Solitary pulmonary metastasis arising thirteen years after liver transplantation for HBV-related hepatocellular carcinoma

We described a 59-year-old male patient who underwent liver transplantation in 1989 for hepatocellular carcinoma (HCC) complicating hepatitis B virus (HBV) cirrhosis. In 2001 (12 years after liver transplantation), he developed a lung metastasis of HCC without intrahepatic recurrence and the resection was done. In July 2003, he was symptom free without any recurrence. HCCmetastasis can develop even after a very long time of liver transplantation. Many HCCs grow slowly, and the growth rate of recurrent tumors in patients receiving immunosuppressive therapy is significantly greater thanthat of those who do not receive immunosuppressive therapy.     

Conversion to sirolimus immunosuppression in liver transplantation recipients with hepatocellular carcinoma： Report of an initial experience

AIM: To report a retrospective analysis of preliminary results of 36 patients who received sirolimus (SRL, Rapa-mune, rapamycin) in a consecutive cohort of 248 liver allograft recipients. METHODS: Thirty-six liver transplant patients with he-patocellular carcinoma (HCC) who were switched to SRL-based immunosuppression therapy from tacrolimus were enrolled in this study. The patients who were diagnosed as advanced HCC before orthotopic liver transplantation (OLT) were divided into group A (n = 11), those who were found to have HCC recurrence and/or metastasis after OLT were assigned to group B (n=18), and those who developed renal insufficiency caused by calcineurin inhibitor (CNI) were assigned to group C (n = 7) after OLT. RESULTS: The patients were followed up for a median of 10.4 mo (range, 3.8-19.1 mo) after conversion to SRL therapy and 12.3 mo (range, 5.1-34.4 mo) after OLT. Three patients developed mild acute cellular rejection 2 wk after initiating SRL therapy, which was fully reversed after prednisolone pulse therapy. In group A, only 1 patient was found to have HCC recurrence and metastasis 12 mo after OLT. In group B, 66.7% (12/18) patients (2 with progressive tumor, 7 with stable tumor and 3 without tumor) were still alive due to conversing to SRL and/ or resection for HCC recurrence at the end of a median follow-up of 6.8 mo post conversion and 10.7 mo post-transplant. In group C, no HCC recurrence was demonstrated in 7 patients, and renal function became normal after SRL therapy. Thrombocytopenia (n = 2), anemia (n = 8), and oral aphthous ulcers (n = 7) found in our cohort were easily manageable. CONCLUSION: The conversion to SRL-based immuno-suppression may inhibit the recurrence and metastasis of HCC and improve CNI-induced renal insufficiency in OLT patients with HCC.     

De novo Hepatocellular Carcinoma after Liver Transplantation

Liver transplantation is the definitive therapy for patients with advanced liver disease and its complications. Patients who are transplanted with a diagnosis of hepatocellular carcinoma (HCC) are at risk of recurrent cancer, and these patients are monitored on a regular basis for recurrence. In contrast, de novo HCC following liver transplantation is a very rare complication, and recipients without HCC at the time of transplantation are not screened. We describe the clinical features of de novo HCC over a decade after achieving a sustained viral response with treatment of hepatitis C and two decades after liver transplantation. Our case highlights the necessity of screening for HCC in the post-transplant patient with advanced liver disease even after viral clearance.     

Multimodal and systemic therapy with cabozantinib for treatment of recurrent hepatocellular carcinoma after liver transplantation: A case report with long term follow-up outcomes

