The Impact of Variant Histology in Patients with Urothelial Carcinoma Treated with Radical Cystectomy: Can We Predict the Presence of Variant Histology?
, Miodrag Acimovic 1,2, Veljko Santric 1,2, Branko Stankovic 1, Predrag Nikic 1,2, Ivan Vukovic 1,2, Milan Radovanovic 1,2, Luka Kovacevic 1, Petar Nale 1 and Uros Babic 1,2,*
Round 1
Reviewer 1 Report
This retrospective single center study explores the frequency and significance of variant histology in the cohort of radical cystectomy patients. Although the author clearly state they are not taking into account the subtypes of histological variants due to the relatively small number of patients with variant histology it would be wise to clearly state the frequency of any given variant pattern. I would also suggest that in the light of suggested neoadjuvant chemotherapy treatment as per Guidelines, authors state the proportion of pts. who received it as it may alter survival in both groups.
It would also be wise to state practical implications on clinical decisions that recognition of variant histology might have.
Author Response
Dear Reviewer,
Thank you very much for taking the time to review our manuscript and for providing constructive feedback.
We have addressed the comments and included changes/additional data, which have improved our manuscript. The response to the comments is below.
Although the author clearly state they are not taking into account the subtypes of histological variants due to the relatively small number of patients with variant histology it would be wise to clearly state the frequency of any given variant pattern.
We thank the reviewer for this comment. We added Table 2 in the manuscript, in which we presented the frequencies of variant histology subtypes.
I would also suggest that in the light of suggested neoadjuvant chemotherapy treatment as per Guidelines, authors state the proportion of pts. who received it as it may alter survival in both groups.
We thank the reviewer for this comment. We would like to mention that the patients underwent radical cystectomy in our center were previously treated in other centers in the country where the application of neoadjuvant chemotherapy is heterogeneous. Given the inadequate quality of those data, we did not consider the use of neoadjuvant chemotherapy in our study.
It would also be wise to state practical implications on clinical decisions that recognition of variant histology might have.
We thank the reviewer for this comment. Data from the literature and guidelines are still controversial regarding the treatment of patients with variant histology. The aim of our study was to demonstrate the association of variant histology with more aggressive forms of the disease. In order to make an adequate conclusion about clinical decisions, it would be necessary to conduct prospective studies with a larger number of patients.
Reviewer 2 Report
Comments and Suggestions for Authors
Dear Authors,
I reviewed with interest the paper entitled “Impact of the Presence of Variant Histology in Patients with Urothelial Carcinoma Treated with Radical Cystectomy. Can We Predict the Presence of Variant Histology?”.
First, I would strongly congratulate with the authors for their hard work for the present manuscript, which covers an actual and very interesting topic such as evaluating the importance of histopathological heterogeneity of urothelial carcinoma of the urinary bladder on the course and prognosis of this disease.
I found the present study interesting and fluent to read
However, I have some comments/concerns:
Minor Revision:
In table 4 have authors tried to weight the Gender variable to the logistic regression. Sex has been shown to have important implications on survival outcomes, especially for Variant Histology.
The Effect of Sex on Disease Stage and Survival after Radical Cystectomy in Non-Urothelial Variant-Histology Bladder Cancer. J Clin Med. 2023 Feb 23;12(5):1776. doi: 10.3390/jcm12051776.
Can authors discuss more on this point?
Did the authors explore the neutrophil-leukocyte ratio as a possible predictor?
The main limitation is the small sample size, are there some population-based analyses (SEER, NCDB etc) with larger cohorts?
Author Response
Dear Reviewer,
Thank you very much for taking the time to review our manuscript and for providing constructive feedback.
We have addressed the comments and provide response below.
First, I would strongly congratulate with the authors for their hard work for the present manuscript, which covers an actual and very interesting topic such as evaluating the importance of histopathological heterogeneity of urothelial carcinoma of the urinary bladder on the course and prognosis of this disease. I found the present study interesting and fluent to read
We thank the reviewer for this comment.
In table 4 have authors tried to weight the Gender variable to the logistic regression. Sex has been shown to have important implications on survival outcomes, especially for Variant Histology.
We thank the reviewer for this comment. Given that in our study we did not observe statistical significant relationship between sex and the presence of variant histology, we did not discuss findings that were not statistically significant in our manuscript. Also, we did not discuss other parameters that did not show statistical significance.
Did the authors explore the neutrophil-leukocyte ratio as a possible predictor?
We thank the reviewer for this comment. Given that both leukocyte and neutrophil values showed statistical significance between the two groups, introducing a new parameter that contains both parameters would potentially lose the predictive value of neutrophils in the logistic regression analysis.
The main limitation is the small sample size, are there some population-based analyses (SEER, NCDB etc) with larger cohorts?
