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Liver Transplant for Posthepatectomy Liver Failure in Hepatoblastoma

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

Introduction

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.

Results

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).

Discussion

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.

Conclusions

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.


References:

  1. Fuchs J, Rydzynski J, Von Schweinitz D, et al. Pretreatment prognostic factors and treatment results in children with hepatoblastoma: a report from the German Cooperative Pediatric Liver Tumor Study HB 94. Cancer. 2002;95(1):172-182. doi:10.1002/cncr.10632
    CrossRef - PubMed
  2. von Schweinitz D, Hecker H, Harms D, et al. Complete resection before development of drug resistance is essential for survival from advanced hepatoblastoma: a report from the German Cooperative Pediatric Liver Tumor Study HB-89. J Pediatr Surg. 1995;30(6):845?852. doi:10.1016/0022-3468(95)90762-9
    CrossRef - PubMed
  3. Sasaki F, Matsunaga T, Iwafuchi M, et al. Outcome of hepatoblastoma treated with the JPLT-1 (Japanese Study Group for Pediatric Liver Tumor) Protocol-1: A report from the Japanese Study Group for Pediatric Liver Tumor. J Pediatr Surg. 2002;37(6):851-856. doi:10.1053/jpsu.2002.32886
    CrossRef - PubMed
  4. Perilongo G, Shafford E, Maibach R, et al. Risk-adapted treatment for childhood hepatoblastoma. final report of the second study of the International Society of Paediatric Oncology: SIOPEL 2. Eur J Cancer. 2004;40(3):411-421. doi:10.1016/j.ejca.2003.06.003
    CrossRef - PubMed
  5. Fuchs J, Rydzynski J, Hecker H, et al. The influence of preoperative chemotherapy and surgical technique in the treatment of hepatoblastoma: a report from the German Cooperative Liver Tumour Studies HB 89 and HB 94. Eur J Pediatr Surg. 2002;12(4):255-261. doi:10.1055/s-2002-34484
    CrossRef - PubMed
  6. Nagino M, Kamiya J, Nishio H, Ebata T, Arai T, Nimura Y. Two hundred forty consecutive portal vein embolizations before extended hepatectomy for biliary cancer: surgical outcome and long-term follow-up. Ann Surg. 2006;243(3):364-372. doi:10.1097/01.sla.0000201482.11876.14
    CrossRef - PubMed
  7. Kubota K, Makuuchi M, Kusaka K, et al. Measurement of liver volume and hepatic functional reserve as a guide to decision-making in resectional surgery for hepatic tumors. Hepatology. 1997;26(5):1176-1181. doi:10.1053/jhep.1997.v26.pm0009362359
    CrossRef - PubMed
  8. Shimada K, Nara S, Esaki M, Sakamoto Y, Kosuge T, Hiraoka N. Extended right hemihepatectomy for gallbladder carcinoma involving the hepatic hilum. Br J Surg. 2011;98(1):117-123. doi:10.1002/bjs.7262
    CrossRef - PubMed
  9. Chan A, Chung PH, Poon RT. Little girl who conquered the “ALPPS”. World J Gastroenterol. 2014;20(29):10208-10211. doi:10.3748/wjg.v20.i29.10208
    CrossRef - PubMed
  10. Wiederkehr JC, Avilla SG, Mattos E, et al. Associating liver partition with portal vein ligation and staged hepatectomy (ALPPS) for the treatment of liver tumors in children. J Pediatr Surg. 2015;50(7):1227-1231. doi:10.1016/j.jpedsurg.2014.10.019
    CrossRef - PubMed
  11. Qazi AQ, Syed AA, Khan AW, Hanif F. Early multifocal recurrence of hepatoblastoma in the residual liver after R0 liver resection with ALPPS procedure: a case report. Ann Transl Med. 2016;4(19):375. doi:10.21037/atm.2016.10.01
    CrossRef - PubMed
  12. Hong JC, Kim J, Browning M, et al. Modified associating liver partition and portal vein ligation for staged hepatectomy for hepatoblastoma in a small infant: how far can we push the envelope? Ann Surg. 2017;266(2):e16-e17. doi:10.1097/SLA.0000000000002217
    CrossRef - PubMed
  13. Kishi Y, Abdalla EK, Chun YS, et al. Three hundred and one consecutive extended right hepatectomies: evaluation of outcome based on systematic liver volumetry. Ann Surg. 2009;250(4):540-548. doi:10.1097/SLA.0b013e3181b674df
    CrossRef - PubMed
  14. Rahbari NN, Garden OJ, Padbury R, et al. Posthepatectomy liver failure: a definition and grading by the International Study Group of Liver Surgery (ISGLS). Surgery. 2011;149(5):713-724. doi:10.1016/j.surg.2010.10.001
    CrossRef - PubMed
  15. Kirnap M, Akdur A, Ozcay F, et al. Liver transplant for fulminant hepatic failure: a single-center experience. Exp Clin Transplant. 2015;13(4):339-343. doi:10.6002/ect.2015.0080
    CrossRef - PubMed
  16. Narkewicz MR, Green M, Dunn S, et al. Decreasing incidence of symptomatic Epstein-Barr virus disease and posttransplant lymphoproliferative disorder in pediatric liver transplant recipients: report of the studies of pediatric liver transplantation experience. Liver Transpl. 2013;19(7):730-740. doi:10.1002/lt.23659
