Hepatoblastoma is the most common pediatric liver tumor and is usually diagnosed before five years of age. It accounts for 1.2% of malignancies in patients less than 15 years of age (1). Recent studies report an increasing incidence of hepatoblastoma in the U.S. from 0.6 to 1.2 per million (2,3). Typically, patients present with an abdominal mass and elevated AFP. Increased risk for development of hepatoblastoma is associated with Beckwith-Wiedemann Syndrome, Familial Adenomatous Polyposis Coli, maternal tobacco exposure and very low birthweight (4-6). Treatment consists of a combination of chemotherapy and surgery, with the goal being attainment of complete local control by surgical resection and eradication of any extrahepatic disease.
By the surgery based Evans staging system, staging was based upon exploratory surgery at diagnosis for all patients. Stage I and II tumors are those resected at diagnosis with microscopically negative and positive margins, respectively. Stage III and IV tumors are unresectable at diagnosis without and with metastatic disease, respectively. The current COG protocol, AHEP0731, uses a risk stratification scheme that is a hybrid of the old Evans system and PRE-TEXT (Pretreatment Extent of disease) used to define the timing and extent of surgical resection (7). In PRE-TEXT, the tumor group (I, II, III, IV) defines the extent of hepatic parenchymal involvement and the PRE-TEXT annotation factors (V, P, E, F, R, C, N, M denoting hepatic veins or vena cava, portal vein, extrahepatic, multifocal, tumor rupture, caudate lobe, lymph node and metastatic disease, respectively) define unique tumor characteristics and the extent of extrahepatic disease. PRE-TEXT I and II tumors have 3 and 2 adjoining sections free of tumor, respectively, and are usually resectable at diagnosis or after neoadjuvant chemotherapy depending on vascular involvement. For PRE-TEXT III and IV tumors, only one or two nonadjoining sections or none, respectively, are free of tumor and major vessel involvement is common. When the vessels or all sections remain involved after chemotherapy the tumor may not be resectable. Recently, the Childhood Hepatic tumors International Collaboration (CHIC) was formed and developed a new risk stratification and staging system based on PRE-TEXT that will be the basis of the upcoming international liver tumors trial.
Complete resection is a critical component for cure in the treatment of hepatoblastoma; however, 60% of tumors are unresectable at the time of diagnosis (8). Neoadjuvant chemotherapy is utilized and is often beneficial in rendering tumors resectable. Commonly, two adjuvant cycles of chemotherapy are reserved for administration post-operatively. Ortega et al. reported 20% of initially unresectable tumors remained unresectable after neoadjuvant chemotherapy. Otte et al. reported a need for liver transplantation for approximately 15% of patients with initially unresectable tumors (9).
Historical perspective: liver transplantation for hepatoblastoma
For patients whose tumors are too extensive to be conventionally resected, liver transplantation can be curative and has become an integral component of current treatment algorithms. In a recent study based on United Network for Organ Sharing (UNOS) registry data, the frequency of liver transplantation for hepatoblastoma increased from five in 1990 to 43 in 2013 (10). A review by Cruz et al. of the National Cancer Institute’s Surveillance, Epidemiology and End Results (SEER) registry [1975–2007], UNOS [1988–2010] and Children’s Hospital of Pittsburgh database [1987–2011] revealed a 20-fold increase in liver transplantation for hepatoblastoma over a 32-year period during which the frequency of hepatoblastoma cases increased 4-fold (11). The authors reported an increase in referral rate for liver transplantation for hepatoblastoma from 5% in early 1990s to 20% after 2004.
Indications for liver transplantation for hepatoblastoma
The Children’s Oncology Group (COG) recommends that only tumors where a segmentectomy or hemihepatectomy can be performed with a 1 cm tumor free margin on the middle hepatic vein and portal bifurcation be performed at diagnosis (1). Generally accepted indications for liver transplantation for hepatoblastoma include unifocal POST-TEXT IV (PRE-TEXT classification following chemotherapy) tumors and/or POST-TEXT III or IV with persistent widespread multifocality or major vessel involvement. Ideally, before a transplant there would be some response to chemotherapy. Depending on the surgeon, patients with POST-TEXT III tumors with major vascular involvement may be considered for an extreme conventional resection (conventional resection with major vascular reconstruction) instead of liver transplantation (7). In the nearly completed Childrens Oncology Group study AHEP0731, results are being analyzed for patients with POST-TEXT III with venous involvement and POST-TEXT IV tumors comparing conventional resection versus liver transplantation.
Contraindications to liver transplantation for hepatoblastoma
Transplant is contraindicated in the presence of any active regional or distant metastatic disease not cleared by chemotherapy or surgery (12,13). The treatment strategy for a patient who present with lung metastases with locally advanced tumors where liver transplantation is necessary to achieve tumor extirpation remain the most challenging subset population. Cruz et al. found that in their analysis of the Children’s Hospital of Philadelphia data, extrahepatic disease present prior to liver transplantation (but which had cleared by CT scan prior to transplant) was the main risk factor for recurrent hepatoblastoma post transplantation (11). Other analyses have found that risk of recurrence was similar for those who cleared with chemotherapy versus resection (10,14,15). Recommendations for bilateral lung palpation at the time of thoracotomy for persistent pulmonary disease following neoadjuvant chemotherapy remain controversial (1).
