Renal-Type Clear Cell Carcinoma of the Prostate: A Histopathological Case Report of a Rare and Underrecognized Variant

Round 1

Reviewer 1 Report (Previous Reviewer 1)

Comments and Suggestions for Authors

Case 2: The authors have provided images of this prostate tumour prior to androgen deprivation therapy, and which appear to be of a typical prostate adenocarcinoma. Areas or foci of cells with morphological differences, including vacuolation or nuclear variations, are typical of prostate cancer and of other solid tumours. The post-treatment prostate tissue images for this patient are typical of prostate tumours following androgen deprivation therapies.

It is concerning that while the authors have provided information about the treatment of patients in response to reviewers’ comments, these details, which are pivotal to the interpretation of pathology, have not been added to the case history. This is misleading for any reader of a manuscript – the case history forms part of the diagnosis and needs to be comprehensive, with clear descriptions of relevant surgical interventions, radiotherapy, drug names and doses and duration of treatments in relation to when tissue samples were obtained. The comments added to the end of the Discussion section about the patient having already received androgen deprivation therapy do not add to interpretation of the pathology images and do not include details relevant to the diagnosis including the drug names and doses, duration of treatment and timespan between cessation of treatment and when the tissue was taken. The 1-month interval between cessation of treatment and surgery are consistent with the histology being a typical response to androgen deprivation therapy. Tumour volume is not relevant – most published images show tumours that are resistant to treatment and which lack evidence of cell death, as is indicated in this case.

In summary, I don’t feel that there is evidence to indicate that the cases represent renal-type clear cell carcinoma of the prostate, in particular Case 2.

Note: The academic analysis of tissues and diagnoses by histopathologists considerably strengthens this field. In this instance, I would recommend collaboration with a specialist prostate pathology group to provide additional input with respect to these cases and to further the academic pathology pursuits of the authors.

Comments on the Quality of English Language

If this manuscript is approved for publication, English language editing will be required minor grammatical errors that distort the meaning of sentences.

Author Response

Comments and Suggestions for Authors

Case 2: The authors have provided images of this prostate tumour prior to androgen deprivation therapy, and which appear to be of a typical prostate adenocarcinoma. Areas or foci of cells with morphological differences, including vacuolation or nuclear variations, are typical of prostate cancer and of other solid tumours. The post-treatment prostate tissue images for this patient are typical of prostate tumours following androgen deprivation therapies.

• Dear reviewer, following this feedback and the reports of the previous reviews, the second case has been removed from the manuscript.

 

It is concerning that while the authors have provided information about the treatment of patients in response to reviewers’ comments, these details, which are pivotal to the interpretation of pathology, have not been added to the case history. This is misleading for any reader of a manuscript – the case history forms part of the diagnosis and needs to be comprehensive, with clear descriptions of relevant surgical interventions, radiotherapy, drug names and doses and duration of treatments in relation to when tissue samples were obtained. The comments added to the end of the Discussion section about the patient having already received androgen deprivation therapy do not add to interpretation of the pathology images and do not include details relevant to the diagnosis including the drug names and doses, duration of treatment and timespan between cessation of treatment and when the tissue was taken. The 1-month interval between cessation of treatment and surgery are consistent with the histology being a typical response to androgen deprivation therapy. Tumour volume is not relevant – most published images show tumours that are resistant to treatment and which lack evidence of cell death, as is indicated in this case.

• Dear reviewer, we do not understand the first statement, on how we have included statements of treatment and at the same time they are missing from the text. Regarding the remainder of the statement, the second case has been removed from the manuscript entirely.

 

In summary, I don’t feel that there is evidence to indicate that the cases represent renal-type clear cell carcinoma of the prostate, in particular Case 2.

• Dear reviewer, case 2 has been removed. In the previous rounds, critique has been placed only on the second case, while no such issues were raised for the first case

 

Note: The academic analysis of tissues and diagnoses by histopathologists considerably strengthens this field. In this instance, I would recommend collaboration with a specialist prostate pathology group to provide additional input with respect to these cases and to further the academic pathology pursuits of the authors.

• No such issues were raised for the first case up to this point. The goal of the manuscript is not for any academic pursuit but rather to report a rare case and showcase the capabilities of local pathologists, as there is no prostate group on a national level. All authors except one are pathologists; if the reviewer would suggest such a group, we would oblige to the best of our abilities to further convince him of the nature of the cases.

 

 

Comments on the Quality of English Language

If this manuscript is approved for publication, English language editing will be required minor grammatical errors that distort the meaning of sentences.

• Thank you for this comment. Changes will be made in the revised version.

Reviewer 2 Report (Previous Reviewer 2)

Comments and Suggestions for Authors

This manuscript has been revised in accordance with the reviewers' comments.

Author Response

Comments and Suggestions for Authors

This manuscript has been revised in accordance with the reviewers' comments.

• Dear reviewer, thank you for this comment.

