Hepatoblastoma

Contents

What is hepatoblastoma

What is hepatoblastoma

Hepatoblastoma is a very rare type of liver cancer that occurs in infants and children accounting for 80% of malignant liver tumors in childhood ¹⁾. Hepatoblastoma typically striking children within the first 3 years of their young lives ²⁾. Hepatoblastoma preferentially affects boys and occurs in infants or very young children at a median age at diagnosis of 16 months ³⁾. Hepatoblastoma incidence is estimated at 1.2–1.5 million children per year, comprising about 1% of all pediatric cancers ⁴⁾. Over the last 3 decades, advances in chemotherapy and newer surgical techniques have improved survival in patients with localized hepatoblastoma, unfortunately, for the 25% of patients with metastasis (hepatoblastoma stage 4), the overall survival remains poor. The treatment has advanced with neo-adjuvant chemotherapy now the standard of care for most cases. Neo-adjuvant chemotherapy and surgical resection produce a cure rate of approximately 70%, a vast improvement over the dismal 30% cure rate in the 1970s ⁵⁾. Prognosis is based on many factors including alpha-fetoprotein (AFP) levels, age at the time of diagnosis, completeness of resection, and clinical stage of the disease ⁶⁾.

What causes hepatoblastoma?

Most cases of hepatoblastoma have unknown cause, but one-third of cases occur in association with specific predisposition syndromes in the setting of normal liver function ⁷⁾. Hepatoblastoma is strongly associated with premature birth, particularly among low birth weight neonates that weigh < 1,000 g ⁸⁾. Hepatoblastoma occurs in children from families affected by familial adenomatous polyposis (FAP), which is associated with an inherited germ line mutation of the adenomatous polyposis coli (APC) gene ⁹⁾. This mutation is also seen in association with Beckwith-Wiedemann syndrome, with which the relative risk of hepatoblastoma is estimated to be 2,280 ¹⁰⁾. Hepatoblastoma has also been observed in patients with Li-Fraumeni syndrome, Edward syndrome (trisomy 18), nephroblastoma, and Down syndrome (trisomy 21) ¹¹⁾. Evidence has also shown an association with preeclampsia and parental tobacco smoking before and during pregnancy ¹²⁾. Other factors thought to play a role in pathogenesis include oxygen therapy, certain medication (furosemide), radiation, plasticizers, and total parenteral nutrition (TPN) ¹³⁾.

The most common genetic mutation involves the Wnt signaling pathway which results in the accumulation of beta-catenin; these mutations are present in a higher proportion of the sporadic cases ¹⁴⁾. By immunohistochemistry, beta-catenin usually shows a membranous staining pattern in the more differentiated fetal types and nuclear staining pattern in the less differentiated histologic types ¹⁵⁾. In aggressive cases, activation of TERT (human telomerase reverse transcriptase) and MYC signaling has been shown ¹⁶⁾.

An American Association for Cancer Research publication suggested that all children with more than a 1% risk of developing hepatoblastoma be screened ¹⁷⁾. This includes patients with Beckwith-Wiedemann, hemihyperplasia, Simpson-Golabi-Behmel, and trisomy 18 syndromes. Screening is by abdominal ultrasound and alpha-fetoprotein determination every 3 months from birth (or diagnosis) through the fourth birthday, which will identify 90% to 95% of hepatoblastomas that develop in these children ¹⁸⁾.

Risk factors for hepatoblastoma

Conditions associated with an increased risk of hepatoblastoma are described in Table 1.

Table 1. Conditions associated with hepatoblastoma

Associated Disorder	Clinical Findings
Aicardi syndrome ¹⁹⁾	Refer to the Aicardi syndrome section of this summary for more information.
Beckwith-Wiedemann syndrome ²⁰⁾	Refer to the Beckwith-Wiedemann syndrome and hemihyperplasia section of this summary for more information.
Familial adenomatous polyposis ²¹⁾	Refer to the Familial adenomatous polyposis section of this summary for more information.
Glycogen storage diseases I–IV ²²⁾	Symptoms vary by individual disorder.
Low-birth-weight infants ²³⁾	Preterm and small-for-gestation-age neonates.
Simpson-Golabi-Behmel syndrome ²⁴⁾	Macroglossia, macrosomia, renal and skeletal abnormalities, and increased risk of Wilms tumor.
Trisomy 18, other trisomies ²⁵⁾	Trisomy 18: Microcephaly and micrognathia, clenched fists with overlapping fingers, and failure to thrive. Most patients (>90%) die in the first year of life.

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Aicardi syndrome

Aicardi syndrome is presumed to be an X-linked condition reported exclusively in females, leading to the hypothesis that a mutated gene on the X chromosome causes lethality in males. The syndrome is classically defined as agenesis of the corpus callosum, chorioretinal lacunae, and infantile spasms, with a characteristic facies. Additional brain, eye, and costovertebral defects are often found ²⁷⁾.

Beckwith-Wiedemann syndrome and hemihyperplasia

The incidence of hepatoblastoma is increased 1,000-fold to 10,000-fold in infants and children with Beckwith-Wiedemann syndrome ²⁸⁾. The risk of hepatoblastoma is also increased in patients with hemihyperplasia, previously termed hemihypertrophy, a condition that results in asymmetry between the right and left side of the body when a body part grows faster than normal ²⁹⁾.

Beckwith-Wiedemann syndrome is most commonly caused by epigenetic changes and is sporadic. The syndrome may also be caused by genetic mutations and be familial. Either mechanism can be associated with an increased incidence of embryonal tumors, including Wilms tumor and hepatoblastoma ³⁰⁾. The expression of both IGFR2 alleles and ensuing increased expression of insulin-like growth factor 2 (IGF-2) has been implicated in the macrosomia and embryonal tumors seen in patients with Beckwith-Wiedemann syndrome ³¹⁾. When sporadic, the types of embryonal tumors associated with Beckwith-Wiedemann syndrome have frequently also undergone somatic changes in the Beckwith-Wiedemann syndrome locus and IGF-2 ³²⁾. The genetics of tumors in children with hemihyperplasia have not been clearly defined.

To detect abdominal malignancies at an early stage, all children with Beckwith-Wiedemann syndrome or isolated hemihyperplasia are screened regularly for multiple tumor types by abdominal ultrasonography ³³⁾. Screening using alpha-fetoprotein (AFP) levels has also been quite helpful in the early detection of hepatoblastoma in these children ³⁴⁾. Because the hepatoblastomas that are discovered early are small, it has been suggested to minimize the use of adjuvant therapy after surgery ³⁵⁾. However, a careful compilation of published data on 1,370 children with (epi)genotyped Beckwith-Wiedemann syndrome demonstrated that the prevalence of hepatoblastoma was 4.7% in those with Beckwith-Wiedemann syndrome caused by chromosome 11p15 paternal uniparental disomy, less than 1% in the two types of alteration in imprinting control regions, and absent in CDKN1C mutation ³⁶⁾. The authors recommended that only children with Beckwith-Wiedemann syndrome caused by uniparental disomy be screened for hepatoblastoma using abdominal ultrasonography and AFP levels every 3 months from age 3 months to 5 years.

Familial adenomatous polyposis

There is an association between hepatoblastoma and familial adenomatous polyposis (FAP); children in families that carry the APC gene have an 800-fold increased risk of hepatoblastoma. However, hepatoblastoma has been reported to occur in less than 1% of FAP family members, so screening for hepatoblastoma in members of families with FAP using ultrasonography and AFP levels is controversial ³⁷⁾. However, one study of 50 consecutive children with apparent sporadic hepatoblastoma reported that five children (10%) had APC germline mutations ³⁸⁾.

Current evidence cannot rule out the possibility that predisposition to hepatoblastoma may be limited to a specific subset of APC mutations. Another study of children with hepatoblastoma found a predominance of the mutation in the 5′ region of the gene, but some patients had mutations closer to the 3′ region ³⁹⁾. This preliminary study provides some evidence that screening children with hepatoblastoma for APC mutations and colon cancer may be appropriate.

In the absence of APC germline mutations, childhood hepatoblastomas do not have somatic mutations in the APC gene; however, hepatoblastomas frequently have mutations in the beta-catenin gene, the function of which is closely related to APC ⁴⁰⁾.

