Anthony D. Pearse

Guidelines for topical photodynamic therapy: report of a workshop of the British Photodermatology Group

Summary Topical photodynamic therapy (PDT) is effective in the treatment of certain non‐melanoma skin cancers and is under evaluation in other dermatoses. Its development has been enhanced by a low rate of adverse events and good cosmesis. 5‐Aminolaevulinic acid (ALA) is the main agent used, converted within cells into the photosensitizer protoporphyrin IX, with surface illumination then triggering the photodynamic reaction. Despite the relative simplicity of the technique, accurate dosimetry in PDT is complicated by multiple variables in drug formulation, delivery and duration of application, in addition to light‐specific parameters. Several non‐coherent and coherent light sources are effective in PDT. Optimal disease‐specific irradiance, wavelength and total dose characteristics have yet to be established, and are compounded by difficulties comparing light sources. The carcinogenic risk of ALA‐PDT appears to be low. Current evidence indicates topical PDT to be effective in actinic keratoses on the face and scalp, Bowens disease and superficial basal cell carcinomas (BCCs). PDT may prove advantageous where size, site or number of lesions limits the efficacy and/or acceptability of conventional therapies. Topical ALA‐PDT alone is a relatively poor option for both nodular BCCs and squamous cell carcinomas. Experience of the modality in other skin diseases remains limited; areas where there is potential benefit include viral warts, acne, psoriasis and cutaneous T‐cell lymphoma. A recent British Photodermatology Group workshop considered published evidence on topical PDT in order to establish guidelines to promote the efficacy and safety of this increasingly practised treatment modality.

Bowen’s disease, solar keratoses and superficial basal cell carcinomas treated by photodynamic therapy using a large-field incoherent light source

Background  Photodynamic therapy (PDT) has not yet been demonstrated to be superior to conventional treatment in the treatment of superficial skin cancers and premalignant skin conditions. A limitation for PDT is the absence to date of a light source suitable for the treatment of larger lesions or ‘field changes’ where several lesions are present on one anatomical site.

The quality of life of 790 patients with photodermatoses

Background  Polymorphic light eruption and erythropoietic protoporphyria (EPP) have been demonstrated to have a moderate and large impact on the quality of life (QoL) of patients, respectively. However, there is little information available about the impact of other photodermatoses on QoL.

Characterization of photosensitivity in the Smith-Lemli-Opitz syndrome: a new congenital photosensitivity syndrome.

Photosensitivity has recently been reported as a feature of the Smith–Lemli–Opitz syndrome (SLO). The aim of this study was to establish the photobiological features of this disorder and to examine the hypothesis that the photosensitivity is caused by the high levels of 7‐dehydrocholesterol found in SLO. All known cases of SLO in the U.K. were reviewed and clinical details of photosensitivity were recorded in detail. The action spectrum of the photosensitive eruption was defined by monochromator light testing. Thirteen of the 23 subjects (57%) had severe photosensitivity, and in 10 there was no photosensitivity. No correlation was identified between levels of 7‐dehydrocholesterol and severity of photosensitivity, suggesting that the photosensitivity in SLO is not caused by a direct phototoxic effect mediated by 7‐dehydrocholesterol. A novel pattern of photosensitivity was observed, with onset of a sunburn‐like erythema on sun‐exposed skin within minutes of sun exposure, which persisted in most cases for up to 24–48 h before fading. Monochromator light testing in three subjects showed an ultraviolet (UV) A‐mediated photosensitivity eruption with greatest photosensitivity at 350 nm. Photosensitivity is a common and prominent feature of SLO and appears to be UVA‐mediated. Elucidation of its biochemical basis may provide insight into normal cutaneous protective mechanisms against UVA‐induced photodamage, and also sun sensitivity in general.

Clinical response and tissue effects of etretinate treatment of patients with solar keratoses and basal cell carcinoma

