肝癌肝移植术后复发机制及其研究进展

本文综述了肝癌患者在肝移植后肝癌复发的机制，原发肿瘤病灶、治疗措施对复发的影响，以及预防复发的防治方法与患者的预后。     

肝癌肝移植术后肿瘤复发转移的防治

肝癌肝移植术后肿瘤复发转移是影响肝移植治疗肝癌疗效的主要因素.深入研究肝癌的生物学特性和肝移植术后患者免疫状态与肿瘤复发转移的关系,筛选准确预测肝癌肝移植的预后指标,对高危复发风险的患者进行有效的干预治疗,对复发转移者进行个体化综合治疗有助于进一步提高肝移植治疗肝癌的疗效.

Abstract：

Post-transplant tumor recurrence and metastasis remain the main obstacles for long-term survival after liver transplantation (LT) for hepatocellular carcinoma (HCC). Measures to explore the HCC biological characteristics and the relationship between post-transplant immuno-suppression and tumor recurrence, to determine precisely the prognostic factors associated with post-transplant recurrence, to intervene effectively for those with high risk of recurrence, and to use individualized multimodality treatment for recurrence and metastasis may improve the therapeutic results of LT for HCC.     

肝癌肝移植术后肝癌复发的研究进展

目前，肝癌是肝移植的适应证之一。根治性肝部分切除的5年生存率仍然在30％左右徘徊，而肝癌肝移植的5年生存率已达到50％左右。虽然肝癌患者肝移植术后早期效果良好，但肿瘤复发和转移导致的远期低存活率严重制约了肝癌肝移植的开展。现就国内外肝癌肝移植术后肝癌复发的原因和防治措施作一综述。     

肝癌行肝移植术后防止肿瘤复发的策略

自1996年肝癌肝移植米兰标准的发布及应用以来,肝移植在治疗肝癌上取得了良好的效果,5年生存率在60～80%。由于术前外周血潜在肿瘤细胞转移,术中肿瘤的种植以及术后免疫抑制药物的应用,肝癌肝移植术后仍然有较高的复发率,严重影响肝癌肝移植预后,即使符合米兰标准得肝癌行肝移植术后肿瘤复发率也达10%～20%。此外,对于肝癌肝移植术后肿瘤复发的患者,目前尚无有效的治疗手段。     

肝癌术后复发补救性肝移植的意义

目前,被广泛接受的补救性肝移植(salvage liver transplantation,SLT)的定义是指对肝功能良好的可切除的原发性肝细胞癌(肝癌)(单个肿瘤直径≤5cm或肿瘤数目≤3个、单个肿瘤直径≤3 cm)首先采取肝癌切除治疗,术后肝癌肝内复发(单个肿瘤直径≤5 cm;多个肿瘤数目≤3个、单个肿瘤直径≤     

肝癌肝移植术后肿瘤复发的防治策略

原发性肝细胞癌(肝癌)是常见的恶性肿瘤之一,大部分肝癌患者合并肝硬化。对于肿瘤位置特殊无法手术切除或合并严重肝硬化无法耐受手术的患者,肝移植就成为较为合适的治疗手段。但是,肝癌肝移植术后肿瘤复发是影响患者长期生存的重要因素。大量研究资料显示,一旦发生肝移植     

