Liver transplantation in primary and secondary tumors of the liver. Review of the literature and perspectives

Liver transplantation for malignancies still remains a controversial issue. There is concern for tumour recurrence, poor results and waste of organs, which in the sitting of organ shortage would penalize patients with non-malignant disease. Many centers worldwide perform liver transplantation (OLT) for hepatocellular (HCC) carcinoma associated with liver cirrhosis; the results in these cases are similar to those of patients transplanted for other indications. On the contrary are very few the centers that perform OLT for tumour other than HCC. This reflects that tumours other than HCC are less common and survival is poor compared to patients transplanted for non-malignant disease. Acceptable indications for OLT in case of tumours other than HCC are liver metastases from neuroendocrine tumours and epithelioid emangio-endothelioma. However should be kept in mind that OLT may offer the sole opportunity to cure the tumour and the underlying disease in some patients while providing meaningful palliation for others. At the present the overall experience with OLT for tumours other than HCC is still not significant and the results are discouraging. There is no evidence that OLT is beneficial for non-HCC tumours. Hopefully for the next future new adjuvant and neoadjuvant therapies combined with OLT would provide improved survival. Nevertheless, long-term survivors continue to be reported suggesting that OLT may be beneficial in individual selected cases with non-HCC tumour.     

Liver transplantation for hepatocellular carcinoma: a single European centre experience

Background With respect to deficient donor grafts and the risk of tumour recurrence, indication for orthotopic liver transplantation (OLT) is still controversial. OLT offers the only chance for both the tumour and the underlying liver disease to be eliminated in patients with hepatocellular carcinoma (HCC) and cirrhosis. The aim of this study was to assess survival and related factors of recurrence.Patients and methods This retrospective study analyses data from 45 patients with HCC (UICC stage I/II, n=16; III, n=13; IV, n=12) treated with OLT between 1992 and 2002 in our centre. There were 39 primary tumours and two recurrent ones after previous surgical resection. Four perioperative deaths were excluded from analysis.Results Mean follow-up was 50.4 months. Five-year rates after OLT were 64% for overall survival, 78% for disease-specific survival, 73% for recurrence-free survival, and 22% for tumour recurrence. No tumour recurrence has been observed so far in patients with tumours of UICC stage I/II. None of the patient characteristics had a significant impact on survival, while tumour stage was significantly correlated with freedom from recurrence.Conclusion Our results demonstrate that the risk of recurrent HCC in liver transplanted patients is low for small and solitary tumours with no vascular invasion (UICC I/II). Even in advanced tumour stages (UICC III/IV), there is a real chance of cure or at least a survival benefit in selected patients.Presented at the workshop on malignant tumours in organ transplantation, Department of Surgery, Ludwig Maximillians University, Munich, 4–5 April 2003     

Liver transplantation for hepatocellular carcinoma in patients without underlying liver disease: a systematic review.

Liver resection is the treatment of choice for hepatocellular carcinoma (HCC) occurring in the absence of underlying chronic liver disease. Orthotopic liver transplantation (OLT) is reserved for patients with unresectable disease but remains controversial. The aim of this study was to review the published literature on OLT for HCC in patients without coexisting chronic liver disease. A Medline-based search identified 126 patients reported in 16 papers over the last 32 years. One third had fibrolamellar HCC (FL-HCC), and two thirds had non-FL-HCC. Recurrence data were given in 55 patients of whom 27 had tumor recurrence. Seventy-five percent of the recurrences occurred within the first 2 years after OLT, although recurrences were reported up to 72 months after OLT for FL-HCC. The 5-year survival rate was greater in patients who underwent transplantation for FL-HCC than for non-FL-HCC (39.4% and 11.2%, respectively). There was insufficient information available to determine the influence of tumor size, distribution, stage, and vascular invasion on survival, although most patients in whom tumor characteristics were specified had advanced disease. This study indicates that FL-HCC carcinoma is a more favorable indication for OLT than non-FL-HCC in patients without underlying liver disease, although more detailed prognostic information is required to improve patient selection.     

