Large B-Cell Lymphomas in the 5th Edition of the WHO-Classification of Haematolymphoid Neoplasms—Updated Classification and New Concepts
Round 1
Reviewer 1 Report
Extremely comprehensive review. The only request I have is to please either include Burkitt lymphoma here as well to aid in the differentiation between DLBCL with Myc and BCL2, HGBCL, NOS, and Burkitt. Especially differentiating HGBCL, NOS and Burkitt is incredibly complex and this would be extremely useful for hematopathologists and clinicians to have in one place.
Author Response
We thank the reviewer for this important comment. Since Burkitt lymphoma is not at least formally within the spectrum of large B-cell lymphomas, we decided to now, as requested by the reviewer, include a paragraph on differential diagnostic considerations in the area of HGBL. This has now been included within the HGBL, NOS chapter (pages 13/14).
Author Response File: 
Author Response.docx
Reviewer 2 Report
The authors report on changes in the upcoming WHO 5 classification with a focus on aggressive B-cell lymphoma, describing each of the 17 subtypes and summarizing the main features. While the manuscript is written well, I am a little puzzeld what will be the novelty compared to the WHO book itself? What are the take-a-way messages for the reader being a hematologist, pathologist or molecular biologist? How does it differ from the recent report in Leukemia on the whole range of LPDs? /doi.org/10.1038/s41375-022-01620-2.
Author Response
We thank the reviewer for this comment. In our view, the purpose of this review is to comprehensively delineate the full spectrum of large B-cell lymphomas (including neighbouring areas), because this topic forms a robust basis within the special edition on aggressive lymphomas in Cancers. Having said that, the main difference to our preceding Leukemia paper is to cover the whole spectrum of large B-cell lymphomas, and not only the entities with major changes. We are aware, however, that this approach contrasts with one of the comments by reviewer 3 (please see below).
Author Response File: Author Response.docx
Reviewer 3 Report
Timely and potentially useful review, but it needs to be re-focused in order to be helpful.
Overarching comments:
- If the scope is to provide an overview of updates to the WHO classification of lymphoid malignancies (rather than a pathological review of DLBCL), then I strongly suggest trimming down significantly what is already known in favor of the newer concepts. If for a given entity nothing has changed vs HAEM4R (eg, TCRBCL, ALK+ LBCL, LYG, others), those sections should be reduced to the essential stating that no changes happened with WHO-HAEM5
- In general, the rationale for changes from HAEM4R to HAEM5 is sometimes not sufficiently explained (which new knowledge specifically allowed a given change?)
- Please comment on the ICC vs. WHO-HAEM5 classifications as it pertains to DLBCL.
- As the complexity of the classification increases, a reflection on the large discrepancy between the nuanced biological differences and the essentially monolithic chemoimmunotherapy approach should be added.
Abstract:
- Suggest replacing family/class with more appropriate terms like "group" and in general avoid slashes.
Body:
- suggest moving lines 40-42 at the top, the opening sentence is a bit abrupt;
- Line 60: The NLPHL is no longer used. please update
- lines 64-65: etiology (what causes a disease) and pathogenesis (how that disease develops) are distinct concepts. I believe you're referring to etiology here.
- lines 64-78: the quick overview of DLBCL pathogenesis is a bit oversimplified to the point where one questions if it's needed. I suggest either shortening it and adding appropriate references or eliminating it and only citing pathogenetic concepts where applicable to support a specific change in classification
- line 86: suggest replacing poor with poorer, since more than half of these pts are cured with RCHOP.
- lines 169-170: what is an "inferior clinical course"?
- lines 212 and 217: please omit “obviously”
- line 221: different, not diverse
- Language needs substantial revision / editing
- Paper needs proofreading due to occasional typos.
Author Response
We thank the reviewer for this comment. While working on this review, we had indeed discussed intensively whether we should concentrate on the changes of WHO-HAEM5 from WHO-HAEM4R exclusively, or give a more comprehensive overview on LBCL (with emphasis on LBCL, obviously). Finally, we agreed that the present paper should not cover these changes exclusively, but illustrate the landscape of LBCL as also detailed in our answer to reviewer 2. We have, however, shortened the respective paragraphs concentrating on new findings since WHO-HAEM4R.
Author Response File: Author Response.docx
Round 2
Reviewer 2 Report
I don't have any additional comments for the authors.
Author Response
We thank reviewers 2 and 3 for their additional comments.
Reviewer 3 Report
Thanks for revising the paper, I hope comments were helpful. This paper will be useful and well received by hematologists
Author Response
We thank reviewers 2 and 3 for their additional comments.
