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Abstract
Objective Plasma energy ablation vaporizes tissues similar to carbon dioxide laser ablation, but is not hindered by the unique hazards and regulation of laser technology. We aimed to evaluate the complication rate and effectiveness of plasma versus laser ablation in the treatment of vulvovaginal high-grade squamous intra-epithelial lesions (HSIL).
Methods We performed a retrospective cohort study of women treated with plasma or carbon dioxide laser ablation for histologically proven HSIL of the vulva or vagina from January 2014 to October 2019 at a single institution. Demographic factors, surgical characteristics, and complications were compared by ablation type using Fisher’s exact tests. Recurrence-free survival was evaluated by ablation type using Kaplan–Meier curves, weighted log-rank tests, and Cox proportional hazards ratio estimates.
Results Forty-two women were included; 50% underwent plasma and 50% underwent carbon dioxide laser ablation. Demographic factors were similar between the groups. 50% (n=21) were immunosuppressed, 45.2% (n=19) had prior vulvovaginal HSIL treatment, and 35.7% (n=15) were current smokers. Most women (n=25, 59.5%) were treated for vulvar HSIL, 38.1% (n=16) for vaginal HSIL. Complication rates did not differ by treatment: 9.5% (n=2) for laser ablation versus 4.8% (n=1) for plasma ablation (p=1.0). Over a median follow-up time of 29.3 months (IQR 11.0–45.0 months), recurrence rates were similar: 28.6% in the laser ablation group versus 33.3% in the plasma ablation group (weighted log rank p=0.43; 24-month HR 0.54, 95% CI 0.15 to 2.01).
Conclusion Plasma energy ablation of vulvovaginal HSIL has similar complication rates and recurrence risk to carbon dioxide laser ablation. This technique could be considered as an alternative treatment modality for vulvovaginal HSIL and warrants further investigation.
- vulvar and vaginal cancer
- vulvar diseases
- vulvar neoplasms
- genital neoplasms
- female
- gynecologic surgical procedures
Data availability statement
Data are available upon reasonable request.
Statistics from Altmetric.com
- vulvar and vaginal cancer
- vulvar diseases
- vulvar neoplasms
- genital neoplasms
- female
- gynecologic surgical procedures
HIGHLIGHTS
Plasma energy ablation has advantages over carbon dioxide laser for vulvovaginal dysplasia treatment
Complication and recurrence rates were similar between plasma and laser ablation treatment cohorts
Plasma energy ablation could be an alternative ablative option for vulvovaginal dysplasia treatment
INTRODUCTION
The incidence of pre-cancerous lesions of the vulva and vagina is rising, likely driven by human papillomavirus (HPV).1 Formerly designated as vaginal/vulvar intra-epithelial neoplasia 1, 2, or 3, these lesions are now classified as low- or high-grade squamous intra-epithelial lesions (LSIL or HSIL) of the vagina or vulva by the World Health Organization.2 Although data on the estimated global incidence of pre-cancerous lesions are limited, in the USA vaginal carcinoma-in-situ occurs in 0.2/100 000 and vulvar carcinoma-in-situ in 2.9/100 000 women annually.3 The incidence of vulvar and vaginal invasive carcinomas has been historically elevated in high-income countries, but recent global estimates suggest that rates in low- and middle-income countries are similarly rising, likely due to immunosuppression and HPV infection.4 5 Seventy-five percent of affected women are pre-menopausal, and given that preservation of sexual function is often a priority, ablative therapy may be the preferred treatment option.1 Access to a variety of treatment options for vulvovaginal HSIL including ablation in these countries is thus extremely important. Ablative procedures are less likely to cause the scarring and distortion of vulvovaginal anatomy incurred by surgical excision, and avoid the prolonged treatment with resultant local pain and irritation often experienced during topical therapy.6 7 Ablation is thus ideal for women with multifocal or recurrent vulvovaginal HSIL.8