Hepatoblastoma histopathology

The cells of hepatoblastoma are similar to fetal liver cells. The histologic types are subdivided into 2 broad categories: epithelial type and mixed type ⁴¹⁾. Hepatoblastomas originate from primitive hepatic stem cells that give rise to the epithelial components of the liver. Classically, these tumors are divided into 2 broad categories: epithelial type (E-HB) and mixed epithelial and mesenchymal type (MEM-HB). Revision of this original classification system resulted in the pathology consensus of the pediatric hepatoblastoma classification system, which retained the subdivision of the histologic types into 2 broad categories, as described above. The epithelial type is subdivided into fetal, embryonal, macrotrabecular small cell undifferentiated and cholangioblastic variants, while the mixed type is subdivided into stromal derivatives and teratoid variants.

The fetal subtype is further stratified into 4 categories: well-differentiated; crowded or mitotically active; pleomorphic, poorly differentiated; and anaplastic. The well-differentiated variant is characterized by a low power view demonstrating alternating light and dark areas due to variable cytoplasmic glycogen content. Assessment at higher power reveals a uniform population of hepatocytes arranged in trabeculae that are 2to 3 cells thick. Extramedullary hematopoiesis is a typical finding, and mitotic rate is low. Description of the other variants is beyond the scope of this article.

The embryonal subtype is the most commonly encountered subtype and consists of basophilic cells with scant cytoplasm and increased mitotic rate that is arranged in nests, trabeculae, acini, pseudorosettes, or sheets. The macrotrabecular subtype is arranged in trabeculae that are more than ten cells thick. The SCU subtype consists of dyscohesive, uniform round cells arranged in sheets with increased mitotic activity. Some cases of SCU have a loss of INI1, suggesting a possible association with primary rhabdoid tumors of the liver. The cholangioblastic variant has bile ducts, typically located at the periphery of the epithelial sheets.

The mixed subtype contains a variable combination of epithelial and mesenchymal components. Most commonly, the epithelial component is fetal or embryonal, and the mesenchymal component is osteoid. Stromal derivatives include spindle cells, osteoid, skeletal muscle, and cartilage. Teratoid features include primitive endoderm, neural derivatives, melanin, squamous and glandular elements ⁴²⁾.

Hepatoblastoma symptoms

Hepatoblastomas usually present with as a single, mildly painful, rapidly enlarging abdominal mass that arises in the right lobe of the liver in 55% to 60% of cases ⁴³⁾. Rapid enlargement of these tumors rarely results in tumor rupture and hemorrhage. Hepatoblastoma tumors may reach up to 25 cm in size. Most tumors are solitary; however, up to 15% of tumors are multifocal. Some cases are associated with non-specific symptoms such as weight loss, failure to thrive or anorexia ⁴⁴⁾. Significant elevations of alpha-fetoprotein (AFP) are observed in 90% of patients, and rarely, a paraneoplastic syndrome can occur.

Hepatoblastoma complications

Hepatoblastoma complications include:

Intraperitoneal tumor rupture
Complications related to chemotherapy
Post-transplant complications
Psychosocial effects of treatment and painful procedures

Hepatoblastoma diagnosis

Ultrasound and either computed tomography (CT) or magnetic resonance imaging (MRI) are the imaging modalities used to define the extent of tumor involvement of the liver and aid in pre-surgical planning. A chest CT can help detect lung metastasis as up to 20% of cases present with metastases; the lung is the most common location of metastases ⁴⁵⁾. After imaging, a biopsy, alpha-fetoprotein (AFP) level, liver function tests, and a hepatitis panel are performed as needed.

Biopsy

A biopsy of a pediatric liver tumor is always indicated to secure the diagnosis of a liver tumor, with the exception of the following circumstances:

Infantile hepatic hemangioma. Biopsy is not indicated in infantile hemangioma of the liver with classic findings on magnetic resonance imaging (MRI). If the diagnosis is in doubt after high-quality imaging, a confirmatory biopsy is done.
Focal nodular hyperplasia. Biopsy may not be indicated or may be delayed in focal nodular hyperplasia with classic features on MRI using hepatocyte-specific contrast agent. If the diagnosis is in doubt, a confirmatory biopsy is done.
Children’s Oncology Group (COG) surgical guidelines ⁴⁶⁾ recommend tumor resection at diagnosis without preoperative chemotherapy in children with PRE-Treatment EXTent of disease (PRETEXT) group I tumors and PRETEXT group II tumors with greater than 1 cm radiographic margin on the vena cava and middle hepatic and portal veins. Therefore, biopsy is not usually recommended in this circumstance.
Infantile hepatic choriocarcinoma. In infantile hepatic choriocarcinoma, which can be diagnosed by imaging and markedly elevated beta-human chorionic gonadotropin (beta-hCG), chemotherapy without biopsy is often indicated ⁴⁷⁾.

Tumor markers

The AFP and beta-hCG tumor markers are very helpful in the diagnosis and management of liver tumors. Although AFP is elevated in most children with hepatic malignancy, it is not pathognomonic for a malignant liver tumor ⁴⁸⁾. The AFP level can be elevated with either a benign tumor or a malignant solid tumor. AFP is very high in neonates and steadily falls after birth. The half-life of AFP is 5 to 7 days, and by age 1 year, it should be less than 10 ng/mL ⁴⁹⁾.

Hepatoblastoma staging

The Children’s Hepatic Tumors International Collaboration constructed a staging and risk stratification system intended to standardize the assessment of hepatoblastoma cancer across the globe. This new staging system is called the Children’s Hepatic Tumors International Collaboration – Hepatoblastoma Stratification and incorporates confirmed prognostic factors from prior risk stratification systems with new additional factors to stratify patients into 4 risk groups.

Found to be most predictive are alpha-fetoprotein (AFP) levels, patient age, Pretreatment Extent of Disease (PRETEXT) group (I, II, III, or IV), the presence of metastases, and PRETEXT annotation factor. PRETEXT group is based on the extent of the tumor in the liver. PRETEXT annotation factor is determined to be positive if at least 1 of the following 5 factors are present: involvement of the vena cava or all 3 hepatic veins, or both (V); involvement of portal bifurcation or both right and left portal veins, or both (P); extrahepatic contiguous tumor extension (E); multifocal liver tumor (F); tumor rupture at diagnosis (R). Gender, low birth weight, prematurity, and Beckwith-Wiedemann syndrome were not found to be significant. Of note, the histologic type was not included in this risk stratification system but may be incorporated at a future date. Validation of these risk groups is in progress ⁵⁰⁾.

Table 2. Definitions of PRETEXT/POST-TEXT group (I, II, II, IV) and PRETEXT grouping system annotations V,P,E,M,C,F,N,R.

PRETEXT/POST-text group	Definition
I	One liver section involved
	Three adjoining sections are tumor free
II	One or two liver sections involved
	Two adjoining sections are tumor free
III	Two or three liver sections involved
	One adjoining section is tumor free
IV	Four liver sections involved
*Annotation:*
V	Venous involvement, V, denotes vascular involvement of the retrohepatic vena cava or involvement of ALL THREE major hepatic veins (right, middle, and left)
P	Portal involvement, P, denotes vascular involvement of the main portal vein and/or BOTH right and left portal veins
E	Extrahepatic involvement of a contiguous structure such as the diaphragm, abdominal wall, stomach, colon, etc.
M	Distant metastatic disease (usually lungs, occasionally bone or brain)
C	Caudate lobe
F	Multifocal tumor nodules
N	Lymph node involvement
R	Tumor rupture

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Hepatoblastoma prognostic factors

Individual childhood cancer study groups have attempted to define the relative importance of a variety of prognostic factors present at diagnosis and in response to therapy ⁵²⁾. A collaborative group consisting of four study groups (International Childhood Liver Tumors Strategy Group [SIOPEL], Children’s Oncology Group, Gesellschaft für Pädiatrische Onkologie und Hämatologie [GPOH], and Japanese Study Group for Pediatric Liver Tumor [JPLT]), termed Childhood Hepatic tumor International Collaboration (CHIC), have retrospectively combined data from eight clinical trials (N = 1,605) conducted between 1988 and 2010. The CHIC published a univariate analysis of the effect of clinical prognostic factors present at the time of diagnosis on event-free survival (EFS) ⁵³⁾. The analysis confirmed many of the findings described below. The statistically significant adverse factors included the following ⁵⁴⁾:

Higher PRETEXT group.
Positive PRETEXT annotation factors:
- V: Involvement all three hepatic veins and/or intrahepatic inferior vena cava.
- P: Involvement of both left and right portal veins.
- E: Contiguous extrahepatic tumor extensions (e.g., diaphragm, adjacent organs).
- F: Multifocal tumors.
- R: Tumor rupture.
- M: Distant metastases, usually lung.
Low AFP level (<100 ng/mL or 100–1,000 ng/mL to account for infants with elevated AFP levels) ⁵⁵⁾.
Older age. Patients aged 3 to 7 years have a worse outcome in the PRETEXT IV group ⁵⁶⁾. Patients aged 8 years and older have a worse outcome than do younger patients in all PRETEXT groups.
In contrast, in the SIOPEL-2 and -3 studies, infants younger than 6 months had PRETEXT, annotation factors, and outcomes similar to that of older children undergoing the same treatment ⁵⁷⁾.

