DOI: 10.1111/j.1468-3083.2011.04175.

JEADV

ORIGINAL ARTICLE

Effectiveness of photodynamic therapy in Bowens disease: an observational and descriptive study in 51 lesions
ndez-Guarino, B. Fleta, J. Alca ntara, P. Jae n M. Truchuelo,* M. Ferna
n y Cajal Hospital, Madrid, Spain 4th year Dermatology specialist resident in University Hospital Ramo *Correspondence: M. Truchuelo. E-mail: maytetd@yahoo.es

Abstract
Introduction Bowen disease (BD) or squamous cell carcinoma (SCC) in situ affects both skin and mucous membranes and has the potential to progress to invasive SCC. Photodynamic therapy (PDT) has been approved recently for the treatment of BD. Some studies have demonstrated its efcacy and good cosmetic outcome. Objective To assess the efcacy of PDT in the treatment of BD. Patients and methods We carried out an observational, retrospective and descriptive study. A total of 47 patients with 51 lesions of BD were included. All the lesions were conrmed with previous cutaneous biopsy. All patients were treated with the standard protocol. Topical methyl-aminolaevulinic acid was occluded during 3 h and followed by illumination with red-light (630 nm, 38 J cm2, 7.5 min). Clinical and uorescence photographs images were taken before each session. All patients received two sessions one week apart. Clinical response was classied in partial or complete response. Fluorescence response was classied in negative, intermediate or intense. The follow-up period and the adverse events observed including pain were also collected. Results A total of 20 men and 27 women with a mean age of 75.57 years old were treated with PDT. Lesions were most frequently located in the lower limbs. Globally, 76.09% of the lesions achieved complete response after 2 sessions with a medium follow-up of 16.61 months. Fluorescence of the lesions disappeared when clinical response was achieved, but not always. The most common adverse effect was an immediate burning sensation. All lesions showed an excellent cosmetic result. Conclusion Photodynamic therapy is an effective treatment for BD in terms of both clinical remission and cosmetic results, with good tolerance and minimal adverse effects. Received: 26 December 2010; Accepted: 17 June 2011

Conict of interest
None.

Funding sources
None.

Introduction
Bowens disease (BD) was rst described in 1912 as a form of intraepidermal (in situ) squamous cell carcinoma (SCC). Most studies suggest a risk of progression to invasive carcinoma of about 35% for ordinary BD and perhaps 10% for erythroplasia of Queyrat (genital lesions which have the histology of BD).1 As it is a frequent and potentially invasive and a metastatic potential,2 dermatologists must be aware of the different therapeutic options available. One of the options, photodynamic therapy (PDT), is of great interest because of its proven efcacy and excellent cosmetic results. This is a novel, selective and non-invasive therapy used in cutaneous oncology and has been recently suggested for BD treatment. The U.S. Food and Drugs Administration approved its use

for actinic keratoses in 1999 and European approval for actinic keratoses and basal cell carcinomas (supercial and nodular <2 mm-thick) followed in 2001.3 In 2006 PDT was suggested for BD treatment as a good or generally good option1 based on several studies that had shown its efcacy and safe use. Most of them employed aminolevulinic acid (ALA) as the photosensitizer cream. Few reports of methyl aminolaevulinate (MAL) PDT, an ester derived from ALA, for BD treatment are to be found in the literature.1,4 We present the second largest study, the largest one in our country (Spain), using MAL-PDT for BD. In addition this is the rst study that evaluates the efcacy of PDT for BD in ordinary medical practice. The aim of the study was to evaluate the clinical efcacy, factors determining different responses, the correlation

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with the uorescence diagnosis as well as the tolerability and cosmetic outcomes and maintenance of response. For this purpose we developed an observational, descriptive and retrospective study in 47 patients with 51 biopsy-proven BD lesions treated with MAL-PDT.

