AUTHOR AND EDITOR INFORMATION

Section 1 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

INTRODUCTION

Section 2 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Background

Hepatoblastoma is the most common liver cancer in children, although it is relatively uncommon compared with other solid tumors in the pediatric age group. During the past several years, pathologic variations of hepatoblastoma have been identified, and techniques for establishing the diagnosis of childhood hepatic tumors have improved. Surgical techniques and adjuvant chemotherapy have markedly improved the prognosis of children with hepatoblastoma. Complete surgical resection of the tumor at diagnosis, followed by adjuvant chemotherapy, is associated with 100% survival rates, but the outlook remains poor in children with residual disease after initial resection, even if they receive aggressive adjuvant therapy. 

Considerable controversy has surrounded the discrepancy between US and international hepatoblastoma therapeutic protocols; surgery and staging are initially advised in the United States, whereas adjuvant therapy is strongly considered internationally. Significant data now support a role for preoperative neoadjuvant chemotherapy if the tumor is inoperable or if the tumor is unlikely to achieve gross total resection at initial diagnosis.¹ Early involvement of hepatologists and liver transplant teams is recommended if the tumor may not be completely resectable even with preoperative adjuvant chemotherapy. Liver transplantation is playing an increasing role in cases in which the tumor is deemed nonresectable after chemotherapy is administered or in "rescue" transplantation when initial surgery and chemotherapy are not successful.^{2, 3} 

Finally, reports state that aggressive surgical intervention may be warranted for isolated pulmonary metastases.^{1, 4}

Pathophysiology

Hepatoblastomas originate from immature liver precursor cells and present morphologic features that mimic normal liver development. Hepatoblastomas are usually unifocal and affect the right lobe of the liver more often than the left lobe. Microvascular spread can extend beyond the apparently encapsulated tumor.

Grossly, the tumor is a tan bulging mass with a pseudocapsule. Cirrhosis is not associated with this tumor. Metastases affect the lungs and the porta hepatis; bone metastases are very rare. CNS involvement has been reported at diagnosis and during relapse. The identification of distinct subtypes and further molecular biological information derived regarding liver ontogenesis and growth regulation of hepatic tumors has recently helped pave the way for a more comprehensive classification system for this disease.

Loss of heterozygosity (LOH) of chromosome arm 11p markers occurs commonly in hepatoblastoma identified in association with Beckwith-Wiedemann syndrome (BWS) and hemihypertrophy. Isochromosome 8q is seen in mixed hepatoblastomas, and trisomy 20 is seen in pure epithelial hepatoblastomas (see Histologic Findings).

Patients with familial adenomatous polyposis (FAP), a syndrome of early-onset colonic polyps and adenocarcinoma, frequently develop hepatoblastomas. Germline mutations in the APC tumor suppressor gene occur in patients with FAP, and mutations in the APC tumor suppressor gene are frequently detected in the colonic polyps and adenocarcinomas associated with FAP. One study estimated that 1 in 20 hepatoblastomas is probably associated with FAP.⁵ Interestingly, APC mutations, although common in patients with hepatoblastoma and FAP, are rare in patients with sporadic hepatoblastomas. Recently, Sanders and Furman reported 2 brothers with hepatoblastoma who had a significant family history of early-onset colon cancer.⁶ Testing of the younger brother revealed a deletion in exon 15 of the APC gene consistent with a diagnosis of FAP.

Loss of function mutations in APC lead to intracellular accumulation of the protooncogene b-catenin, an effector of Wnt signal transduction. b-catenin mutations have been shown to be common in sporadic hepatoblastomas, occurring in as many as 67% of patients. Furthermore, a study in a mouse model of hepatoblastomas induced by toxin exposure detected mutations of the b-catenin protooncogene in 100% of the tumors analyzed (27 of 27).⁷ This finding suggests that alterations in the Wnt signaling pathway likely contribute to the neoplastic process in this particular tumor.

Recent studies on other components of the Wnt signaling pathway have also demonstrated a likely role for constitutive activation of this pathway in the etiology of hepatoblastoma.^{8, 9} Overexpression of human Dickkopf-1, a known antagonist of the Wnt pathway, has been found in hepatoblastoma. The authors postulate that this may be a direct negative feedback mechanism resulting from increased β-catenin commonly found in this tumor.¹⁰

A mutation in the axin gene, also a known antagonist of β-catenin accumulation, has been found in hepatoblastoma and may contribute to the etiology of the smaller percentage of hepatoblastomas in which β-catenin mutations have not been identified, thus implicating the constitutive activation of the Wnt pathway in a significant fraction of hepatoblastomas.^{11, 12} Kuroda et al demonstrated a potential role for transcriptional targeting of tumors with strong β-catenin/T-cell factor activity with oncolytic herpes simplex virus vector.¹³ The hedgehog pathway has also been evaluated and has been found to be a potential therapeutic target for hepatoblastomas in which the Hh pathway is overexpressed or reactivated at an inappropriate time.¹⁴

Increasing evidence suggests that hepatoblastoma is derived from a pluripotent stem cell.¹⁵ This further supports the hypothesis that this tumor arises from a developmental error during hepatogenesis and supports the hypothesis that research particularly focused on these developmental processes governing liver maturation and growth may ultimately lead to more effective targeted therapy for this disease.

Frequency

United States

Hepatoblastoma accounts for 79% of all liver tumors in children and almost two thirds of primary malignant liver tumors in the pediatric age group. Approximately 100 cases of hepatoblastoma are reported per year. The annual incidence of hepatoblastoma in infants younger than 1 year is 11.2 cases per million; in 1990-1995, the annual incidence in children overall was 1.5 cases per million, which is almost double the incidence from 1975-1979. 

