EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Objectives: Predicting the risk of posthepatectomy liver failure is important when performing extended hepatectomy. However, there is no established method to evaluate liver function and improve preoperative liver function in pediatric patients.

Materials and Methods: We show the clinical features of pediatric patients who underwent living donor liver transplant for posthepatectomy liver failure in hepatoblastoma. The subjects were 4 patients with hepatoblastoma who were classified as Pretreatment Extent of Disease III, 2 of whom had distal metastasis (chest wall and lung).

Results: Hepatic right trisegmentectomy was performed in 3 patients and extended left hepatectomy in 1 patient. The median alpha-fetoprotein level at the diagnosis of hepatoblastoma was 986 300 ng/mL (range, 22 500-2 726 350 ng/mL), and the median alpha-fetoprotein level before hepatectomy was 8489 ng/mL (range, 23-22 500 ng/mL). The remnant liver volume after hepatectomy was 33.3% (range, 20% to 34.9%). Four patients had cholangitis after hepatectomy and progressed to posthepatectomy liver failure. The peak serum total bilirubin after hepatectomy was 11.4 mg/dL (range, 8.7-14.6 mg/dL). Living donor liver transplant was performed for these 4 patients with posthepatectomy liver failure, and they did not have a recurrence.

Conclusions: When the predictive remnant liver volume by computed tomography-volumetry before extended hepatectomy for patients with hepatoblastoma is less than 40%, the possibility of posthepatectomy liver failure should be recognized.

Key words : Living donor liver transplant, Pretreatment Extent of Disease III

In hepatoblastoma, the rate of complete surgical resection is correlated with the survival rate; as such, the standard treatment for patients with hepa-toblastoma is complete surgical resection of the primary tumor.^1-4 Fuchs and colleagues reported that radical hepatectomy should be performed when possible with regard to potential of local recurrence.⁵

The indications for liver transplant (LT) for hepatoblastoma are mostly due to unresectable tumor, positive surgical margins, or local recurrence. However, the frequency of posthepatectomy liver failure (PHLF) currently is low. With regard to hepatoblastoma for which neoadjuvant chemotherapy is conducted, when carrying out extended hepatectomy under the conditions of low residual liver volume or function, it is important to take PHLF into consideration. To prevent PHLF in patients receiving neoadjuvant chemotherapy, it is common to perform percutaneous transhepatic portal embolization (PTPE) or associated liver partition with portal vein ligation and staged hepatectomy (ALPPS) in the treatment of adult patients with liver dysfunction so that their remnant liver volume becomes greater than 40%.^6-8 However, there is no established method to evaluate liver function and improve preoperative liver function in pediatric patients; likewise, there have been only a few reports on the effectiveness of the ALPPS in pediatric patients.^9-12

In this study, we describe the clinical features of pediatric patients who underwent living donor LT (LDLT) for patients with established hepatoblastoma and subsequent PHLF. This was a single-center study at our department, the Department of Surgery, Division of Gastroenterological, General and Transplant Surgery, Jichi Medical University.

Materials and Methods

Patients
This study included 386 outpatients who underwent LT between October 1988 and December 2017 at our department and at other facilities. Between February 1997 and May 2017, 4 patients with hepatoblastoma underwent LDLT for PHLF (1 at our department and 3 at other facilities). We evaluated 4 patients (1 male, 3 female) with a median age at the time of extended hepatectomy for hepatoblastoma of 2 years (range,< 1 to 11 years). Four patients with hepatoblastoma were classified as Pretreatment Extent of Disease III, and 2 patients with hepatoblastoma had distal metastasis (chest wall and lung).

Diagnosis of posthepatectomy liver failure and therapeutic strategy for posthepatectomy liver failure
Posthepatectomy liver failure is diagnosed when the peak serum total bilirubin is > 7.0 mg/dL after extended hepatectomy.^13,14 In the event of PHLF, multidisciplinary therapy should be conducted. If no improvement is observed, then it is deemed as an indication for LT.

