| Objective: The aims of this study were to demonstrate the actual impact of spontaneous rupture on the prognosis of patients with hepatocellular carcinoma,to analyze the impact of different treatments on the prognosis of patients with ruptured BCLC stage 0/A hepatocellular carcinoma,and to assess the actual impact of tumor diameter on the prognosis of patients receiving different treatments.To construct a AAA scoring system to predict the prognosis of patients with ruptured BCLC stage 0/A hepatocellular carcinoma based on the albumin-bilirubin(ALBI)grade.Methods: A total of 973 patients with spontaneous rupture of BCLC stage 0/A/B hepatocellular carcinoma and non-ruptured hepatocellular carcinoma in two hepatic surgery centers in China from January,2008 to December,2017 were enrolled to compare their baseline characteristics.Survival curves were plotted using the Kaplan-Meier method,and Log-rank tests were used to compare the prognosis of patients with ruptured hepatocellular carcinoma(r HCC)and patients with non-ruptured hepatocellular carcinoma who underwent hepatectomy and transarterial chemoembolization.r HCC patients were paired 1:1 with nonruptured hepatocellular carcinoma patients by propensity score matching.The cut-off values of 5 cm and 10 cm were used to classify r HCC patients into small r HCC group(S-r HCC,tumor diameter <5 cm),large r HCC group(L-r HCC,tumor diameter 5-10 cm)and huge r HCC group(H-r HCC,tumor diameter 5-10 cm).Survival curves were plotted using the Kaplan-Meier method to compare the overall survival rates between the S-,L-,and H-r HCC groups and between the r HCC group and the non-ruptured hepatocellular carcinoma group.Prognostic factors affecting overall survival and recurrence-free survival of r HCC patients were determined by univariate and multivariate Cox proportional risk regression models.The construction of the AAA(ALBI+AST+AFP)score was based on the ALBI grade and in combination with aspartate aminotransferase(AST)and alpha-fetoprotein(AFP).The predictive capability of AAA score,ALBI grade,AST,and AFP on the prognosis of r HCC patients was compared by time-dependent receiver operating characteristic(ROC)curve and area under curve(AUC).Results: Tumor rupture was an independent prognostic factor of overall survival(OS)and recurrence-free survival(RFS)in patients with spontaneous rupture of hepatocellular carcinoma in BCLC stage 0/A.Patients with spontaneous rupture of hepatocellular carcinoma in BCLC stage 0/A who underwent hepatectomy had a worse prognosis than patients with non-ruptured hepatocellular carcinoma after surgery in the same stage.In contrast,the prognosis of patients with spontaneous rupture of BCLC stage 0/A hepatocellular carcinoma who underwent hepatectomy was comparable to that of patients with non-ruptured BCLC stage B hepatocellular carcinoma who underwent hepatectomy or transcatheter arterial chemoembolization(P=0.780).OS was significantly higher in the Sr HCC group than in the L-r HCC and H-r HCC groups(P<0.001).After propensity score matching,the OS of the S-r HCC group was comparable to that of the non-ruptured hepatocellular carcinoma group with the same tumor diameter(P =0.290).Meanwhile,the L-r HCC and H-r HCC groups had worse OS than non-ruptured hepatocellular carcinoma group with the corresponding tumor diameter(P<0.001).Multivariate Cox regression analysis showed that the degree of cirrhosis(HR=2.393,95%CI: 1.875-3.054,P<0.001),serum alpha-fetoprotein level(HR=2.695,95%CI:1.697-4.280,P<0.001),serum aspartate aminotransferase level(HR=1.572,95%CI: 1.013-2.414,P=0.044)and tumor diameter(HR=1.065,95% CI:0.999-1.134,P=0.050)were independent prognostic factors of OS in patients receiving hepatectomy for r HCC.The AUCs of AAA score predicting 1-year,3-year and 5-year OS were 0.672,0705 and 0.739(ALBI,0.622,0.675 and 0.738;Child-Pugh,0.563,0.563 and 0.610;AFP,0.639,0.637 and 0.675;AST,0.629,0.603 and 0.629).It indicated that AAA score was better than AFP or AST alone in predicting survival at 1,3,and 5 years,and better than ALBI grade or Chlid-Pugh grade.Conclusions: Patients with spontaneous rupture of hepatocellular carcinoma in BCLC stage0/A had a prognosis comparable to that of patients with non-ruptured hepatocellular carcinoma in BCLC