Patients and methods

Patients

An observational, retrospective and descriptive study was developed including biopsy-proven BD diagnosed between November 2004 and November 2009. A total of 51 BD lesions and 47 patients were collected. The study was approved by the hospital ethics committee. Inclusion criteria were: to have untreated primary lesions with a biopsy diagnosis of BD and to have an iconographic registration of the lesions. Exclusion criteria were: age under 18, pregnancy or lactation, active infectious disease, history of photosensitivity or allergy to photosensitizers or lack of any image registration.
Treatment protocol

The images were then evaluated by two dermatologists from our department and classied as complete response (total disappearance of the lesion), incomplete response (reduction but not disappearance of the lesion) or not responders (no changes detected). To avoid unnecessary damage in a noninvasive treatment such as PDT, post-treatment biopsies were obviated in those patients with complete responses and were performed in those where an incomplete response or a recurrence was suspected. The number of recurrences (dened as reappearance of a tumoral lesion after a previous remission) and progressions to invasive carcinoma were collected during the follow-up. In addition uorescence evaluation was classied as negative (no uorescence emitted), intermediate (patched emission, <75%) or intense uorescence (homogeneous and >75%) based on qualitative analysis. Observer concordance was reached in up to 96% of cases. In case of disagreement the evaluation of the most experienced dermatologist was selected. To detect possible side effects the patients were asked for the presence of pain, erythema, ulcerations, scarring or dermatitis immediately after nishing light application and during the following evaluations.

A written medical history and photographs were used to register the localization and extension of the lesions. Photographs of the clinical lesions were taken before and after treatment. A special device camera Olympus C5060 connected to ultraviolet ashes (ClearStone VD-DA digital system) was used before and after treatment to record the uorescence emitted by the tumoral lesions impregnated with MAL cream. Preparation of the skin surface before MAL (Metvix cream; Galderma, Paris, France) application included a gentle, bloodless debridement with a curette, aiming only to remove crusts and scales, scraping 5 mm of the surrounding tissue of normal appearance as indicated by the European guidelines published in 2010.5 Methyl aminolaevulinate was then applied in a 1-mm thick layer on the prepared skin area and left for 3 h. The application was under occlusion with a plastic lm avoiding exposure to cold or hot temperatures or light. Before exposure to light the cream was removed using a swab and the red uorescence of porphyrins was visualized with a Woods light and a photograph was then taken before starting light exposure. Lesions were then irradiated with a red light from a diode lamp (AktiliteR PhotoCure ASA, Oslo, Norway) with the following parameters: 630 nm wavelength, uence 38 J cm2 and exposure time 7.5 min). All patients were treated twice with a treatment interval of 1 week. Avoidance of sun or exposure to intense light was recommended for the following 48 h.
Data analysis

Results
The results are summarized in Tables 14. A total of 47 patients, 20 men and 27 women, with ages ranging from 49 to 92 years (mean age of 75.57 years) diagnosed histologically with BD received MAL-PDT treatment. Five lesions were lost without a post-treatment clinical evaluation.

Table 1 Characteristics of the patients

No of patients No of lesions Mean age Gender Localization of lesions 47 51 75.57 years 20 Men 27 Women Legs: 22 51 (43.14%) Head and neck: 14 51(27.45%) Others: 15 51 (29.41%) 4 47 (0.08%) 18 47 patients (38.30%): 24 BCC 16 SCC 16.61 months Patients 5 47 Lesions 5 51 6 51 (11.76%) recurrences 1 51 progression to SCC Burning 6 47 Pain 1 47

Patients with multiple Bowens disease lesions Patients with several CNMSC

Mean follow-up Patients lost Recurrence or progression of the lesions Patients with side effects

Pre-treatment clinical status was compared with post-treatment results. For this purpose, images were recorded before treatment and one month after the second session a new image registration was performed with clinical and uorescence photographs.

BCC, basal cell carcinoma; CNMSC, cutaneous non-melanoma skin cancer; No, number; SCC, squamous cell carcinoma.

