肝移植治疗肝内胆管癌的研究进展

肝内胆管癌（ICC）是仅次于肝细胞癌的肝脏原发性恶性肿瘤,其发病率在全球范围内呈上升趋势。肝切除术一直是ICC患者外科治疗的首选,而ICC过去由于高肿瘤复发率和较差的生存结果,被视为肝移植禁忌证。目前,ICC肝移植治疗已经取得了诸多重要进展,对于严格筛选的ICC患者,肝移植或在新辅助治疗后肝移植取得了令人鼓舞的生存结果。同时,随着ICC肝移植治疗预后风险分层的完善,也将进一步优化ICC肝移植候选者的选择标准。此外,ICC现代多模式综合治疗的发展,也将进一步指导ICC肝移植术前新辅助治疗方案的选择。ICC肝移植前应用免疫检查点抑制剂也是未来重要的研究方向。本文从ICC肝移植治疗的预后、ICC肝移植的预后风险因素及候选者选择标准、正在进行的试验和挑战进行总结,以期为肝移植治疗ICC提供参考,提高ICC患者的生存质量。     

Intrahepatic cholangiocarcinoma: indication for transplantation

Background/Purpose. Cholangiocarcinoma (CCC) is a rare malignant tumor of the biliary system with a poor prognosis that frequently presents in advanced unresectable stages. A discussion of the role of liver transplantation (LTx) for intrahepatic (IH)-CCC will be presented, based on a review of the international literature. Methods. A search of the international literature related to the topic was performed in the established online databases and databanks. Only those reports with patient series larger than ten were included. Results. The largest series of patients with IH-CCC (n = 186) was reported in the Data Analysis Booklet of the European Liver Transplant Registry (ELTR), revealing 1-, 3-, 5-, 8-, and 10-year survival rates of 58%, 38%, 29%, 23%, and 21%. Other single-center series had comparable or even worse outcomes. More recent experience identified a certain highly selected group of patients who could benefit from LTx in an otherwise unresectable state of disease. Several single-center studies found tumor stage or size, lymph node involvement, and positive surgical margins/contiguous organ infiltration to be predictors of outcome. The recently published Mayo Clinic protocol uses preoperative chemoirradiation and staging at laparotomy before proceeding to liver transplantation, resulting in an early experience with 100% 1-year survival. Conclusions. Generally speaking, IH-CCC is not a favorable indication for liver transplantation. However, there is a highly selected group of patients with early tumor stages potentially benefitting from LTx. Combination with neoadjuvant chemoirradiation may further improve results after LTx. Living-donation LTx may open new therapeutic possibilities to treat patients at an early stage of disease.     

Expanding indications for liver transplantation in the era of liver transplant oncology

Despite numerous advances and emerging data, liver transplantation in the setting of gastrointestinal malignancies remains controversial outside of certain accepted indications. In an era of persistent organ shortage and increasing organ demand, allocation of liver grafts must be considered carefully. While hepatocellular carcinoma and hilar cholangiocarcinoma have become accepted indications for transplantation, tumor size and standardized multi-disciplinary treatment protocols are necessary to ensure optimal patient outcomes. As more studies seeking to expand the oncologic indications for liver transplantation are emerging, it is becoming increasingly clear that tumor biology and response to therapy are key factors for optimal oncologic outcomes. In addition, time from diagnosis to transplantation appears to correlate with survival, as stable disease over time portends better outcomes post-operatively. Identifying aggressive disease pre-transplant remains difficult with current imaging and tissue sampling techniques. While tumor size and stage are important prognostic predictors for most malignancies, patient and tumor selection protocols are necessary. As the fields of medical and surgical oncology continue to evolve, it is clear that a protocolized interdisciplinary treatment approach is necessary for combatting any cancer effectively. Disease stability over time and response to neoadjuvant therapy may be the best predictors for successful patient outcomes and can be easily incorporated in our treatment paradigms. Current data evaluating liver transplantation for expanded oncologic indications such as: expanded criteria hepatocellular carcinoma, intrahepatic cholangiocarcinoma, mixed tumors, and liver limited metastatic colorectal carcinomas, incorporate multi-modal therapies and evaluation of tumor treatment response. While further investigation is necessary, initial results suggest there is an expanded role for transplant surgery in malignancy in a new era of liver transplant oncology.     

