Hepatoblastoma

MONDO:0018666 Pathograph 6 embryonal neoplasm liver cancer

Hepatoblastoma is the most common primary malignant liver tumor of infancy and childhood and is an embryonal liver cancer centered on CTNNB1/WNT activation, frequent beta-catenin/YAP1 coactivation, and persistence of a fetal liver-like progenitor state. Within this disease-level dismech unit, histologic pattern, molecular-risk context, and cancer-predisposition context are treated as flat subtype facets rather than separate disease pages. Disease behavior is shaped by impaired hepatic differentiation, oncofetal transcriptional programs, and risk features such as NFE2L2 activation or unusually low serum alpha-fetoprotein.

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0
Mappings
0
Definitions
0
Inheritance
6
Pathophysiology
2
Histopathology
2
Phenotypes
6
Pathograph
5
Genes
3
Treatments
8
Subtypes
0
Differentials
0
Datasets
0
Trials
0
Models
22
References
1
Deep Research
🏷

Classifications

Harrison's Chapter
cancer solid tumor
ICD-O Morphology
Embryonal Neoplasm
◆

Subtypes

8
histology
Epithelial Hepatoblastoma
Predominantly epithelial tumors spanning fetal, embryonal, crowded fetal, macrotrabecular, or focal small-cell-undifferentiated morphologies without a mesenchymal stromal component.
Show evidence (1 reference)
PMID:33981680 SUPPORT Other
"HB is classified into 2 broad categories: epithelial and mesenchymal type. The majority of HB are epithelial type."
Supports epithelial-predominant histology as the major subtype axis within hepatoblastoma.
Mixed Epithelial and Mesenchymal Hepatoblastoma
Tumors containing epithelial hepatoblastoma elements together with mesenchymal stroma such as osteoid, cartilage, or spindle-cell areas.
Show evidence (1 reference)
PMID:19072985 SUPPORT Other
"Sixty percent of tumors are classified as epithelial, and about 40% as mixed epithelial-mesenchymal, characterized by an admixture of osseous, cartilaginous and, more rarely, skeletal muscle elements [3]."
Supports mixed epithelial-mesenchymal morphology as a recurring hepatoblastoma subtype facet.
Fetal Pattern-Predominant Hepatoblastoma
Histology dominated by fetal hepatocyte-like tumor cells, often associated with lower-risk biology when pure and well differentiated.
Show evidence (1 reference)
PMID:19072985 SUPPORT Other
"Three main histologic subtypes of epithelial HBs are distinguished: fetal, embryonal, and small cell undifferentiated (initially described as anaplastic)."
Supports fetal morphology as a canonical epithelial histology facet within hepatoblastoma.
Embryonal Pattern Hepatoblastoma
Less differentiated epithelial tumors with embryonal morphology and more pronounced proliferative behavior than pure fetal tumors.
Show evidence (1 reference)
PMID:19072985 SUPPORT Other
"Three main histologic subtypes of epithelial HBs are distinguished: fetal, embryonal, and small cell undifferentiated (initially described as anaplastic)."
Supports embryonal morphology as a canonical epithelial histology facet within hepatoblastoma.
Small Cell Undifferentiated Component-Positive Hepatoblastoma
A focal small cell undifferentiated component can occur within hepatoblastoma, but INI1-negative/SMARCB1-deficient small-cell liver tumors should be treated as malignant rhabdoid tumor rather than as a separate hepatoblastoma disease page.
Show evidence (2 references)
PMID:36672416 SUPPORT Human Clinical
"Patients with HB with SCU component or low AFP should be assessed for SMARCB1 mutations and, if confirmed, treated as rhabdoid tumors."
Establishes the practical boundary between hepatoblastoma with an SCU component and SMARCB1-deficient rhabdoid tumors.
PMID:34874751 SUPPORT Human Clinical
"The presence of SCU histology in HB does not appear to adversely affect outcome."
Supports modeling SCU-positive HB as a histologic facet rather than as a distinct high-risk dismech disease entity when rhabdoid tumors are excluded.
molecular risk
C2-Signature Hepatoblastoma
36%
High-risk molecular subgroup with a 16-gene expression signature, frequent metastasis, non-fetal histology, and inferior survival.
Show evidence (2 references)
PMID:33125945 SUPPORT Human Clinical
"Mutations of CTNNB1, NFE2L2 and TERT were found in 135 (78%), 10 (6%) and 10 (6%) patients, respectively, and the adverse C2 subtype of the 16-gene signature in 63 (36%) patients."
Directly supports a clinically meaningful molecular-risk subtype axis within hepatoblastoma.
PMID:33125945 SUPPORT Human Clinical
"C2-patients had more frequent metastatic disease, higher alpha-fetoprotein levels, non-fetal histology and significantly worse 3-year OS (68% versus 95%) and EFS (63% versus 87%) than C1-patients."
Defines the aggressive phenotype and prognosis of the C2 molecular-risk subtype.
predisposition context
Beckwith-Wiedemann Spectrum-Associated Hepatoblastoma
Hepatoblastoma arising in the setting of 11p15 imprinting abnormalities and epigenotype mosaicism characteristic of Beckwith-Wiedemann spectrum.
Show evidence (1 reference)
PMID:37174013 SUPPORT Human Clinical
"Patients with Beckwith-Wiedemann syndrome (BWS), an epigenetic imprinting disorder involving alterations in genes at the 11p15 chromosomal location, are predisposed to develop hepatoblastomas (HBs), which are rare embryonal liver tumors."
Supports Beckwith-Wiedemann spectrum as a cancer-predisposition context for hepatoblastoma.
Familial Adenomatous Polyposis-Associated Hepatoblastoma
Hepatoblastoma arising in children from APC-mutation families with familial adenomatous polyposis, prompting infant surveillance strategies.
Show evidence (1 reference)
PMID:29719120 SUPPORT Human Clinical
"Familial adenomatous polyposis (FAP) due to APC mutation is associated with an increased risk of hepatoblastoma."
Supports APC/FAP-associated hepatoblastoma as a predisposition-context subtype facet.
⚙

