Pediatric Hepatoblastoma: From Developmental Molecular Mechanisms to Innovative Therapeutic Strategies

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This review provides a timely and generally well-structured overview of pediatric hepatoblastoma (HB) as a developmental tumor, highlighting key signaling pathways (e.g., Wnt/β-catenin, Hippo–YAP/TAZ, IGF, PI3K/AKT/mTOR), intratumoral cellular states (fetal-like vs embryonal/stem-like), therapy resistance, and the “immune-cold” tumor microenvironment. The manuscript also discusses emerging directions such as liquid biopsy approaches and translational models, aiming to bridge mechanistic insights with innovative therapeutic strategies. The conceptual framing is appealing and relevant to both clinicians and translational researchers, but I consider if this review contains a section documenting practical pathology of HB, this review will be read by many more clinicians, pathologists, and young researchers. Please consider adding the documentation of pathological characteristics of HB, such as basic histology, histologic pattern (refer WHO classification), differential diagnosis and useful immunohistochemistry. If possible, representative histologic pictures are favorable.

Author Response

Response to Reviewer 1

We sincerely thank the reviewer for the thoughtful and constructive comments. We fully agree that including a section addressing the practical pathological aspects of pediatric hepatoblastoma would significantly enhance the manuscript’s value, particularly for clinicians, pathologists, and early-career researchers.

In response to this suggestion, we have revised the manuscript to include a dedicated section on the pathological features of hepatoblastoma. Specifically, we have incorporated:

• A concise overview of basic histological features, including the main epithelial and mixed epithelial–mesenchymal components
• A description of histological patterns according to the WHO classification (fetal, embryonal, small cell undifferentiated, macrotrabecular, cholangioblastic, and mixed variants)
• A focused discussion on the differential diagnosis, particularly in relation to pediatric liver tumors such as hepatocellular carcinoma, malignant rhabdoid tumor, and metastatic lesions
• A summary of useful immunohistochemical markers (e.g., β-catenin, glypican-3, AFP, CK19, INI1), emphasizing their diagnostic utility

Additionally, we have included representative histological images to illustrate key morphological patterns and support visual recognition.

We believe that these additions improve the practical applicability of the review and broaden its relevance to a multidisciplinary audience, as suggested by the reviewer.

We are grateful for this valuable recommendation.

 

Sincerely,
The Authors

Reviewer 2 Report

Comments and Suggestions for Authors

Scurtu and coauthors provide a timely narrative review of hepatoblastoma, with a clear emphasis on linking developmental biology, intratumoral heterogeneity, and the tumor microenvironment to current risk stratification and emerging therapeutic strategies. The topic is clinically important, and the manuscript is generally well organized and readable. However, several key elements required for a high-impact review are currently underdeveloped, particularly the explicit definition of the review scope/literature basis and a more actionable framework for integrating molecular/biomarker information into surgical, transplant, and systemic treatment decision-making. I therefore recommend major revision to strengthen methodological transparency, strengthen the translational framework and clarify the key actionable conclusions, and more clearly distinguish evidence-supported conclusions from forward-looking hypotheses.

