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Hypovascular hepatic nodule showing hypointensity in the hepatobiliary phase of gadoxetic acid-enhanced MRI in patients with chronic liver disease: Prediction of malignant transformation

Eur J Radiol. 2012;81(11):3072-8

Abstract

Purpose

To investigate the predictive factors of malignant transformation of hypovascular hepatic nodule showing hypointensity in the hepatobiliary phase images of gadoxetic acid-enhanced MRI ( HHN ).

Materials and Methods

The clinical data and imaging findings of dynamic contrast-enhanced computed tomography (DCE-CT) and gadoxetic acid-enhanced MRI for a total of 103 HHNs in 24 patients with chronic liver disease were retrospectively investigated. After the results of follow-up examinations were investigated, HHNs were categorized into the three groups for each comparison: (1) nodules with enlargement and/or vascularization and others, (2) nodules with only enlargement and others, (3) nodules with only vascularization and others. Enlargement and/or vascularization during the follow-up period were defined as malignant transformation of HHN . The frequency of each clinical datum and imaging finding in each group was compared to identify the predictive factors for malignant transformation in HHN .

Results

Multivariate analysis showed that a nodule size of 9 mm or more on the initial gadoxetic acid-enhanced MRI was a significant predictive factor for the enlargement and/or vascularization of HHN ( P < 0.05). On the other hand, the hypoattenuation on the delayed phase imaging of the initial DCE-CT was a significant predictive factor for the enlargement or vascularization of HHN ( P < 0.05).

Conclusion

A nodule size of 9 mm or more on the initial gadoxetic acid-enhanced MRI and hypoattenuation on the delayed phase imaging of initial DCE-CT would be helpful for predicting the outcome of HHN in patients with a risk of hepatocellular carcinoma.

Keywords: Gadoxetic acid, Gd-EOB-DTPA, Magnetic resonance imaging, Hypovascular hepatic nodule, Hepatocarcinogenesis, Hepatocellular carcinoma.

1 Introduction

Hepatocellular carcinoma (HCC) is a highly prevalent disease in the Asia-Pacific region, which accounts for 75–80% of HCC cases worldwide [1] . In most Asian countries, HCC is one of the leading causes of death [1] . With recent advances in imaging modalities, such as computed tomography (CT), magnetic resonance imaging (MRI), and ultrasonography (US), HCC can be diagnosed at an early stage without a pathological examination 1 2 .

Gadoxetic acid (Gd-EOB-DTPA) has been developed as a liver-specific contrast agent for MRI [3] . Because gadoxetic acid works as both an extracellular and a hepatocyte-specific contrast agent, it provides dynamic and hepatocyte-specific hepatobiliary MRI [3] . Gadoxetic acid-enhanced MRI (Gd-EOB-MRI) has been reported to show accurate and sensitive diagnostic performance for HCC compared with dynamic contrast-enhanced (DCE-) CT, superparamagnetic iron oxide-enhanced MRI, and contrast-enhanced US 2 4 . Moreover, Gd-EOB-MRI could take the place of CT during hepatic arteriography (CTHA) and CT during arterial portography (CTAP) for differentiating early HCC from dysplastic nodule (DN) [2] . However, there is some overlap between early HCC and DN in MR findings, including hypovascularity in dynamic contrast-enhanced MRI and hypointensity in the hepatobiliary phase (HBP) of Gd-EOB-MRI [2] . Therefore, it may be difficult to distinguish precisely between the two even on Gd-EOB-MRI. If we can know any of the predictors suggesting malignant transformation, such as enlargement or vascularization, of such hypovascular hepatic nodules showing hypointensity in the HBP of Gd-EOB-MRI ( HHNs ), this information would help physicians decide on treatment and follow-up strategies.

The purpose of the present study was to investigate the predictive factors of malignant transformation of HHNs in patients with a risk of hepatocellular carcinoma.

2 Materials and methods

2.1 Patients

This study was approved by our institutional review board. Written informed consent was waived because the study was retrospective. We first investigated the records of 716 patients who had undergone Gd-EOB-MRI at our institute from May 2008 to May 2010. Patients were selected according to the following criterion. Inclusion and exclusion criteria for this study are shown in Table 1 . After the restricted evaluation by two experienced abdominal radiologists, a total of 24 patients (age range = 55–80 years, average = 67.1 years, Female/Male = 9/15) with 103 hepatic nodules were enrolled in the present study. Twenty of the 24 patients had a history of hepatitis viral infection.

