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  • Füruzan Kacar Döger 1,*,
  • Büşra Ekinci 2 and
  • Yeşim Başal 3

Reviewer 1: Anonymous Reviewer 2: Masaaki Noguchi Reviewer 3: Anonymous

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This manuscript presents a retrospective analysis of 31 cases of extranodal head and neck lymphomas diagnosed over a 6-year period at a single Turkish institution. While the topic is clinically relevant, the manuscript requires substantial revisions in methodology, data consistency, and presentation quality before it can be considered for publication. Below I outline major and minor concerns.

Major Issues

  1. Mortality rate error. The text states a mortality rate of 6.5%, but 4/31 deaths = 12.9%. This must be corrected throughout.
  2. Incomplete sentence (Lines 216–217). The GCB/non-GCB classification sentence is truncated. Additionally, the percentages are wrong: 14/17 = 82.4%, not 80.2%; 3/17 = 17.6%, not 19.8%.
  3. Bcl-2 data discrepancy (Lines 203–204). 14 positive + 14 negative = 28, but the cohort is 31 patients. Three cases are unaccounted for.
  4. M:F ratio inconsistency. Results state 1.6:1, Discussion states 1.16:1. The correct ratio from the data (19:12) is 1.58:1.
  5. Statistical concerns. With n=31 and only 4 events, chi-square tests on small subgroups violate minimum expected frequency assumptions. Fisher's exact test should be used. Kaplan–Meier curves (Figures 5–6) exclude FL, MCL, and HL without explanation, and lack censored tick marks and numbers at risk.
  6. Han's classification (Lines 207–209) is incomplete, and the MUM-1 criterion for non-GCB is missing.

Minor Issues

      7. Numerous language errors: "Clinicopatholoical" → "Clinicopathological."; "IGR" → "IQR"; "%12,9" → "12.9%"; "Kaplan_Meier" → "Kaplan–Meier"; "longrank" → "log-rank"; "cavite" → "cavity"; Turkish characters in Figure 2 legend ("Lenfoma" → "Lymphoma").

      8. Figure quality issues:

Figure 2 (pie chart): Labels are overlapping and difficult to read. A bar chart would be more appropriate for this number of categories.

Figures 5 and 6 (Kaplan–Meier curves): Axis labels use “survivalTime” (camelCase, presumably from SPSS), which should be formatted as “Survival Time (months).”

Histopathology images (Figures 1, 3, 4): Scale bars are absent. Magnification alone is insufficient per journal standards.

      9. CD30 appears twice with different clones (Ber-H2, RTU and M0751, 1/100). If both antibodies were used, the rationale should be explained. Otherwise, remove the duplicate.

      10. Discussion is disproportionately long (~2,500 words for 31 cases) and repeats textbook content. Please condense and focus on what this cohort uniquely contributes.

      11. Treatment regimens are not detailed. Given the retrospective nature of the study, this treatment heterogeneity likely impacts the survival outcomes and must be acknowledged and discussed as a study limitation.

Comments on the Quality of English Language

The manuscript would benefit from further English language editing. While the scientific content is generally clear, there are several typographical errors, including a typo in the title, and some incomplete sentences in the Results section. Additionally, minor formatting issues, such as the occasional use of non-English characters and non-standard numerical formats (e.g., "%12,9"), should be corrected. A thorough proofreading is kindly recommended to polish the text and meet the journal's publication standards.

Author Response

We thank the reviewer for the detailed and constructive comments. We have carefully revised the manuscript to address all concerns. Key revisions are summarized below:

 

  1. Mortality rate and data consistency:

 

Corrected mortality rate to 12.9%.

Completed the GCB/non-GCB classification sentence and corrected percentages (14/17 = 82.4%, 3/17 = 17.6%).

Added BCL-2 IHC results for the three previously missing cases.

Corrected male-to-female ratio to 1.58:1 (19:12).

 

  1. Statistical analyses:

 

Fisher’s exact test now used for subgroup comparisons.

Kaplan–Meier curves revised, exclusions explained.

 

  1. Pathology details:

 

Han’s classification fully described, including MUM-1 criterion.

