Photodiagnosis and Photodynamic Therapy (2005) 2, 157—160

Therapeutic effects of 5-ALA-induced photodynamic therapy in vulvar lichen sclerosus Tomasz Biniszkiewicz MD, PhD a,∗, Anita Olejek b, Iwona Kozak-Darmas b, Aleksander Siero´ na a

Chair and Clinic of Internal Diseases, Angiology and Physical Medicine, Silesian Medical University, ul. Batorego 15, 41-902 Bytom, Poland b Chair and Clinic of Gynaecology and Obstetrics, Silesian Medical University, ul. Batorego 15, 41-902 Bytom, Poland

KEYWORDS Vulvar lichen sclerosus; Photodynamic diagnosis; Photodynamic therapy

Summary Background: Lichen sclerosus (LS) is a rarely diagnosed, chronic inflammatory skin and mucosal condition. Its therapy is difficult and frequently not satisfactory. The data on photodynamic therapy (PDT) of vulva are promising but scanty. The aim of our study was to evaluate the therapeutic efficacy of photodynamic therapy in genital LS in women. Methods: Twenty-four patients with clinical and histopathological diagnosis of lichen sclerosus accompanied with chronic vulvar itching, lasting between 3 months and 11 years, with human papillomavirus (HPV), bacterial and mycotic infections excluded, received three to six PDT cycles (180 J, 700 mW/cm2 ) in 14 days long intervals. Simultaneously they received no topical corticosteroids. Photodynamic diagnosis (PDD) was conducted prior to therapy and 4 weeks after its completion. Results: In 17 patients, the itching ceased completely, in 6 women it decreased, in 1 patient the itching continued, none of the patients presented exacerbation of itching. PDD after completion of therapy revealed in 10 patients normal, green fluorescence of vulva and in 14 women pathological, red fluorescence, usually fainter than before PDT. Conclusion: PDT is an effective therapeutic modality for chronic itching in lichen sclerosus. © 2005 Elsevier B.V. All rights reserved.

Introduction Lichen sclerosus (LS) is a rarely diagnosed, chronic inflammatory skin and mucosal condition, ∗ Corresponding author. Tel.: +48 32 7861630; fax: +48 32 7861630. E-mail address: [email protected] (T. Biniszkiewicz).

described for the first time by Hallopeau in 1878 [1]. Its ethiopathology remains unknown. There is, however, a strong association with autoimmune disorders and immunogenetic studies have demonstrated a link with HLA DQ7 [3]. There have been reports of family members with LS; thus, it may have a genetic link. There are also suggestions of involvement of infectious factors in its origin, such

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158 as atypical mycobacteria, viruses and spirochetes (particularly Borrelia burgdorferi) [2]. Dysfunction of 5-alpha-reductase in the skin is to be another factor predisposing to LS. Lichen sclerosus often coexists with other autoimmunologic morbidities such as vitiligo, type 1 diabetes mellitus or Graves—Basedow disease [3]. Lichen sclerosus affects both women and men of all ages, but occurs most frequently in elderly women. Any area of skin of both sexes may be affected, most commonly lichenic efflorescences origin in female anogenital region. Other frequent localizations are nape and upper areas of thorax. The efflorescences present as papules of different size, irregular, often polygonal, flat, porcelainwhite. The primary papules occur as single or aggregated and then create irregular lamellae, followed by atrophic scars. The skin changes are usually multiple and vast. LS can present itself in a clear form or can be accompanied by hypertrophy, dysplasia or invasive cancer. Clinical symptoms of lichen sclerosus include chronic itching, burning during micturition, inability of sexual intercourses and increased sensibility of vulvar epithelium to inconsiderable mechanical injuries. The long-term sequels of LS include scarring, malignancies and psychosexual dysfunction. The risk of developing squamous cell carcinoma of the vulva approaches 5% in women with vulgar lichen sclerosus [4,5]. The main risk factor for the squamous cell carcinoma of vulva in patients with LS is the squamous hyperplasia in histopathological examination [8]. It is unclear whether the risk of malignancy is changed with the use of corticosteroids, which can trigger a latent infection of human papillomavirus (HPV). Lichen sclerosus presents a therapeutic challenge. Traditional medical management includes potent topical corticosteroids [6]. Other treatments that have been utilized for this condition include testosterone, progesterone, tacrolimus, 5fluorouracil, retinoids, piascledine, surgery and cryosurgery, carbon dioxide laser therapy [4,6—8]. None of these therapies seems to be enough effective. Surgery should be reserved for symptomatic patients who fail to respond conservative treatment. Surgery is followed by a high rate of recurrences. There is still great need for novel treatment strategies for LS. Photodynamic therapy (PDT) with 5-aminolevulinic acid (ALA-PDT) is a well-established treatment regimen for superficial, epithelial, non-melanotic skin tumors, as well as for inflammatory diseases of the skin and virus-induced lesions [9—11]. The list of possible indications for PDT in this area includes basal cell carcinoma, Bowen’s disease, actinic keratosis, Kaposi’s sarcoma, mycosis fun-

