Primary Mucosal Melanoma: Clinical Experience from a Single Italian Center

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

1. Please change the wording in the abstract about "disease localized to distant sites". I know what the authors mean (disease was located at distant sites) but wording is confusing. 

2. RT was significantly related to operation, but surgery was not? How could this be when the percentages in the groups were similar? Almost all studies show a relationship between resectability and survival. 

3. The sample size is very small, even for this disease. Were you unable to combine data with another center?  

Comments on the Quality of English Language

Minor concerns only. See point 1 above, e.g. 

Author Response

Dear Editor and Reviewers,

Thank you very much for providing us with important insights and for the chance to revise the manuscript.

We agree with your suggestions and incorporated them throughout our paper.

Please, find below all our point by point responses.

1) Please change the wording in the abstract about "disease localized to distant sites". I know what the authors mean (disease was located at distant sites) but wording is confusing. 

Thank you, we changed the wording for your suggestion.

2) RT was significantly related to operation, but surgery was not? How could this be when the percentages in the groups were similar? Almost all studies show a relationship between resectability and survival. 

We agree with the Reviewer that this aspect was not sufficiently explained. To clarify, we added data in the Results section about the type of surgery and radiotherapy, and about the criteria to perform surgery and radiotherapy. In this analysis, we included MM from several sub-sites. Surgery was the first choice for localized disease (from all sub-sites) and was performed in 64% of study population. Radiotherapy was performed just for head and neck mucosal melanoma, in adjuvant setting and as exclusive therapy for locally advanced MM, unsuitable for surgery (36% of patients). Moreover, surgery was also performed in one case as debulking to control symptom.

3) The sample size is very small, even for this disease. Were you unable to combine data with another center? 

We agree with the Reviewer about the small sample size of our population, and we cite that as a limitation in the discussion section. However, differently from cutaneous melanoma or other type of cancer (head and neck, colorectal, breast, lung, etc.), there are not referral centers in Italy for mucosal melanoma. Very often, MM patients are treated by the specialists of the sub-sites (for instance, head and neck surgeons for H&N MM, gynecologists for vulvovaginal MM) with dispersion of data. Our analysis is the first attempt to combine data from MM from different sub-sites, treated at the same Institution, even if over a long period of time with the risk of losing some details for the retrospective nature of the work. We add these clarifications in the discussion section, and we will work, in the future, to combine our data with other Center experience.

Reviewer 2 Report

Comments and Suggestions for Authors

I read the article 'Prognostic factors and outcomes of mucosal melanoma in a single Italian Center' with clinical interest.

As highlighted in the introduction, mucosal melanoma (MM) lacks standardized classification, staging, prognostic and predictive factors for response to treatments, making it an 'orphan' disease. I found the article informative and would like to share some thoughts with you.

The study is limited by a small sample size and heterogeneity of sub-sites, making it difficult to draw conclusions.

The most common sub-site is head and neck, with 10 nasal cavities, 1 ethmoid, and 3 oral cavities. Ad hoc statistics on these 14 cases would be informative.

In addition, it is unclear what criterion was used to select only 9 cases for radiotherapy. When considering treatment options for head and neck, it is important to always consider surgery (why did only 64% of pts receive surgery?) and radiotherapy (RT).

The surgical section is biased and lacks important data such as margins and type of surgery.

Surgery remains the cornerstone regardless of location. What were the reasons for not doing it?

It is recommended to specify the criteria for the decision to perform RT or not.

In addition, it is important to specify the outcomes of treatment in relation to the control provided by radiotherapy.

Line 157 is subjective and should be rewritten. The NCCN guidelines (https://www.nccn.org/professionals/physician_gls/pdf/head-and-neck.pdf) strongly recommend postoperative RT.

More information should be provided on the  RT doses and fractionation used. It should also be explained when proton or heavy particle therapy was considered.

Table 3 presents ongoing studies on locally advanced and/or metastatic MM. It may be worth reconsidering the article from this perspective. Readers expect more from the title and materials and methods sections.

The major limitation of this study is its partial vision. The authors heavily analysed systemic medical therapies that are not yet standard, while neglecting the usual clinical practice.

A review of this work is recommended as it has good potential, but it is too focused on medical oncology.

Comments on the Quality of English Language

I have no particular comments about the writing in English. 

Author Response

Dear  Reviewer,

Thank you very much for providing us with important insights and for the chance to revise the manuscript. We agree with your suggestions and incorporated them throughout our paper. Please, find below all our point by point responses.

I read the article 'Prognostic factors and outcomes of mucosal melanoma in a single Italian Center' with clinical interest.

As highlighted in the introduction, mucosal melanoma (MM) lacks standardized classification, staging, prognostic, and predictive factors for response to treatments, making it an 'orphan' disease. I found the article informative and would like to share some thoughts with you.

The study is limited by a small sample size and heterogeneity of sub-sites, making it difficult to draw conclusions.

The most common sub-site is head and neck, with 10 nasal cavities, 1 ethmoid, and 3 oral cavities. Ad hoc statistics on these 14 cases would be informative.

Following your considerations, we added data about the group of head and neck MM in the RESULTS section and the clarification about the staging for head and neck MM in the Methods section, as you can see below.

