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Is magnetic resonance imaging of hepatic hemangioma any different in liver fibrosis and cirrhosis compared to normal liver? Rafael Duran a,b,∗ , Maxime Ronot b,c , Sara Di Renzo b , Bettina Gregoli b , Bernard E. Van Beers b , Valérie Vilgrain b,c a
Centre Hospitalier Universitaire Vaudois, University of Lausanne, Diagnostic and Interventional Radiology, Lausanne, Switzerland Assistance-Publique Hôpitaux de Paris, APHP, Hôpital Beaujon, Department of Radiology, Clichy, France c University Paris Diderot, Sorbonne Paris Cité, INSERM U773, Centre de Recherche Biomédicale Bichat-Beaujon, CRB3 Paris, France b
a r t i c l e
i n f o
Article history: Received 27 November 2014 Received in revised form 16 January 2015 Accepted 19 January 2015 Keywords: Hemangioma Cirrhosis Chronic liver disease Diffusion magnetic resonance imaging MRI Benign liver lesion
a b s t r a c t Purpose: To compare qualitative and quantitative magnetic resonance (MR) imaging characteristics of hepatic hemangiomas in patients with normal, fibrotic and cirrhotic livers. Materials and methods: Retrospective, institutional review board approved study (waiver of informed consent). Eighty-nine consecutive patients with 231 hepatic hemangiomas who underwent liver MR imaging for lesion characterization were included. Lesions were classified into three groups according to the patients’ liver condition: no underlying liver disease (group 1), fibrosis (group 2) and cirrhosis (group 3). Qualitative and quantitative characteristics (number, size, signal intensities on T1-, T2-, and DW MR images, T2 shine-through effect, enhancement patterns (classical, rapidly filling, delayed filling), and ADC values) were compared. Results: There were 160 (69%), 45 (20%), and 26 (11%) hemangiomas in groups 1, 2 and 3, respectively. Lesions were larger in patients with normal liver (group 1 vs. groups 2 and 3; P = .009). No difference was found between the groups on T2-weighted images (fat-suppressed fast spin-echo (P = .82) and single-shot (P = .25)) and in enhancement patterns (P = .56). Mean ADC values of hemangiomas were similar between groups 1, 2 and 3 (2.11 ± .52 × 10−3 mm2 /s, 2.1 ± .53 × 10−3 mm2 /s and 2.14 ± .44 × 10−3 mm2 /s, P = 87, respectively). T2 shine-through effect was less frequently observed in cirrhosis (P = .02). Conclusion: MR imaging characteristics of hepatic hemangioma were similar in patients with normal compared to fibrotic and cirrhotic livers. Smaller lesion size was observed with liver disease and less T2 shine-through effect was seen in hemangiomas developed on cirrhosis, the latter being an important finding to highlight in these patients at risk of developing hepatocellular carcinoma. © 2015 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Hepatic hemangioma is the most common benign liver lesion [1]. Differentiation between hepatic hemangiomas and other liver
Abbreviations: DW, diffusion-weighted; MR, magnetic resonance; ADC, apparent diffusion coefficient; CT, computed tomography; NASH, nonalcoholic steatohepatitis; HCC, hepatocellular carcinoma; ROI, region of interest. ∗ Corresponding author at: University Hospital of Lausanne (CHUV), Department of Diagnostic and Interventional Radiology, BH 10-121, Rue du Bugnon 46, 1011 Lausanne, Switzerland. Tel.: +41 213144444. E-mail addresses: [email protected] (R. Duran), [email protected] (M. Ronot), [email protected] (S. Di Renzo), [email protected] (B. Gregoli), [email protected] (B.E. Van Beers), [email protected] (V. Vilgrain).
lesions is a frequent clinically relevant situation. Precise focal liver lesion characterization is mandatory, particularly in patients with chronic liver disease and cirrhosis who have a much greater risk of developing primary liver malignancy [2]. Unfortunately, tumor characterization may be hampered by the distortion of the hepatic parenchyma due to the fibrotic process. Thus, a thorough understanding of imaging features of hepatic hemangiomas in fibrotic and/or cirrhotic livers is essential. Hemangiomas have been shown to present different characteristics in patients with cirrhosis when compared to non-cirrhotic patients. Mastropasqua et al. [3] found a negative correlation between the number of hepatic hemangioma and the severity of liver disease. While hepatic hemangiomas are considered congenital lesions that do not demonstrate significant change over time [4], a decrease in lesion size with progression of liver disease has
http://dx.doi.org/10.1016/j.ejrad.2015.01.016 0720-048X/© 2015 Elsevier Ireland Ltd. All rights reserved.
Please cite this article in press as: Duran R, et al. Is magnetic resonance imaging of hepatic hemangioma any different in liver fibrosis and cirrhosis compared to normal liver? Eur J Radiol (2015), http://dx.doi.org/10.1016/j.ejrad.2015.01.016
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been reported [5]. Therefore these small lesions may potentially be difficult to differentiate from other hypervascular lesions such as hepatocellular carcinoma (HCC) [5,6]. The diagnostic of hepatic hemangioma relies on imaging characteristics that have been well documented at dynamic contrast material-enhanced computed tomography (CT) and magnetic resonance (MR) imaging, and are considered diagnostic when typical findings are present [6–8]. Typical hemangiomas show a strong hyperintensity on T2-weighted images together with a progressive centripetal filling at dynamic multiphase contrast-enhanced gradient-echo imaging. However, hepatic hemangioma may also display atypical features, such as rapid or delayed enhancement, making the diagnosis more difficult and uncertain [6,9–11]. Controversial data has been reported regarding the enhancement of hemangiomas in the setting of liver disease [3,12]. Recently, it has been shown that T2 shine-through effect was present in more than half of hepatic hemangiomas and was more frequent in lesions with typical features [13]. However, little is known about the diffusion-weighted (DW) MR imaging characteristics of hepatic hemangioma in chronic liver disease and cirrhosis. Overall, it is unclear how imaging characteristics of hepatic hemangiomas are affected by the presence of an underlying liver disease or cirrhosis. Therefore, the purpose of this study was to compare qualitative and quantitative imaging features of hepatic hemangiomas in patients with normal, fibrotic or cirrhotic liver. 2. Materials and methods This retrospective single-center study was conducted in a tertiary hospital for hepatobiliary and pancreatic diseases and was institutional review board approved with a waiver of informed consent. 2.1. Study population Radiologic records of patients who underwent MR imaging of the liver with a DW sequence in the setting of lesion characterization found on ultrasound or CT from January 2011 to July 2012 were reviewed. Patients who had at least one hepatic hemangioma measuring at least 5 mm in minimum diameter and follow-up imaging of at least 12 months were included. Pathological reports including biopsies for characterization of focal liver lesion and liver surgery (resection and transplant) were also reviewed. A total of 155 patients were identified. Thirty-two patients were excluded for the following reasons: hepatic hemangioma measuring less than 5 mm in diameter (n = 7), no DW sequences (n = 8), DW sequences with motion artifacts (n = 8), follow-up imaging of less than 12 months (n = 9), hemangioma on pathological specimen but without MR or DW imaging (n = 8). On the basis of these criteria, 115 patients were selected. The medical and pathological records of these patients were then thoroughly reviewed and patients were further classified in three groups: patients without underlying liver disease (group 1), patients with chronic liver disease (i.e. fibrosis without cirrhosis) (group 2) and patients with cirrhosis (group 3). In group 1, conditions that may have had a potential effect on liver parenchyma such as previous chemotherapy (n = 11), vascular liver disease (n = 2) or patients without known liver disease but who had morphologic changes of the liver on MR imaging (n = 10) or abnormal liver enzymes/function (n = 3) were excluded. Patients with liver steatosis on imaging as sole finding but without known hepatic disease or risk factors for hepatic disease, and with normal liver tests were deemed eligible. Thus, the final study population included a total of 89 patients with 231 hepatic hemangiomas (Fig. 1). Baseline patient characteristics are summarized in Table 1 (Supplementary material).
Fig. 1. Flowchart shows inclusion and exclusion criteria of the study group during the inclusion period. DWI = diffusion-weighted imaging, MRI = MR imaging, HH = hepatic hemangioma.
