Jin-Wen Zhng ,Zhen-Yu Yu ,Hi-Bo Li ,Shu-Hong Yi ,Wei Liu ,Yng Yng ,*,Guo-Ying Wng ,*

a Department of Hepatic Surgery and Liver Transplantation Center,The Third Affiliated Hospital of Sun Yat-sen University,Guangzhou,China

b Organ Transplantation Institute of Sun Yat-sen University,Guangzhou,China

c Organ Transplantation Research Center of Guangdong Province,Guangzhou,China

d Guangdong Key Laboratory of Liver Disease Research,The Third Affiliated Hospital of Sun Yat-sen University,Guangzhou,China

ABSTRACT Patients with recurrent hepatocellular carcinoma (HCC) following liver transplantation (LT) have a poor prognosis owing to rapid tumor progression.Yttrium-90 radioembolization (90Y-RE) has been shown to be a safe and efficacious transarterial radioembolization treatment for patients with advanced HCC.However,to our knowledge,no data are available for patients with recurrent HCC following LT.Here we report a case of severe bile duct complication after transarterial radioembolization with yttrium-90 in a patient who experienced HCC recurrence following LT.The present case suggests that 90Y-RE should be cautiously performed in patients with recurrent HCC following LT.

Keywords:Hepatocellular carcinoma (HCC)Post-liver transplant Yttrium-90 radioembolization (90Y-RE)Complication

1.Background

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide and the fourth most common cause of mortality across the world according to a recent report.1Liver transplantation(LT)is considered one of the most effective radical treatments for HCC;however,HCC recurrence is an issue following LT.Imaging features and tumor biomarkers are predictive factors for tumor recurrence.2However,even with careful selection,the HCC recurrence rate following LT is 8－20%.3－6Furthermore,any expansion of the selection criteria in terms of size and nodule number increases the risk of HCC recurrence.7Early diagnosis of HCC relapse in transplant patients facilitates the treatment of the tumor.However,even today,some patients lose the chance to receive radical treatment.Systemic treatment and locoregional tumor control therapies are used in these patients.Radioembolization is one such locoregional tumor control therapy.Since the 1960s,researchers have been investigating the use of yttrium-90 (90Y) radioembolization (90Y-RE).With the development of glass and resin90Y microspheres in the early 1990s,90Y-RE has become a safe and efficacious treatment method for patients with advanced HCC.8However,limited studies have been conducted on patients with HCC recurrence following LT.Here we report the case of a patient with severe bile duct complication after90Y-RE who had experienced HCC relapse following LT.

2.Case presentation

The patient was a 37-year-old man who had congenital chronic hepatitis B.He was diagnosed with HCC and underwent hepatectomy at the Sun Yat-sen University Cancer Center in November 2014.Following 10 months of regular follow-up,the tumor relapsed; transarterial chemoembolization (TACE) was performed thrice and ablation was performed twice to control the relapsed HCC.However,the tumor could not be controlled well.The patient underwent LT as per the Milan criteria at the First Affiliated Hospital of Jilin University in September 2015.Postoperatively,he recovered well and was discharged.He underwent regular followup and received oral tacrolimus and mycophenolate mofetil as antirejection therapy.However,multiple small lesions were identified in the liver 17 months following LT,and a diagnosis of HCC recurrence was established.The patient was administered sorafenib as targeted cancer therapy,and TACE was performed twice.However,the tumor progressed,and cancer embolus was found in the left portal vein.Thereafter,the targeted drug was changed to lenvatinib.The patient received eight courses of hepatic artery infusion chemotherapy with oxaliplatin,5-fluorouracil,and calcium folinate.Following the hepatic artery infusion chemotherapy,there was a reduction in the size of the hepatic lesions.His liver function recovered well after a short duration of treatment with medications following hepatic artery infusion chemotherapy.However,tumor progression was observed 3 months later.In June 2018,the patient was administered transarterial90Y-RE at a hospital in Hong Kong,China.However,4 weeks following the radioembolization,his liver function gradually deteriorated; this could not be explained as acute rejection or tumor progression.The patient was hospitalized because of the deterioration of his liver function as well as high body temperature along with abdominal distension in August 2018.He was diagnosed to have ischemic-type biliary lesion induced by radioembolization and received liver protection therapy,choleretic therapy,biliary microcirculation improvement treatment,and nutritional support.However,the patient’s symptoms,liver function,and renal function deteriorated(Table.1).His alpha-fetoprotein (AFP) levels gradually increased from 194.7 ng/mL in April 2018 to ＞1210 ng/mL in September 2018.Computed tomography (CT) and magnetic resonance imaging(MRI)findings showed worsening of the hepatic lesions no matter in the number and the volume.Ischemic cholangitis was first observed on magnetic resonance cholangiopancreatography in August 2018 (Fig.1).During the subsequent 12 weeks,the liver function and coagulation status continued to deteriorate despite intensive care.The patient developed severe upper gastrointestinal hemorrhage in October 2018 and died two days later.