Inclusion criteria
1. Gd-EOB-MRI was performed because of a risk of HCC owing to chronic liver disease.
2. Presence of HHN on the initial Gd-EOB-MRI
3. DCE-CT was also performed within one month before or after the initial Gd-EOB-MRI.
4. Follow-up Gd-EOB-MRI or DCE-CT was performed more than 3 months later.
 
Exclusion criteria
1. Subjects who underwent any treatments for HHN after the initial Gd-EOB-MRI
2. Non-hepatocyte-related nodules, such as liver cysts and metastatic liver tumors
3. Hepatic hemangioma that were diagnosed by Gd-EOB-MRI
4. Follow-up Gd-EOB-MRI or DCE-CT was not performed more than 3 months later.
Gd-EOB-MRI: gadoxetic acid-enhanced magnetic resonance imaging, HCC: hepatocellular carcinoma, HHN : hypovascular hepatic nodule showing hypointensity in the hepatobiliary phase of Gd-EOB-MRI, DCE-CT: dynamic contrast-enhanced computed tomography.

Table 1Inclusion and exclusion criteria for this study.

 

2.2 Imaging technique

Gd-EOB-MRI was performed on a clinical 1.5 or 3.0 T MR scanner (Intera Achieva Nova Dual, 1.5 T or 3.0 T, Philips Healthcare, Best, the Netherlands) with sensitivity encoding techniques (SENSE) using a 16- or 32-channel phased-array coil. For dynamic study, fat-suppressed gradient-echo (GRE) T1-weighted imaging (T1WI) with a three-dimensional (3D) acquisition sequence (three-dimensional T1 high-resolution isotropic volume excitation [THRIVE] or enhanced THRIVE [eTHRIVE]) were obtained. A total amount of Gd-EOB-DTPA (EOB Primovist; Bayer HealthCare, Osaka, Japan) based on body weight (0.1 mL/kg) was intravenously injected for 5 s and immediately flushed with 20 mL of physiological saline at the same injection rate using an automatic injector (Nemoto Kyourindo, Tokyo, Japan). This injection rate was designed to minimize truncation artifacts [5] . The scan timing of the first phase of the dynamic study was determined by a test injection method referring to the previous report [6] . Before dynamic study, a test dose of 0.5 mL of Gd-EOB-DTPA was injected and flushed with 20 mL of physiological saline at the same injection rate as described previously. For the HBP, images were obtained 20 min after injection of the contrast agent. Additionally, GRE T1WI with a dual-echo imaging technique (in-phase and out-of-phase), called chemical shift imaging (CSI), was obtained before DCE-MRI. Single-shot turbo spin echo T2-weighted imaging (T2WI) with synchronization of breath, and diffusion-weighted imaging (DWI) with b-values of 0, 500, and 1000 s/mm 2 , were obtained during the DCE-MRI between the early phase and HBP. Details of the sequence parameters of MRI are summarized in Table 2 .

Parameters Unit CSI ssT2WI DWI HBP image
1.5 T
Repetition time (ms) 185.0 4345.0 1542.0 3.6
Echo time (ms) 2.3/4.6 90.0 71.0 1.8
Flip angle (degree) 75 90 90 18
Field of view (mm) 360 × 298 360 × 283 360 × 304 360 × 252
Matrix (frequency × phase)   256 × 148 224 × 123 128 × 70 240 × 168
Slice thickness (mm) 7.0 7.0 7.0 3.0
Slice gap (mm) 1.0 1.0 1.0 −1.5
Number of slices   25 25 25 116
Number of excitations   1 2 1 1
Fat suppression   No SPIR SPIR SPAIR
Respiratory control   Breath-hold Breath-hold Triggered Breath-hold
Band width (Hz/pixel) 1257.4 374.4 28.7 617.3
Scan time of whole slices (min:s) 00:18.5 00:34.0 01:54.0 00:16.8
3.0 T
Repetition time (ms) 160.0 1154.0 1867.0 3.0
Echo time (ms) 1.15/2.27 71.0 55.0 1.4
Flip angle (degree) 60 90 90 10
Field of view (mm) 380 × 329 380 × 299 380 × 299 375 × 298
Matrix (frequency × phase)   240 × 207 112 × 88 112 × 88 252 × 200
Slice thickness (mm) 7.0 7.0 7.0 3.0
Slice gap (mm) 1.0 1.0 1.0 −1.5
Number of slices   25 25 25 133
Number of excitations   1 1 1 1
Fat suppression   No SPAIR SPIR SPAIR
Respiratory control   Breath-hold Breath-hold Triggered Breath-hold
Band width (Hz/pixel) 1898.5 569.6 99.5 723.4
Scan time of whole slices (min:s) 00:14.8 00:30.0 01:39.0 00:17.9
CSI: chemical shift imaging, ssT2WI: single-shot T2-weighted imaging, DWI: diffusion-weighted imaging, HBP image: hepatobiliary phase images, SPIR: spectral presaturation with inversion recovery, SPAIR: spectral attenuated with inversion recovery

Table 2Details of the sequence parameters.

