| Purpose To explore the establishment of rat liver cirrhosis model and to investigate whether intravoxel incoherent motion MRI(IVIM)and dynamic contrast-enhanced MRI(DCE-MRI)can differentiate different types of cirrhosis-related nodules,and can they monitor the cell density and microcirculation changes during malignant transformation of cirrhosis nodules in experimental rat model.Furthermore,we compared the diagnostic efficiency of IVIM and DCE-MRI for RN,LGDN,HGDN and HCC in an experimental rat model.In addition,we evaluated the value of gadoxetate disodium-enhanced MR imaging and IVIM-DWI in differential diagnosis of dysplastic nodules(DN)and hepatocellular carcinoma(HCC)with different degrees of differentiation.We also studied the correlation between IVIM-DWI parameters and cell density of DN and HCC,and whether IVIM-DWI can be used as a method to monitor early malignant transformation of DN.Materials and MethodsSectionl:Fifty male Sprague-Dawley rats(six-week-old,weighing 120-150g)were housed in conventional cages under specific pathogen-free environmental conditions and kept at a special room temperature(22±2?)with a 12 h lighting time.The cirrhosis-related nodules were induced with 50 mg/kg DENA(diethylnitrosan,0.95 g/ml;Sigma)intragastrically once a week for 10?20 weeks.From week 10 to week 20 after induction of cirrhosis-related nodules by DENA,four or five rats were examined in a 3.0 Tesla MR system using IVIM and DCE sequences every 7 days.All rats were sacrificed by cervical dislocation,and the liver was removed after all MRI imaging was completed.To make the pathological tissue and imaging performance as accurate as possible,the harvest liver was cut sequentially into 3 mm thick sections,which approach the MRI transverse plane(Transverse).To determine the nature of the nodules,the harvest nodules were dehydrated,embedded in paraffin,cut into 4 ?m sections and stained with hematoxylin-eosin for histological examination.All nodules were histologically diagnosed by two pathologists and divided into five groups including RNs,LGDNs,HGDNs,HCCwell(Well differentiated hepatocellular carcinoma,Edmondson-Steiner grades 1 and 2)and HCCpoor(Poorly differentiated hepatocellular carcinoma,Edmondson-Steiner grades 3 and 4).To evaluate neoangiogenesis in nodules,liver specimens were also analyzed by immunohistochemical staining using an SMA monoclonal antibody(Envision,two steps)(1:200 dilution).The "unpaired arterial ratio" was calculated by two pathologists in all harvest nodules.Futhermore,the cellularity of cirrhotic nodules,analyzed by two pathologists,which was defined as the area of nucleus of nodules or tumors divided by the total area of the tissue slices(× 100 magnification).The mean value was counted for 3 random fields of × 100 magnification,and their average values were recorded.The DWI imaging and DCE-MRI data were processed using homemade software written in Matlab and the commercial software Omni-Kinetics by two radiologists who were blinded to the pathologic results.Two radiologists calculated the parameters of IVIM and DCE-MRI by delineating the ROI of the lesion.The MRI parameters including true diffusion coefficient(D),pseudo-diffusion coefficient(D*),perfusion fraction(f),apparent diffusion coefficient(ADC),transfer constant(Ktrans),rate constant(Kep)and extravasular extracellular space volume fraction(Ve)were calculated and recorded.Section2:A prospective study of 50 patients with gadoxetate disodium-enhanced MR was conducted in the Department of Radiology,the Second Affiliated Hospital of Dalian Medical University from May 2016 to December 2018.All patients were examined by IVIM-DWI and gadoxetate disodium-enhanced MRI before operation.After the MRI examination and operation were completed,two radiologists who were blinded to the pathologic results,calculated the IVIM parameters including D,D*,f and ADC by using Matlab(IVIM-DWI post-processing software)in the way of delineating the ROI of the lesion.At the same time,the MRI signal intensities(SIs)of the lseion ROI and ROIs in liver parenchyma adjacent to the lesion(Relative Intensity Ratio,RIR)were measured on gadoxetate disodium-enhanced MRI in the hepatiobiliary phases by two radiologists in PACS,who were blinded to the pathologic results.All enrolled patients underwent partial hepatectomy within two weeks after MRI examination,routine HE staining was performed on all surgical specimens.The nodules were divided into LGDNs,HGDNs,HCCwell and HCCpoor by two pathologists,and the cell density of each nodule was calculated.RseultsSectionl:Thirty-five rats were successfully completed the experiment,Among the total 106 nodules,which were revealed by MRI study and corresponding pathological examination,we identified 19 cases of RNs,22 cases of LGDNs,25 cases of HGDNs,20 cases of HCCwell