In contrast, sex, prematurity, birth weight, and Beckwith-Wiedemann syndrome had no effect on event-free survival ⁵⁸⁾.

A multivariate analysis of these prognostic factors has been published to help develop a new risk group classification for hepatoblastoma ⁵⁹⁾. This classification was used to generate a risk stratification schema to be used in international clinical trials.

Other studies of factors affecting prognosis observed the following:

PRETEXT group: In SIOPEL studies, having a low PRETEXT group at diagnosis (PRETEXT I, II, and III tumors) is a good prognostic factor, whereas PRETEXT IV is a poor prognostic factor.[42] (Refer to the Tumor Stratification by Imaging and Evans Surgical Staging for Childhood Liver Cancer section of this summary for more information.)
Tumor stage: In Children’s Oncology Group studies, stage I tumors that were resected at diagnosis and tumors with well-differentiated fetal histology have a good prognosis. These tumors are treated differently than tumors of other stages and histologies ⁶⁰⁾.
Treatment-related factors:
- Chemotherapy: Chemotherapy often decreases the size and extent of hepatoblastoma, allowing complete resection.[45-49] Favorable response of the primary tumor to chemotherapy, defined as either a 30% decrease in tumor size by Response Evaluation Criteria In Solid Tumors (RECIST) or 90% or greater decrease in AFP levels, predicted the resectability of the tumor; in turn, this favorable response predicted overall survival among all CHIC risk groups treated with neoadjuvant chemotherapy on the JPLT-2 Japanese national clinical trial.[50][Level of evidence: 2A]
- Surgery: Cure of hepatoblastoma requires gross tumor resection. Hepatoblastoma is most often unifocal and thus, resection may be possible. If a hepatoblastoma is completely removed, most patients survive, but because of vascular or other involvement, less than one-third of patients have lesions amenable to complete resection at diagnosis ⁶¹⁾. Thus, it is critically important that a child with probable hepatoblastoma be evaluated by a pediatric surgeon; the surgeon should be experienced in the techniques of extreme liver resection with vascular reconstruction and have access to a liver transplant program. In advanced tumors, surgical treatment of hepatoblastoma is a demanding procedure. Postoperative complications in high-risk patients decrease the rate of overall survival ⁶²⁾. Orthotopic liver transplant is an additional treatment option for patients whose tumor remains unresectable after preoperative chemotherapy ⁶³⁾; however, the presence of microscopic residual tumor at the surgical margin does not preclude a favorable outcome ⁶⁴⁾. This may be due to the additional courses of chemotherapy that are administered before or after resection ⁶⁵⁾.
Tumor marker–related factors: Ninety percent of children with hepatoblastoma and two-thirds of children with hepatocellular carcinoma exhibit the serum tumor marker AFP, which parallels disease activity. The level of AFP at diagnosis and rate of decrease in AFP levels during treatment are compared with the age-adjusted normal range. Lack of a significant decrease in AFP levels with treatment may predict a poor response to therapy ⁶⁶⁾. Absence of elevated AFP levels at diagnosis (AFP <100 ng/mL) occurs in a small percentage of children with hepatoblastoma and appears to be associated with very poor prognosis, as well as with the small cell undifferentiated variant of hepatoblastoma.[42] Some of these variants do not express INI1 and may be considered rhabdoid tumors of the liver; all small cell undifferentiated hepatoblastomas are tested for loss of INI1 expression by immunohistochemistry ⁶⁷⁾. Beta-hCG levels may also be elevated in children with hepatoblastoma or hepatocellular carcinoma, which may result in isosexual precocity in boys ⁶⁸⁾.
Tumor histology.

Other variables have been suggested as poor prognostic factors, but the relative importance of their prognostic significance has been difficult to define. In the SIOPEL-1 study, a multivariate analysis of prognosis after positive response to chemotherapy showed that only one variable, PRETEXT, predicted OS, while metastasis and PRETEXT predicted event-free survival ⁶⁹⁾. In an analysis of the intergroup U.S. study from the time of diagnosis, well-differentiated fetal histology, small cell undifferentiated histology, and AFP less than 100 ng/mL were prognostic in a log rank analysis. PRETEXT was prognostic among patients designated group III, but not group IV ⁷⁰⁾.

Hepatoblastoma treatment

Treatment options for newly diagnosed hepatoblastoma depend on the following:

Whether the cancer is resectable at diagnosis.
The tumor histology.
How the cancer responds to chemotherapy.
Whether the cancer has metastasized.

Surgical resection is the mainstay of treatment with resectability of the tumor determining the need for neo-adjuvant or adjuvant chemotherapy. At presentation, approximately 60% of tumors are unresectable ⁷¹⁾. If unresectable and chemotherapy fails to shrink the tumor to a resectable size, a liver transplant can be done and has a good long-term survival rate ⁷²⁾. The benefit of radiation therapy is unclear, with some unresectable cases responding well. Alpha-fetoprotein levels are useful for tracking surgical success and whether the tumor has metastasized ⁷³⁾. An increased risk of post-transplant lymphoproliferative disorder after immunosuppression for liver transplant has been suggested in some publications ⁷⁴⁾.

Cisplatin-based chemotherapy has resulted in a survival rate of more than 90% for children with PRETEXT and POST-Treatment EXTent (POSTTEXT) I and II resectable disease before or after chemotherapy ⁷⁵⁾.

Chemotherapy regimens used in the treatment of hepatoblastoma and their respective outcomes are described in Table 3.

Table 3. Outcomes for Hepatoblastoma Multicenter Trials

Study	Chemotherapy Regimen	Number of Patients	Outcomes
INT0098 (CCG/POG) 1989–1992	C5V vs. CDDP/DOXO	Stage I/II: 50	4-Year Event-Free Survival/Overall Survival:
		Stage I/II: 50	I/II = 88%/100% vs. 96%/96%
		Stage III: 83	III = 60%/68% vs. 68%/71%
		Stage IV: 40	IV = 14%/33% vs. 37%/42%
P9645 (COG)^b 1999–2002	C5V vs. CDDP/CARBO	Stage I/II: Pending publication	1-Year Event-Free Survival:
		Stage I/II: Pending publication	I/II: Pending publication
		Stage III: 38	III/IV: C5V = 51%; CDDP/CARBO = 37%
		Stage IV: 50	III/IV: C5V = 51%; CDDP/CARBO = 37%
HB 94 (GPOH) 1994–1997	I/II: IFOS/CDDP/DOXO	Stage I: 27	4-Year Event-Free Survival/Overall Survival:
		Stage I: 27	I = 89%/96%
		Stage II: 3	II = 100%/100%
	III/IV: IFOS/CDDP/DOXO + VP/CARBO	Stage III: 25	III = 68%/76%
	III/IV: IFOS/CDDP/DOXO + VP/CARBO	Stage IV: 14	IV = 21%/36%
HB 99 (GPOH) 1999–2004	SR: IPA	SR: 58	3-Year Event-Free Survival/Overall Survival:
	SR: IPA	SR: 58	SR = 90%/88%
	HR: CARBO/VP16	HR: 42	HR = 52%/55%
SIOPEL-2 1994–1998	SR: PLADO	PRETEXT I: 6	3-Year Event-Free Survival/Overall Survival:
		PRETEXT I: 6	SR: 73%/91%
		PRETEXT II: 36
		PRETEXT III: 25
	HR: CDDP/CARBO/DOXO	PRETEXT IV: 21	HR: IV = 48%/61%
	HR: CDDP/CARBO/DOXO	Metastases: 25	HR: metastases = 36%/44%
SIOPEL-3 1998–2006	SR: CDDP vs. PLADO	SR: PRETEXT I: 18	3-Year Event-Free Survival/Overall Survival:
		SR: PRETEXT I: 18	SR: CDDP = 83%/95%; PLADO = 85%/93%
		PRETEXT II: 133
		PRETEXT III: 104
	HR: SUPERPLADO	HR: PRETEXT IV: 74	HR: Overall = 65%/69%
		VPE+: 70
		Metastases: 70	Metastases = 57%/63%
		AFP <100 ng/mL: 12
SIOPEL-4 2005–2009	HR: Block A: Weekly; CDDP/3 weekly DOXO; Block B: CARBO/DOXO	PRETEXT I: 2	3-Year Event-Free Survival/OS:
		PRETEXT I: 2	All HR = 76%/83%
		PRETEXT II: 17
		PRETEXT III: 27
		PRETEXT IV: 16	HR: IV = 75%/88%
		Metastases: 39	HR: Metastases = 77%/79%
JPLT-1 1991–1999	I/II: CDDP(30)/THP-DOXO	Stage I: 9	5-Year Event-Free Survival/Overall Survival:
		Stage I: 9	I = NR/100%
		Stage II: 32	II = NR/76%
	III/IV: CDDP(60)/THP-DOXO	Stage IIIa: 48	IIIa = NR/50%
		Stage IIIb: 25	IIIb = NR/64%
		Stage IV: 20	IV = NR/77%
JPLT-2 1999–2010	I: Low-dose CDDP-pirarubicin	PRETEXT I–IV: 212	5-Year Event-Free Survival/Overall Survival:
	I: Low-dose CDDP-pirarubicin		I = NR/100%
	II–IV: CITA		II = NR/89%
			III = NR/93%
			IV = NR/63%
	Metastases: High dose chemotherapy + stem cell transplant		Metastases = 32%

