Local Invasion Patterns Characterized by SARIFA and Tumor Budding Differ and Have Distinct Prognostic Significance in Esophageal Adenocarcinoma and Squamous Cell Carcinoma

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Overall, the manuscript presents contributions to the field of esophageal cancer research, particularly in understanding the distinct roles of SARIFA and tumor budding in prognosis. However, the study's limitations, including its small cohort size and single-center design, suggest that further research is necessary to confirm these findings and enhance their clinical utility.

(line 50-54) I wonder the incidence of esophageal cancer and how fetal (mortality) it is among other malignancies in Hungary, in addition to comparison to other Western societies?

please explain more correctly the incidence of SCC compared to AC among esophageal cancers histologically between Hungary and so called Western countries?

(Abbreviations; line 60, 66, 72, 95, 123, 139, 167, 186, 245, 248, 310,344, and 345) : There are too many abbreviations in this article. Some of them are repetitive but the remaining was shown up once. I think the only one time used abbreviation would be better to be written in full term.

(line 83) What is FABP4 or in full term?

(line 130) What is ITBCC in full term?

(Table 1) I cannot see all the results at a glance, and cannot fully understand. Please revise clearly with readability.

(line 364-371) If you want insist this point in Discussion section, you have to describe the results in Result sections separately with evidence. The study's survival analysis, particularly for adenocarcinomas, did not reach statistical significance, which the authors attribute to the small cohort size. This weakens the strength of the conclusions regarding overall survival.

 

(line 293-299) The findings regarding lymph node metastasis in adenocarcinomas contrast with some previous studies, potentially indicating variability in tumor biology that isn’t fully explored in this paper. 

 

(line 272) I do not agree with this phrase. The results you showed that SARIFA is just correlated with lymph node metastasis with no influence on any survival. Isn’t it?

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

REVIEW

Local Invasion Patterns Characterized by SARIFA and Tumor Budding Differ and Have Distinct Prognostic Significance in Esophageal Adenocarcinoma and Squamous Cell Carcinoma"

 

The manuscript presents an investigation into the prognostic significance of invasion front phenomena, specifically Tumor Budding (TB), Poorly Differentiated Clusters (PDC), and Stroma Areactive Invasion Front Areas (SARIFA), in esophageal squamous cell carcinoma (ESQCC) and esophageal adenocarcinoma (EAC). While the study provides valuable insights into these biomarkers, several aspects could be improved or clarified.

 

1. Limited Sample Size and Statistical Power

The study examines a relatively small cohort of 100 cases (57 ESQCC and 43 EAC), which may limit the statistical power of the findings. The authors acknowledge that the small sample size might have impacted the significance of their results, particularly for EAC, where neither TB nor PDC were significant predictors of survival. Increasing the cohort size or performing a power analysis could strengthen the findings and provide more robust statistical conclusions. Little on this topic is to be found on PubMed (2 articles) thus rendering the small sample size alright to be published as is.

 

2. Retrospective Study Design

The retrospective nature of the study inherently limits the ability to control for confounding factors. The selection of cases over an extended period (2008 to 2021) may introduce variability due to changes in surgical techniques, histopathological assessment standards, and patient management strategies over time. A prospective study design would allow for better control over these variables and potentially yield more consistent and reliable data.

 

3. Lack of External Validation

The study lacks external validation of its findings in an independent cohort. Validating the prognostic significance of TB, PDC, and SARIFA in a separate, external cohort would enhance the generalizability and applicability of the results. It is crucial to demonstrate that these biomarkers perform consistently across different patient populations and settings.

 

4. Incomplete Data on Potential Confounders

The manuscript does not provide comprehensive data on all potential confounders that might affect survival outcomes, such as detailed comorbidities, adjuvant therapies, or precise neoadjuvant treatment regimens. The absence of this information could introduce bias and affect the interpretation of the prognostic value of TB, PDC, and SARIFA and should be added in Materials and methods.

 

5. Over-reliance on Histopathological Assessment

While the study focuses on histopathological markers, it might benefit from incorporating molecular or genetic data that could provide a more comprehensive understanding of the tumor biology. Biomarkers at the molecular level could complement histological findings and improve the predictive accuracy of survival outcomes. This would increase the overall strength of the study; however, it is not mandatory due to difficulties in obtaining such data retrospectively.

 

6. Interpretation of SARIFA Findings

The findings related to SARIFA, particularly its higher prevalence in EAC and its association with lymph node metastases, are intriguing but require further elaboration. The authors suggest that SARIFA might be related to tumor metabolism and lipid-based energy production, yet the mechanistic insights into how SARIFA contributes to worse outcomes remain speculative. More in-depth mechanistic studies are needed to substantiate these claims and provide a clearer biological rationale.

 

7. Clarity and Organization of the Results Section

The Results section could benefit from clearer organization and more explicit connections between the reported findings and their clinical implications. Currently, some findings are presented without sufficient context or explanation of their relevance to clinical practice. A more structured approach, possibly with subheadings, could help guide the reader through the results more effectively.

 

8. Limited Discussion on Clinical Implications

Although the manuscript addresses the prognostic significance of TB, PDC, and SARIFA, there is limited discussion on how these findings could directly influence clinical practice or therapeutic decision-making. Providing more specific guidance on how these markers could be integrated into existing diagnostic or treatment algorithms would enhance the manuscript's impact and relevance to clinicians.

 

Conclusion

Overall, while the manuscript contributes valuable data to the understanding of prognostic markers in esophageal cancer, several areas require further refinement. Addressing these limitations could strengthen the study's conclusions and provide more definitive evidence to support the use of TB, PDC, and SARIFA as prognostic markers in clinical practice.

Comments on the Quality of English Language

Minor spellchecking requiered.

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

well done!