A Retrospective Clinico-Pathological Analysis with Review of Literature of Oral and Cervical Lympho-Epithelial Cysts from a Pathological Perspective

Round 1

Reviewer 1 Report

The article is well written and scientifically sound.

The english language is clear 

This clinico-pathological analysis well describe a vary rare lesion.

The author should better describe the surgical protocol used and if cold blade or other technique were used (ex laser)

From the analysis of the data it appears that could be some recurrent comorbidity among the population studied ? 

Author Response

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Author Response File: Author Response.pdf

Reviewer 2 Report

The manuscript needs an extensive revision and could not be published in the present form. A comprehensive language editing by a native speaker is mandatory to evaluate the research for an eventual publication.

In the abstract the authors indicated that “The aim of the study was to present clinico-pathological characteristics of oral 14 and cervical LECs with a comprehensive review of literature in order create awareness on this un-15 common entity”. The work carried out is insufficient to endorse this purpose. More specifically:

• The literature review has been indicated as a “comprehensive review”. This terminology is meaningless as well as misleading. The author should deeply improve this aspect for a future consideration. Given that the review included in the supplementary file are outdated, I strongly recommend to develop a systematic review of the literature (acc. with PRISMA recommendation) in order to avoid any potential selection biases.
• Despite the small sample size, a statistical analysis will improve the significance and reliability of your research.
• A metanalysis of the published literature (at least formal) is needed to reliably compare the retrieved results with those already reported. The novelty and originality of the article will be strongly improved.
• Has been considered any inclusion and exclusion criteria during the case selection? This should be indicated in MM paragraph

Further suggestions are reported below:

• Some information in the introduction paragraph can be moved to the discussion (as well as lines 64-67)
• The differential diagnosis represents one of the most important aspects in the management of oral and cervical lesions of unknown origin. This implies an utmost careful diagnosis and treatment planning to avoid unfavorable outcomes. The introduction will benefit stressing these aspects (e.g. the treatment algorithm of cervical masses has been debated in the literature for a long time. There are no definite guidelines, but only sparse recommendations, mostly based on surgeons’ experience https://doi.org/10.1002/cnr2.1315)
• The conclusion paragraph lacks a final recommendation based on the retrieved results.
• Lines 183-185 should be removed.

Author Response

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Author Response File: Author Response.pdf

Reviewer 3 Report

Lines 59-60: "out of which the first origin 59 is more widely accepted". None citation were related.

Lines 114-120: The literatura review should provide previous data to support the diagnosis.

Lines 137-138: It is necessary to improve the literature review.

Lines 158-160: No data were associated with the reviewed data. 

Lines 161-164: The literatura data should be improved to support the cited information. 

Lines 178-179: The described conclusion is not supported in the article.

Author Response

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Reviewer 4 Report

The authors have performed the clinico-pathological analysis based on extracting summary statistics from published papers. They should make their contribution clear. If no new numerical analysis has been performed beyond those published literature, what is the novelty of this paper? Besides, what is the central hypothesis and key information that they are trying to deliver? They should do more than simply listing numbers and similar conclusions from other studies.  

The scope of this review is very limited. Nowadays, multi-omics data have been widely considered in all types of complex diseases but are overlooked in this review. See Wu et al. PMID: 30669303. Please discuss in Section 4. Please also include discussion on other (probably more interesting) clinical endpoints such as survival outcomes.

The authors mainly provide a descriptive analysis based on known numbers from different sources. They do not conduct any statistical tests and show p-values. Therefore, those conclusions are not very convincing.

Author Response

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Reviewer 5 Report

The authors conducted a retrospective study to present clinico-pathological characteristics of oral and cervical lympho-epthelial cysts.

The topic is very interesting and not adequate presented in the literature.

The manuscript is well written, However for publication i have the following points:

Title: please add to the title "retrospective" and the information that the cases presented in the study from two centers.

Abstract: Please add in the abstract section findings from the " review of literature"

Introduction:

The sentence Li 39-43 is too long. Please revise and divided to short sentences for better readability.

Please add more rational for conducting the study. What you want to add to the already known about the oral and cervical lympho-epthelial cysts.

Material and methods:

This section is very short. Please add more information about:

the inclusion and exclusion criteria, The period of diagnosed cases, Study parameters.

There is no information about the literature review.

Results:

Table 4 you inserted as supplementary material is very essential for the result section as you mentioned in the title "review of literature" i suggest to insert it in the result section.

Discussion:

It will be good if you add in the discussion information about differential diagnosis and other diagnostics tools (such as MRI, Sonography,....) for better assessment the cysts.