Abbreviations: AFP = alpha-fetoprotein; C5V = cisplatin, 5-fluorouracil (5FU), and vincristine; CARBO = carboplatin; CCG = Children’s Cancer Group; CDDP = cisplatin; CITA = pirarubicin-cisplatin; COG = Children’s Oncology Group; DOXO = doxorubicin; EFS = event-free survival; GPOH = Gesellschaft für Pädiatrische Onkologie und Hämatologie (Society for Paediatric Oncology and Haematology); HR = high risk; IFOS = ifosfamide; IPA = ifosfamide, cisplatin, and doxorubicin; JPLT = Japanese Study Group for Pediatric Liver Tumor; NR = not reported; OS = overall survival; PLADO = cisplatin and doxorubicin; POG = Pediatric Oncology Group; PRETEXT = PRE-Treatment EXTent of disease; SIOPEL = International Childhood Liver Tumors Strategy Group; SR = standard risk; SUPERPLADO = cisplatin, doxorubicin, and carboplatin; THP = tetrahydropyranyl-adriamycin (pirarubicin); VP = vinorelbine and cisplatin; VPE+ = venous, portal, and extrahepatic involvement; VP16 = etoposide.

Footnote: (a) Adapted from Czauderna et al. ⁷⁶⁾ and Meyers et al. ⁷⁷⁾; (b) Study closed early because of inferior results in the CDDP/CARBO arm.

Treatment options for hepatoblastoma that is not resectable or not resected at diagnosis

Approximately 70% to 80% of children with hepatoblastoma have tumors that are not resected at diagnosis. Children’s Oncology Group (COG) surgical guidelines recommend biopsy without an attempt to resect the tumor at diagnosis in children with PRETEXT II tumors with less than 1 cm radiographic margin on the vena cava and middle hepatic vein and in all children with PRETEXT III and IV tumors.

Tumor rupture at presentation, resulting in major hemorrhage that can be controlled by transcatheter arterial embolization or partial resection to stabilize the patient, does not preclude a favorable outcome when followed by chemotherapy and definitive surgery ⁷⁸⁾.

Treatment options for hepatoblastoma that is not resectable or is not resected at diagnosis include the following:

Chemotherapy followed by reassessment of surgical resectability and complete surgical resection.
Chemotherapy followed by reassessment of surgical resectability and orthotopic liver transplant ⁷⁹⁾.
Transarterial chemoembolization (TACE). TACE may be used to improve resectability before definitive surgical approaches ⁸⁰⁾.

In recent years, almost all children with hepatoblastoma have been treated with chemotherapy, and in European centers, children with resectable hepatoblastoma are treated with preoperative chemotherapy, which may reduce the incidence of surgical complications at the time of resection ⁸¹⁾. Treatment with preoperative chemotherapy has been shown to benefit children with hepatoblastoma. In contrast, an American intergroup study of treatment of children with hepatoblastoma encouraged resection at the time of diagnosis for all tumors amenable to resection without undue risk. The study (COG-P9645) did not treat children with stage I tumors of well-differentiated fetal histology with preoperative or postoperative chemotherapy unless they developed progressive disease ⁸²⁾. In this study, most patients with PRETEXT III and all PRETEXT IV tumors were treated with chemotherapy before resection or transplant.

Patients whose tumors remain unresectable after chemotherapy should be considered for liver transplant ⁸³⁾. In the presence of features predicting unresectability, early coordination with a pediatric liver transplant service is critical ⁸⁴⁾. In the COG AHEP0731 (NCT00980460) study, early referral (i.e., based on imaging done after the second cycle of chemotherapy) to a liver specialty center with liver transplant capability was recommended for patients with POSTTEXT III tumors with positive V or P and POSTTEXT IV tumors with positive F.

Evidence (chemotherapy followed by reassessment of surgical resectability and complete surgical resection):

In the SIOPEL-1 study, preoperative chemotherapy (doxorubicin and cisplatin) was given to all children with hepatoblastoma with or without metastases. After chemotherapy, and excluding those who underwent a liver transplant (<5% of patients), complete resection was performed ⁸⁵⁾.
- The chemotherapy was well tolerated.
- Complete resection was obtained in 87% of children.
- This strategy resulted in an overall survival rate of 75% at 5 years after diagnosis.
Identical results were seen in a follow-up international study (SIOPEL-2) ⁸⁶⁾.
The SIOPEL-3 study compared cisplatin alone with cisplatin and doxorubicin in patients with preoperative standard-risk hepatoblastoma. Standard risk was defined as tumor confined to the liver and not involving more than three sectors ⁸⁷⁾.
- The rates of resection were similar for the cisplatin (95%) and cisplatin/doxorubicin (93%) groups.
- The overall survival rates were also similar for the cisplatin (95%) and cisplatin/doxorubicin (93%) groups.
In a pilot study, SIOPEL-3HR, cisplatin alternating with carboplatin/doxorubicin was administered in a dose-intensive fashion to high-risk patients with hepatoblastoma ⁸⁸⁾.
- In 74 patients with PRETEXT IV tumors, 22 of whom also had metastases, 31 became resectable and 26 underwent transplant. The 3-year overall survival of this group was 69% (± 11%).
- Of the 70 patients with metastases enrolled in the trial, the 3-year event-free survival rate was 56% and the overall survival rate was 62%. Of patients with lung metastases, 50% were able to achieve complete remission of metastases with chemotherapy alone (without lung surgery).
SIOPEL-4 (NCT00077389) was a multinational feasibility trial of dose-dense cisplatin/doxorubicin chemotherapy and radical surgery for a group of children with high-risk hepatoblastoma. Surgical removal of all remaining tumor lesions after chemotherapy was performed if feasible (including liver transplant and metastasectomy, if needed). Patients whose tumors were resected or whose livers were transplanted after three cycles of chemotherapy subsequently received two postoperative cycles of carboplatin and doxorubicin. Patients whose tumors remained unresectable after three cycles of chemotherapy received two cycles of very intensive carboplatin and doxorubicin before surgery. The primary tumor masses were identified as PRETEXT II (27%), III (44%), and IV (26%) ⁸⁹⁾.
- Ninety-seven percent of patients (60 of 61) had a partial response with chemotherapy.
- Eighty-five percent of patients (53) underwent complete macroscopic resection; tumor was microscopically present in five patients, all of whom are disease-free survivors.
- Two patients died postoperatively.
- There were 37 partial hepatectomies and 16 liver transplants.
- The study had a total of 62 high-risk patients; 74% of patients (62%–84%) underwent resection. The 3-year disease-free survival (DFS) was 76% and the 3-year overall survival was 83%.
- Of the 16 PRETEXT IV patients, 11 were downstaged after chemotherapy—6 patients to PRETEXT III, 4 patients to PRETEXT II, and 1 patient to PRETEXT I. Twelve tumors became resectable; of these, four patients underwent a partial hepatectomy and eight patients underwent a liver transplant. For patients who presented with PRETEXT IV disease, the 3-year disease-free survival (DFS) was 73% and the 3-year overall survival was 80%.
In approximately 75% of children and adolescents with initially unresectable hepatoblastoma, tumors can be rendered resectable with cisplatin-based preoperative chemotherapy, and 60% to 65% will survive disease-free ⁹⁰⁾.
A combination of ifosfamide, cisplatin, and doxorubicin followed by postinduction resection has also been used in the treatment of advanced-stage disease ⁹¹⁾.