stage B after hepatectomy.Patients with BCLC stage 0/A r HCC with tumor diameter less than 5 cm who underwent hepatectomy had an equal prognosis as patients with non-ruptured hepatocellular carcinoma with the same tumor diameter.BCLC stage 0/A r HCC with a tumor diameter more than 5 cm could have a prognosis comparable to that of patients with non-ruptured hepatocellular carcinoma with the same tumor diameter after transarterial chemoembolization.The AAA score constructed based on the ALBI grade had good predictive capability for the prognosis of patients with ruptured hepatocellular carcinoma of different BCLC stages who underwent hepatectomy.Part Ⅰ: Impact of Hepatectomy on the Prognosis of Spontaneous Rupture of Hepatocellular Carcinoma in BCLC Stage 0/AObjective: Patients with spontaneous rupture of hepatocellular carcinoma usually have a poor prognosis and are classified as primary tumor stage T4 in the TNM staging system,but this view has been controversial.The aim of this study was to demonstrate the actual impact of spontaneous rupture on the prognosis of patients with hepatocellular carcinoma and the positive effect of hepatectomy on the prognosis of patients with spontaneous rupture in BCLC stage 0/A hepatocellular carcinoma.Methods: Eighty-six patients with spontaneous rupture of BCLC stage 0/A hepatocellular carcinoma who underwent hepatectomy and 526 patients with non-ruptured BCLC stage 0/A and B hepatocellular carcinoma who underwent hepatectomy or transcatheter arterial chemoembolization were enrolled in the department of hepatic surgery from January,2008 to December,2017,and their baseline characteristics were compared.Survival curves were plotted using the Kaplan-Meier method,and Log-rank tests were used to compare the prognosis of patients with spontaneous rupture of hepatocellular carcinoma with those with non-ruptured hepatocellular carcinoma.Independent prognostic factors affecting patient survival were analyzed by univariate and multivariate Cox proportional risk regression models.Results: Tumor rupture was an independent prognostic factor for patients with spontaneous rupture of BCLC stage 0/A hepatocellular carcinoma(OS: HR=1.685,95%CI: 1.416-2.006,P<0.001;RFS: HR=1.484,95%CI: 1.267-1.737,P<0.001).Patients with spontaneous rupture of BCLC stage 0/A hepatocellular carcinoma who underwent hepatectomy had a worse prognosis than patients with non-ruptured hepatocellular carcinoma treated with surgery at the same time(OS: HR=3.12,95%CI: 2.24-4.34,P<0.001;RFS: HR=2.26,95%CI: 1.65-3.09,P<0.001).However,the prognosis of patients with spontaneous rupture of BCLC stage 0/A hepatocellular carcinoma who underwent hepatectomy was comparable to that of patients with non-ruptured BCLC stage B hepatocellular carcinoma who underwent hepatectomy or transcatheter arterial chemoembolization(P=0.780).Conclusions: After receiving hepatectomy,patients with spontaneous rupture of BCLC stage 0/A hepatocellular carcinoma can have a comparable prognosis to that of patients with non-ruptured hepatocellular carcinoma in BCLC stage B.Therefore,not all patients with spontaneous rupture of hepatocellular carcinoma should be categorized as primary tumor stage T4.Part Ⅱ: Impact of Tumor Diameter on the Prognosis of Spontaneous Rupture of Hepatocellular Carcinoma in BCLC Stage 0/AObjective: Spontaneous rupture of hepatocellular carcinoma is classified as stage T4 according to the TNM staging system,but its rationality has been controversial.The aim of this study was to evaluate the actual impact of different tumor diameters on the prognosis of patients with spontaneous rupture of hepatocellular carcinoma in BCLC stage 0/A.Methods: Data of 973 patients with hepatocellular carcinoma,including 249 patients with ruptured hepatocellular carcinoma(r HCC)and 724 patients with non-ruptured hepatocellular carcinoma,were collected in two heptatic surgery departments in China from January,2008 to December,2017.With the help of X-tile software,the cut-off values of tumor diameter in 166 patients with r HCC undergoing hepatectomy were determined.Using 5 cm and 10 cm as cut-off values,the r HCC patients were divided into small r HCC group(S-r HCC,tumor diameter <5 cm),large r HCC group(L-r HCC,tumor diameter 5-10 cm)and huge r