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The Cutting Edge |

Treatment of Porokeratosis of Mibelli With Combined Use of Photodynamic Therapy and Fluorouracil Cream FREE

Jacob Levitt, MD; Jason J. Emer, MD; Patrick O. Emanuel, MD
[+] Author Affiliations

Section Editor: Erik J. Stratman, MD
Assistant Section Editor: William D. Aughenbaugh, MD
Assistant Section Editor: Michael P. Heffernan, MD

More Author Information
Arch Dermatol. 2010;146(4):371-373. doi:10.1001/archdermatol.2010.28.
Text Size: A A A
Published online

REPORT OF A CASE

A 45-year-old white man with a medical history that was remarkable for human immunodeficiency virus and AIDS complicated by Kaposi sarcoma presented with a 14-year history of a recurring scaly, pruritic lesion on the dorsal aspect of his left shin. The lesion was refractory to treatment with topical corticosteroids, tazarotene, salicylic acid, and various emollient and keratolytic creams. Recently, the lesion had become increasingly large, pruritic, painful, and cosmetically displeasing. Skin examination of the left dorsal shin area showed a thick, hyperkeratotic plaque with a distinct, raised annular border (Figure 1). A skin biopsy specimen revealed a broad-based parakeratotic column of cells traversing the stratum corneum (cornoid lamella), an underlying epidermis devoid of a granular layer, and dissolution of basal cells with shouldering acantholysis. A sparse, nonspecific, lymphocytic infiltrate was seen in the upper dermis (Figure 2). The clinical and histopathologic features supported a diagnosis of porokeratosis of Mibelli (PM). The patient was treated with a 4-week trial of imiquimod cream followed by an 8-week trial of fluorouracil cream, without success.

Place holder to copy figure label and caption
Figure 1.

Clinical photograph demonstrating porokeratosis of Mibelli on the dorsal aspect of the left shin before photodynamic therapy.

Graphic Jump Location
Place holder to copy figure label and caption
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, shouldering acantholysis, and an absent granular layer (hematoxylin-eosin, original magnification ×100).

Graphic Jump Location

THERAPEUTIC CHALLENGE

Many treatments have been suggested for porokeratosis, and the results have often been disappointing. The approach to treatment is individualized and based on many factors, such as lesion size and location, risk of malignant transformation, and functional and aesthetical considerations. Sun protection, aggressive use of emollients, and observation for signs of malignant degeneration may be all that is needed in many cases. However, if the lesions are widespread or displeasing, curative therapy is warranted.

It has been suggested that a lesion of porokeratosis results from a local or systemic change in immune function that in turn allows the development of atypical clones of keratinocytes. Useful medical modalities should therefore work by inhibiting cell growth and proliferation as well as regulating and modulating keratinocyte differentiation. Oral and topical retinoids,1,2 fluorouracil cream,3 vitamin D3 analogues,4 diclofenac gel,5 and imiquimod cream6 have all been used to treat porokeratosis. Surgical 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 nonscarring.10 Many of the traditional therapies used for PM had previously been used in our patient, without adequate success; therefore, an alternative and novel therapy was attempted.

SOLUTION

While daily treatment with topical fluorouracil cream was continued, 1 session of photodynamic therapy (PDT) with aminolevulinic acid (Levulan Kerastick; DUSA Pharmaceuticals, Wilmington, Massachusetts), using a 2-hour incubation and exposure to blue light (Blu-U; DUSA Pharmaceuticals) for 16 minutes and 40 seconds, was added to the regimen. The combination of these 2 therapies resulted in complete clearance of the lesion at 3 weeks, with sustained clearance during 6 months of follow-up (Figure 3).

Place holder to copy figure label and caption
Figure 3.

Clinical photograph demonstrating the complete clearance of 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 daily topical fluorouracil therapy.

Graphic Jump Location

COMMENT

Porokeratosis is a disorder of abnormal keratinization with many clinical variations. It is characterized by the appearance of 1 or more atrophic patches surrounded by a clinically and histologically unique ridgelike border termed the cornoid lamella. The cornoid lamella is formed by a rapid hyperproliferation of atypical keratinocytes that expands peripherally to form a raised boundary between abnormal and normal cells. Lesions are most commonly found on the extremities, and in the setting of immunosuppression, they are large and rapidly expanding. Most often, the skin lesions of porokeratosis are asymptomatic; however, ulcerative, verrucous, giant, and malignant lesions have been identified.11,12 Risk factors for all forms of porokeratosis include immunosuppression, genetic inheritance, and UV radiation. Microscopic examination of a skin biopsy specimen from an area of suspicion is essential for diagnosis.