A significantly higher rate of hepatoblastomas is observed among low birth weight (LBW) and very low birth weight (VLBW) infants born prematurely.¹⁶

A Children’s Oncology Group (COG) protocol (AEP104C1) is currently investigating exogenous and endogenous causes for the increase in incidence and potential cause of premature births. The study is also exploring potential effectors independent of prematurity and LBW or VLBW. All children with hepatoblastoma diagnosed before age 6 years from 2000-2005 are eligible for retrospective analysis, and prospective analysis will be performed for children diagnosed between June 2005 and December 31, 2008. This is the largest, most comprehensive case-control study of hepatoblastoma performed thus far.

Mortality/Morbidity

A large multicenter COG study included 182 children with hepatoblastoma diagnosed between August 1989 and December 1992.¹⁷ Of these, 9 had stage I disease with favorable histology (FH), 43 had stage I with unfavorable histology (UH), 7 had stage II, 83 had stage III, and 40 had stage IV disease (see Staging).

All 9 patients with stage I and FH received treatment with low-dose doxorubicin and were alive and free of disease. Overall survival rates for all stages 5 years after treatment were 57-69%. The 5-year event-free survival (EFS) rates were 91% for patients with stage I with UH, 100% for stage II, 64% for stage III, and 25% for stage IV.

In general, patients who undergo complete resection of the tumor and adjuvant chemotherapy have a survival rate of 100%. Patients with favorable histology and low mitotic rate with complete resection may not require chemotherapy; for this reason, US protocols have advocated for formal staging and pathologic diagnosis prior to administering any adjuvant chemotherapy.

More recently, data from the International Childhood Liver Tumour Strategy Group (SIOPEL), which used preoperative adjuvant chemotherapy, demonstrated overall survival rates as high as 89% and event-free survival rates as high as 80%.¹⁸ Australian investigators demonstrated that patients treated between 1984 and 2004 also had excellent outcomes, provided surgical margins were clear.¹ No correlation between α-fetoprotein (AFP) levels and outcome was reported in the study.

Other morbidity can result from precancerous medical conditions, operative complications, or toxic effects of chemotherapy. Short- and long-term sequelae and toxic effects of surgical management and chemotherapy are discussed below (see Surgical Care and Medical Care).

Race

White children are affected almost 5 times more frequently than African American children.

Sex

Males are typically affected more frequently than females; the male-to-female ratio is 1.7:1. Male-to-female ratios are somewhat higher in Europe (1.6-3.3:1) and Taiwan (2.9:1).

Age

Hepatoblastoma usually affects children younger than 3 years, and the median age at diagnosis is 1 year. Hepatoblastoma is very rarely diagnosed in adolescence and is exceedingly rare in adults. Occasionally, nests of hepatoblastoma cells are found in hepatocellular carcinoma lesions; this is more common in adults than in children. Older children and adults tend to have a worse prognosis.

CLINICAL

Section 3 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

History

• Patients with hepatoblastoma are usually asymptomatic at diagnosis. Disease is advanced at diagnosis in approximately 40% of patients, and 20% have pulmonary metastases.
• Children with advanced disease may have anorexia.
• Severe osteopenia is present in most patients and regresses with resection of the tumor. Symptoms associated with osteopenia are rare with the exception of pathologic fracture, which is often incidentally identified on routine imaging studies during evaluation of these children.
• Rarely, patients in whom the tumor has ruptured present with symptoms consistent with acute abdomen. Occasionally, patients present with severe anemia resulting from tumor rupture and hemorrhage.
• Family history of early onset intestinal polyps or adenocarcinoma may reveal familial adenomatous polyposis (FAP). A history of hemihypertrophy or BWS should prompt screening using AFP as a marker to detect hepatoblastoma in these patients. For such patients, AFP monitoring should be performed every 3 months until the child is aged at least 4 years. Children who survive hepatoblastoma should be considered for evaluation of FAP, and those patients found to carry an APC mutation need close surveillance because of their increased risk for colonic polyps and frank progression to adenocarcinoma.
• Diagnosing primary malignant liver tumors before clinical signs and symptoms develop is important. Children with a history of chronic hepatitis B infection who have advanced liver disease should be monitored at least every 6-12 months with serum AFP levels and abdominal ultrasonography. Many children with hepatitis B infection are immunotolerant, do not have significant liver abnormalities, and are not at increased risk for liver cancer. Any child with documented cirrhosis for any reason should be periodically monitored with serum AFP level and ultrasonography because of their increased risk of developing a hepatic malignancy associated with advanced liver disease.

Physical

• Hepatoblastoma is usually diagnosed as an asymptomatic abdominal mass. 
• Approximately 10% of patients have incidental findings of hemihypertrophy. 
• Hepatoblastoma can be associated with isosexual precocity. Penile and testicular enlargement without pubic hair is seen in patients with tumors that secrete the b subunit of human chorionic gonadotropin (b-hCG). 
• Late features of BWS, such as midface hypoplasia and slitlike indentations of the earlobe, may occur, but this is rare. 
• Patients with BWS and those with hemihypertrophy should be monitored with serial abdominal ultrasonography and serum AFP level every 3 months until at least age 4 years; some would argue that these patients should be monitored until age 7 years because of the risk of Wilms tumor as well.
• Other associated syndromes and malformations include the following: 
• • Talipes equinovarus
  • Persistent ductus arteriosus
  • Tetralogy of Fallot
  • Extrahepatic biliary atresia
  • Renal anomalies (dysplastic kidney, horseshoe kidney)
  • Cleft palate
  • Dysplasia of the earlobes
  • Goldenhar syndrome
  • Prader-Willi syndrome
  • Meckel diverticulum
• Hepatoblastoma is also seen in association with Simpson-Golabi-Behmel syndrome. Routine screening with AFP level monitoring and abdominal ultrasonography is suggested in these patients, who are also at risk for developing Wilms tumor.