Clarified rationale for use of both CD30 clones

  1. Figures and presentation:

 

Figure 2 replaced with a bar chart.

Kaplan–Meier axes reformatted as “Survival Time (months).”

Scale bars added to all histopathology images (Figures 1, 3, 4).

 

  1. Discussion and treatment:

 

Discussion condensed, focused on the cohort’s unique contributions; redundant textbook content removed.

Treatment regimens summarized; impact of heterogeneity on survival acknowledged as a study limitation.

 

  1. English language and formatting:

 

Manuscript thoroughly proofread and edited; typos, formatting errors, and non-English characters corrected to meet journal standards.

 

We believe these revisions comprehensively address the reviewer’s comments and improve the clarity, accuracy, and scientific rigor of the manuscript. We thank the reviewer again for their valuable suggestions.

                                    Füruzan Döger

Reviewer 2 Report

Comments and Suggestions for Authors

This study retrospectively evaluated and examined patients diagnosed with primary head and neck lymphoma by the Pathology Department between January 2020 and January 2026. However, the following points could be added: 1) What are the OS and PFS (Kaplan-Meier) overall and for each tumor?

2) Please take into account the fact that including repeat patients, such as those who developed symptoms in January 2026, will result in short survival times and make prognostic analysis difficult.

3) It would be helpful to compare this study with reviews of head and neck lymphoma. For example, it would be helpful to compare this study with data such as that in Reference 9, Wei MG, Ann Hematol. 2024; 103:5871-5880.

Author Response

 

We thank the reviewer for these constructive comments.

Kaplan–Meier analyses for overall survival (OS) and progression-free survival (PFS) have been added to the Results section. Given the small and heterogeneous cohort, these analyses are presented for exploratory purposes only and should not be interpreted as evidence of prognostic differences.

 We acknowledge that including patients with very recent diagnoses (e.g., January 2026) results in short follow-up times, limiting the reliability of survival and prognostic analyses. This limitation is now clearly stated in the Methods, Discussion section and study limitations section.

 A comparison with previous studies and reviews of head and neck lymphoma, including the suggested reference (Wei MG, Ann Hematol. 2024; 103:5871–5880), has been added to the Discussion to contextualize our findings.

We believe these revisions address the reviewer’s concerns and clarify the exploratory nature and limitations of the study.

Reviewer 3 Report

Comments and Suggestions for Authors

In this article, Füruzan Kacar Döger et al. present a retrospective single-center study on clinicopathological features of extranodal head and neck lymphomas. The manuscript has descriptive value as a single-center clinicopathologic series of extranodal head and neck lymphomas, but substantial revision is needed before it can be considered for publication. In particular, the pathology workup of aggressive B-cell lymphomas is incomplete for current standards, molecular/cytogenetic limitations should be addressed more explicitly, survival analyses should be toned down as exploratory, and multiple inconsistencies and language issues require correction.

  • Substantial English editing is required; there are many typographical, grammatical, and terminology errors throughout. There is a typo in the title “clinicopatholoGical”.
  • The cohort is too small and heterogeneous for robust survival analysis: Only 31 cases are included, spanning multiple biologically distinct entities (DLBCL, FL, MCL, NKTCL, ALCL, HL), with only 4 deaths. Survival comparisons by diagnosis and site are therefore severely underpowered and should be presented as exploratory only, not as evidence of no prognostic difference.
  • Lines 222-223: The manuscript states 4 deaths among 31 patients, which corresponds to 12.9%, yet also reports a “mortality rate of 6.5%.” This is unclear. Please correct or rephrase.
  • Also, the authors report 14 BCL2-positive and 14 BCL2-negative cases, which reflect a total of 28 rather than 31. Please explain or correct.
  • The DLBCL section is not adequately characterized for current standards: there is no MYC IHC and no MYC/BCL2/BCL6 FISH. In contemporary practice, FISH is used to identify aggressive large B-cell lymphomas with MYC and BCL2 rearrangements, which carry important biologic and therapeutic implications. Current guidance emphasizes that aggressive B-cell lymphomas should undergo FISH-based assessment for MYC with BCL2/BCL6 rearrangements; IHC alone cannot establish double-hit/triple-hit status. For double hit (PMID: PMID: 35653592)
  • In this manuscript, there is a lack of molecular/cytogenetic data that is important, especially for the aggressive B-cell lymphoma subset in the head and neck (i.e. DLBCL).
  • I suggest also adding a small paragraph to the introduction stating that some genetic changes are reported in lymphomas (PMID: PMID: 28804123, 29713087). Epigenetic dysregulation has also emerged as a key mechanism in lymphoma development and progression (PMID: 33229141).
  • In the discussion section: sometimes there is an overinterpretation of the findings despite the very small numbers.

