New Staging Systems Based On HBV Infection Status For Intrahepatic Cholangiocarcinoma

Background: Cancer classification is intended to establish prognosis and enable the selection of the adequate treatment for the best candidates.In addition,it helps researchers to exchange information and design clinical trials with comparable criteria.However,unfortunately,although currently there are several prognostic staging systems for Intrahepatic cholangiocarcinoma(ICC),none of them has been widely recognized,and the main reason may be related to the significant regional differences in ICC risk factors.Chronic HBV infection is the most important risk factor of ICC in domestic population.ICC caused by HBV-related ICC and other factors not only has different clinicopathological characteristics,but also has different prognostic factors and prognosis.It may be more reasonable to establish ICC staging system according to the status of HBV infection,which has not been reported at present.The objectives of the current report were to propose a new prognostic scoring system applicable for ICC and to evaluate the prognostic validity of the Naval Medical University(NMU)staging system and American Joint Committee on Cancer(AJCC)/Union for International Cancer Control(UICC)7th and 8th edition systems.Patients and methods: Clinical data from 1019 patients who underwent curative resection(R0 or R1)for ICC were retrospectively analyzed at the Eastern Hepatobiliary Surgery Hospital between July 2005 and June 2015.According to the status of HBV infection,they were divided into the HBV-related ICC group(H group: serum hepatitis B surface antigen(HBsAg)positive or/and histological HBsAg positive or/and serum HBV NDA positive)and non-HBV-related ICC group(NH group).Univariate and multivariate survival analyses were performed to identify predictors of postoperative outcomes,and simple and effective staging systems(H staging system and NH staging system)were developed,respectively.The validity of the prognostic staging system was prospectively assessed in 434 patients who underwent curative resection(R0 or R1)for ICC between July 2015 and July 2017 at the same institution and compared with the NMU staging system,AJCC/UICC 7th and 8th edition systems.The prognostic power of two prognostic staging systems for ICC patients was quantified using C-index,linear trend χ2 test and AUC(receiver operating characteristic curve,ROC).Result: A total of 1019 ICC patients were included in the primary cohort,including 662 males(65.0%),357 females(35.0%)(male: female = 1.85:1),median age 57(IQR 49-64)years old.The disease-free survival time was 6.11 months,and the 1-,3-,and 5-year recurrence rates were 73%,83%,and 87%,respectively.The median survival time(MST)was 16.10 months,and the 1-,3-,and 5-year survival rates were 52%,27%,and 18%,respectively.Among the 1019 ICC patients,450(44.2%)had HBV-related ICC and 569(55.8%)had non-HBV-related ICC.(1)In the H group: The disease-free survival time was 7.26 months,and the 1-,3-,and 5-year recurrence rates were 67%,79%,and 84%,respectively.The MST was 17.73 months,and the 1-,3-,and 5-year survival rates were 54%,30%,and 21%,respectively.On univariate analysis of the primary cohort,hepatolithiasis(P = 0.005),preoperative serum AST > 37U/L(P < 0.001),serum Pre-ALB < 170mg/L(P < 0.001),γ-GGT > 61U/L(P < 0.001),serum AKP > 129U/L(P < 0.001),serum AFP > 20μg/L(P = 0.002),serum CEA > 10μg/L(P < 0.001),serum CA19-9 > 39U/ml(P < 0.001),multiple tumors(P < 0.001),tumor diameter ≥ 5cm(P < 0.001),vascular invasion(P < 0.001),regional lymph node metastasis(P < 0.001),direct invasion and/or local extrahepatic metastasis(P < 0.001)were closely related to the poor prognosis of ICC patients after partial hepatectomy.On multivariate analysis of the primary cohort,preoperative serum AFP > 20μg/L(hazard ratio(HR)1.307;95% confidence interval(CI)1.002-1.705),serum CEA > 10μg/L(HR 1.450;95% CI 1.011-2.080),serum CA19-9 > 39U/ml(HR 1.381;95% CI 1.089-1.750),multiple tumors(HR 1.556;95% CI 1.228-1.970),tumor diameter ≥ 5cm(HR 1.385;95% CI 1.049-1.828),vascular invasion(HR 1.774;95% CI 1.360-2.314),regional lymph node metastasis(HR 1.742;95% CI 1.284-2.363)were independent predictive factors of survival in ICC.Using the above seven independent prognostic factors,the H staging system was proposed: stage I disease was defined as conforming with zero of the seven predictive factors;stage II disease was defined as conforming with one of the seven predictive factors;stage III disease was defined as conforming with two or three of the seven predictive factors;stage IV disease was defined as conforming with four or more of the seven predictive factors.In primary cohort HBV-related ICC patients were categorized into four subsets with MST 60.00,37.50,14.21,and 8.07 months for stage I to stage IV,respectively;1-year survival rates of 90%,76%,48%,and 21% for stage I to stage IV,respectively;3-year survival rates of 66%,49%,21%,and 3% for stage I to stage IV,respectively;5-year survival rates of 51%,37%,11%,and 2% for stage I to stage IV,respectively.The prognostic power of the H staging system in the primary cohort were higher than the NMU staging system,AJCC 7th and 8th edition systems(value of Cindex,AUC and linear trend χ2 test in H staging system: 0.703,0.787 and 89.383,respectively).