MATERIALS AND METHODS: For head and neck MM, American Joint Committee on Cancer (AJCC) TNM Staging System 8th edition, 2017 was adopted [12]

RESULTS: Among the sub-group of head and neck MM (14 patients), 3 patients had stage II MM, 7 patients had stage III MM, 4 patients had stage IV MM. Resection of the primary tumor was feasible in 10 patients (71%). Among these 10 patients, neck dissection was performed in 3 patients because of suspicious lymph nodes. Surgery was performed for MM with a primary tumor smaller or equal to T4a (AJCC 8th edition), according to guidelines [12]. Post-operative radiotherapy was recommended and performed for all patients who underwent surgery, with a tumor larger or equal to pT3 N0. In addition, one patient received exclusive radiotherapy for cT4b N0 M0 MM; another one with stage II MM underwent radiotherapy for local relapse of the disease after surgery. Radiotherapy consisted in image-guided RT (IGRT) or intensity-modulated radiation therapy (IMRT) for almost the totality of patients (8/9=89%) with dose ranging from 50 to 67.5 Gy (median 2Gy/fraction). The other one received proton therapy on personal preference. […]

Limiting the analysis to head and neck MM, surgery, and radiotherapy, at univariate analysis were both significant. At multivariate analysis, RT was confirmed as an independent predictor of OS (p=0.04).

In addition, it is unclear what criterion was used to select only 9 cases for radiotherapy. When considering treatment options for head and neck, it is important to always consider surgery (why did only 64% of pts receive surgery?) and radiotherapy (RT).

We thank the Reviewer for raising this aspect. Therefore, we added the clarification about this point in the Results section as indicated below.

“Post-operative radiotherapy was recommended and performed for all patients who underwent surgery, with a tumor larger or equal to pT3 N0. In addition, one patient received exclusive radiotherapy for cT4b N0 M0 MM; another one with stage II MM underwent radiotherapy for local relapse of the disease after surgery.”

The surgical section is biased and lacks important data such as margins and type of surgery. Surgery remains the cornerstone regardless of location. What were the reasons for not doing it?

To answer to your question, we added the data reported below.

“Surgery of the primary tumor was performed in 64% of the study population, mostly for patients with localized disease. In one case, debulking surgery was arranged for advanced disease with the aim of controlling local symptoms. Surgery was not performed in those patients with metastatic disease (stage IVB head and neck MM, stage IV MM from other sites or locally advanced disease unsuitable for surgery, such as for gynecological MM). Surgery consisted in resection of the primary tumor in 13 patients, combined with lymph node resection in a further 3 patients. Margins were negative (R0) in 13 patients, positive in 2 patients and not estimable in one case for the fragmentation of the tumor.”

It is recommended to specify the criteria for the decision to perform RT or not. In addition, it is important to specify the outcomes of treatment in relation to the control provided by radiotherapy.

We perfectly agree with the Reviewer observation. Therefore, we specified it in the manuscript, in the Result section.

“Post-operative radiotherapy was recommended and performed for all patients who underwent surgery, with a tumor larger or equal to pT3 N0. In addition, one patient received exclusive radiotherapy for cT4b N0 M0 MM; another one with stage II MM underwent radiotherapy for local relapse of the disease after surgery.”

About the outcomes of treatment in relation to the control provided by radiotherapy, patients received different treatment approaches across 10 years. In some cases, immunotherapy was added after radiotherapy as adjuvant treatment; in other cases, it was not, or chemotherapy was administered. This is the reason why we used OS as an outcome measure. We clarify that point among the limits of the study in the Discussion section.

“Our study is a retrospective one and the interpretation of variables within this dataset is limited by the small sample size, the different stages of disease, and the wide variety of treatments used (both in adjuvant and metastatic setting), across 10 years.”

Line 157 is subjective and should be rewritten. The NCCN guidelines (https://www.nccn.org/professionals/physician_gls/pdf/head-and-neck.pdf) strongly recommend postoperative RT.

We thank the Reviewer for this comment.

We rewritten the sentence in this way: “Although the role of radiotherapy in MM has not been evaluated in prospective trials, it is often recommended in the postoperative management of MMs at the primary site and neck dissection [12, 20].”

More information should be provided on the RT doses and fractionation used. It should also be explained when proton or heavy particle therapy was considered.

Following your indication, we added these data in the Results section.

“Radiotherapy consisted in image-guided RT (IGRT) or intensity-modulated radiation therapy (IMRT) for almost the totality of patients (8/9=89%) with dose ranging from 50 to 67.5 Gy (median 2Gy/fraction). The other one received proton therapy on personal preference.

Table 3 presents ongoing studies on locally advanced and/or metastatic MM. It may be worth reconsidering the article from this perspective. Readers expect more from the title and materials and methods sections.

Thanks again for these comments.

Based on your suggestions, we decided to change the title with one that may be more appropriate to the content of the manuscript. The new title is: “Primary mucosal melanoma: clinical experience from a single Italian Center.”

About Table 3, we included all studies about mucosal melanoma found on clinicaltrials.gov, both in adjuvant/neoadjuvant and metastatic setting. We divided and ordered studies based on setting of disease (resected, neoadjuvant, advanced/metastatic).

The major limitation of this study is its partial vision. The authors heavily analysed systemic medical therapies that are not yet standard, while neglecting the usual clinical practice. A review of this work is recommended as it has good potential, but it is too focused on medical oncology.

We agree with the Reviewer about this aspect, and we added more details about surgery and radiotherapy, that were lacking in the previous manuscript.

Author Response File: Author Response.pdf

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

I thank the authors for considering my humble suggestions. I believe this has allowed for a more comprehensive view of the topic. I have nothing to add. 

Comments on the Quality of English Language

Nothing to add