| Introduction and ObjectiveCurrently, curative hepatectomy remains the best option for early hepatocellular carcinoma(HCC).However, there are two types hepatectomy for HCC, one is anatomical hepatectomy and the other is non-anatomical hepatectomy. The anatomical hepatectomy(A group) is the liver segments and lobes resection according to Couinaud's views. The anatomic hepatectomy general isn`t need block the first hepatic hilum by Pringle method, and request dissect the hepatic-stem and the hepatic vein, then deligation and shearing them. While non- anatomical resection (B group) is the liver resection of a tumor without regard to segmental or lobar anatomy with resection margin at least 1.0cm. Non-anatomical resection usually need block hepatic blood flow by Pringle method, occlusion of hemihepatic blood flow or without occlusion the blood flow. Currently, there wasn`t final conclusion about the prognostic effect of anatomical versus non-anatomical resection for HCC. The standards of evidence based medicine of the published documents were B grade evidence or C grade evidence, without A grade evidence. To research this question, the best method is randomized controlled trial. So we designed this RCT and wanted to reveal which hepatectomy could decrease the recurrence rate, elevate the disease-free survival rate and the overall survival rate.Pathologic large slice can be observed the process of tumour cell and constitution, junctional zone cell and constitution, normal tissue. It can be used to study the distribution, number, and distance of micrometastasis. The liver specimen go along the portal venous flow and the tumour max diameter location cross section were slivered, then manufacture the pathologic large slice of operation specimen. We studied the number,type and distance of micrometastasis, wanted to offer the pathologic evidence for operation type.Hematogenous metastasis is the main metastasis mode of HCC. Currently, AFP mRNA was considered the useful marker of circulating tumor HCC cells. Real time fluorescent quantitation RT-PCR is the ideal method to detect the CTCs because of high performance, high specificity, high sensitivity. 5ml peripheral blood before and after hepatectomy for HCC were collected, then peripheral blood mononuclear cells (PBMCs, contain the CTCs) were extracted, and the AFP mRNA was detected by real-time fluorescent quantitative RT-PCR analysis. To compare the level change of AFP mRNA, we want to offer the cytological evidence for operation type.Methods and Results1. According to the including criteria, excluding criteria and randomization procedure, every HCC patient was done corresponding curative hepatectomy, collected the clinical, operation and pathology datas. All patients were followed with liver biochemistry, AFP serum samples and abdominal ultrasonography every 2 months and chest X-ray every 6 months. A CT scan was performed when a recurrence or metastasis was suspected.The patients were judged whether recurrence according to the recurrence criteria, recorded the death, then analysised whether the recurrence rate, death rate, and operation complication rate were different according to different operation type. Recurrence rates, disease-free survival rate and overall survival rates were evaluated using the Kaplan-Meier method and compared using the Log-rank test. Other factors were analysised about prognosis also.As well as this survey, an analysis of patients with HCC who underwent curative hepatic resection at Institute of Hepatobiliary Surgery, Southwest Hospital between January 2006 and June 2007 was carried out. There were 133 patients were enrolled in this study. Anatomical resection was performed in 67 patients (A group) and non-anatomical resection( B group) in 66 patients. The follow-up by time was March 2008, and median follow-up period after the surgery was 19 months (range, 8–27 months).The following parameters were compared in two groups: patient age, sex, Child-Pugh classification, serum HBsAg, ICGR-15, serum AFP, hepatic function, number and size of tumors, Edmondson grade, liver cirrhosis and TNM grade, and no significant differences were found between A and B groups in terms of the clinicopathologic findings. Postoperative analysis of variables including tumor-free resection margin, operation hemorrhage, perioperative blood transfusion, post-operation liver function, operation time, length of hospital stay, number and type of complications, recurrence rate, death rate, disease-free survival rates, and overall survival rates. The operation hemorrhage of A group(744.8±539.0 ml)is less than that of B group(952.3±634.1 ml)(p=0.044), and the perioperative blood transfusion of A group is less than that of B group(p=0.035). The ALT and TBIL level of A group are lower than those of B group at the 3th-, 5th- post operation day. A case operation-related death occurred in each group. The numbers of complication and man-time complication in two group are 46 and 57 respectively. The complication rate was higher in B group(40.9%,27/66) than in A group (28.4%,19/67), but the difference was not significant(p=0.198). While the man-time complication rate was higher significant in B group(54.5%,36/66) than in A group (31.3%,21/67) (p=0.014). Altogether, 43 (32.3%,43/133) patients experienced tumor recurrence: 33(24.8%, 33/133) had an intrahepatic recurrence and 10(7.5%, 10/133) had an extrahepatic recurrence. The recurrence and metastasis rate was higher significant in B group(42.4%,28/66) than in A group (22.4%,15/67)(p=0.022). The mortality was higher in B group (22.7%,15/66) than in A group (14.9%,10/67), but the difference was not significant(p=0.353).By Kaplan-Meier survival analysis, the 1-year recurrence rates were 22.9% in A group and 41.8% in B group, respectively (p=0.018). The 1-year disease-free survival rates were 75.5% and 48.2%, respectively (p=0.003). The corresponding 1-year overall survival rates were 86.8% and 78.6% (p=0.277). According to univariate factor analysis, we performed the multivariate regression analysis with the Cox proportional hazard