Progress in the study of therapeutic strategies for hepatoblastoma in children

Abstract

Hepatoblastoma (HB) is the most common primary malignant liver tumor in children, representing approximately 50% to 60% of pediatric liver cancers. It predominantly affects children under the age of 3 years, with a slightly higher incidence in boys compared to girls. The main pathological subtypes of HB are epithelial and mixed types. The etiology and pathogenesis are unclear and may be related to factors such as genetics and gene mutations. The diagnosis primarily relies on imaging examinations (including abdominal ultrasound, computed tomography, and magnetic resonance imaging) and serum alpha-fetoprotein testing. Treatment approaches include surgical resection, chemotherapy, and liver transplantation. Surgical resection is currently the only curative option, especially effective for early-stage localized tumors; chemotherapy can be used to shrink tumors before surgery or to manage their progression; liver transplantation is recommended for cases that cannot be surgically removed or for instances where the disease recurs after surgery. Recent advancements have encouraged a multidisciplinary approach to treatment, with ongoing research into new chemotherapeutic and targeted agents. Despite these developments, challenges remain, such as the need for more precise and individualized therapies, chemotherapy resistance that can lead to poor outcomes in some patients, and a shortage of organ donors, along with the risk of immune rejection after transplantation. A thorough synthesis of current therapeutic strategies will establish an evidence-based foundation to enhance the management of HB in children, ultimately improving prognosis and quality of life.

Key Words: Hepatoblastoma; Children; Liver cancer; Surgical resection; Chemotherapy; Targeted therapy

Core Tip: Hepatoblastoma (HB) is the most common malignant liver tumor in children, and its treatment has evolved remarkably in recent years. This review summarizes the latest advances in HB epidemiology, molecular classification, risk stratification, surgical innovations, and systemic therapies. Emphasis is placed on current challenges and critical comparisons of treatment modalities, such as surgical timing, neoadjuvant chemotherapy, liver transplantation, and targeted therapies. By integrating updated evidence and proposing future research directions, this article provides practical insights to guide clinical decision-making and promote individualized, precision therapy in pediatric HB.

INTRODUCTION

Hepatoblastoma (HB) is one of the most common pediatric abdominal malignancies. It is the predominant primary liver tumor in children, primarily affects infants and children under 5 years of age, and typically presents as a painless abdominal mass. Willis first introduced the term “Hepatoblastoma” in 1962, while the earliest documented case dates back to 1898 in British literature[1]. Willis initially characterized HB as an embryonic tumor composed of hepatic epithelial parenchyma. While the overall incidence remains low at approximately 1.8 per 100000, the prevalence of HB has been steadily increasing at an annual rate of 2.5%, paralleling advances in neonatal care and improved survival rates of preterm infants[2].

Current therapeutic approaches for HB encompass chemotherapy, surgical resection, immunotherapy, and targeted therapy. Complete surgical resection remains the only potentially curative treatment. Preoperative neoadjuvant chemotherapy can shrink the tumor and provide access for surgery, and postoperative adjuvant chemotherapy is currently the mainstream treatment for HB. Modern imaging techniques (e.g. diffusion-weighted magnetic resonance imaging, ultrasonography) and neoadjuvant chemotherapy regimens have significantly improved the early diagnosis rate and tumor resectability, and a 5-year survival rate of up to 80% after surgery for HB has been reported[3]. The overall 5-year survival rate for children with recurrent or metastatic HB remains low. Several factors influence the prognosis, including alpha-fetoprotein (AFP) levels, the age at which the diagnosis is made, the completeness of surgical resection, and the clinical stage of the disease. Notably, surgically unresectable tumor is a major factor contributing to treatment failure and poor outcomes[4]. Against this background, a systematic and up-to-date review of current therapeutic strategies for childhood HB is of great significance to improve patient prognosis and optimize individualized treatment plans. Unlike previous reviews, this article not only summarizes conventional approaches such as surgery, chemotherapy, and liver transplantation, but also critically evaluates emerging treatment modalities including targeted therapies and immunotherapies. Moreover, it integrates the most recent clinical trial evidence, analyzes the advantages and limitations of each strategy in different clinical contexts, and proposes a practical decision-making pathway tailored to risk stratification. By offering a comprehensive and analytical perspective, this review aimed to bridge the gap between existing guidelines and evolving clinical practice, thereby providing valuable insights for both researchers and pediatric oncologists.

