with the rapid development of magnetic resonance imaging ( mri ) technology such as improved mri gradient performance , multichannel surface receiver coils , and parallel imaging techniques , functional mri technology has brought revolutionary progress in the diagnosis and study of diseases .
diffusion - weight imaging ( dwi ) can reflect the pathological and physiological information of the lesion on the basis of the microscopic mobility of water , which is called the brownian movement in organisms with various diseases , and it also has an important role in the identification of hepatic tumors [ 29 ] .
previous studies have suggested that the apparent diffusion coefficient ( adc ) of hepatic tumor lesions has distinct differences between benign and malignant tumors , which can distinguish the property of a tumor .
however , inherent limitations exist in diagnosis based on a single exponential model , especially losing sight of the effect of the arteriole - capillary - venule microcirculation in living tissues on adc values . in 1986 ,
proposed the principles of intravoxel incoherent motion ( ivim )   and suggested that using a more sophisticated approach to describe the relationship between signal attenuation in tissues with increasing b value would enable quantitative parameters that separately reflect tissue diffusivity and tissue microcapillary perfusion to be estimated . in 1988 ,
le bihan et al . used a phantom that could show the effects of perfusion using dw imaging .
initially applied ivim to the abdomen in 1999 to evaluate the diffusion coefficient of lesions in the abdominal viscera .
ivim can provide quantitative parameters for the movement of water molecules in tissues and reflect the perfusion condition of the tissue .
ivim - dwi can be obtained through multiple b values , and emphasizes the combined application of the low b value ( < 200 s / mm ) and high b value ( > 200 s / mm ) to accurately and effectively detect and measure the adc value of lesions .
the ivim - dwi technique can be used to estimate the diffusion coefficient of slow or nonperfusion - related diffusion - based molecular diffusion ( d ) , the diffusion coefficient of fast or perfusion - related diffusion based diffusion ( d * ) , and the perfusion - related diffusion fraction ( f ) in the voxel .
this research used the double exponential model to estimate the d value , d * value and f magnitude and compare the diagnostic performance of these parameters in hepatic tumors .
this study was approved by the local ethics committee and written informed consent was obtained from each subject before the examination . from january 2014 to october 2014 ,
a total of 103 subjects with suspicious hepatic tumors underwent multiple - b - value ivim - dwi .
a total of 123 focal hepatic lesions in 89 patients were included in this study after surgical pathologic confirmation . among the 89 patients , 52 patients were male and 37 patients were female .
mean age was 69.7 years old with an age range of 39 to 85 years old .
patients with definite diagnosis were divided into 2 groups according to the extent of tumor progress : benign tumor group ( 40 cases , 57 lesions ) and malignant tumor group ( 49 cases , 66 lesions ) .
final diagnoses were as follows : hemangioma ( 47 lesions in 31 cases ) , liver abscess ( 5 lesions in 4 cases ) , focal nodular hyperplasia ( 4 lesions in 4 cases ) , liver hamartoma ( 1 lesion in 1 case ) , hepatocellular carcinoma ( 40 lesions in 30 cases ) , metastatic liver tumor ( 20 lesions in 13 cases ) , and cholangiocarcinoma ( 6 lesions in 6 cases , table 1 ) .
primary tumors of the metastatic liver tumor were as follows : colorectal carcinoma ( 7 cases ) , pancreatic carcinoma ( 2 cases ) , gastric carcinoma ( 2 cases ) , breast cancer ( 1 case ) , and ampullary carcinoma ( 1 case ) .
size ( given as meanstandard deviation and range ) of the hepatic carcinoma , cholangiocarcinoma , metastatic liver tumor , hepatocellular carcinoma , focal nodular hyperplasia , abscess and hamartoma were 3.111.92 cm ( 1.684.50 cm ) , 3.121.03 cm ( 1.956.43 cm ) , 1.721.35 cm ( 1.303.90 cm ) , 2.841.79 cm ( 1.507.50 cm ) , 3.171.74 cm ( 1.706.00 cm ) , 2.621.43 cm ( 1.605.00 cm ) , and 4.41 cm , respectively .