Ethical approval
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study.

The clinical features of 4 patients with hepatoblastoma with PHLF are shown in Table 1. The median alpha-fetoprotein (AFP) level at the diagnosis of hepatoblastoma was 986 300 ng/mL (range, 22 500-2 726 350 ng/mL), and the median AFP level before extended hepatectomy was 8489 ng/mL (range, 23-22 500 ng/mL). Hepatic right trisegmentectomy was performed in 3 patients, and extended left hepatectomy was performed in 1 patient. The median remnant liver volume after extended hepatectomy was 33.3% (range, 20% to 34.9%). Three patients received neoadjuvant and adjuvant chemotherapy. Four patients had cholangitis after extended hepatectomy and progressed to PHLF. The median peak serum total bilirubin after extended hepatectomy was 11.4 mg/dL (range, 8.7-14.6 mg/dL). The median period from extended hepatectomy to LDLT was 837 days (range, 134-1435 days). Three patients underwent LDLT to address portal hypertension, and 1 patient underwent LDLT to address cholestatic hepatitis. The median pediatric end-stage liver disease (PELD) score or the Model for End-stage Liver Disease (MELD) score at LDLT was 11.4 (range, 5.4-19.1). For patient 1 and patient 3, the LDLT donors were the fathers of the children. For patient 2 and patient 4, the LDLT donors were the children’s mothers. None of the patients after LDLT had a recurrence of hepatoblastoma, and the survival rate of the patients was 100%.

Case presentation at our department
A 2-year-old girl presented with unresectable hepatoblastoma involving segments 4, 5, 6, 7, and 8 and multiple pulmonary metastases (Figure 1, a and b). She was diagnosed as Pretreatment Extent of Disease III, and the AFP level at the diagnosis was 2 726 350 ng/mL. After 6 cycles of neoadjuvant chemotherapy (cisplatin/pirarubicin [CITA] for 4 cycles and ifosfamide, pirarubicin, etoposide, and carboplatin [ITEC] for 2 cycles), computed tomography (CT) examination demonstrated reduction in tumor size and disappearance of multiple pulmonary metastases (Figure 1, c and d). The AFP level before extended hepatectomy was 8489 ng/mL. Hepatic right trisegmentectomy was performed because the tumor was evaluated to have high possibility for resection. She had cholangitis after extended hepatectomy, after which the serum total bilirubin had increased to 12.9 mg/dL. Thereafter, she progressed to PHLF and underwent LDLT to address cholestatic hepatitis. The PELD score was 13.8. The AFP level before LDLT was 44 ng/mL, and she had a recurrence of lung metastasis in the left inferior lobe (Figure 1, e and f). She underwent an ABO-identical LDLT using her mother’s lateral segment graft and simultaneous partial resection of left lung before LDLT. The clinical course is shown in Figure 2. Tacrolimus and methylprednisolone were used for standard posttransplant immunosuppressive therapy. On postoperative day 12 (POD 12), acute cellular rejection was diagnosed by a liver biopsy, and she was treated by mycophenolate mofetil. On POD 21, cytomegalovirus viremia was diagnosed, and she underwent preemptive anti-cytomegalovirus therapy. On POD 42, she was discharged from hospital. She was treated with the preemptive therapy for posttransplant lymphoproliferative disorder (PTLD) due to a high Epstein-Barr viral load (20 000 virus copies per μg of peripheral blood mononuclear cell DNA) that occurred 9 months after LDLT. At last follow-up, she had no recurrence of hepatoblastoma (Figure 1, g and h). Retrospectively, we examined the predictive remnant liver volume before extended hepatectomy and found it to be 34.9% (Figure 3, a-d).