Aetiologies of chronic liver diseases (group 2) were hepatitis B (n = 6), hepatitis C (n = 7), excessive alcohol consumption (n = 1), nonalcoholic steatohepatitis (NASH) (n = 2), autoimmune hepatitis (n = 1), combined hepatitis B and D (n = 1), cardiac hepatopathy (n = 1). Chronic hepatitis was confirmed histologically in 8/19 patients (42.1%), whereas the diagnosis was made by a combination of clinical, biologically data (e.g. hepatitis test) and imaging (e.g. transient elastography) in 11/19 patients (57.9%). In histologically confirmed cases, the extent of fibrosis was graded using the METAVIR score [14]. The METAVIR score was assessed on a five points scale (0 = no fibrosis, 1 = portal fibrosis without septa, 2 = portal fibrosis with few septa, 3 = numerous septa without cirrhosis, 4 = cirrhosis). The activity score was graded according to the intensity of necrotic-inflammatory lesions (A0 = no activity, A1 = mild activity, A2 = moderate activity, A3 = severe activity). Two patients had a score of A1F1, 3 had a score of A1F2, 1 had a score of A1F3 and 2 of A2F3. Patients without histology had mean values of liver stiffness of 9.9 ± 2.1 kPa (normal values: 5.5 ± 1.6 kPa [15]). Aetiologies of cirrhosis (group 3) were hepatitis B (n = 3), hepatitis C (n = 3), excessive alcohol consumption (n = 6), NASH (n = 2), autoimmune hepatitis (n = 1), combined hepatitis B and D (n = 1), combined hepatitis C and excessive alcohol consumption (n = 1). Cirrhosis was confirmed in all patients by means of percutaneous core needle biopsy. 2.2. Reference standard Diagnoses of hemangiomas were established based on a combination of typical imaging features, follow-up and histological examination. On imaging, the diagnosis of hemangioma was established with a combination of the following findings [6–8]: well demarcated and strongly hyperintense on heavily T2-weighted images, and (a) peripheral globular discontinuous enhancement over time on contrast-enhanced dynamic MR images with progressive and centripetal enhancement; or (b) immediate homogeneous enhancement on the arterial phase and iso or hyperintensity compared with surrounding liver parenchyma at the equilibrium
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phase. In the absence of these features, histologic confirmation was required per institutional guidelines.
3. MR imaging Patients were examined with a 1.5-T imager (Intera, Philips Healthcare, Best, the Netherlands) with a maximum gradient strength of 40 mT/m and a slew rate of 200 mT/m/ms using a phased-array surface coil for signal reception. The protocol included a T2-weighted single-shot sequence, a T2weighted fast spin-echo sequence with spectral fat saturation, a T1-weighted dual fast gradient-recalled echo sequence, and a transverse breath-hold three-dimensional T1-weighted fatsuppressed spoiled gradient-recalled echo sequence before and after dynamic injection of .1 mmol/kg of body weight of gadolinium chelates, followed by a 20-mL saline solution flush at a rate of 2 mL/s administered with a power injector. Hepatic arterial-dominant, portal venous, and equilibrium phase sequences were performed 20–25 s, 60–70 s, and 180–200 s after intravenous contrast material injection, respectively. A centric linear k-space sampling was performed. A free-breathing fat-suppressed single-shot echoplanar DW MR sequence was performed before contrast material injection in the transverse plane with tridirectional (frequency encoding, phase-encoding and slice encoding) diffusion gradients to obtain images sensitive to diffusion. Gradient strengths corresponding to b values of 0, 150, and 600 s/mm2 were used with trace (average) image assessment. Fat suppression was implemented by the spectral presaturation with inversion recovery technique. Cardiac gating was not used. No antispasmodic drugs were administered. An ADC map was generated between T2 echoplanar images and the trace image by using the three-point method. The other parameters are summarized in Table 2 (Supplementary material).
4. Image analysis The images were evaluated by two radiologists (R.D. and M.R., with 5 and 7 years of experience in liver imaging, respectively) who were blind to pathological results and clinical data. All MR sequences were read in the same session and the MR characteristics of hemangiomas were determined in consensus.
4.1. Analysis of conventional non-enhanced images The number and size of hepatic hemangiomas were recorded for each patient. The signal intensity of all the hemangiomas was graded on T2- and T1-weighted images as isointense, hypointense or hyperintense in relation to the liver parenchyma. Lesions with high signal intensity on T2-weighted images were also compared to the spleen. Liver steatosis was defined as a decrease in signal intensity in the opposed-phase in comparison to the in-phase gradient echo T1-weighted MR sequence.
4.2. Analysis of contrast-enhanced images Hemangiomas were classified as follows: (i) classical if hemangioma showed early, peripheral, globular, and discontinuous enhancement with progressive centripetal and prolonged enhancement; (ii) rapidly filling if hemangioma showed immediate homogeneous enhancement at the arterial phase and iso or hyperintensity compared with surrounding liver parenchyma at the equilibrium phase [9,11]; (iii) delayed filling if hemangioma shows a lack of enhancement in the arterial phase with a slight peripheral globular enhancement starting in the later phases.
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4.3. Analysis of DW MR images The ADC value and signal intensity for each b value were recorded for each patient. Pixel-based ADC maps were obtained with a commercial workstation by using a monoexponential fit. The largest possible region of interest (ROI) was drawn for each tumor on the trace image in order to encompass as much as possible the lesion (mean surface, 2.3 cm2 ; range, .15–98.5 cm2 ). The ROIs were placed at a level of section on which the lesion had its largest diameter. The ROIs created on the trace images were copied and pasted onto the ADC map. The location of lesions that were not visualized on DW images was determined by using T2-weighted and/or contrast-enhanced T1-weighted images. Three ROIs of at least 1 cm2 (mean, 1.6 cm2 ; range, 1–3.1 cm2 ) were placed in the adjacent liver parenchyma in the same lobe as the lesion and ADC values were then averaged. ROI placement was carefully performed to avoid the liver periphery, the gallbladder, any adjacent main blood vessel and motion artifacts. The presence of T2 shine-through effect was investigated as follows. The signal intensity of the hemangiomas was analyzed on images with a b value of 0, 150, and 600 s/mm2 and the lesions were graded as isointense, hypointense, or hyperintense in relation to the liver parenchyma. T2 shine-through effect was deemed present when the lesion-to-liver contrast was similar or increased with a b value of 600 s/mm2 compared with a b value of 0 s/mm2 and absent if the lesion-to-liver contrast was decreased with a b value of 600 s/mm2 compared with a b value of 0 s/mm2 [16]. 4.4. Statistical analysis Number, size, signal intensities on T1-weighted, T2-weighted and DW images, enhancement patterns of hepatic hemangiomas, mean ADC values and presence of T2 shine-through effect were compared between the three groups. Continuous variables were tested by using the Kruskal–Wallis and Mann–Whitney U tests. Fisher’s exact and Chi-square tests were used in the analysis of contingency tables. Statistical analysis using the cluster mode was omitted in patients with multiple lesions, because it has been shown that hepatic hemangioma characteristics may differ in the same patient [17]. A P-value < .05 was considered statistically significant. Analyses were performed using the SPSS software (version 20.0) (SPSS Inc., Chicago IL). 5. Results A total of 226/231 hepatic hemangiomas (97.8%) were diagnosed using the combination of imaging features and follow-up described above. Five lesions (2.2%) appeared hypointense on T2-weighted images and required histological confirmation (4 lesions in group 1 and 1 lesion in group 3). The median follow-up of the study population was 14.4 months (range, 12–19 months). The median follow-up time of groups 1, 2 and 3 was 14.4 months (range, 12–19 months), 14 months (range, 12–19 months) and 15 months (range, 12–19 months), respectively (P = 0.58). All hepatic hemangiomas remained stable over time. 5.1. Conventional MR images Table 1 summarizes hepatic hemangioma characteristics. Overall, the mean number of lesion per patient was 3, 2.4 and 1.5, for groups 1, 2, and 3, respectively (P = 0.1). Patients with normal liver showed a trend toward a higher number of hepatic hemangiomas (group 1 vs. groups 2 and 3; P = .058). Lesions were significantly larger in patients with normal liver than in patients with fibrosis and/or cirrhosis (group 1 vs. groups 2 and 3; P = .009).
