Successful photodynamic therapy of vulval Paget's disease using a novel patch‐based delivery system containing 5‐aminolevulinic acid

Abstract

A 66 year old Caucasian female attended for treatment of vulval Paget's disease. She had an eight year history of persistent vulval itch, which had been treated unsuccessfully with antifungal, antibiotic and steroid creams. Biopsy at a district hospital revealed groups of large cells with atypical nuclei located within the epidermis with abundant clear to eosinophilic cytoplasm (Fig. 1A). These cells were positive with cytokeratin 7 and negative with cytokeratin 20. A diagnosis of Paget's disease was made. There was no evidence of dermal invasion by tumour. Mammography, colonoscopy and computed tomography of the abdomen were all negative. Pretreatment biopsy showing Paget's disease with large pleomorphic cells (A) and post-treatment biopsy showing complete clearance of Paget cells (B). Clinical examination showed a 4 × 3 cm, purple-red, well-demarcated, moist lesion on the left labia majora. Itch was graded on the visual analogue scale (0 to 10) at 8, becoming worse during the night and interrupting her sleep pattern. The patient was reluctant to undergo surgical excision and an experimental treatment using 5-aminolevulinic acid (ALA)-based photodynamic therapy was offered. Informed consent, as part of a trial protocol, was obtained. The treatment comprised part of an ongoing trial using photodynamic therapy for the treatment of a range of vulval lesions. The trial was performed under local Ethical Committee approval. A bioadhesive patch, which was developed in the School of Pharmacy, Queen's University Belfast, containing 38 mg cm−2 ALA (Crawford Pharmaceuticals, Milton Keynes), was applied and left in place for 5 hours. Upon removal, the absorption of ALA, with subsequent conversion to protoporphyrin IX (PpIX), was confirmed by fluorescence under illumination from a Wood's lamp. This revealed an extension of fluorescence towards the clitoral area, which clinically appeared normal and was reported by the patient as being symptomatic. The target area was exposed to red light of 630 nm generated by an incoherent lamp source (Paterson Lamp, Phototherapeutics, Manchester, United Kingdom), which delivered a light dose of 100 J cm−2 to the fluorescent area. Initially, it had been planned to treat the clinically abnormal area with two sessions of photodynamic therapy, six weeks apart and 24 hours after the first treatment, all symptoms had disappeared completely. However, soon after the second treatment, symptoms reappeared in the area which had shown fluorescence with no clinically apparent abnormalities. Itch was graded as 5. Therefore, the patient was administered a second course of photodynamic therapy to this area consisting of two treatments separated by a one-week interval. All treatments, with the exception of the first, were performed under local anaesthesia using subcutaneous mepivacaine (Scandonest) injection. The vulval pain induced by the illumination settled within a few hours and there was no requirement for post-treatment analgesia. Three months following the first treatment, the itch was occurring only sporadically with its maximum grading of 6 on the visual analogue scale. The clinical appearance of the lesion had changed from purple-red to pale pink with a small number of dispersed red spots. A biopsy, taken at three months following the initial treatment, showed complete clearance of Paget's disease (Fig. 1B). Pre- and post-treatment biopsies were examined by the same consultant gynaecological pathologist (WGM). Paget's disease is a rare, neoplastic condition occurring chiefly on the nipple and areolar region (mammary Paget's disease) from where it can spread to surrounding skin. Extramammary Paget's disease develops predominantly in the anogenital areas. It most commonly affects white, postmenopausal women. The histopathological picture is of characteristically large intraepidermal tumour cells with nuclear atypia and abundant cytoplasm.1 Vulval extramammary Paget's disease may occur in association with endometrial, cervical, bladder, colorectal neoplasia or cancer of Bartholin's gland.2 There is no effective treatment at present. Surgical excision with adequate margin control is associated with high morbidity3 and the multifocal nature means that complete eradication is not guaranteed. Recent and more conservative approaches to the management of extramammary Paget's disease have included laser vaporisation4 and radiotherapy.5 Photodynamic therapy has been applied to the clinical management of a wide range of neoplastic conditions including vulval Paget's disease.6,7 The exposure of sensitised cells to a specific wavelength of light activates a cascade of photochemical and photobiological events causing irreversible damage to tumour tissue. A common photosensitiser prodrug, ALA, has received much attention. The challenge facing delivery of ALA to both intact skin and superficial lesions is the need for prolonged ALA application,8 often exceeding 4 hours and up to 24 hours. It is clear that this period will result in considerable inconvenience to patients if ALA delivery is achieved using the familiar cream formulation. These difficulties are compounded by the location of many vulval lesions between skin folds that are close to the urethra and anus and subjected to substantial frictional stresses. This case report details an innovative delivery strategy that overcomes many of the problems that are specific to the anatomy of the vulva. A water-soluble bioadhesive patch has been developed that delivers a defined dose of ALA, which is comfortable to use and which does not require occlusion (Fig. 2A). Importantly, it remains in place in the ambulant patient, who is free to return home during the drug administration phase. During this period, ALA is converted to PpIX, chiefly within the Paget's cells. This was demonstrated under UV illumination, as shown in Fig. 2B, which shows areas of PpIX-induced red fluorescence in the lesion. Normal skin does not convert ALA to PpIX to any great extent and does not become photosensitised. Bioadhesive patch located on lesion prior to removal (A) and PpIX-induced flourescence in the lesion as viewed under illumination from a Wood's lamp (B). Patients who are either unfit or reluctant to undergo surgery may find photodynamic therapy a promising treatment alternative. Accepted 6 January 2004