Obstetrics & Gynecology:
Surgical Treatments for Vulvar and Vaginal Dysplasia: A Randomized Controlled Trial
von Gruenigen, Vivian E. MD1,2; Gibbons, Heidi E. MS1; Gibbins, Karen BS2; Jenison, Eric L. MD3; Hopkins, Michael P. MD3
From the 1Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University Hospitals Case Medical Center and 2Department of Reproductive Biology, Case School of Medicine, Cleveland, Ohio; and 3Northeastern Ohio Universities College of Medicine (NEOUCOM), Rootstown, Ohio.
Presented in part at the Annual Clinical Meeting of the American College of Obstetricians and Gynecologists, Philadelphia, Pennsylvania, May 1–5, 2004.
Corresponding author: Vivian E. von Gruenigen, MD, University Hospitals Case Medical Center, Division of Gynecologic Oncology, 11100 Euclid Avenue, Room 7128, Cleveland, OH; e-mail: vivian.vongruenigen@UHhospitals.org.
OBJECTIVE: To compare pain, adverse effects and recurrence of dysplasia in patients with vaginal intraepithelial neoplasia or vulvar intraepithelial neoplasia prospectively treated by carbon dioxide laser or ultrasonic surgical aspiration.
METHODS: Patients were randomly assigned to receive treatment by laser or ultrasonic surgical aspiration from 2000–2005. Preoperative biopsy was done to confirm presence of dysplasia. Patients completed a visual analog scale regarding pain and were evaluated at 2–4 weeks to assess scarring, wound healing, and adverse effects. Patients returned every 3 months for 1 year for pelvic examination and cytology to assess recurrence. Follow-up colposcopy and biopsy were used at the discretion of the treating physician. Student t test, χ2, analysis of variance and multiple logistic regression were used for analysis.
RESULTS: One hundred ten patients were randomly assigned. Ninety-six (87.3%) patients completed 1 year follow-up. Mean age of patients was 48.5 years. Mean visual analog scale score was significantly lower in patients treated by ultrasonic surgical aspiration (20.7 compared with 35.1; P=.032). For patients with vulvar lesions, there was less scarring with ultrasonic surgical aspiration (P<.01). Recurrence overall was 25% and was similar for ultrasonic surgical aspiration compared with laser (relative risk 0.96, 95% confidence interval 0.64–1.50, number needed to treat 95.6). Recurrence was associated with younger age (P<.01).
CONCLUSION: Patients treated with ultrasonic surgical aspiration for vulvar and vaginal dysplasia reported less postoperative pain. Vulvar scarring was more common in patients treated by the laser. There was no difference in recurrence of dysplasia during a 1-year follow-up period between the two surgical modalities.
CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00394758
LEVEL OF EVIDENCE: I
The prevalence of human papillomavirus (HPV), associated with sexually transmitted disease, has led to increased risk of genital tract dysplasias and cancer.1 As the incidence of dysplasia has increased, new therapeutic approaches to prevent preinvasive disease from progressing into cancer have been developed. However, the first line of treatment for vulvar intraepithelial neoplasia (VIN) and vaginal intraepithelial neoplasia (VAIN) is not well defined.2–4
Quality-of-life factors in relation to treatment have become increasingly important to patients, particularly to the younger population with this disease.5 Genital dysplasias may be treated with surgery or with topical medical therapy. Upper vaginectomy is a common treatment for higher-grade VAIN, due to the low rates of recurrence.3,6 Similarly, wide local excision is used to treat VIN.4,7,8 Although these incisional surgical procedures are highly effective at excising the dysplasia, adverse effects may include pain, postoperative complications, and physical deformity. Topical creams such as 5-fluorouracil (5-FU) and imiquimod may be incorporated into the treatment of VIN and VAIN, decreasing the need for surgery. With this approach, recurrence rates are high and the common adverse effects of pruritus and burning reduce patient compliance9–12 to these topical therapies. Although widely accepted, they do not have U.S. Food and Drug Administration (FDA) approval for use in lower genital tract dysplasia.13
Carbon dioxide (CO2) laser ablation remains a popular conservative surgical treatment for VIN and VAIN. Reported recurrence rates with this approach range from 25–50%.14–21 This outpatient treatment typically preserves sexual function with minimal adverse effects. Ultrasonic surgical aspiration is a more recent technique and is used commonly for intraoperative tumor debulking of ovarian cancer.22 The use of ultrasonic surgical aspiration in VAIN and VIN allows for the selective removal of diseased tissue while preserving the surrounding normal tissue and providing a specimen that can be sent to cytology for pathologic examination.22–24 More recent research suggests that recurrence of genital tract dysplasia treated with ultrasonic surgical aspiration may be similar to the laser, with recurrence rates that vary between 22% and 35%.24,25
Because both techniques are accepted surgical ablative modalities used in the treatment of vulvar and vaginal dysplasias, our objective was to compare recurrence rates during a 1-year follow-up period between the two surgical modalities and to compare postoperative adverse effects and pain.