Author Response

Response to Reviewer 3

 

We thank the reviewer for the careful reading of our manuscript and the valuable comments provided. We have carefully addressed all points and revised the manuscript accordingly. Our responses to each comment are detailed below.

 

  1. English language, typographical and terminology errors

Reviewer comment: Substantial English editing is required; there are many typographical, grammatical, and terminology errors throughout. There is a typo in the title “clinicopatholoGical.”

 

Response: We have thoroughly revised the manuscript for English language, typographical errors, and terminology issues. The typo in the title has been corrected to “clinicopathological.”

 

  1. Cohort size and survival analysis

Reviewer comment: The cohort is too small and heterogeneous for robust survival analysis: Only 31 cases are included, spanning multiple biologically distinct entities… Survival comparisons should be presented as exploratory only.

 

Response: We agree that the cohort size is small and heterogeneous. We have revised the survival analysis section to emphasize that all survival analyses are exploratory and not intended as evidence of prognostic differences. We have added the following statement to the Results section to clarify the exploratory nature of the survival analyses:

Kaplan–Meier survival analyses were performed for the cohort. No statistically significant differences were observed between lymphoma subtypes or sites. Due to the small sample size and heterogeneity of the cases, all analyses are presented for exploratory purposes only and should not be interpreted as evidence of prognostic differences.”

 

  1. Mortality rate and inconsistencies in BCL2 reporting

Reviewer comment: The manuscript states 4 deaths among 31 patients (12.9%), yet also reports a “mortality rate of 6.5%.” Also, 14 BCL2-positive and 14 BCL2-negative cases are reported, totaling 28 instead of 31.

 

Response: We have corrected the mortality rate to consistently report 12.9%. Regarding BCL2 status. The BCL-2 immunohistochemistry (IHC) results for the three cases with previously missing data have been added to the dataset and the Results section.

 

  1. DLBCL pathology characterization

Reviewer comment: The DLBCL section is not adequately characterized for current standards: no MYC IHC and no MYC/BCL2/BCL6 FISH.

 

Response: We acknowledge that MYC IHC and FISH for MYC/BCL2/BCL6 were not performed. We have added knowledge  section of the study limitations .

 

  1. Molecular/cytogenetic data

Reviewer comment: There is a lack of molecular/cytogenetic data, especially for aggressive B-cell lymphomas.

 

Response: We emphasize that the absence of these data is a limitation of the study.

 

  1. Overinterpretation in discussion

Reviewer comment: Sometimes there is an overinterpretation of findings despite the very small numbers.

 

Response: The Discussion section has been shortened and revised in light of this comment

  1. General statement

We hope that these revisions adequately address the reviewer’s comments and improve the clarity, accuracy, and scientific rigor of the manuscript. We thank the reviewer again for their valuable suggestions.

 

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

The authors have addressed the majority of concerns from the initial review, and the revised manuscript is substantially improved. Only a few minor items remain:

  1. The GCB/non-GCB percentages still read 80.2% and 19.8%. The correct values are 82.4% (14/17) and 17.6% (3/17). Please correct.
  2. The title still contains a typo: “Clinicopatholoical” → “Clinicopathological.”
  3. A few residual language/formatting errors: “four patients (%12,9)” should be “(12.9%)”; Figure 2 legend has “large cel lymphoma” (missing ‘l’).
  4. References 1 and 16 are identical (Vega et al., 2005), as are references 8 and 13 (Etemad-Moghadam et al., 2010). Please merge each pair and renumber citations accordingly.
Comments on the Quality of English Language

The manuscript would benefit from further English language editing. While the scientific content is generally clear, there are several typographical errors, including a typo in the title, and some incomplete sentences in the Results section. Additionally, minor formatting issues, such as the occasional use of non-English characters and non-standard numerical formats (e.g., "%12,9"), should be corrected. A thorough proofreading is kindly recommended to polish the text and meet the journal's publication standards.