(2)In the NH group: The disease-free survival time was 5.76 months,and the 1-,3-,and 5-year recurrence rates were 77%,87%,and 88%,respectively.The MST was 14.95 months,and the 1-,3-,and 5-year survival rates were 50%,25%,and 16%,respectively.On univariate analysis of the primary cohort,hepatolithiasis(P < 0.001),preoperative serum PLT > 300E+09/L(P = 0.001),serum > 37U/L(P = 0.044),serum Pre-ALB < 170 mg/L(P < 0.001),serum γ-GGT > 61U/L(P < 0.001),serum AKP > 129U/L(P < 0.001),serum CEA > 10μg/L(P < 0.001),serum CA19-9 > 39U/ml(P < 0.001),multiple tumors(P < 0.001),tumor diameter ≥ 5cm(P < 0.001),vascular invasion(P = 0.009),neural invasion(P = 0.046),regional lymph node metastasis(P < 0.001),direct invasion and/or local extrahepatic metastasis(P < 0.001)were closely related to the poor prognosis of ICC patients after partial hepatectomy.On multivariate analysis of the primary cohort,hepatolithiasis(HR 1.534;95% CI 1.133-2.078),preoperative serum PLT > 300E+09/L(HR 1.519;95% CI 1.017-1.704),serum Pre-ALB < 170mg/L(HR 1.758;95% CI 1.189-1.939),serum CEA > 10μg/L(HR 1.731;95% CI 1.355-2.211),serum CA19-9 > 39U/ml(HR 1.510;95% CI 1.214-1.878),multiple tumors(HR 2.002;95% CI 1.633-2.454),regional lymph node metastasis(HR 1.565;95% CI 1.257-1.950)were independent predictive factors of survival in ICC.Using the above seven independent prognostic factors,the H staging system was proposed: stage I disease was defined as conforming with zero of the seven predictive factors;stage II disease was defined as conforming with one of the seven predictive factors;stage III disease was defined as conforming with two or three of the seven predictive factors;stage IV disease was defined as conforming with four or more of the seven predictive factors.In primary cohort non-HBV-related ICC patients were categorized into four subsets with MST 60.00,23.50,10.08,and 6.64 months for stage I to stage IV,respectively;1-year survival rates of 92%,66%,32%,and 19% for stage I to stage IV,respectively;3-year survival rates of 64%,32%,10%,and 3% for stage I to stage IV,respectively;5-year survival rates of 61%,23%,4%,and 2% for stage I to stage IV,respectively.The prognostic power of the NH staging system in the primary cohort were higher than the NMU staging system,AJCC 7th and 8th edition systems(value of C-index,AUC and linear trend χ2 test in NH staging system: 0.710,0.810 and 120.187,respectively).A total of 434 ICC patients were included in the validation cohort,including 265 males(61.1%),169 females(38.9%)(male: female = 1.57:1),median age 60(IQR 51-66)years old.The disease-free survival time was 6.90 months,and the 1-year and 3-year recurrence rates were 68% and 87%,respectively.The MST was 25.10 months,and the 1-year and 3-year survival rates were 64% and 40%,respectively.Among the 434 ICC patients,149(34.3%)had HBV-related ICC and 285(65.7%)had non-HBV-related ICC.(1)In the H group: The disease-free survival time was 6.40 months,and the 1-year and 3-year recurrence rates were 67% and 84%,respectively.The MST was 26.64 months,and the 1-year and 3-year survival rates were 63% and 47%,respectively.The prognostic power of the H staging system in the validation cohort were higher than the NMU staging system,AJCC 7th and 8th edition systems(value of C-index,AUC and linear trend χ2 test in H staging system: 0.777,0.800 and 42.338,respectively).(2)In the NH group: The disease-free survival time was 7.18 months,and the 1-year and 3-year recurrence rates were 69% and 87%,respectively.The MST was 24.2 months,and the 1-year and 3-year survival rates were 64% and 37%,respectively.The prognostic power of the NH staging system in the validation cohort were higher than the 7th and 8th AJCC staging systems(value of C-index,AUC and linear trend χ2 test in NH staging system: 0.777,0.722 and 45.668,respectively).Although the value of AUC and linear trend χ2 test in NH staging system was lower than the NUM staging system(value of AUC and linear trend χ2 test in NH staging system: 0.722 and 45.668,respectively),the value of C-index was higher than the NMU staging system(C-index: 0.729 and 0.725).Therefore,it was uncertain whether the prognostic power of NH staging system was higher than the NMU staging system.Conclusions: Compared with the AJCC/UICC ICC staging system in the 7th and 8th editions,the new ICC staging system based on HBV infection may be more accurate and effective in predicting the survival of patients after partial hepatectomy.Whether the new staging system is superior to the NMU staging system will still require further expansion of samples and multicenter validation in the future.