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 vulvovaginal high-grade squamous intraepithelial lesion (HSIL) treatment.
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-October 2019 at a single institution. Demographic, 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-ranks 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 groups. Fifty percent (n=21) were immunosuppressed, 45.2% (n=19) had prior vulvovaginal HSIL treatment, and 35.7% (n=15) were current smokers. Most (59.5% n=25) women 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 (interquartile range: 11.0 – 45.0 months), recurrence rates were similar: 28.6% in the laser ablation vs. 33.3% in the plasma ablation group (weighted log rank p=0.43; 24-month hazard ratio:0.54; [95% CI:0.15–2.01]).
Conclusion:
Plasma energy ablation of vulvovaginal HSIL has similar complication rates and recurrence risk compared to carbon dioxide laser ablation. This technique could be considered as an alternative treatment modality for vulvovaginal HSIL and warrants further investigation.
INTRODUCTION
The incidence of precancerous lesions of the vulva and vagina is rising, likely driven by human papillomavirus (HPV).1 Formerly designated as vaginal/vulvar intraepithelial neoplasia 1, 2, or 3, these lesions are now classified as low or high-grade squamous intraepithelial lesions (LSIL or HSIL) of the vagina or vulva per the World Health Organization.2 Though data are limited to estimate the global incidence of precancerous lesions, in the United States 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 premenopausal, 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, utilizes a class IV laser which are regulated by The American Safety Network Institute and requires 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 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 the 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 regards to safety and access, patient outcomes have not been extensively studied or compared to 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 to carbon dioxide laser ablation in the treatment of vulvovaginal HSIL.
METHODS
This study was approved by the Johns Hopkins Medicine Institutional Review Board (IRB). 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, MD. Ablative treatments were performed with either the carbon dioxide laser or the PlasmaJet® (Plasma Surgical; Roswell, GA) 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 postoperatively, and surveillance exams every 6 months) were reviewed to identify documentation of complications in the first 45 days postoperatively, including: new-onset dyspareunia, scarring, vaginal stenosis, dysuria unexplained by a urinary tract infection, postoperative infection, severe pain requiring unplanned inpatient admission, or severe pain requiring greater than 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 the Wilcoxon rank-sum tests. The primary outcome was the proportion of women experiencing postoperative complications in the first 45 days postoperative. 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. The 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 vs. 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, TX, USA). An alpha level of 0.05 was used for all statistical tests. In accordance with the journal’s guidelines, we will provide our data for the reproducibility of this study in other centers if such is requested.
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. Median age in the overall cohort was 53.5 years (interquartile range: 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) 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).
Table 1:
Demographic and clinical characteristics of women receiving ablative treatment for vulvar or vaginal high-grade squamous intraepithelial lesions, stratified by ablation type.
| Characteristic | Carbon dioxide laser ablation (n=21) | Plasma energy ablation (n=21) |
|---|---|---|
| Median age at ablation in years | 50.8 (43.2 – 57.6) | 54.5 (43.5 – 62.4) |
| Body mass index at time of ablation (kg/m2) | 28.8 (23.6 – 31.6) | 27.5 (23.7 – 32.7) |
| Racial/ethnicity | ||
| White | 11 (52.4) | 9 (41.9) |
| African American | 6 (28.6) | 10 (47.6) |
| Asian | 2 (9.5) | 1 (4.8) |
| Hispanic | 1 (4.8) | 0 (0.0) |
| Native Hawaiian/Pacific Islander | 0 (0.0) | 1 (4.8) |
| Other | 1 (4.8) | 0 (0.0) |
| Smoking history | ||
| Never smoker | 11 (52.4) | 10 (47.6) |
| Former smoker | 3 (14.3) | 3 (14.3) |
| Current smoker | 7 (33.3) | 8 (38.1) |
| Immunosuppression | ||
| None | 12 (57.1) | 9 (42.9) |
| HIV infection | 4 (19.1) | 4 (19.1) |
| Transplant history | 3 (14.3) | 4 (19.1) |
| Treatment of rheumatologic disease | 1 (4.8) | 3 (14.3) |
| Other | 1 (4.8) | 1 (4.8) |
| History of vulvar squamous cell carcinoma | 1 (4.8) | 3 (14.3) |
| History of cervical HSIL | 6 (28.6) | 13 (61.9) |
| History of cervical carcinoma | 2 (9.5) | 1 (4.8) |
| Indication for ablation | ||
| Vulvar HSIL | 14 (66.7) | 11 (52.4) |
| Vaginal HSIL | 6 (28.6) | 10 (47.6) |
| Both vulvar and vaginal HSIL | 1 (4.8) | 0 (0.0) |
| History of treatment for vulvovaginal HSIL | ||
| None | 12 (57.1) | 11 (52.4) |
| Excision only | 2 (9.5) | 5 (23.8) |
| Laser ablation only | 3 (14.3) | 2 (9.5) |
| Excision and laser ablation | 2 (9.5) | 1 (4.8) |
| Topical therapy alone | 2 (9.5) | 0 (0.0) |
| Excisional, topical +/− laser therapy | 0 (0.0) | 2 (9.5) |
| Concurrent excision of vulvovaginal HSIL | 9 (42.9) | 2 (9.5)* |
| Concurrent excision/ablation of perianal HSIL | 2 (9.5) | 1 (4.8) |
| Follow-up duration (months) | 32.4 (1.2–65.1) | 28.8 (17.3–39.7) |
Data are reported as median (interquartile range) or n (%).