Please add to the discussion the study limitations, strength and implication.

Conclusion:

please remove the lines 183-185

Author Response

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Author Response File: Author Response.pdf

Reviewer 6 Report

Trottet et al., presented a wide range of data related to clinico-pathological characteristics of oral and cervical LECs. The paper is within the scope of the journal and the topic is interesting, innovative and relevant for the field. The research is accurate and well described. I just recommend a minor revision of the text (in which there are some little mistakes, as in line 15). The figures are appropriate and well described. The manuscript is well organized, readily understandable and the research of information has been precise, with updated references.

Author Response

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Author Response File: Author Response.pdf

Round 2

Reviewer 2 Report

The review process has been improved and demonstrate a better reliability. A nice charting work has been caried out to present the retrieved results.

A statistical analysis has been added and provided a better demonstration of the reported findings.

Removal of lines 183-185 was referred to the original version of the submitted manuscript. By the way, it has been already removed in the current version.

Conclusion: the revision process has been well conducted and has ensured clear improvements in the topic presentation. The manuscript could be accepted for publication in the present form.

Author Response

Thank you

Reviewer 3 Report

No comment

Author Response

Thank you

Reviewer 4 Report

Thank the reply from the authors but there's no new contribution of this paper. It does not advance from published studies. The statistical test is not correctly applied.

Author Response

Strengths, limitations and implications were added as follows

Limitations of the study include the fact that no information could be identified to support convincingly the theory of pathogenesis of all oral LEC,  long term follow up was not available for most of the cases to determine the outcome. Strengths include the fact that clinicopathological comparison reliably identified some differences between oral and cervical LEC such as the size of the lesion. In addition, it was also identified that inflamed cervical LEC may mimic malignant lesions and should be careful when deciding on definitive treatment based on clinical diagnosis.

Implications: Oral LEC were confirmed to be indolent lesions that are generally not related to HIV status of the patient. Clinicians should be aware that inflamed cervical LEC has  a higher chance of getting misdiagnosed as a malignant lesion

The statistical test is not correctly applied:

Fisher's exact test is a statistical significance test used in the analysis of contingency tables,  it is employed when sample sizes are small. The test is useful for categorical data that result from classifying objects in two different ways.

As our sample is small and does not show normal distribution and also as we are assessing two different categorical variables Fishers exact test was used instead of chi square test. Though the authors have reasons for using the above test as mentioned, If the reviewer can mention the most appropriate test, it can be applied.

Reviewer 5 Report

Unfortunately, the authors did not/or did not adequate address all mentioned points from the last review report.

I invite the authors to read the last review report carefully and work on. If they did not want to address any point, a clarification have to be given.

Adding one sentence is not enough to address some points in the review report.

Author Response

The authors conducted a retrospective study to present clinico-pathological characteristics of oral and cervical lympho-epthelial cysts.

The topic is very interesting and not adequate presented in the literature.

The manuscript is well written, However for publication i have the following points:

Title: please add to the title "retrospective" and the information that the cases presented in the study from two centers.

The word retrospective was added

Abstract: Please add in the abstract section findings from the " review of literature" DONE. Following sentences highlighted in blue has been added

The literature review based analysis of 514 oral LECs confirms that the lesions are observed predominantly in adults in 4^th-5^th decades of life and are relatively small lesions of less than 2cm in diameter. Oral LECs were found to occur predominantly in the tongue and floor of the mouth similar to 88% of lesions in literature.

Introduction:

The sentence Li 39-43 is too long. Please revise and divided to short sentences for better readability. The sentences were broken in to 2 and 3 s

It is found mainly on the floor of the mouth and the lateral border of the tongue. In addition  it can also develop in various intraoral locations such as the buccal vestibule and also the soft palate [4].

Two main theories have been proposed concerning the pathogenesis of the LEC. Knapp's theory [1], suggests that the obstruction of lymphoid crypts induces dilatation and cystic proliferation of the epithelium.  Buchner & Hansen's [2] and Bhaskar's theory [3] assume that cystic proliferation occurs from epithelial cells that persist in lymphoid tissue during embryogenesis. However, both theories fails explain how oral LECs occur in sites without lymphoid tissue.

Please add more rational for conducting the study. What you want to add to the already known about the oral and cervical lympho-epthelial cysts.

The rationale for conducting the study was to highlight the comparison between oral and cervical LEC. None of the clinicopathological studies reviewed contained a comparison between oral and cervical LEC. Authors found it relevant to compare the clinicopathological features of the two entities as these are two lesions that share similar histopathological features but occur at different locations. Comparison was also undertaken to evaluate if there are any striking clinico-pathological differences between the entities other than the location.

