Topical Photodynamic Therapy Using Intense Pulsed Light for Treatment of Actinic Keratosis: Clinical and Histopathologic Evaluation

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1 Topical Photodynamic Therapy Using Intense Pulsed Light for Treatment of Actinic Keratosis: Clinical and Histopathologic Evaluation HYUNG SU KIM, MD,JONG YEOP YOO, MD,KWANG HYUN CHO, MD,OH SANG KWON, MD, AND SANG EUN MOON, MD Department of Dermatology, Seoul National University College of Medicine, Seoul, Korea BACKGROUND. Photodynamic therapy (PDT) is suitable for the treatment of actinic keratosis, and, recently, topical PDT using intense pulsed light as a light source has been reported. However, evaluations of its therapeutic effects have been clinically based. OBJECTIVE. The objective of this study was to confirm the histopathologic resolution of actinic keratosis treated by topical PDT using intense pulsed light as a light source. METHODS. Twelve actinic keratosis lesions in seven patients were treated with 5-aminolevulinic acid PDT using intense pulsed light as a light source. After a single treatment, the clinical response was assessed and histopathologic examinations were performed on clinically resolved lesions. RESULTS. Six of 12 (50%) lesions showed clinical clearance after a single treatment, but histologic examinations showed that only 5 of the 12 (42%) lesions had been removed. No complications, such as pigmentary changes or scarring, were observed. CONCLUSION. Intense pulsed light is potentially an effective light source for PDT. However, the determination of complete remission in actinic keratosis requires caution, and long-term follow-up or histologic confirmation may be required. HYUNG SU KIM, MD, JONG YEOP YOO, MD, KWANG HYUN CHO, MD, OH SANG KWON, MD, AND SANG EUN MOON, MD, HAVE INDICATED NO SIGNIFICANT INTEREST WITH COMMERCIAL SUPPORTERS. PHOTODYNAMIC THERAPY (PDT) is a noninvasive technique that is used to treat many skin diseases. Various combinations of photosensitizers and light sources are used. The most commonly used photosensitizer in dermatology is topical 5-aminolevulinic acid (ALA), and many incoherent lights and lasers are used as light sources. 1 6 Actinic keratosis is a relatively common skin disorder and has the potential to progress to squamous cell carcinoma, and it is a well-known candidate for PDT. Several studies have found that ALA-PDT using an intense pulsed light as a light source clinically improves actinic keratosis, but these results were not proven histopathologically. 7,8 Thus, in the present study, we investigated the histopathologic degree of resolution achieved by topical PDT using intense pulsed light in actinic keratosis. Patients and Methods Seven Korean patients with actinic keratosis, who had been confirmed histologically, were enrolled in this Address correspondence and reprint requests to: Sang Eun Moon, MD, Department of Dermatology, Seoul City Boramae Hospital, 395 Shindaebang 2-dong, Dongjak-gu, Seoul , Korea, or semoon@snu.ac.kr. study. Two were male and five were female. Their mean age was 69.7 years, ranging from 60 to 85 years. There were 12 lesions ranging from cm to cm (Table 1). Just prior to applying topical ALA cream, we removed the lesion crust and tape-stripped the lesion. Twenty percent ALA (Sigma, St Louis, MO, USA) was mixed in an oil-in-water emulsion 9 and applied to the lesion concerned 4 hours prior to treatment as a thick layer (0.2 g/cm 2 ). A plastic film was placed over the ALA cream to increase penetration. The light source used was an Ellipse Flex (Danish Dermatologic Development, Hoersholm, Denmark), which emits a flashlamp-stimulated noncoherent light that is dually filtered to wavelengths from 555 to 950 nm. The dual-mode filtering used in this system removes clinically nonrelevant wavelengths above 950 nm. The fluence was 12 to 16 J/cm 2, and the pulse duration was 20 to 30 ms. Two passages of irradiation were done (Table 2). Patients visited 2, 8, and 12 weeks after treatment. At each follow-up visit, adverse events were checked. At 8 or 12 weeks after treatment, the effect of PDT was evaluated. Subjective evaluations were performed by self-scoring improvement from 0 (no improvement) to 10 (complete improvement). Two investigators evaluated lesion improvement as excellent (100%), good r 2005 by the American Society for Dermatologic Surgery, Inc. ISSN: Dermatol Surg 2005;31:33 37 Published by BC Decker Inc.

