Practical approach to the use of daylight photodynamic therapy with topical methyl aminolevulinate for actinic keratosis: a European consensus.

INTRODUCTION: Daylight-mediated photodynamic therapy has been shown to be an effective therapy for actinic keratoses (AKs) and a simple and tolerable treatment procedure in three randomized Scandinavian studies and two recent Phase III randomized controlled studies in Australia and Europe. OBJECTIVES: To establish consensus recommendations for the use of daylight photodynamic therapy (DL-PDT) using topical methyl aminolaevulinate (MAL) in European patients with AKs. METHODS: The DL-PDT consensus recommendations were developed on behalf of the European Society for Photodynamic Therapy in Dermatology and comprised of 10 dermatologists from different European countries with experience in how to treat AK patients with PDT. Consensus was developed based on literature review and experience of the experts in the treatment of AK using DL-PDT. RESULTS: The recommendations arising from this panel of experts provide general guidance on the use of DL-PDT as a dermatological procedure with specific guidance regarding patient selection, therapeutic indications, when to treat, pre-treatment skin preparation, MAL application and daylight exposure for patients with AK in different countries of Europe. CONCLUSIONS: This consensus recommendation provides a framework for physicians to perform DL-PDT with MAL cream while ensuring efficiency and safety in the treatment of patients with AK in different European countries.

European guidelines for topical photodynamic therapy part 2: emerging indications--field cancerization, photorejuvenation and inflammatory/infective dermatoses.

In addition to established indications in non-melanoma skin cancer in immunocompetent patients, photodynamic therapy (PDT) has been studied for the treatment, and possible prevention, of superficial skin cancers in immunosuppressed patients. As a topical photosensitizer can be applied over large areas, PDT is also increasingly used for field cancerization in photodamaged skin, with evidence of potential to delay the development of actinic keratoses and basal cell carcinoma, although direct evidence of prevention of invasive squamous cell carcinoma remains limited. PDT has been studied in patch/plaque-stage cutaneous T-cell lymphoma, with efficacy more likely in unilesional disease. Accumulating evidence supports the use of PDT in acne and several other inflammatory/infective dermatoses including cutaneous leishmaniasis, although protocols are still to be refined. Despite proven efficacy, PDT is not widely used in viral/genital warts, where pain during treatment can be intense. PDT is a therapeutic option for photorejuvenation, with improvement in fine wrinkles, mottled hyperpigmentation, roughness and sallowness reported.

European guidelines for topical photodynamic therapy part 1: treatment delivery and current indications - actinic keratoses, Bowen's disease, basal cell carcinoma.

Topical photodynamic therapy (PDT) is a widely used non-invasive treatment for certain non-melanoma skin cancers, permitting treatment of large and multiple lesions with excellent cosmesis. High efficacy is demonstrated for PDT using standardized protocols in non-hyperkeratotic actinic keratoses, Bowen's disease, superficial basal cell carcinomas (BCC) and in certain thin nodular BCC, with superiority of cosmetic outcome over conventional therapies. Recurrence rates following PDT are typically equivalent to existing therapies, although higher than surgery for nodular BCC. PDT is not recommended for invasive squamous cell carcinoma. Treatment is generally well tolerated, but tingling discomfort or pain is common during PDT. New studies identify patients most likely to experience discomfort and permit earlier adoption of pain-minimization strategies. Reduced discomfort has been observed with novel protocols including shorter photosensitizer application times and in daylight PDT for actinic keratoses.

Photodynamic therapy for skin field cancerization: an international consensus. International Society for Photodynamic Therapy in Dermatology.

Field cancerization is a term that describes the presence of genetic abnormalities in a tissue chronically exposed to a carcinogen. These abnormalities are responsible for the presence of multilocular clinical and sub-clinical cancerous lesions that explains the increased risks of multiple cancers in this area. With respect to the skin, this term is used to define the presence of multiple non-melanoma skin cancer, its precursors, actinic keratoses and dysplastic keratinocytes in sun exposed areas. The multiplicity of the lesions and the extent of the area influence the treatment decision. Providing at least equivalent efficacy and tolerability, field directed therapies are therefore often more worthwhile than lesion targeted approaches. Photodynamic therapy (PDT) with its selective sensitization and destruction of diseased tissue is one ideal form of therapy for this indication. In the following paper the use of PDT for the treatment of field cancerized skin is reviewed and recommendations are given for its use.

