence was low when high-risk radiological findings were not present (RFS of 71.4% at three years) although the patients were transplanted outside the Milan criteria. Some authors have suggested using serum AFP, PIVKA-II, neutrophil:lymphocyte ratio, and combinations thereof to select patients for LT.30,31 In the current study, serum AFP and PIVKA-II levels were also associated with RFS in the univariate analysis, but were not independent factors in the multivariate analysis. Although there are no universally accepted cutoffs for serum AFP, RFS was better for those with lower AFP levels (<100 ng/ml) than with higher AFP levels (≥100 ng/ml) (83.3% vs. 53.1% at three years, p = 0.019). Again, the risk of recurrence was significantly different according to the presence of high-risk radiological findings both in patients

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Please cite this article in press as: Kim AY et al. Hepatobiliary MRI as novel selection criteria in liver transplantation for hepatocellular carcinoma. J Hepatol (2018), https://doi.org/ 10.1016/j.jhep.2018.01.024

Research Article

Survival probability (%)

A

Transplantation

B

Overall 80

80

60

60

40

40

20

20 0

12 24 36 48 60 72 84 96 Time (month) Number at risk Group: None 80 71 67 62 45 26 16 11 Group: One or More 20 8 5 5 3 1 1 0

Survival probability (%)

A

B

12 24 36 48 60 72 84 96 Time (month)

C

D

E

F

0

0 0

C

Within the Milan criteria

100

100

62 57 54 50 35 21 13 10

0

6

0

D

Beyond the Milan criteria

2

2

2

1

1

1

0

0 0

Low AFP level (<100 ng/ml)

100

100 80

80

60

60

40

40

20

20 0

0 0

12 24 36 48 60 72 84 96 Time (month) Number at risk Group: None 18 14 13 12 10 5 Group: One or More 14 6 3 3 2 0

Survival probability (%)

E

0

12 24 36 48 60 72 84 96 Time (month)

3

1

0

56 52 50 46 32 19 11

6

0

0

0

0

12

0

0

6

4

4

3

1

1

High AFP level ( ≥100 ng/ml) 100 80 60

High-risk radiologic findings None One or More

40 20 0 0

12 24 36 48 60 72 84 96 Time (month) Number at risk Group: None 24 19 17 16 13 Group: One or More 8 2 1 1 0

7

5

5

0

0

0

0

0

Fig. 3. Recurrence-free survival curves according to the presence of highrisk radiological findings. These curves represent overall patients (A), patients within the Milan criteria (B), patients beyond the Milan criteria (C), patients whose alpha-fetoprotein level was <100 ng/ml (D), and patients whose alpha-fetoprotein level was ≥100 ng/ml (E).

with lower AFP levels and in patients with higher AFP levels. Our data show that these MRI features can help to classify patients according to the risk of tumour recurrence after LT, regardless of the Milan criteria and serum tumour markers, suggesting that these MRI features could be helpful in the refinement of current LT criteria. Poor HCC biology is considered a predictor of tumour recurrence after LT, and pathological hallmarks, such as microvascular invasion, and tumour grade and differentiation, are considered to be important features for post-transplantation outcome.7,32 However, although these pathological features can directly dictate tumour biology, they can only evaluated precisely from an explanted liver. Pretransplantation biopsies for pathological evaluation have been suggested,33,34 but are limited by the risk of bleeding, tumour seeding, and sampling errors. Moreover, 6

Fig. 4. Radiological and pathological features of hepatocellular carcinoma with satellite nodules in a 54-year-old male patient. At the tip of the left lateral segment of liver, there is a 6.3-cm hypervascular hepatic mass (arrowheads) with a small adjacent hypervascular nodule (A). These lesions are clearly depicted in the hepatobiliary phase (B). A diffusion-weighted image shows a bright main mass with several tiny satellite lesions (C), and the gross specimen also shows satellite lesions (arrow, D). A new enlarged lymph node around the left diaphragmatic crus (arrow, E) and multiple recurrent hepatic tumours occurred (arrowheads, F) six months after transplantation.

vascular invasion of the tumour cannot be fully evaluated by needle biopsy. Thus, preoperative hepatobiliary MRI has the advantage of being a relatively safe and non-invasive approach that can be readily applied in clinical practice. For patients who have undergone LT or liver resection, MVI is known to be an independent risk factor for patient survival,7,11–13,15,35 and our data also demonstrated that MVI on pathological examination was a significant predictor for recurrence, as well as of intrahepatic metastasis. When radiological features were compared with histological findings, both peritumoural hypointensity in the HBP and a satellite nodule correlated with MVI on histology. When high-risk radiological findings were present, the MVI rate was as high as 95%, while it was 84% for those transplanted outside the Milan criteria. In patients without MVI, high-risk radiological findings were present only in 2% of patients (1/45), while five patients exceeded the Milan criteria (11%) (Table 3). This indicates that the positive predictive value and specificity of high-risk radiological findings are sufficiently high for the prediction of MVI, which explains in part, why high-risk radiological findings performed better than Milan criteria in predicting RFS. Before the present study, many researchers had attempted to predict tumour biology, including MVI, radiologically.22,36–38 Perinodular extension or contiguous multinodular growth of HCC indicates that MVI could be developing in the tumour, and intra- and extrahepatic recurrences can frequently occur. The development of a gadoxetic acid-based MR contrast agent

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JOURNAL OF HEPATOLOGY Table 3. MRI findings associated with microvascular invasion and intrahepatic metastasis.* Variables