The final common pathway in all forms of porokeratosis is a clonal hyperproliferation of atypical keratinocytes resulting in the cornoid lamella.13 Porokeratosis of Mibelli is perhaps the most distinctive variant both clinically and histopathologically. Histologically, the invaginations of the epidermis are wider and deeper, and there is prominent adjacent papillomatosis when compared with the other variants. Aside from this, all variants (and related disorders that harbor cornoid lamellae) seem to represent a uniform reaction pattern of cornoid lamella, diminution of the granular layer, dilated superficial plexus capillaries, and a nonspecific superficial chronic infiltrate.

Photodynamic therapy is a relatively new treatment modality that is currently used for the treatment of various skin cancers, actinic keratosis, and acne. It uses topically applied aminolevulinic acid or methyl aminolevulinate that penetrates damaged or active epidermal cells and is converted to a potent photosensitizing protoporphyrin IX. Studies have shown that 3 mechanisms contribute to the efficacy of PDT: (1) direct cell destruction through the activation of protoporphyrin IX and the subsequent formation of reactive cytotoxic oxygen species; (2) microvascular damage that causes hypoxia and tissue necrosis; and (3) up-regulation of tumor necrosis factor α, interleukin 1, and interleukin 6, which aid in the elimination of tumor tissue.1416 The penetration of light into tissue varies and is conversely proportional to the increasing wavelength. The largest absorption peak of the reactive intermediates is at 410 nm (blue light), with smaller absorption peaks at 505, 540, 580, and 630 nm (red light). Blu-U takes advantage of the largest absorption peak at 417 nm but is limited to a depth of penetration of 1.5 to 2 mm into the epidermis. Red light (>600 nm) requires higher energy levels to achieve the same effect because of the lower protoporphyrin IX light absorption at longer wavelengths, but it has the advantage of a deeper dermal penetration depth of 8 to 10 mm.10

Currently, 3 case reports have reported the use of methyl aminolevulinate PDT with red light for the treatment of disseminated superficial actinic porokeratosis, with varying results,1719 and, to our knowledge, no reports have cited the use of aminolevulinic acid PDT with blue light or in combination with any current traditional therapies for PM. In light of this and the known efficacy of PDT in treating actinic keratosis,20 a disorder similarly characterized by actinically mediated atypical cell proliferation, it is possible that the distinctive histologic features of PM make therapy with both PDT and fluorouracil a potentially useful treatment option when they are used in combination for recalcitrant cases. Photodynamic therapy and fluorouracil work by 2 independent mechanisms of action: (1) PDT selectively targets highly active, atypical cells and causes destruction by the creation of toxic intermediates; and (2) fluorouracil works by inhibiting a major enzyme that is responsible in the rate-limiting step of DNA synthesis, thus selectively inhibiting the rapid division of cells. We hypothesize that PDT was the primary modality responsible for the clearance of the PM lesion given that the patient's condition had not previously responded to fluorouracil monotherapy. We cannot exclude an additive or synergistic effect of fluorouracil to PDT. Nonetheless, PDT with or without combination therapy for PM appears to be safe, effective, and an excellent alternative solution for this therapeutically challenging condition.Article

ARTICLE INFORMATION

Correspondence: Jason J. Emer, MD, Department of Dermatology, Mount Sinai School of Medicine, 5 E 98th St, Fifth Floor, New York, NY 10029 (jason.emer@mssm.edu).

Accepted for Publication: April 6, 2009.

Financial Disclosure: None reported.

Author Contributions: All authors had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Levitt, Emer, and Emanuel. Acquisition of data: Levitt, Emer, and Emanuel. Analysis and interpretation of data: Levitt, Emer, and Emanuel. Drafting of the manuscript: Levitt, Emer, and Emanuel. Critical revision of the manuscript for important intellectual content: Levitt, Emer, and Emanuel. Administrative, technical, or material support: Emanuel. Study supervision: Levitt and Emanuel.

Submissions

Clinicians, residents, and fellows are invited to submit cases of challenges in management and therapeutics to this section. Cases should follow the established pattern. Manuscripts should be prepared double-spaced with right margins nonjustified. Pages should be numbered consecutively with the title page separated from the text (see Instructions for Authors [http://archderm.ama-assn.org/misc/ifora.dtl] for information about preparation of the title page). Clinical photographs, photomicrographs, and illustrations must be sharply focused and submitted as separate JPG files with each file numbered with the figure number. Material must be accompanied by the required copyright transfer statement (see authorship form [http://archderm.ama-assn.org/misc/auinst_crit.pdf]). Preliminary inquiries regarding submissions for this feature may be submitted to Erik J. Stratman, MD (stratman.erik@marshfieldclinic.org). Manuscripts should be submitted via our online manuscript submission and review system (http://manuscripts.archdermatol.com).