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Table 2 Clinical response: total results and variation depending on localization or gender
Total Complete clinical response 35 46 (76.09%) lesions 31 42 (73.81%) patients 11 46 (23.91%) lesions 11 42 (26.19%) patients Localization Legs: 15 22 (81.82%) Head and neck: 9 11 (61.18%) Others: 11 13 (84.61%) Legs: 7 22 (31.82%) Head and neck: 2 11 (18.18%) Others: 2 13 (15.38%) Gender Men 11 17 (64.70%) Women 20 25 (80%) Men 6 17 (35.29%) Women 5 25 (20%)

Partial clinical response

Table 3 Fluorescence evaluation pre- and post- Photodynamic treatment

F. Pre-treatment Intense Intermediate Negative NDA 38 44 (86.36%) 6 44 (13.64%) 0% (13.72%) 7 51 F. Post-treatment 0% 12 36 (33.33%) 24 36 (66.66%) 10 46 (21.74%)

F, uorescence; NDA, no data available.

Table 4 Correlation between uorescence diagnosis post-treatment and clinical response

Post-treatment uorescence Clinical response Complete Intense Intermediate Negative NDA NDA, no data available. 0% 10 35 (28.57%) 17 35 (48.57%) 8 35 (22.86%) Partial 0% 2 11 (18.18%) 7 11 (63.63%) 2 11 (18.18%)

A total of 51 lesions, with a mean longitudinal size of 3.36 cm, were treated. Of the 47 patients, 43 had a single BD lesion and four patients had two coexisting and distant BD lesions. The legs were the most frequent anatomic area affected by BD with a total of 22 51 (43.14%) lesions. Head and neck involvement was detected in 14 51 lesions (27.45%) and other locations (superior extremities, back, buttocks and others) in 15 51 lesions (29.41%). Clinical evaluation detected complete response in up to 35 46 (76.09%) lesions that completed follow-up, whereas incomplete response was detected in 11 46 (23.91%) lesions (Table 2). Regarding the localization, among the lesions located in the head and neck area 9 11 (81.82%) presented a complete response whereas 2 11 (18.18%) had a partial response. Complete response in the legs had reached in 15 22 (68.18%) lesions with a partial response in 7 22 (31.82%). In the rest of localizations a complete response was presented in 11 13 (84.61%) lesions and a partial one in just 2 13 (15.38%). Results with regard to gender showed a complete response in 20 25 (80%) women and in 11 17 (64.70%) men and a partial response in 5 25 (20%) women and in 6 17 (35.29%) men. The association with other cutaneous non-melanoma skin cancers (CNMSC), concomitant or previously diagnosed within

the last 5 years, was present in 18 47 patients (38.30%). Basal cell carcinoma was the most frequent tumour associated with 24 basal cell carcinoma lesions affecting 12 47 patients (25.53%) and 16 squamous cell carcinomas in 6 47 patients (12.76%). Fluorescence evaluation before treatment was classied as intense in 38 44 (86.36%) lesions and intermediate in 6 44 (13.64%) lesions. No negative uorescence results were recorded at that moment. On the other hand after PDT-treatment no lesion showed intense uorescence whereas intermediate uorescence was present in 12 36 (33.33%) lesions and negative uorescence in up to 24 36 (66.66%) lesions. Unfortunately uorescence images were unavailable in 7 51 lesions before treatment and in 10 46 lesions after treatment (Table 3). Among the lesions with incomplete response, 7 11 (63.63%) had negative uorescence post-treatment, 2 11(18.18%) had intermediate uorescence and in 2 11 (18.18%) no data were available. Among the lesions with complete response, 17 35 (48.57%) had negative uorescence post-treatment, 10 35 (28.57%) had intermediate uorescence and 8 35 (22.86%) had no data available (Table 4) (Fig. 1, 2, 3 and 4). A mean follow-up period of 16.61 months from the biopsy acquisition was conducted. During this time recurrences were diagnosed in 6 51 lesions (11.76%). Only one patient showed progression of the BD to invasive SCC. In addition, side effects were registered in only eight patients. Most of them occurred during the light application and consisted of a burning sensation (6 47) and pain (1 47). Only one residual undesirable complication was detected in one patient who developed a scar on his neck. All the patients were satised with the results obtained.