2 34 KIM ET AL: TOPICAL PHOTODYNAMIC THERAPY USING PULSED LIGHT Dermatol Surg 31:1:January 2005 Table 1. Clinical Profiles of Patients Case Age Sex Site of Lesions Number of Lesions Size, cm M Nose F Nose F Both temples, n nose, cheek 4 72 F Both temples n 5 67 F Cheek F Cheek M Nose tip n Size of the largest lesion. (50 99%), fair to poor (1 49%), or none (0%). If a lesion showed an excellent response, a skin biopsy was performed to confirm whether the actinic keratosis had been resolved. When actinic keratosis clinically showed residual lesion or a skin biopsy proved that the lesion remained, we conducted the next PDT. Results Clinical Evaluation The treatment was generally well tolerated, although some patients experienced tolerable pain during the irradiation procedure. Immediately after treatment, erythema and mild edema were seen in all lesions, with crusting followed by uncomplicated healing in 2 or 3 weeks. After a single treatment, five patients were subjectively assessed to have achieved complete improvement. Objectively, an excellent clinical improvement was observed in 6 of the 12 lesions (see Table 2 and Figure 1). Two lesions in case 4 showed good Table 2. Therapeutic Effect after First Treatment Case Pulse Residual Energy, Duration, Subjective Objective Lesion J/cm 2 ms Evaluation Evaluation, % on Biopsy Dropped out Not done n n After second session of photodynamic therapy. Figure 1. (A) Pretreatment. A well-demarcated scaly erythematous patch was found on the cheek. (B) Post-treatment. The actinic keratosis was completely resolved. improvement with clinical residual actinic keratosis and therefore received a second session of PDT. Four lesions in one patient (case 3) achieved a poor response, and the patient opted for another treatment modality; follow-up PDT was not performed in this case. No complications, such as pigmentary changes or scarring, were observed. In summary, 6 of 12 lesions showed clinical resolution after a single treatment. Histopathologic Evaluation A post-treatment skin biopsy was done in the six lesions that achieved an excellent clinical response. PDT caused the disappearance of abnormal keratinocytes from the epidermis, but one lesion revealed atypical cells in the follicular infundibulum (Figure 2). Pretreatment histopathologic findings were compared between actinic keratosis that completely responded and actinic keratosis that failed to respond to treatment. The failed lesions showed more severe change and a moderately thickened epidermis and hyperkeratosis. Atypical cells were present up to the upper part of the epidermis (Figure 3). In summary, the histologic examination showed that 5 of 12 lesions had completely resolved (see Table 2). Discussion The response of actinic keratosis to ALA-PDT is equal to or better than the cure rates achieved using

3 Dermatol Surg 31:1:January 2005 KIM ET AL: TOPICAL PHOTODYNAMIC THERAPY USING PULSED LIGHT 35 Figure 3. Pretreatment histology of the lesion that failed to respond. Marked hyperkeratosis was observed, and abnormal cells were present to the upper epidermis (hematoxylin-eosin stain; original magnification 100). Figure 2. (A) Pretreatment. Atypical cells were found in the basal layer of the epidermis and in the follicular infundibulum (hematoxylineosin stain; original magnification 100). (B) Post-treatment. In the basal layer of the epidermis, no atypical cells were found. However, atypical cells were observed in the follicular infundibulum (hematoxylin-eosin stain; original magnification 100). conventional treatment modalities. ALA-PDT more selectively treats actinic keratosis and the surrounding normal skin and thus achieves better cosmetic results. 10,11 Various kinds of light source have been used for topical ALA-PDT. Intense pulsed light has been described as a light source for the PDT of actinic keratosis as part of photorejuvenation. 7,8 The intense pulsed light system emits a broad spectrum of visible to near-infrared light (500 1,300 nm) with high irradiation density and precisely applies light to target lesions. 12,13 Infrared radiation can cause hyperthermia and accordingly it is best to avoid it. However, some investigators have suggested that mild hyperthermia acts synergistically with PDT. 14 Photodynamically active products can also be generated at wavelengths beyond the activation spectrum of the endogenous photosensitizer protoporphyrin IX. These facts may indicate that broadband illumination at a high intensity may be a more effective light source for ALA-PDT. 15 With ALA-PDT using intense pulsed light as a light source, Ruiz-Rodriguez and colleagues reported a clinical resolution rate of 76.3% and Avram and Goldman reported that 68% of actinic keratosis lesions were resolved by a single treatment. 7,8 However, this evaluation was based on clinical inspections and photographs. Actually, in most studies that have investigated the effects of PDT, histopathologic confirmation of clearance was rarely undertaken. Recently, Calzavara-Pinton histopathologically observed persisting clinically nonvisible actinic keratosis in 3 of 17 apparently cleared lesions. 