Ki-67在肝细胞肝癌患者根治性肝切除术后短期肿瘤复发预测中的价值

Significance of Ki-67 expression in the prognosis of patients with short-term recurrence of hepatocellular carcinoma after radical resection hepatectomy

目的探讨Ki-67在肝细胞肝癌（肝癌）患者肿瘤组织中的表达情况及其在肿瘤完全切除（R0）肝切除术后短期肿瘤复发预测中的价值。方法回顾性研究2003年1月至2008年12月在青岛大学医学院附属医院肝胆外科行R0肝切除术的290例肝癌患者的临床资料。所有患者均签署知情同意书，符合医学伦理学规定。男性242例，女性48例，中位年龄55岁。另取81例癌旁组织标本和79例肝硬化组织标本作对照。收集患者的血清病毒学结果、甲胎蛋白（AFP）、肿瘤直径、肿瘤数目，有否卫星灶、血管癌栓、肝被膜侵犯、区域淋巴结转移及肿瘤组织学分化程度等临床病理学资料，并收集术后随访患者的存活时间、肿瘤复发情况等随访资料。根据随访结果将患者分为复发组和非复发组，复发组进一步分为短期复发组（复发时间≤6个月）和非短期复发组（复发时间〉6个月）。应用组织芯片技术和免疫组织化学方法检测标本中Ki．67的表达情况。采用旷检验比较各组Ki-67阳性表达率的差异，应用Cox比例风险回归模型分析Ki-67阳性表达对肝癌术后短期肿瘤复发预测的价值。结果所有患者接受了随访，中位随访时间42个月（3-105个月）。随访期问共有190例（65．5％）确诊为肝癌复发转移。短期复发组患者59例，占复发组的31．1％。短期复发组中，肝外转移者20例（33．9％），与非短期复发组18例（13．7％）相比，前者肝外转移发生率明显升高，差异有统计学意义（X^2=10．331，P=0．001）。短期复发组病死率94．9％（56／59）明显高于非短期复发组67．2％（88／131）（X^2=20．703，P〈0．001）。肝癌组Ki-67阳性表达206例（71．0％），对照组组织均不表达，差异有统计意义（X^2=209．610，P〈0．001）；短期复发组与非短期复发组的Ki-67阳性表达率分别为84．7％（50／59）和70．2％（92／131），两组比较差异有统计学意义（X^2=4．540，P=0．033）。肿瘤直径〉5cm、肿瘤数目多、有卫星灶、有血管癌栓、区域淋巴结转移、组织学检查为中低分化癌和Ki-67阳性表达的患者术后短期肿瘤复发率明显增高，比较差异均有统计学意义（均为P〈0．05）。Cox比例风险回归模型分析结果示肿瘤直径、血管癌栓、组织学分化程度和Ki-67阳性表达是肝癌患者R0肝切除术后短期肿瘤复发的独立危险因素。结论肝癌组织中Ki-67的阳性表达率增高，Ki-67是预测R0肝切除术后短期肿瘤复发的重要指标，Ki-67阳性提示术后的短期肿瘤复发率高且预后差。

Objective To study the expression of Ki-67 in hepatocellular carcinoma （HCC） and its significanee in the prognosis of patients with short-term recurrence of HCC after radical resection （R0）hepatectomy. Methods Clinical data of 290 HCC patients with R0 hepatectomy in the department of hepatobiliary of the Affiliated Hospital of Medical College Qingdao University from January 2003 to December 2008 were analyzed retrospectively. Local ethical committee approval had been received and that the informed consent of all participating subjects was obtained. Two hundred and forty two patients were males and 48 were females. The mean age of the patients was 55 years old. The other 81 adjacent tissues samples and 79 cirrhotic tissues samples were collected as the control group. Clinical and pathological information was reviewed such as serum markers of hepatic viral infection, alpha-fetoprotein （AFP）, tumor size, multiple lesion, satellite focus, vascular invasion, liver capsule invasion, region lymph node metastasis, and histological differentiation. The patients were followed up after operation. The data of survival time and tumor recurrence were collected. According to the results of follow-up, the patients were divided into recurrence group and non-recurrence group, and the patients in the recurrence group were further divided into short-term recurrence group （recurrence time ≤6 months） and non-short-term recurrence group （recurrence time〉6 months）. The expressions of Ki-67 in these tissues were examined by tissue microarray technology and immunohistochemistry methods. The Chi-square test was used to examine the difference of expression of Ki-67 between these groups and Cox multiple regression model was applied to analyze the positive expression of Ki-67 in the prognosis of patients with short-term recurrence of HCC after R0 hepatectomy. Results All the patients were followed up with the median follow-up time was 42 months （3-105 months）. One hundred and ninety patients （65.5%）were diagnosed recurrence with metastasis during the follow-up period. There were 59 patients （31.1% of the recurrence group ） in the short-term recurrence group. There were 20 cases （33.9%）with extrahepatic metastasis in the short-term recurrence group, while 18 cases （13.7%）in the non-short-term recurrence group. The incidence rate of extrahepatic metastasis of patients in short-term recurrence group was much higher. There was significant difference between two groups （A2=10.331,P=0.001）. The mortality rate in the short-term recurrence group was 94.9% （56/59）, which was higher than that in non-short-term recurrence group 67.2%（88/131 ）（X^2=20.703,P〈0.001）. The positive expression rate of Ki-67 in HCC tissues was 71.0%（206/290）, while no expression of Ki-67 in the adjacent non-cancerous tissues and cirrhotic tissues （X^2=209.610, P〈0.001）. The positive expression rate of Ki-67 was 84.7% （50/59） in the short-term recurrence group and 70.2% （92/131） in the non-short-term recurrence group （X^2=4.540,P=0.033）. The short-term recurrence rate after resection was found much higher in patients with tumor size 〉5 cm, multiple lesion, satellite focus, vascular invasion, liver capsule invasion, region lymph node metastasis, and middle, poor histological differentiation and positive Ki-67 expression （all in P〈0.05）. The tumor size, vascular invasion, differentiation of histological examination and Ki-67 expression were independent factors for the patients with short-term recurrence of HCC after R0 hepatectomy. Conclusions The positive expression rate of Ki-67 is higher in HCC patients＇ tissues, which is an important prognostic factor for patients with short-term recurrence of HCC after R0 hepatectomy. The positive expression of Ki-67 is associated with high incidence of short term recurrence and poor prognosis in HCC patients following resection.