We thank the reviewer for this comment. Available data from the literature related to variant histologies mainly refer to the results of institutions where patients with bladder cancer were treated. An additional complicating fact for larger cohorts is the high percentage of undiagnosed variant histologies in TURBT specimens, which we have noted in the manuscript.
Reviewer 3 Report
The authors noted that the prognosis was worse in the variant histology group compared to the pure urothelial carcinoma group. They concluded that neutrophil count was an independent preoperative factor predicting variant histology.
In general, prognosis is influenced by a variety of factors. The authors should present the results to show that variant histology is an independent predictor of prognosis by the multivariate regression analysis. Then, it is good to show that the independent factor predicting variant histology is neutrophil count.
Author Response
Dear Reviewer,
Many thanks for taking the time to review our manuscript and for providing constructive feedback. The response to the comment is below.
The authors should present the results to show that variant histology is an independent predictor of prognosis by the multivariate regression analysis. Then, it is good to show that the independent factor predicting variant histology is neutrophil count.
We thank the reviewer for this comment. Data from the literature show controversial results regarding the survival of patients with variant histology, especially if adjusted to the stage of the disease. In our study, we showed the observed association of the presence of variant histology with all known prognostic factors of the disease and worse survival. Given the observed association of variant histology with prognostic factors in this study, a multivariate analysis that would include these parameters would potentially lead to the conclusion that presence of variant histology have no observed significance.
Reviewer 4 Report
In this manuscript Authors aimed to examine the association between the presence of variant histology of urothelial carcinoma of the bladder and clinical or pathological factors, as well as survival outcomes in patients treated with radical cystectomy in addition to investigate predictors of the presence of variant histology in the surgical specimen of radical cystectomy.
First, I strongly suggest revising the manuscript for English language grammar and syntax, especially in the “Introduction” and the “Discussion” sections of the manuscript. For example, in multiple instances, Authors relied on very long sentences; shorter, more concise sentence would greatly improve the readability and the flow of the manuscript.
Second, the way to present results should be improved:
- I suggest dividing the entire “Results” section of the manuscript in paragraphs. For example: characteristics of the entire patient cohort, predictors of presence of variant histology, survival outcomes.
- You can avoid presenting all data that clearly are reported in tables.
- It is important to state if table 4 refers to a univariable or a multivariable logistic regression analyses. If this is a univariable analysis you cannot say that number of neutrophils represents an independent predictor of the presence of variant histology in the surgical specimen of radical cystectomy.
- It is not sufficient to just show Kaplan-Meier curves to prove a difference in survival between the two cohorts of patients. First, what type of oncological outcome you decide to examine? Cancer-specific survival or overall survival? Second, you should choose a time point (for example 2 years) and provide some values to compare the magnitude of the difference between patients with and without variant histology. Third, please add a table under the plot showing the number of patient at risk within the two groups. Fourth, if possible, explore the status of variant histology as a predictor of worse survival using the Cox regression models adjusting for other clinically relevant prognostic confounders.
Third, please consider adding a table to describe types and prevalence of variant histology of urothelial carcinoma of the bladder you identified within the study cohort.
Fourth, the limitation’s section of the manuscript should be improved. This is a retrospective study with all the bias shared with similar reports.
Extensive editing of English language is required.
Author Response
Dear Reviewer,
Many thanks for taking the time to review our manuscript and for providing constructive feedback. We have addressed the comment and included changes/additional data, which have improved our manuscript. The response to the comment is below.
First, I strongly suggest revising the manuscript for English language grammar and syntax, especially in the “Introduction” and the “Discussion” sections of the manuscript. For example, in multiple instances, Authors relied on very long sentences; shorter, more concise sentence would greatly improve the readability and the flow of the manuscript.
We thank the reviewer for this comment. We have made numerous changes in the text related to the language and writing style.
I suggest dividing the entire “Results” section of the manuscript in paragraphs. For example: characteristics of the entire patient cohort, predictors of presence of variant histology, survival outcomes.
We thank the reviewer for this comment. Given the relatively short text of the Results section, we believe that by dividing it into subsectionswe would lose the clarity of the text.
You can avoid presenting all data that clearly are reported in tables.
We thank the reviewer for this comment. We tried to present in the text all the results of our study that we considered the most important.
It is important to state if table 4 refers to a univariable or a multivariable logistic regression analyses. If this is a univariable analysis you cannot say that number of neutrophils represents an independent predictor of the presence of variant histology in the surgical specimen of radical cystectomy.
We thank the reviewer for this comment. We would like to clarify that the applied binary logistic regression analysis is a type of statistical analysis that simultaneously analyzes all involved parameters and represents a type of "multivariate" analysis. Therefore, statistically significant predictors can be called independent predictors.