Rationale:Recurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT) remains a major therapeutic challenge. In recent years, new molecular-targeted therapies, such as cabozantinib, have been approved for the treatment of advanced HCC. However, clinical experience with these new drugs in the treatment of HCC in the LT setting is very limited.Patient concerns:In 2003, a 36-year-old woman was referred to the hospital with right upper abdominal pain.Diagnosis:An initial ultrasound of the liver demonstrated a large unclear lesion of the left lobe of the liver. The magnet resonance imaging findings confirmed a multifocal inoperable HCC in a non-cirrhotic liver. Seven years after receiving a living donor LT, pulmonary and intra-hepatic recurrence of the HCC was radiologically diagnosed and histologically confirmed.Interventions:Following an interdisciplinary therapy concept consisting of surgical, interventional-radiological (with radiofrequency ablation [RFA]) as well as systemic treatment, the patient achieved a survival of more than 10 years after tumor recurrence. As systemic first line therapy with sorafenib was accompanied by grade 3 to 4 toxicities, such as mucositis, hand-foot skin reaction, diarrhea, liver dysfunction, and hyperthyroidism, it had to be discontinued. After switching to cabozantinib from June 2018 to April 2020, partial remission of all tumor manifestations was achieved. The treatment of the remaining liver metastasis could be completed by RFA. The therapy with cabozantinib was well tolerated, only mild arterial hypertension and grade 1 to 2 mucositis were observed. Liver transplant function was stable during the therapy, no drug interaction with immunosuppressive drugs was observed.Outcomes:More than 10 years survival after recurrence of HCC after living-donor LT due to intensive multimodal therapy concepts, including surgery, RFA, and systemic therapy with cabozantinib in the second line therapy.Lessons:In conclusion, this report highlights the tolerability and effectiveness of cabozantinib for the treatment of HCC recurrence after LT. We show that our patient with a late recurrence of HCC after LT benefitted from intensive multimodal therapy concepts, including surgery, RFA, and systemic therapy.     

肝细胞癌肝移植术后免疫抑制剂的应用

肝移植已经成为肝细胞癌根治性治疗的重要手段,但术后复发与转移严重限制了肝细胞癌肝移植的疗效。近年来,国内外学者围绕肝移植术后免疫抑制剂的应用与肝细胞癌复发转移的关系进行了一系列研究。现就肝细胞癌肝移植术后免疫抑制剂的临床应用策略及建议作一简述,以更好地指导临床。     

18F-FDG PET/CT纳入肝细胞癌肝移植标准的趋势与价值

肝移植是治疗肝细胞癌(HCC)的有效方法,为降低HCC肝移植术后可能出现较高肿瘤复发率,有学者率先提出著名的Milan标准。但该标准过于严格,部分患者因其肿瘤病变较大或多个结节,虽其生物行为相对“温良”,也被排除在等待肝移植名单之外,随之世界各地出现了众多的“扩大Milan版标准”。HCC组织病理学的微血管侵犯(MVI)、肿瘤组织低分化与HCC肝移植术后较高复发率有显著相关性。复习总结了近年来国内外18氟-脱氧葡萄糖(18F-FDG)PET/CT在HCC肝移植方面的应用文献,发现18F-FDG在HCC病变部位不同的摄取程度,反映了肿瘤组织生物学行为特征即侵袭性的差异;18F-FDG高摄取与HCC病变的MVI、低分化呈正相关;18F-FDG还能敏感、准确地发现HCC肝外转移灶。认为术前18F-FDG PET/CT结果对HCC肝移植预后评估有巨大价值,将其结果纳入HCC肝移植标准是趋势所归,也有望统一“扩大Milan版标准”。建议新的肝移植标准可定义为,原则上遵循Milan标准;对超出Milan标准者,满足HCC病变18F-FDG PET/CT阴性,且排除大血管侵犯和肝外转移。     

Liver transplantation for hepatocellular carcinoma: is zero recurrence theoretically possible?

BACKGROUND: Hepatocellular carcinoma(HCC) recurrence remains a key issue after liver transplantation. This study aimed to determine a subgroup of HCC patients within the Milan criteria who could achieve a theoretical goal of zero recurrence rates after liver transplantation.METHODS: Between 1999 and 2009, 179 patients who received liver transplantation for HCC within the Milan criteria were retrospectively included. Analysis of the factors associated with HCC recurrence was performed to determine the subgroup of patients at the lowest risk of recurrence.RESULTS: Seventy-two percent of the patients received a bridging therapy, including 54 liver resections. Eleven(6.1%) patients recurred within a delay of 19±22 months and ultimately died. Factors associated with recurrence were serum alpha-fetoprotein level 400 ng/m L, satellite nodules, poor differentiation, microvascular invasion and cholangiocarcinoma component. Recurrence rates decreased from 6.1% to 3.1% in patients without any of these factors.CONCLUSIONS: Among HCC patients within the Milan criteria, selecting patients with factors based on histology would allow tending towards zero recurrence, and prior histological assessment by liver biopsy or resection may be essential to rule out poorly differentiated tumors, microvascular invasion,and cholangiocarcinoma component.     