Pathophysiology

6
CTNNB1-Driven WNT/Beta-Catenin Signaling
Somatic CTNNB1 mutations or deletions are the dominant recurrent driver in hepatoblastoma and lead to persistent nuclear beta-catenin activity.
hepatoblast link
Wnt signaling pathway link ↑ INCREASED
liver link
Downstream
Beta-Catenin/YAP1 Coactivation Beta-catenin signaling cooperates with YAP1-dependent transcription
Fetal Hepatic Progenitor State Maintenance Beta-catenin activity reinforces a fetal liver-like differentiation state
Show evidence (2 references)
PMID:32881242 SUPPORT Human Clinical
"Driver mutations in the CTNNB1 gene (encoding β-catenin) are a hallmark of sporadic hepatoblastoma (HBL)."
Supports CTNNB1 alteration as the canonical sporadic driver of hepatoblastoma.
PMID:33125945 SUPPORT Human Clinical
"Mutations of CTNNB1, NFE2L2 and TERT were found in 135 (78%), 10 (6%) and 10 (6%) patients, respectively, and the adverse C2 subtype of the 16-gene signature in 63 (36%) patients."
Quantifies CTNNB1 as the dominant recurrent genetic event in a large clinical cohort.
Beta-Catenin/YAP1 Coactivation
Nuclear beta-catenin and YAP1 co-occur in most hepatoblastomas and act as a cooperative transcriptional module required for robust tumor formation.
positive regulation of gene expression link ⚠ ABNORMAL
Downstream
Fetal Hepatic Progenitor State Maintenance Cooperative transcription sustains immature hepatic identity
Beta-Catenin/YAP1-Dependent Proliferation Joint pathway activation drives tumor cell expansion
Show evidence (3 references)
PMID:24837480 SUPPORT Human Clinical
"We observed nuclear localization of β-catenin and Yap1 in 79% of hepatoblastoma samples but not in most hepatocellular carcinoma or intrahepatic cholangiocarcinoma samples."
Demonstrates that concurrent beta-catenin and YAP1 activation is common in human hepatoblastoma tissue.
PMID:24837480 SUPPORT Model Organism
"Overexpression of constitutively active forms of Yap1 and β-catenin in mouse liver led to rapid tumorigenesis, with 100% mortality by 11 weeks."
Shows that combined activation of YAP1 and beta-catenin is sufficient to drive hepatoblastoma-like tumorigenesis in vivo.
PMID:24837480 SUPPORT In Vitro
"Knockdown of Yap1 or β-catenin in hepatoblastoma cells reduced proliferation in an additive manner."
Supports cooperative dependence of hepatoblastoma cells on both YAP1 and beta-catenin signaling.
Fetal Hepatic Progenitor State Maintenance
Hepatoblastoma retains hepatic progenitor and fetal liver programs rather than completing normal hepatocytic differentiation, aligning the tumor with an immature developmental state.
hepatoblast link
cell differentiation link ↓ DECREASED
liver link
Downstream
Oncofetal Stem-Cell Marker Program Immature hepatic identity is accompanied by oncofetal marker expression
Show evidence (1 reference)
PMID:27775819 SUPPORT Human Clinical
"Our analysis of 88 clinically annotated HBs revealed three risk-stratifying molecular subtypes that are characterized by differential activation of hepatic progenitor cell markers and metabolic pathways:"
Supports persistence of hepatic progenitor-state programs across clinically relevant hepatoblastoma subgroups.
Oncofetal Stem-Cell Marker Program
Aggressive hepatoblastomas express oncofetal and stem-cell-associated markers including LIN28B, HMGA2, SALL4, and AFP, linking fetal identity to high-risk tumor biology.
positive regulation of gene expression link ⚠ ABNORMAL
Downstream
NFE2L2-Mediated Oxidative-Stress Adaptation The aggressive oncofetal state is coupled to NFE2L2 pathway activation
Beta-Catenin/YAP1-Dependent Proliferation The oncofetal C2 transcriptional state is associated with more aggressive tumor behavior
Show evidence (1 reference)
PMID:27775819 SUPPORT Human Clinical
"high-risk tumors were characterized by up-regulated nuclear factor, erythroid 2-like 2 activity; high lin-28 homolog B, high mobility group AT-hook 2, spalt-like transcription factor 4, and alpha-fetoprotein expression; and high coordinated expression of oncofetal proteins and stem-cell markers,..."
Directly supports an oncofetal stem-cell transcriptional program in aggressive hepatoblastoma.
NFE2L2-Mediated Oxidative-Stress Adaptation
A subset of hepatoblastomas acquires NFE2L2-driven stress adaptation that tracks with non-fetal histology, vessel-invasive growth, and worse outcome.
response to oxidative stress link ↑ INCREASED
Downstream
Beta-Catenin/YAP1-Dependent Proliferation Stress adaptation supports survival and growth of aggressive tumor cells
Show evidence (2 references)
PMID:27775819 SUPPORT Human Clinical
"high-risk tumors were characterized by up-regulated nuclear factor, erythroid 2-like 2 activity; high lin-28 homolog B, high mobility group AT-hook 2, spalt-like transcription factor 4, and alpha-fetoprotein expression; and high coordinated expression of oncofetal proteins and stem-cell markers,..."
Supports increased NFE2L2 pathway activity in the aggressive transcriptional state.
PMID:33125945 SUPPORT Human Clinical
"Patients carrying a NFE2L2 mutation had a significantly worse 3-year OS (57% versus 88%) than NFE2L2 wild-type patients and were more likely to have vessel invasive growth and non-fetal histology."
Links NFE2L2 alteration to adverse clinical behavior and non-fetal morphology.
Beta-Catenin/YAP1-Dependent Proliferation
Hepatoblastoma growth depends on beta-catenin/YAP1-driven proliferative output, which can be attenuated experimentally by pathway inhibition.
cell population proliferation link ↑ INCREASED
Show evidence (2 references)
PMID:24837480 SUPPORT In Vitro
"Knockdown of Yap1 or β-catenin in hepatoblastoma cells reduced proliferation in an additive manner."
Demonstrates that hepatoblastoma cell proliferation depends on both beta-catenin and YAP1 activity.
PMID:30863496 SUPPORT Model Organism
"Rapamycin treatment decreased HB burden, almost normalizing liver weight to body weight ratio."
Supports pathway-dependent tumor growth in a beta-catenin/YAP1-driven mouse model and identifies growth-supporting signaling as therapeutically tractable.
✶

Histopathology

2
Hepatoblastoma VERY_FREQUENT
Malignant pediatric liver neoplasm with epithelial or mixed epithelial-mesenchymal morphology.
Show evidence (1 reference)
PMID:33981680 SUPPORT Other
"Hepatoblastoma (HB) is a rare tumor, but it is the most common primary liver malignancy in children and comprised of approximately 1% of all pediatric malignancies."
Supports the core histopathologic disease identity of hepatoblastoma as a pediatric primary liver malignancy.
Embryonal Neoplasm VERY_FREQUENT
Histology reflects embryonal liver differentiation rather than mature hepatocytic architecture.
Show evidence (1 reference)
PMID:37174013 SUPPORT Human Clinical
"Patients with Beckwith-Wiedemann syndrome (BWS), an epigenetic imprinting disorder involving alterations in genes at the 11p15 chromosomal location, are predisposed to develop hepatoblastomas (HBs), which are rare embryonal liver tumors."
Supports embryonal-neoplasm classification as a central morphologic identity for hepatoblastoma.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Hepatoblastoma Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

2
Abdominal Mass VERY_FREQUENT Abdominal HP:0031500
Show evidence (1 reference)
PMID:33981680 SUPPORT Other
"Most often present as abdominal mass and has a raised alpha-fetoprotein levels."
Supports abdominal mass as the characteristic presenting phenotype.
Hepatomegaly FREQUENT Hepatic HP:0002240
Show evidence (1 reference)
PMID:16458842 SUPPORT Other
"Clinical presentation, especially in young children is relatively uniform with abdominal enlargement and a painless tumor, and often specific symptoms develop late."
Supports tumor-related abdominal enlargement consistent with hepatomegaly from a large liver mass.
🧬

Genetic Associations

5
CTNNB1 (Somatic Activating Mutation)
Show evidence (2 references)
PMID:32881242 SUPPORT Human Clinical
"Driver mutations in the CTNNB1 gene (encoding β-catenin) are a hallmark of sporadic hepatoblastoma (HBL)."
Supports CTNNB1 as the hallmark sporadic driver gene.
PMID:33125945 SUPPORT Human Clinical
"Mutations of CTNNB1, NFE2L2 and TERT were found in 135 (78%), 10 (6%) and 10 (6%) patients, respectively, and the adverse C2 subtype of the 16-gene signature in 63 (36%) patients."
Quantifies CTNNB1 as the most frequent recurrent mutation in a large cohort.
NFE2L2 (Somatic Mutation)
Show evidence (1 reference)
PMID:33125945 SUPPORT Human Clinical
"Patients carrying a NFE2L2 mutation had a significantly worse 3-year OS (57% versus 88%) than NFE2L2 wild-type patients and were more likely to have vessel invasive growth and non-fetal histology."
Supports NFE2L2 as an adverse-risk molecular alteration in hepatoblastoma.
TERT (Somatic Promoter Mutation)
Show evidence (1 reference)
PMID:33125945 SUPPORT Human Clinical
"TERT mutations were almost exclusively found in older patients, whereas CTNNB1 mutations showed no association with any clinical feature or outcome."
Supports age-enrichment of TERT mutation within hepatoblastoma.
APC (Germline Predisposition)
Show evidence (2 references)
PMID:29719120 SUPPORT Human Clinical
"Familial adenomatous polyposis (FAP) due to APC mutation is associated with an increased risk of hepatoblastoma."
Supports APC/FAP as a hereditary predisposition mechanism for hepatoblastoma.
PMID:1329510 SUPPORT Human Clinical
"This figure is significantly higher than the 1/100,000 incidence of hepatoblastoma in the general population."
Supports markedly elevated hepatoblastoma risk in FAP families relative to the background population.
11p15 Imprinting Defects / Beckwith-Wiedemann Spectrum (Epigenetic Predisposition)
Show evidence (2 references)
PMID:37174013 SUPPORT Human Clinical
"Patients with Beckwith-Wiedemann syndrome (BWS), an epigenetic imprinting disorder involving alterations in genes at the 11p15 chromosomal location, are predisposed to develop hepatoblastomas (HBs), which are rare embryonal liver tumors."
Supports 11p15/Beckwith-Wiedemann biology as a hepatoblastoma predisposition mechanism.
PMID:37174013 SUPPORT Human Clinical
"We found that 100% of the HBs that underwent NGS panel testing had variants in the CTNNB1 gene."
Supports convergence of BWSp-associated hepatoblastoma on CTNNB1-mutant tumor biology.
💊