1. While the manuscript is positioned as a narrative review, it currently lacks a clear statement of review scope and literature basis (e.g., databases consulted, time window, key concepts/terms guiding coverage, inclusion–exclusion principles, and how different evidence types were prioritized). Even for a narrative review, a concise scope statement is important for readers to judge completeness and potential selection bias, and to understand the evidentiary weight behind specific claims. I recommend adding a short paragraph that explicitly defines the scope and clarifies how the authors weighed prospective trials, retrospective cohorts, omics studies, and preclinical model work.
2. Page 12, Section 7: The emerging-therapy discussion appropriately covers key axes (e.g., mTOR, Wnt/YAP, anti-angiogenic strategies, immunotherapy and epigenetic modulation), but several parts remain principle-based (e.g., “combinations may be needed”) without a sufficiently structured rationale, patient-selection logic, or explicit evidence boundaries, issues that are especially important given hepatoblastoma’s low mutational burden and pediatric safety constraints. I recommend adding a concise combination-strategy matrix (table or schematic) that, for each therapeutic class, specifies: (1) biological rationale and target context, (2) the most plausible combination partners (including how these would interface with standard cisplatin-based regimens and surgical/transplant milestones), (3) candidate biomarkers for selection and on-treatment monitoring (linking to the liquid-biopsy section where relevant), and (4) key feasibility/toxicity considerations in pediatric settings. This would substantially increase the decision-aiding value of the section and help distinguish evidence-supported proposals from forward-looking hypotheses.
3. Page 17, Section 10: A central and compelling thesis is that molecular heterogeneity, microenvironmental features, and liquid-biopsy biomarkers should be integrated into risk stratification and should inform key management decisions (treatment intensity/de-escalation, timing of resection, transplant consideration, and trial enrollment). At present, this integration remains largely conceptual. To strengthen the translational value of the review, I strongly encourage the authors to include a single, high-level decision framework (flowchart/algorithm) that starts from current clinical inputs (e.g., PRETEXT/annotation factors, AFP patterns, resectability, metastatic status) and then layers in proposed biomarker axes (tumor molecular features, ctDNA/miRNA, stemness and microenvironmental signatures), culminating in clearly defined, actionable outputs. Importantly, steps should be labeled as evidence-supported versus hypothesis-generating where appropriate, to avoid overinterpretation.
4. Please define abbreviations at first mention (then use consistently). Example: “...systems such as PRETEXT, serum alpha-fetoprotein levels...” (Page 2) — PRETEXT is used before it is expanded later as “Pretreatment Extent of Disease.”
5. Please standardize terminology (same concept, same phrasing across sections). Example: “anatomy -centered decision -making” (page 17) I recommend consistent phrasing throughout (e.g., “anatomy-centered decision-making” vs “anatomical criteria-based decision-making”).

Overall, this is a timely and generally well-structured narrative review with clear clinical relevance. However, to reach the standard expected for publication, the manuscript requires major revision to improve methodological transparency (review scope and literature basis), to provide a more decision-oriented translational framework linking biology/biomarkers to management choices, and to strengthen the emerging-therapy section with clearer evidence boundaries and a structured, actionable synthesis. I believe these revisions are feasible and would substantially increase the rigor and practical value of the review.

Author Response

Dear Reviewer,

We sincerely thank the reviewer for the thorough and insightful evaluation of our manuscript. We greatly appreciate the recognition of the clinical relevance and conceptual framework of our review. We have carefully addressed all comments and substantially revised the manuscript to improve methodological transparency, strengthen the translational framework, and provide more structured and actionable conclusions. Our point-by-point responses are provided below.

Comment 1. Review scope and literature basis

Reviewer comment:
The manuscript lacks a clear statement of review scope and literature basis.

Response:
We fully agree with the reviewer that explicitly defining the scope and literature basis is important, even for a narrative review. Accordingly, we have added a dedicated paragraph in the Introduction section clarifying:

• the databases consulted (PubMed/MEDLINE, Scopus, Web of Science),
• the time window (primarily 2015–2025, with inclusion of seminal earlier studies),
• the key search concepts (e.g., hepatoblastoma, developmental biology, Wnt/β-catenin, tumor microenvironment, liquid biopsy, risk stratification),
• and the inclusion approach, prioritizing prospective clinical studies where available, followed by large retrospective cohorts, high-quality omics analyses, and mechanistic preclinical models.

We also explicitly state that, given the rarity of hepatoblastoma, evidence is often derived from a combination of clinical and translational studies, and this is now clearly acknowledged as a limitation influencing evidentiary weight across sections.

Comment 2. Emerging therapies – need for structured framework

Reviewer comment:

The emerging therapy section lacks structured rationale, patient-selection logic, and clear evidence boundaries.