16 In our series, 6 of 12 lesions (50%) showed clinical resolution after single ALA-PDT, but a subsequent histopathologic examination showed that one of these 6 lesions contained residual atypical cells. The histopathologic finding that atypical keratinocytes remain in the follicular infundibulum in clinically cleared lesions may provide some suggestions that it may be foci of recurring in PDT. ALA can reach to the sebaceous gland, and photochemical reaction can occur at this level. 17 If insufficient reaction occurs for some reason, for example, owing to a melanin barrier or a low light dose, abnormal cells in the follicular infundibulum can survive and cause a recurrence. In addition, thick, hyperkeratotic actinic keratosis has been reported not to respond effectively to PDT, and the actinic keratosis lesions that failed to respond in our series support this finding. A reduced response may be related to ineffective penetration of ALA and resultant lack of PpIX conversion. 3,18 In several open studies of ALA-PDT on face or scalp actinic keratosis in whites, clearance rates

4 36 KIM ET AL: TOPICAL PHOTODYNAMIC THERAPY USING PULSED LIGHT Dermatol Surg 31:1:January 2005 were reported as 68 to 100% after a single treatment. 1 4,8,18 20 Our study, which was done on more pigmented Asian skins, showed a much lower clearance rate. In a Japanese series reported by Itoh and colleagues, the efficacy of ALA-PDT for actinic keratosis showed an 82% clearance rate for facial lesions, which required three to six treatment sessions. 21 The fact that multiple treatment sessions were required to achieve a higher clearance rate implies some ethnic differences in terms of response to topical PDT owing to skin color differences. Berstein and colleagues showed a reduced photodynamic effect in highly pigmented skin in a guinea pig model. 22 They believed that melanin might moderate the photodynamic effect by absorbing free radicals and light and suggested that skin color could influence PDT response. Thus, to increase the effect, higher light doses may be required, but there is no clear relationship between the complete remission rate and the dosage used. 14 From the results of the Japanese study, although a direct comparison is not possible because different light sources were used, it would appear that repeated treatment would have achieved a higher clearance rate in our series. In addition, we believe that further study is needed to define the appropriate dose. No adverse effects, such as pigmentary changes, were found in our series. This may be related to the small number of patients enrolled and single treatment session used. Adverse reactions are uncommonly encountered. Clark and colleagues reported that 2% of patients showed pigmentary change and 2% had scarring. 4 In conclusion, we believe that intense pulsed light is a potentially effective light source for ALA-PDT and that careful thought is needed concerning clinical response evaluation. References 1. Jeffers EW, McCullough JL, Weinstein GD, et al. Photodynamic therapy of actinic keratoses with topical aminolevulinic acid hydrochloride and fluorescent blue light. J Am Acad Dermatol 2001;45: Karrer S, Barmler W, Abels C, et al. Long-pulse dye laser for photodynamic therapy: investigations in vitro and in vivo. Lasers Surg Med 1999;25: Varma S, Wilson H, Kurwa HA, et al. Bowen s disease, solar keratoses and superficial basal cell carcinomas treated by photodynamic therapy using a large-field incoherent light source. Br J Dermatol 2001;144: Clark C, Bryden A, Dawe R, et al. Topical 5-aminolaevulinic acid photodynamic therapy for cutaneous lesions: outcome and comparison of light sources. Photodermatol Photoimmunol Photomed 2003;19: Goldman MP, Atkin DH. ALA/PDT in the treatment of actinic keratosis: spot versus confluent therapy. J Cosmet Laser Ther 2003;5: Dijkstra AT, Majoie IM, van Dongen JW, et al. Photodynamic therapy with violet light and topical 5-aminolaevulinic acid in the treatment of actinic keratosis, Bowen s disease and basal cell carcinoma. J Eur Acad Dermatol Venereol 2001;15: Ruiz-Rodriguez R, Sanz-Sanchez T, Cordoba S. Photodynamic photorejuvenation. Dermatol Surg 2002;28: Avram DK, Goldman MP. Effectiveness and safety of ALA-IPL in treating actinic keratoses and photodamage. J Drugs Dermatol 2004;3 Suppl:S Itoh Y, Ninomiya Y, Tajima S, Ishibashi A. Photodynamic therapy of acne vulgaris with topical d-aminolaevulinic acid and incoherent light in Japanese patients. Br J Dermatol 2001;144: Kurwa HA, Yong-Gee SA, Seed PT, et al. A randomized paired comparison of photodynamic therapy and topical 5-fluorouracil in the treatment of actinic keratoses. J Am Acad Dermatol 1999;41: Morton CA. The emerging role of 5-ALA-PDT in dermatology: is PDT superior to standard treatments? J Dermatol Treat 2002; 13 Suppl 1:S Raulin C, Greve B, Grema H. IPL technology: a review. Lasers Surg Med 2003;32: Weiss RA, Weiss MA. Intense pulsed light: newer perspective. Dermatol Surg 1997;23: Peng Q, Warloe T, Berg C, et al. 5-Aminolevulinic acid-based photodynamic therapy: clinical research and future challenges. Cancer 1997;79: Kimel