 

DCE-CT was performed with 64-row multidetector CT (Aquilion 64, Toshiba Medical Systems, Tokyo, Japan). The CT parameters were 120 kVp, 100–300 mAs, 0.5 mm collimation, 0.828 pitch factor, and a single-breath-hold helical acquisition of 5 to 8 s depending on liver size. Using these raw data, transverse images were obtained with a slice thickness of 5 mm and no slice gap. A total of 2.0 mL/kg (maximum = 100 mL) of non-ionic iodinated contrast agent (Iopamilon 370, 370 mgI/mL, Bayer HealthCare, Osaka, Japan; or Omnipaque 350, 350 mgI/mL, Dai-ichi Sankyo, Tokyo, Japan) was administered using an automatic injector. It was intravenously administered at a rate of 3.0 mL/s using an automatic injector (Nemoto Kyorindo, Tokyo, Japan). Images of the early and delayed phases, which were scanned 43 and 240 s after the beginning of contrast agent administration, respectively, were used for the assessment.

2.3 Analysis

We retrospectively investigated the clinical data of each patient and the imaging findings of the initial Gd-EOB-MRI and DCE-CT of each HHN .

Clinical data within one month before or after the initial Gd-EOB-MRI were recorded. From the patients’ blood tests, we investigated serum albumin (Alb), serum total bilirubin (TB), alanine aminotransferase (ALT), alpha-fetoprotein (AFP), proteins induced by vitamin K absence or antagonist-II (PIVKA-II), and platelet count (Plt). From the patients’ backgrounds, we investigated gender, age, body mass indices (BMI), length of follow-up, Child–Pugh score, the presence or absence of diabetes mellitus, history of heavy drinking, fatty liver, and hepatitis viral infection. All of these are known as risk factors for hepatocarcinogenesis in chronic liver disease [7] .

Imaging findings were evaluated by the consensus of two radiologists. We defined enlargement and/or vascularization during the follow-up period as malignant transformation of HHN . All nodules were categorized into the three groups for each comparison: (1) nodules that enlarged and/or vascularized during the follow-up period ( mN ) and those that neither enlarged nor vascularized ( nonN ), (2) nodules that only enlarged during a follow-up period ( mNe ) and those that did not ( nonNe ), (3) nodules vascularized during follow-up ( mNv ) and those that did not ( nonNv ). The HBP of Gd-EOB-MRI was used to assess the enlargement, and the size of each nodule was recorded. If a nodule showed more than a 2 mm increase in diameter at the follow-up examination, we regarded the enlargement as positive. Gd-EOB-MRI or DCE-CT was used to assess vascularization. If an early enhancement was observed in part or all of a nodule in the follow-up examination, we regarded the vascularization as positive. The number, frequency, and length of the follow-up period of mN , nonN , mNe , nonNe , mNv and nonNv were also recorded.

Next, we evaluated the findings of CSI, T2WI, and DWI with a b-factor of 1000 s/mm 2 on the initial Gd-EOB-MRI. CSI was used to evaluate fat deposition in nodules. When the signal intensity on out-of-phase images was lower than that on in-phase images, we regarded the presence of fat deposition as positive. Regarding findings on T2WI and DWI, we investigated whether or not each nodule was hyperintense relative to the surrounding liver parenchyma. For the initial DCE-CT, we evaluated whether each nodule was hypo- or isoattenuated on the early and delayed phase images compared with the surrounding liver parenchyma.