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Table 1 Qualitative MR features of hepatic hemangiomas according to the group of patients. Group 2 – fibrotic liver (N = 45
Group 3 – cirrhotic liver (N = 26)
10 (52.6) 4 (21.1) 1(5.3) 4 (21) 13 [5–36]
12 (70.5) 2 (11.8) 2 (11.8) 1 (5.9) 13 [5–24]
1 (0.6%) 6 (3.8%) 153 (95.6%)
0 (0%) 2 (4.4%) 43 (95.6%)
0 (0%) 0 (0%) 26 (100%)
1 (0.4%) 8 (3.5%) 222 (96.1%)
.82
3 (1.9%) 4 (2.5%) 153 (95.6%)
0 (0%) 1 (2.2%) 44 (97.8%)
1 (3.8%) 2 (7.7%) 23 (88.5%)
4 (1.8%) 7 (3%) 220 (95.2%)
.25
3 (1.9%) 157 (98.1%)
2 (4.5%) 43 (95.5%)
1 (3.8%) 25 (96.2%)
6 (2.6%) 119 (97.4%)
.58
11 (20.8%)
2 (10.5%)
1(5.9%)
14 (15.7%)
.62
112 (70%) 20 (12.5%) 28 (17.5%)
30 (66.7%) 4 (8.9%) 11 (24.4%)
15 (57.7%) 5 (19.2%) 6 (23.1%)
157 (68%) 29 (12.6%) 45 (19.4%)
.56
Group 1 – normal liver (N = 160) Number of lesions per patient 1 2 3 4 Size (mm) Fat-suppressed T2-weighted Isointense Hyperintensity relative to liver Hyperintensity relative to liver and spleen Single-shot T2-weighted Isointense Hyperintensity relative to liver Hyperintensity relative to liver and spleen In-phase gradient echo T1-weighted Isointense Low signal intensity relative to liver Opposed-phase gradient echo T1-weighted Decrease liver parenchyma signal intensity (steatosis) Enhancement pattern Classical hepatic hemangioma Rapidly filling hepatic hemangioma Delayed filling hepatic hemangioma
22 (41.5) 12 (22.6) 4 (7.6) 15 (28.3) 21.8 [5–137]
Total (N = 231)
44 (49.4) 18 (20.2) 7 (7.9) 20(22.5) 19.1 [5–137]
P-value
.38
.03
Note: Numbers in parentheses and in square brackets are percentages and ranges, respectively.
There was no statistical difference between the groups in term of signal intensity on fat-suppressed T2-weighted fast spin-echo (P = .82), on single-shot T2-weighted (P = .25) and on T1-weighted sequences (P = .58). No statistical difference was found when comparing enhancement patterns between the three groups (P = .56) or between patient without (group 1) and with (groups 2 and 3) liver disease (P = .5). 5.2. DW MR images The mean ADC values of liver parenchyma were significantly different between groups (P = .005), with higher values in patients of group 1 compared to group 2 (1.52 ± .32 × 10−3 mm2 /s vs. 1.39 ± .28 × 10−3 mm2 /s, P = .024) or group 3 (1.36 ± .2 × 10−3 mm2 /s, P = .006, respectively). No statistical difference was found when comparing mean ADC values of hepatic hemangiomas between groups 1, 2 and 3 (2.11 ± .52 × 10−3 mm2 /s, 2.1 ± .53 × 10−3 mm2 /s and 2.14 ± .44 × 10−3 mm2 /s, P = .87, respectively) and between group 1 vs. groups 2 and 3 (Fig. 2). The mean ADC value of all hemangiomas was significantly higher than that of the surrounding liver (P < .0001). The frequency of T2 shine-through was significantly different between the three groups (84/160 (52.5%), 27/45 (60%) and 7/26 (26.9%), in groups 1, 2, and 3 respectively; overall: P = .02, 1 vs. 2: P = .40, 1 vs. 3: P = 02, and 2 vs. 3: P = 01 (Fig. 3)). T2 shine-through effect was significantly more frequent in normal and fibrotic livers than in cirrhotic patients (P = .0117)(Fig. 4 and Fig. 5). In groups 1 and 2, mean ADC value of hemangiomas showing T2 shine-through effect was significantly lower than hemangiomas without T2 shine-through effect (1.93 ± .49 × 10−3 mm2 /s vs. 2.34 ± .46 × 10−3 mm2 /s, P < .0001, and 1.89 ± .44 × 10−3 mm2 /s vs. 2.44 ± .5 × 10−3 mm2 /s, P .0016, respectively). In group 3, mean ADC value of hemangiomas showing T2 shine-through effect showed a trend toward lower values compared to the lesions without (1.9 ± 0.28 × 10−3 mm2 /s vs. 2.25 ± 0.46 × 10−3 mm2 /s, P = .084).
Fig. 2. Box plots of ADC values of hepatic hemangiomas in the three groups. ADC values of hepatic hemangiomas (HH) were not significantly different between groups 1, 2 and 3 (P = .87). Median is shown as line across each box. Boxes stretch across interquartile range, from lower quartile to upper quartile. Whiskers show the smallest observation and the largest observation (range of values).
6. Discussion This study aimed to describe the qualitative and quantitative imaging features of hepatic hemangiomas in patients without and with chronic liver disease in a large population of patients.
Fig. 3. T2 shine-through effect according to the three groups. Interleaved bars graph shows the presence or absence of the T2 shine-through effect according to the three groups.
Please cite this article in press as: Duran R, et al. Is magnetic resonance imaging of hepatic hemangioma any different in liver fibrosis and cirrhosis compared to normal liver? Eur J Radiol (2015), http://dx.doi.org/10.1016/j.ejrad.2015.01.016
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Fig. 4. Hepatic hemangioma with classical enhancement pattern in a 63-year-old man with known history of alcohol abuse and related liver cirrhosis. (a) On fat-suppressed T2-weighted fast spin-echo and (b) single-shot T2-weighted MR sequences, the hepatic hemangioma (arrow) is hyperintense relative to surrounding liver and spleen. (c) On in-phase gradient-recalled echo T1-weighted MR sequence, the lesion appears hypointense (arrow). (d) On DW MR sequences, the lesion-to-liver contrast is decreased with a b = 600 s/mm2 compared with a b = 0 s/mm2 (arrows, absence of T2 shine-through effect). (e) ADC value of the hepatic hemangioma is 1.92 ± .09 × 10−3 mm2 /s (arrow). (f–i) On dynamic contrast-enhanced MR sequences, the hepatic hemangioma shows early, peripheral, globular, discontinuous and progressive centripetal enhancement (arrows).
We observed differences between patients with and without chronic liver disease. First, there was a trend toward fewer lesions in patients with fibrotic or cirrhotic livers. Second, there was a significant difference in the size of the lesions with larger lesions in patients with normal livers compared to fibrotic and cirrhotic livers, suggesting that the decrease in size and in number could start during fibrosis and before the onset of cirrhosis. This is consistent with previous reports in patients with cirrhosis. Mastropasqua et al. [3] found a significant correlation between the number of hepatic hemangiomas and the severity of liver disease with less lesions in patients with advanced liver disease. Brancatelli et al. [5] demonstrated progressive decrease in the size of hemangiomas over time in 17 cirrhotic patients. Dodd et al. [18] reported only nine hepatic hemangiomas among 508 explanted cirrhotic livers . Hemangiomas developed on chronic liver disease have shown frequent atypical features mainly related to more fibrotic content [18]. Moreover loss overtime of imaging characteristics of hemangiomas was demonstrated in cirrhotic livers in a series using mainly CT as a diagnostic imaging (all 17 patients underwent CT and only 4 had MR imaging) [5]. In the present study, the rate of typical appearing lesions was similar between the groups. The discrepancies between previous series and ours may be explained by different
reasons. First, we used MR imaging which has proven to be the imaging modality with the highest specificity and sensitivity in the diagnostic of hepatic hemangiomas [19]. Thus it is possible that imaging characteristics of hemangiomas may still be recognized on MR imaging while this may not be the case when using CT. Second, our series may be composed of patients with less advanced liver disease as for example none of our cirrhotic patients underwent liver transplantation. Third, a shorter follow-up in our series may also be potential explanation . Overall, if it remains unclear how changes in the hepatic structure as a result of hepatic fibrosis and cirrhosis may influence hepatic hemangiomas, it appears that these changes do not dramatically affect the inner structure of the lesions. This is also supported by the quantitative analysis showing no difference in the mean ADC of hepatic hemangiomas between patients with or without chronic liver disease. This might be explained by a lesser degree of structural alteration of the lesion compared to the progressive accumulation of fibrosis in the surrounding liver. The T2 shine-through effect was analyzed in a series of 149 patients with hemangiomas and it was found to be related to hemangioma characteristics [13]. The T2 shine-through effect was more common in classical and delayed filling hemangiomas
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Fig. 5. Hepatic hemangioma with classical enhancement pattern in a 67-year-old man with known history of alcohol abuse, metabolic syndrome and liver cirrhosis. (a) On fat-suppressed T2-weighted fast spin-echo and (b) single-shot T2-weighted MR sequences, the hepatic hemangioma (arrow) is hyperintense relative to surrounding liver and spleen. (c) On in-phase gradient-recalled echo T1-weighted MR sequence, the lesion appears hypointense (arrow). (d) On DW MR sequences, the lesion-to-liver contrast is similar at b = 600 s/mm2 compared with a b = 0 s/mm2 corresponding to T2 shine-through effect (arrows; hemangioma). There is another lesion which shows increasing lesion-to-liver contrast at b = 600 s/mm2 compared with a b = 0 s/mm2 (arrowheads), corresponding to a hepatocellular carcinoma (HCC) (e) ADC value of the hepatic hemangioma is 1.92 ± .19 × 10−3 mm2 /s (arrow) and of the HCC is 0.89 ± .18 × 10−3 mm2 /s (arrowhead). (f–i) On dynamic contrast-enhanced MR sequences, the hepatic hemangioma shows peripheral, globular, discontinuous and progressive centripetal enhancement (arrows).