Carbon dioxide laser ablation, the most common ablative technique, uses class IV lasers which are regulated by the American Safety Network Institute and require special staff training and special equipment. These lasers have significant fire hazards due to their ability to ignite dry materials and are not readily available globally.9 Plasma energy ablation is another ablative technique that has recently been described in the treatment of endometriosis and ovarian tumor implants.10 11 The plasma energy ablation device consists of a console (the source of argon gas, direct current electricity, and power settings) and a handpiece, in which a low flow stream of argon gas is excited by direct current voltage between bipolar electrodes.12–14 This generates kinetic and thermal energy that can dissect, vaporize, and coagulate tissue, in the same manner as carbon dioxide laser systems.12–14 In contrast to the laser, the energy transferred with plasma ablation decreases rapidly with increased distance of the handpiece to the tissue, significantly reducing the risk of both fire and retinal injury.14 In 2012, the US Food and Drug Administration (FDA) determined that the plasma energy system for tissue vaporization was ‘substantially equivalent’ to the carbon dioxide laser and thus could be used for similar purposes.15
While plasma energy systems have advantages with regard to safety and access, patient outcomes have not been extensively studied or compared with laser ablation for the treatment of vulvovaginal dysplasia. Given the paucity of published data, the objective of this study was to report on the safety, outcomes, and effectiveness of plasma energy ablation compared with carbon dioxide laser ablation in the treatment of vulvovaginal HSIL.
METHODS
This study was approved by the Johns Hopkins Medicine Institutional Review Board. A retrospective cohort study was conducted of all women who received ablative treatment for biopsy-proven vulvovaginal HSIL from January 1, 2014 to October 31, 2019 at Johns Hopkins Hospital, Baltimore, Maryland, USA. Ablative treatments were performed with either the carbon dioxide laser or the PlasmaJet (Plasma Surgical, Roswell, Georgia, USA) plasma energy ablation system.12 Potential subjects were identified through an inquiry of the institutional pathology database system using the terms ‘squamous intraepithelial lesion’, ‘dysplasia’, ‘vulvar’, ‘vaginal’, ‘VIN’, and ‘VAIN’ and were confirmed via review of operating room schedules for ablative procedures of vulvovaginal HSIL. Cervical HSIL lesions were excluded, as excision is the preferred treatment for these lesions.16 If a woman received multiple ablative treatments during the study period (n=1), only the first ablative treatment was included. Women with multi-site vulvovaginal HSIL who underwent concurrent excision of a separate HSIL or LSIL lesion at the time of their ablation (ablation of a clitoral hood lesion, with excision of a labia minora lesion) were included. We excluded women who had evidence of invasive cancer at the time of ablation or in the 12 months prior, or if they had treatment of low-grade lesions only, as these lesions harbor a relatively low risk of carcinogenesis.
Demographic and clinical factors, including immunosuppressed state (HIV positive, on immunomodulating or suppressing medications, or on chronic steroids), smoking history, prior history of lower genital tract malignancy or pre-malignancy, and prior treatment for vulvar or vaginal HSIL were extracted from the electronic medical record. Pathology reports were reviewed to confirm diagnosis of vulvovaginal HSIL prior to or at the time of the ablative procedure. Operative reports were reviewed for details on the ablative procedure, including indication, concurrent excision, and concurrent perianal HSIL ablation. Follow-up surveillance progress notes (typically <6 weeks post-operatively, and surveillance examinations every 6 months) were reviewed to identify documentation of complications in the first 45 days post-operatively, including new-onset dyspareunia, scarring, vaginal stenosis, dysuria unexplained by a urinary tract infection, post-operative infection, severe pain requiring unplanned inpatient admission, or severe pain requiring >30 days of oral or topical medications. Notes were also reviewed to determine any histologic evidence of recurrence.
