Metastatic Renal-Cell Carcinoma of the Oro-Facial Tissues: A Comprehensive Review of the Literature with a Focus on Clinico–Pathological Findings

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The study designed in the standars way. however as sytematic review it should be reviewed major papers within last 2- 3 years while most of refefnces are quite old. 

As major criteria reviewed is about distribution of tumor based on clinical findings so the title is not apprprite for this limited criteria. Authors can integrate some therapeutic findings reviewed papers and more important demographic criterias in different geogrphic locations to have more global data.

Comments on the Quality of English Language

The quality seems appropriate however minor corrections are required

Author Response

The study designed in the standard way. however as sytematic review it should be reviewed major papers within last 2- 3 years while most of references are quite old. 

As major criteria reviewed is about distribution of tumor based on clinical findings so the title is not appropriate for this limited criteria. Authors can integrate some therapeutic findings reviewed papers and more important demographic criteria in different geographic locations to have more global data.

 

We thank the Reviewer for her/his suggestions. We modified the title as suggested. We integrated the discussion section with novel targeted therapies for RCC. Moreover, we inserted among references recent studies regarding this topic (years of publication: 2022-2024). However, after 2020 there are no other relevant reviews and only few case reports, not adding significant findings. Data about geographic location should be very interesting but frequently missing within the paper, maily in case series and review. Thank you for revision 

We thank the Reviewer for her/his suggestions. We modified the title as suggested. We integrated the discussion section with novel targeted therapies for RCC. Moreover, we inserted among references recent studies regarding this topic (years of publication: 2022-2024). However, after 2020 there are no other relevant reviews and only few case reports, not adding significant findings.

Reviewer 2 Report

Comments and Suggestions for Authors

A different style has to be applied to the review article via involving high-quality figures, interesting tables etc.

Lots of author names and their articles were listed, losing almost whole feelings of the readers, discussion part and introduction part were focusing almost on the same topic.

Main analytic topic, eg.CT-MRI-PET-Histopathological confirmation, have to be more clearly emphasized.

Has to be re-written

 

Comments on the Quality of English Language

minor editing.

Author Response

A different style has to be applied to the review article via involving high-quality figures, interesting tables etc.

Lots of author names and their articles were listed, losing almost whole feelings of the readers, discussion part and introduction part were focusing almost on the same topic.

Main analytic topic, eg.CT-MRI-PET-Histopathological confirmation, have to be more clearly emphasized.

Has to be re-written

Dear Reviewer, the paper has been prepared accordingly to the Journal guidelines for review; considering the number of papers and their importance in the fine collection of published cases, numerous references has been listed; also, generally figures are not required for literature review; the tables introduced are a list of the study (cases) emerging from literature, considering that each paper has been carefully evaluated to better highlight the clinical aspect of the relative case, so this should be their own interest;  a section on the radiological investigations and recent advance in imaging of RCC has been introduce and the discussed as required.

Also, we reviewed the paper in all section as required; modified text has been highlighted in yellow.

The paper has been revised by MDPI editing system for language

Thank you for suggestions.

Reviewer 3 Report

Comments and Suggestions for Authors

This is an interesting review article on rare sites of ccRCC metastasis.

There are several points that need to be addressed before publication.

There are sentences that need to be clarified ( eg “Though uncommon  metastatic sites or late meta-chronous metastases (>10 years) are not uncommon…”)

The text requires English editing

In the material section, it is noted that the period for the literature search was the period going from September 2023 to January 2024. Is that correct?

Was bleeding of the lesions reported in any series?

In the table, authors have includes patients with Wilm’s tumors and transitional tumors. These aren’t “Renal Cell Carcinomas” and should be removed from the review.

The discussion section needs to be more focused. For example, the paragraph on differential diagnosis, especially for gingival localizations should be shortened.

The part on TILs does not fit in with was his described previously. The link between early diagnosis and IDMC prognostic criteria is not clear.

Figure 2 isn’t available in the current document

Comments on the Quality of English Language

There are sentences that need to be clarified and the text requires English editing

Author Response

This is an interesting review article on rare sites of ccRCC metastasis.

There are several points that need to be addressed before publication.

There are sentences that need to be clarified ( eg “Though uncommon  metastatic sites or late meta-chronous metastases (>10 years) are not uncommon…”)

Amended, thank you

The text requires English editing

Amended, thank you

In the material section, it is noted that the period for the literature search was the period going from September 2023 to January 2024. Is that correct?

We thank the Reviewer for her/his question. This sentence regards the period that we spent for the literature search and not the period of publication of the studies included in our review.

Was bleeding of the lesions reported in any series?

We thank the Reviewer for her/his question. Yes, it was reported. We specified it in the text as regards some specific oral sites.

In the table, authors have included patients with Wilm’s tumors and transitional tumors. These aren’t “Renal Cell Carcinomas” and should be removed from the review.

We agree with the Reviewer. We removed them.

The discussion section needs to be more focused. For example, the paragraph on differential diagnosis, especially for gingival localizations should be shortened. 