inclusion criteria were as follows : ( 1 ) patients with focal liver lesions detected by computed tomography ( ct ) or ultrasound examination , ( 2 ) patients who were not contraindicated to the mr examination , ( 3 ) patients with focal hepatic lesion > 2 cm in diameter , and ( 4 ) conclusive diagnosis of the lesion using either pathologic or aspiration biopsy confirmation .
exclusion criteria were as follows : ( 1 ) patients who were treated by transarterial chemoembolization or radiofrequency ablation , ( 2 ) patients whose images were of unacceptable quality for the evaluation of focal hepatic lesions on dwi , ( 3 ) patients who are unable to tolerate the examination , and ( 4 ) patients who did not achieve a definite diagnosis .
mri was performed using a 3.0 t whole - body scanner ( discovery mr750 , ge healthcare systems ; milwaukee , wi , usa ) with a ge 8-channel phased - array coil .
all subjects were subjected to limosis for 48 h before the examination and respiratory training to achieve consistency of breathing extent and frequency .
routine mri protocols consisted of transverse t1-weighted imaging ( t1wi ) using 3d gradient - echo pulse lava ( liver acquisition with volume acceleration ) sequences , transverse breath - trigger fat suppressed fast recovery fast spin - echo ( frfse ) t2-weighted imaging ( t2wi ) , and coronal breath - trigger fat suppressed frfse t2wi .
ivim - dwi with respiratory triggering was performed with the following scanning parameters : te=79 ms , tr=6000 ms , matrix size=128160 , fov from 3636 cm to 4040 cm , slice thickness=7 mm , gap=1 mm and scanning time=256 s. eleven b - values were used : 0 , 10 , 20 , 30 , 50 , 80 , 100 , 200 , 400 , 800 , and 1000 s / mm . for b values in ranges of 030 s / mm , 50200 s / mm and 4001000 s / mm , nex was 3 , 2 , and 6 , respectively . transverse and coronal contrast - enhanced dwi imaging was performed with a 3d t1-weighted gradient - echo pulse lava sequence after the administration of gadopentetate dimeglumine ( gd - dtpa ; beilu pharmaceutical , beijing , china ) into the elbow vein at a dose of 0.1 mmol / kg with a rate of 2.53 ml / s by high - pressure syringe .
the contrast agent was followed by using an intravenous bolus administration of 20 ml of saline at the same rate .
scanning parameters were as follows : matrix size=288192 , slice thickness=25 mm , and the layer number of scanning ranged from 70 to 100 .
tr=3.7 ms , te=1.7 ms , rotation angle=12 and breath holding time=1217 s. the arterial , portal venous and delayed phase scans were performed 1820 s , 5560 s and 3 min after contrast injection , respectively .
three diffusivity parameters were defined as follows : diffusion coefficient of slow or nonperfusion - related diffusion - based molecular diffusion ( d , 10 mm / s ) represents true molecular diffusion , diffusion coefficient of fast or perfusion - related diffusion based diffusion ( d * , 10 mm / s ) represents perfusion - related diffusion , and perfusion - related diffusion fraction ( f , % ) represents fractional volume occupied in the voxel by flowing spins .
these diffusivity values were calculated using the ivim model equation described by le bihan et al .
: sb is the signal intensity for a given b value and s0 is the signal intensity at b=0 s / mm .
d was initially determined by the linear least square approach using dwi with a b - value > 200 s / mm .
d * and f were calculated by the nonlinear least - squares approach using the nelder - mead method .
/ s0 ) of relative signal intensity vs. b values from cases of primary hepatocellular carcinoma .
all acquired images were analyzed on a ge advantage workstation 4.6 using the local software of the machine functool ( ge healthcare , milwaukee , wi , usa )   prior to surgery and before pathologic results were known .
two clinically experienced radiologists with more than five 5 years of experience in interpreting hepatic mr images , who were blinded to the final histology or biopsy , evaluated each of the mr images independently .
routine t1wi , t2wi , and dynamic enhanced lava t1wi were provided to confirm the location and size of the lesion when ivim - dw images were evaluated ( figure 2a and figure 3a , 3b ) .
rois were placed on an image with b=0 ( figure 2b and figure 3c ) .
the software automatically copied the roi to each image ( b=101,000 s / mm ) and calculated the average of the signals within the roi for each image while simultaneously recording the d value , d * value and f value , respectively ( figure 2c2e and figure 3d3f ) . in focal hepatic lesions ,
rois were placed in order to avoid necrosis or hemorrhage , ; and rois were drawn as large as possible to cover the solid part of the lesions .
data were analyzed using commercial software ( ibm spss v.19 , armonk , ny ; medcalc v.12 , mariakerke , belgium ) .
diffusion parameters of benign and malignant tumors were compared by mann - whitney u test .
diffusion parameter results between malignant tumor types were compared by kruskal - wallis test followed by bonferroni - corrected mann - whitney u test .
receiver operating characteristic ( roc ) analysis was performed for lesion discriminability between malignant and benign hepatic lesions .
this study was approved by the local ethics committee and written informed consent was obtained from each subject before the examination . from january 2014 to october 2014 ,
a total of 103 subjects with suspicious hepatic tumors underwent multiple - b - value ivim - dwi .
a total of 123 focal hepatic lesions in 89 patients were included in this study after surgical pathologic confirmation . among the 89 patients , 52 patients were male and 37 patients were female .
mean age was 69.7 years old with an age range of 39 to 85 years old .
patients with definite diagnosis were divided into 2 groups according to the extent of tumor progress : benign tumor group ( 40 cases , 57 lesions ) and malignant tumor group ( 49 cases , 66 lesions ) .
final diagnoses were as follows : hemangioma ( 47 lesions in 31 cases ) , liver abscess ( 5 lesions in 4 cases ) , focal nodular hyperplasia ( 4 lesions in 4 cases ) , liver hamartoma ( 1 lesion in 1 case ) , hepatocellular carcinoma ( 40 lesions in 30 cases ) , metastatic liver tumor ( 20 lesions in 13 cases ) , and cholangiocarcinoma ( 6 lesions in 6 cases , table 1 ) .
primary tumors of the metastatic liver tumor were as follows : colorectal carcinoma ( 7 cases ) , pancreatic carcinoma ( 2 cases ) , gastric carcinoma ( 2 cases ) , breast cancer ( 1 case ) , and ampullary carcinoma ( 1 case ) .
size ( given as meanstandard deviation and range ) of the hepatic carcinoma , cholangiocarcinoma , metastatic liver tumor , hepatocellular carcinoma , focal nodular hyperplasia , abscess and hamartoma were 3.111.92 cm ( 1.684.50 cm ) , 3.121.03 cm ( 1.956.43 cm ) , 1.721.35 cm ( 1.303.90 cm ) , 2.841.79 cm ( 1.507.50 cm ) , 3.171.74 cm ( 1.706.00 cm ) , 2.621.43 cm ( 1.605.00 cm ) , and 4.41 cm , respectively .
inclusion criteria were as follows : ( 1 ) patients with focal liver lesions detected by computed tomography ( ct ) or ultrasound examination , ( 2 ) patients who were not contraindicated to the mr examination , ( 3 ) patients with focal hepatic lesion > 2 cm in diameter , and ( 4 ) conclusive diagnosis of the lesion using either pathologic or aspiration biopsy confirmation .
exclusion criteria were as follows : ( 1 ) patients who were treated by transarterial chemoembolization or radiofrequency ablation , ( 2 ) patients whose images were of unacceptable quality for the evaluation of focal hepatic lesions on dwi , ( 3 ) patients who are unable to tolerate the examination , and ( 4 ) patients who did not achieve a definite diagnosis .
mri was performed using a 3.0 t whole - body scanner ( discovery mr750 , ge healthcare systems ; milwaukee , wi , usa ) with a ge 8-channel phased - array coil .
all subjects were subjected to limosis for 48 h before the examination and respiratory training to achieve consistency of breathing extent and frequency .
