Clinicopathological Significances of Peritumoral Budding in Colorectal Cancer: A Detailed Analysis Based on Mucinous and Micropapillary Pattern

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The study evaluated peritumoral budding (PTB) in 266 colorectal cancers and its correlation with clinicopathological features and prognosis. PTB was assessed at the invasive front and graded as high (≥10 buds) or low. High PTB was found in 39.1% of cases and associated with left-sided tumors, lymphatic invasion, nodal and distant metastasis, and higher TNM stage. PTB was significantly higher in non-mucinous compared to mucinous tumors. No association was seen between PTB and micropapillary pattern. Patients with high PTB had worse recurrence-free survival versus low PTB. However, PTB prognostic value differed based on histology - it was significant in cancers with micropapillary pattern but not in those without.

The study has several strengths, including its relatively large sample size, use of recommended hotspot methodology to evaluate PTB, and confirmation of prior links between high PTB and aggressive features and poor prognosis. 

However, the retrospective design limits causal conclusions. Multivariate analysis was lacking to determine if PTB is an independent prognostic marker when adjusted for other known risk factors. Dichotomizing PTB into high and low groups may oversimplify a complex biological phenomenon, and the meaning of intermediate values remains unclear. Please discuss better this issues in the text. The biological mechanisms underlying PTB require further elucidation. 

-Include arrows in Figure 1 to indicate what is being described.

The statement that micropapillary pattern is rare yet found in up to 19.1% of CRCs is confusing. 19% prevalence would not typically be considered rare. Clarification on the exact frequency and terminology is needed.

Details on the study methodology were limited. Please improve. 

The retrospective versus prospective nature, tissue processing methods, and criteria for assessing mucinous component were not clearly specified. 

Table 1: It lacks descriptions of all the tumor classification criteria (cite or describe what defines tumor differentiation. How was vascular invasion researched? Lymphatic invasion? Metastasis? Which metastatic sites were studied? (Description details would make a better paper.)

Figure 2 and 3: Is there only recurrence-free survival? Where are the other survival outcomes?

In summary, while this study provides interesting evidence for PTB prognostic value in CRC, the description of the methodology is the major limitation for publication.

Author Response

We tried to address the points raised by the reviewers as best as we could. The specific responses to the reviewers’ comments are described. In addition, we added about 190 characters through the revision. Please see the attachment.

Author Response File: Author Response.pdf

--------------------------------------------------------------------

Reviewer 2 Report

Comments and Suggestions for Authors

Dear authors,

Thank you for a very interesting paper.

The topic is relevant and important. There are numerous excellent papers discussing the prognostic significance of tumor budding in colorectal cancer.

What is really novel in the paper is correlation with histopathological parameters- with mucinous component and micropappillary pattern. It should be emphasized in the title of the paper, also.

What about other crc patterns- serrated/adenosquamous/medullary- what is already known about PTB in these patterns and why they were not considered in this particular research?

How did the authors differentiated micropapillary pattern from poorly differentiated clusters? 

Fig 1B. It is not clear from the image that this is an invasive front of the colorectal cancer; 

In the discussion, besides analyzing exsisting methodos of PTB grading (it would be enough to explain why you have choosen the two-tired system, the research was not about that, it was the correlation between PTB and various parameters), you should compare your results with already published, and explain differences, if any.

Author Response

We tried to address the points raised by the reviewers as best as we could. The specific responses to the reviewers’ comments are described. In addition, we added about 190 characters through the revision. Please see the attachment.

Author Response File: Author Response.pdf