than in rapid filling ones [13]. In our study, we have shown that the T2 shine-through effect in hemangiomas was also influenced by the underlying liver disease, being less frequent in lesions developed on cirrhosis. A potential explanation for this finding is that in cirrhotic livers, the ADC of the liver is lower and consequently, the liver appears brighter on high b value diffusion-weighted MR images decreasing therefore the lesion-toliver contrast. As persistent hyperintensity compared with liver parenchyma on high b values diffusion-weighted MR images is a criterion that suggest malignancy, this is an important finding to emphasize. Our study has several limitations. First, this study was a retrospective analysis. However, patients with hepatic hemangiomas were included in a consecutive manner limiting potential sampling bias. Second, histological analysis of the liver was not performed in the patients of group 1 and not in all the patients of group 2. However, after careful review of the medical charts none of the included patients of group 1 had a known history of any liver disease. Moreover, patients with any conditions that may have had an effect on the liver parenchyma such previous chemotherapy or any signs of potential liver damage were excluded. In group 2, fibrotic livers were diagnosed by validated non-invasive methods
such as serologic tests and imaging [20,21]. Third, characteristics of hemangiomas were determined in consensus and not in separate reading sessions. Fourth, hemangiomas in fibrotic/cirrhotic livers may undergo fibrotic changes and loose typical imaging characteristics. Thus, our inclusion criteria based on imaging could have missed some lesions. However, atypical lesions in the setting of chronic liver disease are systematically biopsied at our institution. Thus only few lesions, if any, might have been missed. Fifth, diffusion and perfusion were not separated using multiple b values and bi-exponentional fitting. Yet, we wanted to reflect the clinical practice by performing a visual assessment of DW images. Last, higher b values could have been used to mitigate the T2 shinethrough effect. However, the highest b value used in this study (600 s/mm2 ) reflects the current guidelines (500–750 s/mm2 ) in liver DW MR imaging [22,23]. In conclusion, qualitative and quantitative MR imaging features of hepatic hemangiomas were similar in patients with normal compared to fibrotic and cirrhotic livers. Smaller lesion size was observed with chronic liver disease and less T2 shine-through effect was seen in hemangiomas developed on cirrhosis, the latter being an important finding to highlight in these patients at risk of developing HCC.
Please cite this article in press as: Duran R, et al. Is magnetic resonance imaging of hepatic hemangioma any different in liver fibrosis and cirrhosis compared to normal liver? Eur J Radiol (2015), http://dx.doi.org/10.1016/j.ejrad.2015.01.016
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Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.ejrad. 2015.01.016. References [1] Ishak KG, Rabin L. Benign tumors of the liver. Med Clin North Am 1975;59(4):995–1013. [2] El-Serag HB, Kanwal F. Epidemiology of hepatocellular carcinoma in the United States: where are we? Where do we go? Hepatology 2014;60(5):1767–75. [3] Mastropasqua M, Kanematsu M, Leonardou P, Braga L, Woosley JT, Semelka RC. Cavernous hemangiomas in patients with chronic liver disease: MR imaging findings. Magn Reson Imaging 2004;22(1):15–8. [4] Gandolfi L, Leo P, Solmi L, Vitelli E, Verros G, Colecchia A. Natural history of hepatic haemangiomas: clinical and ultrasound study. Gut 1991;32(6):677–80. [5] Brancatelli G, Federle MP, Blachar A, Grazioli L. Hemangioma in the cirrhotic liver: diagnosis and natural history. Radiology 2001;219(1):69–74. [6] Kim T, Federle MP, Baron RL, Peterson MS, Kawamori Y. Discrimination of small hepatic hemangiomas from hypervascular malignant tumors smaller than 3 cm with three-phase helical CT. Radiology 2001;219(3):699–706. [7] Quinn SF, Benjamin GG. Hepatic cavernous hemangiomas: simple diagnostic sign with dynamic bolus CT. Radiology 1992;182(2):545–8. [8] Semelka RC, Brown ED, Ascher SM, Patt RH, Bagley AS, Li W, et al. Hepatic hemangiomas: a multi-institutional study of appearance on T2-weighted and serial gadolinium-enhanced gradient-echo MR images. Radiology 1994;192(2):401–6. [9] Hanafusa K, Ohashi I, Himeno Y, Suzuki S, Shibuya H. Hepatic hemangioma: findings with two-phase CT. Radiology 1995;196(2):465–9. [10] Leslie DF, Johnson CD, Johnson CM, Ilstrup DM, Harmsen WS. Distinction between cavernous hemangiomas of the liver and hepatic metastases on CT: value of contrast enhancement patterns. Am J Roentgenol 1995;164(3): 625–9.
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[11] Vilgrain V, Boulos L, Vullierme MP, Denys A, Terris B, Menu Y. Imaging of atypical hemangiomas of the liver with pathologic correlation. Radiographics 2000;20(2):379–97. [12] Yu JS, Kim KW, Park MS, Yoon SW. Hepatic cavernous hemangioma in cirrhotic liver: imaging findings. Korean J Radiol 2000;1(4):185–90. [13] Duran R, Ronot M, Kerbaol A, Van Beers B, Vilgrain V. Hepatic hemangiomas: factors associated with T2 shine-through effect on diffusion-weighted MR sequences. Eur J Radiol 2014;83(3):468–78. [14] Bedossa P, Poynard T. An algorithm for the grading of activity in chronic hepatitis C. The METAVIR Cooperative Study Group. Hepatology 1996;24(2): 289–93. [15] Roulot D, Czernichow S, Le Clesiau H, Costes JL, Vergnaud AC, Beaugrand M. Liver stiffness values in apparently healthy subjects: influence of gender and metabolic syndrome. J Hepatol 2008;48(4):606–13. [16] Duran R, Ronot M, Kerbaol A, Van Beers B, Vilgrain V. Hepatic hemangiomas: factors associated with T2 shine-through effect on diffusion-weighted MR sequences. Eur J Radiol 2013. [17] Yamashita Y, Ogata I, Urata J, Takahashi M. Cavernous hemangioma of the liver: pathologic correlation with dynamic CT findings. Radiology 1997;203(1):121–5. [18] Dodd 3rd GD, Baron RL, Oliver 3rd JH, Federle MP. Spectrum of imaging findings of the liver in end-stage cirrhosis: part II, focal abnormalities. Am J Roentgenol 1999;173(5):1185–92. [19] Whitney WS, Herfkens RJ, Jeffrey RB, McDonnell CH, Li KC, Van Dalsem WJ, et al. Dynamic breath-hold multiplanar spoiled gradient-recalled MR imaging with gadolinium enhancement for differentiating hepatic hemangiomas from malignancies at 1.5 T. Radiology 1993;189(3):863–70. [20] Bonekamp S, Kamel I, Solga S, Clark J. Can imaging modalities diagnose and stage hepatic fibrosis and cirrhosis accurately? J Hepatol 2009;50(1):17–35. [21] Martinez SM, Crespo G, Navasa M, Forns X. Noninvasive assessment of liver fibrosis. Hepatology 2011;53(1):325–35. [22] Padhani AR, Liu G, Koh DM, Chenevert TL, Thoeny HC, Takahara T, et al. Diffusion-weighted magnetic resonance imaging as a cancer biomarker: consensus and recommendations. Neoplasia 2009;11(2):102–25. [23] Taouli B, Koh DM. Diffusion-weighted MR imaging of the liver. Radiology 2010;254(1):47–66.
