Abstract
We describe a very rare case of recurrent hepatocellular carcinoma (HCC) after living donor liver transplantation (LDLT). A 47-year-old female underwent LDLT for HCC within Milan criteria, receiving a left liver lobe from her 38-year-old husband with an incompatible blood type. Thirty months after LDLT, however, enhanced computed tomography (CT) showed a tumor in her left adrenal gland; after another six months, enhanced CT and positron-emission tomography detected a frontal head bone tumor; enhanced CT performed 54 months after LDLT revealed a recurrent HCC in the liver graft. Each of these three tumors was surgically resected. Two months after hepatic partial resection, an enhanced CT showed another HCC in her liver graft, which was treated with local ablation therapy. One year after the last ablation treatment, the recipient is doing well without evidence of recurrence. At the time of detection of each of these tumors, the patient's serum concentration of hepatitis B virus surface antigen was elevated. Pathological examination showed that the resected tumors were moderately differentiated HCCs. Genotyping by microsatellite analysis confirmed their origin to be metastases of the primary HCC.
Liver transplantation (LT) is a treatment-of-choice for patients with hepatocellular carcinoma (HCC), improving long-term survival in patients who meet certain criteria such as the Milan criteria (1). However, HCCs frequently recur after LT, resulting in high patient mortality rates, especially in patients who no longer meet these criteria (2, 3).
Treatment options for recurrent HCC after LT include surgical resection, local ablation therapy, transcatheter arterial chemoembolization (TACE), systemic targeted-therapy, and radiation therapy. Surgical methods, such as hepatic resection and tumor extirpation, have been reported to improve long-term survival (3, 4). Few reports, however, have assessed outcomes of surgical resection of bone metastases from HCC.
Most HCCs that recur after LT are metastases from the primary tumor. Tumors due to re-activation of hepatitis, however, have been observed in seroconverted asymptomatic carriers and in patients receiving immunosuppressive therapy. We previously described a patient with a de novo HCC in a liver graft following a sustained viral response after living donor LT (LDLT) for advanced HCC and hepatitis C cirrhosis (5). Moreover, we found that microsatellite analysis was useful in confirming the origin of HCC after LDLT (5).
Herein we describe a patient who experienced recurrent HCC after LDLT for advanced HCC and hepatitis B cirrhosis. Subsequent to LDLT, four intra- and extra-hepatic lesions were observed, each accompanied by elevation of hepatitis B surface antigen (HBs-Ag) concentration. The first three tumors were surgically-resected, whereas the fourth was treated by radiofrequency ablation, resulting in a good clinical outcome. Additionally, using microsatellite analysis for genotyping, we found that all four lesions were metastatic recurrences of the primary HCC.
Case Report
A 47-year-old Japanese female was referred to the Kyushu University Hospital for possible LDLT for recurrent HCC and end-stage liver disease due to hepatitis B infection. She was first diagnosed with chronic hepatitis B when aged 35 years. Entecavir therapy was attempted but she discontinued due to nausea. A primary HCC was detected in segment 6 at age 44 years, for which she underwent TACE. One year later, however, follow-up enhanced computed tomography (CT) revealed two intrahepatic recurrences.
Pre-transplant imaging showed that she had cirrhotic liver and two HCCs with a maximum tumor size of 2.0 cm. Her Child-Pugh score was 11 (grade C), and her Model for End-Stage Liver Disease score was 15. She was positive for HBs-Ag, hepatitis B virus envelope antibody, and hepatitis B virus core antigen, with 2.6 log copy/ml of hepatitis B virus DNA. Her serum levels of alpha-fetoprotein (AFP) and des-γ-carboxyprothrombin (DCP) were 2.6 ng/ml and 37 mAU/ml, respectively. The liver donor was the recipient's healthy 38-year-old husband, whose blood type was however incompatible with that of the recipient. A preoperative evaluation of the donor confirmed that he was negative for HBs-Ag and antibody to hepatitis C virus. An extended left lobe and caudate lobe were removed from the living donor and transplanted into the recipient as described. The graft liver weight was 390 g, corresponding to 35.6% of the standard liver volume of the recipient. A pathological examination of the explanted cirrhotic liver revealed four viable HCC nodules, one in segment 4 and three in segment 6. All four lesions were moderately differentiated HCCs, the largest being 3.0 cm, located in segment 6. Fibrous capsule invasion and serosal invasion were observed but there was no evidence of vascular invasion (Figure 1).
Anti-viral chemotherapy with entecavir was started two months before LDLT and continued after LDLT. Hepatitis B virus immunoglobulin G (Hebsbulin IH; Japan Blood Products Org., Tokyo, Japan) was administered during the LDLT and for one week postoperatively. Postoperative immunosuppression was administered and maintained with prednisolone, cyclosporine A (Neoral; Novartis Pharma, Basel, Switzerland), and mycophenolate mofetil (Cellcept; Chugai Pharmaceutical Co., Ltd., Tokyo, Japan).