routine mri protocols consisted of transverse t1-weighted imaging ( t1wi ) using 3d gradient - echo pulse lava ( liver acquisition with volume acceleration ) sequences , transverse breath - trigger fat suppressed fast recovery fast spin - echo ( frfse ) t2-weighted imaging ( t2wi ) , and coronal breath - trigger fat suppressed frfse t2wi .
ivim - dwi with respiratory triggering was performed with the following scanning parameters : te=79 ms , tr=6000 ms , matrix size=128160 , fov from 3636 cm to 4040 cm , slice thickness=7 mm , gap=1 mm and scanning time=256 s. eleven b - values were used : 0 , 10 , 20 , 30 , 50 , 80 , 100 , 200 , 400 , 800 , and 1000 s / mm . for b values in ranges of 030 s / mm , 50200 s
/ mm and 4001000 s / mm , nex was 3 , 2 , and 6 , respectively .
transverse and coronal contrast - enhanced dwi imaging was performed with a 3d t1-weighted gradient - echo pulse lava sequence after the administration of gadopentetate dimeglumine ( gd - dtpa ; beilu pharmaceutical , beijing , china ) into the elbow vein at a dose of 0.1 mmol / kg with a rate of 2.53 ml / s by high - pressure syringe .
the contrast agent was followed by using an intravenous bolus administration of 20 ml of saline at the same rate .
scanning parameters were as follows : matrix size=288192 , slice thickness=25 mm , and the layer number of scanning ranged from 70 to 100 .
tr=3.7 ms , te=1.7 ms , rotation angle=12 and breath holding time=1217 s. the arterial , portal venous and delayed phase scans were performed 1820 s , 5560 s and 3 min after contrast injection , respectively .
three diffusivity parameters were defined as follows : diffusion coefficient of slow or nonperfusion - related diffusion - based molecular diffusion ( d , 10 mm / s ) represents true molecular diffusion , diffusion coefficient of fast or perfusion - related diffusion based diffusion ( d * , 10 mm / s ) represents perfusion - related diffusion , and perfusion - related diffusion fraction ( f , % ) represents fractional volume occupied in the voxel by flowing spins .
these diffusivity values were calculated using the ivim model equation described by le bihan et al .
: sb is the signal intensity for a given b value and s0 is the signal intensity at b=0 s / mm .
d was initially determined by the linear least square approach using dwi with a b - value > 200 s / mm .
d * and f were calculated by the nonlinear least - squares approach using the nelder - mead method .
/ s0 ) of relative signal intensity vs. b values from cases of primary hepatocellular carcinoma .
all acquired images were analyzed on a ge advantage workstation 4.6 using the local software of the machine functool ( ge healthcare , milwaukee , wi , usa )   prior to surgery and before pathologic results were known .
two clinically experienced radiologists with more than five 5 years of experience in interpreting hepatic mr images , who were blinded to the final histology or biopsy , evaluated each of the mr images independently .
routine t1wi , t2wi , and dynamic enhanced lava t1wi were provided to confirm the location and size of the lesion when ivim - dw images were evaluated ( figure 2a and figure 3a , 3b ) .
rois were placed on an image with b=0 ( figure 2b and figure 3c ) .
the software automatically copied the roi to each image ( b=101,000 s / mm ) and calculated the average of the signals within the roi for each image while simultaneously recording the d value , d * value and f value , respectively ( figure 2c2e and figure 3d3f ) . in focal hepatic lesions ,
rois were placed in order to avoid necrosis or hemorrhage , ; and rois were drawn as large as possible to cover the solid part of the lesions .
data were analyzed using commercial software ( ibm spss v.19 , armonk , ny ; medcalc v.12 , mariakerke , belgium ) .
diffusion parameters of benign and malignant tumors were compared by mann - whitney u test .
diffusion parameter results between malignant tumor types were compared by kruskal - wallis test followed by bonferroni - corrected mann - whitney u test .
receiver operating characteristic ( roc ) analysis was performed for lesion discriminability between malignant and benign hepatic lesions .
