Diagnostic Value Of Tumor Perfusion By Triphasic CT Scans In Differentiating Benign And Malignant Lesions Of The Liver,Predicting The Histological Grade Of Hepatocellular Carcinoma

Background and ObjectiveEarly diagnosis and differential diagnosis of hepatic tumors were of great significance for predicting the prognosis and guiding clinical treatment[1].Hepatocellular carcinoma(HCC)is a common malignancy worldwide,with a high mortality and morbidity,with over 500,000 new cases per year[2,3].It predominantly develops in patients with cirrhosis or chronic hepatitis.In traditional triphasic phase CT scans,hepatocellular carcinoma(HCC)show characteristic high density compared with surrounding liver parenchyma in the arterial phase,uniform or low density in the portal phase and low density in the delayed phase[4].According to both European Association for the Study of the Liver(EASL)[5]and American Association for the Study of Liver Diseases(AASLD)[6]guidelines,Arterial phase enhancement(hyperdense compared to surrounding liver parenchyma)with portal venous phase or delayed phase washout of contrast(hypodense compared to surrounding liver parenchyma)is considered diagnostic of HCC in cirrhotic livers.However,not all HCCs show contrast washout on delayed imaging,and not all lesions with contrast washout are HCCs.A minority of W-HCCs are hypodense to surrounding liver on all phases[7].Many hyper-vascular HCCs don’t have contrast washout[8].Contrast washout can also be seen in other liver lesions(including benign and malignant),including regenerative nodules[9],hemangiomas[10],focal nodular hyperplasia[11],adenomas[12],and hyper-vascular metastases[13].As a routine examination for liver tumors,the traditional triphasic CT scans can not fully reflect the hemodynamic changes of the liver due to the individual differences of blood circulation in the liver,causing difficulties in the diagnosis of liver lesions,especially in the differential diagnosis of benign and malignant lesions.CT perfusion imaging can accurately calculate the relevant parameters which reflect the blood supply of the liver,the artery and the portal vein of the lesions.Hepatic CT perfusion is generally performed at many time points(more than 20)after intravenous contrast agent injection,and the enhancement curve derived from CT perfusion could be used to calculate some parameters such as blood volume,blood flow and capillary permeability[14,15].Hemodynamic parameters with high temporal and spatial resolution,good repeatability could be measured at capillary level.CT perfusion parameters can quantitatively reflect the hemodynamic changes of microcirculation and provide morphological,functional information for target lesions.Compared with the traditional triphasic CT scans,one of the objectives of CT perfusion is to improve the detection and acquire quantitative characteristics of liver lesions[15].Treatment methods include liver transplantation,surgical resection,radiofrequency ablation(RFA),transcatheter hepatic arterial chemoembolization(TACE)and targeted therapies.Surgical resection is considered to be one of the most effective treatments for HCC.However,recurrence remains high.Poorly differentiated HCC(P-HCC)has higher tumor recurrence rate,poorer prognosis,and lower survival rate,compared to moderately and well-differentiated HCC[16-19]The reason may be that the incidence of distant metastases of P-HCCs is higher than that of M-HCCs or W-HCCs[20]Many surgeons and oncology experts think the treatment of P-HCCs should be improved.In the current therapy guidelines,due to tumor seeding and the poor outcomes,RFA is not recommended for the treatment of P-HCCs[21]In addition,P-HCC is a contraindication of liver transplantation due to the high recurrence rate and poor survival[22,23].Therefore,accurate preoperative assessment of tumor grade,especially P-HCC,has been increasingly emphasized[24]Hepatocellular carcinoma(HCC)develops a new vascular system through angiogenesis.Tumor angiogenesis is a complex process mediated by multiple angiogenic factors and antiangiogenic factors,which is the key to tumor growth and metastasis[25-27].The arterial blood supply and angiogenesis have been increased during the progression of HCC from low-grade atypical hyperplasia nodules to advanced HCCs[28.29].Angiogenesis of HCC is closely related to the histopathological grading of tumors[30.31]Therefore,quantifying the vascularity of hepatocellular carcinoma is important for the evaluation of histological grade and tumor progression.CT perfusion,as an important technology with rapid development recently,could obtain a series of images and analyze the temporal changes of tumor hemodynamics.It is highly promising as a functional vascular imaging technique that can accurately and noninvasively evaluate the tumor vascularity.However,because of the increased radiation dose and special scanning protocols,CT perfusion of liver is largely unfulfilled clinically.In addition,due to the influence of the respiration and heartbeat,movement displacement changes are easy to occur between different enhancement phases,and the clinical application is also limited to some extent.To address these limitations of traditional CT perfusion,routine tri-phasic scan with simplified model of tumor blood supply which has been developed and validated was applied to this study.The linear combination of the enhancement curves of aorta and portal vein can be used to calculate the hepatic artery and portal vein blood supply coefficients(HAC and PVC)of tumor,and this has been validated as a simple predictive model of liver perfusion.HAC indicates similarity of a lesion’s enhancement curve to the aortic enhancement curve,and PVC showed that the lesions enhancement curve was similar to the portal vein enhancement curve.In a simple model,the HAC and PVC are equivalent to the blood volumes of hepatic artery and portal vein that assumes rapid blood flow and no vascular permeability to contrast[32].GE hemodynamic software(CT kinetics,CK)was developed on the basis of this principle,which uses the imaging date derived