ETIOLOGY

Most tumors are sporadic, but one-third of cases may be associated with Beckwith–Weidmann syndrome, familial adenomatous polyposis, Edward’s syndrome, and Down’s syndrome[5,6]. Preterm birth and low birth weight babies are at higher risk, and parental smoking before or during pregnancy has also been suggested as a risk factor for HB[7].

The locus of the most frequent genetic variation in HB is located in the Wnt pathway[8], and approximately 70%-90% of the genes are mutated. The gene expression pattern and telomerase activity can be used as prognostic factors[9]. Among them, HB with mutations in the CTNNB1 gene is insensitive to chemotherapy and has a low surgical resection rate[8]. The Japanese Study Group for Pediatric Liver Tumors reported that among 212 children with HB, 107 had mutations in the CTNNB1 gene, and 56 had variants in exon 3 of the CTNNB1 gene; in total, about 80% of the genes had mutations. These included the APC gene and the Axin protein gene[10]. Immunohistochemistry showed that β-linker proteins accumulated in tumor cells with aberrant Wnt signaling, and most of the Wnt signaling target genes, such as cyclin D1, survivin, and proto-oncogenes (Myc genes), were highly expressed.

CLINICAL MANIFESTATIONS AND DIAGNOSIS

Clinical manifestations

Irregularly confined hepatic enlargement is the initial symptom of HB, with the mass is located in the right side of the abdomen or the right upper abdomen; 55% to 60% of cases occur in the right lobe of the liver[11]. The tumor grows rapidly, some reaching below the umbilicus or beyond the midline, with a smooth surface, clear margins, moderate hardness, slight ability to move from side to side, and no pressure pain. Most of the tumors are solitary; however, 15% of HB are multifocal. HB has an insidious onset, and in the early stages, the general condition is mostly good except for mild anemia. In the late stage, jaundice, ascites, fever, anemia, weight loss, abdominal wall venous distension, and dyspnea due to a large intra-abdominal mass may occur.

Diagnosis

Elevated AFP level is one of the important diagnostic criteria for HB, and most patients with HB have abnormally elevated AFP levels and their clinical conditions are closely related to AFP levels. The clinical diagnostic criteria include the following: (1) Children younger than 5 years of age with abdominal mass, typical HB imaging manifestations, and abnormal elevation of serum AFP; and (2) Typical imaging manifestations: abdominal computed tomography suggesting single or multiple solid, predominantly soft tissue masses in the liver, with rich blood supply, which may invade important blood vessels and can be seen as foci of calcification and cystic necrosis. Abdominal ultrasound shows a single solid mass and, in a few cases, multiple foci with clear margins and mildly enhanced echogenicity[12].

Pathological types

Pathological types include the following: (1) Epithelial type, fetal type, simple fetal type with low nuclear schizogenic activity (< 2/10 high magnification field of view); fetal type, high nuclear schizogenic activity (≥ 2/10 high magnification field of view); polymorphic fetal type (poorly differentiated type); and mesenchymal fetal type (markedly enlarged nuclei, deep staining, with polymorphism); embryonic type; small-cell undifferentiated type, Integrase interactor 1-1-positive; Integrase interactor 1-1-negative; giant trabecular type; cholangioblast type; and (2) Mixed epithelial and mesenchymal type, mixed type with teratoid features, and mixed type of mesenchymal origin (without teratoid features)[13].

CLINICAL STAGING AND RISK GROUPING

Clinical staging

Pre-treatment extent of disease (PRETEXT) staging vs post-chemotherapy pre-surgical (POST-TEXT) staging: PRETEXT refers only to the extent of tumor involvement in the liver prior to treatment and is mainly used to assess the feasibility of complete resection in primary surgery. POST-TEXT refers to the extent of involvement of the liver mass after chemotherapy, and is mainly used to assess the feasibility of complete resection in deferred surgery.

The PRETEXT system categorizes the liver into four parts. The left lobe of the liver is made up of the lateral part (Couinaud segments I, II, and III) and the medial part (segment IV), while the right lobe is composed of the anterior part (segments V and VIII) and the posterior part (segments VI and VII). The PRETEXT group was formulated by the International Society of Paediatric Oncology Epithelial Liver Tumor Study Group (SIOPEL) for its initial trial, SIOPEL-1[14]. It was then modified in 2007 for the SIOPEL - 3 trial[15]. Each stage’s definitions are presented in Table 1.