Clinical outcomes of liver transplantation for HBV-related hepatocellular carcinoma: data from the NIH HBV OLT study

Han SH, Reddy KR, Keeffe EB, Soldevila‐Pico C, Gish R, Chung RT, Degertekin B, Lok ASF. Clinical outcomes of liver transplantation for HBV‐related hepatocellular carcinoma: data from the NIH HBV‐OLT study.
Clin Transplant 2011: 25: E152–E162. © 2010 John Wiley & Sons A/S. Abstract: Background: Hepatitis B virus (HBV)‐related hepatocellular carcinoma (HCC) is an indication for orthotopic liver transplantation (OLT) in patients with tumor stage within the United Network for Organ Sharing criteria. The number of patients listed for HBV‐related HCC is increasing, while the number of patients listed for HBV‐related cirrhosis is declining presumptively because of the availability of more effective oral nucleos(t)ide analogues. This study presents the final, long‐term outcome of patients transplanted for HBV‐related HCC in the National Institutes of Health (NIH) HBV OLT Study Group. Results: Ninety‐eight patients (52.4%) in the NIH HBV OLT cohort underwent OLT for HBV‐related HCC. With a mean follow‐up of 36.5 months post‐OLT, 12 (12.2%) patients developed recurrence of HCC. Multivariate analysis did not find a statistically significant role of gender, tumor stage at OLT, pre‐OLT HCC treatment, recurrence of HBV, or duration of HCC diagnosis pre‐OLT in predicting HCC recurrence. Serum alpha‐fetoprotein (AFP) level >200 ng/mL at transplant was found to be statistically significant in predicting HCC recurrence (p = 0.003). HCC recurrence was significantly associated with decreased post‐OLT survival. Conclusion: HCC is the most common indication for OLT in patients with chronic hepatitis B in the era of more effective oral antivirals. Serum AFP at the time of OLT is significantly associated with HCC recurrence.     

Resection or transplantation for hepatocellular carcinoma in cirrhotic patients: outcomes based on indicated treatment strategy

BACKGROUND: Surgical resection has been the treatment of choice for hepatocellular carcinoma (HCC), but the resection rate remains low in cirrhotic patients and recurrence is common. Unfavorable results compared with benign disease and the shortage of organ donors have led to a restricted indication for orthotopic liver transplantation (OLT) for HCC. STUDY DESIGN: The aim of this study was to analyze the results of our surgical approach to HCC in patients with cirrhosis. The first treatment strategy indicated in these patients was OLT. From January 1990 to May 1999, 85 patients underwent OLT and the remaining 35 had surgical resection. RESULTS: One-, 3-, and 5-year survival rates were 84%, 74%, and 60% versus 83%, 57%, and 51%, respectively, in the OLT and resection groups (p = 0.34). Hepatic tumor recurrence was much less frequent in the OLT group than in the resection group. The 1-, 3-, and 5-year disease-free survival rates were 83%, 72%, and 60% versus 70%, 44%, and 31%, respectively (p = 0.027). In the multivariate Cox regression analysis, macroscopic vascular invasion was the only factor independently associated with death or recurrence after OLT (p = 0.006). After partial liver resection, the tumors significantly associated with mortality and recurrence in the multivariate analysis were solitary or multiple tumors greater than 2cm with microscopic vascular invasion (pathologic pT3) (p = 0.01). CONCLUSIONS: Our results confirm that in cirrhotic patients, OLT may provide better outcomes than liver resection in carefully selected HCC and that longterm survival is similar to the results of OLT in cirrhotic patients without tumors.     

Malignant liver tumours

Malignant liver tumours can be primary or secondary. The most common primary malignant liver tumours are hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (IHC), while the colorectal and neuroendocrine liver metastases account for the majority of secondary tumours.HCC tends to arise in patients with cirrhosis secondary to hepatitis or alcohol. Diagnosis is usually made on a raised α-fetoprotein and CT and MRI. Treatment options include hepatic resection, transplantation, percutaneous ablation and transarterial chemo-embolization. Treatment is dependent on the Child’s status of the patient, extent of liver disease and the presence of metastatic disease.IHC accounts for 10% of cholangiocarcinomas. Risk factors include primary sclerosing cholangitis and choledochal cysts. Liver resection offers the only chance for cure in these patients.Secondary liver tumours account for 95% of hepatic malignancies, the most common being colorectal liver metastases (CRLM). CRLM are detected during surveillance following surgery for the primary tumour. Liver resection is potentially curative, and more patients are being subjected to liver resection following down-staging of the disease with neoadjuvant chemotherapy.Surgery offers a potential cure for liver tumours. Recent medical advances have made treatment of malignant liver tumours safer and potentially curative.     

