EBV-Driven NK/T-Cell Lymphoproliferative Disorders: Clinical Diversity and Molecular Insights

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This is a well-written and essential review that successfully summarizes the clinical and, more importantly, the rapidly evolving molecular landscape of EBV-driven NK/T-cell lymphoproliferative disorders (LPDs). The core strength lies in the detailed discussion of molecular subtypes in ENKTL and the summary of genomic drivers (JAK/STAT, epigenetic regulators, DDX3X) across the different entities. Addressing the major comments below will significantly improve the manuscript's structure and conceptual synthesis.

Major Comments:

1. The manuscript includes Severe Mosquito Bite Allergy (SMBA) and Systemic EBV-Positive T-Cell Lymphoma of Childhood (STCLC) in the Abstract and Table 1. However, there is no dedicated section to discuss their clinicopathological features, diagnosis, or molecular characteristics in detail. A formal section should be created to cover STCLC and SMBA. For SMBA, the text should explicitly state that the genomic landscape remains "largely unexplored", as mentioned in the Abstract, and reference the molecular data (or lack thereof) from the comprehensive summary table. For STCLC, the information currently mentioned (fulminant course, T-cell phenotype, CD8+, 22q11.2 deletion/translocation, overexpression of p53, survivin, EZH2)  should be consolidated and elaborated upon in its own section.
2. A review paper of this scope requires a formal conclusion to synthesize the key takeaways. The current manuscript ends abruptly after the discussion of STCLC.
3. Revisit and formally discuss the central hypothesis stated in the Abstract: that all EBV-positive NK/T-cell LPDs exist on a "biological continuum of viral oncogenesis". This is a powerful conceptual statement that needs to be fully explored, connecting the molecular findings of CAEBV/HVLPD (chromatin modifier mutations like KMT2D, low driver mutations) to the more aggressive ENKTL/ANKL (JAK/STAT, DDX3X, TP53 mutations).
4. Outline future directions for research, focusing on how these molecular insights will lead to improved risk stratification and targeted treatment strategies (e.g., epigenetic modulators for HEA/HVLPD, JAK/STAT inhibitors for TSIM/ANKL).

Author Response

Reviewer 1

Comments and Suggestions for Authors

This is a well-written and essential review that successfully summarizes the clinical and, more importantly, the rapidly evolving molecular landscape of EBV-driven NK/T-cell lymphoproliferative disorders (LPDs). The core strength lies in the detailed discussion of molecular subtypes in ENKTL and the summary of genomic drivers (JAK/STAT, epigenetic regulators, DDX3X) across the different entities. Addressing the major comments below will significantly improve the manuscript's structure and conceptual synthesis.

Response: We thank the reviewer for the candid comments and suggestions.

 

Major Comments:

 

1. The manuscript includes Severe Mosquito Bite Allergy (SMBA) and Systemic EBV-Positive T-Cell Lymphoma of Childhood (STCLC) in the Abstract and Table 1. However, there is no dedicated section to discuss their clinicopathological features, diagnosis, or molecular characteristics in detail. A formal section should be created to cover STCLC and SMBA.

Response: We have expanded the dedicated  sections for SMBA to include the clinicopathologic features and diagnosis and as mentioned in the manuscript their molecular characteristics have not been explored so I have only included what is currently available in the literature on page 9.

2. For SMBA, the text should explicitly state that the genomic landscape remains "largely unexplored", as mentioned in the Abstract, and reference the molecular data (or lack thereof) from the comprehensive summary table.

Response: We have stated the above recommended statement and referenced the table as suggested. 

3. For STCLC, the information currently mentioned (fulminant course, T-cell phenotype, CD8+, 22q11.2 deletion/translocation, overexpression of p53, survivin, EZH2) should be consolidated and elaborated upon in its own section.

Response: STCLC has its own dedicated section on page 9, and the section already includes all the above suggestions.

4. A review paper of this scope requires a formal conclusion to synthesize the key takeaways. The current manuscript ends abruptly after the discussion of STCLC.

Response: The manuscript does have a section for discussion and conclusions. I am not sure if the correct version was made available to the reviewer.

5. Revisit and formally discuss the central hypothesis stated in the Abstract: that all EBV-positive NK/T-cell LPDs exist on a "biological continuum of viral oncogenesis". This is a powerful conceptual statement that needs to be fully explored, connecting the molecular findings of CAEBV/HVLPD (chromatin modifier mutations like KMT2D, low driver mutations) to the more aggressive ENKTL/ANKL (JAK/STAT, DDX3X, TP53 mutations).

Response: The above statement is the main focus of the discussions and conclusions. This has been expanded highlighted again in the manuscript.

6. Outline future directions for research, focusing on how these molecular insights will lead to improved risk stratification and targeted treatment strategies (e.g., epigenetic modulators for HEA/HVLPD, JAK/STAT inhibitors for TSIM/ANKL).