Causes

As with other pediatric malignancies, the cause of hepatoblastoma is generally unknown. Cancer has been postulated to arise from unregulated cellular differentiation and proliferation. Similarities between the developing fetal liver and the fetal epithelial-type cells of hepatoblastoma are striking. Developing cells of the early fetal liver and the cells of fetal hepatoblastoma are similar in size and configuration. A developmental disturbance during liver formation in embryogenesis likely results in aberrant proliferation of these undifferentiated cells.

Increasing data support a role for aberrant transduction of the Wnt/β-catenin signaling pathway and its molecular targets in hepatoblastoma tumorigenesis. Research in this area may ultimately contribute not only toward a better understanding of this malignant neoplasm but may also lead to more specific molecular-targeted therapies.

• Hepatoblastoma, like Wilms tumor, is associated with BWS and hemihypertrophy, suggesting gestational oncogenic events. 
• Persons with dysplastic kidney or Meckel diverticulum have a higher incidence of this tumor.
• Hepatoblastoma has also been reported to be associated with maternal oral contraceptive exposure, fetal alcohol syndrome, and gestational exposure to gonadotropins.
• Studies performed in Europe suggest an association between LBW, VLBW, and prematurity and hepatoblastoma. The suspected correlation between LBW, prematurity (<1000 g), and hepatoblastoma has now been confirmed in both the United States and Japan.^{19, 20}
• Patients with FAP have a significantly increased incidence of hepatoblastoma and should therefore be screened in early childhood with AFP measurements. 
• A child with neurofibromatosis type 1 (NF1) who developed hepatoblastoma was reported.²¹ Hepatoblastoma has also been reported in association with other cancer predisposition syndromes including FAP, BWS, Li-Fraumeni syndrome, trisomy 18, and glycogen storage disorders.
• Premature infants, particularly those born with LBW or VLBW, are at significantly increased risk of developing hepatoblastoma. The presence of erythropoietin receptors in hepatoblastomas has been postulated to potentially contribute to this increased incidence because many premature infants with LBW or VLBW receive this medication during their time in neonatal intensive care.

DIFFERENTIALS

Section 4 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Other Problems to be Considered

Malignant mesenchymal hepatic tumor (undifferentiated sarcoma, angiosarcoma, fibrosarcoma, leiomyosarcoma, rhabdoid tumor)
Hemangioma
Hemangioendothelioma
Mesenchymal hamartoma, often cystic
Embryonal sarcoma of the liver

WORKUP

Section 5 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Lab Studies

Diagnostic evaluation of a child in whom a liver tumor is suggested should include the following:

• CBC count with differential should be obtained.
• • Normochromic normocytic anemia is often present.
  • Thrombocytosis may be present. In a study by Ortega et al, 60% of patients had platelet counts greater than 500 X 10⁹/L, and 12% had platelet counts greater than 1000 X 10⁹/L.¹⁷
• Liver enzyme levels are moderately elevated in 15-30% of patients.
• AFP is a major serum protein synthesized by fetal liver cells, yolk sacs, and the GI tract. AFP is found in high concentrations in fetal serum and in children with hepatoblastoma, hepatocellular carcinoma, germ cell tumors, or teratocarcinoma. The tumor's ability to synthesize AFP reflects its fetal origin. Embryonal tumors produce less AFP than fetal tumors.
• • Levels of AFP in hepatoblastoma are often as high as 100,000-300,000 mcg/mL. Ortega et al found AFP levels elevated for age in 97% of patients.¹⁷
  • The half-life of AFP is 4-9 days, and levels usually fall to within reference range within 4-6 weeks following resection.
  • Other causes of elevated AFP levels include viral hepatitis, cirrhosis, inflammatory bowel disease, and yolk sac tumors.
  • Although elevated AFP levels are not specific for hepatoblastoma, they provide an excellent marker for response to therapy, disease progression, and detection of recurrent disease.
  • Rarely, a hepatoblastoma can recur as a non–AFP-secreting tumor with metastases, even if the initial tumor was AFP secreting.
  • Interpretation of AFP levels can be difficult because hepatoblastoma tends to occur within the first 2 years of life. Reference range AFP levels are comparatively high at birth and even higher in premature infants, which can complicate interpretation of this value. By age 1 year, adult levels of 3-15 mcg/mL have been reached.
  • Data from the German Cooperative Pediatric Liver Tumor Study showed that both very low (<100 ng/L) and very high (>1,000,000 ng/L) AFP levels are associated with poorer prognosis than intermediate AFP levels.²² 
  • Laboratory- and age-specific AFP values should be used.
  • Baseline testing of glomerular filtration rate (GFR) or creatinine clearance should be performed before cisplatin administration; follow-up studies are needed periodically to assess nephrotoxicity.

Imaging Studies

• Abdominal radiography
• • Plain abdominal films reveal a right upper quadrant abdominal mass.
  • Calcification is seen in approximately 6% of hepatic masses and 12% of hemangiomas.
    
• Ultrasonography
• • Abdominal ultrasonography allows assessment of tumor size and anatomy, which helps in surgical planning.
  • The mass usually appears hyperechoic on abdominal ultrasound images, which is particularly useful in determining vascular involvement (vessels have lower attenuation than surrounding parenchyma).
  • Baseline echocardiography is needed before anthracycline (doxorubicin) administration; follow-up studies are needed to assess cardiotoxicity.
    
• CT scanning
• • CT scanning of the abdomen using contrast reveals patchy enhancement. 
  • CT scanning reveals involvement of nearby structures. Regional lymph nodes are almost never involved.
  • CT scanning of the chest is warranted to assess for pulmonary metastases.
• MRI: This is believed to be superior to CT scanning but does not necessarily add to the anatomic detail seen on CT scans.
• Radionuclide bone scanning: This is recommended to evaluate for bone metastases when a patient is symptomatic. 
• Positron emission tomography (PET) scanning: Studies support a potential role for PET scanning at diagnosis and for follow-up evaluation in hepatoblastoma.²³

Other Tests

• A baseline audiology evaluation is needed before cisplatin or carboplatin administration; follow-up studies are needed to assess ototoxicity.