T. Biniszkiewicz et al. goides, skin metastases, psoriasis, HPV-induced conditions, such as verrucae vulgares and condylomata accuminata, vascular malformations and acne vulgaris. The data on photodynamic therapy of vulva are promising but scanty. Wang et al. [12] reached the complete response rate of 95% and the recurrence rate of 5% after 6—24 months of follow-up in 164 patients with urethral condylomata acuminta, including 16 individuals with penile or vulval condylomatous lesions. Fehr et al. [13] treated 16 patients for condyloma and the complete clearance rate was 66%. There are a few reports on treatment of vulvar intraepithelial neoplasia with 5-aminolaevulinic acid-based photodynamic therapy. Fehr et al. [14] reached 73% of patients disease free 8 weeks after 5-ALA PDT (11 of 15 patients) and three recurrences within the first year of follow-up. Hillemanns et al. [15] reported a complete response in 13 of 25 women with VIN 3, but only in 4 of 15 women with multifocal disease. Kurwa et al. [16] failed to reach response in six patients with persistent VIN 3. Hillemanns et al. [17] enrolled 12 women with lichen sclerosus in a prospective, single-arm pilot study. Four to five hours after topical application of 10 mL of a 20% solution of 5-ALA photodynamic therapy was administered with an irradiation of 80 J/cm2 at an irradiance of 40—70 mW/cm2 . The degree of pruritus was evaluated before and after 6—8 weeks and patients were followed tri-monthly after photodynamic therapy. The patients underwent one to three cycles of PDT. Six to eight weeks after PDT, pruritus significantly improved in 10 of the 12 women. A prolonged effect of photodynamic therapy was reported, with a mean of 6.1 months. In polish material [18], three patients with vulvar lichen sclerosus were photosensitized with 20% 5-aminolevulinic acid paste 4—5 h prior to PDT and irradiated with halogen lamp (630 ± 20 nm) with total energy dose of 120 J/cm2 . Every patient received two cycles of therapy. One of three patients felt considerable improvement, in the other two patients the itching of vulva ceased completely. The aim of our study was to evaluate the therapeutic efficacy of photodynamic therapy in genital LS in women.

Materials and methods We treated 24 patients, with clinical and histopathological diagnosis of lichen sclerosus accompanied with chronic vulvar itching. The histopathological diagnosis was never older than

