Diagnostic Utility of Neutrophil-to-Lymphocyte Ratio in Differentiating Benign and Malignant Ovarian Masses: A Systematic Review
Round 1
Reviewer 1 Report
Comments and Suggestions for AuthorsThank you for inviting me to review the article entitled “Diagnostic Utility of Neutrophil-to-Lymphocyte Ratio in Dif-2 ferentiating Benign and Malignant Ovarian Masses: A Systematic Review”. I read the article with great interest. In this systematic review, the authors evaluated whether the neutrophil-to-lymphocyte ratio (NLR) can serve as a useful marker to differentiate between benign and malignant ovarian masses, synthesizing available evidence to provide a comprehensive assessment of its diagnostic value.
Considering the low costs and availability of indicators, the NLR ratio appears to be an interesting and easily obtainable parameter. On the other hand, the frequency of neutrophils and lymphocytes depends on many factors. It may change in many other diseases, so it may not be a specific marker to differentiate between these two conditions.
Notably, the majority of studies reported higher sensitivity values for detecting malignancy, although some had low specificity, suggesting a tendency to produce false positives in benign cases.
The manuscript would benefit from a major revision addressing all the above-mentioned concerns.
1. Please introduce the abbreviation NLR when it is first explained (Simple Summary, line 15)
2. What diagnostic methods are currently used to differentiate benign and malignant ovarian tumors? Please, describe model ADNEX in the introduction.
3. Please provide the factors that affect the number of neutrophils and lymphocytes.
4. Did the authors stratify the group of patients to eliminate a confounding factor?
5. Is the NLR index used in the diagnosis of other types of cancer? If so, please provide examples of these cancers.
6. In Discussion (line 180-182), the phrase “Authors should discuss the results and how they can be interpreted from the perspective of previous studies and of the working hypotheses. The findings and their implications should be discussed in the broadest context possible. Future research directions may also be highlighted”, should be removed.
7. In Discussion (line 195-197), provide references, please.
Author Response
Comments 1: Please introduce the abbreviation NLR when it is first explained (Simple Summary, line 15)
Response 1: Thank you for this suggestion. We have revised the Simple Summary to explicitly introduce the abbreviation "NLR" at its first mention to ensure clarity.
Comments 2: What diagnostic methods are currently used to differentiate benign and malignant ovarian tumors? Please, describe model ADNEX in the introduction.
Response 2: We agree that context on current methods is important. We have added a brief description of the IOTA ADNEX model to the Introduction, noting that it combines clinical data (such as age and CA-125) with ultrasound features to predict malignancy risk.
Comments 3: Please provide the factors that affect the number of neutrophils and lymphocytes.
Response 3: We have updated the Discussion to clarify that NLR is influenced by various physiological and pathological factors. We listed conditions such as active infections, chronic inflammation, trauma, and corticosteroid use that can affect neutrophil and lymphocyte counts.
Comments 4: Did the authors stratify the group of patients to eliminate a confounding factor?
Response 4: We acknowledge this limitation. We were unable to perform stratification or meta-regression to control for confounding factors. As a statistical rule of thumb, a minimum of 10 studies is generally required per covariate for reliable meta-regression. Since our review included exactly 10 studies total (with only a subset available for certain analyses), we lacked the statistical power to perform this adjustment.
Comments 5: Is the NLR index used in the diagnosis of other types of cancer? If so, please provide examples of these cancers.
Response 5: Yes, NLR is used in other malignancies. We have added examples to the Discussion, noting its prognostic use in colorectal, gastric, and non-small cell lung cancers to illustrate its broader application.
Comments 6: In Discussion (line 180-182), the phrase “Authors should discuss the results and how they can be interpreted from the perspective of previous studies and of the working hypotheses...” should be removed.
Response 6: We apologize for this oversight. The template text has been removed from the revised manuscript.
Comments 7: In Discussion (line 195-197), provide references, please.
Response 7: We have added the appropriate references to support the statement regarding non-cancerous inflammatory conditions (e.g., COVID-19 and systemic inflammation studies).
Reviewer 2 Report
Comments and Suggestions for AuthorsThis is a very interesting article, about the possibility of using the ratio between neutrophiles and lymphocytes as a marker for determining the nature of ovarian tumors. It is a useful and very well constructed meta-analysis, resulting in an extremely clear and pragmatic paper through the analysis of all the data existing in the literature regarding this subject.
The analysis bears a high accuracy with conclusive results. All the chapters are well structured with an impressive clarity. In my opinion, this is a model of a detailed and pragmatic research which can be followed extremely easily, sparing useless details.
There is an inadvertency because both in the simple summary and abstract 8 studies are mentioned which were included in the meta-analysis, but as the material and methods show, there are 10 studies considered.
2 chapters are impressive: the results, which clearly exposes the obtained data via excellent tables, graphs and diagrams. Additionally, the discussions reveal all the weak spots regarding this marker: low specificity, low AUC, lack of a unique cut off value, low SROC curve and the hetrogenity of the studies, introducing multiple biases. The conclusions are clear and concise, the language used is delightful, and the references are well cited.
Author Response
Comments 1: This is a very interesting article, about the possibility of using the ratio between neutrophiles and lymphocytes as a marker for determining the nature of ovarian tumors. It is a useful and very well constructed meta-analysis, resulting in an extremely clear and pragmatic paper through the analysis of all the data existing in the literature regarding this subject. The analysis bears a high accuracy with conclusive results. All the chapters are well structured with an impressive clarity. In my opinion, this is a model of a detailed and pragmatic research which can be followed extremely easily, sparing useless details. There is an inadvertency because both in the simple summary and abstract 8 studies are mentioned which were included in the meta-analysis, but as the material and methods show, there are 10 studies considered. 2 chapters are impressive: the results, which clearly exposes the obtained data via excellent tables, graphs and diagrams. Additionally, the discussions reveal all the weak spots regarding this marker: low specificity, low AUC, lack of a unique cut off value, low SROC curve and the hetrogenity of the studies, introducing multiple biases. The conclusions are clear and concise, the language used is delightful, and the references are well cited.
Response 1: Thank you very much for your highly positive feedback and for appreciating the structure, clarity, and pragmatic approach of our study. We are grateful for your detailed review and kind words regarding our presentation of the results and discussion of the marker's limitations.
Regarding the inconsistency you identified: We sincerely apologize for this oversight. You are absolutely correct that 10 studies were included in the final review (as listed in the Methods and Table 2), while the Abstract and Simple Summary incorrectly stated "eight." We have corrected this error in the revised manuscript to ensure consistency across all sections.
