肝内胆管细胞癌根治性切除的预后影响因素和术中淋巴结清扫意义的分析

发布时间：2018-04-26 02:30

本文选题：肝内胆管细胞癌 + 根治性切除手术　；参考：《第二军医大学》2017年硕士论文

【摘要】：研究背景和目的肝内胆管细胞癌(Intrahepatic cholangiocarcinoma ICC),是来源于肝内胆管二级分支及以上的恶性肿瘤,既往将其与原发性肝细胞癌(Hepatocellular carcinoma HCC)认作为原发性肝癌的两种类型。然而现在越来越多的研究发现,ICC从发生来源、生长方式、浸润倾向、转移特点、影像学表现、治疗及预后上与原发性肝细胞癌都存在较大的差异,因而目前倾向于对ICC进行独立研究。AJCC(American Joint Committee On Cancer)7版已经将ICC进行了独立的TNM分期,关于ICC预后预判的独立模型也已有初步的探索研究,这些都符合将其作为一种独立疾病的认识。目前ICC的主要治疗方式包括:手术切除、局部治疗、全身化疗、放射治疗。其中手术治疗的方式包括:根治性的开腹手术切除、腹腔镜手术切除;局部治疗的方式包括:肝动脉化疗栓塞术(Transarterial chemoembolization TACE)、射频消融术(Radiofrequency ablation RFA)和微波消融术(Microwave ablation MWA),其中腹腔镜同时可用于探查和辅助诊断。由于ICC对放疗及全身化疗敏感性不高,因而放化疗常作为晚期失去手术机会或复发不可再手术患者的辅助治疗或姑息性治疗手段。根治性手术切除则是目前公认的能够改善预后,取得较好效果的外科治疗方式。但值得注意的是,与HCC不同,ICC发生肝脏周围区域淋巴结转移的倾向性十分明显。大量研究报道,淋巴结转移是引起ICC患者术后早期复发与转移,影响长期生存最重要的独立危险因素。因而,若术前评估肿瘤可以被根治性切除,同时淋巴结无转移证据的患者是可能从根治性手术治疗中获益的。然而目前的术前检查手段当中,并没有对淋巴结转移诊断具有高准确度和敏感度的方法,所以ICC的根治性手术治疗过程中除肿瘤本身的切除以外,相关区域内淋巴结情况的探查和清扫切除越来越得到外科领域的重视。在目前研究过程中逐渐认识到,淋巴结的肿大原因多样,炎症、肿瘤转移均可导致,但含肿瘤细胞的淋巴结却不一定完全呈肿大状态,所以根据术中经验性探查结果来决定是否进行淋巴结的摘除活检或清扫似乎并不可靠,可能存在遗留含肿瘤转移的淋巴结于患者体内的风险。常规进行术中淋巴结清扫似乎更为稳妥,目前有研究认为,其能够为预后判断、疾病分期提供有价值的信息,但争议点在于积极的常规淋巴结清扫是否能确实改善患者预后,使患者获益。所以对于术前评估可行根治性切除(R0切除)的ICC患者,是否应在手术中常规进行淋巴结清扫值得进一步研究。为此本研究对行R0切除的ICC患者进行了回顾性分析研究,观察与该类患者预后生存相关的影响因素(包括淋巴结转移在患者术后肿瘤复发和生存中的影响作用),分析术中行淋巴结清扫对患者预后的影响,分析与淋巴结转移相关的影响因素,主要探究常规淋巴结清扫是否具有临床意义。研究方法本研究回顾性收集2010年1月至2015年12月在第二军医大学附属东方肝胆外科医院诊断为肝内胆管细胞癌(ICC),并接受手术治疗的患者病例。纳入标准:(1)术前检查无明确淋巴结转移证据,肝内病灶行根治性切除者(2)术后病理证实为ICC者(3)术中探查发现可疑淋巴结,则进行淋巴结清扫者。剔除标准:(1)非根治性切除者(姑息性切除或术后病理切缘阳性患者)(2)仅行可疑淋巴结摘除活检者(3)病例资料缺失及失访者。(4)死亡原因与疾病本身无关者。最终纳入患者265例(132例行术中淋巴结清扫)。根治性切除定义:完整切除肝内肿瘤病灶,术后病理证实肝内肿瘤病灶切缘阴性,术中探查淋巴结可疑则行淋巴结清扫。淋巴结清扫范围定义:至少包括肝动脉周围、肝十二指肠韧带内淋巴结,可包括肝胃韧带内、胰头周围淋巴结。收集纳入病例的术前临床资料(性别、年龄、乙肝病史、丙肝病史、胆道术史、糖尿病史、高血压病史、术前AFP水平、术前CEA水平、术前CA-199水平、术前TB值、术前ALT值等);术中情况(肿瘤大小、肿瘤周边子灶有无、血管侵犯有无、肝门阻断时间、术中出血量等)以及术后病理资料(肿瘤定性、肿瘤分化程度、肿瘤切缘状态、淋巴结病理结果)以及患者术后随访资料。主要采用Cox单因素分析法对预后影响因素进行单因素分析,以P0.05为标准,具统计学意义因素纳入多因素分析,风险比(HR)表达其为危险或保护因素。采用Kaplan-Meier生存分析法及倾向性配对分析法(PSM),分析术后生存情况并绘制相关生存曲线,采用log-rank法校验生存率,P0.05为差异有统计学意义。采用卡方检验分析术后并发症差异,P0.05为差异有统计学意义。采用logistic回归分析法分析淋巴结转移相关影响因素,P0.05为差异有统计学意义。研究结果截至2015年12月,在265例患者中,观察到复发及转移者共196例(74.0%),死亡151例(57.0%),中位随访时间33.5个月。全部患者1、2、3年无瘤生存率:50%、29%、20%,中位无瘤生存时间11.9个月;1、2、3年总生存率77%、47%、36%,总中位生存时间22.8个月。对预后影响因素进行Cox多因素分析的研究结果显示,影响患者无瘤生存的因素有:糖尿病史(P=0.03,HR 1.626)、术前CA-199高水平(P=0.002,HR 1.001)、肿瘤直径≥5cm(P=0.034,HR 1.410)、肿瘤周边子灶(P=0.012,HR 1.617)、淋巴结清扫(P=0.001;HR 0.451);影响患者总体生存的因素有:术前CA-199高水平(P=0.015,HR 1.001)、肿瘤直径≥5cm(P=0.009,HR 1.639)、血管侵犯(P=0.007;HR 2.526)、淋巴结清扫(P=0.001;HR 0.396)。分组对比结果:(一)PSM前:清扫组132例(复发转移患者79例,占该组59.8%,占总体29.8%,淋巴结病理诊断阳性者52例),未清扫组133例(复发转移患者117例,占该组87.9%,占总体44.2%)。(1)无瘤生存情况比较:1、2、3年无瘤生存率:清扫组65%、41%、30%,未清扫组36%、18%、12%,(P=0.001),中位无瘤生存时间:清扫组18.0个月,未清扫组9.0个月;(2)总体生存情况比较:1、2、3年总生存率:清扫组86%、66%、51%,未清扫组69%、32%、24%,(P=0.001)。中位总生存时间:清扫组42.0个月,未清扫组17.0个月。(二)PSM后:清扫组77例,未清扫组77例。(1)无瘤生存情况比较:1、2、3年无瘤生存率:清扫组68%、47%、36%,未清扫组31%、13%、6%,(P=0.001),中位无瘤生存时间:清扫组22.2个月,未清扫组9.2个月;(2)总体生存情况比较:1、2、3年总生存率:清扫组91%、75%、56%,未清扫组71%、30%、21%,(P=0.001)。中位总生存时间:清扫组46.8个月,未清扫组17.0个月。剔除清扫组淋巴结阳性患者,比较清扫组中淋巴结病理诊断阴性与未清扫患者生存情况:(一)PSM前:清扫淋巴结阴性组80例,未清扫组133例。