Journal of Surgical Oncology 2004;87:139–142
Management of Hepatocellular Carcinoma in Renal Transplant Recipients KENNETH S. CHOK, MBBS, MRCS,1 CHI MING LAM, MS, FRCS (Edin),1* FU KEUNG LI, MBBS, MRCP,2 KELVIN K. NG, MBBS, FRCSEd (Gen),1 RONNIE T. POON, MS, FRCS (Edin), FACS,1 CHUNG MAU LO, MS, FRACS, FRCS (Edin), FACS,1 AND SHEUNG TAT FAN, MS, MD, PhD, FRCS (Edin & Glasg), FACS1 1 Department of Surgery, Centre for the Study of Liver Disease, The University of Hong Kong, Pokfulam, Hong Kong, China 2 Department of Medicine, Centre for the Study of Liver Disease, The University of Hong Kong, Pokfulam, Hong Kong, China
Background and Objective: In Hong Kong where hepatitis B virus (HBV) infection is endemic, hepatocellular carcinoma (HCC) accounts for 20% of all malignant transformations in renal transplant recipients. The aim of the present study was to review the management and outcome of HCC in renal transplant recipients at a specialized surgical center. Method: A retrospective analysis on the data collected prospectively in a tertiary referral center. Results: From January 1991 to December 2002, five renal transplant recipients were diagnosed to have primary HCC and received treatment in our center. There were four men and one woman with a median age of 47 (range, 38–68) years. Four of them had cadaveric renal transplantation whereas one had live donor transplantation. All of them were HBV carriers. The median tumor size was 3.5 cm (range, 1.8–8 cm). All tumors, except one, were diagnosed in sub-clinical stage by surveillance serum afetoprotein assay and percutaneous ultrasonography. Four patients were treated with surgical resection and one received transarterial oily chemoembolization (TOCE) as their primary treatments. There was one peri-operative death and the remaining three surgically treated patients were alive 4, 62, and 64 months after the resection. One patient developed recurrence 18 months after curative resection and was treated with TOCE. The patient with unresectable disease was alive for 50 months after the initial diagnosis. The surgical resection and overall survival rates of these patients were better than the published results. Conclusion: Early detection with regular serum a-fetoprotein assay and ultrasonographic study, vigilant care in the peri-operative period, long-term follow-up for detection and treatment of recurrence, as well as close collaboration between renal physicians and liver surgeons may improve the outcome of treatment of HCC in renal transplant recipients. J. Surg. Oncol. 2004;87:139–142.
ß 2004 Wiley-Liss, Inc.
KEY WORDS: hepatocellular carcinoma; renal transplantation; hepatectomy; TOCE
INTRODUCTION Renal transplantation is the most commonly performed solid organ transplantation. Renal transplant recipients are prone to the infection of hepatitis viruses during their pretransplantation haemodialysis period. Furthermore, they are at a higher risk of developing neoplasms after ß 2004 Wiley-Liss, Inc.
*Correspondence to: Dr. Chi Ming Lam, Department of Surgery, University of Hong Kong Medical Centre, Queen Mary Hospital, 102 Pokfulam Road, Hong Kong, China. Fax: (852) 2816 5284. E-mail:
[email protected] Accepted 14 June 2004 DOI 10.1002/jso.20098 Published online in Wiley InterScience (www.interscience.wiley.com).