Discussion
Bowens disease is a form of intra-epidermal (in situ) SCC with a risk of evolution to invasive carcinoma of about 35% for ordinary BD and even 10% in genital BD.68 It represents a frequent entity and as it can affect visible anatomic areas such as head and neck or extremities, it is of concern not only because of the tumoral implications but also because of the cosmetic problem. Therefore, in our opinion the best treatment should be that with effective results in the absence of negative cosmetic side effects. There is no gold standard treatment. Many different treatment options exist for BD management and all of them have advantages and disadvantages.

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Figures 1 Clinical and uorescence images pre- and post-treatment with photodynamic therapy of BD on the dorsum of the right hand.

Figures 2 Clinical and uorescence images pre- and post-treatment with photodynamic therapy on the back.

The European guidelines, published in 2006, have proven to be of great use in the difcult evaluation of treatment studies of BD. They summarized and classied the grades of BD and the probable treatment of choice with the different options available such as topical 5-Fluorouracil (5-FU), topical imiquimod, cryotherapy, curettage, excision, radiotherapy, laser and PDT.1 There is supportive evidence of superior PDT efcacy and cosmetic results compared with other conventional treatments such as imiquimod, 5-FU, laser or cryotherapy treatment.1,3,9,10 All of

them reported PDT therapy as signicantly more effective and with fewer adverse effects than the other options. Invasive surgical options such as excision should be avoided in legs because of the risk of poor healing and considerable co-morbidity.1 Mohs surgery could be an excellent option for digital BD and some cases of genital BD.11 Although surgical excision is an effective approved treatment it can cause functional loss or cosmetic disgurement and not all patients are suitable for surgery (e.g. immunosuppressive therapies, allergy to local anaesthetics, important

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Figures 3 Clinical and uorescence images pre- and post-treatment with photodynamic therapy of BD plaque located on the left arm. Post-treatment images are rotated 90.

Figures 4 Clinical and uorescence images pre- and post-treatment with photodynamic therapy of a BD plaque located on the trunk.

co-morbidities). Erythroplasia of Queyrat can respond to topical PDT but case-reports of its use urge caution in ensuring sustained response by careful follow-up.12,13 There are several factors to be taken into account before choosing a therapeutic option for BD: expected efcacy, localization of the lesions, patient basal status, infrastructural and economic resources. Some economical comparison studies between different

options, including PDT therapy, for BD treatment have been published with controversial results.14,15 Based on previously published studies (most of them using ALA-PDT instead of MAL-PDT as in our study),3,10,1619 the European guidelines recommended PDT therapy (with ALA or MAL photosensitizer) with a strength of recommendation of A and quality of evidence of I as a good or very good option spe-