Hepatoblastoma is the most common liver tumor of childhood, accounting for approximately 1% of all pediatric malignancies, and the overall survival rate has improved with the advent of the combination of chemotherapy and surgical resection.³ Kirnap and colleagues reported that LT for unresectable hepatoblastoma has resulted in good clinical outcomes.¹⁵ However, PTLD is a major complication after pediatric LT. The mortality rate of PTLD in pediatric LT ranges from 12% to 60%.¹⁶ In addition, Akar Ozkan and colleagues described 1 patient who underwent LDLT to address hepatoblastoma, and this patient died as a result of PTLD.¹⁷ Therefore, we performed the preemptive therapy for PTLD to address the patient’s high Epstein-Barr viral load after LDLT.

In recent years, the overall survival rate without extrahepatic lesions in cases of patients with unresectable hepatoblastoma treated with chemotherapy and LT has become equivalent to the overall survival rate with resectable hepatoblastoma.¹⁸ Patients undergo LT for positive surgical margins or local recurrence after extended hepatectomy for hepatoblastoma.^19-21 There have been few reports describing the outcomes of PHLF in patients with hepatoblastoma treated with LT (Table 2).^22-24 In the presence of low remnant liver volume and function following extended hepatectomy, patients with hepatoblastoma may eventually develop PHLF as a result of adjuvant chemotherapy and postoperative complications such as cholangitis. To assess the preoperative liver function in adults, the liver function measured by an indocyanine green test and CT-volumetry is evaluated before radical hepatectomy. In children, Warmann and colleagues reported that, for the evaluation of CT-volumetry before radical hepatectomy, the predictive remnant liver volume must be determined preoperatively.²⁵ There have been reports of indocyanine green fluorescence imaging being used to evaluate metastases of hepatoblastoma, but no reports have described the assessment of liver function using an indocyanine green test.^26,27 The patients who had a low remnant liver volume after extended hepatectomy for hepatoblastoma were possibly at risk of progression to PHLF because of postoperative complications and chemotherapy. In pediatric patients, we therefore propose that we measure the predictive remnant liver volume by CT-volumetry before extended hepatectomy and evaluate the liver function by indocyanine green test in view of the liver damage caused by neoadjuvant chemotherapy.

It is common to perform PTPE or ALPPS in the treatment of adult patients with neoadjuvant chemotherapy when their remnant liver volume becomes less than 40%.^6-8 In 1982, Makuuchi and colleagues were the first group to perform portal vein embolization to prevent PHLF.²⁸ Portal vein embolization has since been performed in patients receiving hepatectomy of hilar cholangiocarcinoma and liver cancer. The portal vein branch of the planned liver resection is embolized, and radical hepatectomy is performed after enlargement of the remnant liver volume. Percutaneous transhepatic portal embolization is frequently performed in adult patients for whom the current remnant liver volume is predicted to be less than 40%. However, PTPE for patients with hepatoblastoma is less common, and only Terraz and colleagues have reported that PTPE has been performed on pediatric patients.²⁹ In pediatric patients, it may be difficult to perform PTPE because of various technical difficulties. In 2012, Schnitzbauer and colleagues reported a new strategy for inducing hypertrophy of the remnant liver volume by right portal vein ligation combined with in situ liver splitting in 25 patients with malignant liver tumors.³⁰ A new method that is now termed ALPPS31 consists of a 2-stage hepatectomy with initial portal vein ligation and in situ splitting of the liver parenchyma. Associated liver partition with portal vein ligation and staged hepatectomy provides a rapid and consistent hypertrophy of the remnant liver volume, avoiding PHLF.³⁰ In recent years, there have been reports that ALPPS has been performed in patients with hepatoblastoma.^9-12 Because recurrence of tumor after ALPPS for hepatoblastoma has been reported in a small infant, it is important to study the effectiveness of ALPPS regarding long-term prognoses.

When the predictive remnant liver volume is less than 40% before extended hepatectomy for patients with hepatoblastoma, as measured by CT-volumetry, the possibility of PHLF should be recognized.

Volume: 18 Issue: 5 October 2020

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