肝移植术后原发性肝癌复发与乙型肝炎病毒再感染的关系

目的 探讨肝移植术后原发性肝癌复发与HBV再感染的关系.方法 对2004年1月-2008年12月在中山大学附属第三医院因乙型肝炎相关性终末期肝病行肝移植手术并长期随访的340例患者回顾性分析.患者被列入肝移植等待名单后给予核苷(酸)类似物抗病毒治疗,术中和术后均给予核苷(酸)类似物联合低剂量乙型肝炎免疫球蛋白进行预防.术后定期随访并监测患者HBV再感染的发生率及生存率,用多因素COX回归分析筛选出影响术后HBV再感染的危险因素.计量资料用t检验、计数资料用x2检验进行统计学处理.用Kaplan-Meier方法进行生存率分析,对HBV再感染危险因素用COX多因素回归分析,对HBV再感染与原发性肝癌复发的时间进行Spearman线性相关分析.结果 340例患者术后发生HBV再感染33例,术后1、3、5年再感染率分别为7%、10%、13%.HBV再感染的时间为1～21个月,中位数为5个月.原发病为原发性肝癌(风险比为2.98;95%可信区间为1.08～8.25,P＜0.05)、术前HBV DNA载量＞5log10拷贝/ml(风险比为3.99;95%可信区间为1.85～8.62,P＜0.01)是发生HBV再感染的危险因素.原发性肝癌复发者HBV再感染发生率高于未复发者,分别为27.9%和8.7%(风险比为4.58; 95%可信区间为1.88～11.12;P＜0.01).12例患者肝移植术后发生HBV再感染和原发性肝癌复发,两者的复发时间具有相关性(r=0.583,P＜0.05).结论肝移植术后原发性肝癌复发是HBV再感染的危险因素.

Abstract：

Objective To investigate the relationship between hepatocellular carcinoma (HCC)recurrence and hepatitis B virus (HBV) recurrence. Method The clinical data of 340 patients underwent liver transplantation due to HBV related end-stage liver disease and received long-term follow up in our hospital from Jan 2004 to Dec 2008 were retrospectively analyzed. All patients received nucleoside analogues therapy formally before entering into the waiting list and nucleoside analogues combined low-dose HBIG therapy during and after transplantation. Patients were regularly followed up at the outpatient, monitoring the HBV recurrence and survival. Multivariate Cox regression analysis was used to evaluate the risk factors for hepatitis recurrence. Result 33 patients suffered from HBV recurrence post transplantation.The 1-, 3- and 5- year recurrence rates were 7.0%, 10% and 13% respectively. The median HBV recurrence time was 5 months (1-21 months). COX regression analysis revealed that risk factors for HBV recurrence were HCC (HR = 2.98; 95% CI 1.08-8.25; P＜0.05) and pre-transplantation HBV-DNA load over 5 log10 copies/ml (HR = 3.99; 95% CI 1.85-8.62; P＜0.01). Further stratified analysis showed that patients who suffered from carcinoma recurrence had a higher incidence of HBV recurrence than those who did not, which were 27.9% and 8.7% (HR =- 4.58;95% CI 1.88-11.12; P＜0.01) respectively. 12 patients suffered from both HCC and HBV recurrence. Spearman correlation analysis demonstrated a strong correlation between HBV and HCC recurrence times (r= 0.583, P＜0.05). Conclusion Post transplantation HCC recurrence is a risk factor for HBV recurrence.     

Patient with adult‐onset type II citrullinemia beginning 2 years after operation for duodenal malignant somatostatinoma: Indication for liver transplantation

