A Novel Pathological Classification System For Cirrhosis And The Clinicopathological Significance With Hepatocellular Carcinoma

Background Hepatocellular carcinoma(HCC)is a major health problem worldwide as more than 700 000 cases are diagnosed yearly,in which more than 90% of the cases,HCC develops within cirrhosis.The cirrhosis decreases the functional reserve of the remaining liver,as well as the liver function recovery.At the same time,cirrhosis plays a vital role in determining and appropriate surgical strategy for HCC treatment.the severity of cirrhosis was closely associated with liver related event occurrence and tumor recurrence after surgery for HCC patients,also.However,traditional liver fibrosis,inflammation staging system seamed the cirrhosis as one stge of dissise,further sub-classification of histology of cirrhosis have not conducted.Only the Laennec staging system subdivide the cirrhosis,which were used to evaluate the liver biopsy specimens of cirrhosis but the HCC with cirrhosis patient.Traditinal pathological staging system using qualitative or semi-quantitative interpretation method,there is a great subjectivity and large error,can't accurately reflect the degree of cirrhosis and prognosis of surgery patients.Purpose Screening the pathological parameters which can reflect the degree of cirrhosis,we establish a risk assessment model according the risk weight of each parameter.To propose a pathological staging system of liver cirrhosis related to the prognosis of HCC patients.Patients and Methods We reviewed two hundred and sixty clinicopathological date of patients who underwent hepatectomy and diagnosed as HCC with cirrhosis pathologically at the Eastern Hepatobiliary Surgery Hospital(EHBH)between January 2010 and December 2015.In the training group,the patients were divided into three groups according to the degree of liver function recovery of 3 month after surgery(stratified by Child-Pugh stage).The pathologic features of cirrhosis were evaluated systematically,and the pathological parameters were accurately measured and statistically analyzed.The morphology index and the molecular markers were screened out which reflect the degree of cirrhosis.Ordinal Logistic regression was used to screen theindependent risk factors,and the odds ratio(OR)was calculated according to the partial regression coefficient of independent risk factors.The risk evaluation model was established by taking the OR value as the risk weight of each parameter in the model.According the risk assessment model score,the EHBH cirrhosis staging system established.Intraoperative influence factors were used as covariates,analysis of covariance was carried out to detect covariates factors' group effect of score system.The EHBH staging system was derived from 163 training samples,and the prognostic validity was assessed on the corresponding of 97 testing samples.The EHBH staging system and Laennec fibrosis grading system were compared,by comparing the serum and clinical indicators which reflects the liver function and liver injury to assess the predictive value of staging system.Pearson correlation analysis were used to test the correlation between the scores of the EHBH cirrhosis staging system and Laennec fibrosis grading system,Child-Pugh score and MELD score of postoperative liver function.Spearman correlation analysis were used to test the correlation between the the Stageirrhosis stage,Laennec stage and Child-Pugh stage.The differences between the groups were analyzed by the Mann-Whitney test and the area under the curve(AUC)of the ROC curve to examine the differences between the groups and the diagnostic value.Results Stageirrhosis staging system of pathological parameters According to the postoperative liver function indicators' differences between the various groups and the diagnostic value screening significance pathological indicators which can reflect the degree of cirrhosis and have statistical value also.The parameter including the average number of inflammatory cells in the portal area(NICP),ratio of hepatic fibrosis area divided by total area(RFA),density of pseudolobules per square millimeter(DPL),the density of MRP14,the density of Inflammatory cells in hepatic area(DICH),the average diameter of pseudolobules(ADP).The results of univariate Logistic regression analysis showed that NICP(P <0.0001),RFA(P <0.0001),DPL(P <0.0001),MRP14(P <0.0001),DPL(P <0.0001)and DICH(P <0.00001)have statistical significance.Multivariate logistic regression analysis showed that NICP(P=0.011,OR=3.27),RFA(P=0.019,OR=3.07,DPL(P=0.032,OR=2.31),MRP14(P=0.001,OR=3.32)have statistical significance.These four indicators were independent risk factors for cirrhosis,while NICP(P = 0.059)and ADP(P=0.077)were not statistical significance.Establishment of Stageirrhosis staging system The pathological parameters were divided into three grades according to Cut-off values,NICP(A ? 1102,1102>B?2519,C>2519),RFA(A ? 0.1192 2,0.1192>B?0.2040,C>0.2040)DPL(A? 13.13 2,13.13>B?23.67,C > 23.67),density of MRP14(A ?18.4 2,18.4>B?30.1,C> 30.1).The scoring system was constructed according to the weight of the OR value,EHBH Cirrhosis Score=OR1G(NICP)-1+OR2G(RFA)-1+OR3G(DPL)-1+OR4G(MRP14)-1(i.e.System Score=3.27G(NICP)-1+3.07G(RFA)-1+2.31G(DPL)-1+3.32G(MRP14)-1).Then according its Cut-off value the EHBH cirrhosis system is divided into three levels,namely EHBH cirrhosis staging: ? ? 6.85,6.85< ? ? 24.15,? > 24.15.Stageirrhosis staging system validation The Stageirrhosis score and postoperative liver function Child-Pugh and MELD scores were strongly correlated(Child-Pugh,r=0.8058,P<0.0001;MELD,r=0.666,P<0.0001),while the Laennec fibrosis scor were poorly associated with postoperative liver function(Child-Pugh,r=0.2779,P=0.0059;MELD,r=0.3271,P=0.0011).Stageirrhosis score and serum markers which reflect the liver function,including total bilirubin(TBIL)(P<0.0001),albumin(ALB)(P<0.0001),alanine aminotransferase(ALT)(P<0.0001),aspartic transaminase(AST)(P<0.0001),alkaline phosphatase(ALP)(P<0.0001),albumin(ALB)(P<0.0001),albumin globulin ratio(A/G)(P=0.0142),prothrombin time PT(P<0.0001),keratinize(Cre)(P<0.0001)and clinical indicators,including ascites(P=0.0022),encephalopathy(P<0.0001)have a strong correlation.There was no significant correlation between Laennec and TBIL(P=0.1225),ALT(P=0.0746),ALB(P=0.4258),A/G(P=0.7323),PT(P=0.2317),Cre(P=0.2491,ascites(P=0.2031),encephalopathy(P=0.1073),but only correlation with AST(P=0.0005),ALP(P=0.0010).Conclusions Accurate measuring and analysing,and substituting traditional qualitative orsemi-quantitative indicators with quantitative indicators,we proposed a new pathological cirrhosis staging system in HCC patients which related to liver function.The new staging system can be used to accurately determine the degree of liver cirrhosis and be able to predict liver function recovery after liver surgery.