Treatments

3
Cisplatin-Based Neoadjuvant Chemotherapy
Action: chemotherapy MAXO:0000647
Agent: cisplatin ↗ doxorubicin ↗
Cisplatin-based chemotherapy is standard for most unresectable or advanced tumors and is used preoperatively to shrink disease and improve resectability.
Show evidence (2 references)
PMID:28126357 SUPPORT Other
"neoadjuvant chemotherapy is now standard, particularly in unresectable tumors resulting in considerable preoperative tumor shrinkage and sometimes near total ablation of the tumor."
Supports neoadjuvant chemotherapy as standard hepatoblastoma management.
PMID:25349947 SUPPORT Human Clinical
"The majority of stage III and IV hepatoblastomas achieved radiographic resectability after two cycles of chemotherapy."
Demonstrates the resectability benefit of preoperative chemotherapy in advanced hepatoblastoma.
Complete Surgical Resection
Action: surgical procedure MAXO:0000004
Complete extirpation of residual tumor remains essential for cure and is integrated with chemotherapy in most patients.
Show evidence (2 references)
PMID:16458842 SUPPORT Other
"Surgery is the mainstay of treatment for all benign and malignant liver tumors."
Supports surgery as a core treatment modality for malignant pediatric liver tumors including hepatoblastoma.
PMID:16458842 SUPPORT Other
"Hepatoblastomas mostly respond well to chemotherapy. Therefore, this modality should always be combined with surgical resection in these patients and in many cases can reduce the size of a large tumor to resectability."
Supports combining chemotherapy with definitive surgical resection in hepatoblastoma.
Liver Transplantation for Unresectable Liver-Confined Disease
Action: organ transplantation MAXO:0010039
Orthotopic liver transplantation is a curative option for unresectable unifocal or multifocal tumors confined to the liver and should be considered early when PRETEXT extent, vascular involvement, or low AFP suggest failed conservative surgery.
Show evidence (2 references)
PMID:12352881 SUPPORT Human Clinical
"Liver transplantation is an effective treatment for unresectable unifocal or multifocal hepatoblastoma confined to the liver."
Directly supports transplantation as curative therapy for unresectable liver-confined hepatoblastoma.
PMID:34441025 SUPPORT Human Clinical
"Conclusions: In irresectable cases, liver transplantation reveals excellent outcomes in children with hepatoblastoma with an acceptable number of perioperative complications."
Supports favorable modern transplant outcomes in irresectable hepatoblastoma.
🔬

Biochemical Markers

3
Elevated Serum Alpha-Fetoprotein
Show evidence (2 references)
PMID:33981680 SUPPORT Other
"Most often present as abdominal mass and has a raised alpha-fetoprotein levels."
Supports elevated AFP as the characteristic biochemical signature of hepatoblastoma.
PMID:16458842 SUPPORT Other
"Histological diagnosis is essential for differential diagnosis and may only be omitted in some hepatoblastoma patients of the typical age (6 months to 3 years) with an excessively elevated serum-alpha-fetoprotein."
Supports markedly elevated AFP as a clinically meaningful diagnostic biomarker in typical-age hepatoblastoma.
Low Serum Alpha-Fetoprotein at Diagnosis
Show evidence (2 references)
PMID:18166449 SUPPORT Human Clinical
"This study clearly identifies patients with hepatoblastoma and low serum AFP at diagnosis as a high-risk subgroup with extensive disease at diagnosis, poor response to chemotherapy and a poor outcome."
Supports low AFP as a high-risk biomarker context within clinically diagnosed hepatoblastoma.
PMID:17661341 SUPPORT Human Clinical
"Patients who had multifocal lesions and those who had an alpha-fetoprotein (alphaFP) level <100 ng/mL survived only if they underwent transplantation."
Links low AFP to unresectability and transplant dependence in a surgical cohort.
CTNNB1 Circulating Tumor DNA
Show evidence (2 references)
PMID:32881242 SUPPORT Human Clinical
"Our results show that CTNNB1 circulating tumour DNA (ctDNA) is readily detected in patients diagnosed with localised HBL, with serial sampling along the course of therapy and follow up providing a sensitive mechanism to monitor tumour dynamics and response to treatment."
Supports CTNNB1 ctDNA as a dynamic liquid-biopsy biomarker in hepatoblastoma.
PMID:38201440 SUPPORT Human Clinical
"Notably, ctDNA positivity correlated with tumor burden, and ctDNA levels exhibited associations with macroscopic residual disease and treatment response."
Independently supports ctDNA as a biomarker of disease burden and response.
{ }