both the d value ( [ 1.040.34]10 mm / s ) and d * value ( [ 16.57.7]10 mm / s ) in malignant lesions were significantly lower than in benign lesions ( d value [ 1.700.55]10 mm / s , p<0.01 ; d * value [ 21.79.9]10 mm / s , p<0.01 ) .
there was no statistically significantly difference in f value between malignant ( 23.39.5 ) and benign ( 33.514.9 ) lesions ( p=0.13 , table 2 ) .
results of diffusion and perfusion - related parameters by tumor type are shown in table 3 .
cholangiocarcinoma presented significantly higher d values than metastatic liver tumor ( p=0.021 ) and hepatocellular carcinoma ( p=0.002 ) .
similarly , metastatic liver tumor had significantly lower d * values than cholangiocarcinoma ( p=0.016 ) and hepatocellular carcinoma ( p=0.001 ) . according to roc analysis , the average area under the roc curve for predicting malignant lesions was 0.88 ( 0.810.91 ) for d * value and 0.98 ( 0.941.00 ) for d value ( p<0.05 , table 4 ) .
optimal cutoff values calculated by roc analysis ( d , 1.29510 mm / s and d * , 21.8510 mm / s ) provided sufficiently high sensitivity and specificity for both d ( 96.2% and 91.4% , respectively ) and d * ( 90.6% and 82.9% , respectively ) values ( table 4 ) .
functional mr images can reflect the random motion ( brownian movement ) of water molecules in living tissue .
however , quantitative adc values can also be affected by physiological activity and the perfusion effect of the capillary network .
the double exponential model with multi - b - values separates the diffusion and perfusion ( microcirculation ) of water molecules .
it more closely approximates the real adc of the biological tissue , which reflects dwi better than the single exponential model .
the ivim double exponential model assumes that tissue diffusion consists of 2 parts : brownian movement ( d ) due to molecular diffusion , and fast perfusion movement ( d * ) due to blood flow in smaller vessels .
d is the static tissue molecular diffusion ( true diffusion coefficient ) , which is calculated by selecting the high b value ( > 200/mm ) and eliminating the perfusion component .
d * denotes the perfusion - diffusion coefficient , which is the perfusion - related diffusion coefficient due to blood circulation .
perfusion composition of tissue microcirculation is sensitive to mr signal attenuation with low b values ( < 200/mm ) . the perfusion fraction f represents the fractional volume occupied in the voxel by flowing spins linked to the intravascular component or to the microcirculation .
d * is closely associated with blood vessel density in tumor tissues , and f value increases with the growth of the tissue perfusion component . in this study , d
* values were much greater than the corresponding d values , which indicate that d * is sensitive to mr signal attenuation when b value is low .
the d , d * , and f values in our study are similar to a previous study in hepatic adenoma , hepatic cavernous hemangioma , hepatocellular carcinoma , metastatic liver tumor , and cholangiocarcinoma patients .
however , the study of ichikawa et al .   reported higher d , d * , and f values than those in our study .
these may be due to the difference on the manual roi drawing ( manual roi method ) and the number of patients or lesions .
the attribute of the hypovascularity of metastatic liver tumors in this study may also affect these outcomes . in this study , we found both d and d * values in malignant lesions were significantly lower than in benign lesions , which is consistent with the findings of ichikawa et al . .
in contrast to our findings , the study of doblas et al .   reported that pure diffusion coefficients ( d ) were significantly lower in malignant tumors than in benign tumors , while perfusion - related diffusion parameters ( d * ) did not significantly differ between these 2 groups , which was due to the large number of benign hepatocellular lesions ( fnh and adenomas ) in their study .
the d * value of metastatic liver tumors is lower than hepatocellular carcinoma and cholangiocarcinoma , which may be due to the hypovascular property of the metastatic liver tumor .
our findings are consistent with those of a previous study , which reported that d * and f values can reflect the condition of the blood supply , and these values are higher in hypervascular hepatic tumors than in hypovascular hepatic tumors .
this study also used the roc curve to evaluate the diagnostic efficiency of d , d * , and f. the roc curve presents the optimal threshold of d for the diagnosis of benign and malignant tumors is 1.29510 mm / s . sensitivity ( 91.4% ) and specificity ( 96.2% ) of the d value
are both relatively high for identifying the maximum auc ( 0.976 ) , indicating the highest diagnostic efficiency of the d value .
