目的 分析混合型肝细胞-胆管细胞癌(cHCC-CC)的临床病理特征及预后因素.方法 采用回顾性队列研究方法.收集2005年1月至2014年12月中南大学湘雅医院收治的72例原发性肝癌患者的临床病理资料.32例患者经术后病理学检查确诊为原发性cHCC-CC,设为cHCC-CC组;同期40例患者经术后病理学检查确诊为原发性肝细胞肝癌(HCC),设为HCC组.观察指标:(1)临床病理特征:男性、年龄＞ 60岁、HBsAg阳性、AFP阳性、CA19-9阳性、CEA阳性、肝硬化、肝功能Child-Pugh A级、肿瘤直径＞5 cm、肿瘤有包膜、单发肿瘤、伴门静脉癌栓、伴胆管癌栓、淋巴结转移阳性、TNM Ⅰ～Ⅱ期、Edmondson-Steiner Ⅰ～Ⅱ期.(2)手术切除标本病理学检查特征.(3)随访情况:患者中位生存时间,1、3、5年总体生存率和无瘤生存率.(4)cHCC-CC组患者预后因素分析:AFP、CA19-9、肝硬化、肿瘤直径、肿瘤包膜、肿瘤数目、门静脉癌栓、胆管癌栓、淋巴结转移、Edmondson-Steiner分期、术中出血量、术中输血、手术切缘距离.采用门诊和电话方式进行随访,了解患者生存及肿瘤复发、转移情况.随访时间截至2015年10月.计数资料比较采用x2检验.采用Kaplan-Meier法绘制生存曲线,Log-rank检验进行生存分析.采用COX回归模型进行预后因素分析.结果 (1)临床病理特征:cHCC-CC组和HCC组患者CA19-9阳性分别为16例和5例,肿瘤有包膜分别为4例和17例,伴胆管癌栓分别为12例和1例,淋巴结转移阳性分别为6例和1例,两组患者上述指标比较,差异均有统计学意义(x2=10.471,9.723,13.005,4.009,P＜0.05).(2)手术切除标本病理学检查特征:cHCC-CC组患者手术切除标本病理学检查结果显示同时具有HCC样组织和胆管细胞癌样组织细胞特征.免疫组织化学染色检测示肝细胞石蜡抗原、细胞角蛋白7、细胞角蛋白19、祖细胞标志物阳性.HCC组患者仅表现为HCC样组织细胞特征.免疫组织化学染色检测示AFP阳性.(3)随访情况:72例患者均获得术后随访,随访时间为5.0 ～74.0个月,中位随访时间为41.0个月.cHCC-CC组患者中位生存时间为14.5个月,1、3、5年总体生存率分别为62.3％、38.9％、19.1％,1、3、5年无瘤生存率分别为50.0％、23.9％、4.0％.HCC组患者中位生存时间为46.8个月,1、3、5年总体生存率分别为82.3％、57.4％、38.6％,1、3、5年无瘤生存率分别为72.9％、35.6％、17.6％.两组患者总体生存情况和无瘤生存情况比较,差异均有统计学意义(x2=4.231,3.881,P＜0.05).(4) cHCC-CC组患者预后因素分析:单因素分析结果显示:CA19-9、肿瘤包膜、肿瘤数目、胆管癌栓、淋巴结转移、Edmondson-Steiner分期均是影响cHCC-CC患者预后的相关因素(HR=1.824,0.227,0.441,1.421,1.887,2.745,95％可信区间:1.126～2.172,0.118～0.654,0.318 ～0.764,1.071～4.231,1.017 ～5.643,1.223 ～6.421,P＜0.05).多因素分析结果显示:淋巴结转移阳性、Edmondson-Steiner Ⅲ～Ⅳ期是影响cHCC-CC患者预后的独立危险因素(RR=1.658,2.912,95％可信区间:1.027 ～7.542,1.143 ～6.582,P＜0.05).结论 CA19-9阳性、肿瘤无包膜、伴胆管癌栓、淋巴结转移阳性一定程度上可提示cHCC-CC诊断.cHCC-CC预后差于HCC,淋巴结转移阳性、Edmondson-Steiner Ⅲ～Ⅳ期是影响cHCC-CC患者预后的独立危险因素.%Objective To analyze the clinicopathological characteristics and prognostic factors of combined hepatocellular-cholangiocarcinoma (cHCC-CC).Methods The retrospective cohort study was conducted.The clinicopathological data of 72 patients with primary hepatocellular carcinoma (HCC) who were admitted to the Xiangya Hospital of Central South University between January 2005 and December 2014 were collected.Thirty-two patients who were diagnosed with cHCC-CC by postoperative pathological examination were allocated into the cHCC-CC group and 40 patients who were diagnosed with HCC by postoperative pathological examination were allocated into the HCC group.Observation indicators:(1) clinicopathological characteristics:male,age ＞ 60 years,positive hepatitis B surface antigen (HBsAg),positive alpha-fetoprotein (AFP),positive CA19-9,positive carcinoembryonic antigen (CEA),liver cirrhosis,Child-Pugh grade A,tumor diameter ＞ 5 cm,tumor with capsule,solitary tumor,portal vein tumor thrombus (PVTT),cancer thrombus of the bile duct,positive lymph node metastasis,stage Ⅰ-Ⅱ of TNM stage,Edmondson-Steiner stage Ⅰ-Ⅱ;(2) pathological features of surgical incision specimens;(3) follow-up situations:median survival time,1-,3-,5-year survival rates and tumor-free survival rate;(4) prognostic factors analysis of patients with cHCC-CC:AFP,CA19-9,liver cirrhosis,tumor diameter,tumor capsule,number of