We report a 51‐year‐old female patient with adult‐onset type II citrullinemia (CTLN2) who had a history of pancreatoduodenectomy for duodenal somatostatinoma with metastases to regional lymph nodes at age 49 years, paying special attention to indications for liver transplantation. At age 50 years, she developed hepatic encephalopathy with elevation of plasma ammonia and citrulline levels. A diagnosis of CTLN2 was made by DNA analysis of the SLC25A13 gene and treatment with conservative therapies was begun, including a low‐carbohydrate diet and supplementation with arginine and sodium pyruvate. However, despite these treatments, frequent attacks of encephalopathy occurred with markedly elevated plasma ammonia levels. While we were apprehensive regarding the risk of recurrence of somatostatinoma due to immunosuppressive therapy after liver transplantation, the patient was in a critical condition with CTLN2 and it was decided to perform living‐donor liver transplantation using a graft obtained from her son. Her postoperative clinical course was uneventful and she has had an active life without recurrence of somatostatinoma for 2 years. This is the first case of CTLN2 with somatostatinoma. As the condition of CTLN2 patients with rapidly progressive courses is often intractable by conservative therapies alone, liver transplantation should be considered even after surgery for malignant tumors in cases with neither metastasis nor recurrence.     

Sirolimus plus sorafenib in treating HCC recurrence after liver transplantation: a case report

A case of hepatocellular carcinoma (HCC) with pulmonary recurrence after liver transplantation for HCC is presented in this report. The patient showed disease progression on sorafenib therapy demonstrated by computed tomography scans as well as serial serum α-fetoprotein (AFP) elevation. After his immunosuppression therapy was successfully transitioned to sirolimus and a continuation of sorafenib, he achieved partial remission based on RECIST criteria and normalization of AFP. Mammalian target of rapamycin inhibitors including sirolimus alone or in conjunction with sorafenib may be useful in the treatment of post transplant HCC.     

Low recurrence rate of hepatocellular carcinoma following ledipasvir and sofosbuvir treatment in a real‐world chronic hepatitis C patients cohort

The aims of the present study were to evaluate the efficacy and tolerability of ledipasvir/sofosbuvir (LDV/SOF) with or without ribavirin in the treatment of chronic hepatitis C (CHC) in patients with advanced liver disease and to analyse whether the use of LDV/SOF treatment is associated with a new occurrence of hepatocellular carcinoma (HCC) during and after LDV/SOF treatment. The Turkish Early Access Program provided LDV/SOF treatment to a total of 200 eligible CHC patients with advanced liver disease. The median follow‐up period was 22 months. All patients were Caucasian, 84% were infected with genotype 1b, and 24% had a liver transplantation before treatment. The sustained virological response (SVR12) was 86.0% with ITT analysis. SVR12 was similar among patients with Child‐Pugh classes A, B and C disease and transplant recipients. From baseline to SVR12, serum ALT level and MELD score were significantly improved (P < 0.001). LDV/SOF treatment was generally well tolerated. Only one patient developed a new diagnosed HCC. Seventeen of the 35 patients, who had a history of previous HCC, developed HCC recurrence during the LDV/SOF treatment or by a median follow‐up of 6 months after treatment. HCC recurrence was less commonly observed in patients who received curative treatment for HCC compared with those patients who received noncurative treatment (P = 0.007). In conclusion, LDV/SOF with or without ribavirin is an effective and tolerable treatment in CHC patients with advanced liver disease. Eradication is associated with improvements in liver function and a reduced risk of developing a new occurrence of HCC.     

A report of 28 cases of 3-year follow-up after liver transplantation for advanced hepatocellular carcinoma

AIM: To investigate the therapeutic value of liver transplantation for advanced hepatocellular carcinoma (HCC). METHODS: Twenty-eight patients with advanced HCC were treated by liver transplantation from August 2000 to October 2003 at Peking University Third hospital. All the patients were followed up to evaluate the result. RESULTS: The longest follow-up duration was 3 years and 3 mo. Till the end of the follow-up period, 17 patients had already died and 11 were alive. Of those who died, 10 patients died of tumor recurrence, 4 died during the perioperative period, 2 died of variceal bleeding, and 1 died of biliary complication. According to life table method, the 1-, 2-, and 3-year survival rates were 87.5%, 52.5%,and 42.9%, respectively. CONCLUSION: Liver transplantation provides a new treatment under the circumstance of lacking of an effective treatment for advanced HCC at present. Some patients can survive for a relatively long time free of tumor. In our country, if the patients can afford liver transplantation, advanced HCC without extrahepatic metastasis is an indication for liver transplantation at present.     