 

Reviewer 3 Report (New Reviewer)

Comments and Suggestions for Authors

I read our paper with interest. This is a high-quality case report on an underrecognized and rare variant of prostatic adenocarcinoma. There are some points for revision:

1. Title and Abstract:

• Ensure the title is consistent with the "Case Presentation" section. The abstract mentions one case (73-year-old male), but line 57 of the introduction mentions "two such cases". 

   

2. Table 1 (IHC Markers):

In Table 1, the "CK AE1/AE3" row mentions "positive," but the "Reference" column for NKX3.1 is blank. Since you state this is the first report of NKX3.1 positivity, explicitly label it as "Current Case" in the reference column.

3. Discussion Section:

• The discussion regarding the WHO classification (acinar vs. ductal) is insightful. You might consider expanding slightly on why the PAX8 negativity is the "gold standard" for excluding a renal primary in your differential diagnosis.

   

  Conclusion

This is a valuable addition to urological pathology. Correcting the discrepancy regarding the number of cases  will make this a valuable publication.

Author Response

Comments and Suggestions for Authors

I read our paper with interest. This is a high-quality case report on an underrecognized and rare variant of prostatic adenocarcinoma. There are some points for revision:

• Dear reviewer, thank you for this comment.

 

1. Title and Abstract:

 

Ensure the title is consistent with the "Case Presentation" section. The abstract mentions one case (73-year-old male), but line 57 of the introduction mentions "two such cases".

• Dear reviewer, we apologize for this issue with the text. In the previous rounds of review, the manuscript did in fact have two cases of such a tumor, one of the reviewers strongly opposed and requested the removal of the second case, despite numerous revisions and additions to histopathology to convince him that this is indeed such a tumor.

 

 

 

2. Table 1 (IHC Markers):

 

In Table 1, the "CK AE1/AE3" row mentions "positive," but the "Reference" column for NKX3.1 is blank. Since you state this is the first report of NKX3.1 positivity, explicitly label it as "Current Case" in the reference column.

• Thank you for this suggestion.

 

3. Discussion Section:

 

The discussion regarding the WHO classification (acinar vs. ductal) is insightful. You might consider expanding slightly on why the PAX8 negativity is the "gold standard" for excluding a renal primary in your differential diagnosis.

• Dear reviewer, thank you for this suggestion. An addition will be made in this regard.

 

 

 

Conclusion

 

This is a valuable addition to urological pathology. Correcting the discrepancy regarding the number of cases  will make this a valuable publication.

• Dear reviewer, thank you for these ccomments.

Reviewer 4 Report (New Reviewer)

Comments and Suggestions for Authors

Title
1- The title suggests a single case, but the Introduction inconsistently refers to “two cases,” creating ambiguity.

Abstract
2- No explicit mention of patient outcome or follow-up duration in the abstract.

Introduction
3- The Introduction inconsistently mentions reporting “two cases,” whereas only one case is presented in the manuscript, leading to confusion 

Case Presentation
4- Demographic details are incomplete (e.g., ethnicity, relevant family history).
5- Past medical history is briefly mentioned but lacks detail regarding relevance to the present condition.
6- No information on concomitant medications or drug history that may be relevant.
7- Physical examination findings are not described.
8- No description of digital rectal examination (DRE), which is clinically relevant in prostate pathology.
9- A clear schematic figure timeline summarizing key events (presentation, diagnosis, investigations, treatment, follow-up) is missing.
10- Imaging findings are described only as “negative,” without technical details or representative images. (With arrows) (Please expand the details in the figure caption.)
11- Treatment details (androgen blockade regimen, radiotherapy dose/fractionation) are insufficiently described.
12- Rationale for chosen treatment strategy is not discussed.
13- Outcome measures are not clearly defined (e.g., PSA response, imaging follow-up).
14- Please add a table of lab data and tumor markers. ( with reference to range). Also, please add sonography and CT figures.

Discussion
15- The patient’s perspective or experience is not included, which is a CARE-recommended item.

Figures and Tables
16- Figure legends lack sufficient standalone detail (e.g., clearer labeling consistency across panels).
17- Table 1 does not clearly specify the method used to derive literature support (systematic vs narrative review).

General
18- Inconsistent terminology (“renal-type clear cell carcinoma,” “renal-type clear cell acinar adenocarcinoma”) may confuse readers.
19- Minor grammatical and typographical issues reduce clarity in multiple sections: 
19. a. “morphological cases report” → grammatically incorrect; should be “morphological case report.”
19. b. “male aged 73 years” → awkward phrasing; should be “a 73-year-old male.”
19. c. “18.61ng/ml” → missing space and inconsistent unit capitalization; should be “18.61 ng/mL.”
19. d. “Herein, we report two such cases” → factual inconsistency and grammatical issue, as only one case is presented.
19. e. "cerebrovascular incident” → vague and non-idiomatic; should be “cerebrovascular accident” or “stroke.”
19. f. “went uncomplicated” → grammatically incorrect; should be “was uncomplicated.”
19. g. “differing in size cells” → awkward syntax; should be “cells differing in size.”
19. h. “comprised by pale cells” → incorrect verb usage; should be “composed of pale cells.”
19. i. “Neither renal ultrasound nor CT shows evidence” → tense inconsistency; should be “showed no evidence.”