Response:
We thank the reviewer for this important suggestion. To address this, we have revised Section 7 by:

• adding a structured combination-strategy matrix (new Table 4) that integrates:
  (i) biological rationale and target pathway,
  (ii) potential combination partners (including integration with cisplatin-based regimens and surgical/transplant timing),
  (iii) candidate biomarkers for patient selection and treatment monitoring (including liquid biopsy approaches), and
  (iv) key pediatric feasibility and toxicity considerations.
• explicitly distinguishing between evidence-supported approaches (e.g., anti-angiogenic strategies in selected settings) and forward-looking hypotheses (e.g., combinatorial targeting of Wnt/YAP or epigenetic modulation).
• clarifying how these strategies may interface with current standard-of-care pathways rather than being presented as abstract concepts.

We believe this significantly improves the practical and decision-aiding value of the section, as suggested.

Comment 3. Translational integration framework (decision-making algorithm)

Reviewer comment:
The integration of biomarkers into clinical decision-making remains conceptual.

Response:
We strongly agree with this point and have now included a high-level integrative decision framework (Figure 6), starting from established clinical parameters (PRETEXT, AFP dynamics, resectability, metastatic status) and incorporating emerging biological dimensions, including tumor molecular features, cellular states, tumor microenvironment, and liquid biopsy biomarkers.

To improve clarity and translational relevance, we structured the framework to include a unified integration step (“integrated biological risk layer”) before clinical decision outputs. We also explicitly distinguish between evidence-supported components and emerging, hypothesis-generating elements, to avoid overinterpretation and reflect the current state of the field.

Comment 4. Definition of abbreviations

Reviewer comment:
Abbreviations should be defined at first mention.

Response:
We thank the reviewer for noting this. We have carefully revised the manuscript to ensure that all abbreviations are defined at first mention and then used consistently throughout.

Comment 5. Terminology standardization

Reviewer comment:
Terminology should be standardized across sections.

Response:
We agree and have revised the manuscript to ensure consistent terminology throughout.

We are grateful for the reviewer’s constructive and highly valuable feedback. We believe that the revisions, particularly the addition of a clearly defined review scope, the structured therapeutic framework, and the integrative decision-making model, have substantially improved the rigor, transparency, and clinical applicability of the manuscript.

We hope that the revised version meets the expectations for publication and would like to thank the reviewer again for helping us strengthen the manuscript.

 

Sincerely,
The Authors

Reviewer 3 Report

Comments and Suggestions for Authors

The manuscript provides a very detailed overview of pediatric hepatoblastoma, including epidemiology and pathogenesis, diagnosis, staging, treatment (surgery, chemotherapy, transplantation), and follow-up.

It emphasises an integrated therapeutic approach, especially the use of preoperative (neoadjuvant) chemotherapy combined with surgery, discussing complex resections and the role of liver transplantation.

Important staging systems such as SIOPEL (International Society of Pediatric Oncology Liver Tumor Strategy Group) and PRETEXT (Pretreatment Extent of Disease) are highlighted as crucial for clinical management.

The text covers survival rates and prognostic factors, offering a realistic view of long-term outcomes.

Additionally, it discusses targeted therapies and emerging research areas, referencing clinical trials and molecular biology.

However, as a lengthy manuscript, it covers many aspects and may be very dense and difficult to digest for readers who are not specialists in pediatric oncology or liver surgery. The manuscript clearly covers the surgical aspects of hepatoblastoma treatment. However, in a descriptive review, the surgical technique section might not be sufficiently detailed or visually supported for a surgeon trying to understand specific or complex operative steps (e.g., liver resection maneuvers or transplant details). In detailed surgical manuals, descriptions of complex resections typically require anatomical diagrams, procedural drawings, or high-quality intraoperative images. If the manuscript relies solely on textual descriptions, the surgical section, while theoretically sound, may not provide enough practical guidance for surgeons seeking visual understanding or step-by-step instructions. In short, the critique is not that surgery was omitted, but that the presentation of highly technical, visual topics (such as surgery and transplantation) may be limited by the manuscript's format, which might not have room for all necessary diagrams.

Without figures and detailed descriptions, often essential in surgical texts, the section on surgical techniques or transplantation may fall short for surgeons seeking practical, detailed guidance, though references boost its credibility.

