Cisplatin-resistant metastatic hepatoblastoma: Complete response to carboplatin,etoposide, and liver transplantation

A child with stage 4 hepatoblastoma failed to respond to treatment with cisplatin and adriamycin. She then showed a response to carboplatin with complete clearing of pulmonary metastases. Bilobar liver disease persisted, although significantly reduced in size. A liver transplant was subsequently performed and she remains in complete remission 36 months later. After the first course of carboplatin, there was a dramatic rise in alpha-feto protein which then fell exponentially. Carboplatin warrants further study in hepatoblastoma. © 1993 Wiley-Liss, Inc.     

Successful autologous peripheral blood stem cell transplantation with a double-conditioning regimen for recurrent hepatoblastoma after liver transplantation

Abstract:  A four-yr-old boy developed a solitary metastasis nine months after living-related liver transplantation for unresectable hepatoblastoma. After resection of the metastatic lesion, he received an auto-PBSCT with a double-conditioning regimen consisting of melphalan and thiotepa. Auto-PBSCT could be safely performed without any serious regimen-related toxicity or infection. However, transient cessation of tacrolimus during myelosuppression resulted in graft rejection of the liver just after hematological engraftment, but rejection was resolved by tacrolimus and methylprednisolone. The patient is alive and free from disease two yr after auto-PBSCT without any signs of graft rejection. High-dose chemotherapy using this conditioning regimen may be feasible for recurrent hepatoblastoma after liver transplantation in terms of safety and anti-tumor activity.     

Renal function following liver transplantation for unresectable hepatoblastoma

Combination of cyclosporine (CsA) and tacrolimus immunosuppression post-liver transplantation (LT) and the chemotherapeutic drugs used to treat hepatoblastoma (HB), are nephrotoxic. We aimed to determine the severity and duration of nephrotoxicity in children following LT for unresectable HB. We reviewed all children undergoing LT for unresectable HB at the Liver Unit, Birmingham Children's Hospital, UK, from 1991 to July 2000. Thirty-six children undergoing LT for biliary atresia, matched for age and sex, were selected as controls to compare pre- and post-LT renal function. Renal function was determined by estimation of glomerular filtration rate (eGFR) derived from plasma creatinine using Schwartz's formula. Twelve children with HB (mean age of diagnosis 33 months) who underwent LT (mean age 47 months) and 36 controls (mean age of LT 34 months) were studied. CsA was the main immunosuppressive drug used in each group. The median eGFR before, and at 3, 6, 12, 24 and 36 months after LT in HB group was significantly lower than controls (93 vs. 152, 66 vs. 79, 62 vs. 86, 66 vs. 87, 64 vs. 94, 53 vs. 90 mL/min/1.73 m2, respectively; 0.01 < p < 0.03). The reductions in the median eGFR of both the HB group and controls before and at 36 months after LT were 49 and 41%, respectively. At 36 months after LT, there was a trend for partial recovery of the eGFR in the controls but not in the HB group. Children who underwent LT for unresectable HB had renal dysfunction before transplantation that persisted for 36 months after LT.     

Living-related liver transplantation with removal of inferior vena cava for unresectable hepatoblastoma

We report a case of a two-yr-old boy with hepatoblastoma resectable only by total hepatectomy including the vena cava. Successful LTx was performed with a living donor segment without vena cava reconstruction. The tumor was located in the bilateral lobe, surrounding the IVC. In spite of the high-dose chemotherapy, the tumor did not become resectable. LTx was performed using left lateral segment after removal of the IVC combined with total hepatectomy. Because the collaterals were well developed, the patient tolerated the procedure well. The serum AFP level decreased from 186 699 to 8 ng/mL in 11 months after LTx without local recurrence or distant metastasis.     

Rejection is less common in children undergoing liver transplantation for hepatoblastoma

To compare the incidence of acute histologically proven rejection in children who have had a liver transplant for hepatoblastoma with a control group of children transplanted for biliary atresia (EHBA). A retrospective case notes based study was performed. Twenty patients were identified with hepatoblastoma who were transplanted at a single unit between 1991 and 2008. These were matched as closely as possible for age, gender, year of transplant and type of immunosuppression used to the control group transplanted for biliary atresia (n = 60). There was a significant decrease in rate of acute rejection as assessed by the rejection activity index (RAI) in the hepatoblastoma group (75% vs. 50%, respectively, p < 0.04). Chronic rejection was rare in both groups, but twice as common in the biliary atresia group. Equal levels of immunosuppression were achieved in both groups. Renal function was noted to be reduced one yr post‐transplant in both groups, as previously reported. A modified immunosuppression regimen could be considered in children with hepatoblastoma undergoing liver transplantation.     