Comments on the Quality of English Language

18- Inconsistent terminology (“renal-type clear cell carcinoma,” “renal-type clear cell acinar adenocarcinoma”) may confuse readers.
19- Minor grammatical and typographical issues reduce clarity in multiple sections: 
19. a. “morphological cases report” → grammatically incorrect; should be “morphological case report.”
19. b. “male aged 73 years” → awkward phrasing; should be “a 73-year-old male.”
19. c. “18.61ng/ml” → missing space and inconsistent unit capitalization; should be “18.61 ng/mL.”
19. d. “Herein, we report two such cases” → factual inconsistency and grammatical issue, as only one case is presented.
19. e. "cerebrovascular incident” → vague and non-idiomatic; should be “cerebrovascular accident” or “stroke.”
19. f. “went uncomplicated” → grammatically incorrect; should be “was uncomplicated.”
19. g. “differing in size cells” → awkward syntax; should be “cells differing in size.”
19. h. “comprised by pale cells” → incorrect verb usage; should be “composed of pale cells.”
19. i. “Neither renal ultrasound nor CT shows evidence” → tense inconsistency; should be “showed no evidence.”

Author Response

Comments and Suggestions for Authors

Title

• The title suggests a single case, but the Introduction inconsistently refers to “two cases,” creating ambiguity.
• Dear reviewer, we apologize for this issue with the text. In the previous rounds of review, the manuscript did in fact have two cases of such a tumor, one of the reviewers strongly opposed and requested the removal of the second case, despite numerous revisions and additions to histopathology to convince him that this is indeed such a tumor.

 

 

Abstract

• No explicit mention of patient outcome or follow-up duration in the abstract.
• Dear reviewer, this is intentional as to comply with the abstract size

 

Introduction

• The Introduction inconsistently mentions reporting “two cases,” whereas only one case is presented in the manuscript, leading to confusion
• Dear reviewer, we apologize for this issue with the text. In the previous rounds of review, the manuscript did in fact have two cases of such a tumor, one of the reviewers strongly opposed and requested the removal of the second case, despite numerous revisions and additions to histopathology to convince him that this is indeed such a tumor.

 

 

Case Presentation

• Demographic details are incomplete (e.g., ethnicity, relevant family history).
• Details have been added
• Past medical history is briefly mentioned but lacks detail regarding relevance to the present condition.
• Dear reviewer, we have mentioned the concomitant conditions for clarity, noting that the patient had no previous complaints or other malignancy. Adding details on cardiovascular comorbidities to an oncopathological text would add nothing of value, only increase the word count, and serve as filler that may dissuade the reader from reading further.
• No information on concomitant medications or drug history that may be relevant.
• Dear reviewer, please see the previous comments.
• Physical examination findings are not described.
• Details added
• No description of digital rectal examination (DRE), which is clinically relevant in prostate pathology.
• Detail added
• A clear schematic figure timeline summarizing key events (presentation, diagnosis, investigations, treatment, follow-up) is missing.
• Dear reviewer, all procedures were performed within a week; as such, detailing the timeframe will add no value.
• Imaging findings are described only as “negative,” without technical details or representative images. (With arrows) (Please expand the details in the figure caption.)
• Dear reviewer, we have not added any figures from radiology as the focus of the manuscript is on histopathology of this rare tumor, none of the authors are radiologists. As such we cannot comply with this request.
• Treatment details (androgen blockade regimen, radiotherapy dose/fractionation) are insufficiently described.
• As treatment of the patient was performed in another institution, we have no specific data on this. We only have access that the treatment was performed as per local legislation and the NCCN guidelines.
• Rationale for chosen treatment strategy is not discussed.
• Local legislation allows only for NCCN-approved treatment of such cases.
• Outcome measures are not clearly defined (e.g., PSA response, imaging follow-up).
• Timeframe has already been specified within the text,
• Please add a table of lab data and tumor markers. ( with reference to range). Also, please add sonography and CT figures.
• Dear reviewer, apart from PSA, there are no tumor markers for prostate carcinoma. This data has already been added to the text.

 

Discussion

• The patient’s perspective or experience is not included, which is a CARE-recommended item.

-We have already specified in the CARE checklist that such a perspective is not present in the text, nor do 99% of case reports have such a section, as patients rarely have a valuable and specific insight into the disease, while often praising the treatment and personnel behavior. We would like to keep the text academic and not include a section to serve as an advertisement for our institutions or capabilities.