Material and methods:

This section is very short. Please add more information about: Done as follows

The literature review was conducted as follows; an initial search string was carried out to identify articles dealing with LEC with the following keywords; [oral AND lymphoepithelial AND cyst], [intraoral AND lymphoepithelial AND cyst], using several search engines including Google scholar, Medscape and Pubmed.  Articles published from 1966 to 2021 were included. A total of 154 publications were presented directly with the keywords. Abstracts that were present in English were reviewed. 48 non relevant articles that dealt with lymphoepithelial carcinoma, lymphoepithelial sialadenitis were excluded initially.  Thereafter, lymphoepithelial cysts that were associated with parotid glands, studies that dealt with clinico-pathological presentations of cysts other than LEC were excluded. Finally, a total of 10 articles which analyzed clinico-pathological presentations of at least 05 LEC were identified to present the literature review based presentations of LEC[2, 3, 4, 16, 17, 18, 19, 20, 21, 22]. 479 oral LEC were assessed in these studies. In addition, further 29 articles describing the clinico-pathological presentations of 35 oral LEC are presented in the supplementary files [23-52].

the inclusion and exclusion criteria, The period of diagnosed cases, Study parameters. Done as follows

Inclusion criteria were the definitive histological diagnosis of oral or cervical LEC and adequate clinical information available in respective data bases. The cases were excluded in the event that there was inadequate tissue for new H&E sections.

There is no information about the literature review. Following information was added

Table 4 [2-4, 16-22]; presents a summary of case series dealing with more than 5 LECs.  Case reports dealing with single or two lesions amounting in to 35 oral LEC is summarized under supplementary material [23-52], while the summary is included in Table 4. 

Table 4. Literature review based summary of 514 oral LEC

                                                                           * Gender for one patient is not given; T/FOM: Tongue and floor of the mouth

A literature review based on 514 cases of oral LEC revealed a mean age of 38 years and female to male ratio of 1:1.1. Majority of oral LEC were found to develop in the tongue and floor of the mouth (Table 4). In addition, similar to oral LEC presented, literature also indicates that they are small lesions which generally do not exceed more than 2cm [2-4, 16-22].

Results:

Table 4 you inserted as supplementary material is very essential for the result section as you mentioned in the title "review of literature" i suggest to insert it in the result section. Changed and included in results as follows

Table 4. Literature review based summary of 514 oral LEC

                                                                           * Gender for one patient is not given; T/FOM: Tongue and floor of the mouth

Discussion:

It will be good if you add in the discussion information about differential diagnosis and other diagnostics tools (such as MRI, Sonography,....) for better assessment the cysts. Following sentences were added

Though, we do not have data on special investigations that have been used it is possible that an MRI, a CT-scan or an ultrasound would refine the diagnosis of presumption. Ultrasound scanning is the first line method of imaging choice as the lesions are situated superficially. It will be useful to determine if there is any fistula connecting different organs as throat and ear.  On the other hand, it is recommended to perform CT or MRI to determine the exact location of the cyst.

Please add to the discussion the study limitations, strength and implication.

Limitations: No information could be identified to support convincingly the theory of pathogenesis of all oral LEC. Long term follow up was not available for most of the cases to determine the outcome. With respect to current cases unavailability of HIV status of the patients is also a limitation.

Strengths: The clinicopathological comparison reliably identified some differences between oral and cervical LEC such as the size of the lesion. In addition, it was also identified that inflamed cervical LEC may mimic malignant lesions and should be careful when deciding on definitive treatment based on clinical diagnosis.

Implications: Oral LEC were confirmed to be indolent lesions that are generally not related to HIV status of the patient. Clinicians should be aware that inflamed cervical LEC has  a higher chance of getting misdiagnosed as a malignant lesion

Conclusion: Changed as follows

Oral and cervical LECs are two histologically similar cysts that occur in two distinct sites. The main difference between the two lesions was identified as the size of the lesion with oral LEC presenting as significantly smaller lesions compared to cervical LEC. The literature review supports the information observed in our study with respect to age of occurrence, site predilections and size.  Cervical LECs particularly the ones that occur in the parotid region, may require further investigations to exclude BLEL of parotid

please remove the lines 183-185

Following was removed: However, this conclusion was made by comparing data indicated in two studies [8, 12] and hence the literature review of the cervical LEC is non exhaustive.

Round 3

Reviewer 5 Report

Thank you for the revision.