A Novel Pathological Classification System For Microvascular Invasion And The Novel Prognostic Nomograms For Predicting Outcomes Of Patients With Hepatocellular Carcinoma

BackgroundHepatocellular carcinoma is one of the most common malignant tumors in China.Microvascular Invasion(MVI)has been repeatedly confirmed as a poorer prognostic factor for hepatocellular carcinoma(HCC)after resection,even for the small HCC or those treated with transplantation.It has been identified definitely as a bottleneck in prolonging the disease free survival and overall survival of HCC.However,the basic pathological type of MVI has not been proposed,the proposed risk classification of MVI has not been used widely and the classical lassical staging systems could not perform the clinical significance of MVI.PurposeTo propose a basic pathological type of MVI,establish a novel risk pathological classification system for MVI and two sensitive nomograms for predicting postoperative survival and early recurrence of patients with HCC.Patients and MethodsWe reviewed the clinicopathological and follow-up data of 686 consecutive patients who underwent hepatectomy and diagnosed as HCC pathologically at the Eastern Hepatobiliary Surgery Hospital between December 2009 and April 2010(Primary cohort).The pathological type of MVI and the classification system were established based on the systemic studies of histological characteristics of MVI.The independent factors of overall survival and early recurrence were figured out by Kaplan-Meier analysis and the Cox proportional hazards regression analysis.Nomograms were formulated on the results of Cox proportional hazards model analysis of the 686 patients(Primary cohort).The predictive accuracy and discriminative ability of the nomogram were determined by concordance index(C-index)and calibration curve.And finally,the predictive effects of nomograms were compared with five currently classical staging systems on HCC as follows: Barcelona Clinic Liver Cancer staging system(BCLC),Tumor-Node-Metastasis staging system(TNM,seventh edition),Japan Integrated Staging System(JIS),Chinese University Prognostic Index(CUPI)and Hong Kong Liver Cancer Staging system(HKLC).The results were validated with a new 225-patient validation cohort in May and June 2010 at our institution.SPSS Statistics(Version 22.0,IBM,New York,USA)and R softeware(Version 3.2.2,http://www.r-project.org/)were used to analyze all data acquired from this study.ResultsThe pathological types of MVIAccording to the histopathological characters of MVI,MVI could be divided into four pathological types in detail,containing Free type(26.0%),Adhesion type(12.2%),Invasion type(22.9%)and Break type(38.9%);or two pathological types briefly: Non-invasion(Free and Adhesion type,38.2%)and Invasion(Invasion and Break type,61.8%).Kaplan-Meier curve demonstrated that the pathological type of MVI was significantly associated with OS and TTER(P<0.001).The novel classification of MVIMultivariate analysis certified only the number of MVI was significantly associated with early recurrence;the pathological type and number of MVI were both independently related to overall survival with similar hazard ratios(1.7 and 2.0).Hence,these two histologic features were selected as primary risk factors to classify MVI.Based on the quantity of risk factors involved,the patients with MVI were classified as follows: M1,Low risk,no risk factor;M2,Moderate risk,1 risk factor;M3,High risk,2 risk factors.Besides,M0 was for the patients without MVI.Kaplan-Meier curve demonstrated that the novel classification system of MVI could make a satisfying risk evaluation for overall survival(P<0.001)and early recurrence(P<0.001).The establishment,validation and comparison of prognostic nomograms for HCC.On the Cox proportional hazards regression analysis of the primary cohort,eight independent factors,containing AFP,CA19-9,transfusion,diameter,number,capsule,satellite and the classification of MVI,were included to the nomogram for overall survival;Seven independent factors for early recurrence,including age,AFP,diameter,number,capsule,satellite and the number of MVI,were included to the nomogram for early recurrence.Based on these results,the nomograms were established.The C-indices of nomograms for overall survival and early recurrence were 0.78 and 0.72,which were both significantly higher than the following five classical staging systems: BCLC(0.58/0.54),TNM(seventh edition,0.67/0.68),JIS(0.58/0.52),CUPI(0.52/0.55)and HKLC(0.72/0.73).The calibration curves also showed good agreement between the predictions by nomogram and actual observations.The above results were confirmed in the validation cohort except HKLC.In the validation,the C-indices of nomograms for survival and early recurrence were also higher than HKLC,but there were no significantly differences.ConclusionsThe present study demonstrated a pathological type of MVI,established a novel classification system for MVI and draw two prognostic nomograms for overall survival and early recurrence.All of these could make a satisfying prognosis evaluation for early recurrence or long-term survival.Taken together;these tools will provide a valuable frame of reference for the clinical assessment of the risk of postoperative early recurrence,long-term survival and the development of individualized treatment regimens.