Materials and Methods
Twelve white women with biopsy-proven vulvar lichen sclerosus and pronounced pruritus were recruited for this prospective, single-arm pilot study between October 1995 and January 1997. Three of the 15 patients eligible for the study preferred corticoid therapy and were excluded. The study was approved by the university ethical committee, and informed consent was obtained. The mean age was 55 years (range 24–80). Patients who were taking any medication for lichen sclerosus or who had malignancies, cardiovascular disease, or diabetes were excluded. A gynecologic examination including determination of vulvar and cervical cytology was done and results of pregnancy tests in women under age 50 were negative.
5-Aminolevulinic acid was obtained as a solid (hydrochloride form) from Merck KGaA (Darmstadt, Germany). Immediately before use, a 20% solution (weight to weight) was prepared by dissolving the 5-aminole-vulinic acid in sterile 0.9% saline containing propylene glycol and adjusting pH to 5.5 using sodium hydrogen bicarbonate. Ten milliliters of the 20% solution of 5-ami-nolevulinic acid was applied topically to the vulva. After 4–5 hours, fluorescence of 5-aminolevulinic acid–induced porphyrins was seen on the vulva under a short-arc xenon lamp at 390–440 nm with output power of 200 mW (D-Light; Karl Storz GmbH, Tuttlingen, Germany). The skin was viewed through a yellow filter to select an emitted wavelength range of 470–700 nm. Photodynamic therapy was done using an argon ion–pumped dye laser (Lambda Plus; Coherent GmbH, Dieburg, Germany) that emitted light with a 635-nm wavelength (maximum output power 2.1 W). Laser light was coupled into a 600-μm flexible fused silica fiber. Each patient's entire vulva was treated with total irradiation of 80 J/cm2 and with irradiances limited to 70 mW/cm2 to avoid thermal effects. After treatment, a cream base was prescribed (Linola; Dr. A. Wolff GmbH, Bielefeld, Germany).
Patients were monitored for local and systemic toxicity and therapeutic effect on day 1, at 6–8 weeks, and every three months, or whenever symptoms recurred and further therapy was necessary. Patients with persistent pruritus were offered a second cycle of photodynamic therapy after 1–3 weeks. A horizontal visual analog scale was used to evaluate the degree of pruritus or burning caused by lichen sclerosus (0 = no complaints, 1 = slight pain, 2 = moderate pain, and 3 = strong pain). Differences between pretreatment and therapeutic indices were calculated by the Wilcoxon matched-pairs signed-rank test using SPSS software (SPSS for Windows 7.5; SPSS Software GmbH, Munich, Germany). Statistical significance was fixed at P < .05. Results are expressed as observed means ± standard deviation.
Photodynamic therapy incorporating topically applied 20% 5-aminolevulinic acid produced symptomatic relief of vulvar lichen sclerosus in ten of the 12 patients (Figure 1). Two women underwent two cycles of photodynamic therapy, one woman underwent three cycles, and the remaining nine women underwent one cycle each. At the 6- to 8-week follow-up examination, we saw a statistically significant reduction (P < .01) in the visual analogue scale for symptoms. The mean values for pruritus decreased from 2.6 ± 0.4 to 1.0 ± 0.6. At 6-month follow-up, seven of ten women still had symptomatic relief. The duration of symptom reduction was 3–9 months (mean 6.1).
In two premenopausal women, three cycles of photodynamic therapy improved clinical appearance, with complete reduction of itching and soreness. However, there was no improvement in clinical appearance in ten of the 12 women. Eight of these ten women were postmenopausal and had advanced vulvar lichen sclerosus at the time of treatment. The time between applying 20% 5-aminolevulinic acid cream to the vulva and administering photodynamic therapy was 4–6 hours. Shorter times produced insufficient 5-aminolevulinic acid–induced protoporphyrin IX fluorescence. We saw a high porphyrin-specific background fluorescence in all patients, in the region of the hymenal vault and distal vagina.