Periodical follow-up CT scans revealed four episodes of HCC recurrence. Enhanced CT showed a 3.0 cm tumor in the left adrenal gland 30 months after LDLT; this tumor was resected by left adrenalectomy (Figure 2A). Six months later, enhanced CT identified a 1.5 cm frontal head bone tumor, which was resected by right frontal craniotomy (Figure 2B). A 2.0-cm HCC was detected in segment 4 of the allograft 54 months after LDLT, with enhancement in the arterial phase and low density in the portal phase; these findings were consistent with the diagnosis of classical HCC (Figure 2C). Two months later, another HCC, 1.5 cm in diameter, appeared in segment 2 (Figure 2D). Partial hepatic resection of segment 4 (Figure 3A) and radiofrequency ablation (RFA) were performed successfully. At the present time, 12 months after the RFA, the patient is doing well without any evidence of recurrent HCC.
In conjunction with the first recurrence, her serum AFP concentration had increased to 319.4 ng/ml. At the times of the second and third recurrences, her serum levels of DCP had increased to 285 and 156 mAU/ml, respectively. Although she was negative for hepatitis B virus DNA throughout the follow-up period, serum HBs-Ag levels were increased at the times of tumor recurrence, suggesting hepatitis B reactivation or production by cancerous hepatocytes. Pathological examination of the resected lesions showed that all were moderately differentiated HCCs (Figure 3B). The non-cancerous liver parenchyma was not cirrhotic. The pathological findings were unable to clarify whether these HCCs were derived from the recipient (metastasis) or the donor (de novo).
To determine the origin of HCC, we performed microsatellite analysis of DNA extracted from peripheral blood samples taken from the donor and the recipient, the resected HCC in the graft liver and adrenal grand, and the non-cancerous graft liver parenchyma. HCC samples of the explanted liver at the time of LDLT were not available. Six loci in five chromosomes (D5S346, D5S492, D10S1765, D13S171, and D17S855) were examined for each DNA sample. Polymerase chain reaction products for each locus were analyzed using an Applied Biosystems 3130 genetic analyzer and Genemapper software (PE Applied Biosystems, Foster City, CA, USA). The genotypes for all five loci of the HCC in the graft liver and adrenal grand completely matched those of the peripheral blood of the recipient, not the donor. Recipient-specific alleles at all five loci matched those of the HCCs in the graft liver and adrenal grand; none of the alleles were detected in the peripheral blood of the donor or the noncancerous graft liver parenchyma. These findings confirmed that the HCCs were metastatic recurrences of the primary HCC (Figure 4).
Discussion
Reactivation of chronic viral hepatitis and recurrence of HCC are common problems following LT. HCCs tend to recur at 1-3 years, with a mean time from initial recurrence to death of about 1-2 years (3, 6). Recurrent tumors are observed mostly in the lungs, liver, bones, adrenal grands, and abdominal lymph nodes (7). Our patient experienced four recurrent HCCs, one in the left adrenal grand, one in the frontal head bone, and two in the engrafted liver.
Factors predictive of extrahepatic recurrence after LT or hepatectomy include high preoperative serum AFP concentration, large tumor size, high TMN stage, advanced tumor differentiation, microscopic hepatic vein invasion, and intra-hepatic metastasis (8). Massive intraoperative blood loss may also be related to tumor recurrence, suggesting that liver tumor cells may be disseminated during surgery. In our patient, the primary tumors were moderately differentiated HCCs with serosal but not vascular invasion. Serum tumor markers were not significantly elevated.
Most intra-hepatic lesions after LT are metastatic recurrences. Immunosuppressive therapy after LT can reactivate hepatitis B and increase the risk of HCC recurrence. The serum concentration of HBs-Ag in our patient was increased at the time of each HCC recurrence, making the origin of these four lesions of interest. Microsatellite genotyping (5) found that the dominant allelic pattern in the HCCs was metastasis from the primary tumor, suggesting that the increased serum HBs-Ag was due to growth of HCCs, not reactivation of hepatitis B.
The therapeutic strategy for HCC recurrence after LT remains challenging. Local control with surgical resection may improve overall survival, as long as the recurrent tumor is resectable and the patient's performance status is tolerant of surgery (3, 4). Systemic targeted-therapy with a multi-kinase inhibitor (e.g. sorafenib) or mammalian target of rapamycin (e.g. sirolimus, and everolimus) have also been reported to improve prognosis in patients with unresectable HCC (5). Recently, the concomitant use of sorafenib or sirolimus with resection and RFA was found to improve overall survival of patients with recurrences in multiple organs (10). Our patient underwent three surgical resections and RFA for recurrent lesions. Although craniectomy for bone metastasis may be unusual, it resulted in tumor control for 70 months after LT and 40 months after the first recurrence. Further recurrences may benefit from treatment with resection and systemic targeted therapy.
In conclusion, we encountered a patient with recurrent HCC after LDLT who showed good outcomes following local control with repeated surgical treatment. Microsatellite genotyping successfully revealed that the recurrent tumors were metastases of the primary tumor and did not derive from the donor.
Acknowledgements
This work was supported by a grant Grant-in-Aid for Scientific Research (26380201) from the Ministry of Health, Labor and Welfare of Japan.
Footnotes
Conflicts of Interest
The Authors declare no financial or other conflicts of interest with regard to this article.
- Received March 4, 2015.
- Revision received March 15, 2015.
- Accepted March 17, 2015.
- Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved