肝内胆管癌临床病理特征及淋巴结转移特点的多中心回顾性研究(附1321例报告)

摘要

目的 分析肝内胆管癌(ICC)临床病理特征及淋巴结转移特点.方法 采用回顾性病例对照研究方法.收集2007年4月至2017年11月国内12家医疗中心收治的1 321例[第二军医大学附属东方肝胆外科医院182例、西安交通大学第一附属医院173例、陆军军医大学(第三军医大学)第一附属医院156例、中山大学肿瘤防治中心139例、复旦大学附属中山医院128例、上海交通大学医学院附属新华医院113例、大连医科大学附属第一医院109例、天津医科大学肿瘤医院84例、郑州大学第一附属医院65例、川北医学院附属医院62例、南京大学医学院附属鼓楼医院58例、浙江大学医学院附属第二医院52例]ICC患者的临床病理资料.患者完善相关检查后,根据其临床表现及检查结果,由各医疗中心制订治疗方案,行相应手术等治疗,根据术中检查结合患者实际病情决定手术方式.观察指标:(1)实验室检查及治疗情况.(2)临床病理特征与原发肿瘤位置及直径的关系.(3)淋巴结清扫及淋巴结转移诊断情况.(4)临床病理特征与淋巴结转移的关系.符合正态分布的计量资料以(x)±s表示,组间比较采用t检验;偏态分布的计量资料以M(范围)表示.计数资料比较采用x2检验.结果 (1)实验室检查及治疗情况:1 321例患者中,HBV阳性202例,占15.586％(202/1 296);血清AFP阳性(＞20 μg/L)80例,占7.339％(80/1 090);血清CEA阳性(＞5μg/L)329例,占26.299％(329/1 251);血清ALT阳性(＞75 U/L) 207例,占16.587％(207/1 248);血清CA19-9阳性(＞37 U/mL) 590例,占49.789％(590/1 185);血清TBil阳性(＞20 μmol/L)300例,占24.000％(300/1 250).1 321例患者中,1 206例施行手术治疗,其中肝切除术904例,经导管动脉内化疗栓塞术193例,经皮经肝胆管引流72例,内镜逆行胰胆管造影3例,经皮经肝胆管引流+内镜逆行胰胆管造影3例及其他治疗31例;115例原始手术名称记录缺失.(2)临床病理特征与原发肿瘤位置及直径的关系.①患者临床病理特征与原发肿瘤位置的关系:原发肿瘤位于左半肝患者的CA19-9水平≤37 U/mL、38～ 200 U/mL、＞200 U/mL分别为227、91、146例,右半肝分别为282、134、137例;原发肿瘤位于左半肝和右半肝合并肝炎患者分别为67例和111例;原发肿瘤位于左半肝和右半肝合并肝内胆管结石患者分别为73例和47例;两者上述指标比较,差异均有统计学意义(x2=6.710,5.656,12.534,P＜0.05).进一步分析结果显示:合并肝炎患者ICC发病年龄为(63±10)岁,未合并肝炎患者ICC发病年龄为(59±10)岁,两者比较,差异有统计学意义(t=4.840,P＜0.05).②患者临床病理特征与原发肿瘤直径的关系:原发肿瘤直径≤3 cm、＞3 cm且≤5 cm、＞5 cm患者CEA水平≤5 μg/L分别为159、250、229例,＞5 μg/L分别为40、65、95例;ALT水平≤75 U/L分别为165、258、286例,＞75 U/L分别为34、57、36例;TBil水平≤20 μmol/L分别为148、242、281例,＞20 μmol/L分别为51、73、43例;有肿瘤卫星灶分别为37、70、131例;两者上述指标比较,差异均有统计学意义(x2=8.669,6.637,15.129,34.746,P＜0.05).(3)淋巴结清扫及淋巴结转移诊断情况:904例施行肝切除术的患者中,346例行淋巴结清扫,清扫的淋巴结总数为1 894.0枚,每例患者清扫淋巴结数目为5.5枚,中位淋巴结清扫数目为4.0枚(1.0～26.0枚);157例发生淋巴结转移,淋巴结转移率为45.376％(157/346),阳性淋巴结数目为393.0枚,每例患者阳性淋巴结数目为2.5枚.346例行淋巴结清扫的ICC患者,术前影像学检查示淋巴结转移114例,其中术后病理学检查结果确诊淋巴结转移64例、淋巴结未转移50例;术前影像学检查示淋巴结未转移232例,其中术后病理学检查结果确诊淋巴结转移93例、淋巴结未转移139例.影像学检查诊断淋巴结转移的灵敏度为40.8％,特异度为73.5％,诊断准确率为58.7％.(4)临床病理特征与淋巴结转移的关系:ICC患者原发肿瘤位置位于左半肝和右半肝淋巴结转移率分别为51.397％ (92/179)和39.103％(61/156),原发肿瘤直径≤3 cm、＞3 cm且≤5 cm、＞5 cm淋巴结转移率分别为34.615％(18/52)、42.500％(51/120)、52.980％(80/151),CEA水平≤5 μg/L、＞5 μg/L淋巴结转移率分别为40.234％ (103/256)、59.302％(51/86),TBil水平≤20卜mol/L、＞20 μmol/L淋巴结转移率分别为48.790％(121/248)、35.106％ (33/94),上述指标比较,差异均有统计学意义(x2=5.078,6.262,9.456,5.156,P＜0.05).结论 ICC原发部位不同,其有关致病因素可能也存在差异.原发于左半肝的ICC与左半肝内胆管结石密切相关;原发于右半肝的ICC与合并肝炎相关.合并肝炎可能会使ICC患者的发病年龄提前.ICC淋巴结清扫率低,已行淋巴结清扫的患者淋巴结转移率高.淋巴结转移与原发肿瘤位置、原发肿瘤直径、CEA水平、TBil水平有关;左半肝淋巴结转移率高于右半肝,肿瘤直径越大淋巴结转移率越高.%Objective To analyze the clinicopathological features and lymph node metastases characteristics of intrahepatic cholangiocarcinoma (ICC).Methods The retrospective case-control study was conducted.The clinicopathological data of 1 321 ICC patients who were admitted to 12 hospitals from April 2007 to November 2017 were collected,including 182 in the Eastern Hepatobiliary Surgery Hospital of the Second Military Medical University,173 in the First Affiliated Hospital of Xi'an Jiaotong University,156 in the First Hospital Affiliated to Army Medical University (Third Military Medical University),139 in the Cancer Center of Sun Yatsen University,128 in