肝移植在肝癌治疗中的地位与评价

以肝移植治疗原发性肝细胞性肝癌(简称肝癌)，应严格地选择适当的病例：单个肿瘤直径不超过5cm，多发性肿瘤直径小于3cm和肿瘤总数不超过3个，肿瘤没有血管和淋巴结侵犯和肝外转移。如果病人患乙型或丙型肝炎，适当地以有效的抗病毒治疗，病人长期存活率可高达79％。这存活率和肝移植治疗良性末期肝硬化十分接近。没有足够证据显示手术前、后辅助性化疗可提高肝移植治疗肝癌的疗效，适量的免疫功能抑制，有助减低肝癌的复发率。如肝癌病人等待肝移植的时间长，可考虑以TACE，射频或微波治疗以减慢肝癌生长速度。肝移植和部分肝切除的长期治疗结果相差不大，在一小部分病人，如肝硬化程度严重，肝移植可比部分肝切除疗效好。肝移植用于治疗纤维板层肝癌和偶然发现肝癌疗效好。由于肝移植对于其它肝肿瘤例如胆管癌，血管肉瘤和转移性肝肿瘤疗效甚差，因此这些肝肿瘤不宜用肝移植作治疗。     

Results of resection and transplantation for hepatocellular carcinoma in cirrhosis and noncirrhosis

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. Both liver resection (LR) and orthotopic liver transplantation (OLT) are surgical treatment options depending on the size of the tumor and the presence of cirrhosis. Liver cirrhosis is the main reason for the high early postoperative mortality after resection. Even in the Child A stage, extensive resections are not recommended. This study presented the results of surgical treatment (LR or OLT) for HCC in cirrhotic and noncirrhotic livers. We analyzed the data of 76 patients who underwent LR or OLT for HCC from January 2001 to December 2006. In noncirrhotic livers the following resections were performed: 30 right and extended right hemihepatectomies (54.5%); 11 left hemihepatectomies (20%); and 14 mono- or bisegmentectomies (25.5%). In cirrhotic livers the following procedures were performed: in Child A stage 1 right hemihepatectomy, 1 extended right hemihepatectomy, 1 extended left hemihepatectomy, and 4 mono- or bisegmentectomies; and in Child B stage, 3 mono- or bisegmentectomies. Among 11 patients who underwent transplantation, tumors in 2 patients exceeded the Milan criteria. Five patients in the LR group were treated with transarterial chemoembolization before transplantation. LR for HCC in cirrhosis should be performed with caution; there were no long-term survivors in our data. Our study confirmed that OLT shows good long-term survival in early HCC stages. However, this may also be true for stages above the Milan criteria. For HCC in noncirrhotic livers, LR remains the treatment of choice, justifying an extensive surgical approach. Such an approach achieved favorable long term survivals.     

Beyond Milan criteria – chances and risks of expanding transplantation criteria for HCC patients with liver cirrhosis

Abstract:  Orthotopic liver transplantation (OLT) is, apart from resection, one important curative treatment for hepatocellular carcinoma (HCC) in liver cirrhosis, and especially attractive because it eliminates both the tumor and the underlying liver disease. The application of restrictive inclusion criteria for OLT in HCC patients resulted in favorable long-term recurrence-free survival. These criteria, however, exclude a subgroup of patients which, despite advanced tumor size, demonstrate an acceptable outcome. As a consequence, expansion of the strict Milan criteria has been discussed. However, this will also deteriorate the average outcome of OLT in HCC patients. Considering that we run short of donor organs, more sophisticated prediction models for survival after OLT for HCC patients are needed to identify patients who benefit best from OLT. Neoadjuvant treatment that is frequently applied as a bridging technique for patients on the waiting list for OLT could provide useful information on tumor behavior to better predict the risk of post-OLT tumor recurrence. This might also allow expansion of the Milan criteria to patients with good response to downstaging methods without negatively affecting post-OLT survival. Furthermore, alternative scoring systems have been suggested to identify HCC patients that might still benefit from resection instead of OLT, and molecular tools are being explored to provide predictive information on HCC biology. This review discusses the advantages and risks of extended inclusion criteria for OLT and the currently available data on alternative prediction models and bridging methods in HCC patients.     

