Adrenal metastasis of hepatocellular carcinoma (HCC) is rare and can be treated with resection, local ablative therapy, or systemic therapy [1]. According to the Barcelona Clinic Liver Cancer strategy, in advanced stages with extrahepatic metastases, systemic therapy is the first-line treatment option, with an expected survival of more than 2 years [2].

Bone metastasis due to HCC is also rare, with a reported incidence of 3%–20%, and has a very poor prognosis. Moreover, spinal metastases in HCC are even rarer, with frequencies ranging from 0.2% to 2.2%, and are associated with significant morbidity and mortality [3].

Post-liver transplantation (LT) HCC recurrence rates range from 8% to 20% according to a risk group analysis [4]. This recurrence rate has an impact on lower overall survival rates than those observed in non-HCC recipients. Furthermore, post-LT HCC recurrence patterns are different from those in non-transplant settings; as more than 50% are extrahepatic multiple metastases, and disease progression is faster in post-LT settings than in non-transplant settings.

Recent progress in patient selection, intensive surveillance protocols, and perioperative management has improved the survival of HCC recipients. Aggressive management involving locoregional therapy combined with chemotherapy for post-LT HCC recurrence has improved patients’ survival outcomes. Unfavorable factors prognostic factors for survival after HCC recurrence include poorly differentiated original tumors, major vascular invasion observed in explant pathology, unresectable disease, and bone metastases [5]. Prior to 2010, the 3-year survival rate after HCC recurrence following LT treatment was 16%, but the 5-year survival rate subsequently improved to 15%–20% [6].

However, there is no definite treatment for post-LT HCC recurrence. Sorafenib is the most frequently applied treatment, used in 37% of patients, followed by a combination of systemic and locoregional therapies in 18% of patients. Approximately one-third of affected patients receive palliative best supportive care [4].

Herein, we report the case of a patient who was successfully treated for sequential adrenal, spinal, and graft HCC metastases after LT with combined systemic and radiation therapy.

This study was approved by the Institutional Review Board (IRB) at Seoul National University Hospital (IRB No. 2208-001-1345). Informed consent was waived by the IRB due to the retrospective study design.

This report describes the case of a 49-year-old man with acute-on-chronic hepatitis B (HB) and alcoholic-related liver cirrhosis with HCC. His medical Model for End-Stage Liver Disease score without the additional HCC was 37, indicating the need for continuous renal replacement therapy due to encephalopathy, hepatic renal syndrome, and ascites. Variceal bleeding was controlled using balloon-occluded retrograde transvenous obliteration. Deceased donor LT was performed while the patient was admitted to the intensive care unit. The HCC was a treatment-naive, 4.7 cm, single mass (within the Milan criteria) without extrahepatic metastasis or vascular invasion (Fig. 1). The patient’s pretransplant alpha-fetoprotein (AFP) level was 9.3 ng/mL, and the protein induced by vitamin K absence or antagonist-II (PIVKA-II) level was 1,614 mAU/mL. Explant pathology revealed a 4.7-cm single, Edmondson-Steiner grade 2 without vascular invasion. The patient was HB treatment-naive. The pretransplant HB surface antigen (HBsAg) titer was 1,587 IU/mL; the HB e antigen (HBeAg) was negative; anti-HBe was positive, and the HB viral DNA titer was 3,590 IU/mL. The brain-dead donor was 60 years old without a history of HB virus (HBV) infection, and had negative HBsAg, positive anti-HBs, and positive HBV core antibody immunoglobulin G. The donor’s serum HB DNA level was not measured. The patient’s recovery was uneventful, and he was discharged on postoperative day 18.

Quadruple immunosuppression therapy consisted of basiliximab, tacrolimus, steroids, and mycophenolate mofetil. Steroids were discontinued 4 months after transplantation. Dual therapy with tacrolimus and mycophenolate mofetil was administered for 8 months as a maintenance therapy (Fig. 2). The patient was switched to tacrolimus monotherapy because a sufficient tacrolimus trough level was achieved. HB prophylaxis was achieved using combination therapy with HB immunoglobulin (HBIG) and entecavir.

The HCC surveillance protocol in the outpatient clinic used tumor markers, and imaging studies were performed every 4 months for 2 years. After transplantation, both AFP and PIVKA-II levels were within the normal range, and HB seronegative conversion was achieved.

Risk factors for HCC-specific mortality include biomarkers such as high AFP or PIVKA-II levels, 18-FDG PET scan positivity, and tumor number and size [8]. Jamtani et al. [9] reported that the 5-year HCC-specific mortality and recurrence rates in low-risk patients were 2% and 5%, respectively; those in middle-risk patients were 12% and 14%, respectively, and those in high-risk patients were 71% and 82%, respectively. In this particular patient, although the pretransplant HCC was within the Milan criteria, the PIVKA-II level was high. The patient was in critical condition shortly before transplantation, and 18-FDG PET scans were not obtained.

In this case, when the first and second adrenal metastases were found on the surveillance imaging studies, both AFP and PIVKA-II levels were in the normal ranges. For this reason, imaging surveillance of posttransplant HCC recurrence is important. In addition, the PIVKA-II level, instead of the AFP level, increased at the time of bone and graft recurrence. PIVKA-II levels in HCC patients represent a more aggressive tumor nature, as well as metastatic lesions. Thus, follow-up of both AFP and PIVKA-II levels as tumor markers is important, in addition to imaging studies.

A previous study showed that second-line regorafenib after sorafenib treatment increased the overall survival of recipients after transplantation. Locoregional treatment for HCC recurrence, in addition to chemotherapy, was one of the better prognostic factors for overall survival [10]. In this case, RT may have played a role. In a non-transplant setting, 64% of adrenal metastases [7] and 53.9% of bone metastases [8] responded. However, at the time of the adrenal metastasis, we did not administer systemic chemotherapy together with RT because systemic chemotherapy was not covered by the national insurance and the response to the first application of RT at the time of the first adrenal metastasis was good. Regarding immunosuppressant, the use of mTORi may prevent HCC recurrence after transplantation [11]. In this case, an mTORi was used to maintain immunosuppression to reduce tacrolimus.

A retrospective study found that 37% of HCC recurrences were accompanied by HB recurrence, and the intended treatment of HCC led to HBsAg clearance in 57% of cases without tumor marker elevation [12]. In this case, HCC and HB recurrences showed similar trends (Fig. 6). Except for the second adrenal metastasis, HCC recurrence was accompanied by HBsAg reappearance. The lesson we learned from this case is that even if tumor markers are normal, recurrence may be suspected if HBsAg becomes positive without graft dysfunction. When HCC was controlled without changes in the HB prophylactic therapy, HB was cleared. This suggests that there is a positive correlation between HB infection and HCC recurrence [13]. Therefore, it can be inferred that HBsAg clearance reflects the HCC treatment response [14].

Before transplantation, the patient was treatment-naive for HBV with a high viral DNA load, and he experienced HCC and HB recurrence after 18 months. The survival periods after transplantation, primary adrenal metastasis, and bone metastasis were 71, 53, and 17 months, respectively. Stable disease status according to the RECIST criteria [6] is defined as more than 9 months with regorafenib combined with RT without graft failure or rejection. Unfortunately, 9 months after combined treatment with regorafenib and RT, graft HCC recurrence was observed.

In conclusion, combination therapy consisting of systemic and locoregional therapies may prolong patient survival, even after HCC recurrence. HB recurrence along with HCC recurrence without graft dysfunction requires no further treatment, but can be used as a surrogate marker for HCC recurrence and treatment responsiveness.