Source YAML

click to show 
name: Hepatoblastoma
creation_date: '2026-03-16T06:36:16Z'
updated_date: '2026-04-21T03:25:28Z'
description: >-
  Hepatoblastoma is the most common primary malignant liver tumor of infancy and
  childhood and is an embryonal liver cancer centered on CTNNB1/WNT activation,
  frequent beta-catenin/YAP1 coactivation, and persistence of a fetal
  liver-like progenitor state. Within this disease-level dismech unit,
  histologic pattern, molecular-risk context, and cancer-predisposition context
  are treated as flat subtype facets rather than separate disease pages. Disease
  behavior is shaped by impaired hepatic differentiation, oncofetal
  transcriptional programs, and risk features such as NFE2L2 activation or
  unusually low serum alpha-fetoprotein.
categories:
- Pediatric Cancer
- Hepatobiliary Cancer
- Liver Cancer
- Embryonal Tumor
- Solid Tumor
parents:
- embryonal neoplasm
- liver cancer
disease_term:
  preferred_term: hepatoblastoma
  term:
    id: MONDO:0018666
    label: hepatoblastoma
has_subtypes:
- name: Epithelial Hepatoblastoma
  classification: histology
  description: >-
    Predominantly epithelial tumors spanning fetal, embryonal, crowded fetal,
    macrotrabecular, or focal small-cell-undifferentiated morphologies without a
    mesenchymal stromal component.
  evidence:
  - reference: PMID:33981680
    reference_title: "Common and Rare Histological Variants of Hepatoblastoma in Children: A Pathological Diagnosis and Review of the Literature."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HB is classified into 2 broad categories: epithelial and mesenchymal type. The majority of HB are epithelial type."
    explanation: Supports epithelial-predominant histology as the major subtype axis within hepatoblastoma.
- name: Mixed Epithelial and Mesenchymal Hepatoblastoma
  classification: histology
  description: >-
    Tumors containing epithelial hepatoblastoma elements together with
    mesenchymal stroma such as osteoid, cartilage, or spindle-cell areas.
  evidence:
  - reference: PMID:19072985
    reference_title: "SMARCB1/INI1 alterations and hepatoblastoma: another extrarenal rhabdoid tumor revealed?"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Sixty percent of tumors are classified as epithelial, and about 40% as mixed epithelial-mesenchymal, characterized by an admixture of osseous, cartilaginous and, more rarely, skeletal muscle elements [3]."
    explanation: Supports mixed epithelial-mesenchymal morphology as a recurring hepatoblastoma subtype facet.
- name: Fetal Pattern-Predominant Hepatoblastoma
  classification: histology
  description: >-
    Histology dominated by fetal hepatocyte-like tumor cells, often associated
    with lower-risk biology when pure and well differentiated.
  evidence:
  - reference: PMID:19072985
    reference_title: "SMARCB1/INI1 alterations and hepatoblastoma: another extrarenal rhabdoid tumor revealed?"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Three main histologic subtypes of epithelial HBs are distinguished: fetal, embryonal, and small cell undifferentiated (initially described as anaplastic)."
    explanation: Supports fetal morphology as a canonical epithelial histology facet within hepatoblastoma.
- name: Embryonal Pattern Hepatoblastoma
  classification: histology
  description: >-
    Less differentiated epithelial tumors with embryonal morphology and more
    pronounced proliferative behavior than pure fetal tumors.
  evidence:
  - reference: PMID:19072985
    reference_title: "SMARCB1/INI1 alterations and hepatoblastoma: another extrarenal rhabdoid tumor revealed?"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Three main histologic subtypes of epithelial HBs are distinguished: fetal, embryonal, and small cell undifferentiated (initially described as anaplastic)."
    explanation: Supports embryonal morphology as a canonical epithelial histology facet within hepatoblastoma.
- name: Small Cell Undifferentiated Component-Positive Hepatoblastoma
  classification: histology
  description: >-
    A focal small cell undifferentiated component can occur within
    hepatoblastoma, but INI1-negative/SMARCB1-deficient small-cell liver tumors
    should be treated as malignant rhabdoid tumor rather than as a separate
    hepatoblastoma disease page.
  evidence:
  - reference: PMID:36672416
    reference_title: "Outcomes of Patients Treated for Hepatoblastoma with Low Alpha-Fetoprotein and/or Small Cell Undifferentiated Histology: A Report from the Children's Hepatic Tumors International Collaboration (CHIC)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with HB with SCU component or low AFP should be assessed for SMARCB1 mutations and, if confirmed, treated as rhabdoid tumors."
    explanation: Establishes the practical boundary between hepatoblastoma with an SCU component and SMARCB1-deficient rhabdoid tumors.
  - reference: PMID:34874751
    reference_title: "Small Cell Undifferentiated Histology Does Not Adversely Affect Outcome in Hepatoblastoma: A Report From the Children's Oncology Group (COG) AHEP0731 Study Committee."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The presence of SCU histology in HB does not appear to adversely affect outcome."
    explanation: Supports modeling SCU-positive HB as a histologic facet rather than as a distinct high-risk dismech disease entity when rhabdoid tumors are excluded.
- name: C2-Signature Hepatoblastoma
  classification: molecular_risk
  subtype_frequency: 36%
  description: >-
    High-risk molecular subgroup with a 16-gene expression signature, frequent
    metastasis, non-fetal histology, and inferior survival.
  evidence:
  - reference: PMID:33125945
    reference_title: "A combined clinical and biological risk classification improves prediction of outcome in hepatoblastoma patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutations of CTNNB1, NFE2L2 and TERT were found in 135 (78%), 10 (6%) and 10 (6%) patients, respectively, and the adverse C2 subtype of the 16-gene signature in 63 (36%) patients."
    explanation: Directly supports a clinically meaningful molecular-risk subtype axis within hepatoblastoma.
  - reference: PMID:33125945
    reference_title: "A combined clinical and biological risk classification improves prediction of outcome in hepatoblastoma patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "C2-patients had more frequent metastatic disease, higher alpha-fetoprotein levels, non-fetal histology and significantly worse 3-year OS (68% versus 95%) and EFS (63% versus 87%) than C1-patients."
    explanation: Defines the aggressive phenotype and prognosis of the C2 molecular-risk subtype.
- name: Beckwith-Wiedemann Spectrum-Associated Hepatoblastoma
  classification: predisposition_context
  description: >-
    Hepatoblastoma arising in the setting of 11p15 imprinting abnormalities and
    epigenotype mosaicism characteristic of Beckwith-Wiedemann spectrum.
  evidence:
  - reference: PMID:37174013
    reference_title: "Occurrence of Hepatoblastomas in Patients with Beckwith-Wiedemann Spectrum (BWSp)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with Beckwith-Wiedemann syndrome (BWS), an epigenetic imprinting disorder involving alterations in genes at the 11p15 chromosomal location, are predisposed to develop hepatoblastomas (HBs), which are rare embryonal liver tumors."
    explanation: Supports Beckwith-Wiedemann spectrum as a cancer-predisposition context for hepatoblastoma.
- name: Familial Adenomatous Polyposis-Associated Hepatoblastoma
  classification: predisposition_context
  description: >-
    Hepatoblastoma arising in children from APC-mutation families with familial
    adenomatous polyposis, prompting infant surveillance strategies.
  evidence:
  - reference: PMID:29719120
    reference_title: "Hepatoblastoma in patients with molecularly proven familial adenomatous polyposis: Clinical characteristics and rationale for surveillance screening."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Familial adenomatous polyposis (FAP) due to APC mutation is associated with an increased risk of hepatoblastoma."
    explanation: Supports APC/FAP-associated hepatoblastoma as a predisposition-context subtype facet.
pathophysiology:
- name: CTNNB1-Driven WNT/Beta-Catenin Signaling
  description: >-
    Somatic CTNNB1 mutations or deletions are the dominant recurrent driver in
    hepatoblastoma and lead to persistent nuclear beta-catenin activity.
  evidence:
  - reference: PMID:32881242
    reference_title: "Exploration of CTNNB1 ctDNA as a putative biomarker for hepatoblastoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Driver mutations in the CTNNB1 gene (encoding β-catenin) are a hallmark of sporadic hepatoblastoma (HBL)."
    explanation: Supports CTNNB1 alteration as the canonical sporadic driver of hepatoblastoma.
  - reference: PMID:33125945
    reference_title: "A combined clinical and biological risk classification improves prediction of outcome in hepatoblastoma patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutations of CTNNB1, NFE2L2 and TERT were found in 135 (78%), 10 (6%) and 10 (6%) patients, respectively, and the adverse C2 subtype of the 16-gene signature in 63 (36%) patients."
    explanation: Quantifies CTNNB1 as the dominant recurrent genetic event in a large clinical cohort.
  cell_types:
  - preferred_term: hepatoblast
    term:
      id: CL:0005026
      label: hepatoblast
  biological_processes:
  - preferred_term: Wnt signaling pathway
    modifier: INCREASED
    term:
      id: GO:0016055
      label: Wnt signaling pathway
  locations:
  - preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
  downstream:
  - target: Beta-Catenin/YAP1 Coactivation
    description: Beta-catenin signaling cooperates with YAP1-dependent transcription
    evidence:
    - reference: PMID:24837480
      reference_title: "Activation of β-catenin and Yap1 in human hepatoblastoma and induction of hepatocarcinogenesis in mice."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "We observed nuclear localization of β-catenin and Yap1 in 79% of hepatoblastoma samples but not in most hepatocellular carcinoma or intrahepatic cholangiocarcinoma samples."
      explanation: Demonstrates that active beta-catenin signaling is co-occurring with YAP1 activation in the majority of hepatoblastoma tumors, supporting the causal link.
  - target: Fetal Hepatic Progenitor State Maintenance
    description: Beta-catenin activity reinforces a fetal liver-like differentiation state
    evidence:
    - reference: PMID:27775819