Statistical Analyses
Demographic and clinical variables were compared between women by ablation type. Categorical variables were compared using Fisher’s exact tests while continuous variables were compared using Wilcoxon rank-sum tests. The primary outcome was the proportion of women experiencing post-operative complications in the first 45 days after the procedure. Our secondary outcome was recurrence-free survival. We hypothesized that complication and recurrence rates would be similar between the plasma energy and carbon dioxide laser ablation cohorts. Recurrence was defined as histologically proven recurrence of HSIL. Recurrence-free survival was defined as the time from initial ablative procedure to histologically proven recurrence. Women who did not experience recurrence or progression were censored at the date of their last follow-up appointment. Univariate Cox proportional hazards models were used to estimate hazard of recurrence. The proportional hazards assumption was checked using Schoenfeld residuals and a log–log plot. Because the proportional hazards assumption was violated after approximately 30 months (2.5 years) of follow-up, we calculated a weighted log rank statistic to assess differences in recurrence-free survival by ablation type.17 Additionally, we calculated Cox proportional hazard ratios at 6, 12, 18, and 24 months—time points at which the assumption was not violated. Kaplan–Meier curves were constructed to compare recurrence-free survival estimates by ablation type (carbon dioxide laser versus plasma energy) and recurrence was compared using log rank tests. We performed a sensitivity analysis excluding those women who had concurrent excision at the time of ablation. Due to the small sample size and limited number of outcomes, multivariate analyses could not be performed for this subset. All statistical analyses were conducted on Stata statistical software (Stata Statistical Software Release 16, StatCorp, 2019; College Station, Texas, USA). An α level of 0.05 was used for all statistical tests.
RESULTS
Demographic and Clinical Characteristics
A total of 42 women were identified, of whom 50% (n=21) underwent plasma energy ablation and 50% (n=21) underwent carbon dioxide laser ablation during the study period. One woman in the plasma group had no in-person post-operative vulvovaginal examinations at our institution and was thus excluded from the recurrence analyses. The median age of the overall cohort was 53.5 years (IQR 43.2–62.4 years). Almost half of the women (47.6%) were white, 38.1% (n=16) were black, and 6 (14.2%) were of other race. Half (n=21, 50%) were current or former smokers and 50% (n=21) were immunosuppressed. Ten percent (n=4) had a history of prior vulvar squamous cell carcinoma and had undergone treatment more than 12 months prior; no patient had a history of vaginal squamous cell carcinoma. Seven percent (n=3) had a history of cervical carcinoma. There were no differences in these demographic characteristics by ablation type (Table 1).
Demographic and clinical characteristics of women receiving ablative treatment for vulvar or vaginal HSIL stratified by ablation type
Forty-five percent of women (n=19) had undergone at least one treatment for vulvovaginal HSIL in the past before their ablative procedure. Indications for ablation were similar between the two groups, with 59.5% (n=25) of women treated for vulvar HSIL, 38.1% (n=16) treated for vaginal HSIL, and 2.4% (n=1) treated for concurrent vulvovaginal HSIL. At the time of ablation for vulvovaginal HSIL, concurrent surgical excision was performed in 26.2% (n=11) of cases. Concurrent excision occurred more frequently in the laser ablation group (42.9%, n=9) than in the plasma energy ablation group (9.5%, n=2; p=0.03). Finally, 7.1% (n=3) of women underwent concurrent ablation for perianal HSIL at the time of vulvar or vaginal ablation; this did not differ by ablation type (Table 1).
Postoperative Complications
Complications were infrequent in both ablative cohorts; only two women (9.5%) in the laser group and one woman (4.8%) in the plasma energy group experienced a complication (p=1.0; Table 2). In the laser cohort, one patient experienced pain with delayed wound healing requiring oral pain medications for 3 months post-operatively. Another patient had documented dyspareunia attributed to the laser ablation during surveillance. In the plasma ablation group, one patient had severe pain reported in the post-operative care unit which required unplanned inpatient admission. Of note, this patient had undergone concurrent excision and ablation for extensive perianal HSIL. None of the women in either cohort were documented to have vaginal stenosis, dysuria, or post-operative infections in the 45 days following ablation.