One key observation I consider important is that the manuscript heavily relies on precision medicine for the future. Precision medicine depends on databases that are today highly heterogeneous. Many articles lack experimental validation and are mainly observational and correlational. The quality and heterogeneity of data support the development of precision medicine. The manuscript (and modern oncology) emphasizes precision medicine for the future treatment of hepatoblastoma. However, I agree with your point: the success of this approach depends on the standardization and validity of the data in these databases.

Hepatoblastoma is a rare tumor, so data collection often involves multiple centers using non-uniform sampling and molecular analysis protocols.

• Clinical Data: The use of different staging systems (e.g., PRETEXT/POSTTEXT versus others) or variations in chemotherapy protocols further increases clinical heterogeneity, making direct comparisons difficult.
• Molecular Data: To identify molecular subgroups that might benefit from specific therapies (the core of precision medicine), it is crucial that sequencing platforms and bioinformatics analyses are standardized. Without strict standardization, relevant molecular signals can be lost in the noise caused by technical or methodological differences.

As previously mentioned, much of the current literature is based on observational or correlational studies, which can identify associations but cannot establish causality or therapeutic effectiveness.

• The Validation Gap: Precision medicine cannot advance solely through retrospective databases. International prospective clinical trials using molecular profiling as a stratification method are essential. These studies must validate hypotheses derived from observational data.
• Risk of Stalling: Without rapid efforts to standardize data collection protocols—including biological samples, genetic analysis, and clinical outcomes—future decades may be spent generating vast amounts of non-comparable data, hindering the development of accurate, personalized treatments.

Since hepatoblastoma is rare, no single center can gather enough cases to achieve high statistical power. The immediate solution is international standardization led by large cooperative groups (such as COG, SIOPEL, GPOH). These groups must not only agree on treatment protocols but also on the collection and sharing of molecular and clinical data on harmonized platforms, ensuring high-quality data and proper annotation.

In conclusion, this analysis serves as a vital warning: without a comprehensive review of data-collection methods and urgent international standardization, the potential of precision medicine in hepatoblastoma will remain theoretical for decades due to the unreliability caused by heterogeneous, noisy data.

To clarify, without thorough review and global standardization, progress is impossible. Without decisive action, decades will pass fruitlessly as significant noise in the data hampers accurate predictions. No accurate predictions mean no personalized medicine.

I urge the authors to include a chapter that addresses this major challenge facing medicine. Data standardization is a key element that unites all aspects of disease management, including surgery.

I also recognize that you may not be an expert in this field, so I offer a few suggestions:

Data integration and standardization are essential not only for medical oncologists determining chemotherapy plans or biologists identifying molecular targets, but also for surgeons managing hepatoblastoma.

So, surgeons need the same precise and harmonized data standards:

1. Preoperative Planning (Data-Driven Staging)

The surgical approach in hepatoblastoma is often complex and relies on an accurate assessment of tumor resectability, which can change after neo-adjuvant chemotherapy.

• Standardized imaging data: Surgeons depend on high-quality imaging (CT, MRI) to map the tumor and its relation to vital structures (hepatic vessels, portal vein, suprahepatic veins). It is essential that the evaluation of these data, often summarized in the PRETEXT/POSTTEXT system, is standardized internationally. Variability in scan quality or interpretation can lead to inappropriate surgical decisions (e.g., unsuccessful resections or unnecessary caution).
• Residual Liver Volume (RV) Data: Predicting RV after resection is crucial to prevent postoperative liver failure. Accurate measurement and standardization of these calculations (often volumetric) are necessary.

2. Assessment of Response to Neoadjuvant Chemotherapy

Radical surgery (complete resection) is the main goal and a key prognostic factor in hepatoblastoma.

• Post-Chemotherapy Histological Data: Surgeons need to know not just tumor size but also its histological response (tumor necrosis). The percentage of necrosis is a vital prognostic indicator and affects the need for additional post-surgery treatment. Without standardized collection, processing, and reporting of these post-chemotherapy samples, response assessment is unreliable.
• Improving Resectability: Chemotherapy aims to render initially unresectable tumors resectable. Standardized data help determine if the tumor has responded sufficiently to proceed with radical surgery.