Liver transplantation for hilar cholangiocarcinoma

Hilar cholangiocarcinoma was accepted as an indication for liver transplantation at the beginning of the transplantation era. Owing to disappointing long-term results for this indication, and in parallel, encouraging results in patients with benign disease, hilar cholangiocarcinoma has generally not been accepted as an indication for liver transplantation in recent years. To improve results, more aggressive approaches have been used: “abdominal organ cluster transplantation” and “extended bile duct resection”, which lead to increased long-term survival rates. However, with improving results after conventional extrahepatic bile duct resection in combination with partial hepatectomy, extended procedures in combination with liver transplantation never became a real option in the treatment of hilar cholangiocarcinoma. However, new awareness of liver transplantation in the treatment of this cancer has been raised for patients with hilar cholangiocarcinoma in the context of underlying liver diseases such as primary sclerosing cholangitis, which preclude liver resection. Current results show increased survival figures, in particular in well-selected patients with early tumor stages. Further improvements in long-term survival may be reached with new adjuvant and neoadjuvant protocols. Patients with neoadjuvant radiochemotherapy show long-term results similar to those for liver transplantation for other indications. Also, photodynamic therapy and the use of new antiproliferative immunosuppressive agents may be an approach for further improvement of the long-term results. Currently, liver transplantation for the treatment of hilar cholangiocarcinoma should be restricted to centers with experience in the treatment of this cancer and should be taken into consideration in patients with contraindications to liver resection.     

肝移植能否用于治疗胆管癌

胆管癌包括肝内和肝外胆管癌，传统的治疗方法首选根治性手术切除，胆管癌恶性程度高，手术切除率低，病死率高，早期肝移植治疗胆管癌的效果差，多数患者术后早期复发，长期生存率较低，近年随着供体短缺问题越来越严重，一些移植中心已将胆管癌作为肝移植的禁忌证，但也有报道反对这一观点，认为结合放化疗等辅助治疗的肝移植要优于手术切除，能明显提高患者生存率。本文结合文献和我院经验，对肝移植能否用于治疗胆管癌这一有争论的问题进行简单讨论。     

Current status of liver transplantation for hepatocellular cancer

The incidence of hepatocellular cancer is increasing in the United States and is one of the most common cancers worldwide. Traditionally, the gold standard treatment for hepatocellular cancer has been surgical resection, but most patients were not suitable candidates due to advanced disease. Other treatments include locally ablative techniques (cryosurgery, radiofrequency ablation and various injection therapies), chemotherapeutic options and rarely, radiation therapies. In the 1980s, liver transplant emerged as the treatment of choice for end-stage liver disease and also became an option for patients with hepatocellular cancer. When comparing liver transplant with resection in retrospective studies, liver transplant patients had better survival and reduced recurrence. However, not all patients with hepatocellular cancer will be candidates for liver transplant. Size, stage, and histological grade of tumor all affect prognosis after transplant. Use of chemotherapeutic treatments and locally ablative techniques may be beneficial prior to liver transplant, but larger controlled studies are needed. Liver transplant is the most effective treatment for hepatocellular cancer in the subgroup of smaller tumors, but ultimately we are limited by the number of available donors. Future goals in this area include increasing the donor pool and determining optimal management to allow patients to wait for an appropriate donor.     

Is liver transplantation indicated for cholangiocarcinoma?