2.4 Statistical analysis

The frequency of each clinical datum and imaging finding between the two nodule groups ( mN vs. nonN , mNe vs. nonNe , and mNv vs. nonNv ) was compared to identify the predictive factors of malignant transformation in HHN . Clinical data were compared on a patient-by-patient basis. A patient who had both mN and nonN simultaneously was categorized into mN according to our criteria. A patient who had both mNe and nonNe , or both mNv and nonNv , was also categorized into mNe or mNv . The Mann–Whitney U -test was used to compare continuous values, such as patient age, BMI, Alb, TB, ALT, AFP, PIVKA-II, and Plt, between mN and nonN , mNe and nonNe , and mNv and nonNv , whereas Fisher's exact test was used to compare Child–Pugh scores (A vs. B and C) and the presence or absence of diabetes mellitus, history of heavy drinking, fatty liver, and hepatitis viral infection between the same pairs of the two groups.

Imaging findings of Gd-EOB-MRI and DCE-CT between mN and nonN , mNe and nonNe , and mNv and nonNv were compared on a nodule-by-nodule basis using Fisher's exact test. Receiver operating characteristic (ROC) analysis was used to determine the optimal cutoff value of the nodule size on the initial Gd-EOB-MRI. Multivariate analysis was also performed using logistic regression analysis when limited to significant risk factors obtained by the Mann–Whitney U -test or Fisher's exact test. For significant factors obtained by multivariate analysis, the Kaplan–Meier time-to-event curves were used to estimate the cumulative risk of malignant transformation. The log-rank test was also used to compare between the two curves of mN and nonN , mNe and nonNe , and mNv and nonNv . For each test, P < 0.05 was considered significant. All data analysis was performed using IBM SPSS statistics 18.0 (IBM Japan, Tokyo, Japan).

3 Results

3.1 Characteristics of HHNs

Of the 24 patients overall, 12, 9, and 11 had mN , mNe , and mNv , respectively. The numbers of mN and nonN were 31 and 72, respectively. Those of mNe and mNv were 23 and 21, respectively. Thirteen nodules overlapped between mNe and mNv . The summary is shown in Table 3 .

  No. of nodules Frequency (%) Follow-up period (day)
Mean (range)
Nodule size on the initial Gd-EOB-MRI (mm)
Mean (range)
         
mN 31 30.1 430.2 (147–633) 9.3 (5–15)
nonN 72 69.9 480.2 (184–838) 7.9 (5–30)
Total 103 100.0 465.1 (147–838) 8.4 (5–30)
 
Subgroup of mN
mNe 23 a 22.3 b 432.7 (147–559) 9.4 (5–15)
mNv 21 a 20.4 b 421.4 (147–633) 9.4 (5–15)

a 13 of 31 nodules overlapped both subgroups.

b The frequency is calculated per 103 nodules.

Table 3Characteristics of hypovascular hepatic nodules.

 

3.2 Clinical data

There was a significant difference in TB between mN and nonN ( P < 0.05), but there were no significant differences between the groups in other factors ( Table 4 ). TB was not a significant predictive factor by multivariate analysis. There were no significant differences in any factors of the clinical data between mNe and nonNe or between mNv and nonNv .

  mN nonN P value
No. of patients 12 12  
Age, mean (range) 68.2 (55–76) 67.4 (50–80) NS
BMI, mean (range) 22.3 (18.2–26.2) 22.4 (20.5–29.9) NS
Serum albumin, mean (range) [g/dl] 3.6 (2.4–4.7) 3.7 (3.1–4.4) NS
Serum total bilirubin, mean (range) [mg/dL] 1.1 (0.6–2.0) 0.8 (0.4–1.3) <0.05
ALT, mean (range) [unit/L] 58.4 (16–105) 33.0 (13–83) NS
AFP, mean (range) [ng/mL] 39.8 (3.5–42.1) 13.5 (2.9–56.0) NS
PIVKA-II, mean (range) [mAU/mL] 32.4 (8.0–99.0) 2302.2 (14.0–23911.0) NS
Platelet count, mean (range) [×10 3 /μL] 115.8 (40.0–190.0) 114.0 (15.0–227.0) NS
 
Gender (female/male) 5/7 4/8 NS
Child–Pugh score (A/B or C) 10/2 10/2 NS
Diabetes mellitus (with/without) 1/11 2/10 NS
Drinking history (not heavy/heavy) 1/11 2/10 NS
Fatty liver (with/without) 1/11 1/11 NS
Hepatitis viral infection (with/without) 10/2 10/2 NS
NS indicates ‘not significant’, BMI = body mass index, ALT = alanine aminotransferase, AFP = alpha-fetoprotein, PIVKA-II = protein induced by vitamin K absence or antagonist II.

Table 4Patient characteristics and results of statistical analysis between hypovascular hepatic nodules with or without malignant transformation during the follow-up period.