      reference_title: "Genomic analysis of hepatoblastoma identifies distinct molecular and prognostic subgroups."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Our analysis of 88 clinically annotated HBs revealed three risk-stratifying molecular subtypes that are characterized by differential activation of hepatic progenitor cell markers and metabolic pathways:"
      explanation: Supports coupling of the dominant WNT/beta-catenin driver program with persistent hepatic progenitor cell marker expression in clinical hepatoblastoma cohorts.
- name: Beta-Catenin/YAP1 Coactivation
  description: >-
    Nuclear beta-catenin and YAP1 co-occur in most hepatoblastomas and act as
    a cooperative transcriptional module required for robust tumor formation.
  evidence:
  - reference: PMID:24837480
    reference_title: "Activation of β-catenin and Yap1 in human hepatoblastoma and induction of hepatocarcinogenesis in mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We observed nuclear localization of β-catenin and Yap1 in 79% of hepatoblastoma samples but not in most hepatocellular carcinoma or intrahepatic cholangiocarcinoma samples."
    explanation: Demonstrates that concurrent beta-catenin and YAP1 activation is common in human hepatoblastoma tissue.
  - reference: PMID:24837480
    reference_title: "Activation of β-catenin and Yap1 in human hepatoblastoma and induction of hepatocarcinogenesis in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Overexpression of constitutively active forms of Yap1 and β-catenin in mouse liver led to rapid tumorigenesis, with 100% mortality by 11 weeks."
    explanation: Shows that combined activation of YAP1 and beta-catenin is sufficient to drive hepatoblastoma-like tumorigenesis in vivo.
  - reference: PMID:24837480
    reference_title: "Activation of β-catenin and Yap1 in human hepatoblastoma and induction of hepatocarcinogenesis in mice."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Knockdown of Yap1 or β-catenin in hepatoblastoma cells reduced proliferation in an additive manner."
    explanation: Supports cooperative dependence of hepatoblastoma cells on both YAP1 and beta-catenin signaling.
  biological_processes:
  - preferred_term: positive regulation of gene expression
    modifier: ABNORMAL
    term:
      id: GO:0010628
      label: positive regulation of gene expression
  downstream:
  - target: Fetal Hepatic Progenitor State Maintenance
    description: Cooperative transcription sustains immature hepatic identity
    evidence:
    - reference: PMID:24837480
      reference_title: "Activation of β-catenin and Yap1 in human hepatoblastoma and induction of hepatocarcinogenesis in mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Overexpression of constitutively active forms of Yap1 and β-catenin in mouse liver led to rapid tumorigenesis, with 100% mortality by 11 weeks."
      explanation: Co-activation of YAP1 and beta-catenin is sufficient to drive hepatic tumors that recapitulate the immature hepatoblastoma-like lineage state in mouse liver.
  - target: Beta-Catenin/YAP1-Dependent Proliferation
    description: Joint pathway activation drives tumor cell expansion
    evidence:
    - reference: PMID:24837480
      reference_title: "Activation of β-catenin and Yap1 in human hepatoblastoma and induction of hepatocarcinogenesis in mice."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Knockdown of Yap1 or β-catenin in hepatoblastoma cells reduced proliferation in an additive manner."
      explanation: Functional knockdown experiments establish that YAP1/beta-catenin coactivation is required for hepatoblastoma cell proliferation.
- name: Fetal Hepatic Progenitor State Maintenance
  description: >-
    Hepatoblastoma retains hepatic progenitor and fetal liver programs rather
    than completing normal hepatocytic differentiation, aligning the tumor with
    an immature developmental state.
  evidence:
  - reference: PMID:27775819
    reference_title: "Genomic analysis of hepatoblastoma identifies distinct molecular and prognostic subgroups."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our analysis of 88 clinically annotated HBs revealed three risk-stratifying molecular subtypes that are characterized by differential activation of hepatic progenitor cell markers and metabolic pathways:"
    explanation: Supports persistence of hepatic progenitor-state programs across clinically relevant hepatoblastoma subgroups.
  cell_types:
  - preferred_term: hepatoblast
    term:
      id: CL:0005026
      label: hepatoblast
  biological_processes:
  - preferred_term: cell differentiation
    modifier: DECREASED
    term:
      id: GO:0030154
      label: cell differentiation
  locations:
  - preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
  downstream:
  - target: Oncofetal Stem-Cell Marker Program
    description: Immature hepatic identity is accompanied by oncofetal marker expression
    evidence:
    - reference: PMID:27775819
      reference_title: "Genomic analysis of hepatoblastoma identifies distinct molecular and prognostic subgroups."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "high-risk tumors were characterized by up-regulated nuclear factor, erythroid 2-like 2 activity; high lin-28 homolog B, high mobility group AT-hook 2, spalt-like transcription factor 4, and alpha-fetoprotein expression; and high coordinated expression of oncofetal proteins and stem-cell markers, while low-risk tumors had low lin-28 homolog B and lethal-7 expression and high hepatic nuclear factor 1 alpha activity."
      explanation: Documents the tight coupling of progenitor/fetal hepatic transcriptional identity with coordinated oncofetal and stem-cell marker expression in hepatoblastoma.
- name: Oncofetal Stem-Cell Marker Program
  description: >-
    Aggressive hepatoblastomas express oncofetal and stem-cell-associated
    markers including LIN28B, HMGA2, SALL4, and AFP, linking fetal identity to
    high-risk tumor biology.
  evidence:
  - reference: PMID:27775819
    reference_title: "Genomic analysis of hepatoblastoma identifies distinct molecular and prognostic subgroups."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "high-risk tumors were characterized by up-regulated nuclear factor, erythroid 2-like 2 activity; high lin-28 homolog B, high mobility group AT-hook 2, spalt-like transcription factor 4, and alpha-fetoprotein expression; and high coordinated expression of oncofetal proteins and stem-cell markers, while low-risk tumors had low lin-28 homolog B and lethal-7 expression and high hepatic nuclear factor 1 alpha activity."
    explanation: Directly supports an oncofetal stem-cell transcriptional program in aggressive hepatoblastoma.
  biological_processes:
  - preferred_term: positive regulation of gene expression
    modifier: ABNORMAL
    term:
      id: GO:0010628
      label: positive regulation of gene expression
  downstream:
  - target: NFE2L2-Mediated Oxidative-Stress Adaptation
    description: The aggressive oncofetal state is coupled to NFE2L2 pathway activation
    evidence:
    - reference: PMID:27775819
      reference_title: "Genomic analysis of hepatoblastoma identifies distinct molecular and prognostic subgroups."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "high-risk tumors were characterized by up-regulated nuclear factor, erythroid 2-like 2 activity; high lin-28 homolog B, high mobility group AT-hook 2, spalt-like transcription factor 4, and alpha-fetoprotein expression; and high coordinated expression of oncofetal proteins and stem-cell markers, while low-risk tumors had low lin-28 homolog B and lethal-7 expression and high hepatic nuclear factor 1 alpha activity."
      explanation: Establishes that oncofetal/stem-cell program expression is co-regulated with NFE2L2 pathway activation in aggressive hepatoblastoma transcriptomes.
  - target: Beta-Catenin/YAP1-Dependent Proliferation
    description: The oncofetal C2 transcriptional state is associated with more aggressive tumor behavior
    evidence:
    - reference: PMID:33125945
      reference_title: "A combined clinical and biological risk classification improves prediction of outcome in hepatoblastoma patients."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "C2-patients had more frequent metastatic disease, higher alpha-fetoprotein levels, non-fetal histology and significantly worse 3-year OS (68% versus 95%) and EFS (63% versus 87%) than C1-patients."
      explanation: The aggressive C2 transcriptional subtype used here to represent the oncofetal program is associated with metastatic presentation and markedly worse outcomes, supporting a downstream link to sustained tumor aggressiveness.
- name: NFE2L2-Mediated Oxidative-Stress Adaptation
  description: >-
    A subset of hepatoblastomas acquires NFE2L2-driven stress adaptation that
    tracks with non-fetal histology, vessel-invasive growth, and worse outcome.
  evidence:
  - reference: PMID:27775819
    reference_title: "Genomic analysis of hepatoblastoma identifies distinct molecular and prognostic subgroups."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "high-risk tumors were characterized by up-regulated nuclear factor, erythroid 2-like 2 activity; high lin-28 homolog B, high mobility group AT-hook 2, spalt-like transcription factor 4, and alpha-fetoprotein expression; and high coordinated expression of oncofetal proteins and stem-cell markers, while low-risk tumors had low lin-28 homolog B and lethal-7 expression and high hepatic nuclear factor 1 alpha activity."
    explanation: Supports increased NFE2L2 pathway activity in the aggressive transcriptional state.
  - reference: PMID:33125945
    reference_title: "A combined clinical and biological risk classification improves prediction of outcome in hepatoblastoma patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients carrying a NFE2L2 mutation had a significantly worse 3-year OS (57% versus 88%) than NFE2L2 wild-type patients and were more likely to have vessel invasive growth and non-fetal histology."
    explanation: Links NFE2L2 alteration to adverse clinical behavior and non-fetal morphology.
  biological_processes:
  - preferred_term: response to oxidative stress
    modifier: INCREASED
    term:
      id: GO:0006979
      label: response to oxidative stress
  downstream:
  - target: Beta-Catenin/YAP1-Dependent Proliferation
    description: Stress adaptation supports survival and growth of aggressive tumor cells
    evidence:
    - reference: PMID:33125945
      reference_title: "A combined clinical and biological risk classification improves prediction of outcome in hepatoblastoma patients."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Patients carrying a NFE2L2 mutation had a significantly worse 3-year OS (57% versus 88%) than NFE2L2 wild-type patients and were more likely to have vessel invasive growth and non-fetal histology."