    CrossRef - PubMed
  17. Akar Ozkan E, Ozdemir BH, Yilmaz Akcay E, Ok Atilgan A, Haberal M. T-cell acute lymphoblastic leukemia after liver transplant. Exp Clin Transplant. 2014;12 Suppl 1:139-141.
    CrossRef - PubMed
  18. Otte JB. Progress in the surgical treatment of malignant liver tumors in children. Cancer Treat Rev. 2010;36(4):360-371. doi:10.1016/j.ctrv.2010.02.013
    CrossRef - PubMed
  19. Browne M, Sher D, Grant D, et al. Survival after liver transplantation for hepatoblastoma: a 2-center experience. J Pediatr Surg. 2008;43(11):1973-1981. doi:10.1016/j.jpedsurg.2008.05.031
    CrossRef - PubMed
  20. Faraj W, Dar F, Marangoni G, et al. Liver transplantation for hepatoblastoma. Liver Transpl. 2008;14(11):1614-1619. doi:10.1002/lt.21586
    CrossRef - PubMed
  21. Otte JB, Pritchard J, Aronson DC, et al. Liver transplantation for hepatoblastoma: results from the International Society of Pediatric Oncology (SIOP) study SIOPEL-1 and review of the world experience. Pediatr Blood Cancer. 2004;42(1):74-83. doi:10.1002/pbc.10376
    CrossRef - PubMed
  22. Busweiler LA, Wijnen MH, Wilde JC, et al. Surgical treatment of childhood hepatoblastoma in the Netherlands (1990-2013). Pediatr Surg Int. 2017;33(1):23-31. doi:10.1007/s00383-016-3989-8
    CrossRef - PubMed
  23. Pham TA, Gallo AM, Concepcion W, Esquivel CO, Bonham CA. Effect of liver transplant on long-term disease-free survival in children with hepatoblastoma and hepatocellular cancer. JAMA Surg. 2015;150(12):1150-1158. doi:10.1001/jamasurg.2015.1847
    CrossRef - PubMed
  24. Srinivasan P, McCall J, Pritchard J, et al. Orthotopic liver transplantation for unresectable hepatoblastoma. Transplantation. 2002;74(5):652-655. doi:10.1097/00007890-200209150-00011
    CrossRef - PubMed
  25. Warmann SW, Schenk A, Schaefer JF, et al. Computer-assisted surgery planning in children with complex liver tumors identifies variability of the classical Couinaud classification. J Pediatr Surg. 2016;51(11):1801-1806. doi:10.1016/j.jpedsurg.2016.05.018
    CrossRef - PubMed
  26. Yamamichi T, Oue T, Yonekura T, et al. Clinical application of indocyanine green (ICG) fluorescent imaging of hepatoblastoma. J Pediatr Surg. 2015;50(5):833-836. doi:10.1016/j.jpedsurg.2015.01.014
    CrossRef - PubMed
  27. Kitagawa N, Shinkai M, Mochizuki K, et al. Navigation using indocyanine green fluorescence imaging for hepatoblastoma pulmonary metastases surgery. Pediatr Surg Int. 2015;31(4):407-411. doi:10.1007/s00383-015-3679-y
    CrossRef - PubMed
  28. Makuuchi M, Thai BL, Takayasu K, et al. Preoperative portal embolization to increase safety of major hepatectomy for hilar bile duct carcinoma: a preliminary report. Surgery. 1990;107(5):521-527.
    CrossRef - PubMed
  29. Terraz S, Ronot M, Breguet R, et al. Portal vein embolization before extended hepatectomy in a toddler with mesenchymal hamartoma. Pediatrics. 2015;136(4):e1055-1059. doi:10.1542/peds.2015-0179
    CrossRef - PubMed
  30. Schnitzbauer AA, Lang SA, Goessmann H, et al. Right portal vein ligation combined with in situ splitting induces rapid left lateral liver lobe hypertrophy enabling 2-staged extended right hepatic resection in small-for-size settings. Ann Surg. 2012;255(3):405-414. doi:10.1097/SLA.0b013e31824856f5
    CrossRef - PubMed
  31. de Santibanes E, Clavien PA. Playing Play-Doh to prevent postoperative liver failure: the “ALPPS” approach. Ann Surg. 2012;255(3):415-417. doi:10.1097/SLA.0b013e318248577d
    CrossRef - PubMed


DOI : 10.6002/ect.2019.0323


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From the Department of Surgery, Division of Gastroenterological, General and Transplant Surgery, Jichi Medical University, Shimotsuke City, Tochigi, Japan
Acknowledgements: The authors have not received any funding or grants in support of the presented research or for the preparation of this work and have no potential declarations of interest.
Author contributions: Study design: Hirata, Sata. Data collection: Hirata, Sanada, Omameuda, Miyahara, Katano, Yamada, Okada, Onishi, Sakuma. Data analysis: Hirata, Sata. Data interpretation: Hirata, Sata. Preparation of manuscript: Hirata. Literature analysis: Hirata.
Corresponding author: Yuta Hirata, Department of Surgery, Division of Gastroenterological, General and Transplant Surgery, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke City, Tochigi 329-0498, Japan
Phone: +81 285 58 7069
E-mail: yutaktyy1234@jichi.ac.jp