REFERENCES

Grover  CGoel  ANanda  SKhurana  NReddy  BS A case of extensive linear porokeratosis with evaluation of topical tretinoin versus 5-flourouracil as treatment modalities. J Dermatol 2005;32 (12) 1000- 1004
PubMed
McCallister  REEstes  SAYarbrough  CL Porokeratosis plantaris, palmaris, et disseminata: report of a case and treatment with isotretinoin. J Am Acad Dermatol 1985;13 (4) 598- 603
PubMed Link to Article
McDonald  SGPeterka  ES Porokeratosis (Mibelli): treatment with topical 5-fluorouracil. J Am Acad Dermatol 1983;8 (1) 107- 110
PubMed Link to Article
Harrison  PVStollery  N Disseminated superficial actinic porokeratosis responding to calcipotriol. Clin Exp Dermatol 1994;19 (1) 95
PubMed Link to Article
Vlachou  CKanelleas  AMartin-Clavijo  ABerth-Jones  J Treatment of disseminated superficial actinic porokeratosis with topical diclofenac gel: a case series. J Eur Acad Dermatol Venereol 2008;22 (11) 1343- 1345
PubMed Link to Article
Harrison  SSinclair  R Porokeratosis of Mibelli: successful treatment with topical 5% imiquimod cream. Australas J Dermatol 2003;44 (4) 281- 283
PubMed Link to Article
Dereli  TOzyurt  SOzturk  G Porokeratosis of Mibelli: successful treatment with cryosurgery. J Dermatol 2004;31 (3) 223- 227
PubMed
Spencer  JMKatz  BE Successful treatment of porokeratosis of Mibelli with diamond fraise dermabrasion. Arch Dermatol 1992;128 (9) 1187- 1188
PubMed Link to Article
Chrastil  BGlaich  ASGoldberg  LHFriedman  PM Fractional photothermolysis: a novel treatment for disseminated superficial actinic porokeratosis. Arch Dermatol 2007;143 (11) 1450- 1452
PubMed Link to Article
MacCormack  MA Photodynamic therapy in dermatology: an update on applications and outcomes. Semin Cutan Med Surg 2008;27 (1) 52- 62
PubMed Link to Article
Lin  JHHsu  MMSheu  HMLee  JY Coexistence of three variants of porokeratosis with multiple squamous cell carcinomas arising from lesions of giant hyperkeratotic porokeratosis. J Eur Acad Dermatol Venereol 2006;20 (5) 621- 623
PubMed Link to Article
Maubec  EDuvillard  PMargulis  ABachollet  BDegois  GAvril  MF Common skin cancers in porokeratosis. Br J Dermatol 2005;152 (6) 1389- 1391
PubMed Link to Article
Jurecka  WNeumann  RAKnobler  RM Porokeratoses: immunohistochemical, light and electron microscopic evaluation. J Am Acad Dermatol 1991;24 (1) 96- 101
PubMed Link to Article
Kennedy  JCPottier  RHPross  DC Photodynamic therapy with endogenous protoporphyrin IX: basic principles and present clinical experience. J Photochem Photobiol B 1990;6 (1-2) 143- 148
PubMed Link to Article
Morton  CAMcKenna  KERhodes  LEBritish Association of Dermatologists Therapy Guidelines and Audit Subcommittee and the British Photodermatology Group, Guidelines for topical photodynamic therapy: update. Br J Dermatol 2008;159 (6) 1245- 1266
PubMed Link to Article
Gold  MHGoldman  MP 5-Aminolevulinic acid photodynamic therapy: where we have been and where we are going. Dermatol Surg 2004;30 (8) 1077- 1084
PubMed
Nayeemuddin  FAWong  MYell  JRhodes  LE Topical photodynamic therapy in disseminated superficial actinic porokeratosis. Clin Exp Dermatol 2002;27 (8) 703- 706
PubMed Link to Article
Cavicchini  STourlaki  A Successful treatment of disseminated superficial actinic porokeratosis with methyl aminolevulinate–photodynamic therapy. J Dermatolog Treat 2006;17 (3) 190- 191
PubMed Link to Article
Fernández-Guarino  MHarto  APérez-Garcia  BMartin-González  MUrrutia  SJaén  P Photodynamic therapy in disseminated superficial actinic porokeratosis. J Eur Acad Dermatol Venereol 2009;23 (2) 176- 177
PubMed Link to Article
Braathen  LRSzeimies  RMBasset-Seguin  N  et al. International Society for Photodynamic Therapy in Dermatology, Guidelines on the use of photodynamic therapy for nonmelanoma skin cancer: an international consensus: International Society for Photodynamic Therapy in Dermatology, 2005. J Am Acad Dermatol 2007;56 (1) 125- 143
PubMed Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.

Clinical photograph demonstrating porokeratosis of Mibelli on the dorsal aspect of the left shin before photodynamic therapy.

Graphic Jump Location
Place holder to copy figure label and caption
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, shouldering acantholysis, and an absent granular layer (hematoxylin-eosin, original magnification ×100).

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.