MATERIALS AND METHODS
Patients at University Hospitals Case Medical Center (Cleveland, OH) and NEOCUOM consortium hospitals, Akron General Medical Center, Summa Health System (Akron, OH), and Aultman Hospital (Canton, OH) with vulvar or vaginal dysplasias were asked to participate in the study from 2000 to 2005. Eligibility criteria included preoperative pathologic documentation to confirm the presence of dysplasia. All patients were seen preoperatively and treated by one of three gynecologic oncologists. Patients who were aged younger than 18 years or pregnant were not eligible for the study. Patients with dysplasia of grade 3/carcinoma in situ were included at the discretion of the treating surgeon.2,7,16,19 The study protocol was approved by the institutional review boards at all participating hospitals. Women were enrolled in the study by their treating physician and provided informed consent before being randomly assigned to one of the treatment modalities: CO2 laser vaporization or ultrasonic surgical aspiration. Age (50 years or younger and older than 50 years) and site location were used as stratification variables in the randomization assignment. Blocked randomization was carried out by a computer-generated table of random numbers corresponding to treatment assignment. Randomization assignment was given to the treating physician by personnel not involved in the patient’s medical care.
At the time of enrollment, race, marital status, tobacco use, history of sexually transmitted infection, diethylstilbestrol exposure, immunodeficiency, hysterectomy, history of genital tract neoplasia, and previous treatment were recorded. Cytology of the ultrasonic surgical aspiration aspirations were obtained from surgery if available. Human papillomavirus DNA was not collected, because the technology was not available at all institutions at the beginning of the study.
Carbon dioxide laser surgery was performed with the carbon dioxide laser. Depth of tissue destruction was 2 mm vaginally, 1 mm in nonhairy vulvar regions and 3 mm in hairy vulvar regions.19,20 Ultrasonic surgical aspiration was performed with the Cavitron Ultrasonic Surgical Aspirator Excel System (Valleylab, Boulder, CO). The handheld tool vibrates and contains separate irrigation and suction channels. Lesions were removed to the reticular layer of the dermis.23,26
Surgeries were performed in an outpatient setting, with patients given standard discharge instructions regarding postoperative care. The use of topical postoperative symptom control therapies (for example, silver sulfadiazine) were ordered at the discretion of the attending physician. One week after surgery, patients completed a postoperative pain assessment by using a visual analog scale pain scale.27 Patients were seen 2–4 weeks after surgery for follow-up to assess scarring, wound healing, and postoperative adverse effects. Scarring was assessed subjectively at the patient’s postoperative visit to maintain patient compliance. Patients were seen every 3 months for 1 year for physical examination and cytology to assess recurrence. Follow-up colposcopy and biopsies were used at the discretion of the attending physician.
We estimated initially that approximately 37.5% of patients receiving the laser surgery would experience recurrence within the 1-year period. A sample size estimate of 50 patients per group would provide 80% power to detect a decrease in this percentage of 66% or more to approximately 12% in the ultrasonic surgical aspiration group (alpha=0.05, two-tailed test). An additional 10 patients were enrolled (10%) to account for noncompliance and lost to follow-up. This study was designed and powered to test the hypothesis that there was a large difference in recurrence between the two surgical treatments and to assure adequate numbers to test the secondary objectives of pain and complications. Baseline demographic and clinical characteristics were compared between randomization groups by Student t test and χ2 comparison of proportions. Adverse effects were compared between groups by χ2 test. Analysis of recurrence during the 1-year follow-up period was performed using χ2 test and multiple logistic regression analysis. Statistical analysis of visual analog scale scores included Student t test and two-way analysis of variance. All analysis was performed using SPSS 14.0 (SPSS, Inc., Chicago, IL).
One hundred twenty-two women were invited to participate in this prospective study. One hundred ten women were enrolled and randomly assigned to laser or ultrasonic surgical aspiration surgical treatment. Ninety-six women completed the 1-year follow-up end point (87.3% overall). The flow of participants is shown in Figure 1. Fourteen patients (12.7%) were lost to follow-up during the course of the study. Clinical and demographic characteristics of patients completing the study by group are displayed in Table 1 (N=96). There were no differences between groups or between patients who completed the study compared with those who were noncompliant or lost to follow-up. The average age of patients was 48.5±1.3 years (range 18–82 years). The majority of patients had a prior hysterectomy and multifocal disease. Five patients were immunosuppressed. Sixteen patients had both vulvar and vaginal procedures.
Adverse effects between the intervention groups were similar, including minor genital complaints of infection, dysuria, burning, adhesions, and discharge (Table 2, N=96). Patients who were treated for both vulvar and vaginal lesions were classified according to their primary disease location per attending physician. Differences in adverse effects and postoperative complaints were stratified for VAIN and VIN; however, statistical comparisons were made overall by laser or ultrasonic surgical aspiration because there were small numbers for subgroup comparisons. Presence of scarring was measured in vulvar patients only, and there was less scarring with the ultrasonic surgical aspiration (P<.01). Pain (overall in VIN and VAIN patients combined) was decreased in patients treated by ultrasonic surgical aspiration as compared with laser (P=.032, Table 2). Two-factor analysis of variance revealed that patients with VAIN had less pain than VIN patients (mean 15.8 compared with 42.2; F=18.6, P<.01 for group effect). There was no evidence of an interaction effect (P=.61).
