The Prognostic Value of Histopathological Features in Early-Stage Mycosis Fungoides: Insights from a Retrospective–Prospective Cohort Study

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This is a well written manuscript of the histopathological features of mycosis fungoides and its correlation with survival and progression outcome. Given its retrospective nature, it is impressive that the authors were able to analyse the data from the cohort and perform statistical analysis of the parameters studied. Some suggestions for improvement -

1)Include some histopathological images of the lichenoid infiltrate eg what is sparse, moderate or dense and the lymphocytes "keepers" <30 and >30 per 100 keratinocytes. It would be unusual for an article in a dermatopathology journal not to have any histopathology images

2)Avoid unconventional terms eg "premycotic stage" which I assume refers to early stage MF and not prediagnostic stage MF. To avoid confusion, please use for example, "early stage MF". Other term is "lymphocytes keepers" which refers to the tagging of lymphocytes along the basal layer/keratinocytes. The latter is a more conventional and accepted descriptive histopathological feature of MF.

3)The other reason for doing more than 1 biopsy for suspected MF (Line 135) is to increase the sampling sites and diagnostic yield.

It appears that the dense lichenoid infiltrates in MF are likely to be advanced plaque stage MF which has a poorer prognosis and this study has shown that it is so, in terms of survival and progression outcome. To make the article more concise, perhaps the number of charts especially those that do not show statistical significance, can be omitted.

All in all, a very good effort in identifying the classical diagnostic features of MF for prognostication.

Comments on the Quality of English Language

The quality of English is good. Some editing suggested:

Use "histopathological" rather than pathohistological (Lines 38, 87, 125)

Use "clinicopathological correlation" rather than clinical-pathohistological (Lines 124, 134)

Typo - lymphocytes (Line 192)

Diagram 8 is laterally inverted

Author Response

Reviewer 1
This is a well-written manuscript detailing the histopathological features of mycosis fungoides and its correlation with survival and progression outcomes. Given its retrospective nature, it is impressive that the authors were able to analyze data from the cohort and perform statistical analysis of the parameters studied. Some suggestions for improvement -

Include some histopathological images of the lichenoid infiltrate, e.g., what is sparse, moderate, or dense and the lymphocytes "keepers" <30 and >30 per 100 keratinocytes. It would be unusual for an article in a dermatopathology journal not to have any histopathology images.

• We provided collage Figure 1 original images from the study (line 199-208)
• Avoid unconventional terms, e.g., "premycotic stage," which I assume refers to early stage MF and not the prediagnostic stage MF. To avoid confusion, please use, for example, "early stage MF". Another term is "lymphocytes keepers," which refers to the tagging of lymphocytes along the basal layer/keratinocytes. The latter is a more conventional and accepted descriptive histopathological feature of MF.
• We will change and use the term "early stage MF" where possible. We will keep using the term "premycotic" only in the case of the premycotic stage (prediagnostic stage) and make it clear.
• We would like to keep the "newer term" lymphocytes keepers to popularize the term and to point out the importance of this feature (lines 54, 62, 117, 159, table 1).

The other reason for doing more than one biopsy for suspected MF (Line 135) is to increase the sampling sites and diagnostic yield.

• Corrected (line 137).

It appears that the dense lichenoid infiltrates in MF are likely to be advanced plaque stage MF, which has a poorer prognosis, and this study has shown that it is so, in terms of survival and progression outcomes. To make the article more concise, perhaps the number of charts, especially those that do not show statistical significance, can be omitted.

• We will omit some diagrams: Diagram 5, 7, 8 and 9.

All in all, a very good effort in identifying the classical diagnostic features of MF for prognostication.

Comments on the Quality of English Language The quality of English is good. Some editing suggested: Use "histopathological" rather than "pathohistological" (Lines 38, 87, 125).

• Corrected.

 Use "clinicopathological correlation" rather than "clinical-pathohistological" (Lines 124, 134). Typo - "lymphocytes" (Line 192).

• Corrected.

Diagram 8 is laterally inverted.

• We deleted the diagram due to the previous comment.

Reviewer 2 Report

Comments and Suggestions for Authors

The aim of this paper is to correlate the initial morphological alterations with the clinical course of the disease and survival in patients with mycosis fungiides. Although some things are very interesting, I find the manuscript a little complicated to read. I find the introduction quite long and redundant with the histological criteria of the initial phase of the disease repeated several times. Furthermore, I personally struggle to understand the reason for mixing the question of diagnostics in the initial stages of the disease, dedicating an entire paragraph of 15 lines to the morphological study of patch lesions conducted by  Dermatology department of Graz in 2005 and instead then evaluating the implications prognostic of histological features observed in stages Ia, Ib and IIA (early-stage MF). I believe that streamlining the introduction would help in reading the manuscript.

As I already said, the paper has some interesting aspects but I would ask a few things about the case series:

- Table 1 lists 60 patients suffering from parpsoriasis: what do the authors mean by this term?

I-  would also ask you to specify which stage the 10 patients who unfortunately died due to disease progression belonged to. As we know, after adjusting for age and sex, the death rate increased by 30% for patients diagnosed at stage IB compared with stage IA whilst for those diagnosed with stage IIA the death rate was 3.5 times higher than stage IA.

Author Response

 Reviewer 2

The aim of this paper is to correlate the initial morphological alterations with the clinical course of the disease and survival in patients with mycosis fungiides. Although some things are very interesting, I find the manuscript a little complicated to read. I find the introduction quite long and redundant with the histological criteria of the initial phase of the disease repeated several times. Furthermore, I personally struggle to understand the reason for mixing the question of diagnostics in the initial stages of the disease, dedicating an entire paragraph of 15 lines to the morphological study of patch lesions conducted by  Dermatology department of Graz in 2005 and instead then evaluating the implications prognostic of histological features observed in stages Ia, Ib and IIA (early-stage MF). I believe that streamlining the introduction would help in reading the manuscript.

• We accept the comment and we will shorten the the introduction part (lines 122-139)

As I already said, the paper has some interesting aspects but I would ask a few things about the case series:

- Table 1 lists 60 patients suffering from parpsoriasis: what do the authors mean by this term?

• We included all patients diagnosed with small plaque or large plaque parapsoriasis, some of whom later progressed to mycosis fungoides (MF). Given that parapsoriasis is often considered a precursor to MF, this information was crucial for our research. However, for the purposes of this publication, we can omit these results. The relationship between parapsoriasis and MF remains a subject of ongoing research and debate in dermatology. We plan to address this in more detail in a forthcoming publication that focuses on clinical findings.

I-  would also ask you to specify which stage the 10 patients who unfortunately died due to disease progression belonged to. As we know, after adjusting for age and sex, the death rate increased by 30% for patients diagnosed at stage IB compared with stage IA whilst for those diagnosed with stage IIA the death rate was 3.5 times higher than stage IA.

• This data is planned for another article from this study, where we have analyzed stage and clinical findings in terms of progression and survival. I am pleased to see the interest. We will release the publication as soon as possible. This manuscript is focused on histopathology.

Thank you for your valuable comments.