First, what type of oncological outcome you decide to examine? Cancer-specific survival or overall survival?
We thank the reviewer for this comment. We examined overall survival in our study. We have made the above mentioned change in the manuscript in accordance with your suggestion.
Second, you should choose a time point (for example 2 years) and provide some values to compare the magnitude of the difference between patients with and without variant histology.
We thank the reviewer for this comment. In accordance with your suggestions, we added data on the time we followed patients and the length of follow-up of both groups of patients.
Third, please add a table under the plot showing the number of patient at risk within the two groups.
We thank the reviewer for this comment. In accordance with your suggestions, we added the table showing the number of patient at risk within the two groups.
Fourth, if possible, explore the status of variant histology as a predictor of worse survival using the Cox regression models adjusting for other clinically relevant prognostic confounders.
We thank the reviewer for this comment. Data from the literature show controversial results regarding the survival of patients with variant histology, especially if adjusted to the stage of the disease. In our study, we showed the observed association of the presence of variant histology with all known prognostic factors of the disease and worse survival. Given the observed association of variant histology with prognostic factors in this study, a multivariate analysis that would include these parameters would potentially lead to the conclusion that presence of variant histology have no observed significance.
Third, please consider adding a table to describe types and prevalence of variant histology of urothelial carcinoma of the bladder you identified within the study cohort.
We thank the reviewer for this comment. We added Table 2 in the manuscript, in which we presented the frequencies of variant histology subtypes.
Fourth, the limitation’s section of the manuscript should be improved. This is a retrospective study with all the bias shared with similar reports.
We thank the reviewer for this comment. We have addressed the comment and included changes in the manuscript.
Round 2
Reviewer 2 Report
Thank you to the authors for providing an improved version of the manuscript.
Did the authors try to include only the neutrophil/lymph ratio instead of splitting the variables in the Regression? If yes, what was the result?
Lastly, As I said in the first round of comments, Sex has been shown to have important implications on survival outcomes, especially for Variant Histology. Please spend some lines in the discussion. doi: 10.3390/jcm12051776.
Author Response
Dear Reviewer,
Thank you very much for taking the time to review our manuscript and for providing constructive feedback.
We have addressed the comments and included changes/additional data, which have improved our manuscript. The response to the comments is below.
Did the authors try to include only the neutrophil/lymph ratio instead of splitting the variables in the Regression? If yes, what was the result?
Given that we included only statistically significant variables in the regression analysis, we did not try to analyze the neutrophil-to-lymphociyte ratio. We would add that the aim of our study was not to examine inflammatory indices such as NLR.
Lastly, As I said in the first round of comments, Sex has been shown to have important implications on survival outcomes, especially for Variant Histology. Please spend some lines in the discussion. doi: 10.3390/jcm12051776.
We thank the reviewer for this comment. In the revised manuscript, we have included the results of the aforementioned study in the discussion section.
Reviewer 3 Report
The authors have successfully revised the previous manuscript.
Author Response
Dear Reviewer,
Thank you very much for taking the time to review our manuscript and for providing constructive feedback.
The authors have successfully revised the previous manuscript.
We thank the reviewer for this comment.
Reviewer 4 Report
Authors have replied to all my previous comments. Some additional clarifications are required.
I am not so convinced about median survival estimates provided in the text of patients with pure UC (17 months) and patients with VH (14.5 months). If I look at the Kaplan Meier plots it seems that median OS is approximately 20 months and 40 months for VH and UC patients, respectively. Please clarify.
Binary logistic regression is just a logistic regression where the dependent variable of interest can assume values of 0 or 1. You should specify in the text and in Table caption if your model is a multivariable model.
Check the text for incorrect tenses and abbreviations.
None.
Author Response
Dear Reviewer,
Thank you very much for taking the time to review our manuscript and for providing constructive feedback.
I am not so convinced about median survival estimates provided in the text of patients with pure UC (17 months) and patients with VH (14.5 months). If I look at the Kaplan Meier plots it seems that median OS is approximately 20 months and 40 months for VH and UC patients, respectively. Please clarify.
We thank the reviewer for this comment. We hereby apologize for the wrongly entered median survival values in the previous version. Namely, by mistake, instead of median survival, we entered median follow-up values. Thanks to your suggestion, we corrected the mentioned error in the text.
Binary logistic regression is just a logistic regression where the dependent variable of interest can assume values of 0 or 1. You should specify in the text and in Table caption if your model is a multivariable model.
We thank the reviewer for this comment. We used a multivariate model and added the specified correction to the text.
Check the text for incorrect tenses and abbreviations.
We thank the reviewer for this comment. We tried to correct the text in accordance with this comment.
