Hepatoblastoma: Symptoms, Types, Causes and Treatment

Hepatoblastoma is the most common malignant liver tumor in children, yet it remains a rare and complex disease. Most frequently diagnosed in children under the age of 5, hepatoblastoma presents unique challenges in its detection, classification, and treatment. With a blend of advances in molecular biology, surgery, and chemotherapy, survival rates have improved dramatically in recent decades. However, a deeper understanding of its symptoms, subtypes, causes, and optimal management is essential for ensuring the best outcomes for affected children and their families. This article provides a comprehensive overview, synthesizing the latest scientific findings to guide clinicians, patients, and caregivers.

Symptoms of Hepatoblastoma

Recognizing hepatoblastoma early is vital, but its symptoms are often subtle and can be mistaken for more common childhood illnesses. Understanding the key signs can prompt timely diagnosis and intervention.

Symptom	Description	Frequency/Context	Source(s)
Abdominal mass	Firm, often painless lump in abdomen	Most common presentation	15
Abdominal pain	Discomfort or pain in the stomach area	May be present	15
Swelling	Visible or palpable abdominal distension	Frequently observed	15
Weight loss	Unexplained loss of weight	Sometimes observed	15
Nausea/Vomiting	Upset stomach, vomiting episodes	Occasional	15
Jaundice	Yellowing of skin/eyes (rare)	Advanced disease	15
Fever	Intermittent, unexplained fever	Infrequent	15
Early satiety	Feeling full quickly	Mass effect on stomach	15

Table 1: Key Symptoms

Common Signs and Their Presentation

The hallmark of hepatoblastoma is a painless, rapidly enlarging abdominal mass. Parents or caregivers may notice a swelling in the child’s abdomen, or a doctor may feel a lump during a routine physical examination. Occasionally, the child may complain of abdominal pain or fullness, particularly if the tumor is large enough to press on other organs.

Other symptoms, such as weight loss, poor appetite, or vomiting, are less specific and can occur in many pediatric illnesses. Jaundice—yellowing of the skin and eyes—occurs rarely and usually indicates advanced liver involvement or bile duct obstruction.

When to Seek Medical Attention

Due to the non-specific nature of many symptoms, hepatoblastoma is often detected incidentally or when the tumor has already grown significantly. Parents should seek medical advice if their child has an unexplained abdominal mass, persistent discomfort, or other ongoing symptoms listed above.

Laboratory and Imaging Clues

A crucial diagnostic marker is the elevated blood level of alpha-fetoprotein (AFP), which is present in the vast majority of hepatoblastoma cases and helps differentiate it from other liver masses in children 15. Imaging studies such as ultrasound and CT scans are used to confirm the presence and extent of the tumor.

Types of Hepatoblastoma

Hepatoblastoma is not a single disease but encompasses several histological and molecular subtypes. Understanding these distinctions is crucial, as they influence prognosis and treatment strategies.

Subtype	Histological Features	Prognosis	Source(s)
Pure fetal	Resembles fetal liver cells	Best prognosis	1 3 4 5
Embryonal	Less differentiated, aggressive	Intermediate	1 3 4 5
Mixed epithelial	Fetal + embryonal cells	Variable	1 3 4
Small cell	Small, undifferentiated cells	Poor prognosis	3
Mixed epithelial-mesenchymal	Epithelial + mesenchymal (bone, cartilage)	Variable	3
Molecular subtypes	C1, C2A, C2B (gene signature-based)	C2A: worst prognosis	2 11

Table 2: Hepatoblastoma Types and Prognosis

Histological Subtypes

Pure Fetal Type:

• Composed of cells that closely resemble those of a developing fetal liver.
• Most often detected at an early stage.
• Associated with the most favorable prognosis and excellent response to surgery and chemotherapy 1 3 4.

Embryonal Type:

• Contains less differentiated cells, appearing more primitive under the microscope.
• Tends to grow more aggressively and is associated with a worse prognosis than the pure fetal type 1 3 4.

Mixed Epithelial Type:

• Features both fetal and embryonal cells.
• Prognosis varies, depending on the proportion of each component 1 3 4.

Small Cell Undifferentiated Type:

• Consists of small, round, undifferentiated cells.
• Rare, but associated with the poorest outcomes and resistance to standard therapies 3.

Mixed Epithelial-Mesenchymal Type:

• Contains both epithelial (liver-like) cells and mesenchymal elements (such as bone or cartilage).
• Prognosis depends on the specific cellular makeup 3.

Molecular and Metabolic Classifications

Recent research has advanced classification beyond traditional histology, identifying molecular subtypes with unique gene expression signatures.

• C1, C2A, and C2B: Subgroups identified via RNA sequencing, with C2A tumors showing the most aggressive behavior and worst survival 2 11.
• Metabolic Subtypes: Embryonal-like cells are highly glycolytic, while fetal-like cells show different metabolic profiles, suggesting that future therapies may be tailored based on these features 4.

Why Subtyping Matters

Knowing the type of hepatoblastoma is essential for:

• Predicting likely response to therapy.
• Guiding surgical decisions.
• Identifying candidates for new targeted treatments as molecular profiling becomes more routine.

Causes of Hepatoblastoma

The causes of hepatoblastoma are multifactorial, involving genetic, environmental, and developmental factors. While much remains to be discovered, significant advances in molecular genetics have improved our understanding of its origins.

