Treatment of Porokeratosis of Mibelli with Combined Use of Photodynamic Therapy and Fluorouracil Cream

THE CUTTING EDGE

SECTION EDITOR: ERIK J. STRATMAN, MD; ASSISTANT SECTION EDITORS: WILLIAM D. AUGHENBAUGH, MD; MICHAEL P. HEFFERNAN, MD Treatment of Porokeratosis of Mibelli With Combined Use of Photodynamic Therapy and Fluorouracil Cream

Jacob Levitt, MD; Jason J. Emer, MD; Patrick O. Emanuel, MD; Department of Dermatology, Mount Sinai School of Medicine, New York, New York

The Cutting Edge: Challenges in Medical and Surgical Therapeutics

REPORT OF A CASE followed by an 8-week trial of fluorouracil cream, without success. A 45-year-old white man with a medical history that was remarkable for human immunodeficiency virus THERAPEUTIC CHALLENGE and AIDS complicated by Kaposi sarcoma presented with a 14-year history of a recurring scaly, pruritic le- Many treatments have been suggested for porokerato- sion on the dorsal aspect of his left shin. The lesion was sis, and the results have often been disappointing. The refractory to treatment with topical corticosteroids, approach to treatment is individualized and based on tazarotene, salicylic acid, and various emollient and many factors, such as lesion size and location, risk of ma- keratolytic creams. Recently, the lesion had become lignant transformation, and functional and aesthetical con- increasingly large, pruritic, painful, and cosmetically siderations. Sun protection, aggressive use of emol- displeasing. Skin examination of the left dorsal shin lients, and observation for signs of malignant degeneration area showed a thick, hyperkeratotic plaque with a dis- may be all that is needed in many cases. However, if the tinct, raised annular border (Figure 1). A skin biopsy lesions are widespread or displeasing, curative therapy specimen revealed a broad-based parakeratotic column is warranted. of cells traversing the stratum corneum (cornoid It has been suggested that a lesion of porokeratosis re- lamella), an underlying epidermis devoid of a granular sults from a local or systemic change in immune func- layer, and dissolution of basal cells with shouldering tion that in turn allows the development of atypical clones acantholysis. A sparse, nonspecific, lymphocytic infil- of keratinocytes. Useful medical modalities should there- trate was seen in the upper dermis (Figure 2). The fore work by inhibiting cell growth and proliferation as clinical and histopathologic features supported a diag- well as regulating and modulating keratinocyte differ- nosis of porokeratosis of Mibelli (PM). The patient was treated with a 4-week trial of imiquimod cream

Figure 2. Histopathologic examination revealed a broad-based cornoid lamella characteristic of the Mibelli type. The cornoid lamella consists of a column of stacked parakeratotic cells with basophilic pyknotic nuclei, Figure 1. Clinical photograph demonstrating porokeratosis of Mibelli on the shouldering acantholysis, and an absent granular layer (hematoxylin-eosin, dorsal aspect of the left shin before photodynamic therapy. original magnification ϫ100).

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©2010 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/24/2021 entiation. Oral and topical retinoids,1,2 fluorouracil cream,3 4 5 vitamin D3 analogues, diclofenac gel, and imiquimod cream6 have all been used to treat porokeratosis. Surgi- cal options include excision, cryotherapy,7 dermabrasion,8 and laser therapy.9 The benefits of surgical treatment are improved cosmesis and function and removal of lesions that have undergone malignant transformation. The disadvantages include scarring, pain, and lesion recurrence. For these reasons, effective alternatives to surgery are desired, particularly for benign porokeratosis. An ideal form of treatment for this benign chronic condition should be pain free, effective, safe, and non- scarring.10 Many of the traditional therapies used for PM had previously been used in our patient, without ad- equate success; therefore, an alternative and novel therapy was attempted.