肝癌肝移植术后肝癌复发预测指标的研究进展

肝癌肝移植术后肝癌的复发和转移严重制约了肝移植治疗肝癌的效果。移植术后肝癌复发相关预测指标的检测,对早期预防肝癌复发及提高无瘤生存率具有重要临床参考价值。     

肝癌肝移植术后复发的危险因素分析

目的探讨原发性肝癌(HCC)肝移植术后肿瘤复发或转移的危险因素。方法回顾性我院2003年4月至2007年11月期间76例HCC患者行肝移植的临床资料,根据随访期间是否有复发分为复发组(n=23)和未复发组(n=53),总结肿瘤复发的特点。结果 76例患者中23例(30.3%)术后复发。单因素分析显示患者性别(P=0.449)、年龄(P=0.091)、术前是否治疗(P=0.958)、肿瘤数目(P=0.212)和是否伴有HBV/HCV感染(P=0.220)与肿瘤的复发无关,而肿瘤包膜完整性(P=0.009)、肿瘤分期(P=0.002)、肿瘤直径(P<0.001)、血管侵犯(P<0.001)以及术前AFP水平(P=0.044)与肿瘤的复发有关,其中肿瘤直径<5.0 cm(P=0.001)和术后2个月AFP水平恢复正常者(P<0.001)1年复发率更低。多因素分析显示肿瘤直径(P=0.001,OR=6.456,95%CI为2.356～17.680)、血管侵犯(P=0.030,OR=10.653,95%CI为1.248～90.910)以及术前AFP水平(P=0.017,OR=2.601,95%CI为2.196～5.658)是肝移植术后肿瘤复发的独立危险因素。结论对于肿瘤直径>5.0 cm、伴有血管侵犯以及术前AFP水平≥400μg/L尤其术后2个月AFP水平仍高于正常者术后需加强监测,必要时尽早给予抗肿瘤治疗。     

索拉非尼防治肝癌肝移植术后复发的研究进展

<正>原发性肝癌(肝癌)的全球发病率居恶性肿瘤第5位,病死率居第3位[1-3],全球每年大约有70万新发肝癌病例[1,4],造成超过60万人死亡[3-4]。据统计,大约有30%的肝癌患者适合外科治疗,包括肝部分切除、肝移植或者射频消融[5-6]。经过近30年医学的快速发展,肝移植已被公认为是根治肝癌,尤其是超米兰(Milan)标准晚期肝癌的最有效方法[7-10]。虽然肝移植可显著改善     

肝癌肝移植术后肿瘤复发的治疗策略

目的比较肝癌肝移植术后肝内复发的患者分别实施肿瘤切除术、经导管肝动脉灌注化疗栓塞术（TACE）、射频消融术（RFA）、再次原位肝移植术（re—OLT）的临床疗效。方法回顾性分析我中心2004年1月至2009年6月凶肝癌行肝移植手术术后肝内复发的患者53例。其中肿瘤切除术3例,TACE22例,RFA18例,re—OLT10例,观察术前一般情况、术后生存时间、术后并发症、肿瘤进展情况、治疗费用等情况。重点对比分析TACE、RFA、re—OLT三种治疗方法的疗效。结果肿瘤切除术3例,随访4～12个月,均无手术并发症,未见肝脏及远处复发或转移,一般情况良好。TACE组、RFA组与re—OLT组的平均生存时间、累积生存率、各部位进展情况的差异无统计学意义;RFA组的并发症,特别是胆道并发症发生率比TACE组及re—OLT组低;3组的治疗费用的差异有统计学意义,RFA〈TACE〈re—OLT。结论TACE、RFA及re—OLT治疗方法对肝癌肝移植术后肝内复发的治疗效果相近。RFA的并发症及治疗费用明显少于TACE及re—OLT,可作为肝癌肝移植术后肝内复发的首选治疗方案。     

Tumor recurrence after liver transplantation for hepatocellular carcinoma: recurrence pathway and prognostic factors

INTRODUCTION: Liver transplantation (OLT) has been advocated as a good management option for patients with carcinoma hepatocellular (HCC). More recurrences are extrahepatic due to many pathological factors. PATIENTS AND METHODS: From April 1986 to December 2003, we performed 95. OLTs for HCC including 73% men of mean age of 54.7 years and 25.3% not filling Mazzaferro's criteria. RESULTS: The recurrence incidence was 15.8% (n = 15), including only extrahepatic lesions in 11 (mainly lung recurrence, seven) and hepatic plus extrahepatic in four. Main late mortality was due to tumor recurrence (n = 12, 33.3%). No differences were observed among sex, preoperative chemoembolization, age, Child, Okuda, etiology, or satellite nodules. A greater incidence of tumor recurrence was observed with a preoperative biopsy (45.5% vs 5.9%, P = .0001); and alpha fetoprotein (AFP) > 200 ng/mL (37.5% vs 13.3%, P = .08); known HCC (25.5% vs 3.1%, P = .008); vascular invasion (42.1% vs 10.3%, P = .001); > 5 cm single nodule (50% vs 13%, P = .004); more than three nodules (50% vs 13.9%, P = .01); moderately to poorly differentiated tumors (37.5% vs 12.7%, P = .01); pTNM IV (50% vs 8.7%, P = .0001); and not meeting Milan criteria (40.9% vs 9.2%, P = .001). These are the same factors for extrahepatic recurrence. For hepatic recurrence the prognostic factors were: vascular invasion (15.8% vs 1.5%, P = .008), more than three nodules (25% vs 2.5%, P = .004), moderately to poorly differentiated tumors (18.8% vs 1.4%, P = .003), pTNM IV (16.7% vs 1.4%, P = .006), and not meeting Milan criteria (13.6% vs 1.5%, P = .01). CONCLUSIONS: Recurrence incidence with Milan criteria was less than 10%, mainly extrahepatic (lung). Prognostic factors for tumor recurrence were pathological features, namely vascular invasion, more than three nodules, size larger than 5 cm, moderately to poorly differentiated tumors, pTNM IV stage. The use of preoperative chemoembolization did not decrease the recurrence rate. A preoperative biopsy increased the incidence of extrahepatic recurrence.     

