Rare, Yet Targetable: New Perspectives on Ampullary Carcinomas

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This is a high-quality, timely, and clinically relevant narrative review addressing the evolving molecular taxonomy and precision-oncology management of ampullary carcinoma (AC), a rare but increasingly targetable malignancy. The manuscript is well written, logically structured, and extensively referenced, and it successfully proposes a pragmatic “lineage-first, mutation-fast” framework that is useful for clinicians and researchers alike.

The article fits well within the scope of IJMS, particularly at the interface of molecular oncology, translational genomics, and clinical decision-making. With minor clarifications and selective tightening, the manuscript would be suitable for publication.

Minor Comments

1. Epidemiology Section

   • Consider consolidating incidence and demographic data to avoid repetition and slightly tighten the Introduction.

2. Histologic Subtype Survival Figures

   • Where median OS and 5-year survival are cited, briefly indicate whether these values derive from surgical series, registry data, or meta-analyses.

3. Consistency of Terminology

   • Use consistent terms throughout for:

     • “pancreatobiliary” vs “pancreaticobiliary”,

     • “intestinal-type AC” vs “intestinal AC”.

4. Formatting and Style

   • Minor typographical inconsistencies (spacing, hyphenation, line breaks) are present and can be corrected during copy-editing.

   • Ensure uniform abbreviation usage at first mention (e.g., ctDNA, cfDNA).

Author Response

Response to Reviewer 1

We thank the reviewer for the careful evaluation of our manuscript and for the very positive and constructive feedback. We are pleased that the reviewer found the review timely, clinically relevant, and well aligned with the goals of precision oncology in ampullary carcinoma. We have addressed all comments as detailed below.

1. Epidemiology section
   Comment:
   Consider consolidating incidence and demographic data to avoid repetition and slightly tighten the Introduction.

Response:
We agree. The epidemiology section has been edited to consolidate incidence, demographic, and geographic data, eliminating redundancy and improving narrative flow in the Introduction.

2. Histologic subtype survival figures
   Comment:
   Where median OS and 5-year survival are cited, briefly indicate whether these values derive from surgical series, registry data, or meta-analyses.

Response:
We have clarified the source of survival estimates throughout the manuscript, specifying whether data originate from surgical cohorts, national registries, or pooled/meta-analytic series, where applicable.

3. Consistency of terminology
   Comment:
   Use consistent terms throughout for “pancreatobiliary” vs “pancreaticobiliary” and “intestinal-type AC” vs “intestinal AC”.

Response:
We fully agree and have standardized terminology throughout the manuscript. The terms “pancreatobiliary subtype” and “intestinal subtype” are now used consistently in the Abstract, main text, figures, and tables, replacing alternative formulations. These terms were selected to align with contemporary histopathologic and molecular classifications and to ensure internal consistency.

4. Formatting and style
   Comment:
   Minor typographical inconsistencies and uniform abbreviation usage should be corrected.

Response:
All typographical inconsistencies (spacing, hyphenation, line breaks) have been corrected, and abbreviations (e.g., ctDNA, cfDNA) are now uniformly defined at first mention and used consistently thereafter.

Once again, we thank the reviewer for the positive assessment and helpful suggestions, which have strengthened the clarity and presentation of the manuscript.

Reviewer 2 Report

Comments and Suggestions for Authors

The review paper is devoted to epidemiology, peculiarities of clinical characteristics and prognosis as well as specific molecular genetic features of ampullary carcinoma, rare gastrointestinal malignancy. Authors described available clinical trials on management of ampullary carcinoma and several specific genetic abnormalities. The review seems to be relevant to the scope of the journal, and the amount of the reviewed data is enough for the paper, however, there are several issues to be addressed.

