Obstetrics & Gynecology

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Obstetrics & Gynecology:
Original Research

Photodynamic Therapy of Vulvar Lichen Sclerosus With 5‐Aminolevulinic Acid

HILLEMANNS, PETER MD; UNTCH, MICHAEL MD; PRÖVE, FLORIAN; BAUMGARTNER, REINHOLD PhD; HILLEMANNS, MARIJA MD; KORELL, MATTHIAS MD

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Author Information

Department of Obstetrics and Gynecology and the Urology Laser Research Laboratory, Klinikum Grosshadern, Ludwig-Maximilians-University, Munich; and the Institute of Pathology, Technical University of Munich, Munich, Germany.

Address reprint requests to: Peter Hillemanns, MD, Klinik und Poliklinik für Frauenheilkunde, Klinikum Grosshadern, Ludwig-Maximilians-Universität, 81377 Munich, Germany; E-mail: peter.hillemanns@t-online.de

This study was supported by the Bundesministerium für Forschung und Technologie (BMBF no. 0706903A5).

Dr. Peter Hillemanns was supported in part by a grant from the Friedrich Baur Stiftung.

Received March 25, 1998. Received in revised form June 26, 1998. Accepted July 9, 1998.

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Abstract

Objective: To evaluate the therapeutic effect of photodynamic therapy on vulvar lichen sclerosus.

Methods: Twelve women with lichen sclerosus were enrolled in a prospective, single-arm pilot study. Four to 5 hours before photodynamic therapy, 10 mL of a 20% solution of 5-aminolevulinic acid was applied topically to the vulva. Photodynamic therapy was administered with an irradiation of 80 J/cm2 at an irradiance of 40–70 mW/cm2. Light with a wavelength of 635 nm was delivered by an argon ion–pumped dye laser. The degree of pruritus was evaluated using a horizontal visual analog scale before and after 6–8 weeks, and patients were followed tri-monthly after photodynamic therapy.

Results: Two women underwent two cycles of photodynamic therapy, one underwent three cycles, and the remaining nine women underwent one cycle each. Treatment was tolerated moderately well, with eight patients not requiring any analgesia; three treated with opioids intravenously during the procedure, due to burning sensations; and one undergoing separation of adhesions under general anesthesia. Minimal local toxicity included vulvar erythema but no necrosis, sloughing, or scarring. No generalized cutaneous photosensitivity was present. Six to 8 weeks after photodynamic therapy, pruritus significantly improved in ten of the 12 women. A prolonged effect of photodynamic therapy was reported, with a mean of 6.1 months.

Conclusion: Photodynamic therapy after topical application of 5-aminolevulinic acid produced statistically significant relief of symptoms of vulvar lichen sclerosus for an average of 6.1 months with minimal side effects.

Vulvar lichen sclerosus is a nonneoplastic dermatosis of uncertain etiology, with exact prevalence unknown,1 that affects predominantly postmenopausal white women, who present with vulvar pruritus or burning and pale white, sclerotic changes of the vulvar skin. In advanced cases, atrophy of the labia majora and occasional introital stenosis with clitoral adhesions can develop. Over the last several years, the preferred method of treatment of vulvar lichen sclerosus has changed. In the past, lichen sclerosus usually was treated with long-term application of either testosterone or progesterone, but more recently, topical high-potency corticosteroids have become the primary treatment.2,3 A few patients with lichen sclerosus do not respond adequately to topical therapy or do not wish to use topical steroids on a long-term basis. Therefore, new therapies are needed.

Photodynamic therapy is a relatively new technique with unique properties that make it good for local treatment of superficial epithelial disorders. It combines nonthermal laser-derived irradiation of the skin and photosensitizers, such as 5-aminolevulinic acid–induced protoporphyrin IX. Several studies4,5 found that initial interaction of light with the drug generates singlet oxygen and oxygen radicals, such as superoxide or hydroxyl radicals, which are highly reactive oxidants. The photodynamic effect might cause a light-induced cytotoxic effect.6 Photodynamic therapy is a minimally invasive procedure that can be done with or without local anesthesia in office or clinical practice settings. It is less damaging to normal tissue than surgery, radiation, or chemotherapy. The lack of cumulative effects following photodynamic therapy allows for repeat treatments on new, partially responding, or recurrent lesions. Photodynamic therapy has been effective on various neoplastic epithelial lesions, including basal cell carcinoma of the skin, premalignant lesions of the oral cavity, and high-grade dysplasia of Barrett's esophagus.7–9

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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.

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Results

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).

Figure 1
Figure 1
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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.

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Discussion

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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References

1. Wilkinson EJ. Benign diseases of the vulva. In: Kurman RJ, ed. Blaustein's pathology of the female genital tract. New York: Springer-Verlag, 1994;31–86.

2. Dalziel KL, Millard PR, Wojnarowska F. The treatment of vulval lichen sclerosus with a very potent topical steroid (clobetasol propionate 0.05%) cream. Br J Dermatol 1991;124:461–4.

3. Cattaneo A, Carli P, De Marco A, Sonni L, Bracco G, De Magnis A, et al. Testosterone maintenance therapy: Effects on vulvar lichen sclerosus treated with clobetasol propionate. J Reprod Med 1996;41:99–102.

4. Weishaupt KR, Gomer CJ, Dougherty TJ. Identification of singlet oxygen as the cytotoxic agent in photo-inactivation of a murine tumor. Cancer Res 1976;45:2326–9.

5. Willson R. Free radicals, oxygen and radiosensitizing drugs: A very brief introduction. In: Rodgers MAJ, Powers EL, eds. Oxygen and oxy-radicals in chemistry and biology. New York: Academic Press, 1981;309–20.

6. Ochsner M. Photophysical and photobiological processes in the photodynamic therapy of tumours. Photochem Photobiol 1997;39:1–18.

7. Kennedy JC, Pottier RH. Endogenous protoporphyrin IX, a clinically useful photosensitizer for photodynamic therapy. J Photochem Photobiol 1992;14:275–92.

8. Fan KFM, Hopper C, Speight PM, Buonaccorsi G, MacRobert AJ, Bown SG. Photodynamic therapy using 5-aminolevulinic acid for premalignant and malignant lesions of the oral cavity. Cancer 1996;78:1374–83.

9. Regula J, MacRobert AJ, Gorchein A, Buonaccorsi GA, Thorpe SM, Spencer GM, et al. Photosensitation and photodynamic therapy of oesophageal, duodenal, and colorectal tumours using 5 aminolaevulinic acid induced protoporphyrin IX—A pilot study. Gut 1995;36:67–75.

10. Sideri M, Origoni M, Spinaci L, Ferrari A. Testosterone in the treatment of vulvar lichen sclerosus. Int J Gynaecol Obstet 1994;46:53–6.

11. Joura EA, Zeisler H, Bancher-Todesca D, Sator MO, Schneider B, Gitsch G. Short-term effects of topical testosterone in vulvar lichen sclerosus. Obstet Gynecol 1997;89:297–9.

12. Dalziel KL, Wojnarowska F. Long-term control of vulval lichen sclerosus after treatment with a potent topical steroid cream. J Reprod Med 1993;38:25–7.

13. Bracco GL, Carli P, Sonni L, Mestrini G, De Marco A, Taddei GL, et al. Clinical and histologic effects of topical treatment of vulval lichen sclerosus. A critical evaluation. J Reprod Med 1993;38:37–40.

© 1999 The American College of Obstetricians and Gynecologists

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