Overall recurrence rates for laser compared with ultrasonic surgical aspiration were similar (Table 3, N=96). Recurrence during the year after surgery was 24.4% with the ultrasonic surgical aspiration and 25.5% with the laser (relative risk 0.96, 95% confidence interval 0.64–1.50, number needed to treat 95.6). Recurrence rate was higher in VIN patients than in VAIN patients overall, regardless of treatment (16 of 44 [36.4%] compared with 8 of 52 [15.4%]; P=.018). Patients with VIN were younger (mean 53.7±1.59 compared with 42.3±1.94; 95% confidence interval of the difference 6.5–16.4; P<.001) and were more commonly smokers (27 of 44 [61.4%] compared with 17 of 52 [32.7%]; P=.001). Recurrence by surgical treatment in these two subgroups was similar; however power to detect a difference was low. Fifty-three percent of patients treated in this study had received prior therapy for intraepithelial disease (Table 1). There was no difference in the incidence of recurrence after surgical therapy between patients treated for new disease compared with recurrent disease. During the 1-year follow-up period, 24 patients demonstrated recurrence of disease, seven (29.2%) of whom demonstrated persistent disease at their first follow-up visit. All cytology aspirations from the ultrasonic surgical aspiration procedure were within one grade of cytology, with no invasive cancers found, thus this did not change management decisions. All surveillance biopsies after surgery correlated with vaginal Pap tests.
Analysis of recurrence or persistence of disease by multiple logistic regression showed age to be significantly associated with recurrence (Table 4). Disease location, grade, prior history of dysplasia, and smoking history were not significantly associated with recurrence when controlling for age.
Human papilloma virus is the most common sexually transmitted disease and leads to an increased risk of vulvar and vaginal condylomas, dysplasias, and cancer. Both vulvar and vaginal dysplasias may be treated by surgical excision, laser, electrocoagulation, or ultrasonic surgical aspiration. Vulvar intraepithelial neoplasia has also been treated with imiquimod, despite not having FDA approval.11,13 In addition, VAIN has been treated by 5-FU or radiation.28,29 Other times, clinicians may use multiple treatment combinations, for example, laser of the vagina followed by 5-FU.29 Cosmetic concern and pain are important issues for women with a disease that is naturally prone to recurrence and may even affect quality of life.5 The future implementation of the HPV vaccine may decrease the incidence; however, the presently exposed population will need treatment of genital dysplasias for years to come. This prospective randomized trial of CO2 laser compared with ultrasonic surgical aspiration revealed that scarring and pain were decreased with the ultrasonic surgical aspiration; however, there were no differences in recurrence rates.
Even though VIN is more common than VAIN, it seems as though the risk factors, treatment, and recurrence rates are similar despite some differences in treatment.2,3 Recurrence rates range from approximately 10–50%, with lower recurrence rates in those receiving surgical excision.3,21,24,25 The adverse effect profile to any therapy is imperative when multiple choices are available to the clinician. Most studies evaluating the treatment of VIN and VAIN have been remiss in prospectively evaluating patient symptoms. Since the initiation of this protocol, improved measures have been developed to measure symptoms and quality of life.30 Treatment of VAIN and VIN may be complicated by pain, delayed wound healing, scarring, discharge, ulceration, vaginal shortening or stenosis, and sexual dysfunction.14,16,21,25,28,29 In this study there were statistically significant differences favoring the ultrasonic surgical aspiration for less scarring and pain.
The differences in scarring and pain may be related to the surgical tool. The depth of tissue destruction with the laser is operator dependent. Because VIN and VAIN are confined to 0.1 to 0.3 mm of surface epithelium, the laser may unnecessarily remove tissue deep to this layer, causing increased pain.19 Safeguards for the use of laser on the genital tract include brushing the epithelial surface followed by peeling the eschar with gauze, setting the laser on superpulse, and using a hand-held depth gauge to assess depth manually. The ultrasonic surgical aspiration may decrease depth damage secondary to enhancing the cleavage plain and resulting in the separation of the epithelium without disruption of the underlying stroma.26 The device aspirates the cells; therefore, peeling with gauze is unnecessary. The ultrasonic surgical aspiration does not work well below the surface epithelium, allowing an easier dissection plan. In addition, the ultrasonic surgical aspiration may provide less adjacent epithelial damage.26
Our study does not have the power to state that there is no difference in recurrence rate of dysplasia between the two modalities. However, with the available data it seems that if there are differences, they are minimal. We included vulvar and vaginal dysplasias for the power analysis, because the causes and treatments were similar. In addition, our recurrence rate may have increased with longer follow-up; however, we anticipate that this rate would be similar for both treatment groups.
Our results indicated that the ultrasonic surgical aspiration is less painful and has less scarring when compared with the laser and is the treatment of choice between the two modalities. Future studies should include standard measures for adverse effects and to measure quality of life.30
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© 2007 by The American College of Obstetricians and Gynecologists.
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