Liver transplantation in multifocal hepatoblastoma
Transplantation versus resection for patients with multifocal disease remains controversial with some recommending transplantation and others advocating for conventional resection when intrahepatic metastases clear with neoadjuvant chemotherapy (7,15-20). For patients with POST-TEXT IV multifocal tumors without metastatic disease after neoadjuvant chemotherapy, liver transplantation is clearly indicated (1).
Timing of liver transplantation
Prolonged chemotherapy administration attempting to render tumors resectable by conventional resection should be avoided. Several studies indicate that continuing to administer chemotherapy after four cycles does not increase the likelihood of conventional resectability of the tumor (21,22). In such patients, where liver transplantation is required to achieve local control, transplantation after four cycles of neoadjuvant chemotherapy is ideal (7).Unfortunately, this is not always possible due to unpredictable factors such as deceased organ donor availability. Héry et al. reviewed their experience with liver transplantation for hepatoblastoma and reported a wait time of 1–50 days for liver transplant (median 16 days); the authors concluded that delays in timing from last chemotherapy to transplant should be kept as short as possible (15). The concept of early referral for consultation (including consultation via telephone, email or other communication) for liver transplantation versus extreme liver resection was introduced by the current COG protocol AHEP0731 and the feasibility and outcome of this approach has been a major objective of that study. The goal is to decrease excessive toxicity due to prolonged chemotherapy and improve survival. In addition, Otte and others have shown that survival is higher (approximately 80% versus 30–40%) for patients who undergo primary liver transplantation (no attempt at conventional resection) as opposed to those in whom liver transplantation is utilized in the salvage setting (13,15,23-25).
Utilization of living versus cadaveric donors for liver transplantation is dependent on the provider’s/institution’s approach. Benefits of living donor liver transplantation include control of the timing of transplantation resulting on potentially shorter wait times thereby eliminating dependence on cadaveric liver availability, but engender risk of a major operative procedure to a healthy donor (11,15). Benefits to cadaveric donor transplantation include longer blood vessels from cadaveric donor grafts that allow for easier vascular reconstruction (15). Interestingly, Pham et al. reported increased recurrence rate for those who waited longer on the liver transplantation list for a cadaveric donor liver (mean time of 31 versus 15 days for those with recurrence versus those without, respectively) (10).
Complications of liver transplantation
Peri- and post-operative complications following liver transplantation include primary nonfunction, hepatic artery and portal vein thrombosis, bleeding, bile leak, infection, acute cellular rejection, long term immunosuppressive medication complications, post transplant lymphoproliferative disease and chronic rejection (14). Cruz et al. reported an increased risk of hepatic artery thrombosis in patients with hepatoblastoma undergoing liver transplantation compared to those receiving liver transplants for other conditions (11); however, the PLUTO registry did not find any increase in incidence of this complication (26). Héry et al. reported no post-operative mortality in the month post transplant in 13 pediatric patients receiving liver transplantation for hepatoblastoma (15). Four patients experienced complications (bile leak in one patient, arterial thrombosis followed by re-transplantation in three patients). Of 30 patients undergoing liver transplantation for hepatoblastoma at a single institution, four patients developed hepatic artery and/or portal vein thrombosis with all four requiring retransplantation (10). Second malignancies were infrequently reported with one patient with Burkitt Lymphoma four years after surgery (15).
Survival following liver transplantation for hepatoblastoma
Survival results from different institutional reports of liver transplantation for hepatoblastoma are difficult to compare given the inability to compare by patient specifics such as PRE-TEXT/POST-TEXT grouping, chemotherapy regimens, age, comorbidities, timing of transplant from last chemotherapy, utilization of adjuvant chemotherapy post transplantation and status of metastatic disease at the time of transplant. Upon review of 292 patients (in 29 separate publications) with hepatoblastoma who underwent liver transplantation, 76% of patients were alive at the time of publication (Table 1 and Table S1). Of note, some manuscripts reviewed were not included when patients with hepatoblastoma were unable to be separately identified or when it was unclear if the patients had been previously reported. Of 41 patients (with details reported) with rescue liver transplantation after initial attempt at resection, seventeen were alive (41%) compared with 85% of 175 patients with primary liver transplantation. Post-transplant chemotherapy appeared to have been administered for 140 patients; however, it is difficult to assess any relation to outcome given that details were not reported for many patients and many confounding factors exist (for some patients, chemotherapy was given after transplantation for recurrent disease, whereas others did not include these specifics).
Liver transplantation can be curative in certain patients in whom conventional resection is not possible. Early consultation with pediatric liver transplantation specialists is critical in the management of patients with hepatoblastoma who are most likely to need liver transplantation or extreme liver resection and is important for facilitating timely resection by either conventional resection or liver transplantation (7). Though not without its complications (and lifelong immunosuppression), liver transplantation remains the treatment of choice for eligible patients otherwise incurable by conventional resection.
Conflicts of Interest: The authors have no conflicts of interest to declare.
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Cite this article as: Trobaugh-Lotrario AD, Meyers RL, Tiao GM, Feusner JH. Pediatric liver transplantation for hepatoblastoma. Transl Gastroenterol Hepatol 2016;1:44.