 

Figures and Tables

• Figure legends lack sufficient standalone detail (e.g., clearer labeling consistency across panels).
• Dear reviewer, the figures are labeled, and each panel has a detailed caption. If you have a specific request, please note it.
• Table 1 does not clearly specify the method used to derive literature support (systematic vs narrative review).
• Dear reviewer, this is a case report. How are we supposed to perform a meta-analysis for a table in a case report?

 

General

• Inconsistent terminology (“renal-type clear cell carcinoma,” “renal-type clear cell acinar adenocarcinoma”) may confuse readers.
• Acinar is used in the text to differentiate from ductal carcinomas, which are a completely separate group of prostate malignancies.

19- Minor grammatical and typographical issues reduce clarity in multiple sections:

19. a. “morphological cases report” → grammatically incorrect; should be “morphological case report.”
20. b. “male aged 73 years” → awkward phrasing; should be “a 73-year-old male.”
21. c. “18.61ng/ml” → missing space and inconsistent unit capitalization; should be “18.61 ng/mL.”
22. d. “Herein, we report two such cases” → factual inconsistency and grammatical issue, as only one case is presented.
23. e. "cerebrovascular incident” → vague and non-idiomatic; should be “cerebrovascular accident” or “stroke.”

– we do not agree with the use of this terminology

 

19. f. “went uncomplicated” → grammatically incorrect; should be “was uncomplicated.”

– we do not agree with the use of this terminology

 

19. g. “differing in size cells” → awkward syntax; should be “cells differing in size.”

– we do not agree with the use of this terminology

 

19. h. “comprised by pale cells” → incorrect verb usage; should be “composed of pale cells.”
20. i. “Neither renal ultrasound nor CT shows evidence” → tense inconsistency; should be “showed no evidence.”

 - Most of the requests were performed in the text.

 

 

Comments on the Quality of English Language

18- Inconsistent terminology (“renal-type clear cell carcinoma,” “renal-type clear cell acinar adenocarcinoma”) may confuse readers.

19- Minor grammatical and typographical issues reduce clarity in multiple sections:

19. a. “morphological cases report” → grammatically incorrect; should be “morphological case report.”
20. b. “male aged 73 years” → awkward phrasing; should be “a 73-year-old male.”
21. c. “18.61ng/ml” → missing space and inconsistent unit capitalization; should be “18.61 ng/mL.”
22. d. “Herein, we report two such cases” → factual inconsistency and grammatical issue, as only one case is presented.
23. e. "cerebrovascular incident” → vague and non-idiomatic; should be “cerebrovascular accident” or “stroke.”
24. f. “went uncomplicated” → grammatically incorrect; should be “was uncomplicated.”
25. g. “differing in size cells” → awkward syntax; should be “cells differing in size.”
26. h. “comprised by pale cells” → incorrect verb usage; should be “composed of pale cells.”
27. i. “Neither renal ultrasound nor CT shows evidence” → tense inconsistency; should be “showed no evidence.”

- thank you for these comments, changes have been made. Please see prior comments

Round 2

Reviewer 1 Report (Previous Reviewer 1)

Comments and Suggestions for Authors

The authors have amended their manuscript, removing the second case report and focussing on a single case where prior treatment has not precluded definitive diagnosis. I feel that the manuscript is suitable for publication pending minor amendments and basic English language corrections (syntax, grammar). While there is scope for a more academic discussion of the case and the diagnosis in general, there is sufficient information presented for others to understand and use the case report for future research.

1. Line 108: This sentence can be deleted (it applies to older versions of the manuscript where 2 cases were presented).
2. Table 1: As the authors have included reference to their own immunohistochemistry for 2 of the antibodies (CD68, NKX3.1), this information should be added for all antibodies that they tested (to avoid misinterpretation that they only used CD68 and NKX3.1).
3. Table 1: In the column ‘Supported by literature’, the word ‘tested’ should be replaced with ‘reported’. (It is possible that previous authors used but didn’t report results of some immunohistochemical staining if it did not significantly contribute to their report). Where relevant, this correction should also be applied to the text.

Comments on the Quality of English Language

If this manuscript is approved for publication, English language editing will be required minor grammatical errors that distort the meaning of sentences.

Author Response

Reviewer 1:

The authors have amended their manuscript, removing the second case report and focussing on a single case where prior treatment has not precluded definitive diagnosis. I feel that the manuscript is suitable for publication pending minor amendments and basic English language corrections (syntax, grammar). While there is scope for a more academic discussion of the case and the diagnosis in general, there is sufficient information presented for others to understand and use the case report for future research.

• Dear reviewer, thank you for this statement and appreciating our work

 

Line 108: This sentence can be deleted (it applies to older versions of the manuscript where 2 cases were presented).

• Removed, thank you

Table 1: As the authors have included reference to their own immunohistochemistry for 2 of the antibodies (CD68, NKX3.1), this information should be added for all antibodies that they tested (to avoid misinterpretation that they only used CD68 and NKX3.1).