tumor,PVTT,cancer thrombus of the bile duct,lymph node metastasis,Edmondson-Steiner stage,volume of intraoperative blood loss,intraoperative blood transfusion,distant from surgical margin.Follow-up using outpatient examination and telephone interview was performed to detect survival of patients and tumor recurrence or metastasis up to October 2015.Comparison of count data was analyzed using the chi-square test.The survival curve was drawn by the Kaplan-Meier method,and the survival analysis was done using the Log-rank test.The prognostic analysis was done using the COX regression model.Results (1) Clinicopathological characteristics:positive CA19-9,tumor with capsule,cancer thrombus of the bile duct and positive lymph node metastasis were detected in 16,4,12,6 patients in the cHCC-CC group and 5,17,1,1 patients in the HCC group,respectively,with statistically significant differences between the 2 groups (x2=10.471,9.723,13.005,4.009,P ＜ 0.05).(2) Pathological features of surgical incision specimens:pathological results showed that surgical incision specimens in the cHCC-CC group had characteristics of HCC tissues and cholangiocarcinoma tissues.The antigenic activity of hepatic cells in paraffin sections,Cytokeratin 7,Cytokeratin 19 and progenitor cell markers were positive by immunohistochemical staining detection.Patients in the HCC group had characteristics of HCC tissues,with positive AFP using immunohistochemical staining detection.(3) Follow-up situations:all the 72 patients were followed up for 5.0-74.0 months with a median time of 41.0 months.The median survival time,1-,3-,5-year survival rates,1-,3-,5-year tumor-free survival rates were 14.5 months,62.3％,38.9％,19.1％,50.0％,23.9％,4.0％ in the cHCC-CC group and 46.8 months,82.3％,57.4％,38.6％,72.9％,35.6％,17.6％ in the HCC group,respectively,with statistically significant differences in overall survival and tumor-free survival between the 2 groups (x2=4.231,3.881,P ＜ 0.05).(4) Prognostic factors analysis of patients with cHCC-CC:results of univariate analysis showed that CA19-9,tumor capsule,number of tumor,cancer thrombus of the bile duct,lymph node metastasis and Edmondson-Steiner stage were related factors affecting prognosis of patients with cHCC-CC [HR =1.824,0.227,0.441,1.421,1.887,2.745,95％ confidence interval (CI):1.126-2.172,0.118-0.654,0.318-0.764,1.071-4.231,1.017-5.643,1.223-6.421,P ＜ 0.05].Results of multivariate analysis showed that lymph node metastasis and stage Ⅲ-Ⅳ of Edmondson-Steiner stage were independent risk factors affecting prognosis of patients with cHCC-CC (RR =1.658,2.912,95％ CI:1.027-7.542,1.143-6.582,P ＜0.05).Conclusions The positive CA19-9,tumor without capsule,cancer thrombus of the bile duct and positive lymph node metastasis can partly predict cHCC-CC.The prognosis of patients with cHCC-CC is worse than that with HCC.The positive lymph node metastasis and stage Ⅲ-Ⅳof Edmondson-Steiner stage are independent risk factors affecting prognosis of patients with cHCC-CC.
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