PONE-D-20-10673

Survival and Clinicopathological Characteristics of Different Histological Grades of Oral Cavity Squamous Cell Carcinoma: A Single-Center Retrospective Study

PLOS ONE

Dear Dr. Tsai,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, the reviewers and i feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by Jul 31 2020 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

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We look forward to receiving your revised manuscript.

Kind regards,

Dipak Sapkota, PhD

Academic Editor

PLOS ONE

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 [The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.].

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Partly

Reviewer #3: Yes

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: No

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4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: No

Reviewer #3: No

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The authors present a complete and well organised manuscript that highlights the importance of providing histological grade of oral squamous carcinomas. Although the significance of the findings might be deeply related to the demographical and social characteristics of the cohort (betel chewing for example), the main suggestions about the value of the histological grading in OSCC in this report are still universally valuable and in line with practice with other type of malignancies affecting other organs/systems and that are stratified by histological grade.

The authors exclude from the cohort cases of carcinomas of the lip not affecting labial mucosa, but Table 5 reports tumors of the lips, which is confusing. Indicating this group as "labial mucosa" sounds more correct and takes away this confusing.

The authors correctly point that the histological grade might be to a certain degree subjective, and here the grading is performed by only one individual, which should be pointed also in the discussion as one of the challenges with this manuscript.

Finally, the authors use OSCC but also SCC and should keep one form; in page 2 and page 15 "should not be disregarded" might be better expressed as for "should be followed more closely than OSCC in early stages but higher differentiation degree"; in page 12 it should be "poor differentiation" not "poor differentiate"; in page 15 I guess authors mean "diagnostic field" and not "diagnostic filed".

Reviewer #2: Dear authors,

Thank you for the opportunity to review this manuscript in a very interesting topic. I have several concerns about your manuscript pointed bellow. I strongly recommend an English language review. You should considerer to reestructure the manuscript, this atual version is presented in a very confuse way.

Abstract

- The abstract section is very confuse and do not reflect clearly the content of the study.

Introduction

- The introduction section is a little poor, the authors should consider to include one or two more paragraphs to state the problem to the readers.

Patients and Methods

- The authors have to add the number and the date of the ethical board protocol aprouvement. (page 3)

- In my point of view include lip squamous cell carcinoma is a bias in your study. It is well known that, in this location, the neoplasia have a complete different biological behaviour. (page 4)

- The authors have to explain better the histopathological classification, especially how it has been performed, this is the central part of the study. Only one pathologist performed the analysis? How many slides per day? Directly in a microscope? With an image manager program? (page 4)

- Has the immunohistochemistry been performed in a regular basis? How many cases? In wich conditions?(page 5)

- As mentioned, the inclusion of the lip is a bias in your study. In my point of view, the authors should exclude this region. (page 5)

Results

- In general the results were presented in a very confuse way, the authors should rewrite this part of the manuscript. The tables are very difficult to understant and some of them are unnecessary.

Discussion

- In my point of view the discussion section is a bit confuse and include a restrict number of references, considering this is a classic topic (only 18 references in total).

- The authors should rewrite the discussion section according to the reestructured results section in a possible future revised version.

Reviewer #3: Although the finding are significant, the manuscript is not written well. Therefore I advise you to get the help from a language expert. There is a significant amount of literature missing in the reference list.

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While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

PONE-D-20-10673R1

Survival and Clinicopathological Characteristics of Different Histological Grades of Oral Cavity Squamous Cell Carcinoma: A Single-Center Retrospective Study

PLOS ONE

Dear Dr. Tsai,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we still feel that the reviewers' comments are not satisfactorily addressed in the current version. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by Sep 04 2020 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

• A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

We look forward to receiving your revised manuscript.

Kind regards,

Dipak Sapkota, PhD

Academic Editor

PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: (No Response)

Reviewer #2: (No Response)

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

Reviewer #2: Partly

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: No

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: I commend the authors for having worked with the text and accepting our suggestions, and the presentation of the data and the discussion are more complete and precise. The manuscript has improved on the language side as well, but there are still mistakes in the text (page 8 "...grade 2, years, and grade 3 OSCC..."; page 9 "...most..." instead of "...mostly..."; page 16 "re-wide excision" never heard before, I guess the authors mean "wider re-excision").

In page 17 the authors write that "...grading attempts are inexact, subjective, not reproducible." It is also my experience that most squamous carcinomas fall in the definition of moderate grade of differentiation, but the authors are quite sharp in their definition. And just using keratinising vs non keratinising could give the same problem and be potentially subjective. This has been dealt with by other authors who suggested a to-tier grading to improve the concordance of the grading [I can quickly suggest for example Krishnan, Karpagalvi...Patil, J Oral Maxillofac Pathology (2016) and Steigen, Søland...Olsen, J Oral Pathol Med (2020)].

Also, in the text the authors now write that two pathologists classified the material and not just one, but the numbers of the groups were the same as far as I can see, and the authors write nothing on how the two pathologists came to an agreement. Did the pathologists agree on all cases? In this case why do the authors write the grading is not reproducible?

This point (only one pathologist) and a point previously addressed (grade 3 cases should not be "disregarded") have not been addressed in the abstract, that should be corrected as well.

The text is written in good English all in all but the imprecisions deter from the scientific value of the study, real piety since I find the study really useful also in clinical settings, reminding pathologists to provide clinicians with a histological variable that can be evaluated on routinely provided HE slides.

Reviewer #2: The main questions addressed in the first round of revision were not properly answered. Including the lip OSCC is one of the major concern in the manuscript.

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Reviewer #1: No

Reviewer #2: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

PONE-D-20-10673R2

Survival and clinicopathological characteristics of different histological grades of oral cavity squamous cell carcinoma: a single-center retrospective study

PLOS ONE

Dear Dr. Tsai,

Thank you for revising the manuscript according to the reviewers suggestions. The manuscript has improved significantly, but i feel that the manuscript will immensely benefit if you could improve the language (especially the consistent use of 'tense' in the method, result and the discussion sections) of your manuscript. Therefore, i invite you to submit a revised version of the manuscript. 

Please submit your revised manuscript by Sep 13 2020 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

• A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

We look forward to receiving your revised manuscript.

Kind regards,

Dipak Sapkota, PhD

Academic Editor

PLOS ONE

Editor Comments:

Thank you for revising the manuscript according to the reviewers suggestions. The manuscript has improved significantly, but the manuscript still appears inconsistent with respect to the use of 'tense' in the method, result and the discussion sections. Please use a consistent tense to describe the current results as well as results from other researchers.

[Note: HTML markup is below. Please do not edit.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

Survival and clinicopathological characteristics of different histological grades of oral cavity squamous cell carcinoma: a single-center retrospective study

PONE-D-20-10673R3

Dear Dr. Tsai,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

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Kind regards,

Dipak Sapkota, PhD

Academic Editor

PLOS ONE

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Reviewers' comments: