B Lymphoproliferative Neoplasms of Uncertain Biological Significance: Report from the IV Workshop of the Italian Group of Hematopathology and Review of the Literature

Round 1

Reviewer 1 Report

The manuscript on the Workshop of the Italian Group of Hematopathology is dealing with the problematic issue of B lymphoproliferative neoplasms of uncertain biological significance. The presented cases are carefully selected, the discussion is appropriate and helpful for the diagnostic routine and the literature cited adequate.

There are only few points of criticism:

Line 185-187: It is unclear to the Reviewer why the authors diagnosed a composite ISMCN and chronic lymphocytic leukemia. According to the information presented in the text, there was neither a bone marrow biopsy nor an investigation of the peripheral blood to prove the presence of CLL. Therefore, the term CLL should be replaced by “small lymphocytic lymphoma”.

Line 203: the term “atypical CLL” does according to this reviewer’s knowledge not appear in the WHO classification as a disease entity but rather as a CLL with “atypical immunophenotype”.

Lines 304-308. Case no 7: “PCR-analysis confirmed the presence of mycobacterial DNA”. Unfortunately, the authors do not specify which mycobacterium strain has been detected: tuberculosis? , bovis?, atypical? If it was tuberculosis why do the authors not modify their diagnosis as: necrotizing granulomatous  lymphadenitis due to mycobacterium tuberculosis infection?

Legend of Figures 8 C and D. Both figures show plasma cells expressing either kappa or lambda immunoglobulin light chains. It is therefore erroneous to label kappa as positive and lambda as negative. It would be better to state that there is a kappa light chain restriction.

It is also advisable that a native speaker (preferably a pathologist) should review the English of the text. Following points could be amended according to the opinion of this reviewer: 

Line 27: “fixed” could be replaced by “established”

Line 51: “due to the widespread distribution of lymphocytes”. This statement is not entirely fitting in this context. It would be more appropriate to state that “lymphocytes are usually circulating and not sessile cells”.

Lines 82 and 83: the authors repeatedly use “we” in this sentence. It would be better to change the wording. It is not entirely clear whom they mean. It would be better to rewrite the sentence as: a composite form, namely ISFN and ISMCN can be associated with another overt lymphoma as presented in the first three cases of the Workshop.

Line 97-101: “three atypical germinal centers resulted unusually enriched”… does not make any sense. Alternatively the sentence could be changed into: “Early LBL with IRF4 rearrangement has been reported in one case with predominant follicular hyperplasia that exhibited single atypical germinal centers enriched with centroblasts without accompanying tangible body macrophages displaying expression of CD20, CD10, BCL6, IRF4/MUM1, lambda immunoglobulin light chain restriction and a gain and rearrangement of the IRF4 gene.”

Lines 106-107 “these conditions (?) must be integrated with clinical findings and accomplished by a strict follow-up”- this sentence should be reformulated i.e.:…. “These lymphoproliferations have to be assessed in the context of all clinical findings and accompanied by a strict-follow-up…”

Line 129: according to the wording of WHO classification “classical” should be changed into “classic”. As in the following text the term “Hodgkin lymphoma” is frequently mentioned, the authors should use the abbreviation cHL or CHL for all following manuscript sections.

Line 159 instead of “diffuse lymphadenopathies” use “diffuse lymphadenopathy”.

Line 220: Prof. Lazzi should be replaced with Dr. Lazzi.

Line 225 …”were negative for BCL2 by immunohistochemistry and FISH analysis”: not entirely correct and should be changed into: negative for BCL2 by immunohistochemistry and for BCL2 translocation by FISH analysis

Line 242 and 243: “..a 72-year old woman…that performed colonoscopy”: as it seems rather difficult that the patient did perform a colonoscopy by herself, it should be changed into: “underwent colonoscopy”.

Line 249 IGH/BCL2 and IGH/MYC gene rearrangements should be changed into IGH/BCL2 and IGH/MYC as they are genes and not proteins.

Line 264 and during follow up should be replaced with: who during follow up

Line 268 The large cells resulted immunoreactive, should be changed into: were immunoreactive or expressed…

Author Response

Dear Referee,

Thank you for your review and the opportunity to revise our paper on ‘B Lymphoproliferative Neoplasms of Uncertain Biological Significance. Report from the IV Workshop of the Italian Group of Hematopathology and review of the literature.’ The suggestions you offered have been constructive, and we also appreciate your insightful comments on revising several aspects of the paper. Attached you will find the report file.

Kind regards,

The Authors

Author Response File: Author Response.pdf

Reviewer 2 Report

Interesting report on a new field which will interest many readers of the Journal.

This will be interesting to know for how long all the presented cases were followed after diagnosis.

A table listing the different entities and their characteristics may be  interesting to add (another with the clinical cases could be also presented)

Author Response

Dear Referee,

Thank you for your review and the opportunity to revise our paper on ‘B Lymphoproliferative Neoplasms of Uncertain Biological Significance. Report from the IV Workshop of the Italian Group of Hematopathology and review of the literature.’ The suggestions you offered have been constructive, and we also appreciate your insightful comments and suggested additions to the manuscript. Attached you will find the report file.

Kind regards,

The Authors

Author Response File: Author Response.pdf

Reviewer 3 Report

In this report/review, the authors raise the question of B lymphoproliferative neoplasms of uncertain significance from a pathological point of view. This is a very interesting and very well written manuscript. Introduction section very clearly states the state of art in this field. In Conclusion section, the different case reports are discussed in a highly relevant manner. The literature is extensively and adequately cited. This document will be read by the hematopathologist community and will interest the world of hematology.

My comments are minor since I have one minor correction for Introduction, one suggestion for Conclusion and some questions for the case reports.

Introduction, line 102 and 103: indicate that the two cases of in situ high grade B-cell lymphomas were with a MYC rearrangement.

Conclusion: the inflammatory microenvironment of the tumors is poorly evoked at the end of this section and only as a factor favoring the emergence of a B-cell clone. But, as assessed in solid tumors and reported by various authors in B-cell cancers, these inflammatory aspects are also important in terms of immune surveillance. Was the microenvironment (at least T-cells) of these in situ B-cell clones analyzed and discussed during this workshop ? If yes, could the authors give this information for their cases and try to discuss and/or conclude on this matter ?

Specific questions on the different cases

Case #1 as well as other cases with two B-cell clones: could the authors try to answer the question of a common B-cell ancestor, as raised out for case #2 ?

Case #2: could authors indicate whether these two aCLL and ISMCN clones were associated with a leukemic phase ? if yes, which was the circulating clone ? Was it with or without hyper lymphocytosis - in other words, MBL or not ? Was the flow cytometry immunophenotype consistent with that of immunohistochemistry ? If available, what was the cytogenetics of this aCLL ? What was the treatment and the response ?

Case #4: the final diagnosis is not completely clear for a non pathologist. Was it an ISFN or a disseminated high grade FL that minimally invade the right iliac-obturator lymph node ?

Author Response

Dear Referee,

Thank you for your review and the opportunity to revise our paper on ‘B Lymphoproliferative Neoplasms of Uncertain Biological Significance. Report from the IV Workshop of the Italian Group of Hematopathology and review of the literature.’ The suggestions you offered have been constructive, and we also appreciate your insightful comments on revising several aspects of the paper. Attached you will find the report file.

Kind regards,

The Authors

Author Response File: Author Response.pdf