3. Precision Medicine and Surgical Strategy

With advances in precision medicine, molecular data will directly guide surgical plans.

• Biological Risk: If a molecular profile shows a very high risk of recurrence (even after complete resection), future decisions might involve more aggressive approaches (like liver transplant) if resection margins are uncertain, or a more conservative approach for low-risk tumors.
• Standardization of Margin Data: Precise definition of resection margins (R0, R1, R2) is critical, as it directly affects prognosis. International standardization in defining and managing margins is essential.

In summary, data heterogeneity and the absence of international standards (covering imaging, pathology, and outcomes) pose a barrier not only to advancing precision medicine but also to optimize surgical strategies. Surgery, to be effective and safe, depends entirely on accurate and comparable information.

Thank you for your patience through this explanation.

Author Response

Dear Reviewer,

We sincerely thank the reviewer for the detailed, thoughtful, and highly insightful comments. We greatly appreciate the recognition of the comprehensive scope of our manuscript and its integrated clinical perspective. We have carefully considered all points raised and have revised the manuscript accordingly to improve clarity, balance, and translational relevance.

 

Comment 1. Density of the manuscript and surgical section lacking visual/technical detail

Response:
We thank the reviewer for this important observation. We agree that the breadth of topics covered may result in a dense presentation.

Regarding the surgical section, we fully acknowledge that highly technical aspects of liver resection and transplantation are inherently visual and are best conveyed through dedicated surgical atlases or procedural manuscripts including detailed illustrations or intraoperative images. As the primary aim of this work is to provide a translational and integrative narrative review, rather than a surgical manual, we have intentionally maintained a conceptual and clinically oriented discussion of surgical strategies.

Still, to address the reviewer’s concern we have incorporated the suggested aspects in a concise manner to improve completeness and clinical relevance.

We also explicitly acknowledge this limitation in the revised manuscript, emphasizing that complex surgical techniques require dedicated visual and technical resources beyond the scope of the present review.

 

Comment 2. Need for discussion on data heterogeneity and limitations of precision medicine

Response:
We are particularly grateful for this insightful and forward-looking comment. We fully agree that data heterogeneity, lack of standardization, and the predominance of observational studies represent major challenges that may limit the real-world implementation of precision medicine in hepatoblastoma.

In response, we have added a new dedicated subsection 9.5. Data integration, standardization, and limitations of precision medicine in which we address: the heterogeneity of clinical data, including differences in staging systems, treatment protocols, and response assessment; the variability of molecular data, including differences in sequencing platforms, bioinformatic pipelines, and sample processing; the limitations of current evidence, which is largely based on retrospective and correlational studies, with limited prospective validation; the critical need for international standardization efforts, including harmonized protocols for imaging, pathology reporting, molecular profiling, and outcome measures; and the essential role of large cooperative groups (e.g., SIOPEL, COG, GPOH) in enabling prospective, biomarker-driven clinical trials.

We also explicitly highlight the concept of a “validation gap”, emphasizing that the translation of biomarker discoveries into clinical practice requires prospective validation and standardized data infrastructures.

Comment 3. Relevance of data standardization for surgical decision-making

Response:
We strongly agree with the reviewer that data standardization is not only critical for oncology and translational research, but also for surgical planning and decision-making.

Accordingly, we have expanded the discussion to explicitly include the surgical perspective, emphasizing that standardized imaging acquisition and interpretation (including PRETEXT/POSTTEXT staging) are essential for accurate assessment of resectability; volumetric analysis and residual liver volume estimation require consistent methodology to guide safe resection; standardized pathological assessment, including post-chemotherapy tumor necrosis and margin status (R0/R1/R2), is critical for postoperative risk stratification; and future integration of molecular risk profiles may influence surgical strategies, including the balance between resection and transplantation.

We believe that this addition reinforces the central message that data quality and harmonization are foundational across all domains of hepatoblastoma management, including surgery.