Daylight photodynamic therapy for actinic keratosis: an international consensus: International Society for Photodynamic Therapy in Dermatology.

Photodynamic therapy (PDT) is an attractive therapy for non-melanoma skin cancers including actinic keratoses (AKs) because it allows treatment of large areas; it has a high response rate and results in an excellent cosmesis. However, conventional PDT for AKs is associated with inconveniently long clinic visits and discomfort during therapy. In this article, we critically review daylight-mediated PDT, which is a simpler and more tolerable treatment procedure for PDT. We review the effective light dose, efficacy and safety, the need for prior application of sunscreen, and potential clinical scope of daylight-PDT. Three randomized controlled studies have shown that daylight-mediated PDT is an effective treatment of thin AKs. Daylight-mediated PDT is nearly pain-free and more convenient for both the clinics and patients. Daylight-mediated PDT is especially suited for patients with large field-cancerized areas, which can easily be exposed to daylight. Further investigations are necessary to determine at which time of the year and in which weather conditions daylight-mediated PDT will be possible in different geographical locations.

Taking treatment decisions in non-melanoma skin cancer--the place for topical photodynamic therapy (PDT).

BACKGROUND: Epithelial non-melanoma skin cancer (NMSC) like actinic keratosis (AK), Bowen's disease (BD) and basal cell carcinoma (BCC) represent the most common malignancies in the fair skinned population. Epidemiological data reveal high incidences, especially for actinic keratoses, which are basically non-invasive squamous cell carcinomas, but fortunately bear a low risk of mortality for a single lesion. Nevertheless these lesions should be generally treated if other factors such as the state of the patient indicate that this is appropriate. The appearance of new treatment modalities like immuno-modulating topical agents, topical diclofenac, and photodynamic therapy in addition to a long list of already established treatments (curettage, surgery, cryotherapy, topical 5-fluorouracil, and many others) have led to the fact that patients and treating physicians have a large spectrum of therapeutic options to choose from. The same--with some variations--holds true for Bowen's disease and BCC. METHODS: Aim of this article is to offer an overview over NMSCs and their treatment options with emphasis on photodynamic therapy (PDT) as classical indications for PDT, to provide resources for guidelines for the treatment of these diseases, and to position PDT in this context by helping selecting patients that would profit most from topical PDT. RESULTS: Sufficient evidence is available to regard PDT as a standard treatment modality for NMSC. In addition to randomized controlled trials, long-term experience helps to find out the most appropriate treatment modality in a given patient. CONCLUSION: Physicians treating NMSC should have access to PDT and be trained and experienced in its use.

An application of propensity score methods to estimate the treatment effect of corticosteroids in patients with severe cutaneous adverse reactions.

PURPOSE: To investigate whether propensity score (ps) methods could reasonably be applied to estimate the treatment effect on mortality, based on a comparatively small sample of patients with severe cutaneous adverse reactions (SCAR) and who come from different countries where physicians prefer different treatment schemes. METHODS: Ps methods were applied to cope with confounding due to non-randomized treatment assignment for the analysis of the treatment data obtained in the case-control study EuroSCAR. For the study's purpose, the analysis focused on the comparison of the treatments: corticosteroids (STER) and supportive care only (SUPP). RESULTS: 206 French and German patients were treated either with SUPP or STER. Imbalances between treatment groups as well as between the countries were recognized. Concerning the balance between the treatment groups no ps model for the full cohort was satisfying. In addition, the inclusion of a variable for patient's country led to a separation of the patients by country. Thus, we developed ps models for each country separately and estimated the treatment effects (France: odds ratio (OR) 0.52, 95% confidence interval (CI) 0.09-3.10, Germany: OR 0.23, CI 0.06-0.92, Overall: OR 0.33 CI 0.11-1.04). CONCLUSIONS: The application of the ps methods was successful and provided valuable information. We could confirm the findings of the original analysis which was based on standard logistic regression, especially concerning the necessity of a country-specific analysis. The observed country differences in the estimated treatment effects were less pronounced and thus seemed to be more reasonable than those of the past analysis.

[Epidemiology of cutaneous vascular neoplasms and malformations in childhood]. / Epidemiologie kutaner vaskulärer Neu- und Fehlbildungen im Kindesalter.

PURPOSE: A representative compilation of data on the incidence and prevalence of benign cutaneous vascular neoplasms and malformations in childhood has been made. PATIENTS, MATERIALS AND METHODS: A review of the literature has been made and basic data from an own epidemiological survey in the province of Tyrol (Austria) in 6-year-old children are evaluated. RESULTS: For capillary malformations with spontaneous regression (salmon patches), the reported numbers usually vary between 20 and 30% of the newborns, while true, persisting capillary malformations (port-wine stains) can be found in about 1%. Strawberry angiomas are found in about 3% of mature newborns but in up to 12.5% of preterm children. Complex vascular malformations or severe cases of vascular tumours are very rare. CONCLUSION: All in all, vascular lesions are very common findings in childhood, but in most cases harmless and transient in nature. The number of lesions that may require adequate but usually uncomplicated treatment amounts to about one percent of children (strawberry angiomas and port-wine stains). Complex and/or life-threatening severe vascular tumours and malformations that represent a considerable therapeutic challenge are extremely rare events.

[Photodynamic therapy of cutaneous epithelial malignancies. An evidence-based review]. / Photodynamische Therapie bei epithelialen Hauttumoren. Evidenzbasierte Datenlage.

During the last years photodynamic therapy (PDT) has progressively established itself as a standard treatment for non-melanoma skin cancer. A number of clinical studies have demonstrated its efficacy--also compared to other treatment modalities--as well as good acceptance by patients and outstanding cosmetic results. For Bowen disease and superficial basal cell carcinoma, PDT can be regarded as the first-line non-invasive treatment. In the treatment of actinic keratoses PDT should be considered when cosmesis is crucial or in cases of field cancerization. In nodular basal cell carcinoma, effectiveness for lesions up to a thickness of 2 mm is well documented. In summary the evidence level seems sufficient to regard PDT as valuable treatment modality of which patients should not be deprived.

Photodynamic therapy using topical methyl 5-aminolevulinate compared with cryotherapy for actinic keratosis: A prospective, randomized study.

BACKGROUND: Actinic keratoses (AKs) are the most common premalignant tumors. Without treatment, a significant number of patients with AK will experience squamous cell carcinoma. Photodynamic therapy (PDT) using the new highly selective photosensitizer methyl 5-aminolevulinate is a promising new treatment modality for AK. OBJECTIVE: We investigated the complete response rates, cosmetic outcome, and patient satisfaction after photodynamic therapy (PDT) using methyl 5-aminolevulinate (Metvix) versus cryotherapy in the treatment of AKs. METHODS: Patients were randomized to receive either cryotherapy with liquid nitrogen spray or PDT using methyl 5-aminolevulinate cream 160 mg/g, 3 hours application time, and red light (75 J/cm(2)). RESULTS: Efficacy results from 193 patients with 699 lesions (92% face/scalp and 93% thin/moderately thick) were analyzed. Overall complete response rates after 3 months were 69% for PDT and 75% for cryotherapy. Both treatments gave higher response rates in thin lesions (PDT 75%, cryotherapy 80%). PDT gave better cosmetic results and higher patient satisfaction than cryotherapy. CONCLUSION: PDT using methyl 5-aminolevulinate is an attractive treatment option for patients with AK, with a response rate similar to that of cryotherapy, but with superior cosmetic results and high patient satisfaction.

Reduced number of CD1a+ cells in cutaneous B-cell lymphoma.

