Prognostic Factors of Survival for High-Grade Neuroendocrine Neoplasia of the Bladder: A SEER Database Analysis
, Andrea Marchetti 2, Giacomo Nuvola 2, Elisa Tassinari 2, Giuseppe Lamberti 1,2 and Davide Campana 1,2Round 1
Reviewer 1 Report
High-grade neuroendocrine carcinoma is a rare and aggressive vari- 16
ant of bladder cancer. Therefore, there are few studies on prognostic factors of this part of patients. The starting point of this study has certain clinical significance.
1. As far as I know, the TNM staging of tumors from 1975 to 2018 is not uniform in the SEER database, please ask how the authors handled the TNM staging of all patients.
2. Perhaps a flow chart can be added to clarify the data processing process more clearly.
3. Can the author describe the process of univariate multivariate analysis in detail? For example, what variables did the authors include in the multivariate analysis?
Author Response
High-grade neuroendocrine carcinoma is a rare and aggressive variant of bladder cancer. Therefore, there are few studies on prognostic factors of this part of patients. The starting point of this study has certain clinical significance.
Dear Reviewer, we are thankful for your comments and your revision that will surely help to improve our work. Please, find our revised parts in the text in blue.
- As far as I know, the TNM staging of tumors from 1975 to 2018 is not uniform in the SEER database, please ask how the authors handled the TNM staging of all patients.
We analyzed the staging of each individual patient based on the corresponding TNM (according to the classification of the year of diagnosis of each patient) and we evaluated it in order to make it uniform among patients. We specified it in the text (in blue).
“Considering that TNM staging varied throughout the years, we analyzed the TNM staging of each individual patient according to the classification of the year of diagnosis of each patient and we evaluated it in order to make it uniform among patients.”
- Perhaps a flow chart can be added to clarify the data processing process more clearly.
It is not possible to do a flow chart for our work. We extracted data from the SEER database as explained in the “Material and Methods” section.
- Can the author describe the process of univariate multivariate analysis in detail? For example, what variables did the authors include in the multivariate analysis?
In the multivariate analysis, we included all variables of the univariate analysis, both statistically significant and not. We remarked it in the text (in blue).
Reviewer 2 Report
A very interesting and well-written manuscript.
Only few comments.
1. The study was performed up to 2018 - before the present WHO classification was implemented. Is it possible to distinguish between NET G3 and NEC? I assume that they are pooled in your study.
2. Which parameters did you adjust for in the Cox analysis?
3. Patients > 72 years had a poor prognosis. Does the high age reflect a higher morbidity, and have you checked for interaction?
Author Response
A very interesting and well-written manuscript.
Only few comments.
Dear Reviewer, thank you for your revision and your comments that we found relevant to be highlighted. We replied to your comments and clarified in the text the issue that you pointed out (in green).
- The study was performed up to 2018 - before the present WHO classification was implemented. Is it possible to distinguish between NET G3 and NEC? I assume that they are pooled in your study.
NET G3 was introduced for the bladder only in the recent WHO classification of 2022 while we included cases from 1975 to 2018. For NEC is still valid the old distinction in small cell and large cell carcinoma.
- Which parameters did you adjust for in the Cox analysis?
We did not adjust for any parameters in the Cox analysis. We included sex and age in the multivariate analysis.
- Patients > 72 years had a poor prognosis. Does the high age reflect a higher morbidity, and have you checked for interaction?
We did not investigate this interaction but we specified in the text as follows (in green):
“Furthermore, we did not investigate the interaction between older age (>72 years), that could be correlated to a higher morbidity, and poor prognosis.”
Reviewer 3 Report
It is a retrospective, registry-based study on the truly unique and aggressive disease of neuroendocrine carcinoma (NEC). The methodology was correctly chosen and implemented; the conclusions are driven by the well-described results.
Some minor comments were listed below:
1. Were there any data concerning CSS or RFS available? If not, it would be advisable to include it in the limitations as possible comorbidities may have been confounders, although you have mentioned PS.
2. In the tile: did you mean all neuroendocrine tumors are high-grade? There are no specific comments/details of the histopathology in the results, just the division into small cell NEC (SCNEC), large cell NEC (LCNEC), mixed neuroendocrine non-neuroendocrine neoplasia (MiNEN), with the SCNEC being most aggressive. Still, the analysis comprised all the tumors, even though the predominant type was SCNEC (77.6%, n=880).
3. In the search methodology, minor and major surgeries were included. It should be clearly stated in which situations were the minor ones selected (fragile patients, unwilling to undergo radical surgery, part of multimodal treatment?) as this might have clearly influenced OS. There is little place for partial cystectomy (e.g urachal adenocarcinoma) and TURBT might have been used for sampling purposes only. As for “major”, (including total cystectomy, pelvic exenteratio): please define the difference as radical cystectomy in women is in fact anterior pelvic exenteration, please use exenteration rather then latin. Was the approach: Open/laparoscopic or type of urinary diversion that could affect the survival?
4. In the basic characteristics subsection: ‘We calculated the best cut-off for size of the primary tumor to predict survival at 12 months, for the 528 patients with available data, in an unbiased way by ROC curve as 44,5 123 mm (Supplementary Figure 1), with 62,2% sensibility and 62,3% specificity’ - it seems it should be placed in survival analysis.