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transplantation [1]. The reported rates of malignancy after renal transplantation ranged from 2.3 to 6% [2–4]. In Hong Kong where hepatitis B virus (HBV) infection is endemic, up to 10% of the population is a carrier of the virus [5]. One of the most dreadful complications of HBV infection is the development of hepatocellular carcinoma (HCC). Locally, HCC accounted for 20% of cancer development in renal transplant recipients [6]. The management of HCC in this group of patients poses a special problem as they are immunocompromised resulting from the immunosuppressive therapy in addition to the underlying chronic liver diseases. The success of the treatment lies on early detection, vigilant care in the perioperative period, and long-term follow-up for detection and treatment of recurrence. This study aims to review the management and outcome of HCC in renal transplant recipients in a specialized surgical center. PATIENTS AND METHODS This was a retrospective analysis on the data collected prospectively by a research nurse on all the patients admitted to a specialized surgical center for the treatment of primary HCC in a 12-year period, from January 1991 to December 2002. During the study period, 2,725 patients were diagnosed to have primary HCC and received treatment. Among these, five patients had history of renal transplantation before the diagnosis of HCC. Their demographic parameters, treatment, and outcome were reviewed. Screening Strategy for HCC
In our center, imaging surveillance using percutaneous ultrasonography and serum a-fetoprotein concentration measurement was routinely performed for all HBV carriers every 6 months. Any suspected lesions were further evaluated with contrast computed tomography scan or magnetic resonance imaging, and if necessary hepatic angiography with or without post-Lipiodol computed tomography scan. Treatment Strategy for HCC
The treatment protocol for HCC in our center has been described elsewhere [13]. Briefly, patients with HCC are treated primarily with surgical resection if there is no contraindication. Major contraindications for surgery include presence of extrahepatic diseases, bilobar diseases, and main portal venous or inferior vena cava invasion. Poor hepatic functional reserve and a predicted small residual liver volume are other contraindications for resection. Patients with unresectable diseases are treated with transarterial oily chemoembolization (TOCE) using cisplatin, percutaneous ethanol injection therapy (PEIT),
or radiofrequency ablation depending on the number, size, and location of the tumor. RESULTS Demographic Parameters
Five renal transplant recipients (4 men and 1 woman) were diagnosed to have HCC and received treatment. Their median age was 47 (range, 38–68) years. Four of them had cadaveric renal transplantation and one had live donor transplantation. All were treated with cyclosporin A and prednisolone after the renal transplantation. Their clinicopathological characteristics are shown in Table I. All the five patients were carriers of HBV before detection of HCC. The median interval between the renal transplantation and the detection of HCC was 120 (range, 13–192) months. Four patients were asymptomatic and the diagnosis was made by regular screening using serum a-fetoprotein assay (three patients) and percutaneous ultrasonographic study (one patient). One patient presented with hemoperitoneum due to rupture of the HCC. The diagnoses of HCC were all confirmed histologically with the resected specimens or with Tru-cut liver biopsy. The median diameter of the tumor was 3.5 cm (range, 1.8–8 cm). The uninvolved liver showed cirrhosis in four patients and chronic hepatitis in the remaining one. Four patients were of Child’s grade A and one of Child’s B status. Treatment Received
During the 12-year study period, of the 2,725 primary HCC patients treated in our center, 640 (23.5%) patients were suitable for surgical resection. For the five renal transplant recipients, four had surgical resections as the primary treatment of HCC. One patient received TOCE as the primary treatment because of poor hepatic functional reserve. Before the operation, the patients were assessed thoroughly by the renal physician and the anesthesiologist. A strict fluid balance was required in the intraoperative and the perioperative periods. All the patients were monitored closely in the intensive care unit after surgery. Renal toxic drugs such as some analgesic and antibiotics were avoided. The immunosuppressants were kept at the lowest acceptable level. The peri-operative use of contrast imagings were done only in patients in need and performed with care. Outcome
There was one peri-operative death among the four surgically treated patients. This 38-year-old gentleman presented with hemoperiotneum as a result of rupture of the HCC. He was stabilized initially with transarterial
Abbreviations: HBV, hepatitis-B virus infection; HCC, hepatocellular carcinoma; TOCE, transarterial oily chemoembolization; RFA, radiofrequency ablation; PEIT, percutaneous ethanol injection therapy.
