Lymphatic Spread of Non-Small-Cell Lung Cancer: Mechanisms, Patterns, Staging, and Diagnosis

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

1. You have write in the abstract: Non-small cell lung cancer is the most common type of lung cancer; appropriate staging is vital to determine treatment modalities which includes surgery, radiation therapy, chemotherapy, or a combination of those mentioned. Please add which drug combination?
2. Which gene mutation are report in NSCLC?
3. Describe the common Clinical tests used to detect gene mutations in non-small cell lung cancer (NSCLC)?

Author Response

1. You have write in the abstract: Non-small cell lung cancer is the most common type of lung cancer; appropriate staging is vital to determine treatment modalities which includes surgery, radiation therapy, chemotherapy, or a combination of those mentioned. Please add which drug combination?

Thank you for pointing this out. Discussion of treatment modalities is intentionally excluded to maintain focus and avoid deviation from the primary objective of outlining and clarifying diagnostic principles and methods. The scope of this paper is limited to the diagnostic aspects of thoracic malignancies, focusing on lymphatic anatomy, nodal staging, and diagnostic techniques.

2. Which gene mutations are reported in NSCLC?

Another important factor in determining the treatment of NSCLC is genetic analysis. There are numerous genetic mutations that contribute to the pathogenesis of NSCLC. The most frequently observed mutation across all histologic subtypes is TP53, although this alteration is currently considered non-actionable. Among the actionable mutations, KRAS, EGFR, and MET are among the most prevalent and are particularly common in lung adenocarcinoma. Additional significant mutations include LRP1B, FAT3, and KMT2D, with mutation prevalence varying according to histologic subtype, ethnicity, and smoking status. Given the therapeutic implications of these genomic alterations, the National Comprehensive Cancer Network (NCCN) recommends comprehensive molecular profiling for all patients with advanced NSCLC to identify actionable mutations and guide targeted therapy.

We have added this additionally as the fourth paragraph. 

2. Describe the common Clinical tests used to detect gene mutations in non-small cell lung cancer (NSCLC)?

Molecular profiling, which has become standard of care for NSCLC management uses multiple different analytical platforms including PCR, DNA sequencing, Immunohistochemistry, and FISH. Mutations of EGFR, BRAF, MET, and analysis of ROS1, RET, NTRK,  and ALK are currently part of the NSCLC diagnostic standards, and there are emerging biomarkers e.g. KRAS G12C substitutions, and HER2 activating alterations which may enter NSCLC guidelines once corresponding therapies are approved. Currently there are multiple molecular assays to give a full molecular analysis, and there are efforts to integrate multiple assays into one diagnostic path. 

We have added this into the fifth paragraph. 

Reviewer 2 Report

Comments and Suggestions for Authors

 

The review manuscript (lymphatics-3875720) entitled “Lymphatic Spread of Non-Small cell Lung Cancer: Mechanisms, Patterns, Staging and Diagnosis” by Mohamed Salih explored the pathogenesis of lymph node metastasis, current sampling guidelines, patterns of lymph node spread, and evaluated novel lymph node sampling techniques alongside their diagnostic yields. Overall, the current review is interesting and well written.

 

The following are the comments:

1. Diagrams for each section would significantly improve reader comprehension of the author’s clear and thorough explanation of lymphangiogenesis in non-small cell lung cancer (NSCLC), normal lymphatic drainage channels, and nodal metastasis and staging patterns etc.

Author Response

1. Diagrams for each section would significantly improve reader comprehension of the author’s clear and thorough explanation of lymphangiogenesis in non-small cell lung cancer (NSCLC), normal lymphatic drainage channels, and nodal metastasis and staging patterns etc.

Thank you for your review. We have added figures to improve reader comprehension throughout the article.

Figure 1. The International Association for the Study of Lung Cancer (IASLC) lymph node map, including the proposed grouping of lymph node stations.

 

Figure 2. Schematic representation of normal lymphatic drainage. 

 

Figure 3. Developmental signaling pathways in lymphangiogensis.  

Reviewer 3 Report

Comments and Suggestions for Authors

This is a very good and compete review. It explains clearly the anatomy, staging, and diagnostic method for lymphatic spread in NSCLC. The part about EBUS-TBNA and cryobiopsy are especially strong and useful for clinical work. The strucute is clear and the flow of information is good. The references are well selected and up to date. The paper has a practical focus, which is helpful for clinicians.

Some sections contain overlap between the staging and diagnostic techniques, and this could be reduced to make the text shorter and easier to read. Adding one simple figute with the proposed staging algorithm would make the review even clearer for the reader. The section on sentinel node mappin could include more recent information or a short comment on its current clinical role.

Overall, this is a strong anf relevant review that will be of interest to thoracic surgeons, pulmonologists and oncologists

Author Response

Some sections contain overlap between the staging and diagnostic techniques, and this could be reduced to make the text shorter and easier to read. Adding one simple figute with the proposed staging algorithm would make the review even clearer for the reader. The section on sentinel node mappin could include more recent information or a short comment on its current clinical role.

 

Thank you for taking your time to review the article. We agree and have added the following. Liptay et al found that intraoperative sentinel lymph node mapping with technetium-99m is an accurate method of finding the first site of lymphatic lymph node drainage in NSCLC.

 

While several studies have found promising results, sentinel lymph node mapping has not reached the reliability and standardization seen in other cancers such as breast cancer and is not currently standard of care (17). 

To clarify it's current role in the diagnosis of NSCLC. Line 84.