In the United States, unresectable tumors have been treated with chemotherapy before resection or transplant ⁹²⁾. On the basis of radiographic imaging, most stage III and IV hepatoblastomas are rendered resectable after two cycles of chemotherapy ⁹³⁾. Some European centers have also used extended resection of selected POSTTEXT III and IV tumors rather than liver transplant ⁹⁴⁾.

Chemotherapy followed by transarterial chemoembolization (TACE) followed by high-intensity focused ultrasound showed promising results in China for PRETEXT III and IV patients with hepatoblastoma, some of whom were resectable but did not undergo surgical resection because of parent refusal ⁹⁵⁾.

Treatment options for hepatoblastoma with metastases at diagnosis

The outcomes of patients with metastatic hepatoblastoma at diagnosis are poor, but long-term survival and cure is possible ⁹⁶⁾. Survival rates at 3 to 5 years range from 20% to 79% ⁹⁷⁾. To date, the best outcomes for children with metastatic hepatoblastoma resulted from treatment with dose-dense cisplatin and doxorubicin, although significant toxicity was also noted (SIOPEL-4 [NCT00077389] trial) ⁹⁸⁾.

Treatment options for hepatoblastoma with metastases at diagnosis include the following:

Chemotherapy followed by reassessment of surgical resectability.
- If the primary tumor and extrahepatic disease (usually pulmonary nodules) are resectable after chemotherapy, surgical resection followed by additional chemotherapy.
- If extrahepatic metastatic disease is in complete remission after chemotherapy and/or surgical resection of lung nodule but the primary tumor remains unresectable, orthotopic liver transplant.
- If extrahepatic metastatic disease is not resectable or the patient is not a transplant candidate, additional chemotherapy, transarterial chemoembolization (TACE), or radiation therapy.

The standard combination chemotherapy regimen in North America is four courses of cisplatin/vincristine/fluorouracil ⁹⁹⁾ or doxorubicin/cisplatin ¹⁰⁰⁾ followed by attempted complete tumor resection. If the tumor is completely removed, two postoperative courses of the same chemotherapy are usually given. Study results for different chemotherapy regimens have been reported.

High-dose chemotherapy with stem cell rescue does not appear to be more effective than standard multiagent chemotherapy ¹⁰¹⁾.

Evidence (chemotherapy to treat metastatic disease at diagnosis):

A subset of 39 patients presenting with metastases were entered on the SIOPEL-4 (NCT00077389) trial, a multinational feasibility trial of dose-dense cisplatin/doxorubicin chemotherapy and radical surgery for a group of children with high-risk hepatoblastoma. Patients whose tumors were resected or livers transplanted after three cycles of chemotherapy subsequently received two postoperative cycles of carboplatin and doxorubicin. Patients whose tumors were unresectable after three cycles of chemotherapy received two additional cycles of very intensive carboplatin and doxorubicin before surgery ¹⁰²⁾.
- After three cycles of chemotherapy, there was a complete response (only in the metastases) in 20 of 39 patients and a partial response in 18 of 39 patients. Nineteen of the patients who achieved a complete response were alive without disease 3 years after diagnosis.
- Of the patients who achieved a partial response, seven patients underwent metastasectomy near the time of resection or liver transplant, with an OS of 100%. An additional seven patients with residual small pulmonary nodules underwent resection without metastasectomy; of those, six patients did well and one patient recurred.
- Two patients with initial metastases eventually recurred.
- Liver transplant, rather than resection alone, was needed to treat 7 of the 39 patients who presented with metastases.
- For the subset of 39 patients presenting with metastases, the 3-year disease-free survival was 77% and the overall survival was 79%.

In patients with resected primary tumors, any remaining pulmonary metastasis is surgically removed, if possible ¹⁰³⁾. A review of patients treated on a U.S. intergroup trial suggested that resection of metastasis may be done at the time of resection of the primary tumor ¹⁰⁴⁾.

If extrahepatic disease is in complete remission after chemotherapy, and the primary tumor remains unresectable, an orthotopic liver transplant may be performed ¹⁰⁵⁾.

The outcome results are discrepant for patients with lung metastases at diagnosis who undergo orthotopic liver transplant after complete resolution of lung disease in response to pretransplant chemotherapy. Some studies have reported favorable outcomes for these groups ¹⁰⁶⁾, while others have noted high rates of hepatoblastoma recurrence ¹⁰⁷⁾. All of these studies are limited by small patient numbers; additional study is needed to better define outcomes for this subset of patients. Recent clinical trials have resulted in few pulmonary recurrences in children who underwent liver transplants and presented with metastatic disease ¹⁰⁸⁾.

If extrahepatic disease is not resectable after chemotherapy or the patient is not a transplant candidate, alternative treatment approaches include the following:

Nonstandard chemotherapy agents. Nonstandard chemotherapy agents such as irinotecan, high-dose cisplatin/etoposide, or continuous-infusion doxorubicin have been used ¹⁰⁹⁾.
Hepatic arterial chemoembolization (HACE) or transarterial chemoembolization (TACE) ¹¹⁰⁾.
Radiation therapy ¹¹¹⁾.

Treatment options for progressive or recurrent hepatoblastoma

The prognosis for a patient with progressive or recurrent hepatoblastoma depends on several factors, including the following ¹¹²⁾:

Site of recurrence.
Previous treatment.
Individual patient considerations.

Treatment options for progressive or recurrent hepatoblastoma include the following:

Surgical resection. In patients with hepatoblastoma that is completely resected at initial diagnosis, aggressive surgical treatment of isolated pulmonary metastases that develop in the course of the disease, in conjunction with an overall strategy that includes appropriate chemotherapy, may make extended disease-free survival possible ¹¹³⁾. If possible, isolated metastases are resected completely in patients whose primary tumor is controlled.[108] A retrospective study of patients in SIOPEL studies 1, 2, and 3 showed a 12% incidence of recurrence after complete remission by imaging and AFP. Outcome after recurrence was best if the tumor was amenable to surgery. Of patients who underwent chemotherapy and surgery, the 3-year Event-Free Survival was 34%, and the Overall Survival was 43% ¹¹⁴⁾. Percutaneous radiofrequency ablation has been used as an alternative to surgical resection of oligometastatic hepatoblastoma ¹¹⁵⁾. Enrollment in a clinical trial should be considered if all of the recurrent disease cannot be surgically removed. Phase I and phase II clinical trials may be appropriate and should be considered.
Chemotherapy. Analysis of survival after recurrence demonstrated that some patients treated with cisplatin/vincristine/fluorouracil could be salvaged with doxorubicin-containing regimens, but patients treated with doxorubicin/cisplatin could not be salvaged with vincristine/fluorouracil ¹¹⁶⁾. Addition of doxorubicin to vincristine/fluorouracil/cisplatin is under clinical evaluation in the COG study AHEP0731 [NCT00980460]. Combined vincristine/irinotecan and single-agent irinotecan have been used with some success ¹¹⁷⁾. A review of Children’s Oncology Group (COG) phase I and II studies found no promising agents for relapsed hepatoblastoma ¹¹⁸⁾.
Liver transplant. Liver transplant should be considered for patients with nonmetastatic disease recurrence in the liver that is not amenable to resection ¹¹⁹⁾.
Percutaneous ablation. Percutaneous ablation techniques may also be considered for palliation ¹²⁰⁾ or, in some cases, for curative therapy of oligometastatic disease ¹²¹⁾.