(1)无瘤生存情况:1、2、3年无瘤生存率:清扫淋巴结阴性组76%、56%、44%,未清扫组患者36%、18%、12%,(P=0.001)。中位无瘤生存时间:清扫淋巴结阴性组27.9个月,未清扫组9.0个月。(2)总体生存情况比较:1、2、3年总生存率:清扫淋巴结阴性组95%、78%、65%,未清扫组69%、32%、24%,(P=0.001)。中位总生存时间:清扫淋巴结阴性组48.0个月,未清扫组17.0个月。(3)术后并发症情况比较无统计学意义。(二)PSM后:清扫淋巴结阴性组50例,未清扫组50例。(1)无瘤生存情况比较:1、2、3年无瘤生存率:清扫淋巴结阴性组77%、60%、52%,未清扫组32%、22%、15%,(P=0.001),中位无瘤生存时间:清扫淋巴结阴性组38.1个月,未清扫组9.0个月;(2)总体生存情况比较:1、2、3年总生存率:清扫淋巴结阴性组94%、82%、74%,未清扫组68%、40%、28%,(P=0.001)。中位总生存时间:清扫淋巴结阴性组54.0个月,未清扫组18.9个月。患者淋巴结转移影响因素的分析中,肿瘤直径≥5cm(P=0.012,HR 1.859)、术前CA-199高水平(P=0.002,HR 2.415)是影响患者淋巴结转移的独立危险因素。研究结论1.对于接受R0切除的ICC患者,糖尿病史、术前CA-199高水平、肿瘤直径≥5cm、肿瘤伴有子灶是影响患者无瘤生存的独立危险因素;术前CA-199高水平、肿瘤直径≥5cm、血管侵犯是影响患者总生存的独立危险因素。2.术中行淋巴结清扫是接受R0切除的ICC患者术后生存的保护因素。3.分组比较的研究结果显示,行淋巴结清扫可使患者预后得到改善。4.术前CA-199高水平、肿瘤直径≥5cm是ICC患者发生淋巴结转移的独立危险因素。术中淋巴结清扫可以改善ICC患者预后,同时获得淋巴结病理有助于对患者的预后判断及术后辅助治疗策略的制定。术前诊断无明确淋巴结转移证据,评估可根治性切除的ICC患者,尤其是术前CA-199水平较高、肿瘤直径较大的患者在手术过程中应积极常规进行淋巴结清扫。
[Abstract]:Background and objective Intrahepatic cholangiocarcinoma ICC (ICC), which is a malignant tumor derived from the two branches of the intrahepatic bile duct and above, has previously identified the two types of primary hepatocellular carcinoma (Hepatocellular carcinoma HCC) as primary liver cancer. However, more and more studies have found that ICC has occurred. Sources, growth patterns, infiltration tendencies, metastasis characteristics, imaging manifestations, treatment and prognosis are very different from primary hepatocellular carcinoma, so the independent study on.AJCC (American Joint Committee On Cancer) 7 version 7 has been independent TNM staging of ICC, and independent model of prognostic prediction for ICC is also available. There are preliminary exploratory studies that meet the understanding of an independent disease. The main treatments for ICC include surgical resection, local treatment, systemic chemotherapy, radiation therapy. Surgical treatment includes radical open surgery, abdominal hysterectomy, and local treatment of hepatic arteriolarization. Transarterial chemoembolization TACE (TACE), radiofrequency ablation (Radiofrequency ablation RFA) and microwave ablation (Microwave ablation MWA), which can be used for exploration and auxiliary diagnosis. Because ICC is not sensitive to radiotherapy and systemic chemotherapy, chemoradiotherapy often acts as a late loss of operation or relapse. Adjuvant therapy or palliative treatment of reoperative patients. Radical resection is now recognized as a surgical approach to improve the prognosis and achieve better results. However, it is worth noting that, unlike HCC, the tendency of ICC to develop lymph node metastases around the liver is obvious. A large number of studies have reported that lymph node metastases are Early postoperative recurrence and metastasis of ICC patients affect the most important independent risk factors for long-term survival. Therefore, patients who can be excised by preoperative assessment can be excised with radical resection, and patients with no evidence of lymph node metastasis may benefit from radical surgery. However, there is no lymph node metastasis in the current preoperative examination. The diagnosis has high accuracy and