 

3.3 Imaging findings

There were significant differences between mN and nonN in the Fisher's exact test results for the early and delayed phase images of DCE-CT, CSI, and nodule size on the initial Gd-EOB-MRI ( P < 0.05). Multivariate analysis revealed that the nodule size on the initial Gd-EOB-MRI was only a significant predictive factor for the enlargement and/or vascularization of HHN ( P < 0.05). In the comparison between mNe and nonNe , there were significant differences in the Fisher's exact test results for the early and delayed phase images of DCE-CT, CSI, T2WI, and nodule size on the initial Gd-EOB-MRI ( P < 0.05). Multivariate analysis revealed that the finding of the delayed phase image of DCE-CT was only a significant predictive factor for the enlargement of HHN ( P < 0.05). In the comparison between mNv and nonNv , the finding of the delayed phase imaging of DCE-CT was a significant predictive factor for the vascularization of HHN by Fisher's exact test and multivariate analysis again ( P < 0.05). For each comparison, 9 mm was determined as the optimal cutoff value for nodule size on the initial Gd-EOB-MRI by ROC analyses. The summary is shown in Table 5 .

mN vs. nonN mN nonN Fisher's exact test Multivariate analysis
      P value P value Odds ratio (95% CI)
CT (early phase), hypo- or iso-attenuated/others 13/18 13/59 <0.05 0.89 0.84 (0.22–3.25)
CT (delayed phase), hypo- or iso-attenuated/others 19/12 18/54 <0.05 0.66 0.32 (0.09–1.15)
CSI (fat containing), +/− 14/17 16/56 <0.05 0.80 0.76 (0.23–2.51)
T2WI, hyperintense/others 6/25 5/67 NS
DWI, hyperintense/others 0/31 6/66 NS
Nodule size on the initial Gd-EOB-MRI, ≧9 mm/<9 mm 18/13 17/55 <0.05 <0.05 3.12 (1.21–8.37)
mNe vs. nonNe mNe nonNe Fisher's exact test Multivariate analysis
      P value P value Odds ratio (95% CI)
CT (early phase), hypo- or iso-attenuated/others 10/13 16/64 <0.05 0.69 1.33 (0.32–5.49)
CT (delayed phase), hypo- or iso-attenuated/others 15/8 22/58 <0.05 <0.05 0.23 (0.54–0.95)
CSI (fat containing), +/− 12/11 18/62 <0.05 0.73 0.80 (0.23–2.81)
T2WI, hyperintense/others 6/17 5/75 <0.05 0.68 0.23 (0.05–1.11)
DWI, hyperintense/others 0/23 6/74 NS
Nodule size on the initial Gd-EOB-MRI, ≧9 mm/<9 mm 14/9 21/59 <0.05 0.72 2.63 (0.92–7.74)
mNv vs. nonNv mNv nonNv Fisher's exact test Multivariate analysis
      P value P value Odds ratio (95% CI)
CT (early phase), hypo- or iso-attenuated/others 8/13 18/64 NS
CT (delayed phase), hypo- or iso-attenuated/others 12/9 25/57 < 0.05 <0.05 0.33 (0.12–0.88)
CSI (fat containing), +/− 6/15 24/58 NS
T2WI, hyperintense/others 3/18 8/74 NS
DWI, hyperintense/others 0/21 6/76 NS
Nodule size on the initial Gd-EOB-MRI, ≧9 mm/<9 mm 11/10 24/58 NS
NS indicates ‘not significant’, CSI = chemical shift imaging, T2WI/DWI = T2/diffusion-weighted imaging, CI = confidence interval.

Table 5Results of Fisher's exact test and multivariate analyses of imaging finding.

 

3.4 Cumulative risk of malignant transformation of HHNs

Comparative analysis of the two curves showed that the enlargement and/or vascularization occurred earlier in nodules measuring 9 mm or more on the initial Gd-EOB-MRI ( P < 0.01). The 1-year and 1.5-year cumulative risk ± standard error (SE) of the enlargement and/or vascularization were 18.4 ± 6.8% and 35.8 ± 8.8%, respectively ( Fig. 1 a). Moreover, comparative analysis of the two curves showed that the enlargement or vascularization occurred earlier in the nodules showing hypoattenuation on the delayed phase image of DCE-CT ( P < 0.01). The 1-year and 1.5-year cumulative risks ± SE of the enlargement were 13.0 ± 6.1% and 38.3 ± 9.8% ( Fig. 1 b), and those of vascularization were 19.1 ± 7.1% and 29.9 ± 9.4% ( Fig. 1 c).

gr1
 

Fig. 1
(a) Graph of cumulative risk of the enlargement and/or vascularization in 103 HHNs based on differences in nodule size on the initial Gd-EOB-MRI. (b and c) Graphs of enlargement and vascularization in 103 HHNs based on differences in attenuation on the delayed phase imaging of DCE-CT.

 

Example imaging findings of HHN showing enlargement and vascularization during the follow-up period are shown in Fig. 2 .

gr2
 

Fig. 2
A 64-year-old man with hepatitis C-related cirrhosis. (a) Initial Gd-EOB-MRI and DCE-CT. The hepatic nodule in segment 5 of the liver showed no contrast enhancement on the early phase imaging of Gd-EOB-MRI (upper left) and hypointensity with a diameter of 9 mm in the HBP of Gd-EOB-MRI (upper middle). In addition, the nodule showed isointensity on T2-weighted imaging (upper right), fat deposition on chemical shift imaging (in-phase, middle left; out-of-phase, middle center; and subtraction image, middle right), isointensity on diffusion-weighted imaging (lower left), isoattenuation on the early phase imaging of DCE-CT (lower middle), and hypoattenuation on the delayed phase imaging of DCE-CT (lower right). (b) Follow-up Gd-EOB-MRI 1 year and 6 months after the initial examination. The nodule showed the enlargement to 22 mm in diameter and the vascularization on the early phase imaging of Gd-EOB-MRI (left) and hypointensity in the HBP of Gd-EOB-MRI (right).

 

4 Discussion

Gd-EOB-MRI is reportedly useful for the diagnosis of early HCC, but there has remained the problem of differentiating between early HCC and DN because of overlapping imaging findings [2] . However, the present results suggest that associated imaging findings, which were the nodule size on the initial Gd-EOB-MRI and hypoattenuation on the delayed phase image of DCE-CT, would be helpful for predicting the outcome of HHN .

In our results, 31 of 103 HHNs (30.1%) showed malignant transformation during the follow-up period. This was higher than the frequency of malignant transformation reported in Motosugi et al. (11.9%) and slightly higher than that in Kumada et al. (28.6%) 8 9 . These differences might be related to differences in assessment procedures. Especially, the HHNs evaluated in our study were smaller, but the follow-up period was longer compared with the previous reports 8 9 . We thought that the present results, in addition to the results of the previous studies, could offer information useful in predicting the outcome of HHN .

To the best of our knowledge, no report discusses the use of DCE-CT findings to predict the outcome of HHN . As we showed in the present results, hypoattenuation on the delayed phase image of DCE-CT was a significant predictive factor in the malignant transformation of HHN . It has been reported on the utility of delayed phase imaging of DCE-CT for detecting small HCC [10] . There are several possible reasons why HCC shows hypoattenuation on the delayed phase image of DCE-CT. These include the prompt washout of contrast agent due to hypervascularity of HCC, delayed enhancement of hepatic parenchyma due to portal hypertension in cirrhotic liver, and increased cellularity of HCC compared with normal liver parenchyma 10 11 . These hypotheses also may partly explain on the early change of hepatocarcinogenesis, such as the growth of an unpaired artery, a decrease in what aspect of the portal vein, an increase in the density of carcinoma cells. We thought that the delayed phase image of DCE-CT could add important information to help predict the malignant formation of HHN . There is a possibility that the regenerative nodule (RN) shows hypoattenuation on the delayed phase image of DCE-CT [12] , but those nodules uptake Gd-EOB-DTPA and show iso- or hyperintensity in the HBP of Gd-EOB-MRI [13] . Therefore, if the nodule shows both imaging findings, hypoattenuation on the delayed phase image of DCE-CT and hypointensity in the HBP of Gd-EOB-MRI, we should consider that such a nodule is at high risk for malignant transformation.