S, Svaasand LO, Hammer-Wilson M, et al. Demonstration of synergistic effects of hyperthermia and photodynamic therapy using the chick chorioallantoic membrane model. Lasers Surg Med 1992;12: Calzavara-Pinton PG. Repetitive photodynamic therapy with topical delta-aminolevulinic acid as an appropriate approach to the routine treatment of superficial nonmelanoma skin tumors. J Photochem Photobiol B 1995;29: Hongcharu W, Taylor CR, Chang Y, et al. Topical ALAphotodynamic therapy for the treatment of acne vulgaris. J Invest Dermatol 2000;115: Jeffes EW, McCullough JL, Weinstein GD, et al. Photodynamic therapy of actinic keratoses with topical 5-aminolaevulinic acid. Arch Dermatol 1997;133: Szeimes RM, Karrer S, Sauerwald A, Landthaler M. Photodynamic therapy with topical application of 5-aminolaevulinic acid in the treatment of actinic keratoses: an initial clinical study. Dermatology 1996;192: Wolf P, Rieger E, Kerl H. An alternative treatment modality for solar keratoses, superficial squamous cell carcinomas and basal cell carcinomas. J Am Acad Dermatol 1993;28: Itoh Y, Ninomiya Y, Henta T, et al. Topical delta-aminolevulinic acid-based photodynamic therapy for Japanese actinic keratoses. J Dermatol 2000;27: Berstein EF, Thomas GF, Smith PD, et al. Response of black and white guinea pig skin to photodynamic treatment using 514-nm light and dihematoporphyrin ether. Arch Dermatol 1990;126: Commentary The evolving practice of combining 5-aminolevulinic acid (ALA)-based photodynamic therapy (PDT) with intense pulsed light (IPL) holds many attractions. If it were possible to confirm the efficacy of IPL-PDT in the treatment of actinic keratoses (as well as basal cell carcinoma and Bowen s disease), then the convenience of treatment would be greatly enhanced. Instead of illumination times of 8 to 20 minutes with currently available light sources, the time could be reduced to a matter of seconds. The Holy Grail might be to find a formulation of ALA that requires only 30 minutes or less of application to be photoactive. Penetration-enhancing bases such as pluronic lecithin organogel might hold some promise in this regard. 1 An IPL- PDT treatment could then be completed well inside an hour, with only one visit a distinct advantage over the present situation.

5 Dermatol Surg 31:1:January 2005 KIM ET AL: TOPICAL PHOTODYNAMIC THERAPY USING PULSED LIGHT 37 Currently, level 1A evidence exists from randomized controlled studies of the superior effectiveness of PDT using methyl- ALA and red light in the treatment of actinic keratoses when compared with cryotherapy or placebo. 2 Such evidence does not yet exist for IPL when used as the light source. The concept is nonetheless promising because there would be no need to have a dedicated PDT light source and the treatment could be routinely combined with IPL photorejuvenation. The second-generation IPL reported in this article used a wavelength band of 555 to 950 nm, thereby eliminating the longer infrared light from 950 to 1,200 nm found in most firstgeneration IPLs. The median wavelength of the power spectrum for the 555 to 950 nm band is positioned at 726 nm. 3 Given that one of the favored light activation bands for protoporphyrin IX (the photoactive porphyrin that results from application of ALA) is around 630 nm, the benefit of such broad-spectrum light from IPL is perhaps somewhat questionable. A more restricted wavelength band from 530 to 750 nm, which is available from the same manufacturer reported in this article, has a median wavelength at 660 nm, 3 which is much closer to the 630 nm absorption peak for protoporphyrin IX. It would be very interesting to investigate the effectiveness of the narrower spectrum for this application. The use of IPL in darker skin types is contentious, and the lack of complications in this small study is intriguing. At a theoretic level, one can anticipate significant potential for blistering and postinflammatory hyperpigmentation. When dealing with actinic keratoses, it is likely that more epidermal and dermal heating is required to ablate the dysplastic epidermis. The size of the actinic keratoses in this study raises the possibility of a diagnosis of Bowen s disease, and it is certainly relevant that those actinic keratoses that failed to clear were more hyperkeratotic. Repeated treatment, as suggested by the authors, is probably necessary to improve efficacy. It would be surprising if this report were not followed by a flurry of research activity with IPL-PDT looking at the whole range of variables, with both photosensitizers and IPL dosing. References CARL VINCIULLO, MB, BS, FACD Perth, Western Australia 1. Jones M. The history of pluronic lecithin organogel. Int J Pharmaceut Compound 2003;7: Freeman M, Vinciullo C, Francis D, et al. A comparison of photodynamic therapy using topical methyl aminolevulinate with single cycle cryotherapy in patients with actinic keratosis: a prospective randomized study. J Dermatol Treat 2003;14: Bjerring P, Christiansen K, Troilus A, et al. Facial photo rejuvenation using two different intense pulsed light wavelength bands. Lasers Surg Med 2004;34:120 6.