1. Abbreviation list is missing.
2. Author Contributions, Funding and Data Availability Statement sections are empty.
3. The moderate English editing should be provided. Several typos should be eliminated; the text should be edited to be more concise and to sound more scientifically. In Figure 2 wording in French should be corrected.
4. The Table or Figure summarizing the specific genetic abnormalities described in subsections 2.4.2-2.4.7 and associated changes in cell signaling should be provided (or Figure 2 should be updated). Are any characteristic epigenetic changes described for ampullary carcinoma in the literature (epigenetic modifications, changes in microRNA expression, formation of non-canonical DNA structures)?
5. Authors mentioned complementary diagnostic tools (circulating tumor DNA (ctDNA), exosomal nucleic acids, and circulating tumor-associated cells). Is any practical case described in the clinical practice?
6. Authors should reformulate the Conclusions and Introduction sections to reach the necessary level of scientific novelty.

Comments on the Quality of English Language

The moderate English editing should be provided. Several typos should be eliminated; the text should be edited to be more concise and to sound more scientifically. In Figure 2 wording in French should be corrected.

Author Response

Response to Reviewer 2

We thank Reviewer 2 for the detailed and constructive comments, which have helped improve the completeness, clarity, and translational relevance of the manuscript. All points have been addressed as outlined below.

1. Abbreviation list is missing
   Response:
   An abbreviation list has now been added to the manuscript, including all abbreviations used in the text, figures, and tables.
2. Author Contributions, Funding, and Data Availability sections are empty
   Response:
   The Author Contributions, Funding, Data Availability Statement, and Conflicts of Interest sections have been fully completed in accordance with MDPI guidelines.
3. English editing and correction of typos; Figure 2 wording
   Comment:
   Moderate English editing is required; typos should be eliminated; Figure 2 wording in French should be corrected.

Response:
The manuscript has undergone comprehensive English-language editing to improve clarity, concision, and scientific tone. All typographical errors and formatting inconsistencies have been corrected. Figure 2 wording has been fully revised and corrected to English.

4. Summary of genetic abnormalities and signaling pathways
   Comment:
   A table or figure summarizing genetic abnormalities and associated signaling changes should be provided (or Figure 2 updated).

Response:
Figure 2 has been updated to include mutations mentioned in 2.4.2-2.4.7. The description of the figure has also been updated to mention color-coded according to their preferential association with intestinal, pancreatobiliary, or shared/mixed ampullary carcinoma + a list of abbreviations found in the table. This organization mirrors the histologic subtype distribution shown in the corresponding pie chart and directly addresses the reviewer’s request.

5. Epigenetic alterations in ampullary carcinoma
   Comment:
   Are characteristic epigenetic changes described in the literature?

Response:
A dedicated paragraph (2.4.8) addressing epigenetic alterations has been added. We discuss available evidence on DNA methylation changes, chromatin-remodeling gene involvement (notably SWI/SNF components), and microRNA dysregulation relevant to ampullary and periampullary tumors. We also explicitly note the absence of systematic data on non-canonical DNA structures (e.g., G-quadruplexes), highlighting this as a knowledge gap.

6. Complementary diagnostic tools (ctDNA, exosomes, circulating tumor cells)
   Comment:
   Is any practical clinical case described?

Response:
We have added a clinically oriented paragraph (1.2.) describing real-world applications of liquid biopsy in ampullary and periampullary carcinoma, including bile-derived ctDNA obtained during ERCP, with discussion of concordance with tissue genotyping and potential prognostic implications. Limitations and the need for validation are explicitly acknowledged.

7. Reformulation of Introduction and Conclusions to improve scientific novelty
   Comment:
   Authors should reformulate the Introduction and Conclusions to reach the necessary level of scientific novelty.

Response:
Both the Introduction and Conclusion sections have been revised. The revised text now moves beyond descriptive synthesis to emphasize clinical operationalization, clearly articulates the novelty of the proposed “lineage-first, mutation-fast” framework, delineates the limits of extrapolation from related gastrointestinal malignancies, and defines priorities for ampullary carcinoma–specific translational and clinical research.

We thank Reviewer 2 for these insightful comments, which have significantly improved the rigor, clarity, and translational relevance of the manuscript.

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

No further comments