Table 1 Pre-treatment staging system.

Stage	Specifics
PRETEXT/POST-TEXT I	Only one liver section is involved by the tumor
PRETEXT/POST-TEXT II	Tumor involves two contiguous sections of the liver
PRETEXT/POST-TEXT III	Tumor involves three liver sections, or two non-contiguous sections
PRETEXT/POST-TEXT IV	Tumor involves all four liver sections

Pre-treatment extent of disease and post-chemotherapy pre-surgical stages are based on the number of liver sections involved by the tumor before and after preoperative chemotherapy. PRETEXT: Pre-treatment extent of disease; POST-TEXT: Post-chemotherapy pre-surgical.

Even though PRETEXT can be utilized to anticipate tumor resectability, it has certain drawbacks. Differentiating genuine invasion beyond the anatomical limits of a specific liver section from tumor compression and displacement, particularly at the time of diagnosis, is challenging. Additionally, it remains difficult to tell the difference between vascular invasion and involvement, especially when imaging is insufficient. The assignment of the PRETEXT group shows a moderate degree of variability among different observers. In a report using data from the SIOPEL-1 study, the agreement between the preoperative PRETEXT group and postoperative pathological results was merely 51%, with 37% and 12% having over- and underestimated PRETEXT, respectively[16].

Risk grouping

The Children’s Oncology Group (COG)/Evans staging system based on surgical outcome and resectability has been used in the United States for many years to group children with hepatocellular carcinoma and to determine treatment options[17] (Table 2). In China, according to the risk stratification criteria of the SIOPEL and COG, and considering the actual situation in China, children with first-diagnosed HB were classified into extremely low-risk, low-risk, intermediate-risk, and high-risk groups[12] (Table 3).

Table 2 Evan’s surgical stage.

Stage	Specifics
I	Complete gross resection with clear margins
II	Gross total resection with microscopic residual disease at margin of resection
III	Gross total resection with nodal involvement or tumor spill or incomplete resection with gross residual intrahepatic disease
IV	Metastatic disease with either complete or incomplete resection

Evans surgical staging system assesses the extent of tumor resection and presence of metastasis in hepatoblastoma patients.

Table 3 Risk stratification criteria for hepatoblastoma.

Risk group	Stratification criteria
Very low risk	Postoperative COG stage I with well-differentiated fetal histology
Low risk	Meets any of the following	Serum AFP ≥ 100 ng/mL, PRETEXT stage I or II, and absence of high-risk features
		Portal vein involvement (P+)
		Inferior vena cava or hepatic vein involvement (V+)
		Distant metastasis (M+)
		Extrahepatic abdominal disease (E+)
		Tumor rupture or intraperitoneal hemorrhage (H+)
		Lymph node involvement (N+)
	Postoperative COG stage I or II with non-pure fetal and non-small-cell undifferentiated histology
Intermediate risk	Meets any of the following	Preoperative PRETEXT stage III
		Postoperative COG stage I or II with small-cell undifferentiated histology
		Postoperative COG stage III
High risk	Meets any of the following	Serum AFP < 100 ng/mL
		Preoperative PRETEXT stage IV
		Postoperative COG stage IV
		Portal vein (P+) or inferior vena cava/hepatic vein involvement (V+)

COG: Children’s Oncology Group; AFP: Alpha-fetoprotein; PRETEXT: Pre-treatment extent of disease; P⁺: Portal vein involvement; V⁺: Hepatic vein or inferior vena cava involvement; M⁺: Distant metastasis; E⁺: Extrahepatic abdominal disease; H⁺: Tumor rupture or intraperitoneal hemorrhage; N⁺: Lymph node involvement.