      explanation: Clinical association of NFE2L2 mutations with aggressive proliferative/invasive disease behavior supports NFE2L2-driven stress adaptation feeding into sustained tumor proliferation.
- name: Beta-Catenin/YAP1-Dependent Proliferation
  description: >-
    Hepatoblastoma growth depends on beta-catenin/YAP1-driven proliferative
    output, which can be attenuated experimentally by pathway inhibition.
  evidence:
  - reference: PMID:24837480
    reference_title: "Activation of β-catenin and Yap1 in human hepatoblastoma and induction of hepatocarcinogenesis in mice."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Knockdown of Yap1 or β-catenin in hepatoblastoma cells reduced proliferation in an additive manner."
    explanation: Demonstrates that hepatoblastoma cell proliferation depends on both beta-catenin and YAP1 activity.
  - reference: PMID:30863496
    reference_title: "mTOR inhibition affects Yap1-β-catenin-induced hepatoblastoma growth and development."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Rapamycin treatment decreased HB burden, almost normalizing liver weight to body weight ratio."
    explanation: Supports pathway-dependent tumor growth in a beta-catenin/YAP1-driven mouse model and identifies growth-supporting signaling as therapeutically tractable.
  biological_processes:
  - preferred_term: cell population proliferation
    modifier: INCREASED
    term:
      id: GO:0008283
      label: cell population proliferation
histopathology:
- name: Hepatoblastoma
  finding_term:
    preferred_term: Hepatoblastoma
    term:
      id: NCIT:C3728
      label: Hepatoblastoma
  frequency: VERY_FREQUENT
  description: >-
    Malignant pediatric liver neoplasm with epithelial or mixed
    epithelial-mesenchymal morphology.
  evidence:
  - reference: PMID:33981680
    reference_title: "Common and Rare Histological Variants of Hepatoblastoma in Children: A Pathological Diagnosis and Review of the Literature."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Hepatoblastoma (HB) is a rare tumor, but it is the most common primary liver malignancy in children and comprised of approximately 1% of all pediatric malignancies."
    explanation: Supports the core histopathologic disease identity of hepatoblastoma as a pediatric primary liver malignancy.
- name: Embryonal Neoplasm
  finding_term:
    preferred_term: Embryonal neoplasm
    term:
      id: NCIT:C3264
      label: Embryonal Neoplasm
  frequency: VERY_FREQUENT
  description: >-
    Histology reflects embryonal liver differentiation rather than mature
    hepatocytic architecture.
  evidence:
  - reference: PMID:37174013
    reference_title: "Occurrence of Hepatoblastomas in Patients with Beckwith-Wiedemann Spectrum (BWSp)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with Beckwith-Wiedemann syndrome (BWS), an epigenetic imprinting disorder involving alterations in genes at the 11p15 chromosomal location, are predisposed to develop hepatoblastomas (HBs), which are rare embryonal liver tumors."
    explanation: Supports embryonal-neoplasm classification as a central morphologic identity for hepatoblastoma.
phenotypes:
- category: Abdominal
  name: Abdominal Mass
  frequency: VERY_FREQUENT
  diagnostic: true
  description: >-
    Most children present with a painless enlarging abdominal mass caused by the
    underlying liver tumor.
  phenotype_term:
    preferred_term: Abdominal mass
    term:
      id: HP:0031500
      label: Abdominal mass
  evidence:
  - reference: PMID:33981680
    reference_title: "Common and Rare Histological Variants of Hepatoblastoma in Children: A Pathological Diagnosis and Review of the Literature."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Most often present as abdominal mass and has a raised alpha-fetoprotein levels."
    explanation: Supports abdominal mass as the characteristic presenting phenotype.
- category: Hepatic
  name: Hepatomegaly
  frequency: FREQUENT
  description: >-
    Tumor-associated liver enlargement contributes to abdominal enlargement and
    a palpable upper abdominal mass.
  phenotype_term:
    preferred_term: Hepatomegaly
    term:
      id: HP:0002240
      label: Hepatomegaly
  evidence:
  - reference: PMID:16458842
    reference_title: "Management of liver tumors in childhood."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Clinical presentation, especially in young children is relatively uniform with abdominal enlargement and a painless tumor, and often specific symptoms develop late."
    explanation: Supports tumor-related abdominal enlargement consistent with hepatomegaly from a large liver mass.
biochemical:
- name: Elevated Serum Alpha-Fetoprotein
  biomarker_term:
    preferred_term: alpha-fetoprotein
    term:
      id: NCIT:C16278
      label: Alpha-Fetoprotein
  notes: >-
    Serum AFP is elevated in most hepatoblastomas and is used for diagnosis,
    response assessment, and surveillance.
  evidence:
  - reference: PMID:33981680
    reference_title: "Common and Rare Histological Variants of Hepatoblastoma in Children: A Pathological Diagnosis and Review of the Literature."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Most often present as abdominal mass and has a raised alpha-fetoprotein levels."
    explanation: Supports elevated AFP as the characteristic biochemical signature of hepatoblastoma.
  - reference: PMID:16458842
    reference_title: "Management of liver tumors in childhood."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Histological diagnosis is essential for differential diagnosis and may only be omitted in some hepatoblastoma patients of the typical age (6 months to 3 years) with an excessively elevated serum-alpha-fetoprotein."
    explanation: Supports markedly elevated AFP as a clinically meaningful diagnostic biomarker in typical-age hepatoblastoma.
- name: Low Serum Alpha-Fetoprotein at Diagnosis
  biomarker_term:
    preferred_term: alpha-fetoprotein
    term:
      id: NCIT:C16278
      label: Alpha-Fetoprotein
  notes: >-
    AFP below 100 ng/mL at diagnosis defines a biologically concerning context
    that should prompt reassessment for SMARCB1-deficient rhabdoid tumor and
    consideration of transplant referral when unresectability features are
    present.
  evidence:
  - reference: PMID:18166449
    reference_title: "Hepatoblastoma with a low serum alpha-fetoprotein level at diagnosis: the SIOPEL group experience."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This study clearly identifies patients with hepatoblastoma and low serum AFP at diagnosis as a high-risk subgroup with extensive disease at diagnosis, poor response to chemotherapy and a poor outcome."
    explanation: Supports low AFP as a high-risk biomarker context within clinically diagnosed hepatoblastoma.
  - reference: PMID:17661341
    reference_title: "Features predicting unresectability in hepatoblastoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients who had multifocal lesions and those who had an alpha-fetoprotein (alphaFP) level <100 ng/mL survived only if they underwent transplantation."
    explanation: Links low AFP to unresectability and transplant dependence in a surgical cohort.
- name: CTNNB1 Circulating Tumor DNA
  notes: >-
    CTNNB1-mutant ctDNA can be detected in plasma and tracks tumor burden,
    residual disease, and treatment response in molecularly informative cases.
  evidence:
  - reference: PMID:32881242
    reference_title: "Exploration of CTNNB1 ctDNA as a putative biomarker for hepatoblastoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our results show that CTNNB1 circulating tumour DNA (ctDNA) is readily detected in patients diagnosed with localised HBL, with serial sampling along the course of therapy and follow up providing a sensitive mechanism to monitor tumour dynamics and response to treatment."
    explanation: Supports CTNNB1 ctDNA as a dynamic liquid-biopsy biomarker in hepatoblastoma.
  - reference: PMID:38201440
    reference_title: "Quantitative ctDNA Detection in Hepatoblastoma: Implications for Precision Medicine."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Notably, ctDNA positivity correlated with tumor burden, and ctDNA levels exhibited associations with macroscopic residual disease and treatment response."
    explanation: Independently supports ctDNA as a biomarker of disease burden and response.
genetic:
- name: CTNNB1
  association: Somatic Activating Mutation
  notes: >-
    CTNNB1 mutation or exon 3 deletion is the dominant somatic driver in
    sporadic hepatoblastoma and establishes the core WNT/beta-catenin program.
  evidence:
  - reference: PMID:32881242
    reference_title: "Exploration of CTNNB1 ctDNA as a putative biomarker for hepatoblastoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Driver mutations in the CTNNB1 gene (encoding β-catenin) are a hallmark of sporadic hepatoblastoma (HBL)."
    explanation: Supports CTNNB1 as the hallmark sporadic driver gene.
  - reference: PMID:33125945
    reference_title: "A combined clinical and biological risk classification improves prediction of outcome in hepatoblastoma patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutations of CTNNB1, NFE2L2 and TERT were found in 135 (78%), 10 (6%) and 10 (6%) patients, respectively, and the adverse C2 subtype of the 16-gene signature in 63 (36%) patients."
    explanation: Quantifies CTNNB1 as the most frequent recurrent mutation in a large cohort.
- name: NFE2L2
  association: Somatic Mutation
  notes: >-
    NFE2L2 mutation marks an aggressive subset with non-fetal histology,
    vessel-invasive growth, and inferior survival.
  evidence:
  - reference: PMID:33125945
    reference_title: "A combined clinical and biological risk classification improves prediction of outcome in hepatoblastoma patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients carrying a NFE2L2 mutation had a significantly worse 3-year OS (57% versus 88%) than NFE2L2 wild-type patients and were more likely to have vessel invasive growth and non-fetal histology."
    explanation: Supports NFE2L2 as an adverse-risk molecular alteration in hepatoblastoma.
- name: TERT
  association: Somatic Promoter Mutation
  notes: >-
    TERT mutations occur in a minority of tumors and are enriched in older
    children compared with the usual infant-predominant age distribution.
  evidence:
  - reference: PMID:33125945
    reference_title: "A combined clinical and biological risk classification improves prediction of outcome in hepatoblastoma patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "TERT mutations were almost exclusively found in older patients, whereas CTNNB1 mutations showed no association with any clinical feature or outcome."