Complications documented within 45 days post-ablative treatment
Recurrence-free Survival
The median follow-up duration after ablation was 29.3 months (IQR 11.0–45.0 months) in the overall cohort: 32.4 months (IQR 1.2–65.1) in the laser group and 28.8 months (IQR 17.3–39.7) in the plasma energy group (p=0.39). A total of 69% (n=29) of the overall cohort had at least 18 months follow-up (66.7% in the laser group vs 71.4% in the plasma group, p=1.0). In total, 31.0% (n=13) of women experienced recurrent vulvar or vaginal HSIL, 28.6% (n=6) in the laser group and 33.3% (n=7) in the plasma group. There was no difference in the proportion of women who were recurrence-free at 6, 12, 18, or 24 months (Table 3).
Proportion of women treated with ablation for vulvovaginal HSIL who were recurrence-free and estimated Cox proportional hazard ratios at 6, 12, 18, and 24 months
At 12 months, 71.4% of the laser group and 89.1% of the plasma energy group were recurrence-free (HR 0.33, 95% CI 0.06 to 1.82) and, at 24 months, 64.3% of the laser group and 76.3% of the plasma group were recurrence-free (HR 0.54, 95% CI 0.14 to 2.01). There was no difference in recurrence-free survival (weighted log rank p=0.43; Figure 1). Median recurrence-free survival was not reached for the laser group compared with 35.5 months for the plasma ablation group.
Kaplan–Meier survival curve demonstrating recurrence-free survival in the laser and plasma energy ablative groups.
On sensitivity analysis excluding those with concurrent excision (n=11), recurrence-free survival estimates were not statistically different overall (weighted log rank p=0.24). At 12 months, the HR favored plasma energy ablation (HR 0.09, 95% CI 0.01 to 0.77) but was based on just five total recurrence events, four in the laser group and one in the plasma group. Additionally, the test of proportional hazards was violated after 12 months and further HRs could not be calculated (see Online supplementary table S1 for estimates of HR on sensitivity analyses and Online supplemental figure S1 for Kaplan–Meier survival curve).
Supplemental material
No women developed cancer directly after ablation. However, five women (12.2%) ultimately progressed to invasive squamous cell carcinoma cancer after HSIL recurrence, two in the laser group and three in the plasma energy cohort.
DISCUSSION
Summary of Main Results
Our study showed that both carbon dioxide laser ablation and plasma energy ablation are safe and well tolerated for the treatment of histologically-proven vulvar or vaginal HSIL, with rare and similar complication rates. Moreover, with a median follow-up time of over 2 years, approximately one-third of patients experienced a recurrence regardless of ablation type.
Results in the Context of Published Literature
In the present study, complications were comparable to the published literature on carbon dioxide laser ablation and other ablative techniques.18–20 Side effects of carbon dioxide laser therapy are reported to occur in 10–20% of patients and can include pruritus, pain, burning, delayed wound healing, infection, and scarring/anatomic distortion.21–23 While there are limited data on the adverse effects following plasma energy ablation of vulvovaginal HSIL, one study reported that the only complication in one of eight women was urinary retention.24 In our study, pain was the only complication that occurred with either laser ablation or plasma ablation. With laser ablation, the pain experienced was more long-term with one patient experiencing dyspareunia and the other requiring long-term medication. The pain experienced by the one patient who underwent plasma ablation was severe (requiring inpatient management) but more acute in nature. Given that these complications were rare in both cohorts, our study supports the view that consideration of plasma energy ablation is reasonable given its similar side effect profile.