• Corrected, thank you

Table 1: In the column ‘Supported by literature’, the word ‘tested’ should be replaced with ‘reported’. (It is possible that previous authors used but didn’t report results of some immunohistochemical staining if it did not significantly contribute to their report). Where relevant, this correction should also be applied to the text.

-Thank you, corrected

Reviewer 4 Report (New Reviewer)

Comments and Suggestions for Authors

I accept it. 

Author Response

Reviewer 4:

I accept it.

• Dear reviewer, thank you for appreciating our work

This manuscript is a resubmission of an earlier submission. The following is a list of the peer review reports and author responses from that submission.

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This manuscript reports 2 cases that the authors have diagnosed as clear cell renal type acinar adenocarcinomas, a rare tumour entity, Unfortunately, I cannot recommend the manuscript for publication at this time as there is insufficient evidence to support this conclusion for either of the 2 cases presented. Immunohistochemical staining has been performed for only one of the cases, and further immunostains are required to support a diagnosis of clear cell renal type acinar adenocarcinoma. No immunostains have been performed on the 2^nd case and the appearance of the images (cytoplasmic clearing, nuclear features) is typical of residual prostate cancer following androgen deprivation therapy. Based on the images and information presented, neither case is convincingly a clear cell renal type acinar adenocarcinoma.

Comments on the Quality of English Language

In general, the manuscript is easy to understand. However, minor editing of English language will be required to remove words and phrases that haven't translated well. Some of these are in lines 40, 45, 55, 56, 57, 80, 81, 87, 136.

Abstract, line 14: The authors state "while not being prevalent in terms of malignancy-related deaths". This implies that prostate cancer is not a common cause of cancer death, which is incorrect (as stated in lines 35-36). English language editing will be useful for correcting this type of error.

Author Response

Comments and Suggestions for Authors

This manuscript reports 2 cases that the authors have diagnosed as clear cell renal type acinar adenocarcinomas, a rare tumour entity, Unfortunately, I cannot recommend the manuscript for publication at this time as there is insufficient evidence to support this conclusion for either of the 2 cases presented. Immunohistochemical staining has been performed for only one of the cases, and further immunostains are required to support a diagnosis of clear cell renal type acinar adenocarcinoma. No immunostains have been performed on the 2nd case and the appearance of the images (cytoplasmic clearing, nuclear features) is typical of residual prostate cancer following androgen deprivation therapy. Based on the images and information presented, neither case is convincingly a clear cell renal type acinar adenocarcinoma.

• Dear reviewer, thank you for these comments. Further IHC testing has been performed in the revised version of the manuscript with both PAX8 and NKX3.1, the most specific antibodies in our laboratory to differentiate between CCRCC and prostate carcinoma, together with the initially presented IHC markers.
• Regarding your recent point, yes, cytoplasmic vacuolation is typical for prostate malignancies following deprivation therapy; however, this extent of clearing is rare. Furthermore, if this was a treatment-related change, especially one that is so diffuse, residual carcinoma would not involve such a large volume of the prostate, as there would be regression. These aspects have been expanded upon in the discussion. If the respected review again contradicts these statements, we are willing to remove the second case from the report, as we have exhausted all antibody possibilities available worldwide to prove the histogenesis of the tumor as originating from the prostate. The extent of the tumor clearly shows that it did not respond to the treatment initiated, both clinically and in the percentage of the tumor histology relative to the prostate parenchyma itself.

 

 

Comments on the Quality of English Language

In general, the manuscript is easy to understand. However, minor editing of English language will be required to remove words and phrases that haven't translated well. Some of these are in lines 40, 45, 55, 56, 57, 80, 81, 87, 136.

• Thank you for noting these typographical errors; changes will be made in the revised version.

 

Abstract, line 14: The authors state "while not being prevalent in terms of malignancy-related deaths". This implies that prostate cancer is not a common cause of cancer death, which is incorrect (as stated in lines 35-36). English language editing will be useful for correcting this type of error.

• Compared to its overall incidence, the related death rate is significantly lower as a percentage of other malignancies. This has already been stated within the manuscript.

Reviewer 2 Report

Comments and Suggestions for Authors

The authors reported cases of renal-type clear cell carcinoma of the prostate, a rare histological type of prostate cancer. It is important to accumulate information on rare cases, and this paper is considered to be significant. However, there is still some information missing, and the manuscript needs to be further expanded.

 

Specific comments

1. There is very little information about treatment. It is necessary to provide specific details about treatment and progress.
2. It is recommended to show the results of PSA immunohistochemistry. Previous reports suggest that PSA immunohistochemistry-negative cases tend to have a poor prognosis. Hormone therapy may not be effective in PSA immunohistochemistry-negative cases, and there may be good and poor prognosis types of renal-type clear cell carcinoma of the prostate.
3. Is the title "Clear Cell Renal Type Acinar Adenocarcinoma of the Prostate" correct? Previous reports have often referred to it as "renal-type clear cell carcinoma of the prostate." Please consider this.
4. There seem to be a lot of vocabulary mistakes. If necessary, you should have your work proofread. Are the following words correct? Please check.