Procedures

• Pathologic diagnosis: Before commencing therapy, surgical diagnosis must be made. Surgical resection is the usual manner in which material for pathologic assessment is obtained. Open biopsy is performed when complete surgical resection is not possible. Needle biopsy is not recommended because these lesions usually are highly vascular.

Histologic Findings

Standardizing criteria for histologic classification of hepatoblastoma has been suggested because of the significant variation in the current medical literature. Particular attention to the subtypes of this tumor and direct correlation with clinical outcomes is increasingly being incorporated into all major protocols internationally.²⁴

Six histologic variants of hepatoblastoma have been described, as follows:

• Epithelial type
• • Fetal pattern
  • Embryonal and fetal pattern
  • Macrotrabecular pattern
  • Small cell undifferentiated pattern
• Mixed epithelial and mesenchymal type
• • With teratoid features
  • Without teratoid features

Pure epithelial tumors account for approximately 56% of cases; they contain varying amounts of fetal cells, embryonal cells, or both. Within this group, purely fetal tumors account for 31% of hepatoblastomas; embryonal tumors account for 19% of hepatoblastomas; and macrotrabecular tumors and small cell undifferentiated types each account for 3% of hepatoblastomas. The remaining 44% of hepatoblastomas are mixed tumors containing primitive mesenchymal tissue and specialized derived components, such as myofibroblastic, chondroid, and osteoid tissues in addition to epithelial elements. Mixed tumors may express teratoid features. Teratoid hepatoblastomas are admixed with various heterologous structures of epithelial or mesenchymal origin.

Fetal cells are smaller than normal hepatocytes and have low nuclear-to-cytoplasmic (N/C) ratios and infrequent mitoses; cells form slender cords. Embryonal cells have a higher N/C ratio and more mitoses; they resemble early ducts of embryonal liver. Extramedullary hematopoiesis can be associated with mixed tumors. In tumors that have been completely resected, pure fetal histologic (PFH) results (with a 92% rate of disease-free survival) are associated with better prognosis than other histologic types, which have an overall disease-free survival rate of 57%. The absence of mitoses is a good prognostic sign. In advanced disease in which tumors cannot be completely resected, PFH results do not predict a better outcome.

Staging

Staging of hepatoblastoma is based on degree of surgical resection, histologic evaluation, and presence of metastatic disease. The system cited here is based on the work of von Schweinitz et al.²⁵

• Stage I
• • The tumor is completely resectable via wedge resection or lobectomy.
  • The tumor has PFH results.
  • The AFP level is within reference range within 4 weeks of surgery.
• Stage IIA
• • The tumor is completely resectable.
  • The tumor has histologic results other than PFH (UH).
• Stage IIB
• • The tumor is completely resectable.
  • AFP findings are negative at time of diagnosis (ie, no marker to follow).
• Stage IIC
• • The tumor is completely resected or rendered completely resectable by initial radiotherapy or chemotherapy or microscopic residual disease is present. 
  • The AFP level is elevated 4 weeks after resection.
• Stage III (any of the following)
• • The tumor is initially unresectable but is confined to one lobe of liver.
  • Gross residual disease is present after surgery.
  • Tumor ruptures or spills preoperatively or intraoperatively.
    
  • Regional lymph nodes are involved.
• Stage IV: Distant bone or lung metastasis is present.

European groups have also developed a staging system through SIOPEL-1; the system uses the predictive value of pretreatment extent of disease (PRETEXT) in order to stage patients and determine which therapy is most appropriate.¹⁸ Using this system, physicians are able to refer higher risk patients for evaluation by liver transplant teams earlier with improved outcomes. These groups also advocate for chemotherapy treatment of lung metastases followed by surgical resection, with attempts for negative surgical margins providing optimal outcomes.

Which staging regimen is preferred among the Children’s Cancer Group (CCG) staging, Pediatric Oncology Group (POG) staging, and the European group staging is still actively discussed. However, for comparability reasons, following one staging regimen has been suggested, and international collaboration with consistency is ideal for this rare tumor.

TREATMENT

Section 6 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Medical Care

European groups, such as the International Society for Paediatric Oncology (SIOP), and groups in the United Kingdom and Australia, have been instrumental in demonstrating a role for preoperative adjuvant chemotherapy in improving surgical and overall outcomes. The European cooperative groups have also been very influential in encouraging a role for liver transplantation in patients with tumors deemed nonresectable. They have also developed criteria that can be used to determine which patients will benefit most from preoperative adjuvant chemotherapy as well as which patients should be referred early on for consideration for liver transplantation.