Therapeutic effects of 5-ALA-induced photodynamic therapy in vulvar lichen sclerosus 6 weeks. Chronic vulvar itching duration ranged from 3 months to 11 years. All of the women were Caucasian, mean age 58. Most of them presented with multifocal lesions. Prior to therapy, all the patients signed informed consent. The study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki. There were no general exclusion criteria, except for known neoplastic diseases of female reproductive organs. Also the vulvar HPV infection was excluded in all the women by means of QRT-PCR (TaqMan), as well as bacterial or mycotic infection. Before the photodynamic procedures, the standard gynecological infection was performed. Photosensitizer—–5-aminolaevulinic acid—–was obtained as a solid from Medac, Germany. Twenty percent 5-aminolaevulinic acid paste was prepared in the hospital pharmacy. One hundred and fifty minutes after topical application of about 10 g of 5-ALA paste, photodynamic diagnosis (PDD) was conducted, using Xilix Lung-LIFE system with 442 HeNe laser as a light source. For fluorescence examination, the Olympus cystoscope was attached to sensitive RGB camera of the Xilix system. RGB and fluorescence images were stored in Xilix Lung-LIFE system memory and later transferred to PC. The areas clinically changed presented pathological red or brownish fluorescence of Protoporphyrin IX. Immediately afterwards all the fluorescecnt areas were irradiated with Diomed 630 PDT semiconductor laser, with energy dose 180 J and fluence rate 700 mW/cm2 . The procedure was performed without anaesthesia. Every patient underwent three to six therapy cycles in 14 days intervals. During PDT and between last therapy and final examination, the patients received no topical corticosteroids. Four weeks after the last therapy, the patients underwent final clinical and photodynamic verification.

Results The treatment procedures were tolerated well. No analgesia was necessary during and after the completion of the therapy. Some patients felt intense warmth and pain during therapy, requiring 1—2 min interruption of the procedure. Minimal local toxicity included vulvar erythema without necrosis or scarring. We noticed no general cutaneous photosensitivity symptoms. Symptoms: • • • •

in 17 patients the itching ceased completely in six women it decreased in one patient the itching continued none of the patients presented exacerbation of itching

159

PDD after completion of therapy: • in 10 patients normal, green fluorescence of vulva • in 14 women pathological, red fluorescence, usually fainter than before PDT

Discussion Our results confirm the previous observations that 5-aminolevulinic acid-mediated photodynamic therapy may be a useful method of treatment of vulvar lichen sclerosus. None of our patients presented exacerbation of itching and only one of them felt no improvement following photodynamic therapy. One must consider that the duration of itching ranged from 3 months to 11 years and in many of our patients the classical therapy of lichen sclerosus was so far completely ineffective. It is also important that all our patients were HPV-negative, as Abdel-Hady et al. [19] suggested that high-risk HPV infection may play a role in the observed poor response of lower genital lesions to topical PDT. We are now working on larger group of patients, completing the hitherto analysis of symptoms and PDD images with histopathological examination. It is possible, however, that the symptomatic improvement and withdrawal of symptoms does not result from the deterioration of histopathological changes and that the risk of recurrence of itching as well as risk of malignancy still exists. That is why the other field of analysis should be a long-term follow-up of the symptomatically cured patients—–the data of Hillemanns et al. [17] show that the average lasting of improvement is about 6.1 months. We managed to follow-up 7 of our 17 patients who presented with complete cessation of itching. Six of them are still itching-free, the average time of follow-up is 18 months and the longest one is 24 months. In one patient, itching returned in 3 months, but it was weaker than before PDT. These data are not complete, however, and the result may be disturbed, as the satisfied patients are usually more eager to make themselves subject to control. The time interval between ALA application and illumination has not been well established yet. It ranged between 2—3 h [14] and 4—5 h [17,18]. We chose the shorter time interval as we have good own results with topical use of ALA and 2 h protocol in different skin and mucousal conditions, such as basal cell carcinoma and leukoplakia. Photodynamic therapy of vulva seems to be an effective, relatively painless procedure, leaving no local long-lasting after effects. It is not very expensive either. In our center, we estimate the cost

160 of one therapeutic procedure with topical use of ALA at about 30 euro, and the whole cycle of six procedures at 180 euro. In our opinion, there are no contraindications against extension or repeat of therapy in case of recurrence of itching as well as in cases without complete histopathological response.

Conclusion PDT is an effective therapeutic modality for chronic itching in lichen sclerosus.

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