( 1 ) the most obvious difference between benign and malignant tumors is the component of abnormal cell proliferation .
altered nucleo - cytoplasmic ratio and nuclear atypia in malignant tumor cell induce the limited diffusion of water molecules and increase the true diffusion of the tissue .
( 2 ) the component separation of perfusion - diffusion and true molecular diffusion by the double exponential model resulted in the calculation , in which the d value is closer to the actual adc of the biological tissue .
the perfusion - diffusion is due to the irregular perfusion of the microcirculation in the blood capillary .
the relatively small sample size and the selection of lesion types in this study may have affected interpretation of results .
more realistic d , d * , and f values can be obtained by using more dwi images of low b values and high b values during ivim imaging , contributing to the qualitative and quantitative identification of the diagnosis .
d and d * are both valuable in the diagnosis of hepatic tumors , but d is more reliable in property identification . the diagnostic value of the perfusion parameter obtained by ivim may reduce the dependency for liver contrast medium clinically .
ivim is an ideal examination method when dynamic enhanced scan period ( arterial phase ) fails or for contrast medium sensitivity , especially for senile patients and infants .
thus , there is an overbalance in the distribution of tumor types , which is limited by the subjects in the hospital .
second , using 3 parameters is unstable , in contrast to using a single parameter ; which can easily cause errors in the d * value .
in particular , when the f value is small ( low perfusion proportion ) , the quality of the d * image decreases and the chance for more errors on the d * value is higher .
third , the liver is a locomotive organ that can affect ivim parameters . finally , multi - b - value technology prolongs scanning time , which is onerous for patients .
ivim dwi can provide more essential d , d * , and f values by using sufficiently low b values and high b values , which contributes to the qualitative and quantitative diagnosis of hepatic tumors .
the d value was proven to be a more reliable parameter than the d * value for distinguishing between malignant and benign hepatic lesions .
 backgroundthis study aimed to evaluate the diagnostic value of the d value , d * value , and f magnitude for identifying benign and malignant hepatic tumors using intravoxel incoherent motion ( ivim ) diffusion - weighted imaging ( dwi).material / methodsdata of 89 cases ( 123 lesions ) with hepatic tumor confirmed by surgical pathology and postoperative follow - up were retrospectively collected . among these cases , 40 cases were benign hepatic tumors ( 57 lesions ) and 49 cases were malignant hepatic tumors ( 66 lesions ) . 
 all subjects underwent conventional mri with t1wi , t2wi , multi - b - value dwi , and dynamic enhanced lava scan . 
 diffusion - weighted images with 11 b values ( 0 , 10 , 20 , 30 , 50 , 80 , 100 , 200 , 400 , 800 , and 1000 s / mm2 ) were obtained to calculate true molecular diffusion ( d ) , perfusion - related diffusion coefficient ( d * ) , and perfusion fraction ( f ) . 
 the diagnostic performance in differentiating between malignant and benign hepatic lesions was analyzed.resultsmalignant lesions had a significantly lower d value ( [ 1.040.34]103 mm2/s ) and d * value ( [ 16.57.7]103 mm2/s ) compared to benign lesions ( d value : [ 1.700.55]103 mm2/s , p<0.01 ; d * value : [ 21.79.9]103 mm2/s , p<0.01 ) . 
 there was no statistically significant difference in f values between malignant ( 23.39.5 ) and benign lesions ( 33.514.9 , p=0.13 ) . 
 in addition , d exhibited a better diagnostic performance than d * in terms of the area under the curve , sensitivity , and specificity when identifying malignancies from benign lesions.conclusionsd and d * are significant parameters for diagnosing hepatic tumors . 
 moreover , the d value is a more reliable parameter in distinguishing benign and malignant hepatic tumors . 
Background
Material and Methods
Patients
MRI
Image analysis
Statistical analysis
Results
Discussion
Conclusions