5. Line 138 – surgery ‘performed’ or ‘conducted’ etc.
6. Line 146 why did histology make no difference? – please comment in the discussion.
7. The N+ feature: was the number of lymph nodes removed/extent of lymphadenectomy /the extent of lymph nodes involvement included in the analysis or the data were unavailable?
8. In line 196: ‘in case of positive lymph nodes, this benefit (of surgery) is lost.’ Is there a role for neoadjuvant treatment to change the prognosis? Is it the immunotherapy a possible solution?
9. Please add explanation or correct typing error in Suppl table 2, fourth row: 72aa (and the same in suppl table 4).
Author Response
It is a retrospective, registry-based study on the truly unique and aggressive disease of neuroendocrine carcinoma (NEC). The methodology was correctly chosen and implemented; the conclusions are driven by the well-described results.
Dear Reviewer, thank you very much for your comments that will surely improve our work. We corrected the manuscript according to your suggestions. You can find the changes in the manuscript in red.
Some minor comments were listed below:
- Were there any data concerning CSS or RFS available? If not, it would be advisable to include it in the limitations as possible comorbidities may have been confounders, although you have mentioned PS.
CSS was not evaluated and RFS was not available from the registry. We included these limitations in the text (in red). We also specified that older age, thus a likely higher morbidity, was not investigated as a confounding factor (in green).
“Furthermore, we did not investigate the interaction between older age (>72 years), that could be correlated to a higher morbidity, and poor prognosis.”
“We did not perform cancer-specific survival and relapse-free survival analysis due to lacking data on the majority of patients.”
- In the tile: did you mean all neuroendocrine tumors are high-grade? There are no specific comments/details of the histopathology in the results, just the division into small cell NEC (SCNEC), large cell NEC (LCNEC), mixed neuroendocrine non-neuroendocrine neoplasia (MiNEN), with the SCNEC being most aggressive. Still, the analysis comprised all the tumors, even though the predominant type was SCNEC (77.6%, n=880).
We included in the analysis only patients with high grade neuroendocrine carcinoma (that includes small cell, large cell, NEC and mixed histologies with neuroendocrine carcinoma component). We excluded neuroendocrine tumors (NET G1 and G2).
“As for histology, we included only patients with high-grade neuroendocrine carcinoma and we excluded neuroendocrine tumors (NET) G1 and G2.”
- In the search methodology, minor and major surgeries were included. It should be clearly stated in which situations were the minor ones selected (fragile patients, unwilling to undergo radical surgery, part of multimodal treatment?) as this might have clearly influenced OS. There is little place for partial cystectomy (e.g urachal adenocarcinoma) and TURBT might have been used for sampling purposes only. As for “major”, (including total cystectomy, pelvic exenteratio): please define the difference as radical cystectomy in women is in fact anterior pelvic exenteration, please use exenteration rather then latin. Was the approach: Open/laparoscopic or type of urinary diversion that could affect the survival?
We used registry data that do not include information on specific clinical situations of patients before surgery so we could not assess if patients undergoing minor procedures were more fragile or unwilling to perform major surgery. Furthermore, there is no data available on type of surgery or urinary diversion but we do not consider these factors relevant in terms of oncologic outcomes.
We also discussed the difference of radical cystectomy in women.
We corrected exenteratio in exenteration.
“It has to be underlined that in women, radical cystectomy consists of anterior pelvic exenteration (removal of urethra, lower part of the ureters, uterus, cervix, vagina, and bladder).”
- In the basic characteristics subsection: ‘We calculated the best cut-off for size of the primary tumor to predict survival at 12 months, for the 528 patients with available data, in an unbiased way by ROC curve as 44,5 123 mm (Supplementary Figure 1), with 62,2% sensibility and 62,3% specificity’ - it seems it should be placed in survival analysis.
We shifted this part in the survival analysis.
- Line 138 – surgery ‘performed’ or ‘conducted’ etc.
We corrected as suggested.
- Line 146 why did histology make no difference? – please comment in the discussion.
We commented on this in the discussion, as suggested.
“In addition, we did not find a statistically significant difference in OS according to histology (p=0.148). This may be due to the fact that the majority of the included patients were SCNEC and, also, suggests a common scant prognosis of high-grade histologies, as reported for neuroendocrine neoplasia arising in other organs.”
- The N+ feature: was the number of lymph nodes removed/extent of lymphadenectomy /the extent of lymph nodes involvement included in the analysis or the data were unavailable?
The requested data was unavailable. We specified it in the text (in red).
“Data on the extent of lymphadenectomy and number of positive lymph nodes was not available.”
- In line 196: ‘in case of positive lymph nodes, this benefit (of surgery) is lost.’ Is there a role for neoadjuvant treatment to change the prognosis? Is it the immunotherapy a possible solution?
Immunotherapy has not been evaluated in high-grade neuroendocrine carcinoma of the bladder. With regards to neoadjuvant treatment, we discussed it the discussion section. We added a part to this discussion (in red):
“The role of neoadjuvant chemotherapy appears to be more relevant in patients without lymph nodal involvement [20], similarly to the urothelial counterpart.”
- Please add explanation or correct typing error in Suppl table 2, fourth row: 72aa (and the same in suppl table 4).
We corrected the typo.
