Liver transplantation (LT) is an established treatment for patients with liver cirrhosis and/or hepatocellular carcinoma (HCC). Patient selection according to institutional eligibility criteria contributes to the reduction of HCC recurrence after LT, but a considerable number of LT recipient mortality is still associated with HCC recurrence [1-5]. HCC recurrence usually occurs during the first a few years after LT, although late recurrence after 5 years has been sporadically reported. Because of the rarity of very late HCC recurrence occurring over 10 years after LT [6,7], early detection is difficult and treatment strategy for HCC recurrence have not yet been established. There are still no reliable recommendations or consensuses for the management of very late posttransplant recurrence of HCC, particularly peritoneal metastasis [8]. We herein describe one case of peritoneal metastasis of HCC that occurred 12 years after LT, and survived for 7 years after HCC recurrence.

A 53-year-old male underwent living-donor liver transplantation (LDLT) for hepatitis B virus-associated liver cirrhosis and HCC. This patient had no history of HCC treatment before LT. The pretransplant model for end-stage liver disease was 38 with hepatic encephalopathy. The pretransplant serum alpha-fetoprotein (AFP) level was 16 ng/mL. The donor was his 20-year-old son. A modified right liver graft weighing 610 g, which was equivalent to a recipient-to-graft weight ratio of 0.98, was implanted according to standard procedures of adult LDLT. Explant liver pathology showed a single 1.5 cm-sized HCC without microvascular invasion, and therefore met the Milan criteria.

At the age of 65 years which was 12 years after LT, the patient showed very slow elevation of AFP levels, although being within the normal range, over 3 months of outpatient clinic follow-ups (Fig. 1). An abdomen computed tomography (CT) scan taken 6 months prior to the AFP rise showed no abnormalities. The pelvis was not included at this abdomen CT scan. A subsequent abdomen-pelvis CT scan revealed a 4 cm-sized mass at the pelvis (Fig. 2). A [18F]-fluorodeoxyglucose positron emission tomography (PET)-CT scan showed hypermetabolic uptake of the pelvis tumor (Fig. 3). During these imaging studies, the serum AFP level was gradually elevated but was still within the normal range (Fig. 1). These findings suggested that the mass was likely to be HCC recurrence. Because the tumor was solitary, we decided to perform metastasectomy.

Figure 1. Serial measurement of tumor marker levels before and during 7 years after metastasectomy. AFP, alpha-fetoprotein.

Figure 2. Computed tomography taken at 12 years after transplantation showing a pelvis mass (arrow).

Figure 3. Positron emission tomography showing a hypermetabolic-uptake mass at the pelvis (arrow).

Open laparotomy was performed, and two masses were excised with equivocal tumor-negative resection margins (Fig. 4). A pathological analysis confirmed that the masses were metastatic HCCs. After excision, the patient’s AFP level dropped (Fig. 1). However, 6 months later, it slowly increased again, although it was still within the normal range. Follow-up CT and PET scans revealed multiple seeding nodules at the pelvis (Fig. 5). The patient underwent treatment with low-dose calcineurin inhibitor, sirolimus, and full-dose sorafenib, and displayed no serious adverse side-effects. Growth of the peritoneal seeding nodules was visualized on follow-up CT scans, and sorafenib therapy was stopped after 2 years of administration. The immunosuppressive regimen was switched to everolimus monotherapy after its Korean National Health Insurance coverage. During the 7 years after HCC recurrence was diagnosed, the patient showed very slowly growing tumors (Fig. 6) with progressive elevation of AFP levels (Fig. 1), but was doing well, without significant deterioration of his quality of life. Protein induced by vitamin K antagonist or absence-II (PIVKA-II) level began to elevate from 6 years after recurrence. At the age of 72 years, which was 7 years after HCC recurrence, he was hospitalized several times due to deterioration of his general condition, and rapid progression of recurrent HCC. He finally passed away due to far advanced progression of HCC at the age of 72 years with posttransplant survival of 19 years.

Figure 4. Follow-up computed tomography images showing progressive growth of the recurrent masses at 4 years (A), 5 years (B), 6 years (C), and 7 years (D) after metastasectomy (arrows).

Figure 5. Gross image of the resected metastatic pelvis mass with very narrow tumor-negative resection margins.

Figure 6. Follow-up computed tomography (A) and positron emission tomography (B) images taken at 6 months after metastasectomy showing recurrent multiple lesions (arrows).