Treatment of hepatocellular carcinoma

Opinion statement The incidence of hepatocellular carcinoma (HCC) is increasing in the United States. Several modalities are available for the treatment of HCC, and decisions regarding the optimal choice of therapy are based on tumor burden and severity of liver disease. Classification systems are helpful for prognostic purposes and to guide in the choice of therapy. Surgical resection is a mainstay of therapy for patients with solitary small tumors and preserved liver function (noncirrhotic or Child-Pugh class A cirrhotic patients without portal hypertension). Unfortunately, a minority of patients is eligible for resection, and postoperative recurrence or de novo HCC is common. Liver transplantation offers the best chance of curing HCC in cirrhotic patients. Patients with a solitary tumor less than 5 cm or no more than three tumors each 3 cm or less have a survival rate of 70% with less than 20% recurrence at 5 years. Access to liver transplantation is limited by organ availability, and tumor progression during the waiting period can lead to ineligibility. Ethanol injection and radiofrequency ablation are effective modalities to ablate small tumors (generally <5 cm) in patients who are not candidates for resection or liver transplantation. These modalities can also be used to treat HCC prior to liver transplantation. Transarterial chemoembolization is used to treat patients with multifocal or large HCC who are ineligible for other therapies. Chemotherapeutic agents are infused into the tumor via the hepatic artery along with embolic material in order to induce tumor necrosis. This technique should be used in selective patients with relatively preserved liver function, absence of portal vein thrombosis, or encephalopathy. Limited data exist to support the use of this modality as a primary treatment option for small HCC. Chemotherapeutic or hormonal therapies have a limited role in the management of patients with HCC. Despite mixed outcomes, we routinely use the somatostatin analog octreotide in advanced, multifocal HCC. Emerging therapies should focus on treatment of small tumors and targeted pharmacologic therapy for advanced disease.     

Brain metastasis of hepatocellular carcinoma detected after liver transplantation

AIM: We report the case of a patient with hepatocellular carcinoma submitted to liver transplantation, who subsequently manifested tumor recurrence initially as brain metastasis. CASE DESCRIPTION: A 48-year-old male cirrhotic patient with hepatitis C infection, and two focal hepatic lesions, had a cytologic and histologic diagnosis of hepatocellular carcinoma. Before transplant, he was submitted to adjuvant treatment with a combination of arterial embolization and intratumoral ethanol injection. In the 3rd month post-liver transplantation, the patient developed headache, nausea and vomiting, without any neurological impairment. Brain computed tomography and magnetic resonance imaging identified an expansive hypervascular lesion with internal bleeding. Evaluation of the surgical explant revealed macroscopic invasion of portal vessels. CONCLUSION: Brain metastasis of a hepatocellular carcinoma after liver transplantation may occur. This metastasis may have occurred before or soon after the transplant. Patients with hepatocellular carcinoma, awaiting liver transplant, should be screened for cerebral metastasis. Vascular invasion may indicate hematogenic dissemination of the tumor.     

Organ tolerance following cadaveric liver transplantation for chronic graft-versus-host disease after allogeneic bone marrow transplantation

A paediatric patient was treated with orthotopic liver transplantation after he developed cirrhosis of the liver due to chronic graft-versus-host disease (GVHD) following allogeneic bone marrow transplantation. His pre-existing chronic GVHD of the skin disappeared and immunosuppressive therapy could be gradually tapered and finally withdrawn 71 months after liver transplantation. Two and a half years after discontinuation of all immunosuppressive therapy, the patient is in excellent condition with neither signs of chronic GVHD nor rejection of the liver graft.     

肝移植术后肝癌复发防治进展

肝移植是根治性治疗肝癌的方法之一,但肝移植术后肝癌复发严重影响移植患者的长期生存。通过积极的预防措施,免疫抑制剂调整,早期发现以及全面制订肝癌复发后的干预措施,有助于提高肝癌肝移植患者临床疗效并改善长期生存。为了进一步改善肝移植患者预后,从预防复发及复发后的治疗两大方面对肝移植术后肝癌复发的最新防治进展进行归纳和总结。     