3.Discussion

LT has become the standard treatment for patients with HCC who fulfill the Milan criteria;it is associated with better outcomes compared with surgical resection.9Despite careful selection and therapeutic advancements,the HCC recurrence rate following LT remains high,especially in patients with HCC who meet the expanded transplant criteria.Treatment strategies for patients with post-transplant HCC recurrence depend on the extent and location of the recurrent tumor.Surgical resection and ablation are considered curative treatments.If these treatments are not feasible,palliative treatments such as TACE,oral multikinase inhibitor administration,or radiotherapy should be considered.10

Fig.1.Magnetic resonance cholangiopancreatography image showing the typical changes in ischemic cholangitis.This figure shows multiple stenoses and intrahepatic bile duct dilation.These are the typical imaging features of ischemic cholangitis.

In selective internal radiation therapy (SIRT) using90Y-tagged loaded microspheres,high-energy β-radiation is emitted toward locoregional tumors.Radioactive90Y-impregnated microspheres are directly infused into the hepatic artery,which is the predominant artery supplying blood to the tumor in HCC; these microspheres are trapped in tumor microcirculation,releasing βradiation toward the tumor.11,12Observational studies from Europe and the United States have demonstrated the safety and efficacy of SIRT for unresectable HCC.13,14An increasing number of studies have suggested that90Y-RE is a viable option for treating patients with unresectable HCC and recurrent HCC.13－16Some publications have even shown that90Y-RE provides a new chance for patients with HCC to undergo LT,17,18with few reports showing that90Y-RE can be used to cure recurrent HCC following LT.

The referential delivery of90Y microspheres via the hepatic artery might minimize the radiation exposure of the noncancerous liver parenchyma;however,we believe that90Y microspheres may damage the normal tissue,especially the intrahepatic bile ducts in the transplanted liver,owing to the aberrant dissemination of radioactivity.We reported that one of our patients with recurrent HCC following LT was treated with90Y-RE and experienced radioactive biliary damage.

In our patient,although90Y-RE was curative for the recurrent tumor lesions in the liver at the beginning,it became ineffective in the treatment of the recurrent tumor that progressed in the liver.Moreover,90Y-RE gradually leads to severe radioactive biliary damage in the transplanted liver,eventually causing patient death.To our knowledge,there are no reported cases of biliary damage after SIRT for hepatic neoplasia following LT; furthermore,the mechanism of the biliary damage caused by90Y-RE remains unclear.

The mechanical occlusion of the biliary arterioles and radiation injury to the biliary tracts may lead to certain complications.Duringthe infusion of90Y-impreganted microspheres to the tumor via the hepatic arterial circulation,the microspheres inevitably enter the biliary arteriole and emit radiation toward the biliary tracts.A study has reported that mechanical occlusion of the arterioles by 30-μm microspheres can contribute to ischemic injury.19However,in an animal study,the finding of gastrointestinal complications following SIRT showed that ulcerations typically do not develop after TACE or when nonradioactive microspheres are injected into the hepatic arteries; this supports the hypothesis that radiation injury,rather than ischemia,is responsible for these mucosal ulcerations.20However,to our knowledge,there is still no evidence on radiation injury to the biliary tract.

Table1 Changes in biochemical indexes of the patient.

Delayed diagnosis of biliary lesions caused by SIRT is common owing to several reasons.The first is nonspecificity of symptoms such as high body temperature,abdominal distension,symptoms mimicking those of jaundice,and acute rejection.The second is that following90Y-RE,the evaluation of intra- or extrahepatic activity and liver dosimetry is difficult,and the clinician might have little experience in evaluating the complications resulting from90Y-RE.CT/MRI was performed for our patient.However,we could not establish an early diagnosis of biliary lesions.Some studies have suggested that90Y positron emission tomography－CT is a more accurate method for post-procedural imaging.21The biliary tract of the transplanted liver is vulnerable and the damage caused is irreversible; therefore,the diagnosis and treatment of biliary lesions caused by90Y were difficult,and the patient died 4 months after receiving90Y-RE.

Due consideration is necessary before performing90Y-RE in patients with post-transplant HCC recurrence.Clinicians must consider radiation-associated toxicity in any SIRT-treated patient who develops biliary lesions,especially in patients who have undergone LT.Physicians who treat patients who have received90Y-RE should be familiar with the spectrum of complications and be alert with respect to the onset of delayed and/or nonspecific adverse effects.

Authors’ contributions

All the authors conducted literature search and wrote the manuscript.

Declaration of competing interest

The authors declare that they have no conflict of interest.

Acknowledgements

This work was supported by the National 13th Five-Year Science and Technology Plan Major Projects of China (2017ZX10203205-006-001,2017ZX10203205-001-003),Guangdong Natural Science Foundation(2016A030313278),Science and Technology Program of Guangdong Province (2017B020209004,20,169,013),and Guangdong Key Laboratory of Liver Disease Research (2017B030314027).