Beyond the Milan criteria Morphological typey Non-smooth tumour margin Distinctive tumour margin Satellite nodule Peritumoural enhancement in AP Tumour capsule/ pseudocapsule Peritumoural hypointensity in HBP Apparent diffusion coefficientà High-risk radiological findings

Microvascular invasion (+) (n = 55)

Microvascular invasion () (n = 45)

p value

Intrahepatic metastasis (+) (n = 28)

Intrahepatic metastasis () (n = 72)

p value

27 40 42 46 8 8

5 15 17 40 0 2

<0.001 <0.001 <0.001 0.451 0.008 0.178

18 23 25 20 7 4

14 32 34 66 1 6

<0.001 <0.001 <0.001 0.020 <0.001 0.460

28

21

0.673

10

39

0.097

13

1

0.002

6

8

0.207

1.04 ± 0.20

1.11 ± 0.28

0.140

1.02 ± 0.17

1.09 ± 0.26

0.111

19

1

<0.001

11

9

0.005

* y

Analyses were undertaken using the Chi-square, Fisher’s exact, and Mann-Whitney U tests. AP, arterial phase; HBP, hepatobiliary phase. Numbers are the sums of extranodular growth or confluent multinodular type in morphological type. Numbers are means ± standard deviations.

à

(e.g. Gd-EOB-DTPA) has made possible a better understanding of the biological characteristics of HCC and their relationship with histological differentiation. Recent research has revealed that decreased peritumoural uptake of hepatobiliary agents on gadoxetic acid-enhanced MRI correlates with MVI of HCC.35,36,39,40 According to Kitao et al., the signal intensity of HCC in the HBP decreases in accordance with decreased expression of immunohistochemical organic anion-transporting polypeptide 8 (OATP8), which correlates with a decline in histological differentiation.37,41 In areas of peritumoural hypointensity of the liver parenchyma, expression of OATPs and canalicular transporter multidrug resistance-associated protein 2 receptors decreases, probably because of hemodynamic changes associated with tumour obstruction of minute portal veins.36 This assumption is also supported by a previous study using CT arterial portography in patients with HCC that revealed that peritumoural hemodynamic changes are related to minute portal venous invasion.20 Our study demonstrated that satellite nodules that can be identified on preoperative MRI are another significant risk factor for tumour recurrence. This result accorded with previous studies that reported that satellite lesions are one of the major causes of HCC recurrence after LT.42 Satellite nodules, corresponding to intrahepatic metastasis on histology, are known to derive from the main tumour via the portal vein, which acts as an efferent tumour vessel.43–45 This might explain our result that the presence of a satellite nodule on preoperative MRI was significantly associated with the presence of intrahepatic metastasis in the pathological findings. However, according to a previous report, 19% of HCC nodules of 3.0 cm or less in diameter had satellite nodules that were unidentifiable in pretreatment evaluations,45 and one study reported that the overall sensitivity for detecting satellite lesions in pre-transplant imaging was less than 30%.46 Thus, careful evaluation to identify satellite nodules on preoperative MRI is important when deciding on LT for HCC because the results are relevant in predicting patient prognosis. Our study has some limitations. First, for the purpose of the study, we included only those patients who had undergone preoperative MRI evaluation. Given the retrospective nature of this study, no specific reason for performing MRI before LT

was identified, but it was assumed that a patient with clinical characteristics of poor tumour biology had undergone preoperative MRI. Therefore, there could be selection bias associated with our study. Second, our cohort comprised treatment-naïve as well as treatment-experienced patients. For patients who had a treatment history, prior treatment (e.g. TACE) can alter MR findings, and their MRI features could have different meanings for treatment-naïve and -experienced patients. In our data set, high-risk radiological findings were associated with RFS both in treatment-naïve and treatment-experienced patients (Table S4), suggesting that high-risk radiological findings are helpful for assessing both treatment-naïve and -experienced patients. When further stratified according to the Milan criteria, RFS was significantly different according to the presence of high-risk radiological findings for treatment-naïve patients transplanted within the Milan criteria, treatment-naïve patients transplanted outside the Milan criteria, and treatmentexperienced patients transplanted outside the Milan criteria. RFS was not significantly different according to high-risk radiological findings for treatment-experienced patients transplanted within the Milan criteria. However, because the sample size for each group was relatively small, further studies are needed to confirm these findings. Third, because our cohort comprised Korean patients, mainly with hepatitis B virus, the generalisability of our results to other ethnicities or patients with other aetiologies needs to be validated. Our findings suggest that these high-risk radiological features can be a useful tool to rule out patients who might not benefit from LT, but that this conclusion needs to be validated in other studies before being fully included as LT selection criteria in addition to conventional Milan criteria and other biological parameters (e.g. AFP levels). In conclusion, peritumoural hypointensity in the HBP and satellite nodules on preoperative hepatobiliary MRI were significant predictors for tumour recurrence after LT for HCC. These high-risk radiological findings were independent factors associated with RFS, and correlated with histological MVI. These highrisk radiological findings were not only helpful in assessing patients transplanted outside the Milan criteria, but also for patients transplanted within the Milan criteria. Our data indicate that hepatobiliary MRI could be a useful tool in further

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Research Article

Transplantation

refinement of current LT selection criteria, and that it should be a valuable component of the pre-LT evaluation toolset in clinical practice.

Conflict of interest The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details.

Supplementary data Supplementary data associated with this article can be found, in the online version, at https://doi.org/10.1016/j.jhep.2018.01.024.

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