p<0.05
HIV: Human immunodeficiency virus
HSIL: high grade intraepithelial lesion
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 with laser ablation group – 42.9% (n=9) – compared to 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 2 women (9.5%) in the laser group and 1 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 postoperatively. 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 postoperative 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 postoperative infections in the 45 days following ablation.
Table 2:
Complications documented within 45 days post-ablative treatment.
| Complication | Carbon dioxide laser ablation (n=21) N (%) | Plasma energy ablation (n=21) N (%) |
|---|---|---|
| Any complication | 2 (9.5) | 1 (4.8) |
|
| ||
| Persistent dysuria (without infection) | 0 | 0 |
| New-onset dyspareunia | 1 (4.8%) | 0 |
| Scarring causing discomfort | 0 | 0 |
| Postoperative infection requiring intervention | 0 | 0 |
| Pain requiring inpatient management | 0 | 1 (4.8%) |
| Pain requiring medication >30 days postoperative | 1 (4.8%) | 0 |
Recurrence-free survival
The median follow-up duration after ablation was 29.3 months (interquartile range: 11.0 – 45.0 months) in the overall cohort: 32.4 months (interquartile range: 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, comprised of 28.6% (n=6) in the laser group and 33.3% (n=7) in the plasma group. There was no difference in proportion of women who were recurrence-free at 6, 12, 18, or 24 months. (Table 3).
Table 3:
Proportion of women treated with ablation for vulvovaginal HSIL who are recurrence-free and estimated Cox proportional hazard ratios at 6, 12, 18 and 24 months.
| Percent recurrence-free |
|||
|---|---|---|---|
| Time since ablation (months) | Laser ablation | Plasma ablation | Hazard ratio (95% CI) |
| 6 months | 85.7% | 95.0% | 0.35 (0.03–3.90) |
| 12 months | 71.4% | 89.1% | 0.33 (0.06–1.83) |
| 18 months | 64.3% | 76.3% | 0.54 (0.15–2.01) |
| 24 months | 64.3% | 76.3% | 0.54 (0.15–2.01) |
At 12 months, 71.3% of the laser vs. 89.1% of the plasma energy group was recurrence-free (hazard ratio: 0.33 (95% confidence interval (CI): 0.06–1.82)). At 24 months, 64.3% of the laser vs. 76.3% of the plasma group was recurrence-free (hazard ratio: 0.54; 95% CI: 0.14–2.01). 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 vs. 35.5 months for the plasma ablation group.
Figure 1:
Kaplan-Meier survival curve demonstrating recurrence-free survival in laser vs. 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 hazard ratio favored plasma energy ablation (hazard ratio: 0.09, 95%CI: 0.01–0.77), but was based on just 5 total recurrence events, 4 in the laser group and 1 in the plasma group. Additionally, the test of proportional hazards was violated after 12 months and further hazards ratios could not be calculated (see supplementary Table S1 for estimates of hazard ratio on sensitivity analyses and Figure S1 for Kaplan Meier survival curve).
No women developed cancer directly after ablation. However, 5 women (12.2%) ultimately progressed to invasive squamous cell carcinoma cancer after HSIL recurrence, 2 in the laser group and 3 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 a third of patients recurred 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 pruritis, pain, burning, delayed wound healing, infection, and scarring/anatomic distortion.21,22 23 While there is limited data on the adverse effects following plasma energy ablation of vulvovaginal HSIL, one study reported that the only complication in 1 of 8 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 1 patient experiencing dyspareunia and the other requiring long-term medication. The pain experienced by the 1 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 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 20–50%, 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, and immunosuppression, and multifocal or large lesions.20 A recent systematic review demonstrated that 23% of women recurred 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 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 not in fact differential treatment effects on short vs. 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 two techniques’ longer term (> 1–2 year) outcomes, the median follow-up time for the study was over two years. There are few studies of ablation techniques with similar follow-up rates greater than two 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 record 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 compared 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 indicated 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 also has comparable side effects and recurrence rates 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.
Supplementary Material
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
Acknowledgements:
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 statement:
None of the authors declare any competing interests. Dr. Rebecca Stone reports personal consulting fees from Astra Zeneca and is on an advisory board for GlaxoSmithKline, unrelated to the present work.
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