Liver Resections for Metastases from Intraabdominal Leiomyosarcoma

This paper discusses liver resection for intraabdominal leiomyosarcoma metastases as a therapy for carefully selected patients. Of the 83 hepatectomies performed from 1992 to 1996, five were resections for liver metastases due to intraabdominal leiomyosarcoma, in 3 patients. The surgical indication was single liver metastases, without any evidence of extrahepatic disease. No mortality occurred during surgery and the longest survival was 38 months. We concluded that liver resection for leiomyosarcoma metastases can be performed, allowing a long term survival in an occasional patient.     

Surgical Treatment of Hepatocellular Carcinoma beyond Milan Criteria. Results of Liver Resection, Salvage Transplantation, and Primary Liver Transplantation

Background There is no clear consensus regarding the best treatment strategy for patients with advanced hepatocellular carcinoma (HCC). Methods Patients with cirrhosis and HCC beyond Milan who had undergone liver resection (LR) or primary orthotopic liver transplantation (OLT) between November 1995 and December 2005 were included in this study. Pathological tumor staging was based on the American Liver Tumor Study Group modified Tumor-Node-Metastasis classification. Results A total of 23 HCC patients were primarily treated by means of LR, 5 of whom eventually underwent salvage OLT. An additional 32 patients underwent primary OLT. The overall actuarial survival rates at 3 and 5 years were 35% after LR, and 69% and 60%, respectively, after primary OLT. Recurrence-free survival at 5 years was significantly higher after OLT (65%) than after LR (26%). Of the patients who underwent LR, 11 (48%) experienced HCC recurrence only in the liver; 6 of these 11 presented with advanced HCC recurrence, poor medical status, or short disease-free intervals and were not considered for transplantation. Salvage OLT was performed in 5 patients with early stage recurrence (45% of patients with hepatic recurrence after LR and 22% of all patients who underwent LR). At a median of 18 months after salvage OLT, all 5 patients are alive, 4 are free of disease, and 1 developed HCC recurrence 16 months after salvage OLT. Conclusion For patients with HCC beyond Milan criteria, multimodality treatment—including LR, salvage OLT, and primary OLT—results in long-term survival in half of the patients. When indicated, LR can optimize the use of scarce donor organs by leaving OLT as a reserve option for early stage HCC recurrence.     

肝细胞癌移植术后肿瘤复发的评估、预防和治疗

肝移植是经过选择的肝癌患者有效的治疗方法之一,但是约有20%的肿瘤复发率限制了肝癌、肝硬化移植术后的长期生存.尽管有些临床指标会强烈提示复发风险和术前肿瘤肝外转移,从而放弃肝移植.事实上,术后肿瘤复发往往是由于术前或术中出现肝外微转移病灶进一步发展的结果.由于器官的紧缺,肿瘤局部治疗以及外科肝部分切除术成为肝移植术前等待期间的桥梁.而且,更积极的外科切除包括切除肝肿瘤以及肝外孤立的转移灶.这些创造性方案是否能改变生存率目前还不清楚,需要长期的随访才能判定其效果.     

原发性肝癌与非肝癌病人行肝移植治疗的比较研究

目的：探讨我国目前肝癌与非肝癌病人行肝移植治疗的风险及长期生存效果。方法：回顾性总结21例晚期肝癌病人行肝移植手术治疗风险及长期生存情况，并与同期所行另外19例非肝癌病人的肝移植进行比较。结果：晚期肝癌病人的手术前凝血状态好于因其它非肝癌原因而接受肝移植的病人，与此相应的手术中出血量、需要输血量、术中输液总量均少于非肝癌病人，手术中因出血而导致的低血压时间短，手术后较恢复顺利，围手术期病死率低。虽然肿瘤复发所致的远期死亡率明显高于非肝癌病人，但是，总生存率与非肝癌病人无明显区别，部分病人可长期无瘤生存。结论：现阶段肝移植仍是失去根治性切除机会的肝癌病人的有效治疗手段，术后部分病人有无瘤长期生存的可能性。     