Hepatoblastoma prognosis

Prognosis is based on numerous factors including age of diagnosis, PRETEXT group, metastases, alfa fetal protein (AFP) levels, histologic subtype, completeness of resection, and clinical stage of the disease. With certainty, the well-differentiated fetal subtype is associated with a better prognosis compared with small cell undifferentiated and macrotrabecular, which are linked to unfavorable prognosis ¹²²⁾. Alfa-fetoprotein is typically high upon diagnosis, but a significant drop after neo-adjuvant chemotherapy portends a better response to treatment. Younger age of diagnosis has historically been a poor prognostic factor; however, recent studies have called this into question, providing evidence that these younger patients do just as well as older children ¹²³⁾. Specifically, children younger than 1 year of age have a better prognosis and children greater than 6 years of age have a worse prognosis ¹²⁴⁾. Tumor presence at the resection margin, multifocality, and metastases have been shown to be poor prognostic factors. Beta-catenin expression has been shown to be associated with a lower period of event-free survival, while EpCAM expression has been associated with higher tumor viability and a poorer response to neo-adjuvant chemotherapy ¹²⁵⁾.

Hepatoblastoma survival rate

The 5-year overall survival rate for children with hepatoblastoma is 70% ¹²⁶⁾. Neonates with hepatoblastoma have outcomes comparable to older children up to age 5 years ¹²⁷⁾.

References [ + ]