In our study, vulvovaginal HSIL recurrence rates were similar to those reported after treatment with ablation, topical agents, or surgical excision, and recurrence rates were comparable between the plasma energy ablation and laser ablation groups.18–20 Published recurrence rates after carbon dioxide laser ablation of vulvovaginal HSIL range from 20% to 50%, a wide range that is influenced by small sample sizes, disparate follow-up times, and heterogeneity of risk factors that influence recurrence including smoking status, immunosuppression, and multifocal or large lesions.20 A recent systematic review reported a recurrence rate of 23% after carbon dioxide laser ablation, similar to the 30% we report in our study.25 Given that recurrence rates were similar between ablative strategies in our study and that these are comparable to recurrence rates in the literature, this suggests that plasma ablation is a reasonable alternative treatment strategy for patients. In our study, the proportional hazards assumption was violated after 30 months (2.5 years), indicating that the short- and long-term effect on recurrence-free survival may be differential by ablation type. While there was no statistical difference in recurrence at any time point, it is interesting to note that the proportion of patients who were recurrence-free at 24 months was higher for plasma ablation, while the overall recurrence-free survival was longer for laser ablation. While this is likely due to the small sample size and subsequent strong influence of individual events, further studies are necessary to ensure that there are no differential treatment effects on short-term versus long-term recurrence outcomes between the two ablation groups.
Strengths and Weaknesses
While this study is limited by the retrospective nature and small sample size, it is the first to our knowledge to specifically examine complications and outcomes for plasma ablation. The FDA has determined that the plasma energy ablation system is sufficiently similar to the carbon dioxide laser ablation to be used in similar scenarios, and our study provides valuable real-world data on patient outcomes using the plasma energy system to treat vulvovaginal HSIL. Additionally, while the follow-up times varied by cohort (though not statistically different), limiting our ability to compare the longer term (>1–2-year) outcomes of the two techniques, the median follow-up time for the study was over 2 years. There are few studies of ablation techniques with similar follow-up rates greater than 2 years, and this is thus a major strength of the study. Finally, we lacked standardized adverse event reporting and could not differentiate same from new-site recurrence. However, extensive and detailed review of the medical records was performed which allowed identification of all complications. Another strength of this study was the large number of immunosuppressed women included. While this may limit the generalizability of our results to an immunocompetent population, these women are at increased risks of recurrence which is promising when comparing recurrence rates in the current study to those previously reported in immunocompetent populations.26
Implications for Practice and Future Research
Plasma energy ablation of vulvovaginal HSIL had similar complication rates and recurrence risk to carbon dioxide laser ablation in this retrospective study. Furthermore, plasma energy ablation offers advantages over carbon dioxide laser ablation in terms of safety and necessary training and expertise. Our results indicate that plasma energy ablation is a viable alternative to carbon dioxide laser ablation. This strategy may be particularly important internationally in countries where there may be limited access to the laser, and where immunosuppressed patients may be more likely to have multi-focal disease.
Conclusion
We demonstrate that plasma energy ablation has comparable side effects and recurrence rates to carbon dioxide laser therapy in the treatment of vulvovaginal HSIL. Larger prospective studies or randomized controlled trials are needed to better evaluate its long-term efficacy. Ours results suggest that plasma energy ablation may be a reasonable alternative to carbon dioxide laser therapy, particularly in practice areas with limited access to the laser technology.
Data availability statement
Data are available upon reasonable request.
Ethics statements
Patient consent for publication
References
Supplementary materials
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Footnotes
Twitter @amandanfader
Contributors AB and KL were responsible for the conception and data analysis. They were also responsible for data interpretation, along with TM, AF, SW, RS, JSF, and EJT. TM, ON and AA participated in data collection and management. AB, ON and KL drafted the initial manuscript. All authors reviewed and critically revised the manuscript, and all authors approved the manuscript in its final version prior to submission for publication.
Funding The statistical analysis was supported by the Johns Hopkins Institute for Clinical and Translational Research (ICTR) which is funded in part by Grant Number UL1 TR003098 from the National Center for Advancing Translational Sciences (NCATS), a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research. The contents of this article are solely the responsibility of the authors and do not necessarily represent the official view of the Johns Hopkins ICTR, NCATS or NIH.
Competing interests RS reports personal consulting fees from Astra Zeneca and is on an advisory board for GlaxoSmithKline, unrelated to the present work.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.