• Chemotherapy
• • The most important advance in the care of children with hepatoblastoma has been the discovery of effective chemotherapy. Initial reports showed the efficacy of vincristine (VCR), cyclophosphamide (CPM), and doxorubicin with 5-fluorouracil (5-FU). This regimen was based on reports that suggested the efficacy of these agents in children and adults with liver tumors.
  • Cisplatin is the most active single agent used to treat hepatoblastoma. Doxorubicin is active as well. These agents are currently being combined in clinical trials. Attempts to reduce the ototoxic effects of cisplatin have led to the use of carboplatin; however, whether this agent will be as effective as cisplatin against hepatoblastoma remains to be seen. No direct randomized control trial has addressed this question to date.
  • The Intergroup Liver Tumor study showed similar efficacy of the cisplatin/5-FU/VCR regimen and the cisplatin plus doxorubicin regimen.²⁶ Because the latter regimen was more toxic, the cisplatin/5-FU/VCR combination is regarded as standard in hepatoblastoma. The Intergroup Liver Tumor study demonstrated that intensification of therapy by alternating platinum analogs increased the risk of adverse outcome in children with unresectable or metastatic hepatoblastoma. The cisplatin/5-FU/VCR regimen was shown to be superior in this trial. Early referral for evaluation for liver transplantation is encouraged in these patients.
  • Preoperative chemotherapy can completely eradicate metastatic pulmonary disease and multinodular liver disease. Some authors recommend that all patients undergo preoperative chemotherapy, although patients may present in a setting in which resection occurs first. 
  • Chemotherapy is usually started approximately 4 weeks after surgery to allow liver regeneration. A minimum of 2 weeks should pass after surgery before administration of cytotoxic agents. 
  • Recent international data continue to support the role of neoadjuvant preoperative chemotherapy with improvements in survival. Data from Italy in a cohort of 13 children with hepatoblastoma also support a role for etoposide and epirubicin when combined with cisplatin, with EFS and overall survival rates at 5 years of 84% and 88%, respectively.²⁷ 
  • Treatment usually consists of 6 cycles of chemotherapy administered every 2-4 weeks; AFP levels are used as a guide to determine response to therapy. 
  • In addition to the drugs discussed above, carboplatin and etoposide have been used along with liver transplantation for advanced or recurrent disease with some success. Paclitaxel is also used in patients with extremely high-risk disease.
  • Use of neoadjuvant (preoperative) chemotherapy can often render a previously inoperable tumor more easily resectable. Some data from tumor xenografts suggest that these tumors may respond to irinotecan. Irinotecan has indeed shown activity in relapsed or refractory hepatoblastoma but has not yet been used for front-line therapy. 
  • Gemcitabine has been used with some partial responses in phase II trials. Combination therapy with other agents may improve outcomes in patients with relapsed/recurrent disease, perhaps providing decreased time to progression.
  • An approach with limited pediatric application is hepatic artery chemoembolization (HACE), which has been used successfully in some liver tumors in adults.
  • Promising studies performed in mice suggest a role for antiangiogenic agents, such as vascular endothelial growth factor (VEGF), in suppressing tumor growth in hepatoblastoma.²⁸ A considerable amount of preclinical data have also demonstrated a role for multidrug resistance 1 (MDR1) inhibition as potentially leading to an improved response to chemotherapy in tumors that have otherwise become refractory to treatment because of a drug resistance mechanism.^{29, 30}
  • A few isolated studies have reported patients receiving only chemotherapy with survival at greater than 5 years.³¹
• Radiotherapy
• • Doses used for treatment of hepatoblastoma are usually 1200-2000 centigray (cGy). These dose limits are based on the liver's limited ability to regenerate after radiation.
  • Radiotherapy may be used when microscopic disease is seen at the resection margins; in general, preoperative chemotherapy should minimize this.
  • Adjuvant radiotherapy may have a role in the treatment of chemoresistant pulmonary metastases.

Surgical Care

• Because of the rarity of this disease and to optimize results, children with extensive hepatoblastoma should be managed and treated in centers affiliated with experienced liver transplant teams and with surgeons familiar with this diagnosis and familiar with complex decisions regarding planning for resection. These surgical and liver transplant teams work closely with oncologists, pathologists, and radiologists to provide optimal outcomes.
• The hepatoblastoma can be completely resected at diagnosis in approximately one third of patients, those who have stage I or II disease. In 60% of patients, hepatoblastomas are localized but are unresectable at diagnosis. Approximately 10% of patients have metastases at diagnosis, most commonly to the lungs. These figures vary depending on the age of the patient at diagnosis, the size of the tumor, and the expertise of the surgical staff available for the procedure. Heroic efforts to resect tumors "up front" should be avoided, and adjuvant chemotherapy should be strongly considered when subtotal resection with microscopic margins is possible or when surgical morbidity is expected to be high.
• Initial resection of operable primary tumors by lobectomy is the standard of care. Occasionally, pulmonary lesions are resected. This can occur after chemotherapy as well, with the ultimate goal for negative surgical margins for all disease. 
• The following cases warrant early referral to a transplant surgeon:
• • Multifocal or large solitary lesions
  • Tumors involving all 4 sectors of the liver
  • Unifocal, centrally located tumors that involve the main hilar structures or main hepatic veins
• Second-look laparotomy is warranted if AFP levels remain elevated following resection. Local porta hepatis nodal sampling is performed rather than true nodal dissection because nodal involvement is rare.
• The most frequent complication of surgery is intraoperative hemorrhage; loss of the entire blood volume is not uncommon. 
• In cases involving a substantial portion of the liver, particularly when diaphragmatic extension precludes complete surgical resection, liver transplantation has been advocated. Liver transplantation has also been considered in the presence of unresectable disease following neoadjuvant (preoperative) or adjuvant (postoperative) chemotherapy. Living related-donor transplantation may be considered in some situations as well. Early involvement of the liver transplant team and the hepatology team is essential because delays can adversely affect outcomes. 
• Results from numerous cooperative international large group studies on hepatoblastoma continue to support a role for preoperative adjuvant chemotherapy in those tumors not easily respectable up front.^{4, 32, 33, 34, 22} Some authors advocate using adjuvant chemotherapy preoperatively, even when resection may be successful up front. The controversy over this is considerable,³⁵ but all are in agreement that complete resection with no residual disease is ultimately the most important prognostic factor for improved survival results in hepatoblastoma. Hence, any treatment, medical or surgical, that leads to an improvement in gross total resection is the goal.
• Increasing evidence suggests that arterial chemoembolization is feasible in patients with unresectable hepatoblastoma, patients who are not candidates for liver transplant, or both.
• Liver transplantation has an increasing role in children with nonresectable tumors or in those who show chemotherapy resistance. Overall 5-year survival is as high as 70-89% in some series. Early referral and collaboration with liver transplant centers is encouraged. Whether posttransplant chemotherapy is indicated is controversial.
• Thoracotomy and resection of pulmonary metastases also have a role, with some patients having long-term disease-free survival when aggressive attempts are made to surgically eradicate all areas of disease.

