The subject discussed in the present study is remarkably interesting. Tumor stroma is one of the key elements in cancer progression, and it contains important cell types (e.g. cancer-associated fibroblasts) that can regulate cancer spread and influence the most fatal event, metastasis, through the production of growth factors and extracellular matrix. Some studies have described that tumor with a high stromal content can benefit from stromal growth factors, resulting in more aggressive behavior and poor survival. Some previous studies demonstrated thar the assessment of TSR has a promising prognostic value and can be implemented with minimum efforts in routine head and neck pathology. Herein, the authors explore these aspects in a very important sample (n=583 cases) and also, demonstrated that cancer associated fibroblasts (CAFs)-stroma ratio (CSR) contributed to the prognostic value of TSR. The study is very interesting , well conducted but several aspects should be addressed. I have few suggestions and criticisms that I will describe point by point.
Introduction

-“ Annually, 270,000 people are affected by oral cancer worldwide, and roughly 90% of cases are oral squamous cell carcinoma (OSCC), which usually develop in the lingual buccal, and gingival areas with a mortality rate of 40%–50% (Parkin et al., 2005, Vokes et al., 1993)” Revise this sentence and use more recently data from GLOBOCAN or similar.
Cancer statistics for the year 2020: An overview. Ferlay J, Colombet M, Soerjomataram I, Parkin DM, Piñeros M, Znaor A, Bray F.Int J Cancer. 2021 Apr 5. doi: 10.1002/ijc.33588. Online ahead of print. PMID: 33818764
Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. CA Cancer J Clin. 2021 May;71(3):209-249. doi: 10.3322/caac.21660. Epub 2021 Feb 4.PMID: 33538338

• “Whether adopting neck lymph node dissection partly depends on the pathological diagnosis through hematoxylin and eosin stained slides (H&E;) focusing on the tumor cell… I agree with the paragraph however the HE analysis does not focus only on the tumor cell itself but on the livers/compromised margins, on having or not perineural and vascular invasion. Review these aspects.

• The last paragraph of the introduction needs to be well revised. Recently, Dr. Ilmo Leivo's group published a systematic review on this subject, and I think it would be important to bring the main findings of this study. Please, point out the limitations of the studies carried out so far to justify this one. Focus in make clear what is the aim of your study not the results of it here in the introduction.
  Clinical significance of tumor-stroma ratio in head and neck cancer: a systematic review and meta-analysis. Almangush A, Alabi RO, Troiano G, Coletta RD, Salo T, Pirinen M, Mäkitie AA, Leivo I.BMC Cancer. 2021 Apr 30;21(1):480.

Methods
-It will be very nice to have the results based on the 8AJCC edition.
- Did you do a sample size calculation to arrive at this number of 100 patients?
- What it means FAP, it would be anti-fibroblast activating protein? Please describe this information in the text.
- Describe the histopathological classification grade (I, II and III)because it was describe in the results/table . What was the classification used?

Results
Table 1- describe that the grade is histopathological grade
The analysis of DOI will be very interesting and should be compared to TSR
Very nice figures, congratulations!

Discussion
- “TSR is a histological characteristic with great potential and received more and more attentions particularly in colon, breast cancer as we mentioned before. “ grest potential for what? Explain more and add references. Bring to this paragraph the prognostic aspect reported until now for OSCC and also the main results that you have in the present paper.

• Pleaser, remove all this paragraph… In my opinion, this paragraph discusses methodological points. I honestly do not see it as something so relevant to be discussed in the face of so much other important data. “ The study digitally assess the TSR in oral cancer using the Mesker method (Mesker et al., 2007). Concretely, we chose a 3.2-mm2 circle to perform TSR scoring, which was exactly parallel to the *10 objection in light microscopy. A study has indicated that the diameter of a light microscope does not differ in the final score (van Pelt et al., 2018). All slides were scored three times to avoid intra-observer variability. Finally, Kappa coefficient reached perfect agreement though in the beginning only 0.762; most initial…”

I strongly suggest that the authors organize the discussion in the same way as they did in the results. Discuss the main findings in the following order. Confront the existing literature that was included in the systematic review by Dr Leivo's group. Follow the topics: The prognostic value of the TSR/ TSR stratified by clinically crucial subgroups/ The CAFs–stroma ratio(CSR) essentially advanced to the prognostic value of TSR.
Some points that caught my attention in the sample included in this study and that differ from many studies on OSCC maybe should be discussed.
- Characteristic of the sample : “ Most tumors were oral tongue cancers (56.11%), male (62.13%), no lymph node metastasis (73.67%)…” probably no advanced cases. Usually, the diagnosis of OSCC is late ( grade III and IV). Other point was the tumor location. Usually OSCC are more frequent in tongue , floor of the mouth . Gingiva and buccal mucosa are not frequent sites. Could you discuss about these points?

I suggest to discuss your results with the articles about this issue.
-Niranjan KC, Sarathy NA. Prognostic impact of tumor-stroma ratio in oral squamous cell carcinoma - a pilot study. Ann Diagn Pathol. 2018;35:56–61. doi: 10.1016/j.anndiagpath.2018.05.005.
- Almangush A, Heikkinen I, Bakhti N, Mäkinen LK, Kauppila JH, Pukkila M, Hagström J, Laranne J, Soini Y, Kowalski LP, Grénman R, Haglund C, Mäkitie AA, Coletta RD, Leivo I, Salo T. Prognostic impact of tumour-stroma ratio in early-stage oral tongue cancers. Histopathology. 2018;72(7):1128–1135.
- Mascitti M, Zhurakivska K, Togni L, Caponio VCA, Almangush A, Balercia P, Balercia A, Rubini C, Lo Muzio L, Santarelli A, Troiano G. Addition of the tumour-stroma ratio to the 8th edition American joint committee on Cancer staging system improves survival prediction for patients with oral tongue squamous cell carcinoma. Histopathology. 2020;77(5):810–822.
-Dourado MR, Miwa KYM, Hamada GB, Paranaíba LMR, Sawazaki-Calone Í, Domingueti CB, Ervolino de Oliveira C, Furlan ECB, Longo BC, Almangush A, Salo T, Coletta RD. Prognostication for oral squamous cell carcinoma patients based on the tumour-stroma ratio and tumour budding. Histopathology. 2020;76(6):906–918.
-Bello IO, Almangush A, Heikkinen I, Haglund C, Coletta RD, Kowalski LP, Mäkitie AA, Nieminen P, Leivo I, Salo T. Histological characteristics of early-stage oral tongue cancer in young versus older patients: a multicenter matched-pair analysis. Oral Dis. 2020;26(5):1081–1085. doi: 10.1111/odi.13288. [

The authors did a good job revising the article. However, the new version is very confusing and hard to follow because it is not "clean". Please submit a new version without the track change.
I suggest that authors revise the results
- "Overall Ultimately, 298 patients were scored as high stroma, and 283 patients we..." it got very awkward to start with this description of the results. The authors should initially describe the sample and then bring this result.
- The summary description of the results suggested by reviewer 2 was excellent!
- I would like to read again a clean version of the article.

I thank the authors for sending the new version. The changes have been made. Great work, congratulations!