We modified it accordingly, we thank the Reviewer.

The part on TILs does not fit in with was his described previously. The link between early diagnosis and IDMC prognostic criteria is not clear.

Amended, thank you

Figure 2 isn’t available in the current document

Reviewer 4 Report

Comments and Suggestions for Authors

In the review entitled “Metastatic Renal Cell Carcinoma to the Oro-Facial Tissues: a Comprehensive Review of the Literature with Focus on the Clear Cell Subtype”, the authors provided a literature review and analysis of the existing research on oro-facial metastases from renal cell carcinoma (RCC) with a special focus on the most common variant clear cell RCC. Among the 160 analyzed studies, the authors identified 211 cases of oro-facial metastases of RCC, with a higher incidence in males than females, and an average patient age of 59.8 years. Of these, 122 cases were histologically diagnosed as ccRCC (57.8%). tongue, mandible, and gingiva were the most affected sites. The clinical manifestations of soft tissue metastases varied, with exophytic masses often accompanied by pain, as well as radiolucent lesions usually seen in bone metastases. The authors provided two interesting figures summarizing the PRISMA flow chart for reporting systematic reviews and RCC prevalence of lesions by site of involvement. Additionally, the authors provided seven informative tables summarizing metastases of renal carcinoma to the oral cavity, data analysis of oro-facial metastases of RCC, and metastases of ccRCC to the oro-facial tissues and clinical radiological presentation. From the discussion, it was concluded that early detection of RCC presents a diagnostic challenge, particularly when the clinical examination is restricted to the cevico-facial region. In spite of these limitations, early diagnosis and the introduction of adjuvant treatments are likely to significantly improve patients' outcomes. The summarized information is interesting.

Comments: 

1) In lines 132-133, the authors stated that “The reading, selection, and analysis of the articles included in this review were performed by a single clinician”. Have the authors considered that this approach may raise potential concerns about bias? To limit the risk of individual bias, multiple reviewers should evaluate and select articles independently to ensure a comprehensive and balanced assessment to limit the risk of individual bias.

 

2) In section#2 (Material and Methods), specific inclusion criteria should be described.

3) The authors are advised to make the table captions stand-alone. To this end, authors are advised to provide a list of abbreviations describing the full names of all the listed abbreviations within the table.

 

4) The work lacks future directions that will include limitations and what is the next step to translate these findings to clinical settings.

 

5) In line 357, the “conclusions” section should be replaced by “Conclusions and future directions”.

 

6) To enhance the readership of the current work, it is better to divide the discussion section into numbered subsections to make it clear for readers. In the discussion, additional details of targeted therapies of RCC are advised.

7) The authors are advised to carefully revise the reference section. The authors are advised to remove the month from each reference. Please, follow the journal instructions in this regard.

 

8) In lines 17-18, is there a specific reason to make “Oro-facial Metastases” and “Clear Cell Renal Cell Carcinoma” capitalized within the text? Please, address this point in the entire manuscript.

 

9) Some typos/grammar/syntax errors are present in the manuscript which need to be addressed, for example:

 

A) In lines 19-20, the authors state “Clinical differential diagnosis has been widely discussed to provide the clinicians all the useful information”. Please, consider correcting the statement to “Clinical differential diagnosis has been widely discussed to provide clinicians with all the useful information”.

 

B) In line 28, the authors state “In the oro-facial tissues the sites mostly involved are the oral mucosa”. Please, add a comma after “tissues”.

 

C) In lines 118-119, the authors state “The terms “renal metastasis” or “renal metastases” or “clear cell renal cell carcinoma” AND “oral” o “Head and Neck” were alternatively used”. Please, correct the term “o” to “or”.

 

10) In the captions of tables 1 and 2, please remove “all caps” from the caption. 

 

Comments on the Quality of English Language

Moderate editing of the English language is required. 

Some typos/grammar/syntax errors are present in the manuscript which need to be addressed, for example:

A) In lines 19-20, the authors state “Clinical differential diagnosis has been widely discussed to provide the clinicians all the useful information”. Please, consider correcting the statement to “Clinical differential diagnosis has been widely discussed to provide clinicians with all the useful information”.

 

B) In line 28, the authors state “In the oro-facial tissues the sites mostly involved are the oral mucosa”. Please, add a comma after “tissues”.

 

C) In lines 118-119, the authors state “The terms “renal metastasis” or “renal metastases” or “clear cell renal cell carcinoma” AND “oral” o “Head and Neck” were alternatively used”. Please, correct the term “o” to “or”.