Cutaneous B-cell lymphoma is difficult to distinguish from pseudolymphoma. The histologic pattern and monoclonal restriction (immunohistochemical analysis and molecular biology) are the criteria used for differentiating these entities. CD1a+ dendritic cells have been observed in the infiltrates of T-cell lymphoma, but the presence of these CD1a+ cells has not been compared in B-cell lymphoma and pseudolymphoma. We studied the presence of CD1a+ cells on frozen sections of 23 B-cell lymphomas, 13 pseudolymphomas, and 17 T-cell lymphomas by immunohistochemical analysis. We found abundant CD1a+ dendritic cells in only 1 (4%) of 23 B-cell lymphomas, whereas in 8 (62%) of 13 pseudolymphomas and 17 (100%) of 17 T-cell lymphomas, strong CD1a staining was present. Our study demonstrates a distinct pattern of CD1a staining in the infiltrates of B-cell lymphoma and pseudolymphoma that may be of value in the differential diagnosis of these skin disorders.

Combined dermatofibroma: co-existence of two or more variant patterns in a single lesion.

AIMS: Based on a series of 25 cases, we define and characterize combined dermatofibroma, a tumour comprising two or more variant patterns of dermatofibroma in a single lesion. METHOD AND RESULTS: Dermatofibroma may present with a wide variety of architectural, cellular or stromal peculiarities. Architectural peculiarities include deep penetration, atrophy, collarette formation, fascicular to plexiform architecture, massive haemorrhage, prominent haemangiopericytoma-like vascularity and palisading; cellular peculiarities the presence of epithelioid cells, clear cells, granular cells, prominent myofibroblastic differentiation and atypical giant cells ('monster cells'); or stromal peculiarities such as prominent sclerosis, mucin, haemosiderin and cholesterotic deposits. In combined dermatofibromas two or more of these features are seen in complex or inhomogenous combination such as the silhouette of a deep penetrating dermatofibroma with an 'ordinary' storiform pattern in the upper and granular cell differentiation in the lower part of the lesion; or a dermatofibroma with ordinary features in the upper, prominent sclerosis in the middle and clear cells in the lower portion of the lesion; or the characteristic epidermal collarette and cells of epithelial cell histiocytoma with a plexiform ('neurothekeoma-like') architecture surrounded by a myxoid stroma with spindle-shaped to stellate cells. Clinically, these lesions preferentially occur on the lower extremities of young to middle-aged females, frequently with the diagnosis of a fibrohistiocytic lesion. Apart from one recurrence follow-up was uneventful in all other cases. Immunohistochemically, lesions are consistently positive with KiM1p, variably positive for factor XIIIa, smooth muscle specific actin and with KP1 (CD68), NK1C3 and E9. CONCLUSION: Recognition of combined dermatofibroma allows the histopathologist to apply a confident benign label to unusual lesions which might otherwise elude diagnosis, or tempt description of 'new' entities and to avoid a misdiagnosis of malignancy.

Non-Langerhans cell histiocytoses. A new unifying concept.

Based on our series of 111 cases of non-Langerhans cell histiocytoses, we present a new unifying concept for this rare group of disorders. The common denominator is the monocyte/ macrophage, which presents with various histologic features probably due to the influence of cytokines. Non-Langerhans cell histiocytoses are classified according to the predominant mononuclear (vacuolated, spindle-shaped, xanthomatized, scalloped, and oncocytic) and/or multinucleate (Touton, ground-glass appearance, Langhans, and foreign body) histiocytic cell types. Variable mixtures of these cell types produce common polymorphous patterns with prominence of vacuolated, spindle-shaped, and xanthomatized histiocytes in juvenile xanthogranulomas and of scalloped and oncocytic histiocytes in adult xanthogranulomas. Rarely, unusual monomorphous reaction patterns are observed: mostly vacuolated histiocytes are seen in the mononuclear variant of xanthogranulomas, (early benign cephalic histiocytosis, and generalized eruptive histiocytoma. Xanthomatized histiocytes predominate papular xanthoma and rarely xanthoma disseminatum, whereas spindle-shaped histiocytes are evident in spindle cell xanthogranuloma and progressive nodular histiocytosis, scalloped histiocytes are evident in most cases of xanthoma disseminatum, and finally oncocytic histiocytes are evident in reticulohistiocytoma and multicentric histiocytosis. Immunohistochemical, ultrastructural, and clinical findings can rationally be adjusted to this unifying concept of non-Langerhans cell histiocytoses. The time course of lesions, the age of the patients, and the presence or absence of underlying internal diseases are, or may, at least partially, be related to and thus explain variations on the theme of the non-Langerhans cell histiocytic reaction.