model, and multivariate analysis identified five factors (anatomic resection , micrometastasis, blood lost volume>600ml, AFP mRNA level before operation>150.0 and tumor diameter) as significantly influencing the recurrence rate, and three factors (anatomic resection , micrometastasis and tumor bouncary fuzziness ) as significantly influencing the disease-free survival rate. Anatomic resection was confirmed to be an independent favorable factor for disease-free survival.2. The boundary, tumor amicula and macroscopic metastasis of the resection specimens were observed and recorded, and tumour diameter, RM, specimens length were measured. After the specimens were fixed, they were manufactured large pathologic slices. The number, type and distance of micrometastasises and Edmondson grade were observed by light microscope. The distances of micrometastasises on unfixed liver resection specimen were calculated again by the shrinkage rate of the fixed specimen from each specimen on the pathologic section. In this study, micrometastasis was identified as two types: (1) microscopic tumor thrombus and (2) tumor satellite micronodules.In total, 133 patients were studied and their liver resection specimens were manufactured large pathologic slices. We observed 54.9% (73/133) resection specimens had micrometastases and found 136 micrometastases. There were 13.2% (18/136) tumor satellite micronodules and 86.8% (118/136) microscopic tumor thrombus. There were 61.0% (83/136) microscopic portal vein tumor thrombus, 15.4% (21/136) microscopic liver vein tumor thrombus and 10.3% (14/136) microscopic tumor thrombus difficulty identify. The distances median of micrometastasises was 3.6mm and range was (1.1mm-20.2mm).The intrahepatic micrometastases were correlated with tumour diameter, amicula integrity, pTNM stage and Edmondson grade, not correlated with tumor numbers and serum AFP. Altogether, 58.2% (39/67) A group patients had micrometastases and 78 micrometastases were found: 51 microscopic portal vein tumor thrombus, 10 tumor satellite micronodules, 9 microscopic liver vein tumor thrombus and 8 microscopic tumor thrombus difficulty identify. While 51.5% (34/66) B group patients had micrometastases and 58 micrometastases were found: 32 microscopic portal vein tumor thrombus, 8 tumor satellite micronodules, 12 microscopic liver vein tumor thrombus and 6 microscopic tumor thrombus difficulty identify. The micrometastases rate was no significant in A group (58.2%, 39/67) and in B group (51.5%, 34/66) (p=0.334). The numbers of micrometastases and microscopic portal vein tumor thrombus in A group were higher than those in B group with Mann-Whitney U test(p=0.043, p=0.000). By Kaplan-Meier survival analysis, the 1-year recurrence rates were 19.7% in no micrometastases group and 43.1% in micrometastases group, respectively (p=0.005). The 1-year disease-free survival rates were 76.0% and 49.4%, respectively (p=0.001). The corresponding 1-year overall survival rates were 88.5% and 78.3% (P = 0.032).3. The 5ml peripheral vein blood from 133 HCC patients were collected before and after hepatectomy into heparin tubes, then the peripheral blood mononuclear cells (PBMCs, contain the CTCs) were extracted, the all RNA was extracted and the AFP mRNA was detected by real-time fluorescent quantitative RT-PCR analysis. The peripheral vein blood from 8 patients with hepatitis B and cirrhosis, 4 patients with hyperplasia, 8 patients with hepatic hemangioma, 10 healthy volunteers were collected and AFP mRNA were detected as control groups.The sensitivity was determined theoretically at 1 AFP mRNA positive cell in approximately to 106-107 of mononuclear blood cells.The median data of AFP mRNA level of HCC was 3.97×10-3(9.1×10-7～6.52×10-1), and higher significant than those of control groups(p=0.000). The median data of AFP mRNA level after hepatectomy was (1.673×10-2, range: 8.0×10-7～5.170×10-1), and higher significant than that of before hepatectomy (3.974×10-3, range: 9.0×10-7～6.518×10-1) (p=0.000). The level of AFP mRNA was no different between A group and B group before hepatectomy. The AFP mRNA level was higher in the B group (median, 2.24×10-2, range: 4.3×10-6～5.10×10-1)than in A group (median, 1.35×10-2, range:1.32×10-6～4.17×10-1), but the difference was not significant (p=0.092). The AFP mRNA level before hepatectomy was correlated with tumour diameter, micrometastasis and pTNM stage, and not correlated with tumor numbers, serum AFP, amicula integrity, and Edmondson grade. The AFP mRNA level before and after hepatectomy were correlated with recurrence, disease-free survival and overall survival. By Kaplan-Meier survival analysis, the 1-year recurrence rates were 20.7% in the low AFP mRNA level before hepatectomy group and 44.7% in the high AFP mRNA level before hepatectomy group, respectively (p=0.003). By Kaplan-Meier survival analysis, the 1-year recurrence rates were 23.4% in the low AFP mRNA level after hepatectomy group and 43.3% in the high AFP mRNA level after hepatectomy group, respectively (p=0.015).Conclusions1. Compare to non-anatomical hepatectomy, anatomical hepatectomy can degrade the early recurrence rate and elevate the early disease-free survival rates. The main reason is that the micrometastasis of HCC are mostly microscopic portal vein tumor thrombus and anatomical hepatectomy can clear more micrometastasis.2. Compare to non-anatomical hepatectomy, anatomical hepatectomy can decrease operation hemorrhage, depress the liver function lesion, decrease complication.3. The other early recurrence factors of HCC are operation hemorrhage, micrometastasis, AFP mRNA level before hepatectomy and tumor diameter.4. Analysis of AFP mRNA by real-time fluorescent quantitative RT-PCR is a very sensitive method for detecting circulating HCC cells,and can indicate the presence of hematogenous metastasis in patients with HCC. HCC cells can be released into the blood circulation because of hepatectomy. Monitoring AFP mRNA in peripheral vein blood may predict recurrence and prognosis for HCC.
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