Surgical treatment

For resectable HB at diagnosis: Complete tumor resection remains the core treatment for HB, directly influencing long-term prognosis[18]. Surgical techniques have evolved from marginal resection to non-anatomic and anatomic hepatic segmental resection[19]. Approximately 20%-30% of children diagnosed with HB can have their tumors resected immediately. According to the COG guidelines, for children that have PRETEXT I and II tumors with distinct margins (more than 1 cm) in the vena cava, middle hepatic vein, and portal vein, tumor resection without preoperative chemotherapy is advised. The outcomes for patients who had complete resection at the time of diagnosis are comparable to those of patients with positive microscopic margins[20,21]. Primary resection indications include the following: (1) ASA score 1-2; (2) Residual liver > 35% functional; (3) Single tumor in PRETEXT I/II with adequate clearance from vital vessels (≥ 1 cm); and (4) Anticipated microscopic residuals (COG II) not requiring reoperation. Deferred surgery indications include (1) PRETEXT III/IV, after neoadjuvant chemotherapy and biopsy for diagnosis; (2) POST-TEXT I/II after chemotherapy, or POST-TEXT III without vital vessel involvement; (3) POST-TEXT IV with involvement of vena cava or portal vein, referred for complex surgery or transplantation; and (4) Residual metastatic lesions after chemotherapy may still be resectable.

There is debate regarding residual liver volume after HB treatment. A 1-cm surgical margin is difficult in younger patients due to small liver syndrome. Some studies suggest no significant differences in recurrence or survival between complete resection and positive margins[22]. Nevertheless, complete resection remains the gold standard. Surgical intervention is crucial, especially for chemotherapy-resistant lung metastases. Future efforts should focus on advanced imaging, molecular markers, and minimally invasive techniques.

For unresectable or unresected HB at diagnosis: 70%-80% of children with HB have unresectable tumors at diagnosis. COG guidelines recommend biopsy for PRETEXT II (with margins < 1 cm) and all PRETEXT III/IV cases, without initial resection. Treatment options include the following: (1) Reassess surgical resectability after chemotherapy; (2) In situ liver transplantation after chemotherapy[23,24]; and (3) Transarterial chemoembolization or radioembolization to improve resectability[25,26].

In European centers, preoperative chemotherapy is often used to reduce surgical complications. However, a United States study (COG-P9645) recommended resecting all resectable tumors at diagnosis without chemotherapy unless progressive disease occurs[27,28].

If the tumor remains unresectable post-chemotherapy, liver transplantation should be considered[23,29,30]. In the COG AHEP0731 study, patients with POST-TEXT III tumors (“hepatic vein or inferior vena cava” or “portal vein involvement”) or POST-TEXT IV (focal lesions in multiple segments) should be referred for transplantation after the second chemotherapy cycle. Advances in imaging and surgical methods have led some clinics to adopt aggressive surgical treatments with survival rates similar to transplantation, avoiding post-transplantation complications. Sunil et al[19] showed better long-term survival with primary liver transplantation for unresectable cases compared to secondary liver transplantation. Preoperative 3D liver models may reduce complications.

CHEMOTHERAPY

Chinese guidelines

The Chinese diagnostic and treatment guidelines recommend chemotherapy based on risk groups as follows: (1) Extremely low-risk: No chemotherapy, follow-up after surgery; (2) Low-risk: C5V regimen (cisplatin, 5-FU, vincristine), 4-6 cycles; (3) Intermediate-risk: C5VD regimen (cisplatin, 5-FU, vinblastine, adriamycin), 6-8 cycles; and (4) High-risk: 1 cycle of cisplatin + adriamycin, followed by surgery if feasible; if not, change to isocyclophosphamide + carboplatin + etoposide, 8-10 cycles.

USA treatment

Unresectable tumors are treated with chemotherapy. Most stage III/IV tumors are resectable after two rounds of chemotherapy[31], using a combination of isocyclophosphamide, cisplatin, and adriamycin.

For metastatic HB at diagnosis

Survival rates for metastatic HB range from 20% to 70% over 3-5 years[32-34]. Treatment strategies include: (1) Reassess surgical resectability after chemotherapy, and resect primary and extrahepatic metastases (usually pulmonary) if feasible; if metastases are in remission and the primary tumor remains unresectable, in situ liver transplantation is needed; and (2) For unresectable metastatic disease, additional chemotherapy, transarterial chemoembolization, transarterial radioembolization, or radiation may be required[35].