the Zhongshan Hospital of Fudan University,113 in the Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine,109 in the First Affiliated Hospital of Dalian Medical University,84 in the Tianjin Medical University Cancer Institute and Hospital,65 in the First Affiliated Hospital of Zhengzhou University,62 in the Affiliated Hospital of North Sichuan Medical College,58 in the Affiliated Drum Tower Hospital of Nanjing University Medical School and 52 in the Second Affiliated Hospital of Zhejiang University School of Medicine.Treatment planning was respectively determined by comprehensive hospitals according to clinical features and results of related examinations.Surgical procedures were performed based on the results of intraoperative examinations and patients' conditions.Observation indicators:(1) laboratory examination and treatment situations;(2) relationship between clinicopathological features and primary tumor location and diameter;(3) diagnosis of lymph node dissection and metastases;(4) relationship between clinicopathological features and lymph node metastases.Measurement data with normal distribution were represented as x±s,and comparison between groups was done by the t test.Measurement data with skewed distribution were described as M (range).Comparison of count data were analyzed using the chi-square test.Results (1) Laboratory examination and treatment situations:of 1 321 patients,cases and percentages of positive hepatitis B virus (HBV),positive serum alpha-fetoprotein (AFP) (＞ 20 μg/L),positive serum carcinoembryonic antigen (CEA) (＞ 5 μg/L),positive serum alanine transaminase (ALT) (＞75 U/L),positive serum CA19-9 (＞37 U/mL) and positive serum total bilirubin (TBil) (＞20 μmol/L) were respectively 202,80,329,207,590,300 and 15.586％ (202/1 296),7.339％(80/1 090),26.299％ (329/1 251),16.587％ (207/1 248),49.789％(590/1 185),24.000％ (300/1 250).Of 1 321 patients,1 206 underwent surgery,including 904 with hepatectomy,193 with transcatheter arterial chemoembolization (TACE),72 with percutaneous transhepatic biliary drainage (PTBD),3 with endoscopic retrograde cholangiopancreatography (ERCP),3 with PTBD + ERCP and 31 with other treatments;115 had missing registration of surgical procedures.(2) Relationship between clinicopathological features and primary tumor location and diameter:① Relationship between clinicopathological features and primary tumor location:cases with CA19-9 level ≤ 37 U/mL,38-200 U/mL and ＞ 200 U/mL were respectively 227,91,146 with primary tumor located in left liver and 282,134,137 with primary tumor located in right liver.Cases combined with hepatitis and intrahepatic bile duct stone were respectively 67,73 with primary tumor in left liver and 111,47 with primary tumor in right liver,with statistically significant differences in above indictors (x2 =6.710,5.656,12.534,P＜0.05).The results of further analysis showed that incidence age of ICC was (63± 10)years old in patients with hepatitis and (59± 10) years old in patients without hepatitis,with statistically significant differences (t =4.840,P＜0.05).