Depending on the size of the area requiring irradiation, exposure of up to 40 minutes was necessary to reach total irradiation of 80 J/cm2 by using an irradiance between 40 and 70 mW/cm2. All patients reported a burning sensation during the procedure, although the actual temperature of the vulvar skin was not elevated during photodynamic therapy. Three of the 12 patients asked for a break during the treatment, and intravenous opioids were required in three other patients. One patient had adhesions of the clitoris and anterior introitus, which were separated under general anesthesia. No patient had local necrosis or ulcerations in the treatment field. The principal complaint of five of the 12 patients was mild, burning discomfort of the irradiated skin 4–8 hours after photodynamic therapy. Women with fair complexions tended toward more pronounced erythema. Erythema tended to disappear after 1–3 days. Systemic effects and generalized cutaneous photosensitization did not occur, and no shielding against light exposure was necessary after therapy. Two or three cycles of photodynamic therapy, incorporating topical 5-aminolevulinic acid application and done in 1- to 2-week intervals, did not lead to cumulative or increased side effects. No long-term alterations of the skin, such as scarring, pigmentation, or nonhealing erosion, were observed.
Our results show that photodynamic therapy with pretreatment with 5-aminolevulinic acid relieves the symptoms of vulvar lichen sclerosus. Ten of 12 women had significant reductions in symptoms, documented using the visual analog scale, after photodynamic therapy, and relief of symptoms lasted for 3–9 months. The majority of patients in our series were postmenopausal and presented with advanced stages of vulvar lichen sclerosus. Clinical evaluation 6–8 weeks after therapy showed only minor improvement in the gross appearance of the vulva. Our study protocol did not require biopsies after treatment. The effect of photodynamic therapy at the microscopic level is unknown. The conversion to protoporphyrin IX on topical application of 20% aminolevulinic acid on the vulva is not specific to lichen sclerosus and is seen also in normal vulvar skin after 4–5 hours. Thus, photodynamic therapy might be useful in a variety of other disorders of the vulva, eg, vulvodynia, lichen ruber, or vulvar psoriasis.
Only minor short-term side effects of local erythema were seen after therapy. Treatment with up to three cycles of photodynamic therapy at weekly intervals did not increase side effects but did result in marked improvement of clinical features and made sexual intercourse possible for one young patient. Further study is needed to determine whether multiple treatment cycles of photodynamic therapy might lead to significant reduction in severity of clinical and histologic features in older patients.
Different treatments have been used to manage vulvar lichen sclerosus, including corticosteroids, testosterone, progesterone, estrogens, and operative methods such as laser therapy, cryosurgery, and vulvectomy. The usefulness of topical testosterone for treating vulvar lichen sclerosis is controversial.3,10 Topical testosterone therapy can have metabolic side effects that require individualized dosage and close clinical control, with evaluation of serum testosterone to prevent virilization.11 Recent studies indicate that potent topical steroid clobetasol propionate has good therapeutic effect and might be the therapy of choice for vulvar lichen sclerosus.2,3 Systemic side effects of clobetasol propionate therapy have not been reported to date.12 However, about 25% of patients do not respond to clobetasol treatment, and contact dermatitis is well documented.13 Physicians and patients are concerned that potent topical steroids might cause epidermal atrophy and predispose patients to secondary infections.
There is a need for a reliable, nonsteroidal, therapeutic alternative to topical testosterone and clobetasol. Our results suggest that photodynamic therapy using 5-aminolevulinic acid as a photosensitizer is a novel alternative treatment for vulvar lichen sclerosus. Local cytotoxic effects are minimal, and generalized cutaneous photosensitization is absent. According to our data, there will be a recurrence of the symptoms of the lichen sclerosus after photodynamic therapy; however, this chronic disease will recur in most cases regardless of treatment, even wide vulvectomy. Therefore, we should be as cautious as possible with any destructive therapy. Photodynamic therapy using 5-aminolevulinic acid can be performed safely and repeatedly on an outpatient basis because it is less destructive than even a carbon dioxide laser and it preserves the integrity of the vulvar skin.
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