1.	↵	Maternal and infant birth characteristics and hepatoblastoma. McLaughlin CC, Baptiste MS, Schymura MJ, Nasca PC, Zdeb MS. Am J Epidemiol. 2006 May 1; 163(9):818-28.
2.	↵	Bell D, Ranganathan S, Tao J, Monga SP. Novel Advances in Understanding of Molecular Pathogenesis of Hepatoblastoma: A Wnt/β-Catenin Perspective. Gene Expr. 2017;17(2):141–154. doi:10.3727/105221616X693639 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5311458
3.	↵	Pritchard J , Brown J , Shafford E . et al. Cisplatin, doxorubicin, and delayed surgery for childhood hepatoblastoma: a successful approach—results of the first prospective study of the International Society of Pediatric Oncology. J Clin Oncol. 2000;18:3819–28.
4.	↵	Epidemiology of primary hepatic malignancies in U.S. children. Darbari A, Sabin KM, Shapiro CN, Schwarz KB. Hepatology. 2003 Sep; 38(3):560-6.
5, 41.	↵	Musick SR, Babiker HM. Cancer, Hepatoblastoma. [Updated 2018 Dec 1]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2019 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK534795
6, 13, 16, 42, 124.	↵	Czauderna P, Lopez-Terrada D, Hiyama E, Häberle B, Malogolowkin MH, Meyers RL. Hepatoblastoma state of the art: pathology, genetics, risk stratification, and chemotherapy. Curr. Opin. Pediatr. 2014 Feb;26(1):19-28.
7.	↵	Rodriguez-Galindo C, Pappo AS. Tumors of the Liver. In: Kufe DW, Pollock RE, Weichselbaum RR, et al., editors. Holland-Frei Cancer Medicine. 6th edition. Hamilton (ON): BC Decker; 2003. Available from: https://www.ncbi.nlm.nih.gov/books/NBK13085
8.	↵	Increased risk of hepatoblastoma among immature children with a lower birth weight. Tanimura M, Matsui I, Abe J, Ikeda H, Kobayashi N, Ohira M, Yokoyama M, Kaneko M. Cancer Res. 1998 Jul 15; 58(14):3032-5.
9.	↵	Garber JE , Li FP , Kingston JE . et al. Hepatoblastoma and familial adenomatous polyposis. J Natl Cancer Inst. 1998;80:1626–8.
10.	↵	Debaun MR , Tucker MA . Risk of cancer during the first four years of life in children from the Beckwith-Wiedemann syndrome registry. J Pediatr. 1998;132(3 Pt 1):398–400. https://www.ncbi.nlm.nih.gov/pubmed/9544889
11.	↵	Finegold MJ, Lopez-Terrada DH, Bowen J, Washington MK, Qualman SJ., College of American Pathologists. Protocol for the examination of specimens from pediatric patients with hepatoblastoma. Arch. Pathol. Lab. Med. 2007 Apr;131(4):520-9.
12.	↵	Heck JE, Meyers TJ, Lombardi C, Park AS, Cockburn M, Reynolds P, Ritz B. Case-control study of birth characteristics and the risk of hepatoblastoma. Cancer Epidemiol. 2013 Aug;37(4):390-5
14.	↵	Curia MC, Zuckermann M, De Lellis L, Catalano T, Lattanzio R, Aceto G, Veschi S, Cama A, Otte JB, Piantelli M, Mariani-Costantini R, Cetta F, Battista P. Sporadic childhood hepatoblastomas show activation of beta-catenin, mismatch repair defects and p53 mutations. Mod. Pathol. 2008 Jan;21(1):7-14.
15, 74.	↵	Ng K, Rana A, Masand P, Patel K, Heczey A, Goss J, Himes R. Fatal Central Nervous System Post-Transplant Lymphoproliferative Disease in a Patient Who Underwent Liver Transplantation for Hepatoblastoma. J. Pediatr. Gastroenterol. Nutr. 2018 Jan;66(1):e21-e23
17, 18.	↵	Kalish JM, Doros L, Helman LJ, et al.: Surveillance Recommendations for Children with Overgrowth Syndromes and Predisposition to Wilms Tumors and Hepatoblastoma. Clin Cancer Res 23 (13): e115-e122, 2017
19, 27.	↵	Kamien BA, Gabbett MT: Aicardi syndrome associated with hepatoblastoma and pulmonary sequestration. Am J Med Genet A 149A (8): 1850-2, 2009
20.	↵	Weksberg R, Shuman C, Smith AC: Beckwith-Wiedemann syndrome. Am J Med Genet C Semin Med Genet 137C (1): 12-23, 2005.
21.	↵	Giardiello FM, Petersen GM, Brensinger JD, et al.: Hepatoblastoma and APC gene mutation in familial adenomatous polyposis. Gut 39 (96): 867-9, 1996.
22.	↵	Ito E, Sato Y, Kawauchi K, et al.: Type 1a glycogen storage disease with hepatoblastoma in siblings. Cancer 59 (10): 1776-80, 1987
23.	↵	Turcotte LM, Georgieff MK, Ross JA, et al.: Neonatal medical exposures and characteristics of low birth weight hepatoblastoma cases: a report from the Children’s Oncology Group. Pediatr Blood Cancer 61 (11): 2018-23, 2014.
24.	↵	Buonuomo PS, Ruggiero A, Vasta I, et al.: Second case of hepatoblastoma in a young patient with Simpson-Golabi-Behmel syndrome. Pediatr Hematol Oncol 22 (7): 623-8, 2005 Oct-Nov.
25.	↵	Tan ZH, Lai A, Chen CK, et al.: Association of trisomy 18 with hepatoblastoma and its implications. Eur J Pediatr 173 (12): 1595-8, 2014
26.	↵	PDQ Pediatric Treatment Editorial Board. Childhood Liver Cancer Treatment (PDQ®): Health Professional Version. 2019 Jun 13. In: PDQ Cancer Information Summaries [Internet]. Bethesda (MD): National Cancer Institute (US); 2002-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK65790
28, 35.	↵	Trobaugh-Lotrario AD, Venkatramani R, Feusner JH: Hepatoblastoma in children with Beckwith-Wiedemann syndrome: does it warrant different treatment? J Pediatr Hematol Oncol 36 (5): 369-73, 2014
29.	↵	Clericuzio CL, Martin RA: Diagnostic criteria and tumor screening for individuals with isolated hemihyperplasia. Genet Med 11 (3): 220-2, 2009.
30.	↵	Weksberg R, Shuman C, Smith AC: Beckwith-Wiedemann syndrome. Am J Med Genet C Semin Med Genet 137C (1): 12-23, 2005
31.	↵	Algar EM, St Heaps L, Darmanian A, et al.: Paternally inherited submicroscopic duplication at 11p15.5 implicates insulin-like growth factor II in overgrowth and Wilms’ tumorigenesis. Cancer Res 67 (5): 2360-5, 2007
32.	↵	Albrecht S, Hartmann W, Houshdaran F, et al.: Allelic loss but absence of mutations in the polyspecific transporter gene BWR1A on 11p15.5 in hepatoblastoma. Int J Cancer 111 (4): 627-32, 2004
33.	↵	Clericuzio CL, Martin RA: Diagnostic criteria and tumor screening for individuals with isolated hemihyperplasia. Genet Med 11 (3): 220-2, 2009
34.	↵	Clericuzio CL, Chen E, McNeil DE, et al.: Serum alpha-fetoprotein screening for hepatoblastoma in children with Beckwith-Wiedemann syndrome or isolated hemihyperplasia. J Pediatr 143 (2): 270-2, 2003
36.	↵	Mussa A, Molinatto C, Baldassarre G, et al.: Cancer Risk in Beckwith-Wiedemann Syndrome: A Systematic Review and Meta-Analysis Outlining a Novel (Epi)Genotype Specific Histotype Targeted Screening Protocol. J Pediatr 176: 142-149.e1, 2016
37, 38.	↵	Aretz S, Koch A, Uhlhaas S, et al.: Should children at risk for familial adenomatous polyposis be screened for hepatoblastoma and children with apparently sporadic hepatoblastoma be screened for APC germline mutations? Pediatr Blood Cancer 47 (6): 811-8, 2006
39.	↵	Hirschman BA, Pollock BH, Tomlinson GE: The spectrum of APC mutations in children with hepatoblastoma from familial adenomatous polyposis kindreds. J Pediatr 147 (2): 263-6, 2005
40.	↵	Koch A, Denkhaus D, Albrecht S, et al.: Childhood hepatoblastomas frequently carry a mutated degradation targeting box of the beta-catenin gene. Cancer Res 59 (2): 269-73, 1999.
43.	↵	Hiyama E. Pediatric hepatoblastoma: diagnosis and treatment. Transl Pediatr. 2014 Oct;3(4):293-9.
44, 45.	↵	Zhong S, Zhao Y, Fan C. Hepatoblastoma with pure fetal epithelial differentiation in a 10-year-old boy: A rare case report and review of the literature. Medicine (Baltimore). 2018 Jan;97(2):e9647
46.	↵	Risk-Based Therapy in Treating Younger Patients with Newly Diagnosed Liver Cancer. https://www.cancer.gov/about-cancer/treatment/clinical-trials/search/v?id=NCT00980460&r=1
47.	↵	Yoon JM, Burns RC, Malogolowkin MH, et al.: Treatment of infantile choriocarcinoma of the liver. Pediatr Blood Cancer 49 (1): 99-102, 2007
48.	↵	Boman F, Bossard C, Fabre M, et al.: Mesenchymal hamartomas of the liver may be associated with increased serum alpha foetoprotein concentrations and mimic hepatoblastomas. Eur J Pediatr Surg 14 (1): 63-6, 2004
49.	↵	Blohm ME, Vesterling-Hörner D, Calaminus G, et al.: Alpha 1-fetoprotein (AFP) reference values in infants up to 2 years of age. Pediatr Hematol Oncol 15 (2): 135-42, 1998 Mar-Apr.
50, 122.	↵	Meyers RL, Maibach R, Hiyama E, Häberle B, Krailo M, Rangaswami A, Aronson DC, Malogolowkin MH, Perilongo G, von Schweinitz D, Ansari M, Lopez-Terrada D, Tanaka Y, Alaggio R, Leuschner I, Hishiki T, Schmid I, Watanabe K, Yoshimura K, Feng Y, Rinaldi E, Saraceno D, Derosa M, Czauderna P. Risk-stratified staging in paediatric hepatoblastoma: a unified analysis from the Children’s Hepatic tumors International Collaboration. Lancet Oncol. 2017 Jan;18(1):122-131
51.	↵	Czauderna P, Haeberle B, Hiyama E, et al. The Children’s Hepatic tumors International Collaboration (CHIC): Novel global rare tumor database yields new prognostic factors in hepatoblastoma and becomes a research model. Eur J Cancer. 2016;52:92–101. doi:10.1016/j.ejca.2015.09.023 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5141607
52.	↵	Aronson DC, Schnater JM, Staalman CR, et al.: Predictive value of the pretreatment extent of disease system in hepatoblastoma: results from the International Society of Pediatric Oncology Liver Tumor Study Group SIOPEL-1 study. J Clin Oncol 23 (6): 1245-52, 2005.
53, 55, 59.	↵	Meyers RL, Maibach R, Hiyama E, et al.: Risk-stratified staging in paediatric hepatoblastoma: a unified analysis from the Children’s Hepatic tumors International Collaboration. Lancet Oncol 18 (1): 122-131, 2017
54, 56, 58, 60, 61.	↵	Czauderna P, Haeberle B, Hiyama E, et al.: The Children’s Hepatic tumors International Collaboration (CHIC): Novel global rare tumor database yields new prognostic factors in hepatoblastoma and becomes a research model. Eur J Cancer 52: 92-101, 2016
57.	↵	Dall’Igna P, Brugieres L, Christin AS, et al.: Hepatoblastoma in children aged less than six months at diagnosis: A report from the SIOPEL group. Pediatr Blood Cancer 65 (1): , 2018