肝癌肝移植术后肝癌复发研究新进展

肝癌肝移植术后肝癌复发是影响受者预后的重要原因。研究影响肝癌肝移植术后肝癌复发的因素,降低复发率是提升受者生存的关键。近年来,国内外学者从移植术前、术中、术后三个方面开展了大量研究,并发现受者选择标准、降期治疗、生物标志物、术中出血量、供肝缺血时间、免疫抑制剂方案、全身辅助治疗等因素可影响复发。这些研究成果对于肝癌肝移植术后肝癌复发的防治具有重要意义。     

原发性肝癌肝切除术后复发患者的肝移植治疗

目的观察肝移植治疗原发性肝癌肝切除术后复发患者的疗效。方法回顾性分析11例原发性肝癌肝切除术后复发接受经典原位肝移植治疗的受者的临床资料,观察移植效果。结果在围手术期,1例术后发生移植肝功能不全和凝血功能障碍并发肾功能衰竭死亡;1例术后出现急性胰腺炎,给予生长抑素治疗10d缓解;2例发生急性排斥反应,行大剂量甲泼尼龙冲击治疗3d逆转。10例受者顺利出院。出院后,3例分别于术后第5个月、第7个月、第19个月死于肝癌复发,1、2年受者存活率分别为72．7％（8／11）和63．6％（7／11）,至今最长存活的1例已达4年余。获长期存活的受者肝癌肝切除术前原发病均为小肝癌,肝切除术后复发行肝移植时肝癌均符合Milan标准。结论小肝癌行肝癌肝切除术后应密切随访,如发现肝癌复发且符合Milan标准可考虑行肝移植治疗,患者仍有可能获较长时间生存。     

肝癌肝移植术后复发的危险因素及预防

原发性肝癌作为肝移植的主要适应证之一,经历了肯定、被否定和再认识的发展过程。在肝移植的起始阶段,原发性肝癌曾作为主要的适应证,但由于对适应证标准的掌握不够严格、科学,许多晚期肝癌病例进入了肝移植的适应范围,使肝移植的远期生存率降低。20世纪80年代,对肝癌的肝移植治疗由于高复发率和3年存活率不超过30%而使人气馁;20世纪90年代初期,Iwatsuki等和Bisumuth等确定了与复发相关的临床病理学危险因子并进而由Mazzafero等发展为Milan标准。尽管Milan标准在全世界范围内的采用使肝癌肝移植5年生存率已达50%以上,但肝癌肝移植的复发仍…     

Accuracy of staging as a predictor for recurrence after liver transplantation for hepatocellular carcinoma