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Is magnetic resonance imaging of hepatic hemangioma any different in liver fibrosis and cirrhosis compared to normal liver? Rafael Duran a,b,∗ , Maxime Ronot b,c , Sara Di Renzo b , Bettina Gregoli b , Bernard E. Van Beers b , Valérie Vilgrain b,c a
Centre Hospitalier Universitaire Vaudois, University of Lausanne, Diagnostic and Interventional Radiology, Lausanne, Switzerland Assistance-Publique Hôpitaux de Paris, APHP, Hôpital Beaujon, Department of Radiology, Clichy, France c University Paris Diderot, Sorbonne Paris Cité, INSERM U773, Centre de Recherche Biomédicale Bichat-Beaujon, CRB3 Paris, France b
a r t i c l e
i n f o
Article history: Received 27 November 2014 Received in revised form 16 January 2015 Accepted 19 January 2015 Keywords: Hemangioma Cirrhosis Chronic liver disease Diffusion magnetic resonance imaging MRI Benign liver lesion
a b s t r a c t Purpose: To compare qualitative and quantitative magnetic resonance (MR) imaging characteristics of hepatic hemangiomas in patients with normal, fibrotic and cirrhotic livers. Materials and methods: Retrospective, institutional review board approved study (waiver of informed consent). Eighty-nine consecutive patients with 231 hepatic hemangiomas who underwent liver MR imaging for lesion characterization were included. Lesions were classified into three groups according to the patients’ liver condition: no underlying liver disease (group 1), fibrosis (group 2) and cirrhosis (group 3). Qualitative and quantitative characteristics (number, size, signal intensities on T1-, T2-, and DW MR images, T2 shine-through effect, enhancement patterns (classical, rapidly filling, delayed filling), and ADC values) were compared. Results: There were 160 (69%), 45 (20%), and 26 (11%) hemangiomas in groups 1, 2 and 3, respectively. Lesions were larger in patients with normal liver (group 1 vs. groups 2 and 3; P = .009). No difference was found between the groups on T2-weighted images (fat-suppressed fast spin-echo (P = .82) and single-shot (P = .25)) and in enhancement patterns (P = .56). Mean ADC values of hemangiomas were similar between groups 1, 2 and 3 (2.11 ± .52 × 10−3 mm2 /s, 2.1 ± .53 × 10−3 mm2 /s and 2.14 ± .44 × 10−3 mm2 /s, P = 87, respectively). T2 shine-through effect was less frequently observed in cirrhosis (P = .02). Conclusion: MR imaging characteristics of hepatic hemangioma were similar in patients with normal compared to fibrotic and cirrhotic livers. Smaller lesion size was observed with liver disease and less T2 shine-through effect was seen in hemangiomas developed on cirrhosis, the latter being an important finding to highlight in these patients at risk of developing hepatocellular carcinoma. © 2015 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Hepatic hemangioma is the most common benign liver lesion [1]. Differentiation between hepatic hemangiomas and other liver
Abbreviations: DW, diffusion-weighted; MR, magnetic resonance; ADC, apparent diffusion coefficient; CT, computed tomography; NASH, nonalcoholic steatohepatitis; HCC, hepatocellular carcinoma; ROI, region of interest. ∗ Corresponding author at: University Hospital of Lausanne (CHUV), Department of Diagnostic and Interventional Radiology, BH 10-121, Rue du Bugnon 46, 1011 Lausanne, Switzerland. Tel.: +41 213144444. E-mail addresses: [email protected] (R. Duran), [email protected] (M. Ronot), [email protected] (S. Di Renzo), [email protected] (B. Gregoli), [email protected] (B.E. Van Beers), [email protected] (V. Vilgrain).
lesions is a frequent clinically relevant situation. Precise focal liver lesion characterization is mandatory, particularly in patients with chronic liver disease and cirrhosis who have a much greater risk of developing primary liver malignancy [2]. Unfortunately, tumor characterization may be hampered by the distortion of the hepatic parenchyma due to the fibrotic process. Thus, a thorough understanding of imaging features of hepatic hemangiomas in fibrotic and/or cirrhotic livers is essential. Hemangiomas have been shown to present different characteristics in patients with cirrhosis when compared to non-cirrhotic patients. Mastropasqua et al. [3] found a negative correlation between the number of hepatic hemangioma and the severity of liver disease. While hepatic hemangiomas are considered congenital lesions that do not demonstrate significant change over time [4], a decrease in lesion size with progression of liver disease has
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been reported [5]. Therefore these small lesions may potentially be difficult to differentiate from other hypervascular lesions such as hepatocellular carcinoma (HCC) [5,6]. The diagnostic of hepatic hemangioma relies on imaging characteristics that have been well documented at dynamic contrast material-enhanced computed tomography (CT) and magnetic resonance (MR) imaging, and are considered diagnostic when typical findings are present [6–8]. Typical hemangiomas show a strong hyperintensity on T2-weighted images together with a progressive centripetal filling at dynamic multiphase contrast-enhanced gradient-echo imaging. However, hepatic hemangioma may also display atypical features, such as rapid or delayed enhancement, making the diagnosis more difficult and uncertain [6,9–11]. Controversial data has been reported regarding the enhancement of hemangiomas in the setting of liver disease [3,12]. Recently, it has been shown that T2 shine-through effect was present in more than half of hepatic hemangiomas and was more frequent in lesions with typical features [13]. However, little is known about the diffusion-weighted (DW) MR imaging characteristics of hepatic hemangioma in chronic liver disease and cirrhosis. Overall, it is unclear how imaging characteristics of hepatic hemangiomas are affected by the presence of an underlying liver disease or cirrhosis. Therefore, the purpose of this study was to compare qualitative and quantitative imaging features of hepatic hemangiomas in patients with normal, fibrotic or cirrhotic liver. 2. Materials and methods This retrospective single-center study was conducted in a tertiary hospital for hepatobiliary and pancreatic diseases and was institutional review board approved with a waiver of informed consent. 2.1. Study population Radiologic records of patients who underwent MR imaging of the liver with a DW sequence in the setting of lesion characterization found on ultrasound or CT from January 2011 to July 2012 were reviewed. Patients who had at least one hepatic hemangioma measuring at least 5 mm in minimum diameter and follow-up imaging of at least 12 months were included. Pathological reports including biopsies for characterization of focal liver lesion and liver surgery (resection and transplant) were also reviewed. A total of 155 patients were identified. Thirty-two patients were excluded for the following reasons: hepatic hemangioma measuring less than 5 mm in diameter (n = 7), no DW sequences (n = 8), DW sequences with motion artifacts (n = 8), follow-up imaging of less than 12 months (n = 9), hemangioma on pathological specimen but without MR or DW imaging (n = 8). On the basis of these criteria, 115 patients were selected. The medical and pathological records of these patients were then thoroughly reviewed and patients were further classified in three groups: patients without underlying liver disease (group 1), patients with chronic liver disease (i.e. fibrosis without cirrhosis) (group 2) and patients with cirrhosis (group 3). In group 1, conditions that may have had a potential effect on liver parenchyma such as previous chemotherapy (n = 11), vascular liver disease (n = 2) or patients without known liver disease but who had morphologic changes of the liver on MR imaging (n = 10) or abnormal liver enzymes/function (n = 3) were excluded. Patients with liver steatosis on imaging as sole finding but without known hepatic disease or risk factors for hepatic disease, and with normal liver tests were deemed eligible. Thus, the final study population included a total of 89 patients with 231 hepatic hemangiomas (Fig. 1). Baseline patient characteristics are summarized in Table 1 (Supplementary material).
Fig. 1. Flowchart shows inclusion and exclusion criteria of the study group during the inclusion period. DWI = diffusion-weighted imaging, MRI = MR imaging, HH = hepatic hemangioma.