肝移植术后乙型肝炎复发患者的预后分析

目的 分析肝移植术后乙型肝炎复发患者的预后及其相关资料.方法 回顾性分析天津市第一中心医院器官移植中心1998年12月至2009年11月因乙型肝炎相关终末期肝病行肝移植术,且术后接受小剂量乙型肝炎免疫球蛋白联合核苷(酸)类似物预防乙型肝炎复发的1506例患者资料.对其中出现复发病例的资料及其预后进行分析.所有患者术后均行HBV相关血液学检测,检测HBV DNA水平、肝功能,HBV血液学标志物阳性时行肝脏病理学活组织检查,随访至2010年11月.生存分析及复发率采用Kaplan-Meier生存分析,复发率及生存率的比较采用log-rank test检验.结果 共有38例肝移植术后病例确诊为乙型肝炎复发,中位随访时间为45.1个月,非肝癌肝移植患者乙型肝炎中位复发时间为31.8个月(0.3 ～ 72.8个月),肝癌肝移植患者乙型肝炎中位复发时间为13.7个月(0.3 ～ 66.6个月);8例患者检测出HBV耐药基因变异;18例病例接受恩替卡韦或阿德福韦酯挽救治疗,病毒复制转为阴性,肝功能恢复正常;其中22例病例由于肝癌复发、肝功能衰竭及其他原因死亡,16例病例生存.结论 HBV耐药基因变异及肝癌复发是肝移植术后乙型肝炎复发的重要原因,良性肝病肝移植患者乙型肝炎复发后接受阿德福韦酯或恩替卡韦挽救治疗可获得较好预后,而肝癌肝移植术后乙型肝炎复发患者预后较差.     

A randomized controlled trial of Licartin for preventing hepatoma recurrence after liver transplantation

Orthotopic liver transplantation (OLT) is the only curative therapy of HCC with underlying cirrhosis, but due to HCC metastasis and recurrence, its benefit is limited to a small population who meet the strict selection criteria. We previously reported that Licartin ([131I] mAb HAb18G/CD147) was safe and effective in treating HCC patients, and its antigen, HAb18G/CD147, was closely related to HCC invasion and metastasis. Here, we reported a randomized controlled trial to assess the post-OLT antirecurrence efficacy of Licartin in advanced HCC patients. We randomized 60 post-OLT patients with HCC, who were at tumor stage 3/4 and outside the Milan criteria before OLT, into 2 groups. Three weeks after OLT, the treatment group received 15.4 MBq/kg of Licartin, while the control group received placebo intravenously for 3 times with an interval of 28 days. At 1-year follow-up, the recurrence rate significantly decreased by 30.4% (P = 0.0174) and the survival rate increased by 20.6% (P = 0.0289) in the treatment group, compared with those in the control group. For the control group versus the treatment group, the hazard ratio for recurrence was 3.60 (95% confidence interval [CI], 1.50-8.60) and that for death was 3.87 (95% CI, 1.23-12.21). Licartin treatment also resulted in an earlier decreased AFP level and a longer time of normal AFP level than placebo (P = 0.0016). No Licartin-related toxic effects were observed. Conclusion: Licartin is a promising drug for preventing post-OLT tumor recurrence in advanced HCC patients excluded by the currently strict criteria for OLT. HAb18G/CD147 can be a good drug target.     

Recurrence of hepatocellular carcinoma: multicentric occurrence or intrahepatic metastasis? A viewpoint in terms of pathology

Recurrence after successful surgical or nonsurgical treatment of hepatocellular carcinoma (HCC) is caused either by intrahepatic metastasis or by metachronously multicentric occurrence. Intrahepatic metastasis is a major cause of recurrence of advanced HCCs with varying degrees of vascular invasion, and multicentric occurrence is a frequent cause of recurrence in small HCCs with no obvious vascular invasion. It is estimated that at least 20% of small HCCs have a high probability of recurrence due to multicentric occurrence, based on the finding that adenomatous hyperplasia (AH) and/or atypical adenomatous hyperplasia (AAH), which are considered premalignant lesions, are found in the vicinity of resected small HCCs with liver cirrhosis. However, because neither AH nor AAH occur in HCC cases without liver cirrhosis, most recurrence of HCC in noncirrhotic liver is considered to be due to intrahepatic metastasis or to de novo hepatocarcinogenesis. In a survey of autopsy cases of liver cirrhosis with small HCC, smaller HCC nodules were found in other liver slices in 50% of cases, and it is estimated that approximately 50% of HCC is already multicentric in the early stage.