BACKGROUND: Tumor number, size, and macrovascular invasion (MacroVI) are the most widely used predictors of survival after liver transplantation (LT) for hepatocellular carcinoma (HCC). We analyzed all patients undergoing LT for HCC at our center to establish the accuracy of preoperative clinical staging and to determine which patients have a higher probability of being understaged. METHODS: In all, 118 patients with confirmed HCC after LT from April 1991 to October 2004 at our institution were reviewed. All patients were monitored with serial imaging every 3 months to ensure their eligibility for LT within Milan criteria. Understaging in the 118 patients was defined as evidence on explant pathology that Milan criteria (TNM stage pT1 or pT2) had been exceeded. RESULTS: Five-year DFS was 78% with a recurrence rate of 15% after a median follow-up after LT of 30 months. On explant pathology, 43% (51/118) of patients exceeded Milan criteria and had a worse DFS (1 year, 95% vs. 87%; 3 year, 87% vs. 64%; P=0.03) compared to those who met LT criteria. Understaging was more likely in patients with imaging characteristics of > or = 2 tumor nodules (P=0.005) and tumor growth > 0.25 cm/month (P=0.02) and pathologic findings of vascular invasion (P=0.001) and bilobar tumors (P=0.002). CONCLUSIONS: Preoperative imaging every 3 months while on the waiting list frequently understages HCC as assessed by explant pathology. Recurrence after LT often occurred in patients that were understaged. Improving the accuracy of clinical staging and inclusion parameters will ensure proper organ allocation and acceptable outcomes after LT.     

Survival after liver transplantation for hepatocellular carcinoma

BACKGROUND: Selection criteria for patients with hepatocellular carcinoma (HCC) suitable for liver transplantation (LT) include tumor size and number and vascular invasion. There has been a recent trend to expand the transplant criteria for HCC. We reviewed our experience to determine survival following LT based on tumor characteristics. METHODS: A retrospective analysis was performed on 72 patients with HCC who underwent LT between 1985 and July 2002. The Milan criteria were applied for LT candidacy for HCCs that were deemed unresectable from anatomical considerations and/or the severity of underlying cirrhosis. Patients were divided into four groups: group 1: patients with known HCC who satisfied the selection criteria (n = 22); group 2: patients with known HCC that exceeded the criteria (n = 17); group 3: patients with incidental HCC found at pathological examination of the explant (n = 33); group 4: contemporary LT recipients without HCC (n = 935). RESULTS: In the known HCC group, the interval between listing as status 2 and transplantation was 72.2 +/- 133.6 days (median 23 days). Three-year patient survival was 80.2% in group 1, 35.8% in group 2, 63.2% in group 3, and 81.5% in group 4. In group 2 patients, the tumors were significantly larger, had more nodules, and were more often bilobar. In group 3, five (15%) exceeded the criteria mainly because of tumor size and four patients died within 3 years post-LT (three from tumor recurrence). CONCLUSION: Liver transplantation for HCC yields acceptable survival in early-stage tumors, particularly if transplanted soon after listing. Long-term survival was inferior in patients with multiple tumors and tumors that were greater than 5 cm in diameter.     

Partial necrosis on hepatocellular carcinoma nodules facilitates tumor recurrence after liver transplantation

BACKGROUND: The presence of partial necrosis in hepatocellular carcinoma (HCC) nodules is a common histologic finding after liver transplantation, but its correlation with tumor recurrence has never been investigated. METHODS: we retrospectively reviewed the outcome of 54 patients with a single histologically proven HCC after liver transplantation. All cases had a survival of more than 6 months, and patients treated preoperatively had a transarterial chemoembolization (TACE) procedure. Since 1996, our center has applied the Milan criteria. Correlations between tumor recurrences and clinicopathologic variables, including the presence of partial necrosis, were performed. Etiologic factors for HCC partial necrosis were also investigated. RESULTS: Sixteen of 54 (29.6%) HCC nodules presented partial necrosis, and 4 (25%) of them developed HCC recurrence compared with 1 of 38 (2.6%) cases without this histologic finding (P<0.05). Partial necrosis was related to TACE procedure (P<0.05), patient age less than 50 years (P<0.05), and tumor diameter greater than 2 cm (P<0.05). Multivariate analysis showed only TACE as an independent variable. The other variables related to the five (9.3%) tumor recurrences were HCC diameter greater than 2 cm (P<0.05), year of liver transplantation before 1996 (P<0.05), and the presence of satellite nodules (P<0.05). The Cox regression analysis showed the presence of partial necrosis as an independent variable related to tumor recurrence. The analysis of the recurrence-free survival confirmed the results of the recurrence rate. CONCLUSION: Partial necrosis was a risk factor for tumor recurrence after liver transplantation. Patients and procedures should be selected while also bearing in mind the side-effect of incomplete necrosis of the nodules.