Indeterminate cell histiocytosis--a clinicopathological entity with features of both X- and non-X histiocytosis.

An otherwise healthy 50-year-old woman presented with a 6-month history of having developed more than 100 generalized, non-confluent, reddish-brown, partially yellow-coloured papules. A non-epidemotropic, monomorphous infiltrate of vacuolated mononuclear, and occasionally multinuclear, histiocytes, positive for factor XIIIa and macrophage markers HAM56 and KiM1p, was consistent with the clinical impression of generalized eruptive histiocytomas. However, the additional reactivity for S100 protein, in the absence of features of histiocytosis X, suggested a diagnosis of indeterminate cell histiocytosis (ICH). Further immunohistochemical studies, performed on snap-frozen material, characterized the lesions as being diffusely positive with LN3 (HLA-DR), Leu4 (CD3) and Leu3 (CD4), the infiltrate in the upper dermis as reactive for OKT6 (CD1) and IOT6c (CD1c), and the infiltrate in the lower dermis as reactive for a variety of macrophage markers. Ultrastructural studies showed various non-specific features of histocytic disorders, but no Birbeck granules. Our findings confirm those of previous reports suggesting that ICH is a distinct histiocytic entity, characterized by immunophenotypic features of both X- and non-X histiocytoses. Generalized eruptive histiocytoma seems to be an early indeterminate stage of various non-X histiocytic syndromes including ICH, multicentric reticulohistiocytosis, xanthogranuloma and xanthoma disseminatum. The distribution pattern of the various X/non-X histiocytic markers suggests dermal arrest of antigen-presenting cells during their physiological trafficking from the skin to the lymph nodes.

Deep penetrating dermatofibroma versus dermatofibrosarcoma protuberans. A clinicopathologic comparison.

A study of the clinical, histological, and immunohistochemical features of 20 cases of deep penetrating dermatofibroma (DPDF) and eight cases with 14 specimens (eight primary, one reexcision, five secondary tumors) of dermatofibrosarcoma protuberans (DFSP) showed distinct entities. Clinically, DPDF usually appeared as a nodule (approximately 2 cm) of the (lower) limbs, whereas DFSP affected the trunk (shoulder) with irregularly arranged plaques or nodules (> 5 cm). Histologically, DPDF showed a regular silhouette with a smooth, nodular (four of 20) or scalloped (16 of 20) lower margin and variable sclerosis (nine of 20); DFSP, irregularly infiltrated fatty tissue in a lacelike/honeycomb (eight of 14), multilayered (three of 14), or mixed pattern (three of 14), but without sclerosis. Immunohistochemically, DPDF was mostly negative with QBEnd 10 (CD34; 18 of 20) but positive for factor XIIIa (17 of 20), actin (HHF35; 10 of 20), and metallothionein (MT; 12 of 20). DFSP was positive for CD34 (13 of 14), yet with some sparing of central tumor parts, highly cellular tumor nodules, and myxoid areas; factor XIIIa and MT were consistently negative, as was HHF35 in 11 of 14 cases. In a multivariate analysis of histologic and immunohistochemical criteria, the combination of sclerosis and labeling with MT was most valid (p = 0.0001) for diagnosis: all DPDF showed either labeling with MT in "early" (metabolically active) lesions or sclerosis in "late" lesions, not present in DFSP.