    explanation: Supports age-enrichment of TERT mutation within hepatoblastoma.
- name: APC
  association: Germline Predisposition
  notes: >-
    Germline APC mutation in familial adenomatous polyposis increases childhood
    hepatoblastoma risk and motivates early-life surveillance in affected
    families.
  evidence:
  - reference: PMID:29719120
    reference_title: "Hepatoblastoma in patients with molecularly proven familial adenomatous polyposis: Clinical characteristics and rationale for surveillance screening."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Familial adenomatous polyposis (FAP) due to APC mutation is associated with an increased risk of hepatoblastoma."
    explanation: Supports APC/FAP as a hereditary predisposition mechanism for hepatoblastoma.
  - reference: PMID:1329510
    reference_title: "Risk of hepatoblastoma in familial adenomatous polyposis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This figure is significantly higher than the 1/100,000 incidence of hepatoblastoma in the general population."
    explanation: Supports markedly elevated hepatoblastoma risk in FAP families relative to the background population.
- name: 11p15 Imprinting Defects / Beckwith-Wiedemann Spectrum
  association: Epigenetic Predisposition
  notes: >-
    Beckwith-Wiedemann spectrum creates an epigenetic predisposition context for
    hepatoblastoma through abnormal 11p15 imprinting and mosaic overgrowth
    biology, with frequent convergence on CTNNB1 mutation in the tumor.
  evidence:
  - reference: PMID:37174013
    reference_title: "Occurrence of Hepatoblastomas in Patients with Beckwith-Wiedemann Spectrum (BWSp)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with Beckwith-Wiedemann syndrome (BWS), an epigenetic imprinting disorder involving alterations in genes at the 11p15 chromosomal location, are predisposed to develop hepatoblastomas (HBs), which are rare embryonal liver tumors."
    explanation: Supports 11p15/Beckwith-Wiedemann biology as a hepatoblastoma predisposition mechanism.
  - reference: PMID:37174013
    reference_title: "Occurrence of Hepatoblastomas in Patients with Beckwith-Wiedemann Spectrum (BWSp)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We found that 100% of the HBs that underwent NGS panel testing had variants in the CTNNB1 gene."
    explanation: Supports convergence of BWSp-associated hepatoblastoma on CTNNB1-mutant tumor biology.
treatments:
- name: Cisplatin-Based Neoadjuvant Chemotherapy
  description: >-
    Cisplatin-based chemotherapy is standard for most unresectable or advanced
    tumors and is used preoperatively to shrink disease and improve
    resectability.
  treatment_term:
    preferred_term: chemotherapy
    term:
      id: MAXO:0000647
      label: chemotherapy
    therapeutic_agent:
    - preferred_term: cisplatin
      term:
        id: CHEBI:27899
        label: cisplatin
    - preferred_term: doxorubicin
      term:
        id: CHEBI:28748
        label: doxorubicin
  evidence:
  - reference: PMID:28126357
    reference_title: "Hepatoblastoma."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "neoadjuvant chemotherapy is now standard, particularly in unresectable tumors resulting in considerable preoperative tumor shrinkage and sometimes near total ablation of the tumor."
    explanation: Supports neoadjuvant chemotherapy as standard hepatoblastoma management.
  - reference: PMID:25349947
    reference_title: "Effect of neoadjuvant chemotherapy on resectability of stage III and IV hepatoblastoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The majority of stage III and IV hepatoblastomas achieved radiographic resectability after two cycles of chemotherapy."
    explanation: Demonstrates the resectability benefit of preoperative chemotherapy in advanced hepatoblastoma.
- name: Complete Surgical Resection
  description: >-
    Complete extirpation of residual tumor remains essential for cure and is
    integrated with chemotherapy in most patients.
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: MAXO:0000004
      label: surgical procedure
  evidence:
  - reference: PMID:16458842
    reference_title: "Management of liver tumors in childhood."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Surgery is the mainstay of treatment for all benign and malignant liver tumors."
    explanation: Supports surgery as a core treatment modality for malignant pediatric liver tumors including hepatoblastoma.
  - reference: PMID:16458842
    reference_title: "Management of liver tumors in childhood."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Hepatoblastomas mostly respond well to chemotherapy. Therefore, this modality should always be combined with surgical resection in these patients and in many cases can reduce the size of a large tumor to resectability."
    explanation: Supports combining chemotherapy with definitive surgical resection in hepatoblastoma.
- name: Liver Transplantation for Unresectable Liver-Confined Disease
  description: >-
    Orthotopic liver transplantation is a curative option for unresectable
    unifocal or multifocal tumors confined to the liver and should be considered
    early when PRETEXT extent, vascular involvement, or low AFP suggest failed
    conservative surgery.
  treatment_term:
    preferred_term: organ transplantation
    term:
      id: MAXO:0010039
      label: organ transplantation
  evidence:
  - reference: PMID:12352881
    reference_title: "Orthotopic liver transplantation for unresectable hepatoblastoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Liver transplantation is an effective treatment for unresectable unifocal or multifocal hepatoblastoma confined to the liver."
    explanation: Directly supports transplantation as curative therapy for unresectable liver-confined hepatoblastoma.
  - reference: PMID:34441025
    reference_title: "Liver Transplantation Is Highly Effective in Children with Irresectable Hepatoblastoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Conclusions: In irresectable cases, liver transplantation reveals excellent outcomes in children with hepatoblastoma with an acceptable number of perioperative complications."
    explanation: Supports favorable modern transplant outcomes in irresectable hepatoblastoma.
references:
- reference: PMID:1329510
  title: "Risk of hepatoblastoma in familial adenomatous polyposis."
  found_in:
  - Hepatoblastoma-deep-research-openai.md
  findings: []
- reference: PMID:12352881
  title: "Orthotopic liver transplantation for unresectable hepatoblastoma."
  found_in:
  - Hepatoblastoma-deep-research-openai.md
  findings: []
- reference: PMID:16458842
  title: "Management of liver tumors in childhood."
  found_in:
  - Hepatoblastoma-deep-research-openai.md
  findings: []
- reference: PMID:17661341
  title: "Features predicting unresectability in hepatoblastoma."
  found_in:
  - Hepatoblastoma-deep-research-openai.md
  findings: []
- reference: PMID:18166449
  title: "Hepatoblastoma with a low serum alpha-fetoprotein level at diagnosis: the SIOPEL group experience."
  found_in:
  - Hepatoblastoma-deep-research-openai.md
  findings: []
- reference: PMID:19072985
  title: "SMARCB1/INI1 alterations and hepatoblastoma: another extrarenal rhabdoid tumor revealed?"
  found_in:
  - Hepatoblastoma-deep-research-openai.md
  findings: []
- reference: PMID:24837480
  title: "Activation of β-catenin and Yap1 in human hepatoblastoma and induction of hepatocarcinogenesis in mice."
  found_in:
  - Hepatoblastoma-deep-research-openai.md
  findings: []
- reference: PMID:25349947
  title: "Effect of neoadjuvant chemotherapy on resectability of stage III and IV hepatoblastoma."
  found_in:
  - Hepatoblastoma-deep-research-openai.md
  findings: []
- reference: PMID:27775819
  title: "Genomic analysis of hepatoblastoma identifies distinct molecular and prognostic subgroups."
  found_in:
  - Hepatoblastoma-deep-research-openai.md
  findings: []
- reference: PMID:28126357
  title: "Hepatoblastoma."
  found_in:
  - Hepatoblastoma-deep-research-openai.md
  findings: []
- reference: PMID:29719120
  title: "Hepatoblastoma in patients with molecularly proven familial adenomatous polyposis: Clinical characteristics and rationale for surveillance screening."
  found_in:
  - Hepatoblastoma-deep-research-openai.md
  findings: []
- reference: PMID:30794807
  title: "β-Catenin and Yes-Associated Protein 1 Cooperate in Hepatoblastoma Pathogenesis."
  found_in:
  - Hepatoblastoma-deep-research-openai.md
  findings: []
- reference: PMID:30863496
  title: "mTOR inhibition affects Yap1-β-catenin-induced hepatoblastoma growth and development."
  found_in:
  - Hepatoblastoma-deep-research-openai.md
  findings: []
- reference: PMID:31835848
  title: "Malignant Rhabdoid Tumor, an Aggressive Tumor Often Misclassified as Small Cell Variant of Hepatoblastoma."
  found_in:
  - Hepatoblastoma-deep-research-openai.md
  findings: []
- reference: PMID:32881242
  title: "Exploration of CTNNB1 ctDNA as a putative biomarker for hepatoblastoma."
  found_in:
  - Hepatoblastoma-deep-research-openai.md
  findings: []
- reference: PMID:33125945
  title: "A combined clinical and biological risk classification improves prediction of outcome in hepatoblastoma patients."
  found_in:
  - Hepatoblastoma-deep-research-openai.md
  findings: []
- reference: PMID:33981680
  title: "Common and Rare Histological Variants of Hepatoblastoma in Children: A Pathological Diagnosis and Review of the Literature."
  found_in:
  - Hepatoblastoma-deep-research-openai.md
  findings: []
- reference: PMID:34441025
  title: "Liver Transplantation Is Highly Effective in Children with Irresectable Hepatoblastoma."
  found_in:
  - Hepatoblastoma-deep-research-openai.md
  findings: []
- reference: PMID:34874751
  title: "Small Cell Undifferentiated Histology Does Not Adversely Affect Outcome in Hepatoblastoma: A Report From the Children's Oncology Group (COG) AHEP0731 Study Committee."
  found_in:
  - Hepatoblastoma-deep-research-openai.md
  findings: []
- reference: PMID:36672416
  title: "Outcomes of Patients Treated for Hepatoblastoma with Low Alpha-Fetoprotein and/or Small Cell Undifferentiated Histology: A Report from the Children's Hepatic Tumors International Collaboration (CHIC)."
  found_in:
  - Hepatoblastoma-deep-research-openai.md
  findings: []
- reference: PMID:37174013
  title: "Occurrence of Hepatoblastomas in Patients with Beckwith-Wiedemann Spectrum (BWSp)."
  found_in:
  - Hepatoblastoma-deep-research-openai.md
  findings: []
- reference: PMID:38201440
  title: "Quantitative ctDNA Detection in Hepatoblastoma: Implications for Precision Medicine."
  found_in:
  - Hepatoblastoma-deep-research-openai.md
  findings: []