from triphasic CT scans to calculate the relevant perfusion parameters(HAC,PVC,AEF,et al).It could apply these parameters to further study reflecting the hepatic pathophysiological changes.In addition,CT kinetics(CK)software can remove the effect of respiratory and other movement by motion calibration.Moreover,it can significantly reduce the radiation dose compared with the traditional CT perfusion.In the liver,the role of perfusion parameters in differentiating common benign and malignant lesion and predicting the histological grade of HCC has not yet been determined.Here,we evaluated the role of perfusion parameters by traditional tri-phasic CT scans in the differentiation of benign and malignant lesions and prediction of the pathological grading.This report was mainly divided into two parts.The first part was to investigate quantitative measures and heterogeneity of perfusion parameters in the differential diagnosis of hepatocellular carcinoma(HCC)and hemangioma.The second part was to evaluate the role of quantitative perfusion parameters,corresponding histogram parameters and tumor attenuation by traditional tri-phasic CT scans in predicting histological grade of HCC.Part Ⅰ Heterogeneity Analysis of Triphasic CT Scan Perfusion Parameters in Differential Diagnosis of Hepatocellular Carcinoma and HemangiomaObjective:This study is to investigate quantitative measures and heterogeneity of perfusion parameters in the differential diagnosis of hepatocellular carcinoma(HCC)and hemangioma.Methods:In total,32 HCC and 44 hemangioma(types 1,2,and 3)cases were included in this retrospective study.Hepatic Artery Coefficient(HAC),Portal Vein Coefficient(PVC)and Arterial Enhancement Fraction(AEF)were calculated.Tumor heterogeneity was analyzed.Perfusion parameters and corresponding percentiles were compared between the HCC and hemangioma(especially atypical hemangioma)cases,as well as between the substantial lesion part and surrounding normal tissue.Results:The mean value,and the 10th,50th,75th,and 90th percentiles of PVC were significantly lower in the HCC cases than the types 1 and 2 hemangioma cases(P<0.01).Moreover,the 90th percentile PVC in the HCC cases were also significantly lower than the type 3 hemangioma cases(P<0.01),while the mean value,and all the percentiles of AEF in the HCC cases were higher than the types 2 and 3 hemangioma cases(P<0.01).The 10th percentile HAC in the HCC cases were higher than the type 2 hemangioma cases(P<0.05).The mean value,and the 10th,50th percentile HAC in the HCC cases were higher than the type 3 hemangioma cases(P<0.05).However,there was no statistically significant difference in HAC between the HCC and type 1 hemangioma cases(P>0.05).Conclusion:Quantitative measurement of perfusion parameters and heterogeneity analysis show significance differences in the early detection and differential diagnosis of HCC and hemangioma cases,which might contribute to increasing the diagnostic accuracy.Part Ⅱ Tumor attenuation,Tumor Perfusion Parameters and Histogram Analysis by Triphasic CT Scans Predict Histological Grade of Hepatocellular CarcinomaObjective:Preoperative noninvasive histological evaluation of hepatocellular carcinoma(HCC)remains a challenge.Tumor perfusion is significantly associated with the development and aggressiveness of HCC.Here,we evaluated the role of quantitative perfusion parameters,corresponding histogram parameters and tumor attenuation by traditional tri-phasic CT scans in predicting histological grade of HCCMethods:A total of 52patients with pathologically confirmed HCC were enrolled in this retrospective study.According to the presence of poorly differentiated components(PDC),HCCs were divided into two groups:16 cases with PDC(P-HCCs);36 cases without PDC(NP-HCCs),including well-differentiated(n=11),moderately differentiated HCCs(n=25).The values of tumor attenuation on different scanning phases were measured.Liver perfusion parameters and histogram parameters were calculated from CT imaging.The relationship of tumor attenuation,liver perfusion parameters and histogram parameters with histological grade of HCC was analyzed.Receiver operating characteristic(ROC)curve analysis was used to determine the optimal ability of the parameters to predict the tumor histological grade.Results:The variance of Arterial Enhancement Fraction(AEF)was significant higher in HCCs without poorly differentiated components(PDC)(NP-HCCs)than in HCCs with PDC(P-HCCs)(P<0.05).The difference in flow between total tumor and total liver flow(AHF=HFtumor-HFliver)and relative flow(rHF=△HF/HFliver)were significantly higher in NP-HCCs than in P-HCCs(both P<0.05).The difference in Portal Vein Coefficient(PVC)between tumor and liver tissue(△PVC)and the △PVC/liver PVC ratio(rPVC)were significantly higher in patients with NP-HCCs than in patients with P-HCCs(both P<0.05).The AUC of △PVC and rPVC were both 0.697.In addition,they had a higher sensitivity of 84.2%and specificity of only 56.2%.However,the △HF and rHF had a higher specificity of 87.5%with AUC of 0.681 and 0.673,respectively.The combination of rHF and rPVC,△HF+△PVC showed the highest AUC of 0.732 with sensitivity of 57.9%,63.2%and specificity of 93.8%,87.5%,respectively.The P-HCC cases had significantly decreased values of tumor attenuation on the unenhanced phase(TAu),portal phase(TAp)and equilibrium phase(TAe)(P<0.05).The difference of tumor attenuation between the portal phase and the unenhanced phase(TAp-TAu)of the P-HCC cases was decreased than that of the NP-HCC cases(P<0.05),whereas the difference of attenuation between the equilibrium phase and portal phase(TAe-TAp)was significantly higher in the P-HCC cases than that in the NP-HCC cases(P<0.05).TAp had the highest AUC and the value was 0.921.Conclusion:Liver perfusion parameters,corresponding histogram parameters,the tumor attenuation on different phases and the tumor attenuation differences among different phases in patients with HCC derived from traditional tri-phasic CT scans may be helpful to noninvasively and preoperatively predict the degree of the differentiation of HCC.