sensitivity, so in the process of radical operation of ICC, except for the resection of the tumor itself, the exploration and removal of lymph nodes in the related areas are becoming more and more important in the field of surgery. The lymph nodes containing tumor cells are not necessarily completely enlarged, so it seems unreliable to determine whether the lymph nodes are removed by biopsy or dissection according to the results of empirical exploration. More prudent, there is now a study that it can provide valuable information for prognostic judgement and disease staging, but the controversial point is whether positive conventional lymph node dissection can indeed improve patients' prognosis and benefit patients. So, for preoperative assessment of surgical excision (R0 excision), ICC patients should be routinely performed during the operation. Lymph node dissection is worthy of further study. To this end, a retrospective analysis of R0 excised ICC patients was conducted to observe the factors associated with the survival of the patients (including lymph node metastasis in the postoperative recurrence and survival of the patients), and to analyze the effect of lymph node dissection on the prognosis of the patients. Analysis of the influencing factors associated with lymph node metastasis, mainly to explore whether conventional lymph node dissection is of clinical significance. The research method is a retrospective collection of patients who were diagnosed as intrahepatic cholangiocarcinoma (ICC) in the Eastern Department of hepatobiliary surgery affiliated to Second Military Medical University from January 2010 to December 2015. (1) there was no clear evidence of lymph node metastasis before operation, the radical excision of the intrahepatic lesions (2) the pathological confirmation was ICC (3) the suspected lymph nodes were detected during the operation (3), then the lymph node dissection was carried out. (1) the non radical excision (palliative resection or postoperative pathologically positive patients) (2) only performed suspicious lymph node excision biopsy. (3) missing cases and missing persons. (4) the cause of death was not related to the disease itself. Finally, 265 cases (132 cases of intraoperative lymph node dissection) were included. Radical excision was defined as a complete resection of the intrahepatic tumor, and the postoperative pathology confirmed the negative margin of the intrahepatic tumor, and the lymph node dissection was performed in the intraoperative exploration of lymph nodes. Lymph node dissection. Definition of sweep scope: at least including the hepatic and duodenal ligaments around the hepatic artery, including the lymph nodes in the hepato duodenal ligament, including the hepatic and gastric ligaments, and the lymph nodes around the head of the pancreas. The preoperative clinical data (sex, age, hepatitis B, hepatitis C, biliary tract, diabetes, hypertension, AFP, preoperative CEA, preoperative CA-199, and preoperative CA-199) were collected. The preoperative TB value, preoperative ALT value, etc., intraoperative conditions (tumor size, tumor peripheral