Although the majority of HCC recurrence occurs during the first few years after LT, a small number of patients experience very late recurrence, sometimes as late as 10 years or more after transplantation [8]. Advanced HCC beyond the Milan criteria is often associated with early HCC recurrence. In contrast, the majority of patients showing late recurrence have HCCs within the Milan criteria [6]. Because of its rarity, it is difficult to identify delayed or very late HCC recurrence early. Such very late recurrence is diagnosed only after the manifestation of symptoms, or is incidentally detected during routine follow-up imaging studies. From 5 years post-transplantation onwards, our institution performs life-long surveillance imaging studies for LT recipients every 2 years [6-9].

Measurements of HCC tumor markers including serum AFP and PIVKA-II levels are simple tests that can be done during regular outpatient visits. In patients who had elevated AFP levels prior to LT, there is a high probability of AFP elevation at the time of HCC recurrence. We previously reported that the ability of AFP testing to detect posttransplant HCC recurrence is dependent on the pretransplant AFP levels, showing HCC detection sensitivities of approximately 40%, 50%, and 90% in patients with pretransplant AFP levels of ≤20 ng/mL, 21–200 ng/mL, and >200 ng/mL, respectively [6]. Detection of PIVKA-II levels plays an important complementary role in the diagnosis of HCC recurrence, although the sensitivity and specificity of PIVKA-II testing are lower than those of AFP testing [10-12]. Concurrent measurement of AFP and PIVKA-II levels improves the sensitivity of HCC recurrence detection. A Japanese study revealed that AFP and PIVKA-II levels were measured every 1–2 months after LT, but confirmation of HCC recurrence through imaging studies took 17–208 days after the observed increases in the levels of tumor markers [13].

Compared with those that recur early, very late posttransplant HCCs may have less aggressive tumor biology, as shown in the present case, which showed very slow progression. However, it is important that posttransplant HCC recurrence is itself a strong evidence of aggressive tumor biology. Therefore, the therapeutic strategy for very late HCC recurrence should be similar to that for early recurrence. Surgical resection of metastatic lesions is the most effective therapy for recurrent HCC in LT recipients. We previously reported a beneficial effect of surgical metastasectomy of metachronous pulmonary and adrenal metastases from HCCs on patient survival [14,15]. There are only a small number of studies supporting the resection of tumors arising from peritoneal seeding of HCC, and resection of peritoneal metastases should only be considered in patients whose primary liver neoplasm is under control and who have no metastases in other organs [16-18].

In LT recipients with HCC recurrence, metastasectomy is not considered to be curative because it is a kind of local control treatments. There is a high probability of further tumor recurrence from residual tumor cells due to inevitable immunosuppression. Thus, conversion to treatment with a mammalian target of rapamycin (mTOR) inhibitor and systemic chemotherapy should be considered. Treatment with the mTOR inhibitor, everolimus, is associated with a low rate of HCC recurrence in LT recipients [19-23].

The multikinase inhibitor sorafenib is an effective therapy for HCC [24,25]. Although it was reported that sorafenib noticeably improves the survival of patients with advanced HCC [26,27], its therapeutic effect on posttransplant HCC recurrence is still largely unknown [28-30]. Because of its availability as an adjuvant chemotherapy, we have frequently administered sorafenib for LT recipients with HCC recurrence.

Combination therapy with sorafenib and mTOR inhibitor, in addition to locoregional treatment, has been performed frequently in the current Korean setting. A Korean single institution study found that 12 patients who received combination therapy with sorafenib and sirolimus had better post-recurrence survival outcomes than 27 patients receiving best supportive care for post-transplant HCC recurrence [31]. Furthermore, in a Spanish multi-center study involving 31 LT recipients with HCC recurrence, combination therapy resulted in a partial response in a single patient and stable disease in 13 patients, giving an overall clinical benefit rate of 53.8% [32].

Lifelong surveillance is necessary for LT recipients because HCC recurrence can occur after prolonged periods, as shown in the present case. Since the majority of late HCC recurrence are diagnosed subclinically [7-9], surveillance through regular tumor marker examination is the cornerstone of follow-up studies to detect HCC recurrence in a timely manner.

In conclusion, for very late peritoneal metastasis of HCC, aggressive multi-modality therapeutic treatment appears to be effective to prolong overall patient survival.

There was no funding related to this study.

All authors have no conflicts of interest to declare.

Conceptualization: MJK, SH. Data curation: All. Formal analysis: MJK, SH, GWS, DBM, DHJ, CSA, GCP. Investigation: SH. Methodology: All. Visualization: SH. Writing - original draft: MJK, GWS, DHJ, CSA, TYH, GCP. Writing - review &editing: MJK, SH.