Another significant predictive factor of malignant formation was the nodule size on the initial Gd-EOB-MRI. As the diagnostic and treatment algorithm for HHN suggested 2 14 , a needle biopsy is proposed for HHN of more than 15 mm in diameter, and follow-up is recommended for those less than 15 mm in diameter when they showed hypointensity in the HBP of Gd-EOB-MRI. Needle biopsy is essential for histopathological confirmation, but it is difficult for small nodules because histological samples are small and might lead to the underestimation of the diagnosis of early HCC 2 14 . Therefore, the ability to detect early changes in hepatocarcinogenesis in such small lesions in imaging would be helpful. The size of a hepatic nodule is an important finding for the assessment of multistep hepatocarcinogenesis 8 9 15 . According to a previous report [15] , nodules larger than 15 mm in diameter were probably early HCC, but there was an overlap in size range from 5 mm to 10 mm between DN and early HCC. The results of our ROC analyses showed that the cutoff value for nodule size between mN and nonN was 9 mm, which was included in the overlapping size range of DN and early HCC. This cutoff was similar to that of Motosugi et al. but smaller than that of Kumada et al. 8 9 . This difference might derive from the difference in the length of the follow-up periods for HHNs .

As we mentioned above, the significant predictive factors for the enlargement and/or vascularization of HHN were different from those for only enlargement or vascularization. Because 13 of 31 HHNs were categorized into both mNe and mNv in the present study, we speculated that this overlap might affect the results of the multivariate analysis.

Fat deposition is known as an important imaging and histopathological finding of HCC, and is attributed to a relative decrease in the blood supply caused by diminished portal supply and immature arterial neovascularization 2 16 . Fat deposition is generally not seen in RN or in low-grade DN, whereas it is found in about 40% of high-grade DN and well-differentiated HCC [17] . Therefore, fat detection in HHNs is thought to be helpful for predicting malignant formation. However, our multivariate analysis results showed that fat detection on CSI was not finally a significant predictor of malignant formation. This result was inconsistent with the previous result by Motosugi et al. [9] . The reason was unclear, but one possibility is that the HHNs were smaller in our study. That is, our subjects included greater numbers of ‘less malignant’ nodules than those in the previous report [9] . In fact, fat deposition appeared during the follow-up period in some hepatic nodules (data not shown). However, its change was not considered because fat deposition was evaluated only on the initial Gd-EOB-MRI in our assessment procedure. A similar discussion might be launched for hypoattenuation of the early phase imaging of DCE-CT. This finding indicates a decrease in intranodular arterial blood supply which is a step of hepatocarcinogenesis [18] . In addition, we speculate that it reflects fat deposition because, in the present study, 18 of 31 nodules simultaneously showed hypoattenuation on the early phase imaging of DCE-CT and fat deposition on CSI.

Clinical data obtained from blood tests and patient background information were not useful for predicting malignant transformation of HHNs , even though only TB showed significant differences between patients with mN and nonN by Fisher's exact test. The result that mN showed significantly higher TB than nonN might reflect the increased rate of HCC in association with the progress of liver cirrhosis.

There were several limitations in this study. First, the patient population was relatively small. We excluded several patients who underwent treatment because they underwent a needle biopsy for confirmation instead of a follow-up examination. Second, the follow-up period of each subject was not constant. If a fixed follow-up interval was set, we could calculate more accurately the cumulative incidence of malignant transformation of HHN . Third, we assessed the presence of vascularization by follow-up Gd-EOB-MRI or DCE-CT. It is desirable to assess vascularization by CTHA because of its high sensitivity at depicting hepatic arterial supply in the hepatic nodule. Only a few patients underwent CTHA during follow-up in our study. Because of its invasiveness, this modality seems not appropriate as a follow-up method of HHN . Fourth, hepatitis viral activity is one of the most important risk factors for hepatocarcinogenesis 19 20 . However, the activity of hepatitis B or C virus was not considered in the present study because it had been examined in only half of the patients with hepatitis viral infection around the date of initial Gd-EOB-MRI.

In conclusion, a nodule size of 9 mm or more on the initial Gd-EOB-MRI and hypoattenuation on the delayed phase imaging of initial DCE-CT were significant predictive factors for malignant transformation of HHN in patients with a risk of hepatocellular carcinoma.

Conflict of interest

Daisuke Kakihara: unrestricted research grants from Bayer AG and Philips Healthcare.