In line 55, “derivefrom” “derive from”

In line 56, “mol;ecular” “molecular”

In line 57, “connextion” “connection”

In line 73, “picnotically” “pycnotically” or “pyknotically”

In line 81, “nuclein” “nuclei”

In line 82, “picnotic” “pycnotic” or “pyknotic”

In line 97, “reatment” “treatment”

In line 136, “muc” “?”

Author Response

The authors reported cases of renal-type clear cell carcinoma of the prostate, a rare histological type of prostate cancer. It is important to accumulate information on rare cases, and this paper is considered to be significant. However, there is still some information missing, and the manuscript needs to be further expanded.

• Dear reviewer, thank you for these comments, according changes will be made to the manuscript text.

Specific comments

 

There is very little information about treatment. It is necessary to provide specific details about treatment and progress.

• Relevant changes will be made to these sections

It is recommended to show the results of PSA immunohistochemistry. Previous reports suggest that PSA immunohistochemistry-negative cases tend to have a poor prognosis. Hormone therapy may not be effective in PSA immunohistochemistry-negative cases, and there may be good and poor prognosis types of renal-type clear cell carcinoma of the prostate.

• Dear reviewer, thank you for these comments, relevant sections will be expanded. Both patients presented with elevated PSA. We are however unable to perform PSA IHC, as we no longer stock this antibody in our lab, as in the past it has lead to issues with diagnosis, exactly in cases of low-PSA prostatic carcinoma.

Is the title "Clear Cell Renal Type Acinar Adenocarcinoma of the Prostate" correct? Previous reports have often referred to it as "renal-type clear cell carcinoma of the prostate." Please consider this.

• This will be revised

There seem to be a lot of vocabulary mistakes. If necessary, you should have your work proofread. Are the following words correct? Please check.

In line 55, “derivefrom” “derive from”

 

In line 56, “mol;ecular” “molecular”

 

In line 57, “connextion” “connection”

 

In line 73, “picnotically” “pycnotically” or “pyknotically”

 

In line 81, “nuclein” “nuclei”

 

In line 82, “picnotic” “pycnotic” or “pyknotic”

 

In line 97, “reatment” “treatment”

 

In line 136, “muc” “?”

 

• Thank you for noting these typographical errors, they will be revised.

Reviewer 3 Report

Comments and Suggestions for Authors

This manuscript presents two cases of clear cell renal-type acinar adenocarcinoma of the prostate, a highly unusual and underrecognized histopathological variant. The article is well-structured and follows the conventional format for a case report, including background, case descriptions, discussion, and conclusion. The topic is clinically relevant and of interest to both urologists and pathologists, as it highlights diagnostic challenges and the importance of differentiating rare entities from metastatic renal carcinomas.

Overall, the paper contributes valuable information to the limited literature on this rare prostatic neoplasm. However, some issues regarding language clarity, methodological detail, and figure presentation should be addressed before publication.

Major Comments

1. Novelty and Clinical Significance

   • The article provides meaningful insight by describing two cases, which strengthens the rarity and relevance of this entity. However, the novelty could be emphasized more clearly in the Introduction—specifically how this report advances understanding compared to previously published single-case reports.

2. Histopathological and Immunohistochemical Details

   • While the morphological description is adequate, the immunohistochemical panel could be discussed in more detail.

     • Were PSA and PAX8 tested in both cases? These are crucial for the differential diagnosis.

     • Including a table summarizing immunohistochemical markers (positive/negative) for both cases would improve clarity.

3. Figures and Legends

   • The figure legends are informative, but the manuscript would benefit from higher-resolution micrographs and consistent labeling (A, B, C, D) throughout.

   • It would also be useful to include immunohistochemical figures for both cases, not only Case 1.

4. Discussion Depth

   • The discussion is well-grounded in literature but could be expanded by exploring the molecular or genetic implications of this variant, if any have been reported.

   • Consider briefly discussing potential therapeutic implications or whether this variant behaves differently prognostically from typical acinar adenocarcinomas.

5. Language and Grammar

   • The English is understandable but needs editing for clarity and flow. Frequent issues include missing articles ("the", "a"), inconsistent verb tenses, and typographical errors (“derivfrom,” “mol;ecular,” “connextion,” etc.). A thorough language revision by a native or professional editor is recommended.

6. Reference: consider this article related to histological variant in urological conditions (DOI: 10.1016/j.euo.2025.03.019) 

Comments on the Quality of English Language

The good of english is fine. 