Subfocus, vascular invasion, portal blocking time, intraoperative bleeding amount, etc.) and postoperative pathological data (tumor qualitative, tumor differentiation, tumor margin status, lymph node pathological results) and postoperative follow-up data of patients. The main use of Cox single factor analysis method A single factor analysis of prognostic factors was carried out with P0.05 as the standard, statistical factors were included in multiple factor analysis, risk ratio (HR) was expressed as a risk or protective factor. Kaplan-Meier survival analysis and propensity paired analysis (PSM) were used to analyze the survival situation and draw related survival curves, and log-rank method was used to check the students. The survival rate and P0.05 were statistically significant. Using the chi square test to analyze the differences in postoperative complications, P0.05 was statistically significant. Logistic regression analysis was used to analyze the influence factors of lymph node metastasis, and the difference was statistically significant. The results of the study as of December 2015, were observed in 265 patients with recurrence and metastasis. A total of 196 cases (74%) were killed in 151 cases (57%) with a median follow-up of 33.5 months. The total 1,2,3 tumor free survival of all patients was 50%, 29%, 20%, and median survival time was 11.9 months; the total survival rate of 1,2,3 was 77%, 47%, 36%, and total median survival time was 22.8 months. The results of Cox multivariate analysis of prognostic factors showed that the patients had no tumor. The factors of survival were: diabetes mellitus (P=0.03, HR 1.626), high level of CA-199 (P=0.002, HR 1.001), tumor diameter more than 5cm (P=0.034, HR 1.410), peripheral tumor (P=0.012, HR 1.617), lymph node dissection (P=0.001; HR 0.451), and the factors affecting the survival of the patients. 9, HR 1.639, vascular invasion (P=0.007; HR 2.526), lymph node dissection (P=0.001; HR 0.396). (1) before PSM: 132 cases (79 cases of recurrent and metastatic patients, 59.8% in the group, 29.8% of the total, 52 cases of lymph node pathological diagnosis), 133 cases in the non dissection group (117 cases of relapse and metastasis, accounting for 87.9%, total 44.2%). (1) no tumor. Survival comparison: 1,2,3 year free survival rate: 65%, 41%, 30% in the scavenging group, 36%, 18%, 12%, (P=0.001), the median survival time: 18 months in the scavenging group, and 9 months in the non cleaning group; (2) the overall survival rate: the total survival rate of 1,2,3: the cleaning group 86%, 66%, 51%, 69%, 32%, and (P=0.001). Group 42 months, unscavenged group 17 months. (two) PSM after the cleaning group 77 cases, unscavenging group 77 cases. (1) no tumor survival comparison: 1,2,3 year free survival rate: scavenging group 68%, 47%, 36%, 31%, 13%, 6%, (P=0.001), median survival time: cleaning group 22.2 months, unscavenging group for two months; total survival comparison: 1,2,3 year total birth The survival rate: 91%, 75%, 56%, 71%, 30%, 21%, (P=0.001) in the dissection group. The median total survival time was 46.8 months in the cleaning group