Liver transplantation (OLTx) has been investigated as a mode of therapy for malignancies. The efficacy of OLTx for the treatment of cholangiocarcinoma (CCA) has been somewhat controversial. We review the current literature on resective procedures for CCA and show that isolated intrahepatic CCA has a slightly better survival than extrahepatic disease. Results of OLTx for CCA are then reviewed, with specific attention to the experience at our center. Our results demonstrate that 1-year patient survival was 53%, and disease-free survival at 3 years was only 13%. Specific issues pertaining to the timing of OLTx in primary sclerosing cholangitis are then addressed. In summary, we believe that OLTx for known CCA results in a very poor patient survival. Those with incidental CCA found on explant histopathologic evaluation, without lymphatic involvement, may result in acceptable patient survival. Received for publication on June 6, 1997; accepted on July 7, 1997     

肝内胆管细胞癌预后因素分析

目的研究影响肝内胆管细胞癌（ICC）手术预后的因素，探讨提高ICC疗效的途径。方法回顾分析1996年12月至2003年6月在我院手术治疗的183例ICC病人的临床资料，对成功随访到的132例病人用Cox回归模型，选择15个对预后可能产生影响的因素进行统计学分析。结果132例外科手术治疗病人1，3，5年生存率分别为51．3％、21．6％和11．8％，统计分析结果显示病人的预后与手术方式、病理分型、是否淋巴结转移以及术前血清CA19—9水平显著相关，而与是否输血、放疗、化疗、肿瘤大小、肝硬化、AFP、TBIL、A／G（白球蛋白比）、性别、年龄等无明显相关。结论规则性肝叶切除＋淋巴结清扫手术是ICC主要的治疗措施；对于术后肝内复发和淋巴结转移的积极预防和治疗是提高ICC生存率的主要策略。     

Orthotopic liver transplantation after extended bile duct resection as treatment of hilar cholangiocarcinoma First long-terms results

Abstract Although the surgical treatment of hilar cholangiocarcinoma represents the only potentially curative option, survival figures remain low over the long term. After hilar and partial hepatic resections for hilar cholangiocarcinoma, loco-regional tumor recurrence appears as the primary site of failure. From April 1992 to April 1996, 14 patients underwent extended bile duct resections. Extended bile duct resections combine total hepatectomy, partial pancreatoduodenectomy, and liver transplantation in an attempt to eradicate the entire biliary tract without dissecting the hepatoduodenal ligament. The postoperative 60-day mortality rate was 14% ( n = 2). The rate of curative resections was 93% (13 of 14 extended bile duct resections). One- and 4-year survival rates after curative resections were 56% and 30%, respectively. The rate of curative resections increased by combining total hepatectomy, partial pancreatoduodenectomy, and liver transplantation, i.e., extended bile duct resection. However, survival figures have not improved accordingly. Therefore, this extended surgical procedure has to be implemented with caution and possibly not without modifications (e.g., multimodal treatment).     

肝移植手术技术的现状和展望

随着终末期肝病患者数量逐年增加,肝移植手术作为有效治疗手段,其安全性和疗效是需要考虑的重要问题,肝移植技术也成为了新的研究热点。多年来,经过广大研究者们的不懈努力,肝移植技术在不断创新与发展,研究者们相继开展了劈离式肝移植、无缺血肝移植、异种肝移植、多米诺肝移植、肝切除联合Ⅱ~Ⅲ段部分肝移植的延期全肝切除、脾窝异位辅助性肝移植及磁吻合等肝移植技术,为扩大供者池、提高肝移植疗效、改善肝移植受者生活质量奠定了基础。本文就肝移植手术技术的探索与发展、创新与改进方面进行综述和展望,以期为肝移植的临床应用提供参考。     

Liver transplantation for cholangiocarcinoma

Liver transplantation following high dose neoadjuvant radiotherapy with chemosensitization achieves excellent results for patients with early stage, unresectable hilar cholangiocarcinoma or cholangiocarcinoma arising in the setting of primary sclerosing cholangitis.     

肝脏移植在治疗肝脏恶性肿瘤中的作用

目的 探讨我国目前原位肝脏移植在治疗肝脏恶性肿瘤中的作用以及围手术期的处理，进一步提高肝脏移植治疗肝脏恶性肿瘤的疗效。方法 18例肝脏恶性肿瘤肝脏移植病人术后采用全身化疗复发转移灶采用手术切除或介入化疗。结果 肝脏移植术后甲胎蛋白短期内降为正常者6例，虽有下降但未降至正常者2例。术后肝癌肝内复发4例次，肺转移3例次，骨转移1例次，肿瘤复发多在术后6－12个月。结论 （1）小肝癌、胆管细胞癌可行肝脏移植，中晚期肝癌行肝脏移植需综合考虑；（2）肿瘤复发转移灶采用手术切除或介入化疗。     