References

  • [1] M. Kudo, K.H. Han, N. Kokudo, et al. Liver Cancer Working Group report. Japanese Journal of Clinical Oncology. 2010;40(Suppl. 1):i19-i27
  • [2] M. Kudo. Will Gd-EOB-MRI change the diagnostic algorithm in hepatocellular carcinoma?. Oncology. 2010;78(Suppl. 1):87-93
  • [3] T.J. Vogl, S. Kümmel, R. Hammerstingl, et al. Liver tumors: comparison of MR imaging with Gd-EOB-DTPA and Gd-DTPA. Radiology. 1996;200(1):59-67
  • [4] H. Akai, S. Kiryu, I. Matsuda, et al. Detection of hepatocellular carcinoma by Gd-EOB-DTPA-enhanced liver MRI: comparison with triple phase 64 detector row CT. European Journal of Radiology. 2011;80(2):310-315
  • [5] A. Tanimoto, J.M. Lee, T. Murakami, A. Huppertz, M. Kudo, L. Grazioli. Consensus report of the 2nd International Forum for Liver MRI. European Radiology. 2009;19(Suppl. 5):S975-S989
  • [6] K. Shinozaki, K. Yoshimitsu, H. Irie, et al. Comparison of test-injection method and fixed-time method for depiction of hepatocellular carcinoma using dynamic steady-state free precession magnetic resonance imaging. Journal of Computer Assisted Tomography. 2004;28(5):628-634
  • [7] R. Tateishi, K. Koike. Identification of high-risk group for hepatocellular carcinoma. Hepato-Biliary-Pancreatic Imaging. 2010;21:167-172
  • [8] T. Kumada, H. Toyoda, T. Tada, et al. Evolution of hypointense hepatocellular nodules observed only in the hepatobiliary phase of gadoxetate disodium-enhanced MRI. American Journal of Roentgenology. 2011;197(1):58-63
  • [9] U. Motosugi, T. Ichikawa, K. Sano, et al. Outcome of hypovascular hepatic nodules revealing no gadoxetic acid uptake in patients with chronic liver disease. Journal of Magnetic Resonance Imaging. 2011;34(1):88-94
  • [10] J.H. Lim, D. Choi, S.H. Kim, et al. Detection of hepatocellular carcinoma: value of adding delayed phase imaging to dual-phase helical CT. American Journal of Roentgenology. 2002 Jul;179(1):67-73
  • [11] S. Monzawa, T. Ichikawa, H. Nakajima, Y. Kitanaka, K. Omata, T. Araki. Dynamic CT for detecting small hepatocellular carcinoma: usefulness of delayed phase imaging. American Journal of Roentgenology. 2007;188(1):147-153
  • [12] E. Quaia, V. Alaimo, E. Baratella, et al. The added diagnostic value of 64-row multidetector CT combined with contrast-enhanced US in the evaluation of hepatocellular nodule vascularity: implications in the diagnosis of malignancy in patients with liver cirrhosis. European Radiology. 2009;19(3):651-663
  • [13] M.K. Seale, O.A. Catalano, S. Saini, P.F. Hahn, D.V. Sahani. Hepatobiliary-specific MR contrast agents: role in imaging the liver and biliary tree. Radiographics. 2009;29(6):1725-1748
  • [14] M. Kudo, N. Izumi, N. Kokudo, et al. Management of hepatocellular carcinoma in Japan: Consensus-Based Clinical Practice Guidelines proposed by the Japan Society of Hepatology (JSH) 2010 updated version. Digestive Diseases. 2011;29(3):339-364
  • [15] M. Sakamoto, S. Hirohashi, Y. Shimosato. Early stages of multistep hepatocarcinogenesis: adenomatous hyperplasia and early hepatocellular carcinoma. Human Pathology. 1991;22(2):172-178
  • [16] M. Kudo. Multistep human hepatocarcinogenesis: correlation of imaging with pathology. Journal of Gastroenterology. 2009;44(Suppl. XIX):112-118
  • [17] K. Taguchi, S. Aishima, S. Matsuura, et al. Significance of the relationship between irregular regeneration and two hepatocarcinogenic pathways: “De Novo” and so-called “Dysplastic Nodule-Hepatocellular Carcinoma” sequence. Journal of Surgical Oncology. 2005;92(November (2)):100-103
  • [18] M. Hayashi, O. Matsui, K. Ueda, et al. Correlation between the blood supply and grade of malignancy of hepatocellular nodules associated with liver cirrhosis: evaluation by CT during intraarterial injection of contrast medium. American Journal of Roentgenology. 1999;172(4):969-976
  • [19] C.J. Chen, H.I. Yang, J. Su, et al. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. JAMA. 2006;295(1):65-73
  • [20] M.H. Lee, H.I. Yang, C.L. Jen, et al. Community and personal risk factors for hepatitis C virus infection: a survey of 23,820 residents in Taiwan in 1991–2. Gut. 2011;60(5):688-694

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