Right posterior sectionectomy Asymptomatic 192 39 Chronic hepatitis 47 M
þ
5.0
Left lateral sectionectomy TOCE, RFA, and PEIT Asymptomatic Asymptomatic 120 192 204 5 Cirrhosis Cirrhosis 54 44 F M
þ þ
1.8 3.5
4
62
Alive, intra-hepatic recurrence on TOCE treatment Alive, disease-free Alive, active disease on treatment Alive, disease-free Asymptomatic 13 305 Cirrhosis 68 M
þ
2.3
64 50
0.5 Death (Day 16)
Embolization followed by extended right hepatectomy Wedge resection Hemoperitoneum 60 1,587 8 Cirrhosis 38 M
þ
Age Sex
HBV status
Liver status
Size of tumor (cm)
Serum a-fetoprotein concentration (hg/ml)
TABLE I. Summary of the Five Renal Transplant Recipients With HCC
Interval from transplant to HCC detection (months)
Presentation
Treatment received
Outcome
Overall survival (months)
HCC in Renal Transplant Recipients
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embolization and subsequently had an extended right hepatectomy. He developed sepsis and liver failure and succumbed 16 days after the resection. For the remaining three patients, they all had stage II diseases (TNM staging) and were alive for 4, 62, and 64 months after surgery. Two of them were disease-free, and one developed recurrence 18 months after resection and was treated with TOCE. The patient with unresectable disease was alive 50 months after the diagnosis of HCC. He received TOCE as the primary treatment followed by a combination of aggressive liver directed therapy with radiofrequency ablation and PEIT. DISCUSSION HBV infection is an important cause of morbidity and mortality in renal transplant recipients. In France, it was found that up to 50% of HBsAg-positive patients had evidence of persistent viral replication after renal transplant, and 28% developed cirrhosis [14]. Among the cirrhotic patients, 23% developed HCC [14]. In Asia where hepatitis virus infection is endemic, HCC accounted for 12–20% of all malignant transformations encountered after renal transplantation [3,6]. In nonendemic areas, the most common sites of tumor development reported after renal transplantation are the skin and lips [2,4]. The pathogenesis of HCC in renal transplant recipients is not yet known, although it might be related to the administration of immunosuppressants [7]. Epidemiological study has shown that HCC in renal transplant recipients was more prevalent in HBV infection endemic areas [8]. Thus, it is reasonable to propose a synergistic effect of HBV infection and immunosuppression on the development of HCC in renal transplant recipients. The outcome of patients with HCC is generally poor. Surgery provides the only hope for prolonged survival and occasional cure [9]. However, the majority of patients are not suitable for resection. Among the 2,725 patients with primary HCC treated in the 12-year period, only 640 (23.5%) patients were suitable for surgical resection. The prognoses of HCC in renal transplant recipients are particularly poor as the experience of taking care of this high-risk group of patients is scarce in most centers. In one review on the published reports, only three out of nine renal transplant recipients with HCC were suitable for surgical resection. Furthermore, only one patient survived for more than 1 year [10]. Although this was a small series, the present report reflected the experience of a single specialized center for the treatment of HCC. The surgical resection rate and the overall survival of our patients were better than the published results. The improved survival in our patients
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may be partly attributed to the time-lag with early detection of the HCC while it was at the asymptomatic stage. However, the relatively small tumor and the high surgical resection rate may be the main contributing factors for the prolonged survival. Although the value of regular screening for HCC in HBsAg carriers is still controversial [15], it has been shown that, early detection of HCC with screening could improve the resection rate and prolong survival [6,11]. In a recent report on the screening of asymptomatic patients, the tumor size was found to be smaller and the clinicopathological stage earlier when compared with those of symptomatic patients [11]. Furthermore, earlier detection of HCC was translated to a higher rate of surgical resection and longer survival. Therefore, provision of regular screening using the serum a-fetoprotein assay and percutaneous ultrasonographic study as practiced in our institution for this group of high-risk patients may improve their overall outcome. Last but not least, a close collaboration between the renal physician and liver surgeons in the management of these patients starting at the earliest period of care, is important for a favorable outcome. The importance of a very strict fluid balance and a reduced dosage of immunosuppressants during the peri-operative period can never be overemphasized. The avoidance of renal toxic drugs including intravenous contrast is also crucial. Adequate hydration and the use of N-acetylcysteine may reduce the incidence of contrast nephropathy [12]. REFERENCES 1. Penn I, Hammond W, Brettschneider L, et al.: Malignant lymphomas in transplantation patients. Transplant Proc 1969;1: 106–112.
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