Liver transplantation for unresectable hepatocellular carcinoma in patients without liver cirrhosis

Summary Hepatocellular carcinoma (HCC) arising in noncirrhotic and nonfibrotic liver (NC‐HCC) is a rare type of malignancy frequently found in healthy young individuals. Partial liver resection is the treatment of choice with expected 5‐year survival rates between 40% and 70%. As a result of absence of any symptom, a considerable number of patients are diagnosed when the malignancy has progressed to an advanced stage and the tumor has turned already unresectable. Some other patients suffer from intrahepatic recurrence after previous liver resection that cannot be re‐resected or locally ablated. In these situations, liver transplantation (LT) may be the only potentially curative treatment. The indication for LT in NC‐HCC patients, however, is not well established. The preliminary results of recent analysis of the European Liver Transplant Registry (ELTR) together with a literature review identified over 150 patients transplanted for NC‐HCC during the last 15 years. In contrast to the historical data, these studies showed 5‐year survival rates at 50–70% in well‐selected patients. Important determinants of poor outcome are macrovascular invasion, lymph node involvement, and time interval of <12 months when LT is used as rescue therapy for intrahepatic recurrence after a previous partial liver resection. Interestingly, outcomes after both liver resection and LT for NC‐HCC are much less influenced by tumor size than is the case with cirrhotic HCC. A large tumor size per se should, therefore, not to be seen as a strict contraindication for performing LT in patients with NC‐HCC.     

Malignant liver tumours

The liver is commonly affected by malignant tumours, both primary and secondary. The majority of liver tumours are diagnosed radiologically and MRI and CT scan are accurate at detecting even small tumours. Hepatocellular carcinoma (HCC) is the most common primary tumour and often presents on the background of liver cirrhosis. The curative options for HCC are liver resection and transplant. However non-curative management such as radiofrequency ablation (RFA) and trans-arterial chemo-embolization (TACE) can prolong survival in patients not suited to curative management. Cholangiocarcinoma is a less common malignancy but unfortunately has poorer outcomes. It affects the bile ducts and treatment relies on resection of the affected liver and biliary tree, requiring reconstruction of the biliary drainage system. Postoperative morbidity is high and long term survival is often short. Colorectal liver metastases (CLM) are the most common liver tumours. With improvements in preoperative chemotherapy and surgical techniques such as portal vein embolization (PVE) and two stage resections, curative resection with good long term outcomes are often achieved.     

Liver resection and transplantation — Therapeutic concepts in surgical treatment of hepatic metastases

Summary Background: Surgical procedures such as liver resection or liver transplantation are the only treatment modalities that provide a chance of cure for patients with liver metastases. Methods: This report reviews results of liver resection and liver transplantation for liver metastases from colorectal cancer and neuroendocrine tumors as compared to the natural course. Results: Overall 5 year survival after curative liver resection for colorectal metastases ranges between 25 and 48%. The operative mortality is between 0 and 5%. Risk factors for tumor recurrence are more or less defined. Reresections of metastases can be performed with comparable mortality rates and results. Liver transplantation for unresectable colorectal metastases offers a median survival of 28 months, but the chance of cure only for individual patients. Exclusion of patients with positive lymph nodes of the primary tumor improves median survival. As there are alternative treatment options for neuroendocrine metastases, indication for liver resection or transplantation is not clearly defined, but the chance of cure by means of surgical treatment should not be missed. Curative resections of neuroendocrine liver metastases can achieve 5-year survival rates of more than 80%. Conclusions: Radical surgical removal of liver metastases from colorectal and neuroendocrine cancer can improve the prognosis for selected patients. Further improval is expected from a multimodal approach.      

肝细胞癌综合治疗选择与策略

肝细胞癌的治疗包括手术切除、肝动脉化疗栓塞（TACE）和局部消融等多种方法。肝脏功能和肿瘤状况是决定是否可行手术的最主要的2个因素。合并门静脉、胆管癌栓仍应积极争取手术。除手术外,肝移植和局部消融是另两种根治性治疗方法,目前一般用于符合Milan标准的早期肝癌（单发肿瘤,直径≤5cm;多发肿瘤,数目≤3个,最大直径≤3cm）。前者要求肝功能失代偿,后者要求肝功能Child—PutghA、B级且不适合手术切除。TACE是不适合根治性治疗的中晚期肝癌的首选方法,选择性的与手术、射频消融、放疗、索拉非尼联用以提高疗效。局限性肝内病灶而又不适合局部消融的肝细胞癌可使用放疗,尤其是肝外转移灶。索拉非尼目前仍主要用于晚期肝细胞癌。免疫治疗是肝细胞癌辅助治疗方法。充分了解各种治疗方法特点,把握适应证,合理综合治疗肝细胞癌,以提高肝细胞癌整体疗效。     