Consultations

A multidisciplinary approach in children with malignancy is necessary to ensure that appropriate care is safely administered with minimal toxicity. The team usually consists of specialized pediatric nurses, pediatric surgeons, pharmacologists with expertise in dealing with chemotherapy in children, nutritionists, social workers, child life specialists, and subspecialists in areas such as pediatric gastroenterology, neurology, cardiology, and infectious diseases. Early referral to liver transplant centers is encouraged for nonresectable tumors or those that show chemotherapy resistance. Referral to a radiation oncologist with pediatric experience may also be indicated.

Diet

Adequate nutrition is necessary for childhood growth and development. Maintaining adequate nutritional status is also important to maximize response to therapy. Many of the treatments may result in compromised nutritional status. Children undergoing radiotherapy or chemotherapy, particularly children younger than 5 years, typically require enteral or parenteral supplementation, often with electrolyte supplementation as well. Occupational therapists and child life specialists may be consulted to help with behavioral issues related to feeding, particularly in infants and toddlers.

Activity

Specific postoperative limitations on activity may be necessary, and, occasionally, some activities are limited because of central line placement or severe immunosuppression and myelosuppression associated with therapy; otherwise, no specific limitations are placed on activity. Most children are encouraged to attend daycare or school and participate in normal play essential to childhood development. Contact sports should be avoided during therapy, especially during periods of thrombocytopenia.

MEDICATION

Section 7 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

All chemotherapy orders are written and countersigned by pediatric oncologists. Most children are treated according to clinical protocols used in multiple institutions. For patients with refractory disease, a phase I or II trial is usually considered. Information on clinical trials is usually accessible through the National Cancer Institute (NCI) Web site and linked sites. The resources presented below should serve as guidelines only.

Antineoplastic agents have a narrow therapeutic index, and effective doses usually cause significant toxic effects. Any physician or other practitioner caring for children with cancer must be familiar with the indications, appropriate dosages, and toxic effects of the chemotherapy agents prescribed. They must also be familiar with any special considerations regarding age, weight, pharmacokinetic variations (ie, drug absorption, distribution, metabolism, excretion), coexisting medical problems, or possible pharmacokinetic interactions. To minimize risk to the patient, only practitioners familiar with the toxic effects and potential complications should prescribe antineoplastic agents.

Full discussion of the agents typically used in treating hepatoblastoma is beyond the scope of this article, but brief summaries of the drugs most commonly used are provided below.

Drug Category: Antineoplastic agents, alkylating agents, metal salts

The mechanism of action is similar to that of alkylating agents, namely, binding and cross-linking DNA strands.

Drug Category: Antitumor antibiotics, natural products

These agents are usually derived from microorganisms and have various antitumor mechanisms. All interfere with the DNA structure or the breakage-resealing process.

Drug Category: Topoisomerase II inhibitors, natural products

These plant alkaloids inhibit the topoisomerases that interfere with the normal DNA breakage-resealing reaction and cause single-strand breaks in DNA.

Drug Category: Antineoplastic antimetabolites

These agents are close structural analogs of vital intermediates in the biosynthetic pathways of nucleic acids and proteins. They either inhibit synthesis of cellular macromolecules and their building blocks or are incorporated into the macromolecules, resulting in a defective product.

Drug Category: Mitotic inhibitors, natural products

These plant alkaloids bind to microtubular proteins, inhibiting RNA synthesis by disrupting DNA formation.

Drug Category: Colony-stimulating factors

These agents promote growth and differentiation of myeloid progenitor cells. They may improve survival and function of granulocytes.

FOLLOW-UP

Section 8 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Further Inpatient Care

• Follow-up care: Children may be admitted to the hospital to expedite the diagnostic workup or when severe signs or symptoms are present. For medically stable patients, the workup can be performed in the outpatient setting. A central line is typically placed when the patient is scheduled for biopsy or resection. Double-lumen central lines are preferred if vessel access is adequate because this allows concurrent administration of multiple parenteral medications. 
• Multidisciplinary evaluation: The child is initially evaluated by a pediatric oncologist and surgeons with expertise in childhood malignancies. Evaluation should be performed at a pediatric cancer center. Once the diagnosis is established and the staging workup is completed, the patient and family are instructed on the diagnosis and therapeutic options. Most children and families are offered participation in cooperative group trials. Once the treatment plan is developed, chemotherapy is most frequently administered in the inpatient setting. However, with improvements in supportive care, some chemotherapy may be administered in the outpatient setting. Following completion of the treatment cycle, patients are discharged home with detailed instructions for home care and outpatient follow-up visits. 
• Patients who undergo liver transplantation require a multidisciplinary team with experienced hepatologist and liver transplant surgeons as well as the team outlined above.

Further Outpatient Care

• Patients are periodically monitored in the clinic after each course of therapy to assess for complications and response to therapy. 
• Myelosuppression and pancytopenia are common complications, and a CBC count with a platelet count is obtained once or twice weekly.
• Some drugs, such as cisplatin and carboplatin, affect renal function and require close monitoring of electrolytes and oral or parenteral electrolyte supplementation.
• Blood product support is provided when the hemoglobin drops below 8 g/dL, symptoms of anemia are present, the platelet count drops below 10,000 X 10⁹/L, or any signs of bleeding are evident.
• Fever must be treated as a medical emergency during therapy because the risk of a bacterial or fungal infection is high in patients with myelosuppression.
• Children with central lines are susceptible to bacteremia and life-threatening sepsis. In addition, all children with central lines must receive appropriate antimicrobial prophylaxis against subacute bacterial endocarditis (SBE) for all procedures, including dental procedures.
• Close contact with the liver transplant team is required for patients who require this treatment. All medical decisions for patients with this complex condition should be communicated to all members of the team including oncologists, primary surgeon, hepatologists, and transplant surgeons.
• Late effects clinics are available at most major oncology centers, and children with hepatoblastoma should be referred to these clinics if they remain disease free for more than 2 years. Even if the risk of recurrence decreases with time, these children are still at risk for late effects, which include secondary cancers (etoposide and anthracycline), cardiotoxicity (anthracycline), renal toxicity (platinum agents), ototoxicity (platinum agents), and potential speech and developmental delays due to therapy administered.
• Psychosocial team members, child life experts, medical social workers, nutritionists, and all care providers can help families adjust to life after cancer and can also help encourage a cancer preventive lifestyle for these at-risk patients.