Figure 3. Clinical photograph demonstrating the complete clearance of SOLUTION porokeratosis of Mibelli after the addition of photodynamic therapy with aminolevulinic acid (2-hour incubation) and blue light (Blu-U; DUSA Pharmaceuticals, Wilmington, Massachusetts)(16 minutes 40 seconds) to While daily treatment with topical fluorouracil cream was daily topical fluorouracil therapy. continued, 1 session of photodynamic therapy (PDT) with aminolevulinic acid (Levulan Kerastick; DUSA Pharma- ceuticals, Wilmington, Massachusetts), using a 2-hour Photodynamic therapy is a relatively new treatment incubation and exposure to blue light (Blu-U; DUSA Phar- modality that is currently used for the treatment of vari- maceuticals) for 16 minutes and 40 seconds, was added ous skin cancers, actinic keratosis, and acne. It uses topi- to the regimen. The combination of these 2 therapies re- cally applied aminolevulinic acid or methyl aminolevu- sulted in complete clearance of the lesion at 3 weeks, with linate that penetrates damaged or active epidermal cells sustained clearance during 6 months of follow-up and is converted to a potent photosensitizing protopor- (Figure 3). phyrin IX. Studies have shown that 3 mechanisms con- tribute to the efficacy of PDT: (1) direct cell destruction COMMENT through the activation of protoporphyrin IX and the sub- sequent formation of reactive cytotoxic oxygen species; Porokeratosis is a disorder of abnormal keratinization with (2) microvascular damage that causes hypoxia and tis- many clinical variations. It is characterized by the ap- sue necrosis; and (3) up-regulation of tumor necrosis fac- pearance of 1 or more atrophic patches surrounded by a tor ␣, interleukin 1, and interleukin 6, which aid in the clinically and histologically unique ridgelike border elimination of tumor tissue.14-16 The penetration of light termed the cornoid lamella. The cornoid lamella is formed into tissue varies and is conversely proportional to the by a rapid hyperproliferation of atypical keratinocytes that increasing wavelength. The largest absorption peak of the expands peripherally to form a raised boundary be- reactive intermediates is at 410 nm (blue light), with tween abnormal and normal cells. Lesions are most com- smaller absorption peaks at 505, 540, 580, and 630 nm monly found on the extremities, and in the setting of im- (red light). Blu-U takes advantage of the largest absorp- munosuppression, they are large and rapidly expanding. tion peak at 417 nm but is limited to a depth of penetra- Most often, the skin lesions of porokeratosis are asymp- tion of 1.5 to 2 mm into the epidermis. Red light (Ͼ600 tomatic; however, ulcerative, verrucous, giant, and ma- nm) requires higher energy levels to achieve the same lignant lesions have been identified.11,12 Risk factors for effect because of the lower protoporphyrin IX light ab- all forms of porokeratosis include immunosuppression, sorption at longer wavelengths, but it has the advantage genetic inheritance, and UV radiation. Microscopic ex- of a deeper dermal penetration depth of 8 to 10 mm.10 amination of a skin biopsy specimen from an area of sus- Currently, 3 case reports have reported the use of picion is essential for diagnosis. methyl aminolevulinate PDT with red light for the treat- The final common pathway in all forms of porokerato- ment of disseminated superficial actinic porokeratosis, sis is a clonal hyperproliferation of atypical keratinocytes with varying results,17-19 and, to our knowledge, no re- resulting in the cornoid lamella.13 Porokeratosis of Mi- ports have cited the use of aminolevulinic acid PDT with belli is perhaps the most distinctive variant both clinically blue light or in combination with any current tradi- and histopathologically. Histologically, the invaginations tional therapies for PM. In light of this and the known of the epidermis are wider and deeper, and there is promi- efficacy of PDT in treating actinic keratosis,20 a disorder nent adjacent papillomatosis when compared with the other similarly characterized by actinically mediated atypical variants. Aside from this, all variants (and related disor- cell proliferation, it is possible that the distinctive his- ders that harbor cornoid lamellae) seem to represent a uni- tologic features of PM make therapy with both PDT and form reaction pattern of cornoid lamella, diminution of the fluorouracil a potentially useful treatment option when granular layer, dilated superficial plexus capillaries, and a they are used in combination for recalcitrant cases. Pho- nonspecific superficial chronic infiltrate. todynamic therapy and fluorouracil work by 2 indepen-

