Biomolecular Prognostic Markers Of Intrahepatic Cholangiocarcinoma

?Background and aims?Intrahepatic cholangiocarcinoma(ICC)is a rare malignancy that arises from epithelial cells of the biliary system and ranks only behind of human hepatocellular carcinoma(HCC).The morbidity and mortality of ICC has drastically increased over the past decades worldwide.ICC has some features such as: making early diagnosis difficult,rapid progress,high grade of malignance,poor prognosis,etc.Currently,surgical resection is considered the most effective treatment of ICC at an early stage,and is only way to provide long-term survival time for patients.But the fact is that most patients are not eligible for resection because of a delayed diagnosis.Moreover,the high rate of recurrence and metastasis is a major reason that causes shorten survival.It is significant to explore more sensitive and specific molecular markers on ICC,which will contribute to the early diagnosis,the detection of recurrence and metastasis,monitoring of prognosis,as well as the development of molecular targeted therapy.In this study,we made a comprehensive survey with ICC pathological markers in our hospital and investigated the relationship between biomolecular markers and clinicopathological features and prognosis of patients of ICC.Our results will provide a new focus for the ICC molecular classification and the development of targeted drugs.?Methods?From 2005-01-01 to 2010-12-31,a total of 483 patients underwent hepatectomy for ICC at Shanghai Eastern Hepatobiliary Surgery Hospital were include in this study.All of the patients had been diagnosed by pathology.The retrospective study was adopted.The patients were given followed-up by telephone and the last followed-up time was 2016-11-23.The Kaplan-Meier(K-M)method was used to describe overall survival and disease-free survival curves,and the Log-rank test was used to compare the differences.The univariate analysis and multivariate analysis were performed using the COX regression model.Finally,the chi-square test was used to analyze the relationship between biomolecular markers and clinicopathological features.?Results?Among the 483 patients,there were 312 men(64.6%)and 171 women(35.4%)with male-to-female ratio of 1.82:1.The average age was 55 years.Until the end of the study,a total of 51 patients were lost to follow-up,and 387 patients died.There were 432 patients received complete follow-up data,the median survival was 11.53 months after surgery,and the overall survival rates of 1-,3-,5-year were 49.1%,17.6% and 11.3%,respectively;the disease-free survival rates of 1-,3-,5-year were 15.9%,2.8% and 1.3%,respectively,with the median disease-free survival of 4.53 months.(1)Results of univariate and multivariate analysis showed that AFP > 20 ug/L,CEA > 10 ug/L,and CA19-9 > 39 U/ml,pre-ALB < 170 mg/L,hepatolithiasis,lymph node metastasis,distant metastasis,number of tumors(p = 0.008,0.010,0.013,0.009,0.030,<0.001,0.002,0.028,HR = 1.448,1.481,1.356,1.424,1.515,1.742,1.593,2.104)were independent prognostic factors affecting patients postoperative survival of ICC.(p < 0.05).(2)The biomolecule markers of ICC in our hospital included CK18,CK19,AQP-1,MUC1,p53,COX-2,CA19-9,Ki67,?-catenin,HER-2,PCNA,CD34,Gly-3,pCEA.Results of univariate analysis showed that CK18,CK19,AQP-1,MUC1 were relevant prognostic factors affecting patients overall survival after liver resection of ICC,p = 0.013,0.028,0.002,0.029.Results of COX regression analysis showed that AQP-1,MUC1 were the independent biomolecular prognostic markers affecting the overall survival of ICC patients after liver resection,AQP-1(p = 0.006,HR = 0.669,95%CI: 0.502-0.892),MUC1(p = 0.012,HR = 1.616,95%CI: 1.111-2.349).Results of the chisquare test showed that AQP-1 negative expression was correlated with GGT > 61 U/L(p < 0.001)and microvascular tumor thrombosis(p = 0.023);MUC1 positive expression was correlated with CA19-9 > 39 U/ml(p < 0.001).(p < 0.05).(3)Results of multivariate analysis showed that AQP-1(p = 0.011,HR = 0.652,95%CI: 0.468-0.907)was the independent factor affecting ICC patients with postoperative disease-free survival.(p < 0.05).?Conclusions?AQP-1,MUC1 were the independent biomolecular prognostic markers affecting the overall survival of ICC patients after liver resection,which were expected to be molecular targets for ICC therapy.