In/Out Patient Meds

• Infection prophylaxis: Chemotherapy agents cause myelosuppression and immunosuppression. Prophylaxis against Pneumocystis jiroveci, which causes Pneumocystis carinii pneumonia, is recommended for all patients. The drug of choice is trimethoprim-sulfamethoxazole (2.5 mg/kg/dose of trimethoprim administered orally twice daily) administered on 3 consecutive days per week. Prophylaxis is initiated before chemotherapy and is continued for at least 3 months after completing therapy.
• Colony-stimulating factors: Granulocyte colony-stimulating factor (G-CSF) support has become common in pediatric oncology as the intensity of chemotherapy has increased. The doses recommended are 5-10 mcg/kg/d, starting 24-36 hours after the last dose of chemotherapy. G-CSF administration is continued for 10-14 days or until the absolute neutrophil count (ANC) is greater than 2,000-10,000/mcL.
• Erythropoietin: The use of erythropoietin is discouraged because of reports that hepatoblastoma has receptors for this agent and may therefore be stimulated to grow from exogenous sources.

Transfer

• With supervision by the oncology team, routine care can be performed by the primary care provider for patient convenience. CBC counts and blood chemistries may be obtained and blood products may be administered by primary care providers. 
• Some patients may even be evaluated and treated for febrile neutropenia by the primary care provider. However, the primary care provider must maintain close contact with the subspecialist physicians and transfer the patient to the pediatric oncology center for any complications that require specialized care.

Deterrence/Prevention

• The cause of hepatoblastoma is unknown. Because onset of hepatoblastoma is in patients at a young age, investigators have focused on events before conception and during gestation. Factors for which evidence is limited or inconsistent include medications, hormones, birth characteristics, congenital anomalies, previous spontaneous abortion or fetal death, alcohol consumption, tobacco use, and paternal occupational exposures. 
• Children with hemihypertrophy or BWS and children born to individuals affected by familial adenomatous polyposis (FAP) should be screened regularly using blood AFP levels as dictated in current protocols. Children found to harbor a FAP mutation should be monitored periodically for the development of polyps by a gastroenterologist as they reach the teenage years.

Complications

• At diagnosis: Tumor rupture may occur, resulting in acute abdomen or severe hemorrhage, both of which constitute medical emergencies. Intraoperative and postoperative complications may occur as a result of resection or biopsy procedures.
• During therapy: Complications can develop with the administration of chemotherapy. Myelosuppression and immunosuppression place the patient at risk for bleeding and infection. After several cycles of therapy, organ toxicity may occur; for example, renal function or hearing may be impaired.
• Posttransplantation: Complications due to liver transplantation can develop and require close long-term follow-up by the liver transplant team.
• Long term: Particular attention must be paid to cardiac, renal, and hearing status to assess for the toxic effects of anthracyclines, cisplatin, or carboplatin. Psychosocial effects of frequent painful procedures, hospitalizations, and interference with normal childhood growth and development must be addressed, and children and families must be referred to appropriate specialists when needed. The family's psychosocial needs are affected greatly by having a child with cancer.

Prognosis

• See Mortality/Morbidity.

Patient Education

• Medications: To ensure compliance and good medical care, patient and family understanding regarding the importance of treatment and the toxic effects of the medications is critical. In addition, patients and their families should learn to recognize and identify signs and symptoms of complications that require urgent medical care.
• Long-term follow-up surveillance: After completion of therapy, patients in whom treatment was successful require close surveillance for any signs or symptoms of recurrent disease. Follow-up care includes monitoring AFP levels, physical examination, and diagnostic imaging. Because most recurrences occur during the first 2 years following treatment, most protocols recommend close follow-up monitoring during this interval. Hepatoblastoma does not usually recur more than 3 years after completion of therapy.
• Long-term issues: Growth and development and long-term toxic effects on organs are long-term issues. Patients who remain free of recurrent disease for 5 years are considered cured; long-term follow-up monitoring to assess the impact of therapy on growth, development, and organ toxicity is essential. Patients are usually monitored by pediatric oncologists, but some sequelae may require the involvement of other subspecialist health care providers.
• Other issues: Most centers have late effects clinics, and all children treated for cancer should continue to see their oncology providers regularly to monitor for potential long-term complications of therapy. When appropriate, most centers help transition to an adult provider, with guidelines on what to watch for and which tests should be performed to monitor for potential late effects. A cancer-preventive lifestyle is encouraged and includes avoiding passive or primary tobacco exposure, wearing sunscreen, healthy eating habits, maintaining a healthy weight, and an exercise regimen.

MISCELLANEOUS

Section 9 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Medical/Legal Pitfalls

• Prompt referral to a pediatric oncology center for multidisciplinary evaluation and appropriate care is essential because childhood cancer is a rare disease. The vast majority of patients initially present for evaluation to either the primary care provider or a general surgeon. A surgeon without expertise in the management of pediatric tumors may attempt to perform a biopsy or resection of a mass without the necessary resources to obtain and process tumor samples for histologic and molecular genetics studies. Without these studies, assigning risk and administering appropriate therapy become difficult.
• The field of pediatric oncology has benefited from the high level of patient participation in clinical trials. Pediatric oncologists must be effective in communicating the goals of clinical trial protocols and obtaining informed consent from patients and families. A thorough discussion of the potential benefits and risk of clinical trial participation is warranted. Without compromising the family's enthusiasm and desire to achieve a cure for the patient, the oncologist must make them aware that complications during both the standard of care and clinical trial therapies can result in death.