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cially in large and multiple lesions located in poor healing sites.1,20,21 Immunosuppressed subjects are specically good candidates for this non-invasive treatment although lower healing rates should be expected.21,22 Data concerning longer-term clearance rates following standard treatments for BD are limited. The previously published studies suggest an initial clinical clearance response for ALA PDT of 80100% with a recurrence rate of 010% at 12 months.1 The clinical clearance rates published for MAL-PDT are of 7387.8% after 3 months.4,9 In our study, which is to our knowledge the second largest one using MAL-PDT, the efcacy rates are in agreement with those previously mentioned but with higher recurrence rates (14.28%). Although no direct comparison between MAL and ALA formulations has been undertaken, MAL-PDT seems to achieve clearance rates similar to ALA-PDT and our study contributes to support this belief. It is reasonable to assume that the top evidence ratings awarded in clinical guidelines can also be applied to MAL-PDT.23,24 Comparison between wavelengths showed red light superiority.25 No studies comparing non-coherent lights with lasers have been developed.18,26,27 There have been no publications comparing different uencies or different parameters. It seems that the clinical thickness and some histological elements (cell atypia and lesion depth) could be predictors of treatment response.4 In our study the worst clinical response rates were detected in the BD lesions located in the legs (complete response of 68.18% vs. 81.82% in BD located in head and neck areas and 84.61% in those located in other areas). This is in agreement with previous reports which suggested that acral lesions, particularly the legs, had a worse outcome.28 Women seemed to present a slightly better response in our study. In agreement with previous reports no correspondence was detected between the size of the lesions and subsequent clinical response.4 PDT is especially of great interest for large or multiple lesions and those located over poor healing sites such as the legs, which are the most common areas involved in our study. In the present study the treatment was generally well tolerated and few side effects were registered. No patient needed anaesthesia. All patients were satised with the results. This was comparable to previously published studies where good or excellent outcome was reached in up to 90% of patients.9 The association with other CNMSC was present in 18 47 patients (38.30%). Basal cell carcinoma was diagnosed in 12 47 patients (25.53%) and squamous cell carcinomas in 6 47 patients (12.76%). Prevalence of basal cell carcinoma is difcult to establish but it has been reported to be 1.83% in Spain (CI 95%: 00.1083) whereas prevalence of squamous cell carcinoma in our country seems to be lower, 0.3% (CI 95%: 00.145).29 It has been reported that the risk of developing a subsequent skin cancer of a specic type depends on the type of prior CNMSC and number of prior skin tumours of that type.30 In particular, a possible association between BD and other cutaneous cancers has been suggested.31,32 Correlation between clinical response of cutaneous cancers to PDT and uorescence diagnosis has been previously reported.3335

To our knowledge this is the rst study in the English medical literature which specically correlates clinical response and uorescence diagnosis in BD. Despite the correlation between clinical and uorescence in pre-treated lesions (positivity in all of the 44 studied lesions: 38 intense and 6 intermediate) this correlation was not maintained in post-treated lesions: 63.63% of the lesions with incomplete response had negative uorescence and 28.57% with complete response (where negative uorescence should be expected) had intermediate uorescence, suggesting that uorescence could be useful in the initial diagnosis but not in the evaluation of treatment efcacy. We hypothesize this could be explained by a false positivity due to a more intense inammatory response to PDT with a possible persistent subclinical inammation in those with complete response. In addition the presence of some sparse atypic keratinocytes due to a more intense photodamage in those areas could lead to a false uorescence positivity.36 There are several limitations to our study which is observational and retrospective with just a 5 year survey; the number of patients lost in the uorescence evaluation and the absence of routine posttreatment biopsies. To determine the exact role of uorescence diagnosis in the evaluation of the efcacy after MAL-PDT more major studies are needed. This could be of great interest to avoid unnecessary biopsies during the follow-up period. We are aware that uorescence has less sensitivity than histological analysis but it has the advantage of avoiding an invasive procedure for the patient and it evaluates the complete area of the lesion. In addition in those patients where uorescence fails to detect the persistence or recurrence of the tumoral lesion (false negative patients), a close followup would detect them without risk to the patients. Our clinical resolution rates (76.09% complete and 23.91% partial) and recurrence rates of 14.28% were according to previously published data. Up to 30% of histological recurrence rates have been reported at 12 months after PDT treatment4,9 and we believe that, although less sensitive, a clinical and uorescence evaluation could avoid post-treatment histological assessment and therefore preserve the non-invasive and cosmetic outcomes of the technique. The followup period of 12 months that is generally recommended5 should efciently detect the possible failures of the procedure. In summary, we present a MAL-PDT study where there was a clinical efcacy in most patients with maintenance of response and with very good tolerability. As BD has a very low risk of metastatic potential, MAL-PDT may represent an interesting option especially in patients with multiple and large lesions, lesions located in poor healing areas, patients unsuitable for surgery or patients with important cosmetic necessities. The role of uorescence diagnosis for the evaluation of the clinical response remains to be elucidated.

References
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