Patient with advanced intrahepatic cholangiocarcinoma with long-term survival successfully treated with a combination of surgery and chemotherapy

Intrahepatic cholangiocarcinoma (ICC) is a relatively rare malignancy arising from the biliary epithelium. Prognosis is typically poor. Currently, aggressive surgical resection is the only treatment modality that offers patients any chance of long-term survival. Here, we present the case of a 57-year-old woman in whom we diagnosed ICC, with the tumor occupying the entire left and caudate hepatic lobes and daughter nodules in the right lobe. She underwent hepatectomy of segments I to VI, combined with intraoperative microwave coagulation therapy for nodules in the residual liver. Three months after the surgical resection, she had recurrence of the disease. The patient subsequently received weekly intraarterial chemotherapy with irinotecan (CPT-11), and a partial response was observed which persisted for 18 months. Subsequent computed tomography revealed the regrowth of three tumors, and she therefore underwent a repeat resection 24 months after the first surgical operation. In postoperative-month (POM) 32, she received systemic chemotherapy with tegatur/gimeracil/oteracil potassium (S-1)/cisplatin for multiple small nodules in her lung. Following three cycles of chemotherapy with a stable disease response, partial resections of the lung were performed. Third and fourth hepatectomies were performed in POMs 46 and 59, respectively. Five years and 5 months after the first hepatectomy, she is alive with small lesions in her lung. This multimodal approach may be effective for ICC.     

肝内胆管癌肝移植及其综合治疗

肝移植是治疗肝内胆管癌（ICC）的有效手段,由于ICC侵袭性强、易淋巴结转移,肝移植术后肿瘤复发率较高,需要严格掌握适应证。直径≤2 cm的单发ICC肝移植效果良好,进展期ICC则需先进行包括局部治疗和全身化学药物治疗（化疗）在内的新辅助治疗,根据新辅助治疗的反应决定是否进行肝移植,并于术后进行个体化辅助治疗。目前已经发现多个胆管癌基因突变靶点及靶向治疗药物。肝移植术前、术后辅以综合治疗可拓展ICC肝移植的适应证,改善受者预后。本文从ICC肝移植治疗、ICC肝移植术前新辅助治疗和术后辅助治疗以及ICC靶向治疗等方面进行综述。     

难治性复发肝肿瘤的肝移植

目的探讨难治性复发肝肿瘤行肝移植的难点及围手术期处理注意事项。方法总结2003年9月至2004年9月我科施行的14例肝移植，其中难治性复发肝肿瘤9例（A组），其余5例术前未接受任何有创治疗（B组），分析两组术前治疗情况、术中探查情况、病肝游离时间、无肝期时间、术中出血、输血及止血药物使用情况、手术死亡率、术后肾上腺糖皮质激素的减撤及化疗等情况。结果A组术中病肝游离时间、无肝期时间明显较B组长，出血、输血量及止血药物的用量均明显大于B组，手术死亡2例均为A组病例。术后存活的肝癌病例均行全身化疗，肾上腺糖皮质激素于3个月内停药，至今均无瘤生存。结论难治性复发肝肿瘤的肝移植较一般肝移植手术难度大，对术者要求更高，术中监护和补充凝血因子极为重要。围手术期抗肿瘤治疗、术后尽早减撤肾上腺糖皮质激素对术后无瘤生存有积极意义。     