We are grateful for the reviewer’s thoughtful and comprehensive critique. We believe that the addition of a dedicated section on data standardization and the clarification of the scope and limitations of the surgical discussion have significantly improved the manuscript. These revisions strengthen both the scientific rigor and the clinical applicability of our review.

 

Sincerely,

The authors

Reviewer 4 Report

Comments and Suggestions for Authors

• The authors should clarify if figures 1 and 2 are fully original and free from any copyright, also as regards any items included in it.
• A table describing the main articles (trials) supporting the use of the "Innovative Therapeutic Strategies" should be drafted and added. 
• A figure showing/summarizing the therapeutic strategies according to sequential lines could be helpful. 
• The difficult access to (innovative) medicines, especially in developing countires, should be discussed (see: PMID: 34416203, PMID: 41107757, etc.), perhaps not only related to hepatobastoma, but in general for rare/pediatric cancers, which also regards the diagnostic aspects and access to molecular diagnosis, which can be also improved through a joint effort/network with centers in developed countries, as discussed by some authors (refer to: PMID: 36276064). A specific section should be drafted to describe this important aspect.
• The conclusion should provide clearer and more practical take home messages. 
• References should be updated and completed based on the new table(s) and section(s).

Comments on the Quality of English Language

See above

Author Response

Dear Reviewer,

We sincerely thank the reviewer for these valuable and constructive suggestions, which have helped us improve the clarity, transparency, and practical relevance of our manuscript. We have addressed each point as detailed below.

Comment 1. Originality and copyright of figures

Response:
We thank the reviewer for raising this important point. We confirm that Figures 5 and 6 are fully original and were created by the authors specifically for this manuscript. No copyrighted material has been reproduced. All graphical elements are original or generated using standard software tools, and no third-party images requiring permission have been included (Please see the Acknowledgments section). Figure 1-4 are original and we have approval from the Ethics Committee of “Saint Mary” Emergency Children Hospital, Iasi, Romania for publication.

Comment 2. Table summarizing key trials supporting innovative therapies

Response:
We agree that a structured overview of key studies would significantly enhance the practical value of the manuscript. Accordingly, we have added a new table (Table 5) summarizing the main clinical and translational studies supporting emerging therapeutic strategies in hepatoblastoma.

This table includes therapeutic class, study type, key findings, and level of evidence, allowing readers to better distinguish between evidence-supported approaches and investigational

Comment 3. Figure summarizing therapeutic strategies (sequential lines)

Response:
We thank the reviewer for this insightful suggestion. However, we respectfully consider that incorporating a detailed figure summarizing therapeutic strategies according to sequential lines may oversimplify the complexity of hepatoblastoma management, which is highly dependent on individual patient factors, staging systems, and institutional protocols.

Moreover, we aimed to maintain a balanced and concise presentation, and the inclusion of such a schematic could increase the overall density of the manuscript without providing substantial additional clarity beyond the structured discussion already presented in the text. Therefore, we have chosen not to include this figure, while ensuring that therapeutic strategies are clearly and logically described throughout the manuscript.

Comment 4. Access to innovative therapies and global disparities

Response:
We fully agree that access to innovative therapies and diagnostic tools represents a critical and often under-recognized challenge, particularly in the context of rare pediatric cancers.

In response to the reviewer’s comment, we have added a dedicated subsection 9.6. Access to innovative therapies and global disparities in pediatric oncology), which addresses the following key aspects: disparities in access to chemotherapy, targeted therapies, and transplantation; limited availability of molecular diagnostics (e.g., sequencing and liquid biopsy approaches); infrastructural and economic barriers in low- and middle-income countries; the importance of international collaboration and data-sharing networks; and the role of cooperative initiatives in improving access to standardized care.

Relevant references (including PMID: 34416203, 41107757, and 36276064) have been incorporated to support and contextualize this discussion.

Comment 5. Conclusions – more practical take-home messages

Response:
We agree and have revised the Conclusions section to provide clearer and more actionable take-home messages.

Comment 6. References update

Response:
We have updated and expanded the reference list to incorporate the newly added table and sections, including literature on therapeutic strategies, global disparities, and data standardization.

