Living donor liver transplantation for hepatoblastoma with Beckwith-Wiedemann syndrome
Sasaki K, Kasahara M, Fukuda A, Shigeta T, Tanaka H, Nakagawa S, Mitsui K, Harada R, Nakagawa A. Living donor liver transplantation for hepatoblastoma with Beckwith-Wiedemann syndrome. Pediatr Transplantation 2010: 14: E89-E92. @ 2009 John Wiley & Sons A/S.
Abstract: BWS is one of the most well-known somatic overgrowth syndromes, which is characterized by macroglossia, organomegaly, abdominal wall defects, and predisposition to embryonal tumors, such as Wilms’ tumor, hepatoblastoma, and adrenocortical carcinoma. We report a case of BWS in a girl with unresectable hepatoblastoma, who received a planned LVDT following neo-adjuvant chemotherapy. This is the first case report of liver transplantation for patients with BWS. Tumor surveillance after transplantation would be necessary to detect possible recurrence of the original disease and development of other malignancies.
Kazunari Sasaki1, Mureo Kasahara1, Akinari Fukuda1, Takanobu Shigeta1, Hideaki Tanaka2, Satoshi Nakagawa3, Kazumasa Mitsui4, Ryoko Harada4 and Atsuko Nakagawa 5
1Department of Transplantation Surgery, National Center for Child Health and Development, 2Department of Pediatric Surgery, National Center for Child Health and Development, 3Department of Intensive Care, National Center for Child Health and Development, 4Department of Pediatrics, Toho University Omori medical Center, 5Department of Pathology, National Center for Child Health and Development, Tokyo, Japan
Key words: Beckwith-Wiedemann - transplantation - hepatoblastoma
Mureo Kasahara, Department of Transplantation Surgery, National Center for Child Health and Development, Tokyo, Japan Tel .: +81-03-3416-0181 Fax: +81-03-3416-2222 E-mail: kasahara-m@ncchd.go.jp
Accepted for publication 26 March 2009
BWS is one of the most well-known somatic overgrowth syndromes with a frequency of one per 13 700 births (1). BWS is characterized by macroglossia, organomegaly, hemihyperplasia, increased birth weight, and abdominal wall defects. It also carries an increased risk of embryonal tumors, such as Wilms’ tumor, hepatoblastoma, adrenocortical carcinoma, and rhabdomyosarcoma. If these complications and malignant tumors are managed successfully, developmental progress is usually normal (2). The risk of tumor occurrence declines with age, and approaches the baseline risk of cancer in general population after the age of 10 yr (3).
Hepatoblastoma is the second most frequent malignant tumor among the BWS patients and is
Abbreviations: AFP, alpha-fetoprotein; BWS, Beckwith- Wiedemann syndrome; CT, computed tomography; LDLT, living donor liver transplantation; MMF, mycophenolate mofetil; OLT, orthotopic liver transplantation.
also the most frequent liver malignancy in the pediatric population (4, 5). The introduction of cisplatin-based chemotherapy improved the prognosis of childhood hepatoblastoma by achieving about 80% long-term survival using a combination of surgical resection and optimal chemotherapy. However, complete surgical resection remains a prerequisite for cure even with the advances in chemotherapeutic agents (6).
Although neo-adjuvant chemotherapy renders the primary tumors resectable in many cases, factors limiting the possibility of undergoing a radical resection still remain; for example, inva- sion of the main vascular trunks, extension of the tumor to all hepatic sections, and intrahepatic recurrence. In these situations, OLT has emerged during the last decade as a valid therapeutic option (7) which, along with total hepatectomy, might be an alternative treatment modality for unresectable hepatoblastoma.
We report a case of LDLT in a patient with unresectable hepatoblastoma and BWS. To our knowledge, this is the first case report of LDLT in such a patient.
Patient
The patient was a girl aged one yr and eight months, who was delivered by a cesarean section at 32 wk and six days of gestation, following a preterm rupture of the membrane. The infant weighed 2839 g and showed typical findings of BWS at birth, such as omphalocele, macroglos- sia, hypoglycemia, hemihypertrophy, and large birth weight and length. Radical operation for omphalocele was performed and the patient was followed as an out-clinic patient.
At 12 months of age, the patient was admitted for abdominal distension with a palpable hard abdominal mass. A series of CT scans revealed a huge, partially enhanced tumor completely occupying the left lateral segment of the liver and almost all of the right lobe. Chest CT revealed multiple nodules in the lower lobe of the right lung. The serum AFP level was 1 510 000 ng/mL. The patient was diagnosed with the pretreatment extent of disease (PRETEXT) IV + M hepatoblastoma with multiple lung metastases.
The patient was treated under the Japanese Pediatric Liver Tumor Study Group-2 protocol with seven courses of CITA (cisplatin, 80 mg/m2
+ adriamycin, 60 mg/m2) and one course of ITEC (ifosfamid, 6 g/m2 + carboplatin, 400 mg/ m2 + adriamycin, 60 mg/m2) (8). Evaluation after chemotherapy showed a marked decrease in tumor size and complete disappearance of lung metastases. The serum AFP level decreased to 49.8 ng/mL. Despite the decrease in size, the hepatoblastoma was still unresectable as the tumor, located just above the middle hepatic vein, occupied the entire lateral segment close to the posterior branch of the right portal vein (Fig. 1). The patient was referred to our hospital for LDLT.