62.	↵	Becker K, Furch C, Schmid I, et al.: Impact of postoperative complications on overall survival of patients with hepatoblastoma. Pediatr Blood Cancer 62 (1): 24-8, 2015.
63.	↵	McAteer JP, Goldin AB, Healey PJ, et al.: Surgical treatment of primary liver tumors in children: outcomes analysis of resection and transplantation in the SEER database. Pediatr Transplant 17 (8): 744-50, 2013.
64, 89, 97, 98, 102, 105, 106, 108.	↵	Zsiros J, Brugieres L, Brock P, et al.: Dose-dense cisplatin-based chemotherapy and surgery for children with high-risk hepatoblastoma (SIOPEL-4): a prospective, single-arm, feasibility study. Lancet Oncol 14 (9): 834-42, 2013
65.	↵	Schnater JM, Aronson DC, Plaschkes J, et al.: Surgical view of the treatment of patients with hepatoblastoma: results from the first prospective trial of the International Society of Pediatric Oncology Liver Tumor Study Group. Cancer 94 (4): 1111-20, 2002
66.	↵	Van Tornout JM, Buckley JD, Quinn JJ, et al.: Timing and magnitude of decline in alpha-fetoprotein levels in treated children with unresectable or metastatic hepatoblastoma are predictors of outcome: a report from the Children’s Cancer Group. J Clin Oncol 15 (3): 1190-7, 1997
67, 88.	↵	Zsíros J, Maibach R, Shafford E, et al.: Successful treatment of childhood high-risk hepatoblastoma with dose-intensive multiagent chemotherapy and surgery: final results of the SIOPEL-3HR study. J Clin Oncol 28 (15): 2584-90, 2010
68.	↵	Schneider DT, Calaminus G, Göbel U: Diagnostic value of alpha 1-fetoprotein and beta-human chorionic gonadotropin in infancy and childhood. Pediatr Hematol Oncol 18 (1): 11-26, 2001 Jan-Feb.
69.	↵	Brown J, Perilongo G, Shafford E, et al.: Pretreatment prognostic factors for children with hepatoblastoma– results from the International Society of Paediatric Oncology (SIOP) study SIOPEL 1. Eur J Cancer 36 (11): 1418-25, 2000
70, 76.	↵	Czauderna P, Lopez-Terrada D, Hiyama E, et al.: Hepatoblastoma state of the art: pathology, genetics, risk stratification, and chemotherapy. Curr Opin Pediatr 26 (1): 19-28, 2014
71.	↵	Meyers RL, Tiao G, de Ville de Goyet J, Superina R, Aronson DC. Hepatoblastoma state of the art: pre-treatment extent of disease, surgical resection guidelines and the role of liver transplantation. Curr. Opin. Pediatr. 2014 Feb;26(1):29-36
72.	↵	Uchida H, Sakamoto S, Sasaki K, Takeda M, Hirata Y, Fukuda A, Hishiki T, Irie R, Nakazawa A, Miyazaki O, Nosaka S, Kasahara M. Surgical treatment strategy for advanced hepatoblastoma: Resection versus transplantation. Pediatr Blood Cancer. 2018 Dec;65(12):e27383
73.	↵	Hiyama E. Pediatric hepatoblastoma: diagnosis and treatment. Transl Pediatr. 2014 Oct;3(4):293-9
75, 81, 86.	↵	Perilongo G, Shafford E, Maibach R, et al.: Risk-adapted treatment for childhood hepatoblastoma. final report of the second study of the International Society of Paediatric Oncology–SIOPEL 2. Eur J Cancer 40 (3): 411-21, 2004
77.	↵	Meyers RL, Tiao G, de Ville de Goyet J, et al.: Hepatoblastoma state of the art: pre-treatment extent of disease, surgical resection guidelines and the role of liver transplantation. Curr Opin Pediatr 26 (1): 29-36, 2014
78.	↵	Madanur MA, Battula N, Davenport M, et al.: Staged resection for a ruptured hepatoblastoma: a 6-year follow-up. Pediatr Surg Int 23 (6): 609-11, 2007
79.	↵	Khan AS, Brecklin B, Vachharajani N, et al.: Liver Transplantation for Malignant Primary Pediatric Hepatic Tumors. J Am Coll Surg 225 (1): 103-113, 2017
80.	↵	Xianliang H, Jianhong L, Xuewu J, et al.: Cure of hepatoblastoma with transcatheter arterial chemoembolization. J Pediatr Hematol Oncol 26 (1): 60-3, 2004
82, 92, 100.	↵	Malogolowkin MH, Katzenstein HM, Meyers RL, et al.: Complete surgical resection is curative for children with hepatoblastoma with pure fetal histology: a report from the Children’s Oncology Group. J Clin Oncol 29 (24): 3301-6, 2011
83.	↵	Pham TA, Gallo AM, Concepcion W, et al.: Effect of Liver Transplant on Long-term Disease-Free Survival in Children With Hepatoblastoma and Hepatocellular Cancer. JAMA Surg 150 (12): 1150-8, 2015
84.	↵	D’Antiga L, Vallortigara F, Cillo U, et al.: Features predicting unresectability in hepatoblastoma. Cancer 110 (5): 1050-8, 2007
85.	↵	Pritchard J, Brown J, Shafford E, et al.: Cisplatin, doxorubicin, and delayed surgery for childhood hepatoblastoma: a successful approach–results of the first prospective study of the International Society of Pediatric Oncology. J Clin Oncol 18 (22): 3819-28, 2000
87.	↵	Perilongo G, Maibach R, Shafford E, et al.: Cisplatin versus cisplatin plus doxorubicin for standard-risk hepatoblastoma. N Engl J Med 361 (17): 1662-70, 2009
90.	↵	Aronson DC, Meyers RL: Malignant tumors of the liver in children. Semin Pediatr Surg 25 (5): 265-275, 2016
91.	↵	von Schweinitz D, Hecker H, Harms D, et al.: Complete resection before development of drug resistance is essential for survival from advanced hepatoblastoma–a report from the German Cooperative Pediatric Liver Tumor Study HB-89. J Pediatr Surg 30 (6): 845-52, 1995
93.	↵	Venkatramani R, Stein JE, Sapra A, et al.: Effect of neoadjuvant chemotherapy on resectability of stage III and IV hepatoblastoma. Br J Surg 102 (1): 108-13, 2015
94.	↵	Fonseca A, Gupta A, Shaikh F, et al.: Extreme hepatic resections for the treatment of advanced hepatoblastoma: Are planned close margins an acceptable approach? Pediatr Blood Cancer 65 (2): , 2018
95.	↵	Wang S, Yang C, Zhang J, et al.: First experience of high-intensity focused ultrasound combined with transcatheter arterial embolization as local control for hepatoblastoma. Hepatology 59 (1): 170-7, 2014
96, 99.	↵	Ortega JA, Douglass EC, Feusner JH, et al.: Randomized comparison of cisplatin/vincristine/fluorouracil and cisplatin/continuous infusion doxorubicin for treatment of pediatric hepatoblastoma: A report from the Children’s Cancer Group and the Pediatric Oncology Group. J Clin Oncol 18 (14): 2665-75, 2000
101.	↵	Karski EE, Dvorak CC, Leung W, et al.: Treatment of hepatoblastoma with high-dose chemotherapy and stem cell rescue: the pediatric blood and marrow transplant consortium experience and review of the literature. J Pediatr Hematol Oncol 36 (5): 362-8, 2014
103.	↵	Perilongo G, Brown J, Shafford E, et al.: Hepatoblastoma presenting with lung metastases: treatment results of the first cooperative, prospective study of the International Society of Paediatric Oncology on childhood liver tumors. Cancer 89 (8): 1845-53, 2000
104.	↵	Meyers RL, Katzenstein HM, Krailo M, et al.: Surgical resection of pulmonary metastatic lesions in children with hepatoblastoma. J Pediatr Surg 42 (12): 2050-6, 2007
107, 119.	↵	Austin MT, Leys CM, Feurer ID, et al.: Liver transplantation for childhood hepatic malignancy: a review of the United Network for Organ Sharing (UNOS) database. J Pediatr Surg 41 (1): 182-6, 2006
109, 117.	↵	Zsíros J, Brugières L, Brock P, et al.: Efficacy of irinotecan single drug treatment in children with refractory or recurrent hepatoblastoma–a phase II trial of the childhood liver tumour strategy group (SIOPEL). Eur J Cancer 48 (18): 3456-64, 2012
110.	↵	Malogolowkin MH, Stanley P, Steele DA, et al.: Feasibility and toxicity of chemoembolization for children with liver tumors. J Clin Oncol 18 (6): 1279-84, 2000
111.	↵	Habrand JL, Nehme D, Kalifa C, et al.: Is there a place for radiation therapy in the management of hepatoblastomas and hepatocellular carcinomas in children? Int J Radiat Oncol Biol Phys 23 (3): 525-31, 1992
112, 114.	↵	Semeraro M, Branchereau S, Maibach R, et al.: Relapses in hepatoblastoma patients: clinical characteristics and outcome–experience of the International Childhood Liver Tumour Strategy Group (SIOPEL). Eur J Cancer 49 (4): 915-22, 2013
113.	↵	Shi Y, Geller JI, Ma IT, et al.: Relapsed hepatoblastoma confined to the lung is effectively treated with pulmonary metastasectomy. J Pediatr Surg 51 (4): 525-9, 2016
115, 121.	↵	Yevich S, Calandri M, Gravel G, et al.: Reiterative Radiofrequency Ablation in the Management of Pediatric Patients with Hepatoblastoma Metastases to the Lung, Liver, or Bone. Cardiovasc Intervent Radiol 42 (1): 41-47, 2019
116.	↵	Malogolowkin MH, Katzenstein HM, Krailo M, et al.: Redefining the role of doxorubicin for the treatment of children with hepatoblastoma. J Clin Oncol 26 (14): 2379-83, 2008
118.	↵	Trobaugh-Lotrario AD, Meyers RL, Feusner JH: Outcomes of Patients With Relapsed Hepatoblastoma Enrolled on Children’s Oncology Group (COG) Phase I and II Studies. J Pediatr Hematol Oncol 38 (3): 187-90, 2016
120.	↵	Liu B, Zhou L, Huang G, et al.: First Experience of Ultrasound-guided Percutaneous Ablation for Recurrent Hepatoblastoma after Liver Resection in Children. Sci Rep 5: 16805, 2015
123.	↵	Dall’Igna P, Brugieres L, Christin AS, Maibach R, Casanova M, Alaggio R, de Goyet JV, Zsiros J, Morland B, Czauderna P, Childs M, Aronson DC, Branchereau S, Brock P, Perilongo G. Hepatoblastoma in children aged less than six months at diagnosis: A report from the SIOPEL group. Pediatr Blood Cancer. 2018 Jan;65, 1
125.	↵	Kiruthiga KG, Ramakrishna B, Saha S, Sen S. Histological and immunohistochemical study of hepatoblastoma: correlation with tumour behaviour and survival. J Gastrointest Oncol. 2018 Apr;9(2):326-337
126.	↵	Perilongo G, Malogolowkin M, Feusner J: Hepatoblastoma clinical research: lessons learned and future challenges. Pediatr Blood Cancer 59 (5): 818-21, 2012.
127.	↵	Trobaugh-Lotrario AD, Chaiyachati BH, Meyers RL, et al.: Outcomes for patients with congenital hepatoblastoma. Pediatr Blood Cancer 60 (11): 1817-25, 2013.