Title: Risk factors for residual lesions after total hysterectomy in patients with high-grade
cervical intraepithelial neoplasia
Version: 1 Date: 21 Feb 2024
Reviewer:  Sathone Boonlikit
Reviewer's report:
To the authors
General comments
The study is a retrospective chart review from one institute. The purpose of this study is to predict
the risk factors of residual lesions in patients with high-grade cervical intraepithelial neoplasia
undergoing total hysterectomy. This research setting is difficult to achieve in many countries
where hysterectomy is rarely performed in treating CIN2/3 at the present time.
I will address each section of the manuscript separately as follows.
Title:  Ok
Introduction
-Cancer Report 2022 or 2023 can be used.
-Second paragraph describing about The 2014 BETHESDA system for reporting cervical
cytology should be shorten or removed as it is not relevant to context of this study.
-LEEP should be mentioned more in regard to background, advantage and disadvantage.
Material and methods
-Should have detail of surgical technique , instrument , machine used.
-The definition of “residual lesion” should be defined and shown in this this section.
-What is a definition of ECC in this study, To my understanding , I  think that it was ECC at
time of colposcopy (preoperative ECC). However in the literature, few study analyzed  about
this kind of ECC. Most of them reported ECC in the other meaning. Some studies and guidelines
focused  on ECC at time of LEEP (intraoperative ECC or post operative ECC). The authors
should give a definition of ECC in this section,
- Moreover , what does “ positive ECC” mean? It should be also defined in this section.
Normally, ECC result showing # CIN2 is only our concern. While ECC showing CIN1 or HPV
would not matter in clinical concern.
Results:
- The detail of the histology specimen of hysterectomy should be present either in text or table.
- Were there any “the histology-proved microinvasive or invasive carcinoma” in hysterectomy
specimen?   In general, it would be possible to occur in cases who underwent hysterectomy after
incomplete LEEP for CIN2/3. From literature, the incidence of varies around 0.9-9.6 %. There
would be such cases in a considerable number (212)  hysterectomized patients in this study. This
is one of concern to avoid hysterectomy in this circumstance.  If there were many cases who had
residual invasive cancer, the detail and characteristics of those women should be present.
-There should be detail of VAIN in regard to the location of lesion , size and mulitfocality.
Discussion :
- The data in this study should be reviewed regarding statistical interpretation. The odds
ratio (OR) is a measure of how strongly an event is associated with exposure.  OR >1
indicates increased occurrence of an event. OR <1 indicates decreased occurrence of an event
(protective exposure).  Therefore, “glandular involvement and VAIN” which had OR <1 were
the independent protective factors , not  risk factors as written in discussion and in abstract. The
outcome is quite unexpected especially “VAIN”as the concomitant VAIN and CIN2/3 should
be the factor increasing the rate of residual dysplasia in uterine specimen.
-The risk factors in this study were only a positive margin , positive ECC .Therefore, discussing
regarding this matter in the all paragraph must be changed.
- Authors should discuss more in this matter and should have possible explanation regarding
the factor glandular involvement and VAIN which had OR less than 1
- Theoretically, ECC after LEEP (at time after remove LEEP specimen) appears to be a strong
predictor  for residual disease on post-LEEP specimens and there have been many studies
looking in this matter.  The value of ECC  during follow-up period for patients with CIN2/3 after
LEEP is evidenced as ECC can detect early recurrent lesions after LEEP in patients with CIN2+.
However, the evidence about “positive ECC at time of colposcopy and association with residual
disease in hysterectomy is less. Few studies reported the relationship between preoperative ECC
and recurrent/residual HSIL after LEEP.  The relationship between preoperative ECC and post-
LEEP recurrent/residual HSIL remains unclear.  It would be great if the authors can discuss
more about ECC, comparing the data with previous studies.
Conclusion:   - Conclusion should be consistent with the major objective of the study.  In
the authors’ study , the conclusion were probably written as “the risk factors predicting
residual disease in hysterectomy were  a positive margin , positive ECC”  There should not be
recommendation to perform total hysterectomy  based on  scientific data from this study.
- In fact, at present, standard guideline do not recommend first-line hysterectomy in patients
who have LEEP done and have those risk factors including positive LEEP margin, glandular
involvement, positive ECC and VaIN I-III.    ASCCP 2019, for instance, suggest “repeat
conization or hysterectomy, if a repeat conization is not feasible, is acceptable” in this regard.
- Grammar may be improved.
Wording correction
Line # 84   endometrial curettage (ECC) changed to  endocervical curettage
Lint # 88    What does LCT stand for?
Line # 116   basal  margin  should be changed to………Deep margin? or stromal margin ?
Line # 133   Shoud give more detail about location VAIN i.e. upper , middle , lower vaginal
canal and what method  to treat concomitant VIAN. It is very important in case VAIN is located
in upper vaginal canal involving or close to SIL lesion at cervix.
Line # 138   Table 1 should have detail of hysterectomy specimen, how many residual disease
Line#144   OR less than 1  glandular involvement and VAIN is protective factors , not risk factor
Line # 170   Cannot find this percent (42%)  in any result section or table 2
Table 2 show total 75 cases who had residual disease in hysterectomy specimen eligible for
analysis of margin. Of those, 61 cases had positive leep margin. It equals to 81.3%.
Author should mention their result that “in the present study, most…% of margin positive was
endocervical margin
Line# 199-200    Authors should cite standard guideline “Patients < 25 years or those who
are concerned about the  effect of treatment on future pregnancy outcomes,  observation is
recommended.” ASCCP2019
Line# 201    “conization” Did authors mean leep or conization?  The term “excision” would
be more up-to-date.
Line# 201-202   Nowadays, the desire not to preserve uterus in women who complete family
is not indication to perform hysterectomy for CIN anymore. Should refer to standard guideline
(i.e.ASCCP)  “In pts # 25 years who are not concerned about the  effect of treatment on future
pregnancy outcomes, repeat excision or observation is acceptable.”
Line# 208    Glandular is protective factor seen from Odd ratio less than 1,   authors should give
possible explaination to this findings.
Line# 229   VAIN is protective factor. Please elaborate the reason of this finding.
Line#231   If the patients had CIN with concomitant VAIN. Performing hysterectomy might
take the risk of cutting through the VAIN lesion, increasing the post-hysterectomy VAIN which
is difficult to treat.
Recommendation:
Accepted after major correction, revision and review.