Clinical photograph demonstrating the complete clearance of 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 daily topical fluorouracil therapy.

Graphic Jump Location

Tables

References

Grover  CGoel  ANanda  SKhurana  NReddy  BS A case of extensive linear porokeratosis with evaluation of topical tretinoin versus 5-flourouracil as treatment modalities. J Dermatol 2005;32 (12) 1000- 1004
PubMed
McCallister  REEstes  SAYarbrough  CL Porokeratosis plantaris, palmaris, et disseminata: report of a case and treatment with isotretinoin. J Am Acad Dermatol 1985;13 (4) 598- 603
PubMed Link to Article
McDonald  SGPeterka  ES Porokeratosis (Mibelli): treatment with topical 5-fluorouracil. J Am Acad Dermatol 1983;8 (1) 107- 110
PubMed Link to Article
Harrison  PVStollery  N Disseminated superficial actinic porokeratosis responding to calcipotriol. Clin Exp Dermatol 1994;19 (1) 95
PubMed Link to Article
Vlachou  CKanelleas  AMartin-Clavijo  ABerth-Jones  J Treatment of disseminated superficial actinic porokeratosis with topical diclofenac gel: a case series. J Eur Acad Dermatol Venereol 2008;22 (11) 1343- 1345
PubMed Link to Article
Harrison  SSinclair  R Porokeratosis of Mibelli: successful treatment with topical 5% imiquimod cream. Australas J Dermatol 2003;44 (4) 281- 283
PubMed Link to Article
Dereli  TOzyurt  SOzturk  G Porokeratosis of Mibelli: successful treatment with cryosurgery. J Dermatol 2004;31 (3) 223- 227
PubMed
Spencer  JMKatz  BE Successful treatment of porokeratosis of Mibelli with diamond fraise dermabrasion. Arch Dermatol 1992;128 (9) 1187- 1188
PubMed Link to Article
Chrastil  BGlaich  ASGoldberg  LHFriedman  PM Fractional photothermolysis: a novel treatment for disseminated superficial actinic porokeratosis. Arch Dermatol 2007;143 (11) 1450- 1452
PubMed Link to Article
MacCormack  MA Photodynamic therapy in dermatology: an update on applications and outcomes. Semin Cutan Med Surg 2008;27 (1) 52- 62
PubMed Link to Article
Lin  JHHsu  MMSheu  HMLee  JY Coexistence of three variants of porokeratosis with multiple squamous cell carcinomas arising from lesions of giant hyperkeratotic porokeratosis. J Eur Acad Dermatol Venereol 2006;20 (5) 621- 623
PubMed Link to Article
Maubec  EDuvillard  PMargulis  ABachollet  BDegois  GAvril  MF Common skin cancers in porokeratosis. Br J Dermatol 2005;152 (6) 1389- 1391
PubMed Link to Article
Jurecka  WNeumann  RAKnobler  RM Porokeratoses: immunohistochemical, light and electron microscopic evaluation. J Am Acad Dermatol 1991;24 (1) 96- 101
PubMed Link to Article
Kennedy  JCPottier  RHPross  DC Photodynamic therapy with endogenous protoporphyrin IX: basic principles and present clinical experience. J Photochem Photobiol B 1990;6 (1-2) 143- 148
PubMed Link to Article
Morton  CAMcKenna  KERhodes  LEBritish Association of Dermatologists Therapy Guidelines and Audit Subcommittee and the British Photodermatology Group, Guidelines for topical photodynamic therapy: update. Br J Dermatol 2008;159 (6) 1245- 1266
PubMed Link to Article
Gold  MHGoldman  MP 5-Aminolevulinic acid photodynamic therapy: where we have been and where we are going. Dermatol Surg 2004;30 (8) 1077- 1084
PubMed
Nayeemuddin  FAWong  MYell  JRhodes  LE Topical photodynamic therapy in disseminated superficial actinic porokeratosis. Clin Exp Dermatol 2002;27 (8) 703- 706
PubMed Link to Article
Cavicchini  STourlaki  A Successful treatment of disseminated superficial actinic porokeratosis with methyl aminolevulinate–photodynamic therapy. J Dermatolog Treat 2006;17 (3) 190- 191
PubMed Link to Article
Fernández-Guarino  MHarto  APérez-Garcia  BMartin-González  MUrrutia  SJaén  P Photodynamic therapy in disseminated superficial actinic porokeratosis. J Eur Acad Dermatol Venereol 2009;23 (2) 176- 177
PubMed Link to Article
Braathen  LRSzeimies  RMBasset-Seguin  N  et al. International Society for Photodynamic Therapy in Dermatology, Guidelines on the use of photodynamic therapy for nonmelanoma skin cancer: an international consensus: International Society for Photodynamic Therapy in Dermatology, 2005. J Am Acad Dermatol 2007;56 (1) 125- 143
PubMed Link to Article

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