1. Introduction

Hepatoblastoma (HB) is a rare malignant blastomatous tumor of the liver characterized by various combinations of epithelial and mesenchymal cellular lineages that recapitulate early stages of liver ontogenesis. Hepatoblastoma usually occurs in children and is most commonly diagnosed before the age of 5 years, with an incidence of approximately 1.5 cases per million children per year [18]. Very rarely, hepatoblastoma develops in older children and adults.

Hepatoblastoma accounts for less than 5% of all malignant tumors in children. The tumor occurs more frequently in children with low birth weight and is associated with several molecular and cytogenetic abnormalities, including frequent mutations in the Wnt/β-catenin signaling pathway [16].

Morphologically, hepatoblastomas are divided into epithelial and mixed epithelial–mesenchymal types. Epithelial tumors are further classified into fetal, embryonal, macrotrabecular, and small cell undifferentiated subtypes, whereas mixed epithelial–mesenchymal hepatoblastomas are subdivided into tumors with or without teratoid features. The small cell undifferentiated subtype may demonstrate rhabdoid features associated with loss of expression of the INI1 gene, similar to malignant rhabdoid tumors [11]. Although hepatoblastomas are aggressive tumors with a high rate of recurrence and metastasis, modern treatment approaches provide excellent outcomes. To improve treatment effectiveness, molecular profiling is increasingly used to enable more precise risk stratification.

Clinically, the disease usually presents with abdominal enlargement, possible abdominal pain, elevated levels of α-fetoprotein (AFP), and the presence of a solitary hepatic mass [6]. Individuals with familial adenomatous polyposis (FAP)—a syndrome characterized by early development of colorectal polyps and adenocarcinoma—frequently develop hepatoblastoma [8,15]. In addition, mutations in β-catenin are commonly found in sporadic hepatoblastomas, occurring in approximately 67% of patients [12]. Recent studies have shown that other components of the Wnt signaling pathway may also contribute to constitutive pathway activation leading to hepatoblastoma development [14]. Accumulating evidence suggests that hepatoblastoma originates from a pluripotent stem cell [13].

Syndromes associated with an increased incidence of hepatoblastoma include:

• Beckwith–Wiedemann syndrome

• Edwards syndrome

• Down syndrome

• Aicardi syndrome

• Li–Fraumeni syndrome

• Goldenhar syndrome

• von Gierke disease

• familial adenomatous polyposis [9,10]

Although hepatoblastoma remains a rare neoplasm, current approaches to its classification and pathomorphological analysis necessitate standardized reporting of biopsy and resection specimens.

Histological Classification. The modern classification identifies several major histological types of hepatoblastoma:

1. Epithelial type, including:

• Fetal

o fetal with low mitotic activity (well-differentiated)

o mitotically active fetal (“crowded fetal”)

o pleomorphic

2. Embryonal

3. Small cell undifferentiated (SCU)

• SMARCB1 (INI1)-negative

• SMARCB1 (INI1)-positive

4. Cholangioblastic

5. Macrotrabecular

6. Mixed epithelial–mesenchymal (with or without teratoid elements)

The teratoid variant is a rare morphology characterized by elements of neuroectoderm, melanin, and endodermal tissues [17].

Epithelial forms reflect different stages of hepatocyte differentiation: fetal morphology demonstrates features of more mature tissue, whereas embryonal variants represent more primitive structures with a high nuclear-to-cytoplasmic ratio (Fig. 1).

Figure 1. Epithelial hepatoblastoma, pure fetal type. Alternating light and dark areas are observed; the light areas correspond to hepatoblasts with clear cytoplasm due to the accumulation of glycogen and lipids, which are absent in hepatoblasts forming the darker regions. Magnification ×100, H&E

Epithelial hepatoblastoma, pure fetal type. Alternating light and dark areas are observed; the light areas correspond to hepatoblasts with clear cytoplasm due to accumulation of glycogen and lipids, which are absent in hepatoblasts forming the darker regions. Magnification ×100, H&E.

Morphological Characteristics. The fetal subtype is characterized by uniform polygonal cells with round nuclei, moderately eosinophilic cytoplasm, and low mitotic activity. This morphology usually correlates with a favorable prognosis and good resectability. In contrast, embryonal components display larger, angulated nuclei and a higher proliferative activity.

The small cell undifferentiated (SCU) variant consists of small round cells with scant cytoplasm and dense nuclear chromatin. Historically, it has been associated with a poor prognosis. However, differentiation from morphologically similar rhabdoid-like liver tumors requires INI1 immunohistochemistry and genetic testing (Fig. 4) [1]. Mixed types contain mesenchymal tissue elements, including osseous or cartilaginous matrix, as well as teratoid structures, reflecting more complex differentiation pathways of precursor cells (Figs. 2–3) [2].

Figure 2. Mixed epithelial–mesenchymal hepatoblastoma. The tumor contains embryonal and fetal epithelial components intermingled with mesenchymal elements including fibrous, osteoid, and squamous differentiation. Magnification ×100, H&E

Figure 3. Mixed epithelial–mesenchymal hepatoblastoma with teratoid features, including embryonal and fetal epithelial components intermingled with osteoid and neural elements containing melanin. Magnification ×100, H&E

Figure 4. Small immature cells with an increased nuclear-to-cytoplasmic ratio forming a diffuse growth pattern. Magnification ×100, H&E

Table 1. Histological classification of hepatoblastoma

Immunohistochemistry and Molecular Pathology

The immunohistochemical profile is an important diagnostic tool for confirming the diagnosis and determining the tumor subtype. Commonly used markers include:

• Glypican-3 (GPC3): positive expression in most hepatoblastoma variants

• β-catenin: nuclear/cytoplasmic localization correlates with activation of the Wnt signaling pathway

• EpCAM: highly expressed and may reflect greater tumor viability after chemotherapy

• CK19, CK7: useful for identifying cholangioblastic components

Genetic analyses have revealed a high frequency of CTNNB1 mutations, as well as activation of other oncogenic pathways, indicating molecular heterogeneity and potential therapeutic targets [1].

Table 2. Immunohistochemical profile of hepatoblastoma

Clinical Significance of Subtypes. Histological subtypes have prognostic significance. For example, pure fetal morphology in a completely resected tumor is associated with a favorable outcome, whereas the presence of small cell undifferentiated elements or low AFP levels is associated with a more aggressive clinical course [2].

Table 3. Morphology and Clinical Correlation

2. Reporting Recommendations

The International Collaboration on Cancer Reporting (ICCR) recommends including the following parameters in pathology reports for hepatoblastoma:

• histological tumor subtype

• presence of mesenchymal or teratoid components

• degree of differentiation / mitotic activity

• immunohistochemical profile

• presence of vascular invasion

• correlation with clinical and molecular data [5]

3. Conclusions

Pathomorphological examination of hepatoblastoma is a key component in diagnosis and risk stratification for patients with this rare tumor. Recent international recommendations aim to standardize morphological and immunohistochemical approaches, thereby improving diagnostic accuracy, prognostic assessment, and therapeutic management.