Sincerely,
The Authors

Reviewer 5 Report

Comments and Suggestions for Authors

The manuscript entitled Pediatric Hepatoblastoma: From Developmental Molecular Mechanisms to Innovative Therapeutic Strategies is a narrative review that describes the current challenges of anatomy based hepatoblastoma classification and summarizes the recent developments of the molecular insights and precision medicine integration, to achieve better therapy outcomes. The topic is timely and relevant. The structure is clean and comprehensive. The logic is mostly accurate. However, the manuscript has a strong AI-tone and used AI generated image, which make the whole paper less credible. I suggest below minor revisions to improve the manuscript quality: 

1. The images were generated with low quality AI models. Figure 1 even used AI generated histology image, which has no identifiable features for PRETEXT. I recommend the authors to use real images for these. The texts on this AI model are also poorly handled with has low resolution. The authors should also edit the texts. Figure 3 was described in Line 235 but was not included in the manuscript. The authors should provide figure 3. Line 168, Table 1 was typed as Table I.
2. The discussion of molecular pathways lacks substances. E.g. The authors cited single cell sequencing papers and clonal expansion papers to prove hepatoblastoma have intratumor heterogeneity, but they did not explain what the distinct cell populations in it are, and why this contributes to the clinical challenge. E.g.2. It is widely accepted Wnt, Hippo, PI3K affect proliferation and differentiation. But how do they quantitatively affect pathology of HB should be compared. The authors cited the necessary studies to compare the contribution of different pathways but did not expand to explain the details of either pathway. Explaining the details of molecular mechanism will increase the novelty of the review and make this read less like AI-generated content.
3. Line 440: In standard-risk disease, cisplatin monotherapy achieves excellent survival with reduced toxicity. This is not accurate and needs reference.
4. Line 940: DOI and paper information are inconsistent. 

Author Response

Response to Reviewer

We would like to thank the reviewer for the thorough evaluation and constructive suggestions, which have helped us improve the quality and clarity of the manuscript. We have addressed all comments point-by-point below.

Comment 1. AI tone and use of AI-generated images

Response: We appreciate this observation. The manuscript has been carefully revised to improve clarity, scientific depth, and overall academic tone.

Regarding the figures, we agree that the use of AI-generated images, particularly for histological representation, may reduce scientific credibility. Therefore:

• Figure 1 has been fully replaced with representative histopathological images from our personal collection, ensuring the presence of identifiable and diagnostically relevant features
• The use of AI-generated schematics has been limited to conceptual illustrations only. However, if the editors or reviewers deem their inclusion unsuitable, we will promptly remove them.

We believe that replacing the histological content with real images significantly enhances the scientific value and reliability of the manuscript.

 Comment 2. Missing Figure 3

Response:
Thank you for noting this omission. Figure 3 has been removed from its original place and included in the revised manuscript at section 10.3 as Figure 6, being appropriately described and referenced in the text.

 

Comment 3. Table formatting (Table 1 vs Table I)

Response:
This has been corrected.

Comment 4. Insufficient depth in molecular pathways discussion

Response:
We thank the reviewer for this important comment. We have expanded this section to improve clarity.

Specifically, we have:

• Added a more detailed description of intratumoral cellular heterogeneity, including fetal-like, embryonal, and stem-like/progenitor populations, and their functional and clinical relevance
• Clarified how these distinct cellular states contribute to therapy resistance and clinical heterogeneity
• Expanded the discussion of key signaling pathways (Wnt/β-catenin, Hippo–YAP/TAZ, PI3K/AKT/mTOR), including their specific roles in proliferation vs differentiation and their relative contribution to tumor biology, based on available literature

These revisions aim to increase the scientific value and originality of the review.

Comment 5. Line 440 – statement on cisplatin monotherapy

Response:
We agree that this statement required clarification and proper referencing. The sentence has been revised and is now supported by appropriate literature.

Comment 6. Line 940 – DOI inconsistency

Response:
We re-checked the reference against PubMed/journal records and corrected the bibliographic metadata to ensure full consistency with the DOI.