Author Response

This manuscript presents two cases of clear cell renal-type acinar adenocarcinoma of the prostate, a highly unusual and underrecognized histopathological variant. The article is well-structured and follows the conventional format for a case report, including background, case descriptions, discussion, and conclusion. The topic is clinically relevant and of interest to both urologists and pathologists, as it highlights diagnostic challenges and the importance of differentiating rare entities from metastatic renal carcinomas.

• Dear reviewer, thank you for these comments.

 

Overall, the paper contributes valuable information to the limited literature on this rare prostatic neoplasm. However, some issues regarding language clarity, methodological detail, and figure presentation should be addressed before publication.

 

Major Comments

Novelty and Clinical Significance

 

The article provides meaningful insight by describing two cases, which strengthens the rarity and relevance of this entity. However, the novelty could be emphasized more clearly in the Introduction—specifically how this report advances understanding compared to previously published single-case reports.

• Thank you for these comments, we will perform changes to the manuscript.

 

 

Histopathological and Immunohistochemical Details

 

While the morphological description is adequate, the immunohistochemical panel could be discussed in more detail.

 

Were PSA and PAX8 tested in both cases? These are crucial for the differential diagnosis.

• Thank you for these comments, PAX8 and NKX3.1 IHC staining has been included for boths cases. We, however, no longer stock PSA in our laboratory as it has caused issues with diagnosis in the peas, especially in cases of low-PSA malignancies of the prostate.

 

Including a table summarizing immunohistochemical markers (positive/negative) for both cases would improve clarity.

• Changes will be made.

 

Figures and Legends

 

The figure legends are informative, but the manuscript would benefit from higher-resolution micrographs and consistent labeling (A, B, C, D) throughout.

• Figures will be changed with new panel additions.

 

It would also be useful to include immunohistochemical figures for both cases, not only Case 1.

• New panels will be introduced for the figures.

 

Discussion Depth

 

The discussion is well-grounded in literature but could be expanded by exploring the molecular or genetic implications of this variant, if any have been reported.

• Thank you for this suggestion. However, considering the rarity and the fact that we report only two cases based on morphology and IHC, and since we have no access to or experience with molecular analysis, we prefer to avoid discussion topics outside of our expertise to prevent making incorrect assumptions regarding this entry.

 

Consider briefly discussing potential therapeutic implications or whether this variant behaves differently prognostically from typical acinar adenocarcinomas.

• Thank you for this suggestion. As seen from their case, both patients are doing well for now. Once again, we would like to avoid making statements outside of our field of expertise.

 

Language and Grammar

 

The English is understandable but needs editing for clarity and flow. Frequent issues include missing articles ("the", "a"), inconsistent verb tenses, and typographical errors (“derivfrom,” “mol;ecular,” “connextion,” etc.). A thorough language revision by a native or professional editor is recommended.

• Thank you, according changes will be made.

 

Reference: consider this article related to histological variant in urological conditions (DOI: 10.1016/j.euo.2025.03.019)

• Thank you for this suggestion, however, the proposed manuscript is outside the scope of the presented cases, and I would prefer not to include it.

Reviewer 4 Report

Comments and Suggestions for Authors

The author reported two rare subtypes of prostate cancer. Although the second patient did not undergo a biopsy for bone metastasis, it can be inferred from the literature and the patient's disease course that this subtype of prostate cancer has the potential to metastasize. The author's report helps to further understand this rare subtype.

Author Response

The author reported two rare subtypes of prostate cancer. Although the second patient did not undergo a biopsy for bone metastasis, it can be inferred from the literature and the patient's disease course that this subtype of prostate cancer has the potential to metastasize. The author's report helps to further understand this rare subtype.

 

• Dear reviewer thank you for these comments.

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

1. I feel that the authors have not presented sufficient information to diagnose Case 2 (section 2.1) as a renal-type clear cell carcinoma of the prostate. (1) No (histopathology) images have been presented of the pre-treatment prostate tumour and no review of the pathology has been described to indicate that the original prostate cancer either did or did not exhibit regions with a clear cell type morphology (prior to treatment with androgen deprivation therapy). While prostate cancers can change morphology as the disease progresses, the appearance of a clear cell morphology following androgen deprivation therapy is consistent with the well-established treatment response of prostate tumour cells to this treatment. (2) Was the patient still receiving androgen deprivation treatment when he was referred to the authors’ hospital for surgery? How long had treatment been stopped prior to surgery? If the patient was still receiving or had very recently stopped androgen deprivation therapy, this would confound a definitive diagnosis of renal-type clear cell carcinoma of the prostate based on morphological criteria. (3) The authors state that the clear cell morphology of the tumour is not due to the androgen deprivation therapy that the patient had received because the tumour volume was large. However, tumour volume exhibiting this morphology is not a criterion for recognition of this response to androgen deprivation therapy.
2. Serum PSA levels have not been included for patient 2 (they are included for patient 1). These should be added.
3. Line 128: Gleason grade should not be reported after androgen deprivation therapies (see https://www.pathologyoutlines.com/topic/prostatetreatmenteffect.html).