Prognostic factors for event‐free survival in liver transplantation for hepatoblastoma: A single‐center experience

Hepatoblastoma (HB) is the most common malignant liver tumor in children. Twenty percent of the cases may remain unresectable after neoadjuvant chemotherapy and, for these patients, liver transplant (LT) is an accepted therapeutic option. To analyze the risk factors to event‐free survival (EFS) that influence the clinical outcome of patients with HB receiving LT, we retrospectively analyzed 21 patients with HB who underwent LT between January 1, 2005, and May 1, 2018. Overall survival (OS) was 90%. The univariate analysis shows that the AFP level at the time of LT was associated with a higher risk of EFS. With a ROC curve analysis, we established a cutoff point value of AFP levels at 16 000 ng/dL, with a sensitivity of 71.43% and a specificity of 85.71%. Multivariate analysis showed that patients with higher values of pretransplant AFP (>16 000 ng/dL) had a significantly higher risk of EFS than those transplanted with lower levels (HR: 10.180; 95% CI: 1.54‐66.97; P = .02). Efforts should be made to improve the selection of candidates for LT for unresectable HB, aiming at a better definition of chemoresistance as a risk factor of poor outcomes.     

High survival rates after liver transplantation for hepatoblastoma and hepatocellular carcinoma

Kosola S, Lauronen J, Sairanen H, Heikinheimo M, Jalanko H, Pakarinen M. High survival rates after liver transplantation for hepatoblastoma and hepatocellular carcinoma.
Pediatr Transplantation 2010: 14:646–650. © 2010 John Wiley & Sons A/S. Abstract: Unresectable malignant liver tumors may be treated by LTx. We evaluated the results of LTx for HB and HCC. All patients transplanted for HB or HCC between 1990 and 2007 were included. Effects of histologic tumor type, primary tumor resection, disease staging, and serum AFP levels at diagnosis and at transplantation on disease recurrence and survival were evaluated. Twelve patients with median age of five (range, 2–16) were transplanted and followed for a median of 11 (2–18) yr. Six patients had HB and six had HCC. At diagnosis, eight patients were staged as PRETEXT III and four patients as PRETEXT IV. Two patients had pulmonary metastases. All patients received neoadjuvant chemotherapy. Median time from diagnosis to LTx was seven (2–133) months. At LTx, none of the patients had radiological evidence of extrahepatic disease, and the median AFP level was 85 (6–15 180) μg/L. No routine chemotherapy after LTx was used.The overall one‐, five‐, and 10‐yr cumulative survival rates were 100%, 80%, and 67%, respectively. Survival was comparable between the two tumor types (4/6 for both). Two deaths occurred secondary to tumor recurrence, one of each tumor type. Both of these patients had an AFP response of <99%. Six of eight patients with primary LTx survived, when compared to two of four transplanted after primary resection. PRETEXT tumor staging had no effect on survival. LTx even without post‐transplantation chemotherapy is an effective treatment option for unresectable HB and HCC with comparable survival. Incomplete AFP response to chemotherapy and primary tumor resection were associated with decreased survival.     

小儿亲体部分肝移植治疗肝母细胞瘤(附1例报告)

目的探讨小儿部分亲体肝移植治疗肝母细胞瘤的临床经验。方法对1例患肝母细胞瘤的4岁男童实施母亲供肝,左外肝叶亲体部分肝移植。结果供体于术后7d痊愈出院,受体于术后22d出院,无并发症。随访24个月,小儿生长发育良好,正常上学,无特殊不适。结论实施小儿亲体部分肝移植扩大了供肝来源,临床疗效好,可作为治疗肝母细胞瘤等小儿终末期肝病的有效治疗方法。     

Chemoresistant hepatoblastoma in a patient with mosaic trisomy 18 treated with orthotopic liver transplantation

We present a 9-month-old male with mosaic trisomy 18 with a right hepatic lobe mass. The tumor was completely resected and identified as pure fetal histology hepatoblastoma but contained increased mitotic activity. Adjuvant chemotherapy consisted of cisplatin, vincristine, and 5-fluorouracil. After the first and fourth cycles of chemotherapy, recurrent tumor developed. The patient underwent rescue orthotopic liver transplantation, and is currently alive without evidence of hepatoblastoma 28 months after transplantation. This report demonstrates the use of orthotopic liver transplantation in a child with mosaic trisomy 18 and hepatoblastoma.     