LDLT was performed with an interval of eight months between the onset of hepatoblas- toma and transplantation and with an interval of four wk between the last course of chemo- therapy and transplantation. Induction of anes- thesia was performed routinely with no notable intubation difficulty. The operation employed a standard LDLT technique and added portacav- al shunting to prevent tumor cell dissemination by operative manipulation of the native liver. It lasted 10 h and 18 min with a blood loss of 730 mL and with cold and warm ischemic times as 23 and 32 min, respectively. The donor was the patient’s mother, aged 38 yr, whose blood type was identical to that of the patient. The donor’s surgery began immediately after con- firming that the recipient had no peritoneal dissemination and that the cytodiagnosis of
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ascites was negative. The left lobe graft weighed 265 g and the graft-to-recipient weight ratio was 2.21%.
The explanted native liver weighed 401 g and showed two macroscopic hepatoblastomas; one, located in the left lateral lobe, was 5 cm in size and the other, located in the right lobe, was 2 cm in size. Microscopically, both tumors showed viable cells, even though they mostly consisted of fibrous tissue.
Immunosuppression treatment consisted of tacrolimus and MMF. Methylprednisolone was administered only at the time of graft reperfu- sion, intraoperatively (10 mg/kg) and tacrolimus administration was started one day before trans- plantation. The target whole-blood trough level of tacrolimus was 10-12 ng/mL for the first two wk, approximately 10 ng/ml for the following two wk, and 5-10 ng/ml thereafter.
There were no notable intraoperative or post- operative complications and the patient was discharged on the 30th day. The patient’s serum AFP levels after transplantation were normal until now. The patient received CPT-11-based adjuvant chemotherapies, which were started 43 days after the transplantation surgery. The patient was doing well 18 months after LDLT without any signs of tumor recurrence.
Discussion
Indication of OLT for hepatoblastoma became an established valid therapeutic option after publication of several studies, such as that of the International Childhood Liver Tumour Strat- egy Group (SIOPEL) and of the United Network for Organ Sharing database (9, 10). Otte et al. reported comprehensive data on OLT for unre- sectable hepatoblastoma, based on international experiences and by reviewing the results of SIOPEL-1 (7). The five-yr overall survival rate in SIOPEL-1 was 75%, and the six-yr overall survival rate in worldwide experience was 82% for primary OLT patients (patients who had no previous hepatectomy). In complete tumor resec- tion and intrahepatic recurrence after partial hepatectomy were the usual indication of rescue transplant; however, the five-yr overall survival rate of SIOPEL-1 and six-yr overall survival rate in worldwide experience were 40% and 30%, respectively. These authors expressed a view that OLT should be considered for every child presenting an unresectable disease caused by the involvement of all four liver sectors or caused by the involvement of three sectors, when complete tumor excision by partial hepatectomy is unlikely. These ideas have been generally
accepted in liver transplantation programs worldwide.
In this case, we performed LDLT following an indication of unresectable PRETEXT IV + M hepatoblastoma with chemoreactive multiple lung metastases, which were not viable at the time of transplantation. The unique feature of our case was the presence of BWS in the recipient, which made it necessary to investigate whether BWS was an obstacle to transplantation.
In the perioperative and short-term post- operative follow-up period, we experienced no particular obstacle derived from BWS. In long- term post-operative follow-up period, it is neces- sary to take into account not only tumor recurrence but also predisposition of BWS patients to embryonal tumors, especially Wilms’ tumor. Despite only 18 months follow-up, this patient had no hepatoblastoma recurrence and other embryonal tumor occurrence. In light of the predisposition, we had employed the tumor surveillance protocol for BWS patients with ordinary post-transplantation following up pro- tocol. The most widely accepted protocol for BWS patient is as follows: abdominal ultraso- nography focusing on the liver and kidney and adrenal glands every three months until the age of eight yr; serum AFP measurement every three months until the age of four yr; and routine abdominal palpation by a physician (11).
In the present case, we selected tacrolimus and MMF for the immunosuppression regimen as steroid-free immunosuppression may reduce opportunistic infections and malignancies in already immunocompromised children with hepatoblastoma because of reiterated preopera- tive chemotherapy (12, 13). On the other hand, a previous study of LDLT for hepatoblastoma commented that the potential benefit of steroid- free immunosuppression in preventing hepato- blastoma recurrence requires further evaluation (14). Although numerous experimental initiatives have repeatedly demonstrated an oncological benefit to rapamycin therapy; however, we could not use it in this case because it was not approved in Japan at the present time.
We conclude that BWS patients with hepato- blastoma may be candidates for LDLT because the problem is not technical in these cases but the problem is development of embryonic tumor risk. The life expectancy of BWS patients is long when we can control those malignancies. Introduction of post-transplanta- tion embryonal tumor surveillance certainly will help in this point.
Sasaki et al.
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