For recurrent HB

Treatment options for recurrent HB include the following: (1) Surgical resection: For isolated lung metastases, aggressive surgery may extend disease-free survival[36]; (2) Chemotherapy: Patients initially treated with cisplatin, vincristine, and fluorouracil may respond to adriamycin regimens, but those previously treated with adriamycin and cisplatin cannot benefit from vincristine and fluorouracil[37]; (3) Liver transplantation: Considered for non-metastatic recurrence within the liver and those not suitable for resection[27]; and (4) Percutaneous ablation: An alternative to surgical resection for oligometastatic HB or as palliative care[38,39].

IMMUNOTHERAPY AND TARGETED THERAPY

Immune checkpoint inhibitors and macrophage-targeted therapies primarily act on the body’s immune regulatory mechanisms against tumors, aiming to counteract immune evasion. For patients with refractory or metastatic HB, immunotherapy may elicit an immune response against HB tumor cells, thereby inhibiting tumor progression. A study has reported the efficacy of the immune checkpoint inhibitor pembrolizumab in a patient with PRETEXT stage III HB, achieving a complete remission lasting 22 months; however, recurrent pulmonary metastases eventually occurred[40].

The targeted agent sorafenib, when combined with (cisplatin + doxorubicin) chemotherapy, has demonstrated partial responses in adult liver cancer patients, yet resistance to sorafenib commonly arises in pediatric solid tumors[41]. Ongoing investigations are evaluating the therapeutic potential of chimeric antigen receptor T cells or humanized antibodies such as codrituzumab targeting GPC3 and AFP in HB[42]. Nevertheless, the efficacy of anti-PD-1 monoclonal antibodies in HB remains limited, potentially due to the tumor’s low mutational burden. Whether the prognosis can be improved through mutation-based patient selection or combination with conventional chemotherapy warrants further exploration[40].

PROGNOSIS

Efficacy evaluation criteria

Efficacy evaluation criteria including: (1) Complete remission: Physical examination and computed tomography or magnetic resonance imaging show that the tumor has completely disappeared and AFP is normal for more than 4 weeks; (2) Partial remission: The tumor shrinks by ≥ 50% without any evidence of new development or disease progression; (3) Stable disease: Tumor shrinkage < 50% without any evidence of tumor enlargement or new lesions; (4) Progressive disease: Tumor enlargement ≥ 25%, or new tumor or elevated AFP; and (5) Recurrence: Confirmed by biopsy; clear imaging evidence and three consecutive increases in serum AFP within 4 weeks.

The 5-year overall survival rate for children with HB is 70%

The prognosis of neonates with HB is comparable to that of older children under 5 years of age[43]. Unfavorable factors affecting prognosis include: (1) Advanced PRETEXT group[20]; (2) Positive PRETEXT annotation factors (V: Involvement of the hepatic vein or the inferior vena cava; P: Involvement of both the left and the right portal vein; E: Spread of extrahepatic tumor; F: Multifocal tumor; R: Rupture of the tumor; M distant metastasis)[44]; (3) Low AFP level[45]; and (4) Older age. In the PRETEXT IV group, patients aged 3 years to 7 years had a poorer prognosis[46]; patients aged 8 years and above all had a worse prognosis than younger patients[47].

CONCLUSION AND FUTURE PERSPECTIVES

In recent years, with continuous advancements in the diagnosis and treatment of pediatric HB, the overall prognosis of affected patients has markedly improved. Nevertheless, due to its pronounced clinical heterogeneity, complex pathological subtypes, and the therapeutic challenges associated with high-risk variants, HB remains a critical and formidable focus in pediatric oncology. This review systematically summarizes the current understanding of HB, encompassing its pathogenesis, diagnostic evaluation, staging systems, risk stratification, surgical strategies, chemotherapy regimens, indications for liver transplantation, and emerging therapeutic approaches, aiming to provide a comprehensive and structured theoretical foundation for clinical practice.

Building upon established treatment paradigms, this review integrates the latest literature to update recent progress in the fields of targeted and immunotherapy for HB. In summary, the diagnosis and treatment of HB have entered the era of precision medicine. The future development of therapeutic strategies urgently requires deeper investigations into molecular mechanisms, more refined risk stratification models, and clinical validation of novel therapeutic modalities. We hope this review not only serves as a systematic decision-making reference for clinicians but also offers theoretical guidance and conceptual inspiration for researchers exploring future directions.