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Date: 11/14/2022
To: "Matthew K Wagar"
From: "The Green Journal" [email protected] Subject: Your Submission ONG-22-1743
RE: Manuscript Number ONG-22-1743
Beneath the Surface: Fluorescein Mapping in Vulvar Paget's Disease Dear Dr. Wagar:
Thank you for sending us your work for consideration for publication in Obstetrics & Gynecology. Your manuscript has been reviewed by the Editorial Board and by special expert referees. The Editors would like to invite you to submit a revised version for further consideration.
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REVIEWER COMMENTS:
Reviewer #1:
The paper is clearly written. The methods are clear and there are illustrative cases, images and video material.
My only concern about this paper pertains to the audience for this work. Do general gynecologists manage vulvar Paget's disease? Even at this center, only 8 patients received the diagnostic approach over 7 years. Given that this condition is rare and associated with malignancy, would this paper be of greater interest to gyn oncologists?
I also found table 2 cumbersome. The key point is in the text (lines 128-9): all patients had biopsies outside the grossly visible lesion but within the margins delineated by IV fluorescein. Maybe the key points of table 2 could be further summarized in text?
View Letter
1 of 2 11/22/2022, 11:30 AM
Reviewer #2:
This is a well-written paper examining use of Fluorescein to delineate the extend of vulvar Paget's disease during surgery.
The authors clearly outline the technique with instructive photos. This is not a new concept but I believe many younger physicians, who care for these patients, may be unaware of this simple, useful technique. Primary limitation of this case series is no data on recurrence rates.
Reviewer #3:
This manuscript offers what could be classed as a case series, describing 8 patients with vulvar Paget's disease who underwent a 2 step treatment involving fluorescein facilitated biopsy mapping followed by vulvectomy.
50. The management of recurrent vulvar Pagets is not necessarily the primary focus here?
64. Prior cases described in references appear to use similar approach?
81. Would the invasive disease refer to vulvar carcinoma?
84. The addition of the video was very helpful, but the 2 step process described may not be the first time its described in writing, if prior published? May be better to describe an expansion and affirmation of this process in your 8 patients?
95. Does the fluorescein lighting up the subdermal vasculature correlate with other pathologies, such as VIN , LS?
98. If necessary, can additional IV flourescein be administered? Was it ever not enough time to achieve? Is there any visual or other danger to use of the Woods lamp?
128-131. Comparing the described results to the table, its unclear what is meant by 4/8 having positive margins on final vulvectomy specimen (line306). Are these the patients described as having satellite lesion?
134. There are 2 patients described as completing 5 years of surveillance without evidence of disease, and median followup on the 8 was 32 months. Does that mean that the 4 / 8 with positive margins described in the table had further surgery?
184. Its unclear what the selection bias refers to? Does that mean other patients were considered for the series but were not included?
192. Due to the off label use of fluoroscein did the process require any special consents or IRB involvement?
-- Sincerely,
Shannon K. Laughlin-Tommaso, MD, MPH Associate Editor, Gynecology
The Editors of Obstetrics & Gynecology
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View Letter
2 of 2 11/22/2022, 11:30 AM
Shannon K. Laughlin-Tommaso, MD, MPH Associate Editor, Gynecology
Obstetrics and Gynecology November 21, 2022
Dear Dr. Laughlin-Tommaso,
Subject: Manuscript Number ONG-22-1743
Thank you for your email and the opportunity to revise our manuscript and accompanying video,
“Beneath the Surface: Fluorescein Mapping in Vulvar Paget's Disease”. We appreciate the reviewers’ additional comments. After thoughtful consideration of each of these comments, we have made additional manuscript revisions.
We have included the reviewer comments in bold below and responded to them point-by-point indicating the line number where we addressed each concern and described the changes we have made. We confirm that all parties included in the video and figures provided written consent to obtain and distribute these images. The revised manuscript has been submitted through Editorial Manager.
We hope the revised manuscript is better suited for publication in Obstetrics and Gynecology.
We are happy to consider further revisions, and we thank you for the interest in this manuscript.
Sincerely,
Matthew K. Wagar, MD
Fellow, Division of Gynecologic Oncology Department of Obstetrics and Gynecology
University of Wisconsin School of Medicine and Public Health
REVIEWER COMMENTS:
Reviewer #1:
The paper is clearly written. The methods are clear and there are illustrative cases, images and video material.
My only concern about this paper pertains to the audience for this work. Do general gynecologists manage vulvar Paget's disease? Even at this center, only 8 patients received the diagnostic approach over 7 years. Given that this condition is rare and associated with malignancy, would this paper be of greater interest to gyn oncologists?
Thank you very much for your comments. Regarding the management of vulvar Paget’s disease (VPD), at our institution this condition is managed by Gynecologic Oncologists. However, due to lack of access to specialists as well as the majority of these patients presenting with non-
invasive disease, in many areas of the country and internationally this condition is managed by and within the scope of practice of general gynecology. As such, the reach of the journal will allow for dissemination to a wider audience capable of treating this condition. Additionally, the fluorescein technique described within the manuscript could be utilized to delineate the extent of necessary resection needed to adequately treat VPD, which may prompt referral from general gynecologist to subspecialist.
I also found table 2 cumbersome. The key point is in the text (lines 128-9): all patients had biopsies outside the grossly visible lesion but within the margins delineated by IV fluorescein. Maybe the key points of table 2 could be further summarized in text?