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©2010 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/24/2021 dent mechanisms of action: (1) PDT selectively targets a novel treatment for disseminated superficial actinic porokeratosis. Arch Dermatol. highly active, atypical cells and causes destruction by the 2007;143(11):1450-1452. 10. MacCormack MA. Photodynamic therapy in dermatology: an update on applica- creation of toxic intermediates; and (2) fluorouracil works tions and outcomes. Semin Cutan Med Surg. 2008;27(1):52-62. by inhibiting a major enzyme that is responsible in the 11. Lin JH, Hsu MM, Sheu HM, Lee JY. Coexistence of three variants of porokera- rate-limiting step of DNA synthesis, thus selectively in- tosis with multiple squamous cell carcinomas arising from lesions of giant hy- hibiting the rapid division of cells. We hypothesize that perkeratotic porokeratosis. J Eur Acad Dermatol Venereol. 2006;20(5):621- 623. PDT was the primary modality responsible for the clear- 12. Maubec E, Duvillard P, Margulis A, Bachollet B, Degois G, Avril MF. Common ance of the PM lesion given that the patient’s condition skin cancers in porokeratosis. Br J Dermatol. 2005;152(6):1389-1391. had not previously responded to fluorouracil mono- 13. Jurecka W, Neumann RA, Knobler RM. Porokeratoses: immunohistochemical, therapy. We cannot exclude an additive or synergistic light and electron microscopic evaluation. J Am Acad Dermatol. 1991;24(1): effect of fluorouracil to PDT. Nonetheless, PDT with or 96-101. 14. Kennedy JC, Pottier RH, Pross DC. Photodynamic therapy with endogenous pro- without combination therapy for PM appears to be safe, toporphyrin IX: basic principles and present clinical experience. J Photochem effective, and an excellent alternative solution for this Photobiol B. 1990;6(1-2):143-148. therapeutically challenging condition. 15. Morton CA, McKenna KE, Rhodes LE; British Association of Dermatologists Therapy Guidelines and Audit Subcommittee and the British Photodermatology Group. Guidelines for topical photodynamic therapy: update. Br J Dermatol. 2008;159 Accepted for Publication: April 6, 2009. (6):1245-1266. Correspondence: Jason J. Emer, MD, Department of Der- 16. Gold MH, Goldman MP. 5-Aminolevulinic acid photodynamic therapy: where we have been and where we are going. Dermatol Surg. 2004;30(8):1077-1084. matology, Mount Sinai School of Medicine, 5 E 98th St, 17. Nayeemuddin FA, Wong M, Yell J, Rhodes LE. Topical photodynamic therapy in Fifth Floor, New York, NY 10029 (jason.emer@mssm disseminated superficial actinic porokeratosis. Clin Exp Dermatol. 2002;27 .edu). (8):703-706. Author Contributions: All authors had full access to all 18. Cavicchini S, Tourlaki A. Successful treatment of disseminated superficial ac- the data in the study and take responsibility for the in- tinic porokeratosis with methyl aminolevulinate–photodynamic therapy. J Der- matolog Treat. 2006;17(3):190-191. tegrity of the data and the accuracy of the data analysis. 19. Ferna´ndez-Guarino M, Harto A, Pe´rez-Garcia B, Martin-Gonza´lez M, Urrutia S, Study concept and design: Levitt, Emer, and Emanuel. Ac- Jae´n P. Photodynamic therapy in disseminated superficial actinic porokeratosis. quisition of data: Levitt, Emer, and Emanuel. Analysis and J Eur Acad Dermatol Venereol. 2009;23(2):176-177. interpretation of data: Levitt, Emer, and Emanuel . Draft- 20. Braathen LR, Szeimies RM, Basset-Seguin N, et al; International Society for Pho- todynamic Therapy in Dermatology. Guidelines on the use of photodynamic therapy ing of the manuscript: Levitt, Emer, and Emanuel. Criti- for nonmelanoma skin cancer: an international consensus: International Society cal revision of the manuscript for important intellectual con- for Photodynamic Therapy in Dermatology, 2005. J Am Acad Dermatol. 2007; tent: Levitt, Emer, and Emanuel. Administrative, technical, 56(1):125-143. or material support: Emanuel. Study supervision: Levitt and Emanuel. Financial Disclosure: None reported. Submissions

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