影响原发性肝癌肝移植治疗的预后因素分析

目的分析影响肝癌肝移植术后生存率和无瘤生存率的危险因素,探讨国内肝移植治疗肝癌的选择标准。方法对67例接受同种异位原位肝移植治疗的原发性肝癌病人的基本资料和肿瘤相关资料包括术前病情分级、血清AFP水平、术前辅助治疗以及肝癌大小、数目、pTNM分期、肿瘤恶性程度分级等因素进行单因素和多因素分析。结果术后1年、2年累积生存率为77%、67%,6个月和12个月无瘤生存率为66%和58%。单因素分析显示对肝癌肝移植术后累积生存率影响有统计学意义的因素为CHILD分级(MELD积分)和肝外大血管侵犯;多因素分析影响肝癌肝移植术后无瘤生存率有统计学义的因素是肿瘤大小、大血管侵犯和肿瘤分化程度。结论影响肝癌肝移植术后生存率的因素仍是术前患者肝功能状态。对存在大血管侵犯的肝癌患者需严格控制肝移植术适应证,而无血管侵犯的患者在选择肝移植治疗时肿瘤大小指标可较米兰标准适当放宽。     

Are Patients with Child's A Cirrhosis and Hepatocellular Carcinoma Appropriate Candidates for Liver Transplantation?

We aimed to estimate the survival benefit derived from transplantation in patients with stage II hepatocellular carcinoma (HCC) and Child's A cirrhosis, defined as the mean lifetime with transplantation minus the mean lifetime with treatments other than transplantation. We calculated the posttransplantation survival of all adult, first-time, deceased-donor, liver transplant recipients in the United States since the introduction of the Model for End-Stage Liver Disease based priority system in February 2002 (n = 36,791). We estimated the posttreatment survival of patients with Child's A cirrhosis and stage II HCC treated by radiofrequency ablation (RFA) ± transarterial chemoembolization (TACE) or surgical resection by conducting a systematic review of the medical literature. In patients with Child's A cirrhosis and stage II HCC, the estimated median survival benefit of liver transplantation compared to RFA ± TACE was 1.5 months at 3 years (range -3.5 to 5.6) and 5.7 months at 5 years (range 0.7-11.4), whereas compared to surgical resection it was 0.7 months at 3 years (range -2.9 to 3) and 2.8 months at 5 years (range -4.4 to 5.7). Liver transplantation in patients with stage II HCC and Child's A cirrhosis results in a very low survival benefit and may not constitute optimal use of scarce liver donor organs.     

Management of colorectal liver metastases

Hepatic metastases occur in 60% of patients following resection for colorectal cancer. Liver resection is the only curative option, with one third of resected patients alive at five years. In those developing recurrence in the liver following resection, further liver surgery may be curative, with similar 5 years survival rates of about 30%. Until recently surgery was feasible in only 15–25% of patients with colorectal liver metastases. New strategies, such as downstaging chemotherapy, portal vein embolization and two‐stage hepatectomy, may increase the resectability rate by 15%. Earlier detection of liver metastases would increase resectability, although good follow‐up trials are lacking. Once suspected, colorectal liver metastases are staged by spiral CT, CT portography and MRI, which have similar overall accuracies. Mortality following liver resection is less than 5% in major centres, with a morbidity rate of 20% to 50%. Prognostic scoring systems can be used to predict the likely cure rate with resection. Pulmonary metastases occur in 10–25% of patients with resected colorectal cancer, but are limited to the lung in only 2% of cases. In these selected cases surgery provides long‐term survival in 20–40%, and repeat lung resection has shown similar rates. For patients with unresectable disease, chemotherapy and ablation techniques have been demonstrated to prolong survival, although chemotherapy alone has been shown to improve quality of life.