Aetiologies of chronic liver diseases (group 2) were hepatitis B (n = 6), hepatitis C (n = 7), excessive alcohol consumption (n = 1), nonalcoholic steatohepatitis (NASH) (n = 2), autoimmune hepatitis (n = 1), combined hepatitis B and D (n = 1), cardiac hepatopathy (n = 1). Chronic hepatitis was confirmed histologically in 8/19 patients (42.1%), whereas the diagnosis was made by a combination of clinical, biologically data (e.g. hepatitis test) and imaging (e.g. transient elastography) in 11/19 patients (57.9%). In histologically confirmed cases, the extent of fibrosis was graded using the METAVIR score [14]. The METAVIR score was assessed on a five points scale (0 = no fibrosis, 1 = portal fibrosis without septa, 2 = portal fibrosis with few septa, 3 = numerous septa without cirrhosis, 4 = cirrhosis). The activity score was graded according to the intensity of necrotic-inflammatory lesions (A0 = no activity, A1 = mild activity, A2 = moderate activity, A3 = severe activity). Two patients had a score of A1F1, 3 had a score of A1F2, 1 had a score of A1F3 and 2 of A2F3. Patients without histology had mean values of liver stiffness of 9.9 ± 2.1 kPa (normal values: 5.5 ± 1.6 kPa [15]). Aetiologies of cirrhosis (group 3) were hepatitis B (n = 3), hepatitis C (n = 3), excessive alcohol consumption (n = 6), NASH (n = 2), autoimmune hepatitis (n = 1), combined hepatitis B and D (n = 1), combined hepatitis C and excessive alcohol consumption (n = 1). Cirrhosis was confirmed in all patients by means of percutaneous core needle biopsy. 2.2. Reference standard Diagnoses of hemangiomas were established based on a combination of typical imaging features, follow-up and histological examination. On imaging, the diagnosis of hemangioma was established with a combination of the following findings [6–8]: well demarcated and strongly hyperintense on heavily T2-weighted images, and (a) peripheral globular discontinuous enhancement over time on contrast-enhanced dynamic MR images with progressive and centripetal enhancement; or (b) immediate homogeneous enhancement on the arterial phase and iso or hyperintensity compared with surrounding liver parenchyma at the equilibrium
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phase. In the absence of these features, histologic confirmation was required per institutional guidelines.
3. MR imaging Patients were examined with a 1.5-T imager (Intera, Philips Healthcare, Best, the Netherlands) with a maximum gradient strength of 40 mT/m and a slew rate of 200 mT/m/ms using a phased-array surface coil for signal reception. The protocol included a T2-weighted single-shot sequence, a T2weighted fast spin-echo sequence with spectral fat saturation, a T1-weighted dual fast gradient-recalled echo sequence, and a transverse breath-hold three-dimensional T1-weighted fatsuppressed spoiled gradient-recalled echo sequence before and after dynamic injection of .1 mmol/kg of body weight of gadolinium chelates, followed by a 20-mL saline solution flush at a rate of 2 mL/s administered with a power injector. Hepatic arterial-dominant, portal venous, and equilibrium phase sequences were performed 20–25 s, 60–70 s, and 180–200 s after intravenous contrast material injection, respectively. A centric linear k-space sampling was performed. A free-breathing fat-suppressed single-shot echoplanar DW MR sequence was performed before contrast material injection in the transverse plane with tridirectional (frequency encoding, phase-encoding and slice encoding) diffusion gradients to obtain images sensitive to diffusion. Gradient strengths corresponding to b values of 0, 150, and 600 s/mm2 were used with trace (average) image assessment. Fat suppression was implemented by the spectral presaturation with inversion recovery technique. Cardiac gating was not used. No antispasmodic drugs were administered. An ADC map was generated between T2 echoplanar images and the trace image by using the three-point method. The other parameters are summarized in Table 2 (Supplementary material).
4. Image analysis The images were evaluated by two radiologists (R.D. and M.R., with 5 and 7 years of experience in liver imaging, respectively) who were blind to pathological results and clinical data. All MR sequences were read in the same session and the MR characteristics of hemangiomas were determined in consensus.
4.1. Analysis of conventional non-enhanced images The number and size of hepatic hemangiomas were recorded for each patient. The signal intensity of all the hemangiomas was graded on T2- and T1-weighted images as isointense, hypointense or hyperintense in relation to the liver parenchyma. Lesions with high signal intensity on T2-weighted images were also compared to the spleen. Liver steatosis was defined as a decrease in signal intensity in the opposed-phase in comparison to the in-phase gradient echo T1-weighted MR sequence.
4.2. Analysis of contrast-enhanced images Hemangiomas were classified as follows: (i) classical if hemangioma showed early, peripheral, globular, and discontinuous enhancement with progressive centripetal and prolonged enhancement; (ii) rapidly filling if hemangioma showed immediate homogeneous enhancement at the arterial phase and iso or hyperintensity compared with surrounding liver parenchyma at the equilibrium phase [9,11]; (iii) delayed filling if hemangioma shows a lack of enhancement in the arterial phase with a slight peripheral globular enhancement starting in the later phases.
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4.3. Analysis of DW MR images The ADC value and signal intensity for each b value were recorded for each patient. Pixel-based ADC maps were obtained with a commercial workstation by using a monoexponential fit. The largest possible region of interest (ROI) was drawn for each tumor on the trace image in order to encompass as much as possible the lesion (mean surface, 2.3 cm2 ; range, .15–98.5 cm2 ). The ROIs were placed at a level of section on which the lesion had its largest diameter. The ROIs created on the trace images were copied and pasted onto the ADC map. The location of lesions that were not visualized on DW images was determined by using T2-weighted and/or contrast-enhanced T1-weighted images. Three ROIs of at least 1 cm2 (mean, 1.6 cm2 ; range, 1–3.1 cm2 ) were placed in the adjacent liver parenchyma in the same lobe as the lesion and ADC values were then averaged. ROI placement was carefully performed to avoid the liver periphery, the gallbladder, any adjacent main blood vessel and motion artifacts. The presence of T2 shine-through effect was investigated as follows. The signal intensity of the hemangiomas was analyzed on images with a b value of 0, 150, and 600 s/mm2 and the lesions were graded as isointense, hypointense, or hyperintense in relation to the liver parenchyma. T2 shine-through effect was deemed present when the lesion-to-liver contrast was similar or increased with a b value of 600 s/mm2 compared with a b value of 0 s/mm2 and absent if the lesion-to-liver contrast was decreased with a b value of 600 s/mm2 compared with a b value of 0 s/mm2 [16]. 4.4. Statistical analysis Number, size, signal intensities on T1-weighted, T2-weighted and DW images, enhancement patterns of hepatic hemangiomas, mean ADC values and presence of T2 shine-through effect were compared between the three groups. Continuous variables were tested by using the Kruskal–Wallis and Mann–Whitney U tests. Fisher’s exact and Chi-square tests were used in the analysis of contingency tables. Statistical analysis using the cluster mode was omitted in patients with multiple lesions, because it has been shown that hepatic hemangioma characteristics may differ in the same patient [17]. A P-value < .05 was considered statistically significant. Analyses were performed using the SPSS software (version 20.0) (SPSS Inc., Chicago IL). 5. Results A total of 226/231 hepatic hemangiomas (97.8%) were diagnosed using the combination of imaging features and follow-up described above. Five lesions (2.2%) appeared hypointense on T2-weighted images and required histological confirmation (4 lesions in group 1 and 1 lesion in group 3). The median follow-up of the study population was 14.4 months (range, 12–19 months). The median follow-up time of groups 1, 2 and 3 was 14.4 months (range, 12–19 months), 14 months (range, 12–19 months) and 15 months (range, 12–19 months), respectively (P = 0.58). All hepatic hemangiomas remained stable over time. 5.1. Conventional MR images Table 1 summarizes hepatic hemangioma characteristics. Overall, the mean number of lesion per patient was 3, 2.4 and 1.5, for groups 1, 2, and 3, respectively (P = 0.1). Patients with normal liver showed a trend toward a higher number of hepatic hemangiomas (group 1 vs. groups 2 and 3; P = .058). Lesions were significantly larger in patients with normal liver than in patients with fibrosis and/or cirrhosis (group 1 vs. groups 2 and 3; P = .009).