肝移植治疗成人慢加急性肝功能衰竭的现状

慢加急性肝功能衰竭(ACLF)是慢性肝病或肝硬化急性失代偿期的最严重形式, 往往同时合并肝外器官功能衰竭, 患者短期预后极差。ACLF的触发病因复杂多样, 其分期及器官功能衰竭的类型和定义各不相同, 目前尚无统一的ACLF诊断标准, 难以直接预测和比较不同地域ACLF的总体发病率和预后情况。越来越多的研究证据表明, 肝移植在ACLF外科治疗中发挥重要作用, 但其价值尚存争议。目前ACLF具体的入院处理和治疗方案, 包括ICU的监护治疗、器官功能的支持维护、肝移植手术指征和时机选择等方面, 尚未形成统一的标准化流程或意见。ACLF患者是否应较其他潜在的肝移植等待受者在供者分配方面更具有优先权亦无定论。此外, 人工肝支持系统在ACLF移植前桥接治疗中的应用价值尚需更多的前瞻性对照研究来进一步证实。因此, 本文就肝移植在成人ACLF外科治疗中的指征选择、手术疗效及影响因素、手术时机选择、供肝资源分配及移植前桥接治疗等方面进行探讨, 以期为ACLF肝移植治疗的未来临床研究提供新的方向。     

肝门部胆管癌术中淋巴结清扫的研究现状

淋巴结转移是严重影响肝门部胆管癌(HCCA)患者手术预后的独立因素。淋巴结清扫是肝门胆管癌根治性切除术的重要内容,但关于术中淋巴结清扫的定义、范围及清扫数目仍存在较多争议。针对以上问题近年来国内外有较多研究,也有不少新观点。现有观点认为,术中常规对肝十二指肠韧带内、肝总动脉旁和胰头十二指肠后方的淋巴结(第12、8、13组)进行骨骼化清扫能够为HCCA患者带来明显的生存获益,但术中清扫腹腔干、腹主动脉及下腔静脉等周围淋巴结是否能为患者带来生存获益尚不明确;术中适当增加淋巴结清扫数目,不仅能够明显改善N0期患者的生存预后,还可提高阳性淋巴结的检出率,为疾病的分期获得足够的信息,但过度增加淋巴结清扫数目在实际操作中不仅难以实现,还可能导致术后并发症的发生率增加。因此,肝门部胆管癌术中淋巴结清扫相关问题尚需进一步研究。     

肝内胆管癌术后复发的治疗

影响肝内胆管癌(intrahepatic cholangiocarcinoma,ICC)肝切除术后远期生存的主要因素是肝内复发和肝外转移。再切除适用于复发性肿瘤单发、至复发时间较长、肝功能良好的病人,但术后再复发率仍较高。对于术后较早期肝内复发、肿瘤直径不超过3 cm、数目不超过3个的ICC,消融治疗可达到与再切除相似的远期预后。对于不适合再切除或消融的肝内复发ICC,可考虑行经肝动脉栓塞化疗(tansarterial arterial chemoembolization,TACE)或钇-90经肝动脉放射性栓塞。对于术后发生肝外转移的ICC,应联合消融、TACE、系统性化疗、靶向治疗以及姑息治疗等多种治疗手段,以进一步延长病人的生存时间。     

Hepatopancreatoduodenectomy for perihilar cholangiocarcinoma following laparoscopic total gastrectomy

IntroductionSurgical resection is the only curative treatment for perihilar cholangiocarcinoma. However, Hepatopancreatoduodenectomy (HPD) procedure remains controversial in regard to the balance between the survival benefit and high risk of mortality and morbidity.Presentation of caseA 72-year-old man who was revealed the dilation of intrahepatic hepatic duct by computed tomography after laparoscopic total gastrectomy was referred to our hospital. The patient had undergone laparoscopic total gastrectomy with Roux-en-Y esophageal-jejunostomy reconstruction 1 year previously. By several examinations, we consequently diagnosed this case as a perihilar cholangiocarcinoma and performed HPD. Histological examination revealed a well differentiated adenocarcinoma without lymph-node metastasis and a negative margin of liver parenchyma and pancreas. He was recovered from a grade B pancreatic fistula by conservative therapy and discharged post-operatively on day 64 in good health. The patient received postoperative systemic chemotherapy with gemcitabine for 6 months. 16 months after surgery, the patient has had no recurrence.DiscussionHPD for biliary and cancers after total gastrectomy is a challenging procedure with high morbidity and mortality rates. However, this procedure can provide the chance for long-term survival if curative resection is feasible.ConclusionThis case was the first report of hepatopancreatoduodenectomy following laparoscopic total gastrectomy.