Author Response

In the review entitled “Metastatic Renal Cell Carcinoma to the Oro-Facial Tissues: a Comprehensive Review of the Literature with Focus on the Clear Cell Subtype”, the authors provided a literature review and analysis of the existing research on oro-facial metastases from renal cell carcinoma (RCC) with a special focus on the most common variant clear cell RCC. Among the 160 analyzed studies, the authors identified 211 cases of oro-facial metastases of RCC, with a higher incidence in males than females, and an average patient age of 59.8 years. Of these, 122 cases were histologically diagnosed as ccRCC (57.8%). tongue, mandible, and gingiva were the most affected sites. The clinical manifestations of soft tissue metastases varied, with exophytic masses often accompanied by pain, as well as radiolucent lesions usually seen in bone metastases. The authors provided two interesting figures summarizing the PRISMA flow chart for reporting systematic reviews and RCC prevalence of lesions by site of involvement. Additionally, the authors provided seven informative tables summarizing metastases of renal carcinoma to the oral cavity, data analysis of oro-facial metastases of RCC, and metastases of ccRCC to the oro-facial tissues and clinical radiological presentation. From the discussion, it was concluded that early detection of RCC presents a diagnostic challenge, particularly when the clinical examination is restricted to the cevico-facial region. In spite of these limitations, early diagnosis and the introduction of adjuvant treatments are likely to significantly improve patients' outcomes. The summarized information is interesting.

Comments:  

1) In lines 132-133, the authors stated that “The reading, selection, and analysis of the articles included in this review were performed by a single clinician”. Have the authors considered that this approach may raise potential concerns about bias? To limit the risk of individual bias, multiple reviewers should evaluate and select articles independently to ensure a comprehensive and balanced assessment to limit the risk of individual bias.

 We apologize for the mistake. The analysis was performed by four reviewers, we modified the text accordingly.

2) In section#2 (Material and Methods), specific inclusion criteria should be described. 

We modified the section accordingly, better specifying the inclusion criteria.

3) The authors are advised to make the table captions stand-alone. To this end, authors are advised to provide a list of abbreviations describing the full names of all the listed abbreviations within the table. 

Amended, thank you for the suggestion. 

4) The work lacks future directions that will include limitations and what is the next step to translate these findings to clinical settings.

 A paragraph has been included at the end of conclusions, thank you for the suggestion.

5) In line 357, the “conclusions” section should be replaced by “Conclusions and future directions”. 

 Amended, thank you

6) To enhance the readership of the current work, it is better to divide the discussion section into numbered subsections to make it clear for readers. In the discussion, additional details of targeted therapies of RCC are advised.

We modified the discussion accordingly, thank you for the suggestion.

7) The authors are advised to carefully revise the reference section. The authors are advised to remove the month from each reference. Please, follow the journal instructions in this regard. 

Amended, thank you

8) In lines 17-18, is there a specific reason to make “Oro-facial Metastases” and “Clear Cell Renal Cell Carcinoma” capitalized within the text? Please, address this point in the entire manuscript.

 Amended, thank you

9) Some typos/grammar/syntax errors are present in the manuscript which need to be addressed, for example:

1. A) In lines 19-20, the authors state “Clinical differential diagnosis has been widely discussed to provide the clinicians all the useful information”. Please, consider correcting the statement to “Clinical differential diagnosis has been widely discussed to provide clinicians with all the useful information”.

  Amended, thank you

1. B) In line 28, the authors state “In the oro-facial tissues the sites mostly involved are the oral mucosa”. Please, add a comma after “tissues”.

   Amended, thank you

1. C) In lines 118-119, the authors state “The terms “renal metastasis” or “renal metastases” or “clear cell renal cell carcinoma” AND “oral” o “Head and Neck” were alternatively used”. Please, correct the term “o” to “or”.

 Amended, thank you

10) In the captions of tables 1 and 2, please remove “all caps” from the caption. 

Amended, thank you

Moderate editing of the English language is required. 

Amended, thank you

Round 2

Reviewer 3 Report

Comments and Suggestions for Authors

Some of the comments have not been taken into account.

The  text needs to be broadly reviewed and synthetized. The text should be more focused.

Some of the articles on non renal cell carcinomas have not been removed from  table 1

Some of the data  present in the discussion is not  relevant ( eg Schultz V  et al, the data on the IDMC prognostic groups...) Current treatments are mostly immunotherapy combinations (IO-IO and IO- VEGFR TKIs) with little room for mTOR inhibitors

Comments on the Quality of English Language

The formulation of the text is complicated

Author Response

Author's Reply to the Review Report (Reviewer 3)

Some of the comments have not been taken into account.

We are sorry for it but all the required changes have been clearly done in the last revised version.

The  text needs to be broadly reviewed and synthetized. The text should be more focused.

Considering that the paper is a review with a minimum of word the text may appear long and not synthetized.

Some of the articles on non renal cell carcinomas have not been removed from  table 1

We cordially want to apologize for this, as this was missing in the previous version, although required by reviewer. In the current version, non renal tumors have been removed from table and consequently from the general count of lesion and relative % values.

Some of the data  present in the discussion is not  relevant ( eg Schultz V  et al, the data on the IDMC prognostic groups...)

These data have been removed accordingly

Current treatments are mostly immunotherapy combinations (IO-IO and IO- VEGFR TKIs) with little room for mTOR inhibitors

This point has been introduced to underline to most common therapies at the present.

Reviewer 4 Report

Comments and Suggestions for Authors

The authors adequately addressed the raised comments.

Author Response

Thank you for your time