Special Concerns

• The cornerstone of pediatrics is the prevention and treatment of disease to foster the normal growth and development of children. Use of chemotherapy in infants, children, and adolescents with cancer presents many challenges to the pediatric oncologist, who must strive to maintain a balance between the appropriate administration of curative therapy and the minimization of the long-term toxic effects of that therapy. 
• Understanding the effects that chemotherapy may have on the growth and development of children is important. For example, when administered to infants, cisplatin and carboplatin may have ototoxic effects that affect language development, vincristine may have neurotoxic effects that interfere with motor development, and any chemotherapy agent may cause refractory nausea and emesis that lead to food aversion. Recognizing these sequelae is vital to allowing appropriate intervention. 
• Equally important is the understanding that several physiologic processes during infancy and childhood can affect the pharmacokinetics and pharmacodynamics of drugs. Body composition varies during infancy, childhood, and adolescence. Total body water and extracellular fluid volumes are larger in the first year of life, and blood volume and fat composition do not approach adult levels until adolescence. Protein binding is lower during the first year of life, thereby increasing the amount of unbound drug. These variables affect the distributed volume of drugs; therefore, drug doses are calculated differently in infants. 
• Drug doses in pediatric oncology are calculated most commonly using body surface area (BSA). However, because the BSA is larger in relation to an infant's weight, the use of BSA for dose calculation results in a larger dose per weight in infants than in older children and adults. As a result, many physicians use chemotherapy doses based on weight in kilograms rather than BSA in infants. 
• The practice of altering dosing in infants may be unwise because any rational approach should be based on the pharmacokinetic behavior of each agent. As more is learned about the pharmacokinetics of drugs and their relationship to efficacy and toxicity, the use of pharmacokinetically guided dosing may become more common. 
• Data are lacking concerning the disposition of most antineoplastic agents in young children and infants. However, guidelines are available for doxorubicin, etoposide, teniposide, and VCR. The caveat is that only a small number of infants were included in the studies used to formulate most of these recommendations. In addition, not all studies included analysis of plasma-binding proteins, unbound drug systemic clearance, and other relevant factors.
• Because evidence of increased toxicity with VCR and doxorubicin is lacking, adjustment of dosing by weight rather than BSA is recommended in infants or children younger than 2 years and in those with a BSA less than 0.5 m². Drugs that are excreted via the kidney can have limited clearance in young infants because the percentage of the cardiac output that reaches the kidneys is only 5% in infants, whereas it is 25% in an older child or adult.
• Ifosfamide and, less frequently, cyclophosphamide can cause renal tubular injury manifested as Fanconi syndrome, metabolic acidosis, hypokalemia, hypophosphatemia, proteinuria, or rickets. The chronic nature of these injuries may interfere with normal growth and requires close follow-up monitoring. Cisplatin and, less frequently, carboplatin can cause glomerular injury manifested as acute or chronic decrease in the GFR.
• The heart is another organ at risk for early and late toxic effects. Anthracyclines have been useful in the treatment of a large number of pediatric cancers; however, the use of anthracyclines, especially in high cumulative doses, can lead to development of cardiomyopathy. Several studies have suggested that age is an important risk factor for this complication because these drugs appear to damage cardiac myocytes and limit the heart's ability to grow.
• Several agents (ie, carboplatin, cisplatin, CPM, ifosfamide) require prehydration to achieve adequate renal perfusion, urine filtration, and bladder flow and to avoid delayed excretion or bladder toxicity. The use of high-dose therapy in children frequently results in myelosuppression requiring blood product support. 
• Treatment of infectious diseases is also very important in the pediatric population. Advances in the care and support of the patients with neutropenia who are febrile have improved the survival rate in children. Prophylactic antibiotics commonly are used in patients on immunosuppressive therapy to prevent P carinii pneumonia.
• Drugs that modify the toxicity of antineoplastic agents (mesna, amifostine, leucovorin) and the availability of hematopoietic growth factors (G-CSF, granulocyte-macrophage colony-stimulating factor [GM-CSF]) have allowed the use of the maximally tolerated doses of many chemotherapy agents and the development of more dose-intensive protocols.
• Future directions include the following: 
• • The need for better chemotherapeutic options, with better efficacy and less toxicity, is clear. Bioinformatics and genetic profiling may identify new patterns correlating with prognosis and, thus, potential therapeutic targets. The significance of molecular genetic abnormalities seen in human malignancy is just beginning to be understood, and these molecular abnormalities need to be correlated with a patient's clinical prognosis.
  • Most pediatric chemotherapeutic protocols (eg, COG, SIOP) have incorporated molecular genetic testing of tumor specimens and, in some cases, normal tissues as control. This information is being collected to determine the prognostic significance of oncogene mutations, translocations, gene rearrangements, and tumor suppressor genes, and, in some cases, to determine treatment options. Current research efforts may ultimately identify specific molecular targets that can be used to develop more specific chemotherapeutic agents.
  • Microarray technology currently is being used to determine the molecular profiles of malignancies to better define therapies targeted to specific molecular profiles. Microarray technology was used to analyze patterns of TP53-mediated gene expression, which will undoubtedly contribute to the understanding of how inactivation of this tumor suppressor gene contributes to neoplasia. This information may be used to guide treatment options. Pediatric solid tumors may ultimately be candidates for this type of genetic profiling as well.
  • As physicians gain a better understanding of the molecular abnormalities inherent in cancer cells and critically analyze the prognostic significance and therapeutic implications of the abnormalities, the ability to modify treatment based on this information increases. Sometimes, this means administering more aggressive therapy to patients, thus potentially increasing the chance for long-term survival. At other times, this involves sparing the patient unnecessary toxic effects of therapy. More specifically targeted therapies are likely to have less general systemic toxicity.
  • Identification of the aberrant expression of genes involved in regulation of cellular growth and differentiation and clinical correlation of these abnormalities will likely lead to improvements in therapeutic options for patients with cancer.