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Table 1 Qualitative MR features of hepatic hemangiomas according to the group of patients. Group 2 – fibrotic liver (N = 45
Group 3 – cirrhotic liver (N = 26)
10 (52.6) 4 (21.1) 1(5.3) 4 (21) 13 [5–36]
12 (70.5) 2 (11.8) 2 (11.8) 1 (5.9) 13 [5–24]
1 (0.6%) 6 (3.8%) 153 (95.6%)
0 (0%) 2 (4.4%) 43 (95.6%)
0 (0%) 0 (0%) 26 (100%)
1 (0.4%) 8 (3.5%) 222 (96.1%)
.82
3 (1.9%) 4 (2.5%) 153 (95.6%)
0 (0%) 1 (2.2%) 44 (97.8%)
1 (3.8%) 2 (7.7%) 23 (88.5%)
4 (1.8%) 7 (3%) 220 (95.2%)
.25
3 (1.9%) 157 (98.1%)
2 (4.5%) 43 (95.5%)
1 (3.8%) 25 (96.2%)
6 (2.6%) 119 (97.4%)
.58
11 (20.8%)
2 (10.5%)
1(5.9%)
14 (15.7%)
.62
112 (70%) 20 (12.5%) 28 (17.5%)
30 (66.7%) 4 (8.9%) 11 (24.4%)
15 (57.7%) 5 (19.2%) 6 (23.1%)
157 (68%) 29 (12.6%) 45 (19.4%)
.56
Group 1 – normal liver (N = 160) Number of lesions per patient 1 2 3 4 Size (mm) Fat-suppressed T2-weighted Isointense Hyperintensity relative to liver Hyperintensity relative to liver and spleen Single-shot T2-weighted Isointense Hyperintensity relative to liver Hyperintensity relative to liver and spleen In-phase gradient echo T1-weighted Isointense Low signal intensity relative to liver Opposed-phase gradient echo T1-weighted Decrease liver parenchyma signal intensity (steatosis) Enhancement pattern Classical hepatic hemangioma Rapidly filling hepatic hemangioma Delayed filling hepatic hemangioma
22 (41.5) 12 (22.6) 4 (7.6) 15 (28.3) 21.8 [5–137]
Total (N = 231)
44 (49.4) 18 (20.2) 7 (7.9) 20(22.5) 19.1 [5–137]
P-value
.38
.03
Note: Numbers in parentheses and in square brackets are percentages and ranges, respectively.
There was no statistical difference between the groups in term of signal intensity on fat-suppressed T2-weighted fast spin-echo (P = .82), on single-shot T2-weighted (P = .25) and on T1-weighted sequences (P = .58). No statistical difference was found when comparing enhancement patterns between the three groups (P = .56) or between patient without (group 1) and with (groups 2 and 3) liver disease (P = .5). 5.2. DW MR images The mean ADC values of liver parenchyma were significantly different between groups (P = .005), with higher values in patients of group 1 compared to group 2 (1.52 ± .32 × 10−3 mm2 /s vs. 1.39 ± .28 × 10−3 mm2 /s, P = .024) or group 3 (1.36 ± .2 × 10−3 mm2 /s, P = .006, respectively). No statistical difference was found when comparing mean ADC values of hepatic hemangiomas between groups 1, 2 and 3 (2.11 ± .52 × 10−3 mm2 /s, 2.1 ± .53 × 10−3 mm2 /s and 2.14 ± .44 × 10−3 mm2 /s, P = .87, respectively) and between group 1 vs. groups 2 and 3 (Fig. 2). The mean ADC value of all hemangiomas was significantly higher than that of the surrounding liver (P < .0001). The frequency of T2 shine-through was significantly different between the three groups (84/160 (52.5%), 27/45 (60%) and 7/26 (26.9%), in groups 1, 2, and 3 respectively; overall: P = .02, 1 vs. 2: P = .40, 1 vs. 3: P = 02, and 2 vs. 3: P = 01 (Fig. 3)). T2 shine-through effect was significantly more frequent in normal and fibrotic livers than in cirrhotic patients (P = .0117)(Fig. 4 and Fig. 5). In groups 1 and 2, mean ADC value of hemangiomas showing T2 shine-through effect was significantly lower than hemangiomas without T2 shine-through effect (1.93 ± .49 × 10−3 mm2 /s vs. 2.34 ± .46 × 10−3 mm2 /s, P < .0001, and 1.89 ± .44 × 10−3 mm2 /s vs. 2.44 ± .5 × 10−3 mm2 /s, P .0016, respectively). In group 3, mean ADC value of hemangiomas showing T2 shine-through effect showed a trend toward lower values compared to the lesions without (1.9 ± 0.28 × 10−3 mm2 /s vs. 2.25 ± 0.46 × 10−3 mm2 /s, P = .084).
Fig. 2. Box plots of ADC values of hepatic hemangiomas in the three groups. ADC values of hepatic hemangiomas (HH) were not significantly different between groups 1, 2 and 3 (P = .87). Median is shown as line across each box. Boxes stretch across interquartile range, from lower quartile to upper quartile. Whiskers show the smallest observation and the largest observation (range of values).
6. Discussion This study aimed to describe the qualitative and quantitative imaging features of hepatic hemangiomas in patients without and with chronic liver disease in a large population of patients.
Fig. 3. T2 shine-through effect according to the three groups. Interleaved bars graph shows the presence or absence of the T2 shine-through effect according to the three groups.
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Fig. 4. Hepatic hemangioma with classical enhancement pattern in a 63-year-old man with known history of alcohol abuse and related liver cirrhosis. (a) On fat-suppressed T2-weighted fast spin-echo and (b) single-shot T2-weighted MR sequences, the hepatic hemangioma (arrow) is hyperintense relative to surrounding liver and spleen. (c) On in-phase gradient-recalled echo T1-weighted MR sequence, the lesion appears hypointense (arrow). (d) On DW MR sequences, the lesion-to-liver contrast is decreased with a b = 600 s/mm2 compared with a b = 0 s/mm2 (arrows, absence of T2 shine-through effect). (e) ADC value of the hepatic hemangioma is 1.92 ± .09 × 10−3 mm2 /s (arrow). (f–i) On dynamic contrast-enhanced MR sequences, the hepatic hemangioma shows early, peripheral, globular, discontinuous and progressive centripetal enhancement (arrows).
We observed differences between patients with and without chronic liver disease. First, there was a trend toward fewer lesions in patients with fibrotic or cirrhotic livers. Second, there was a significant difference in the size of the lesions with larger lesions in patients with normal livers compared to fibrotic and cirrhotic livers, suggesting that the decrease in size and in number could start during fibrosis and before the onset of cirrhosis. This is consistent with previous reports in patients with cirrhosis. Mastropasqua et al. [3] found a significant correlation between the number of hepatic hemangiomas and the severity of liver disease with less lesions in patients with advanced liver disease. Brancatelli et al. [5] demonstrated progressive decrease in the size of hemangiomas over time in 17 cirrhotic patients. Dodd et al. [18] reported only nine hepatic hemangiomas among 508 explanted cirrhotic livers . Hemangiomas developed on chronic liver disease have shown frequent atypical features mainly related to more fibrotic content [18]. Moreover loss overtime of imaging characteristics of hemangiomas was demonstrated in cirrhotic livers in a series using mainly CT as a diagnostic imaging (all 17 patients underwent CT and only 4 had MR imaging) [5]. In the present study, the rate of typical appearing lesions was similar between the groups. The discrepancies between previous series and ours may be explained by different
reasons. First, we used MR imaging which has proven to be the imaging modality with the highest specificity and sensitivity in the diagnostic of hepatic hemangiomas [19]. Thus it is possible that imaging characteristics of hemangiomas may still be recognized on MR imaging while this may not be the case when using CT. Second, our series may be composed of patients with less advanced liver disease as for example none of our cirrhotic patients underwent liver transplantation. Third, a shorter follow-up in our series may also be potential explanation . Overall, if it remains unclear how changes in the hepatic structure as a result of hepatic fibrosis and cirrhosis may influence hepatic hemangiomas, it appears that these changes do not dramatically affect the inner structure of the lesions. This is also supported by the quantitative analysis showing no difference in the mean ADC of hepatic hemangiomas between patients with or without chronic liver disease. This might be explained by a lesser degree of structural alteration of the lesion compared to the progressive accumulation of fibrosis in the surrounding liver. The T2 shine-through effect was analyzed in a series of 149 patients with hemangiomas and it was found to be related to hemangioma characteristics [13]. The T2 shine-through effect was more common in classical and delayed filling hemangiomas
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Fig. 5. Hepatic hemangioma with classical enhancement pattern in a 67-year-old man with known history of alcohol abuse, metabolic syndrome and liver cirrhosis. (a) On fat-suppressed T2-weighted fast spin-echo and (b) single-shot T2-weighted MR sequences, the hepatic hemangioma (arrow) is hyperintense relative to surrounding liver and spleen. (c) On in-phase gradient-recalled echo T1-weighted MR sequence, the lesion appears hypointense (arrow). (d) On DW MR sequences, the lesion-to-liver contrast is similar at b = 600 s/mm2 compared with a b = 0 s/mm2 corresponding to T2 shine-through effect (arrows; hemangioma). There is another lesion which shows increasing lesion-to-liver contrast at b = 600 s/mm2 compared with a b = 0 s/mm2 (arrowheads), corresponding to a hepatocellular carcinoma (HCC) (e) ADC value of the hepatic hemangioma is 1.92 ± .19 × 10−3 mm2 /s (arrow) and of the HCC is 0.89 ± .18 × 10−3 mm2 /s (arrowhead). (f–i) On dynamic contrast-enhanced MR sequences, the hepatic hemangioma shows peripheral, globular, discontinuous and progressive centripetal enhancement (arrows).