We believe that these revisions have significantly improved the scientific rigor, clarity, and overall quality of the manuscript. We are grateful for the reviewer’s insightful comments.

 

Sincerely,
The Authors

Reviewer 6 Report

Comments and Suggestions for Authors

The authors present hepatoblastoma as a developmental malignancy driven by disrupted hepatic signaling networks rather than a purely anatomical disease. They argue that, despite significant therapeutic progress, current risk stratification remains largely anatomy-based and insufficiently reflects underlying biological heterogeneity. The review aims to integrate recent advances in molecular biology, tumor stemness, and microenvironmental dynamics with emerging translational and targeted strategies. The manuscript highlights aberrant activation of key developmental pathways—particularly Wnt/β-catenin, Hippo–YAP, IGF, and mTOR—as central drivers of proliferation, stem-like phenotypes, and therapeutic resistance. The authors emphasize the potential of liquid biopsy, multi-omics profiling, and novel therapeutic approaches, while noting their limited integration into current clinical algorithms. The review supports a shift toward biologically integrated management frameworks in pediatric hepatoblastoma. Incorporating molecular stratification into therapeutic decision-making is proposed as essential for advancing precision medicine and improving outcomes, particularly in high-risk disease.

I consider is necessary a major revision; here are several comments:

1. What is the origin of the figures..to write into the caption.
2. To complete the legends for Fig 1 and for Fig 2, respectively, with significance of abbreviations from the images
3. To complete the description of main mechanisms implicated in hepatoblastoma formation, in table 2 and figure 2 the Notch signaling; this is essential for regulating cell fate decisions during liver development, and its dysregulation promotes hepatoblastoma progression.
4. To include an abbreviations list.

Author Response

Response to Reviewer

We sincerely thank the reviewer for the thorough and insightful evaluation of our manuscript. We

greatly appreciate the recognition of the clinical relevance and the proposal that incorporating molecular stratification into therapeutic decision-making is essential for advancing precision medicine and improving outcomes, particularly in high-risk disease.

We have carefully addressed all the reviewers' comments and substantially revised the manuscript to improve it. Our point-by-point responses are provided below.

Comment 1. What is the origin of the figures?

Response: Figures 1-4 are from the author's collection, and we have the Ethics Committee of Saint Mary Emergency Children's Hospital approval for publication. We also confirm that Figures 5 and 6 are fully original and were created by the authors specifically for this manuscript. No copyrighted material has been reproduced. All graphical elements are original or generated using standard software tools, and no third-party images requiring permission have been included (Please see the Acknowledgments and Institutional Review Board Statement sections).

Comment 2. To complete the legends for Fig 1 and for Fig 2, respectively, with significance of abbreviations from the images

Response: Initial Figure 1 was deleted. For figures 1-6 we completed the legends with the significance of abbreviations

 

Comment 3. To complete the description of the main mechanisms implicated in hepatoblastoma formation, including the Notch signaling.

Response: We agree that the Notch signaling is essential for regulating cell fate decisions during liver development, and that its dysregulation promotes hepatoblastoma progression. We have made an addition to the text and Table 2 to highlight the importance of Notch signaling in hepatoblastoma.

Comment 4. To include an abbreviations list.

Response: We included an abbreviations list at the end of the manuscript.

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

Thank you for the thoughtful revision, my comments have been fully addressed, and I recommend acceptance as revised.

Reviewer 3 Report

Comments and Suggestions for Authors

I sincerely thank the authors for carefully considering all my comments and suggestions. They have thoroughly revised the manuscript to address the issues I raised, significantly improving its clarity, structure, and scientific rigor. Intellectual honesty should be the foundation of all human endeavors, and scientific research is no exception, as it ensures that findings are reported transparently, methods are described accurately, and conclusions are drawn responsibly from the available evidence.

Reviewer 6 Report

Comments and Suggestions for Authors

The new variant is more complete. Regarding the figures 1-4 that are replacing the Fig. 1 from previous variant, in this variant each of them should have into the legend: "from the author's collection", mentioning which author.