Successful treatment of unresectable advanced hepatoblastoma: Living liver transplantation after surgical removal of lung metastasis

Miyamura T, Yoshida R, Yagi T, Matsukawa H, Chayama K, Ishida T, Washio K, Morishita N, Oda M, Morishima T. Successful treatment of unresectable advanced hepatoblastoma: Living liver transplantation after surgical removal of lung metastasis.
Pediatr Transplantation 2011: 15: E87–E91. © 2010 John Wiley & Sons A/S. Abstract: Hepatoblastoma is a rare malignant tumor of the liver in children. Intensive combination chemotherapy has increased the number of surgically resectable cases and improved prognosis markedly. However, unresectable cases and cases with residual metastasis, including lung metastases, have a poor prognosis. In these refractory cases, treatment strategy has not been established. On the other hand, living liver transplantation has been shown to be effective in cases of advanced hepatoblastoma, but its effectiveness in cases with residual distant metastases after chemotherapy remains unclear. We report one successful case of advanced unresectable hepatoblastoma with multiple lung metastases. Intensive chemotherapy consisting of high‐dose chemotherapy with autologous hematopoietic stem cell transplantation was not effective. We performed living liver transplantation after surgical resection of residual lung metastases, which were histologically viable. After liver transplantation, the level of tumor marker decreased gradually. The patient experienced no severe complications. This case suggested that living liver transplantation could be effective in cases of advanced refractory hepatoblastoma after control of distant metastases.     

Use of a donor iliac vein graft for reconstruction of the inferior vena cava in liver transplantation for hepatoblastoma with caval extension

Complete microscopic tumor resection is critical for successful treatment of hepatoblastoma, and this may include when liver transplantation is required. For tumors involving the IVC or PV, complete resection should include the involved IVC or PV to ensure full tumor clearance. When this is required, the venous reconstruction at transplant or post‐excision can be challenging. We present the management of an 18‐month‐old girl with PRETEXT Stage IV (P, V, F) hepatoblastoma and IVC involvement, where native caval resection and reconstruction was required. The preoperative staging following neoadjuvant chemotherapy was POSTTEXT Stage IV (P, V, F). An orthotopic liver transplantation was performed using a left lateral segment graft from a deceased adult donor. With native hepatectomy, retrohepatic IVC resection from just above the hepatic venous confluence to just above the entry of the right adrenal vein was performed. For caval reconstruction, a venous graft from a deceased donor was used. The graft included the lower IVC with the right common iliac vein and a short stump of the left common iliac vein. The common iliac was a perfect size match for the IVC, and the three natural ostia matched the upper cava, lower cava, and the outflow from the donor left hepatic vein. The patient had an uneventful postoperative course and remains well and disease‐free 2 years after transplant with continued patency of the reconstructed cava. When indicated, a donor iliac vein graft with its natural ostia should be considered in caval reconstruction for pediatric liver transplantation.     

Adriamycin and cis-platinum administered by continuous infusion preoperatively in hepatoblastoma unresectable at presentation

Hepatoblastoma deemed surgically unresectable at presentation is fatal unless conversion to resectability is attained. We report a series of six consecutive patients, ranging in age from newborn to 5.75 years with hepatoblastoma unresectable at presentation, either because of size of tumor or its anatomical boundaries, or because of metastatic disease. All were treated with preoperative continuous infusions of cis-platinum and Adriamycin. All achieved resect-ability, and there was only one operative death. The five surviving patients are alive and free of disease off therapy. Potential benefit may accrue from preoperative chemotherapy in most cases of hepatoblastoma.     