Comments on the Quality of English Language

English language is generally good, however the manuscript would benefit by English language editing as incorrect word usage has led to some inaccurate statements. The following are examples of some instances where this has occurred.

1. Abstract lines 15-16: As stated in the previous review, the phrase “while not being prevalent in terms of malignancy-related deaths” means that prostate cancer is not a common cause of cancer death. As this is incorrect (prostate is a common cause of cancer-associated death), the sentence needs to be changed. This is an English language issue – the authors’ intended meaning (which is not a focus of this manuscript) is not conveyed by the language that they are using.
2. Abstract lines 22-23 (and line 71): The authors could use the term ‘pleomorphic’ rather than ‘differing in size’. ‘Differing in size’ cannot be used as an adjective, therefore if the authors prefer to use this term, the sentence should be re-structured by an English language editor.
3. Line 36: The phrase “the malignancy-related deaths” should be “the malignancy-related death rate”. (The number of deaths is very high, the number of deaths as a proportion of the number of (prostate cancer) diagnoses (the death “rate”) is not as high as for other cancers, as detailed by the authors).
4. Line 140: ‘much come common’ should be ‘much more common’.
5. Line 166: ‘Immunohistochemical parkers’ should be ‘Immunohistochemical markers’.

Author Response

Reviewer 1:
Comments and Suggestions for Authors
I feel that the authors have not presented sufficient information to diagnose Case 2 (section 2.1) as a renal-type clear cell carcinoma of the prostate. (1) No (histopathology) images have been presented of the pre-treatment prostate tumour and no review of the pathology has been described to indicate that the original prostate cancer either did or did not exhibit regions with a clear cell type morphology (prior to treatment with androgen deprivation therapy). While prostate cancers can change morphology as the disease progresses, the appearance of a clear cell morphology following androgen deprivation therapy is consistent with the well-established treatment response of prostate tumour cells to this treatment. (2) Was the patient still receiving androgen deprivation treatment when he was referred to the authors’ hospital for surgery? How long had treatment been stopped prior to surgery? If the patient was still receiving or had very recently stopped androgen deprivation therapy, this would confound a definitive diagnosis of renal-type clear cell carcinoma of the prostate based on morphological criteria. (3) The authors state that the clear cell morphology of the tumour is not due to the androgen deprivation therapy that the patient had received because the tumour volume was large. However, tumour volume exhibiting this morphology is not a criterion for recognition of this response to androgen deprivation therapy.

- Dear reviewer, thank you for these valuable comments. We have retrieved the slides of the initial biopsy from the original institution and included the new findings of the primary biopsy. The original biopsy does show clear cell and cell vacuolation changes similar in some aspects to chromophobe renal cell carcinoma. Androgen deprivation was stopped only for one month prior to the currently presented intervention. If the images from the original biopsy are not confirmatory enough, we still propose the removal of the second case so that we may at least proceed with the first case for publication.

Serum PSA levels have not been included for patient 2 (they are included for patient 1). These should be added.
- We have also included the PSA values prior to the first biopsy – 44ng/ml

Line 128: Gleason grade should not be reported after androgen deprivation therapies (see https://www.pathologyoutlines.com/topic/prostatetreatmenteffect.html).
- Thank you for your comment. Changes have been made, and we will remember this information for future cases in our practice.

Comments on the Quality of English Language
English language is generally good, however the manuscript would benefit by English language editing as incorrect word usage has led to some inaccurate statements. The following are examples of some instances where this has occurred.

Abstract lines 15-16: As stated in the previous review, the phrase “while not being prevalent in terms of malignancy-related deaths” means that prostate cancer is not a common cause of cancer death. As this is incorrect (prostate is a common cause of cancer-associated death), the sentence needs to be changed. This is an English language issue – the authors’ intended meaning (which is not a focus of this manuscript) is not conveyed by the language that they are using.

- Thank you for this comment, changes will be implemented.

Abstract lines 22-23 (and line 71): The authors could use the term ‘pleomorphic’ rather than ‘differing in size’. ‘Differing in size’ cannot be used as an adjective, therefore if the authors prefer to use this term, the sentence should be re-structured by an English language editor.
- Thank you for this comment, the change has been incorporated.

Line 36: The phrase “the malignancy-related deaths” should be “the malignancy-related death rate”. (The number of deaths is very high, the number of deaths as a proportion of the number of (prostate cancer) diagnoses (the death “rate”) is not as high as for other cancers, as detailed by the authors).
- Thank you for this comment, the change has been incorporated.

Line 140: ‘much come common’ should be ‘much more common’.
- Thank you for this comment, the change has been incorporated.

Line 166: ‘Immunohistochemical parkers’ should be ‘Immunohistochemical markers’.
- - Thank you for this comment, the change has been incorporated.

Reviewer 3 Report

Comments and Suggestions for Authors

accept