Cause/Factor	Description	Relative Risk/Impact	Source(s)
Sporadic mutations	Random, non-inherited gene alterations	Majority of cases	5 6
Wnt/β-catenin pathway	Mutations in CTNNB1 gene (β-catenin)	Present in up to 90% of cases	1 4 5 6
Familial syndromes	Beckwith–Wiedemann, FAP	Strongly increases risk	7
Low birth weight	<1,500g: ~20x risk; 1,500–2,500g: ~2x	Significant	7
Parental tobacco use	Smoking before/during pregnancy	Possible increased risk	7
Liver progenitor cells	Cell of origin; developmental arrest	Key in tumor initiation	1 8

Table 3: Causes and Risk Factors

Genetic and Molecular Drivers

Wnt/β-catenin Pathway Activation:

• The vast majority of hepatoblastomas harbor mutations in the CTNNB1 gene, resulting in abnormal accumulation and activation of β-catenin protein 1 4 5 6.
• This molecular pathway is crucial for cell growth and differentiation during liver development, and its dysregulation leads to unchecked cell proliferation—a hallmark of cancer.
• These mutations are typically somatic (acquired, not inherited) and found in tumor tissue, not in every cell of the body.

Other Pathways:

• Activation of the Notch, MAPK, and PI3K/AKT/mTOR pathways has also been observed, especially in more aggressive tumor subtypes 1 3 8.
• Upregulation of specific genes (e.g., LIN28B, TOP2A, TUG1) has been linked to risk stratification and tumor behavior 2 10 11.

Inherited and Perinatal Factors

Inherited Syndromes:

• Children with Beckwith–Wiedemann Syndrome or Familial Adenomatous Polyposis (FAP) have a significantly increased risk, though these conditions account for only a small percentage of cases 7.

Low Birth Weight:

• A striking association exists between very low birth weight (<1,500g) and hepatoblastoma: risk is increased 20-fold compared to normal birth weight children 7.
• Moderately low birth weight (1,500–2,500g) also doubles the risk.

Environmental Risk Factors:

• Some evidence suggests parental tobacco exposure before or during pregnancy may increase risk, but findings are not yet definitive 7.

Developmental Origin

Hepatoblastoma appears to arise from hepatic progenitor or "blast" cells—immature liver cells arrested at various stages of differentiation 1 8. This is supported by both histological and molecular evidence, with certain subtypes resembling fetal or embryonal liver tissue.

Treatment of Hepatoblastoma

Modern management of hepatoblastoma is a multidisciplinary endeavor, relying on a combination of chemotherapy, surgery, and, in select cases, liver transplantation. Ongoing advances in molecular targeting and risk stratification continue to improve outcomes.

Treatment Modality	Indication/Use	Outcome/Survival	Source(s)
Surgical resection	Localized, resectable tumors	Best chance of cure	12 13 14 15
Neoadjuvant chemotherapy	Shrink unresectable tumors; pre-surgery	Improves resectability	12 13 14 15
Liver transplantation	Unresectable, advanced, or multi-lobar disease	High survival in select cases	13 14 15
Adjuvant chemotherapy	Post-surgery, high-risk residual disease	Reduces recurrence	14 15
Targeted therapies	For refractory/aggressive tumors	Under investigation	10 11 14
Risk stratification	Tailored therapy based on subtype/genetics	Individualized treatment	2 11 14

Table 4: Hepatoblastoma Treatment Modalities

Surgery: The Cornerstone

Complete surgical resection of the tumor remains the only definitive cure 12 13 14 15. Whenever possible, surgeons aim to remove the tumor with adequate margins while preserving enough healthy liver for normal function. Advances in surgical techniques have expanded options even for tumors close to major blood vessels 14.

Chemotherapy: Before and After Surgery

• Neoadjuvant (preoperative) chemotherapy is now standard, especially for tumors that are large or initially unresectable. Cisplatin-based regimens can dramatically shrink tumors, making surgery possible or safer 12 13 14 15.
• Adjuvant (postoperative) chemotherapy is used to eliminate microscopic residual disease and decrease recurrence risk, particularly in high-risk cases 14 15.

Liver Transplantation

In situations where the tumor cannot be safely removed—due to size, location, or multifocality—liver transplantation offers an excellent chance of cure 13 14 15. Outcomes are especially favorable when performed after effective chemotherapy to control tumor spread.

Emerging Therapies and Personalization

• Targeted Therapies: Research is ongoing into drugs that target molecular drivers (e.g., Wnt/β-catenin pathway, TUG1, Fanconi anemia pathway), with agents like bortezomib showing promise in experimental models 10 11 14.
• Risk Stratification: Molecular and genetic profiling now aid in assigning patients to risk categories, allowing for more tailored therapy intensity and reducing toxicity for low-risk patients 2 11 14.

Long-Term Outcomes and Challenges

Thanks to combined modality therapy, overall survival rates now approach 70–80%, with even better outcomes in low-risk, resectable cases 12 13 14. However, challenges remain for children with metastatic, recurrent, or small cell histology tumors, who may benefit from novel therapies and clinical trials 14.

Conclusion

Hepatoblastoma, though rare, is a highly heterogeneous and treatable childhood liver cancer. Early recognition of symptoms, accurate subtyping, and advances in combined therapy have dramatically improved outcomes. Ongoing research into its molecular underpinnings promises even more personalized and effective treatments in the future.

Main Points Covered:

• Hepatoblastoma presents most often as a painless abdominal mass in young children, sometimes with nonspecific symptoms.
• There are multiple histological and molecular subtypes, each with distinct prognoses and implications for therapy.
• The causes involve a combination of genetic mutations (notably in the Wnt/β-catenin pathway), inherited syndromes, low birth weight, and developmental factors.
• Treatment is multidisciplinary, centering on surgery and chemotherapy, with liver transplantation reserved for advanced cases.
• Future management will increasingly rely on molecular profiling to guide personalized therapy, with research into targeted treatments ongoing.

By understanding the complex nature of hepatoblastoma, clinicians and families can work together towards timely diagnosis, optimal treatment, and the best possible outcomes for affected children.