than in rapid filling ones [13]. In our study, we have shown that the T2 shine-through effect in hemangiomas was also influenced by the underlying liver disease, being less frequent in lesions developed on cirrhosis. A potential explanation for this finding is that in cirrhotic livers, the ADC of the liver is lower and consequently, the liver appears brighter on high b value diffusion-weighted MR images decreasing therefore the lesion-toliver contrast. As persistent hyperintensity compared with liver parenchyma on high b values diffusion-weighted MR images is a criterion that suggest malignancy, this is an important finding to emphasize. Our study has several limitations. First, this study was a retrospective analysis. However, patients with hepatic hemangiomas were included in a consecutive manner limiting potential sampling bias. Second, histological analysis of the liver was not performed in the patients of group 1 and not in all the patients of group 2. However, after careful review of the medical charts none of the included patients of group 1 had a known history of any liver disease. Moreover, patients with any conditions that may have had an effect on the liver parenchyma such previous chemotherapy or any signs of potential liver damage were excluded. In group 2, fibrotic livers were diagnosed by validated non-invasive methods
such as serologic tests and imaging [20,21]. Third, characteristics of hemangiomas were determined in consensus and not in separate reading sessions. Fourth, hemangiomas in fibrotic/cirrhotic livers may undergo fibrotic changes and loose typical imaging characteristics. Thus, our inclusion criteria based on imaging could have missed some lesions. However, atypical lesions in the setting of chronic liver disease are systematically biopsied at our institution. Thus only few lesions, if any, might have been missed. Fifth, diffusion and perfusion were not separated using multiple b values and bi-exponentional fitting. Yet, we wanted to reflect the clinical practice by performing a visual assessment of DW images. Last, higher b values could have been used to mitigate the T2 shinethrough effect. However, the highest b value used in this study (600 s/mm2 ) reflects the current guidelines (500–750 s/mm2 ) in liver DW MR imaging [22,23]. In conclusion, qualitative and quantitative MR imaging features of hepatic hemangiomas were similar in patients with normal compared to fibrotic and cirrhotic livers. Smaller lesion size was observed with chronic liver disease and less T2 shine-through effect was seen in hemangiomas developed on cirrhosis, the latter being an important finding to highlight in these patients at risk of developing HCC.
Please cite this article in press as: Duran R, et al. Is magnetic resonance imaging of hepatic hemangioma any different in liver fibrosis and cirrhosis compared to normal liver? Eur J Radiol (2015), http://dx.doi.org/10.1016/j.ejrad.2015.01.016
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ARTICLE IN PRESS R. Duran et al. / European Journal of Radiology xxx (2015) xxx–xxx
Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.ejrad. 2015.01.016. References [1] Ishak KG, Rabin L. Benign tumors of the liver. Med Clin North Am 1975;59(4):995–1013. [2] El-Serag HB, Kanwal F. Epidemiology of hepatocellular carcinoma in the United States: where are we? Where do we go? Hepatology 2014;60(5):1767–75. [3] Mastropasqua M, Kanematsu M, Leonardou P, Braga L, Woosley JT, Semelka RC. Cavernous hemangiomas in patients with chronic liver disease: MR imaging findings. Magn Reson Imaging 2004;22(1):15–8. [4] Gandolfi L, Leo P, Solmi L, Vitelli E, Verros G, Colecchia A. Natural history of hepatic haemangiomas: clinical and ultrasound study. Gut 1991;32(6):677–80. [5] Brancatelli G, Federle MP, Blachar A, Grazioli L. Hemangioma in the cirrhotic liver: diagnosis and natural history. Radiology 2001;219(1):69–74. [6] Kim T, Federle MP, Baron RL, Peterson MS, Kawamori Y. Discrimination of small hepatic hemangiomas from hypervascular malignant tumors smaller than 3 cm with three-phase helical CT. Radiology 2001;219(3):699–706. [7] Quinn SF, Benjamin GG. Hepatic cavernous hemangiomas: simple diagnostic sign with dynamic bolus CT. Radiology 1992;182(2):545–8. [8] Semelka RC, Brown ED, Ascher SM, Patt RH, Bagley AS, Li W, et al. Hepatic hemangiomas: a multi-institutional study of appearance on T2-weighted and serial gadolinium-enhanced gradient-echo MR images. Radiology 1994;192(2):401–6. [9] Hanafusa K, Ohashi I, Himeno Y, Suzuki S, Shibuya H. Hepatic hemangioma: findings with two-phase CT. Radiology 1995;196(2):465–9. [10] Leslie DF, Johnson CD, Johnson CM, Ilstrup DM, Harmsen WS. Distinction between cavernous hemangiomas of the liver and hepatic metastases on CT: value of contrast enhancement patterns. Am J Roentgenol 1995;164(3): 625–9.
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[11] Vilgrain V, Boulos L, Vullierme MP, Denys A, Terris B, Menu Y. Imaging of atypical hemangiomas of the liver with pathologic correlation. Radiographics 2000;20(2):379–97. [12] Yu JS, Kim KW, Park MS, Yoon SW. Hepatic cavernous hemangioma in cirrhotic liver: imaging findings. Korean J Radiol 2000;1(4):185–90. [13] Duran R, Ronot M, Kerbaol A, Van Beers B, Vilgrain V. Hepatic hemangiomas: factors associated with T2 shine-through effect on diffusion-weighted MR sequences. Eur J Radiol 2014;83(3):468–78. [14] Bedossa P, Poynard T. An algorithm for the grading of activity in chronic hepatitis C. The METAVIR Cooperative Study Group. Hepatology 1996;24(2): 289–93. [15] Roulot D, Czernichow S, Le Clesiau H, Costes JL, Vergnaud AC, Beaugrand M. Liver stiffness values in apparently healthy subjects: influence of gender and metabolic syndrome. J Hepatol 2008;48(4):606–13. [16] Duran R, Ronot M, Kerbaol A, Van Beers B, Vilgrain V. Hepatic hemangiomas: factors associated with T2 shine-through effect on diffusion-weighted MR sequences. Eur J Radiol 2013. [17] Yamashita Y, Ogata I, Urata J, Takahashi M. Cavernous hemangioma of the liver: pathologic correlation with dynamic CT findings. Radiology 1997;203(1):121–5. [18] Dodd 3rd GD, Baron RL, Oliver 3rd JH, Federle MP. Spectrum of imaging findings of the liver in end-stage cirrhosis: part II, focal abnormalities. Am J Roentgenol 1999;173(5):1185–92. [19] Whitney WS, Herfkens RJ, Jeffrey RB, McDonnell CH, Li KC, Van Dalsem WJ, et al. Dynamic breath-hold multiplanar spoiled gradient-recalled MR imaging with gadolinium enhancement for differentiating hepatic hemangiomas from malignancies at 1.5 T. Radiology 1993;189(3):863–70. [20] Bonekamp S, Kamel I, Solga S, Clark J. Can imaging modalities diagnose and stage hepatic fibrosis and cirrhosis accurately? J Hepatol 2009;50(1):17–35. [21] Martinez SM, Crespo G, Navasa M, Forns X. Noninvasive assessment of liver fibrosis. Hepatology 2011;53(1):325–35. [22] Padhani AR, Liu G, Koh DM, Chenevert TL, Thoeny HC, Takahara T, et al. Diffusion-weighted magnetic resonance imaging as a cancer biomarker: consensus and recommendations. Neoplasia 2009;11(2):102–25. [23] Taouli B, Koh DM. Diffusion-weighted MR imaging of the liver. Radiology 2010;254(1):47–66.
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