Response: The outline for future research focusing on treatment strategies have been expanded in the discussion

Reviewer 2 Report

Comments and Suggestions for Authors

The manuscript is timely because it brings together and compares the various lymphoproliferative disorders associated with EBV.
It is understood that the focus is on LPDs originating from T or NK lymphocytes, but it is interesting to mention that the main leukocyte usually infected by EBV is the B lymphocyte.
It is necessary to standardize the acronyms, displaying the full name the first time it is cited and keeping the acronyms for subsequent mentions of each name.
SMBA is described textually as "severe mosquito-bite hypersensitivity" on line 43. The name that originates the acronym, however, is Severe Mosquito Bite Allergy.
In the caption of Figure 1, it is suggested to replace "H&E" with "H&E stain" to avoid confusion with the information in the figure.
In Table 2, it is important to identify the name for the acronym "OS". The same applies to the acronyms PTCL and NOS, on line 161.
It is important to standardize the spacing before the reference. Single spacing is suggested. Examples without spacing are on lines 138, 214, 225, 235, 251. Check throughout the text.
In the caption of figure 2, the author cites item "(F)" without identifying the marker. There is still doubt as to whether it would be CD8 or CD56.
In figure 3, it is suggested to group patients with KMT2D and BCOR. The presentation sequence could be HV-5, HV-7, HV-15, HV-20, HV-8, HV-23, HV-41, HV-22, HV-40, HV-43, HV-18, CT1, CT2, CT3.

Author Response

Comments and Suggestions for Authors

1. The manuscript is timely because it brings together and compares the various lymphoproliferative disorders associated with EBV.

Response: We thank the reviewer for the kind comments.

2. It is understood that the focus is on LPDs originating from T or NK lymphocytes, but it is interesting to mention that the main leukocyte usually infected by EBV is the B lymphocyte.

Response: We have included this in the introduction on page 1.

3. It is necessary to standardize the acronyms, displaying the full name the first time it is cited and keeping the acronyms for subsequent mentions of each name.

Response: The manuscript has been checked and acronyms are standardized, displaying the full name the first time it is cited.

4. SMBA is described textually as "severe mosquito-bite hypersensitivity" on line 43. The name that originates the acronym, however, is Severe Mosquito Bite Allergy.

Response: SMBA has been corrected to Severe Mosquito Bite Allergy.

5. In the caption of Figure 1, it is suggested to replace "H&E" with "H&E stain" to avoid confusion with the information in the figure.

Response: "H&E" has been replaced with "H&E stain in the caption of figure 1.

6. In Table 2, it is important to identify the name for the acronym "OS". The same applies to the acronyms PTCL and NOS, on line 161.

Response: OS has been expanded to overall survival and PTCL NOS to peripheral T cell lymphoma, not otherwise specified.

7. It is important to standardize the spacing before the reference. Single spacing is suggested. Examples without spacing are on lines 138, 214, 225, 235, 251. Check throughout the text. Response: single spacing is used for the references.
8. In the caption of figure 2, the author cites item "(F)" without identifying the marker. There is still doubt as to whether it would be CD8 or CD56.

Response: The F has been correctly written to be identified as CD8.

9. In figure 3, it is suggested to group patients with KMT2D and BCOR. The presentation sequence could be HV-5, HV-7, HV-15, HV-20, HV-8, HV-23, HV-41, HV-22, HV-40, HV-43, HV-18, CT1, CT2, CT3.

Response: Figure 3 is a copyrighted figure that we included in the manuscript with permission. Unfortunately since it is cited as such, we cannot modify it.

Reviewer 3 Report

Comments and Suggestions for Authors

This is a well-written review article which summarizing recent findings (including clinical diversity and molecular insights) about EBV-driven NK/T-cell lymphoproliferative disorders. These diseases include ENKTL, ANKL, ENTNKL, CAEBV, HVLPD, SMBA, STCLC. I have a few comments and suggestions which need to be addressed:

1) Line 46, Page 2, “ENKTCL” should be “ENKTL”, for the consistence in the text.

2) Line 291, Page 9, Figure 4 is missing in the manuscript although mentioned in the text.

3) Line 327-328, Page 10, “such as risk HLA alleles and immune response gene polymorphisms”, please give some examples for HLA alleles and gene polymorphisms.

4) Line 332, Page 10, “particular environmental factors that further influence disease risk”, please give some examples for environmental factors.

5) In Discussion and Conclusions part, they should discuss current and major challenge for treatment of EBV+ NK/T-cell lymphoproliferative disorders.

Author Response

This is a well-written review article which summarizing recent findings (including clinical diversity and molecular insights) about EBV-driven NK/T-cell lymphoproliferative disorders. These diseases include ENKTL, ANKL, ENTNKL, CAEBV, HVLPD, SMBA, STCLC. I have a few comments and suggestions which need to be addressed:

 

• Line 46, Page 2, “ENKTCL” should be “ENKTL”, for the consistence in the text.

Response: ENKTCL has been corrected to ENKTL.

• Line 291, Page 9, Figure 4 is missing in the manuscript although mentioned in the text.

Response: We apologize for this error, there is no figure 4 and we have deleted it.

• Line 327-328, Page 10, “such as risk HLA alleles and immune response gene polymorphisms”, please give some examples for HLA alleles and gene polymorphisms.

Response: We have included some examples as requested.

• Line 332, Page 10, “particular environmental factors that further influence disease risk”, please give some examples for environmental factors.

Response: We have included some examples as requested.  

• In Discussion and Conclusions part, they should discuss current and major challenge for treatment of EBV+ NK/T-cell lymphoproliferative disorders.

Response: We have discussed the current and major challenges for treatment of EBV+ NK/T-cell lymphoproliferative disorders.

 

 

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

The author has already addressed the issues I was concerned about.