② Relationship between clinicopathological features and primary tumor diameter:cases with primary tumor diameter ≤ 3 cm,with 3 cm ＜ primary tumor diameter ≤ 5 cm and with primary tumor diameter ＞ 5 cm were respectively 159,250,229 with CEA level ≤ 5 pg/L and 40,65,95 with CEA level ＞ 5 μg/L and 165,258,286 with ALT level ≤ 75 U/L and 34,57,36 with ALT level ＞ 75 U/L and 148,242,281 with TBil level ≤ 20 μmol/L and 51,73,43 with TBil level ＞ 20 μmol/L,and 37,70 and 131 patients had satellite loci of tumor,with statistically significant differences in above indictors (x2=8.669,6.637,15.129,34.746,P＜0.05).(3) Diagnosis of lymph node dissection and metastases:of 904 patients with hepatectomy,346 received lymph node dissection,total number,number in each patient and median number of lymph node dissected were respectively 1 894.0,5.5 and 4.0 (range,1.0-26.0);157 had lymph node metastases,with a rate of lymph node metastasis of 45.376％ (157/346),number and number in each patient of positive lymph node were respectively 393.0 and 2.5.Of 346 patients with lymph node dissection,114 had lymph node metastasis by preoperative imaging examination,postoperative pathological examinations confirmed 64 with lymph node metastasis and 50 without lymph node metastasis;232 didn't have lymph node metastasis by preoperative imaging examination,postoperative pathological examinations confirmed 93 with lymph node metastasis and 139 without lymph node metastasis.The sensitivity,specificity and diagnostic accuracy by imaging examination were respectively 40.8％,73.5％ and 58.7％.(4) Relationship between clinicopathological characteristics and lymph node metastases:lymph node metastasis rate was respectively 51.397％ (92/179) in patients with primary tumor located in left liver,39.103％ (61/156) in patients with primary tumor located in right liver,34.615％(18/52) in patients with primary tumor diameter ≤ 3 cm,42.500％(51/120) in patients with 3 cm ＜ primary tumor diameter ≤ 5 cm,52.980％(80/151) in patients with primary tumor diameter ＞ 5 cm,48.790％(121/248) in patients with CEA ≤ 5 μg/L,59.302％ (51/86) in patients with CEA ＞ 5 μg/L,40.234％ (103/256) in patients with TBil ≤ 20 μmol/L,35.106％ (33/94) in patients with TBil ＞ 20 μmol/L,with statistically significant differences in above indictors (x2 =5.078,6.262,9.456,5.156,P ＜ 0.05).Conclusions The related etiological factors may be different due to different primary location of ICC.Primary tumor in left liver is significantly associated with intrahepatic bile duct stone of left liver,and primary tumor in right liver is associated with combined hepatitis,while combined hepatitis could lead early occurrence of ICC.At present,there is a low rate of lymph node dissection in ICC patients and a high lymph node metastasis rate in patients receiving lymph node dissection.Lymph node metastasis is associated with primary tumor location and diameter,levels of CEA and TBil.Lymph node metastasis rate in left liver is higher than that in right liver,and is getting higher with increased primary tumor diameter.