Thank you for this feedback. The table has been edited for clarity. Specifically columns
delineating patients whose mapping biopsies demonstrated subclinical disease and readmission rates within 30 days of surgery were removed. This information is outlined in the text in lines 131-135.
Reviewer #2:
This is a well-written paper examining use of Fluorescein to delineate the extend of vulvar Paget's disease during surgery. The authors clearly outline the technique with instructive photos. This is not a new concept but I believe many younger physicians, who care for these patients, may be unaware of this simple, useful technique. Primary limitation of this case series is no data on recurrence rates.
Thank you for your comments. At the time of this writing, no patients included in this case series have experienced a recurrence with a median follow up time of 32 months. This has been addended in line 138 for clarity.
Reviewer #3:
This manuscript offers what could be classed as a case series, describing 8 patients with
vulvar Paget's disease who underwent a 2 step treatment involving fluorescein facilitated
biopsy mapping followed by vulvectomy.
50. The management of recurrent vulvar Pagets is not necessarily the primary focus here?
Thank you for your comments. This has been edited in line 50 to reflect the primary focus of the article which is treatment of VPD.
64. Prior cases described in references appear to use similar approach?
Prior literature previously published in Obstetrics and Gynecology detailing a similar technique utilized intravenous fluorescein to delineate the extent of VPD which was then outlined and marked with a pen prior to radical vulvectomy which was completed during the same anesthesia event(1). Our technique describes a modified two-step process relying on directed biopsies and subsequent pathology to aid in vulvectomy planning. This has been edited to reflect this with clarity in lines 84-85.
81. Would the invasive disease refer to vulvar carcinoma?
Yes invasive disease refers to vulvar carcinoma and/or invasive vulvar Paget’s disease which can be present in up to 12% of patients with VPD(2). This has been edited for clarity in line 82.
84. The addition of the video was very helpful, but the 2 step process described may not be the first time its described in writing, if prior published? May be better to describe an expansion and affirmation of this process in your 8 patients?
As above our technique is modified and expanded upon from prior literature. To our knowledge this is the first description of this technique proposed to the literature, this has been addended in line 86.
95. Does the fluorescein lighting up the subdermal vasculature correlate with other pathologies, such as VIN , LS?
We are unaware of available literature on the utilization of fluorescein in pre-clinical or clinical settings for the identification of VIN or lichen sclerosus.
98. If necessary, can additional IV flourescein be administered? Was it ever not enough time to achieve? Is there any visual or other danger to use of the Woods lamp?
If necessary, IV fluorescein can be re-administered. The area of interest fluoresces for 1-2 minutes allowing for ample time to delineate the areas of interest with a marking pen, in our practice we do not typically need to re-administer given these reasonable time constraints. We are unaware of any visual or dermatologic risk of Woods lamp usage for the short amount of time needed to complete the mapping procedure.
128-131. Comparing the described results to the table, its unclear what is meant by 4/8 having positive margins on final vulvectomy specimen (line306). Are these the patients described as having satellite lesion?
Each of the four patients found to have a positive margin on final vulvectomy specimen had an
edge of the specimen in which VPD was present, despite attempts to achieve a negative margin
utilizing the IV fluorescein mapping technique. This is similar to rates of positive surgical
margins reported elsewhere in the setting of VPD (3). This has been addended in lines 132-138 for clarity.
134. There are 2 patients described as completing 5 years of surveillance without
evidence of disease, and median followup on the 8 was 32 months. Does that mean that the 4 / 8 with positive margins described in the table had further surgery?
This is correct, given that current data has not been able to correlate margin status with risk of VPD recurrence it is our practice to not re-excise patients with positive margins but observe and monitor for clinical signs of recurrence. This has been clarified in lines 141-42.
184. Its unclear what the selection bias refers to? Does that mean other patients were considered for the series but were not included?
In our practice patients with VPD may be managed with excisional procedures with or without fluorescein mapping, topical treatments such as Imiquimod or in some cases external beam radiation therapy. Depending on decision making between the patient and their surgeon it is possible that patient’s more inclined to undergo surgery would select this option for a variety of reasons related to their own history, characteristics of their lesion or surgeon preferences. This would contribute to bias in this series of patient’s as they were selected sequentially in a retrospective manner. This has been addended in lines 196-197 for clarity.
192. Due to the off label use of fluoroscein did the process require any special consents or IRB involvement?
This practice is considered standard of care at our institution and did not require special consents. Given that this data was abstracted retrospectively, this series was deemed IRB exempt. We have added IRB exemption to lines 139-140.
References
1. Misas JE, Cold CK, Hall FW. Vulvar Paget Disease: Fluorescein-Aided Visualization of Margins. Obstet Gynecol. 1991;77(1):156–9.
2. Fanning J, Lambert HCL, Hale TM, Morris PC, Schuerch C. Paget’s disease of the vulva:
Prevalence of associated vulvar adenocarcinoma, invasive Paget’s disease, and recurrence after surgical excision. Am J Obstet Gynecol [Internet]. 1999;180(1 I):24–7. Available from:
http://dx.doi.org/10.1016/S0002-9378(99)70143-2
3. van der Linden M, Meeuwis KAP, Bulten J, Bosse T, van Poelgeest MIE, de Hullu JA. Paget disease of the vulva. Crit Rev Oncol Hematol [Internet]. 2016;101:60–74. Available from:
http://dx.doi.org/10.1016/j.critrevonc.2016.03.008