HCC group(H-r HCC,tumor diameter >10 cm).Patients with r HCC were matched 1:1 with patients with non-ruptured hepatocellular carcinoma using propensity score matching,and patients with non-ruptured hepatocellular carcinoma(n=136)and patients with r HCC(n=136)were successfully matched.Survival curves were plotted using the Kaplan-Meier method to compare the overall survival between the three groups of r HCC and between the r HCC group and the non-ruptured hepatocellular carcinoma group.Independent prognostic factors for r HCC patients after hepatectomy were analyzed by univariate and multivariate Cox proportional risk regression models.Results: OS was significantly higher in the S-r HCC group than in the L-r HCC and H-r HCC groups(P<0.001).After propensity score matching,OS in the S-r HCC group was comparable to that in the non-ruptured hepatocellular carcinoma group of the same diameter(P=0.290).Multivariate Cox regression analysis showed that the degree of cirrhosis(HR=2.393,95%CI: 1.875-3.054,P<0.001),serum alpha-fetoprotein level(HR=2.695,95%CI: 1.697-4.280,P<0.001),serum aspartate aminotransferase level(HR=1.572,95%CI: 1.013-2.414,P=0.044)and tumor diameter(HR=1.065,95%CI: 0.999-1.134,P=0.050)were independent prognostic factors of r HCC patients after hepatectomy.Conclusions: r HCC patients with tumor diameter less than 5cm can achieve the equal prognosis as patients with non-ruptured hepatocellular carcinoma after hepatectomy.r HCC patients with tumor diameter more than 5cm can also achieve the comparable prognosis as patients with non-ruptured hepatocellular carcinoma after transcatheter arterial chemoembolization.Part Ⅲ: Evaluation of Albumin-Bilirubin Grade in Predicting the Prognosis of Patients with Spontaneous Rupture of Hepatocellular Carcinoma in BCLC stage 0/AObjective: The aims of this study were to evaluate and compare the value of albuminbilirubin(ALBI)grade and Child-Pugh score in predicting the prognosis of patients with spontaneous rupture of hepatocellular carcinoma in BCLC stage 0/A,and to construct an ALBI-based score for predicting the prognosis of patients with spontaneous rupture of hepatocellular carcinoma in BCLC stage 0/A.Methods: Two hundred and forty-nine patients with ruptured hepatocellular carcinoma,including 155 patients in BCLC stage 0/A,were enrolled from two hepatic surgery departments in China from January,2008 to December,2017.The ALBI grade was calculated and scored,and patients were graded according to ALBI grade and Child-Pugh score.The survival curves were plotted by Kaplan-Meier method,and the overall survival between different grades were compared by Log-rank test.Independent prognostic factors were analyzed by univariate and multivariate Cox regression models.The AAA(ALBI+AST+AFP)score was constructed based on ALBI grade,combined with serum aspartate aminotransferase(AST)level and alpha-fetoprotein(AFP)level.The predictive capability of AAA score,ALBI grade,AST,and AFP on the prognosis of r HCC patients was compared by time-dependent receiver operating characteristic(ROC)curve and area under curve(AUC).Results: Univariate Cox regression analysis showed that the degree of cirrhosis,serum AST level,total bilirubin level,albumin level,AFP level,tumor size,tumor number,ALBI grade,Child-Pugh score and AAA score were all associated with the prognosis(P<0.05).Multivariate Cox regression model analysis showed that tumor diameter(HR=1.673,95%CI: 1.04-2.681,P=0.003),degree of cirrhosis(HR=2.078,95% CI: 1.708-2.528,P<0.001),AFP(HR=1.598,95% CI: 1.697-3.224,P<0.001),AST(HR=1.562,95%CI: 1.132-2.157,P<0.001)and AAA score(HR=1.553,95%CI: 1.071-2.371,P=0.042)were independent prognostic factors in BCLC 0/A r HCC patients after hepatectomy.AAA score was better than AFP or AST alone in predicting survival at 1,3,and 5 years,and better than ALBI grade or Chlid-Pugh grade.Conclusions: Compared with Child-Pugh score,ALBI grade had a better capability for predicting the prognosis of r HCC patients in BCLC stage 0/A undergoing hepatectomy.The AAA score constructed based on ALBI grade had a good predictive capability for the prognosis of patients with ruptured hepatocellular carcinoma in different BCLC stages after hepatectomy. |
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