and 20 cases of HCCpoor.With the increase of nodule malignancy,all the DCE-MRI parameters gradually increased.The Ktrans,kep and Ve values of all HCC were significantly higher than those of DNs and RNs(all p<0.05).Compared with the five different types of nodules,the values of Ktrans,Kep and Ve were significantly higher in HCCpoor than HGDNs,LGDNs and RNs(both p<0.05).The Ktrans values were higher in HCCpoor than HCCwell(p<0.05).The values of Ktrans were higher in HCCwell than LGDNs and RNs(both p<0.05).The Ktrans values were higher in HGDNs than in LGDNs(p<0.05).There was no significant difference between HCCwell and HGDNs among those parameters.The D values and ADC values decreased with increasing grade of nodule malignancy.The D and ADC values were significantly lower in HCCpoor and HCCwell than HGDN,LGDN and RN(all p<0.05).The D and ADC values were significantly lower in HCCpoor than in HCCwell.Only the D values of HGDNs were significantly lower than those of LGDNs among these parameters.The D values and ADC values of HGDN were lower than those of RN(both p<0.01).The f values of HCCpoor and HCCwell were higher than those of RN(both p<0.05).There was no significant difference between LGDN and RN among those IVIM parameters.In the diagnosis of RNs and HGDNs,ROC analyses demonstrated that Ktrans had higher AUROC than D,ADC.For the diagnosis of RNs and HCCwell,D had higher AUROC than ADC,Ktrans and Kep.For the diagnosis of LGDNs and HGDNs,Ktrans had a higher AUROC than D.The D had higher AUROC than ADC and Ktrans in the diagnosis of LGDNs and HCCwell.As for HDGN and HCCwell,the AUROC of D was higher than ADC.In the diagnosis of HCCwell and HCCpoor,D had a higher AUROC than ADC and KtransThe Unpaired arterial ratio of HCCpoor was significantly higher than that of HCCwell,HGDNs,LGDNs and RNs.There Unpaired arterial ratio of HCCwell,HGDNs,LGDNs and RNs were significantly different,and HGDNs was higher than LGDNs and RNs.Poor to moderate positive correlations were observed between kep and unpaired arterial ratio(r=0.381,p<0.01),and between Ktrans and Unpaired arterial ratio(r=0.531,p<0.01).There were moderate negative correlations between D and cellularity(r=-0.624,p<0.01),and between ADC and cellularity(r=-0.526,p<0.01).Section2:A total of 75 cases of HCCs and DNs,including 15 cases of LGDNs,20 cases of HGDNs,21 cases of HCCwell and 19 cases of HCCpoor were found in 50 patients.The ADC and D values decreased gradually from LGDNs to HCCpoor.s The D and ADC values were significantly lower in HCCs than HGDNs and LGDNs(all p<0.01).The D and ADC values were significantly lower in HCCpoor than in HCCwell.The D values of HGDNs were significantly lower than those of LGDNs.The D values and ADC values were negatively correlated with those different type nodules(rd=-0.703,rADC=-0.700,both p<0.01).There were moderate negative correlations between D and cellularity(r=-0.691,p<0.01),and between ADC and cellularity(r=-0.652,p<0.01).The RIR were significantly lower in HCCpoor and HCCwell than LGDNs(both p<0.01).The RIR of HCCpoor were lower in HCCpoor than HCCwell and HGDNs(both p<0.01).In the diagnosis of LGDN and HGDN,ROC analyses demonstrated that RIR had higher AUROC than D.For the diagnosis of LGDN and HCCwell,LGDN and HCCpoor,RIR had higher AUROC than D and ADC.For distinguishing HGDN from HCCwell,the AUC of D was higherr than that of ADC,while RIR had no diagnostic value.As for the differential diagnosis of HGDN and HCCpoor,D had higher AUROC than ADC and RIR.In the diagnosis of two different types of HCC(HCCwell and HCCpoor),the AUC of RIR was higher than that of D and ADC.Conclusion.Our initial animal study indicates that DCE-MRI and IVIM-DWI are noninvasive methods that could reflect the two characteristics of angiogenesis and increased cell density during the malignant transformation of cirrhosis nodules.Elevated Ktrans and reduced D,ADC suggested the malignant transformation of nodules to HCC.In clinical practice,the signal intensity ratio of lesions to hepatic tissues on gadoxetate disodium-enhanced MRI in the hepatiobiliary phases had high value in differentiating LGDN from HCC,HGDN from HCCpoor,and HCC with different differentiation degree,but it had no diagnostic value in differentiating HGDN from HCCwell,while IVIM-DWI could be used as an important complementary sequence of gadoxetate di sodium-enhanced MRI,due to its high value for the identification of HGDN and HCCwell.In addition,IVIM-DWI has the advantages of simple acquisition and without injection of contrast agent,futhermore it has high value in differentiating LGDN from HGDN,LGDN from HCC,HGDN from HCC poor,and different types of HCC.In clinical scenario,IVIM-DWI could be used as one of the routine sequences for follow-up of cirrhosis nodules. |
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