Title: A Retrospective Study for Long-term Oncologic and Obstetric Outcomes in Cervical
Intraepithelial Neoplasia Treated with Loop Electrosurgical Excision Procedure: Focus on
Surgical Margin and Human Papillomavirus
Version: 2 Date: 26 Dec 2023
Reviewer's report:
The authors explore a highly intriguing and relevant subject that received considerable attention
in the literature. However, I suggest implementing significant revisions to enhance the paper's
readability.
Firstly, in the study design, it's crucial to specify the particular HPV assay used both before
and after LEEP for CIN2-3. This distinction is vital to differentiate between HPV persistence
and new infections by different HPV genotypes after surgical treatment. This topic has been
extensively discussed in existing literature, particularly focusing on qualitative HPV testing
without genotype-specific information and HPV assays with extended or full-genotyping. If
the authors have utilized qualitative HPV testing, it presents a significant bias due to the
inability to confirm HPV genotype persistence. This should be addressed in the Discussion
section. Additionally, I recommend referencing the following articles for comparison: “Bottari
F, Iacobone AD, Passerini R, Preti EP, Sandri MT, Cocuzza CE, Gary DS, Andrews JC. Human
Papillomavirus Genotyping Compared With a Qualitative High-Risk Human Papillomavirus
Test After Treatment of High-Grade Cervical Intraepithelial Neoplasia: A Systematic Review.
Obstet Gynecol. 2019;134:452-462.”; “Bottari F, Iacobone AD, Boveri S, Preti EP, Franchi
D, Mariani L, Preti M, Landoni F, Passerini R, Sandri MT. Onclarity Human Papillomavirus
Extended Genotyping in the Management of Cervical Intraepithelial Neoplasia 2+ Lesions. J
Low Genit Tract Dis. 2019;23:39-42.”; “Iacobone AD, Radice D, Sandri MT, Preti EP, Guerrieri
ME, Vidal Urbinati AM, Pino I, Franchi D, Passerini R, Bottari F. Human Papillomavirus Same
Genotype Persistence and Risk of Cervical Intraepithelial Neoplasia2+ Recurrence. Cancers
(Basel). 2021;13:3664.”.
Another concern arises from the definition of “disease recurrence or persistence”. The authors
include CIN1 after treatment within this definition. However, it's well established that “treatment
failure” refers to the occurrence of CIN2+ post-treatment necessitating re-excisional surgical
treatment during follow-up, not merely the presence of CIN1, which signifies viral infection
persistence and could be managed conservatively. The authors should extensively discuss this
topic in the Discussion and explain their classification of CIN1 as “disease recurrence or
persistence”. Moreover, CIN1 following LEEP for CIN2-3 might result from a new genotype
infection post-treatment and should not be immediately retreated. Please consider referencing
the following papers for Discussion: “Bonde J, Bottari F, Iacobone AD, Cocuzza CE, Sandri
MT, Bogliatto F, Khan KS, Ejegod DM, Gary DS, Andrews JC. Human Papillomavirus Same
Genotype Persistence and Risk: A Systematic Review. J Low Genit Tract Dis. 2021;25:27-37.”;
“Spinillo A, Gardella B, Iacobone AD, Dominoni M, Cesari S, Alberizzi P. Outcome of
Persistent Low-Grade Cervical Intraepithelial Neoplasia Treated With Loop Electrosurgical
Excision Procedure. J Low Genit Tract Dis. 2016;20:307-11.”.
Could the authors specify why “LEEP again” (19 patients) or “hysterectomy” (3 patients) were
performed immediately after treatment in the “Results” section? Most international guidelines
do not recommend immediate re-treatment for positive surgical margins, except for women
diagnosed with cervical adenocarcinoma in situ who wish to preserve fertility. Women with
clear resection margins might be at risk of relapse due to viral persistence or multifocal lesions.
Conversely, most women with involved margins might not develop recurrence over time due to
thermal tissue effect on the residual cervix and viral clearance. Therefore, achieving negative
surgical margins should consider potential risks of adverse obstetrical outcomes, especially in
young women, as extensively discussed by “Kyrgiou et al. BMJ. 2016;354:i3633.”. I suggest
considering this argument extensively in the “Discussion” section, given that the paper's
second objective explores obstetric outcomes post-LEEP, albeit in a single-center and relatively
small population. Please refer to the following references for further reading: ““Kyrgiou M.,
Athanasiou A., Paraskevaidi M., Mitra A., Kalliala I., Martin-Hirsch P., Arbyn M., Bennett
P., Paraskevaidis E. Adverse obstetric outcomes after local treatment for cervical preinvasive
and early invasive disease according to cone depth: Systematic review and meta-analysis.
BMJ. 2016;354:i3633.”; “Kyrgiou M, Valasoulis G, Stasinou SM, Founta C, Athanasiou A,
Bennett P, Paraskevadis E. Proportion of cervical excision for cervical intraepithelial neoplasia
as a predictor of pregnancy outcomes. Int J Gynaecol Obstet. 2015;128:141-7.”; “Athanasiou
A, Veroniki AA, Efthimiou O, Kalliala I, Naci H, Bowden S, Paraskevaidi M, Arbyn M,
Lyons D, Martin-Hirsch P, Bennett P, Paraskevaidis E, Salanti G, Kyrgiou M. Comparative
effectiveness and risk of preterm birth of local treatments for cervical intraepithelial neoplasia
and stage IA1 cervical cancer: a systematic review and network meta-analysis. Lancet Oncol.
2022;23:1097-1108.”.
I'm curious how the authors interpreted the significance of “positive margins” for residual
or recurrent disease when exocervical, endocervical, and both margins were not significant
(see Table 2). A recent meta-analysis by Arbyn et al. highlighted that while margin status is
significantly associated with treatment failure, it's not a precise predictor of CIN2+ recurrence
due to heterogeneous sensitivity and low reproducibility in assessing resection margins. Please
extensively explore this potential bias in the analysis (see “Arbyn M., Redman C.W.E., Verdoodt
F., Kyrgiou M., Tzafetas M., Ghaem-Maghami S., Petry K.U., Leeson S., Bergeron C., Nieminen
P., et al. Incomplete excision of cervical precancer as a predictor of treatment failure: A
systematic review and meta-analysis. Lancet Oncol. 2017;18:1665–1679.”).
Lastly, I recommend reviewing the text for minor spelling and grammatical errors. It would also
be helpful to specify any abbreviations used (e.g., 'IIOC') and complete the reference 18.