classifications:
  icdo_morphology:
    classification_value: Embryonal Neoplasm
  harrisons_chapter:
  - classification_value: cancer
  - classification_value: solid tumor
📚

References & Deep Research

References

22
PMID:1329510
Risk of hepatoblastoma in familial adenomatous polyposis.
No top-level findings curated for this source.
PMID:12352881
Orthotopic liver transplantation for unresectable hepatoblastoma.
No top-level findings curated for this source.
PMID:16458842
Management of liver tumors in childhood.
No top-level findings curated for this source.
PMID:17661341
Features predicting unresectability in hepatoblastoma.
No top-level findings curated for this source.
PMID:18166449
Hepatoblastoma with a low serum alpha-fetoprotein level at diagnosis: the SIOPEL group experience.
No top-level findings curated for this source.
PMID:19072985
SMARCB1/INI1 alterations and hepatoblastoma: another extrarenal rhabdoid tumor revealed?
No top-level findings curated for this source.
PMID:24837480
Activation of β-catenin and Yap1 in human hepatoblastoma and induction of hepatocarcinogenesis in mice.
No top-level findings curated for this source.
PMID:25349947
Effect of neoadjuvant chemotherapy on resectability of stage III and IV hepatoblastoma.
No top-level findings curated for this source.
PMID:27775819
Genomic analysis of hepatoblastoma identifies distinct molecular and prognostic subgroups.
No top-level findings curated for this source.
PMID:28126357
Hepatoblastoma.
No top-level findings curated for this source.
PMID:29719120
Hepatoblastoma in patients with molecularly proven familial adenomatous polyposis: Clinical characteristics and rationale for surveillance screening.
No top-level findings curated for this source.
PMID:30794807
β-Catenin and Yes-Associated Protein 1 Cooperate in Hepatoblastoma Pathogenesis.
No top-level findings curated for this source.
PMID:30863496
mTOR inhibition affects Yap1-β-catenin-induced hepatoblastoma growth and development.
No top-level findings curated for this source.
PMID:31835848
Malignant Rhabdoid Tumor, an Aggressive Tumor Often Misclassified as Small Cell Variant of Hepatoblastoma.
No top-level findings curated for this source.
PMID:32881242
Exploration of CTNNB1 ctDNA as a putative biomarker for hepatoblastoma.
No top-level findings curated for this source.
PMID:33125945
A combined clinical and biological risk classification improves prediction of outcome in hepatoblastoma patients.
No top-level findings curated for this source.
PMID:33981680
Common and Rare Histological Variants of Hepatoblastoma in Children: A Pathological Diagnosis and Review of the Literature.
No top-level findings curated for this source.
PMID:34441025
Liver Transplantation Is Highly Effective in Children with Irresectable Hepatoblastoma.
No top-level findings curated for this source.
PMID:34874751
Small Cell Undifferentiated Histology Does Not Adversely Affect Outcome in Hepatoblastoma: A Report From the Children's Oncology Group (COG) AHEP0731 Study Committee.
No top-level findings curated for this source.
PMID:36672416
Outcomes of Patients Treated for Hepatoblastoma with Low Alpha-Fetoprotein and/or Small Cell Undifferentiated Histology: A Report from the Children's Hepatic Tumors International Collaboration (CHIC).
No top-level findings curated for this source.
PMID:37174013
Occurrence of Hepatoblastomas in Patients with Beckwith-Wiedemann Spectrum (BWSp).
No top-level findings curated for this source.
PMID:38201440
Quantitative ctDNA Detection in Hepatoblastoma: Implications for Precision Medicine.
No top-level findings curated for this source.

Deep Research

1
Manual Pubmed Review ▸
Hepatoblastoma: Manual Curation Notes
n/a 22 citations 2026-04-13T05:23:29Z

Hepatoblastoma: Manual Curation Notes

Modeling decisions used for the YAML

  • The dismech entry was kept at the Hepatoblastoma disease-page level rather than splitting into separate files for pure fetal, embryonal, SCU, or predisposition-associated cases.
  • Subtypes were modeled as flat facets rather than page-worthy child diseases: histology (epithelial, mixed epithelial and mesenchymal, fetal, embryonal, SCU-component-positive), molecular risk (C2-signature), and predisposition context (Beckwith-Wiedemann spectrum, familial adenomatous polyposis).
  • MONDO remains the disease anchor (MONDO:0018666 hepatoblastoma). NCIT is used where the current schema supports oncology-grounded descriptors, chiefly disease-level histopathology and biomarkers.
  • INI1-negative/SMARCB1-deficient small-cell liver tumors were treated as a boundary condition for hepatoblastoma curation rather than as a hepatoblastoma subtype with its own dismech page.

Core disease mechanism

The shared disease program is dominated by CTNNB1/WNT activation. Clinical and liquid-biopsy studies consistently identify CTNNB1 as the dominant recurrent driver in sporadic hepatoblastoma (PMID:32881242; PMID:33125945). This sits upstream of a broader developmental cancer program rather than defining several separate dismech pages.

Hepatoblastoma also shows frequent beta-catenin/YAP1 coactivation. Human tumor tissue demonstrates concurrent nuclear localization of beta-catenin and YAP1 in most cases, and model systems show that combined activation is tumorigenic whereas either pathway alone is insufficient for the same phenotype (PMID:24837480; PMID:30794807). This justified splitting WNT activation and YAP1 cooperation into separate but connected pathophysiology nodes.

The tumor preserves a fetal hepatic progenitor state rather than completing normal hepatocytic differentiation. Pretreatment molecular profiling supports clinically relevant subgroups defined by hepatic progenitor markers and metabolic programs (PMID:27775819). That developmental-arrest concept was modeled separately from the upstream CTNNB1/YAP1 driver nodes.

Aggressive cases show an oncofetal stem-like program and NFE2L2-linked stress adaptation. High-risk tumors are enriched for LIN28B, HMGA2, SALL4, AFP, and NFE2L2 activity, while the C2/NFE2L2-mutant context correlates with non-fetal histology, vessel invasion, metastasis, and inferior survival (PMID:27775819; PMID:33125945). Those were split into separate mechanistic nodes to keep the graph atomic.

Experimental therapy papers also support a downstream growth-support module in beta-catenin/YAP1-driven tumors. In vitro knockdown of either arm reduces growth, and rapamycin reduces tumor burden in a Yap1/beta-catenin mouse model (PMID:24837480; PMID:30863496). This was used to support a distinct proliferation node rather than folding all growth effects into the upstream signaling nodes.

Subtype and histopathology notes

Histology remains a major facet axis. Reviews and clinicopathologic series support broad separation into epithelial versus mixed epithelial-mesenchymal tumors, with fetal, embryonal, and SCU morphologies inside the epithelial axis (PMID:33981680; PMID:19072985).

The key boundary update from the more recent literature is that SCU does not by itself define a separate aggressive hepatoblastoma disease program once rhabdoid tumors are excluded. Modern COG and CHIC analyses show that INI1-negative/SMARCB1-deficient small-cell tumors should be treated as malignant rhabdoid tumor, while SCU component-positive hepatoblastoma without rhabdoid reclassification does not independently worsen outcome (PMID:34874751; PMID:36672416; PMID:31835848). That directly affected the final YAML:

  • SCU is modeled as a flat histology facet inside Hepatoblastoma.
  • INI1-negative liver tumors are described as a classification boundary, not as a Hepatoblastoma child page.
  • The disease-level histopathology grounding uses NCIT for Hepatoblastoma and Embryonal Neoplasm.

Predisposition contexts

Two predisposition contexts are strong enough to warrant explicit subtype facets without separate disease pages.

  • Beckwith-Wiedemann spectrum (BWSp): hepatoblastoma arises in the setting of 11p15 imprinting abnormalities and epigenotype mosaicism, with frequent convergence on CTNNB1 mutation in the tumor (PMID:37174013).
  • Familial adenomatous polyposis (FAP): APC mutation confers childhood hepatoblastoma risk and motivates infant surveillance in affected families (PMID:29719120; PMID:1329510).

These were modeled as predisposition_context subtypes instead of separate dismech entries because the shared tumor mechanism still converges on the same disease-level beta-catenin/oncofetal program.

Phenotype and biomarker notes

The most stable disease-level presentation remains painless abdominal mass with tumor-associated hepatomegaly/abdominal enlargement (PMID:33981680; PMID:16458842).

Alpha-fetoprotein (AFP) is the core biomarker. Most tumors show elevated serum AFP, which supports diagnosis and monitoring, while AFP below 100 ng/mL marks a clinically important context that overlaps with SMARCB1-reclassified rhabdoid tumors and failed conservative surgery (PMID:33981680; PMID:16458842; PMID:18166449; PMID:17661341).

CTNNB1 ctDNA is an emerging molecular biomarker that tracks tumor burden, residual disease, and response (PMID:32881242; PMID:38201440).

Treatment notes

Current management is still organized around cisplatin-based preoperative chemotherapy, complete surgical resection when feasible, and liver transplantation for unresectable liver-confined disease (PMID:28126357; PMID:25349947; PMID:16458842; PMID:12352881; PMID:34441025; PMID:17661341).

Because the schema’s oncology-specific treatment support is split between MAXO actions and NCIT regimen descriptors, the YAML keeps generic treatment actions in MAXO and uses CHEBI agents for the specific cytotoxics. An NCIT regimen term would only be preferable here if a stable hepatoblastoma-specific regimen term were already available in the local ontology slice.

Reference set used in curation

  • PMID:1329510
  • PMID:12352881
  • PMID:16458842
  • PMID:17661341
  • PMID:18166449
  • PMID:19072985
  • PMID:24837480
  • PMID:25349947
  • PMID:27775819
  • PMID:28126357
  • PMID:29719120
  • PMID:30794807
  • PMID:30863496
  • PMID:31835848
  • PMID:32881242
  • PMID:33125945
  • PMID:33981680
  • PMID:34441025
  • PMID:34874751
  • PMID:36672416
  • PMID:37174013
  • PMID:38201440