Author Response

We would like to thank the reviewer for the positive and constructive feedback. We are pleased that the revised manuscript has significantly improved. We have carefully addressed the remaining minor comments as follows:

 

  1. GCB/non-GCB percentages

We thank the reviewer for noting this discrepancy. The percentages have been corrected to 82.4% (14/17) and 17.6% (3/17) in the revised manuscript.

 

  1. Typographical error in the title

The typographical error in the title (“Clinicopatholoical”) has been corrected to “Clinicopathological.”

 

  1. Language and formatting errors

All indicated issues have been corrected. Specifically, “four patients (%12,9)” has been revised to “(12.9%),” and the typo in Figure 2 legend (“large cel lymphoma”) has been corrected. In addition, the manuscript has been carefully reviewed to eliminate similar typographical and formatting inconsistencies.

 

  1. Duplicate references

We thank the reviewer for identifying this issue. References 1 and 16, as well as 8 and 13, have been merged accordingly, and all citations have been renumbered in the revised manuscript.

 

Comments on the Quality of English Language

The manuscript has undergone thorough English language editing and proofreading to improve clarity, grammar, and overall readability. Typographical errors, incomplete sentences, and formatting inconsistencies have been carefully corrected.

 

We hope that these revisions satisfactorily address the reviewer’s comments.

Reviewer 3 Report

Comments and Suggestions for Authors

  • There is still a typographical error in the title of the article; please revise accordingly.

  • The limitations section requires further improvement. It should explicitly and clearly address the limitations previously raised, ensuring they are adequately detailed and discussed : 

    1. DLBCL pathology characterization

    Reviewer comment: The DLBCL section is not adequately characterized for current standards: no MYC IHC and no MYC/BCL2/BCL6 FISH.

    Response: We acknowledge that MYC IHC and FISH for MYC/BCL2/BCL6 were not performed. We have added knowledge  section of the study limitations .

    1. Molecular/cytogenetic data

    Reviewer comment: There is a lack of molecular/cytogenetic data, especially for aggressive B-cell lymphomas.

    Response: We emphasize that the absence of these data is a limitation of the study.

Comments on the Quality of English Language

  • The manuscript would benefit from overall English language editing to improve clarity, grammar, and readability.

Author Response

Response to Reviewer

 

We would like to thank the reviewer for the careful evaluation of our manuscript and for the constructive comments, which have helped us improve the quality of our work. We have addressed all comments as detailed below.

 

  1. Typographical error in the title

We thank the reviewer for pointing this out. The typographical error in the title has been corrected. The revised title now reads:

“Clinicopathological Features of Extranodal Head and Neck Lymphomas.”

 

  1. Limitations section

We appreciate this important comment. The limitations section has been revised and expanded to explicitly address the previously raised concerns. The relevant points have now been clearly stated and discussed in the manuscript.

 

  1. DLBCL pathology characterization

We agree with the reviewer that MYC immunohistochemistry and FISH analyses for MYC, BCL2, and BCL6 are important for current diagnostic standards. However, these analyses were not available for our cases due to technical and/or resource limitations. This has now been clearly stated in the limitations section of the revised manuscript.

 

  1. Molecular/cytogenetic data

We acknowledge the lack of molecular and cytogenetic data, particularly for aggressive B-cell lymphomas. This limitation has now been explicitly emphasized in the revised manuscript.

 

  1. English language quality

We thank the reviewer for this suggestion. The manuscript has undergone careful language editing to improve clarity, grammar, and overall readability.

 

We hope that these revisions meet the reviewer’s expectations.

Füruzan Döger