and 17 months in the non cleaning group. The lymph node positive patients in the dissection group were compared with the negative and non dissection patients in the cleaning group: (1) before PSM: 80 cases of negative lymph node negative group and 133 in the non dissection group. (1) non tumor survival: 1,2,3 years of tumor free survival: 76%, 56%, 44%, 36%, 18%, 12%, (P=0.001) in the group of uncleared lymph nodes, 36%, 18%, 12%, (P=0.001). The total survival rate of the dissection lymph node negative group was 27.9 months, and the undissection group was 9 months. (2) total survival rate of the group (2): the total survival rate of the lymph node negative group: cleaning lymph node negative group 95%, 78%, 65%, uncleared. Group 69%, 32%, 24%, (P=0.001). Median total survival time: 48 months of lymph node negative group and 17 months in non cleaning group. (3) postoperative complications were not statistically significant. (two) after PSM: 50 cases of lymph node negative group and 50 cases in non cleaning group. (1) no tumor survival rate: 1,2,3 year free survival rate: lymph node negative group 77%, 60 %, 52%, 32%, 22%, 15%, (P=0.001), median survival time: 38.1 months of lymph node negative group and 9 months in the non cleaning group; (2) total survival comparison: 1,2,3 year total survival rate: 94%, 82%, 74%, lymph node negative group, 94%, 40%, 28%, (P=0.001). Median total survival time: cleaning lymph node negative group for 22% months. 18.9 months in the non cleaning group. In the analysis of the factors affecting lymph node metastasis, the tumor diameter was more than 5cm (P=0.012, HR 1.859), and the preoperative CA-199 level (P=0.002, HR 2.415) was an independent risk factor affecting the lymph node metastasis. Conclusion 1. for R0 excised ICC patients, diabetes history, preoperative CA-199 high, tumor diameter more than 5cm, Tumor associated with subfoci is an independent risk factor for cancer free survival. Preoperative CA-199 high level, tumor diameter more than 5cm, vascular invasion is an independent risk factor affecting the total survival of the patient. Lymph node dissection in.2. surgery is a protective factor for the survival of ICC patients undergoing R0 resection. The results of.3. group comparison show that lymphadenectomy Cleaning can improve the prognosis of patients with the high level of CA-199 before.4., and the tumor diameter more than 5cm is an independent risk factor for lymph node metastasis in ICC patients. Intraoperative lymph node dissection can improve the prognosis of ICC patients, while obtaining lymph node pathology is helpful to the prognosis of patients and the formulation of postoperative adjuvant therapy strategy. The preoperative diagnosis is not clear. The evidence of lymph node metastasis is used to evaluate the ICC patients with radical resection, especially the high level of CA-199 before operation. The patients with larger diameter should take positive routine lymph node dissection during the operation.

【学位授予单位】：第二军医大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R735.8

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