Glomerular filtration rate in liver transplant for unresectable hepatoblastoma

Most children with hepatoblastoma manifest, at the time of LT, a decrease in renal function due to chemotherapy that could be further deteriorated by the use of calcineurin inhibitors. The purpose of this work was to examine the long‐term follow‐up of renal function in a cohort of children transplanted for unresectable hepatoblastoma. We present a retrospective observational study of 10 pediatric patients who received a LT for unresectable hepatoblastoma between 1996 and 2016. All patients included in this study were followed up on a regular basis and were assessed for GFR before transplantation and at least once a year during follow‐up. All patients received standardized chemotherapy treatment for hepatoblastoma and immunosuppression according to hospital protocols. There was a marked decrease in GFR at the time of the LT in five patients presenting renal complications during the pretransplant cycles of chemotherapy. Three patients, one of them with prior kidney involvement, presented complications after LT, namely acute kidney failure and decrease in GFR. Those patients who presented with the lowest GFR at the time of LT eventually recovered renal function at levels similar to the rest of the group on follow‐up. Chemotherapy‐induced nephrotoxicity is a concern in patients treated for hepatoblastoma. Some individuals will develop low GFR after chemotherapy; therefore, strict follow‐up is recommended, as low GFR may affect the doses of subsequent chemotherapy and immunosuppression. Stabilization of GFR levels and occasional improvement can be observed in the post‐transplant period.     

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.     

Surgical treatment of hepatoblastoma

Surgical resection remains the cornerstone of cure in hepatoblastoma (HB). Meticulous review of contrast enhanced CT/MR imaging facilitates PRETEXT and POST‐TEXT grouping to determine optimal timing and desired extent of liver resection. Excellent knowledge of liver anatomy is essential and the dissection must ensure protection of the vascular inflow and outflow to the remaining liver at all times. Referral to a liver specialty center in advanced cases may facilitate resectability. Potential surgical complications include bleeding, vascular injury, cardiac arrest, liver failure, and bile leak. The risk of complications can be minimized with preoperative planning, appropriate referral, and precise surgical technique. Pediatr Blood Cancer 2012; 59: 800–808. © 2012 Wiley Periodicals, Inc.     

Liver transplantation for hepatoblastoma: indications and contraindications in the modern era

In the past 20 yr, a dramatic improvement has been achieved in the outcome of children with hepatoblastoma by combining cisplatin based chemotherapy and surgery. Treatment of patients in the USA is an exception to the rule that all patients should receive neoadjuvant chemotherapy. It is paramount that surgical resection be complete, both macro- and microscopically. Complete tumor resection can be achieved after chemotherapy with a partial hepatectomy when the intrahepatic extent is limited to 1-3 sectors. In multifocal (and solitary) hepatoblastomas invading all four liver sectors, and in centrally located tumors with close proximity to the major veins, the SIOPEL-1 study and an extensive review of the world experience have shown that primary transplantation provides high, long term, disease-free survival rate in the range of 80%. In contrast, the results of rescue transplants for incomplete tumor resection or disease recurrence after partial hepatectomy are disappointing (in the range of 30%). Hazardous attempts at partial hepatectomy in children with extensive hepatoblastoma should be discouraged. Guidelines are provided for early referral of children with extended hepatoblastoma to a transplant surgeon. There is a trend for a better patient survival after living related liver transplantation. Patients who will become candidates to liver transplantation should be treated with chemotherapy following the same protocols as for children undergoing a partial hepatectomy. There is a concern about cumulative nephrotoxicity of calcineurin inhibitors and chemotherapeutic drugs. Recent data suggest that these patients tolerate lower Tacrolimus trough blood levels than those transplanted for non-malignant conditions, without increasing the risk of acute rejection. Due to the rarity of the disease, these children should be treated in specialized centers.     

Technical refinement in living‐donor liver transplantation for hepatoblastoma with main portal vein tumor thrombosis – a pullout technique

We present a case of a two‐yr‐old boy diagnosed with HBT with complete main PVTT. HBT was located in the bilateral lobe with PVTT involving the confluence of the SMV and the SpV. Cisplatin‐based neoadjuvant chemotherapy was delivered; main tumor shrank and AFP levels decreased to below one hundredth. However, PVTT remained in the bilateral portal branches to the main trunk of PV. We describe the technical details of the portal venous tumor thrombectomy that was succeeded by a LDLT. The patient remained healthy 2.5 yr after LDLT, showing good patency of the PV with no evidence of recurrence of tumor.