Patients with basal cell carcinoma and solar keratoses were treated with etretinate. Substantial and prolonged clinical improvement was seen. All patients with solar keratoses showed a decrease in the mean area and number of lesions and eight patients demonstrated complete healing clinically. Two patients experienced recurrence at 9 months after completion of treatment. Histometric and cell kinetic measurements on the epidermis of skin samples from these patients were performed. They revealed epidermal thickening and increased deoxyribonucleic acid (DNA) synthesis both in lesions and in clinically uninvolved skin following treatment. Assessments were also made of enzyme activities in lesions and uninvolved skin with the use of established quantitative cytochemical techniques. Significant reduction in levels of succinic dehydrogenase activity following etretinate treatment was detected in solar keratoses and in basal cell carcinomas. This was also the case for uninvolved skin of patients with solar keratoses. Glucose-6-phosphate dehydrogenase (G6PD) activity was significantly reduced following etretinate treatment in solar keratoses and in basal cell carcinomas, but uninvolved skin did not exhibit significant changes. These changes are in contrast to those previously reported in normal subjects, where the activity increased, but are similar to those observed in patients with ichthyotic disorders. The alterations in the cytochemical profile following administration of etretinate in the lesions of patients reported here are consistent with the view that the drug promotes a more normal pattern of epidermal differentiation. We favor the view that etretinates antineoplastic action is exerted by preferentially allowing differentiation of normal epidermal cells and inhibiting dysplastic cells.

Actinic keratoses and the epidermis on which they arise

The appearance of the epidermis and epidermal autoradiographic labelling indices were compared in actinic keratoses and paralcsional skin in seventeen patients after injection of tritiated thymidine. The skin of the buttock area was also studied as a ‘non‐sun exposed’ control. Labelling indices obtained from skin removed after i h were as follows: actinic keratoses 17.4%; paralesional skin 11.2%; buttock skin 5.4%.

Photosensitivity associated with the Smith–Lemli–Opitz syndrome

A case of severe photosensitivity in a girl with the Smith–Lemli–Opitz syndrome is reported. Children with this recessively inherited metabolic disorder of cholesterol metabolism present with a variety of congenital abnormalities of the nervous system and internal organs in association with varying degrees of mental retardation. Photosensitivity is a feature which has previously only briefly been mentioned in the literature in association with this syndrome. However, more recently, it has become apparent that photosensitivity is not uncommon among children with the Smith–Lemli–Opitz syndrome, although the nature of the photosensitivity in these patients has remained undefined. Our patient has suffered from sunlight intolerance since early infancy, with redness and pruritus of sun‐exposed skin developing within minutes of sun exposure. Monochromator ultraviolet (UV) radiation and visible light testing revealed an immediate and persistent reaction to low‐dose UVA at 350 nm, and an abnormal erythemal response to visible light at 400 nm.

In vivo photoinduction of metallothionein in human skin by ultraviolet irradiation.

The aims of this study were to confirm and substantiate the in vivo cutaneous induction of metallothionein (MT) in human skin by UVR, which we have reported in brief previously, and to make a preliminary attempt to characterize the time course of this phenomenon. Buttock skin in 32 volunteers was irradiated with 2 MED of UVB and biopsies were taken at 24 h from matched non‐irradiated and irradiated sites. In the kinetic study, skin biopsies from six volunteers were taken at 0, 2, 8, 24, and 48 h after 2 MED UVB irradiation. MT was immunolocalized in formalin‐fixed, paraffin‐embedded tissue with the monoclonal antibody E9 by an indirect immunoperoxidase method. Statistically significant differences between immunocytochemical scores were identified between non‐irradiated (NI) and irradiated (I) skin within suprabasal keratinocytes (mean: NI=1·2, I=5·1; P=0·01), superficial dermal fibroblasts (mean: NI=2, I=43; P<0·001), mid‐dermal fibroblasts (mean: NI=0, I=27; P<0·001), and deep dermal fibroblasts (mean: NI=0,1=11; P<0·001. In the kinetic study, no consistent rise in MT score with time was observed for the epidermal component. In dermal fibroblasts, however, the first statistically significant rise in immunocytochemically detectable MT was detected at 2 h and this was found to plateau beyond 8 h. These results confirm that ambient levels of UV irradiation are capable of inducing MT in human skin in vivo. Taken together with the relative rapidity of the response, this suggests a physiological photoprotective role for MT in human skin cells. The lack of a kinetic increase in epidermal MT may be due to high basal levels. Induction of MT in dermal fibroblasts may reflect the effects of a diffusible factor released from keratinocytes after UVR.

Melanin content and distribution in the surface corneocyte with skin phototypes

Summary An individuals sensitivity to sunlight is traditionally assessed by the Boston or Fitzpatrick classification of skin type. The ability to tan depends, to some degree, on the melanin content of the epidermis. In the study reported here, surface corneocytes in exposed skin and unexposed skin have been assessed using a surface stripping slide mounting technique and an Optomax V image analyser, with which the percentage of corneocyte area occupied by melanin granules has been taken as the melanin content index (MCI). There was a significantly different MCI between different skin types for bolh exposed (P<0.0001) and unexposed (P<0.0001) areas using the Kruskal‐Wallis one‐way ANOVA test. There was also a positive significant correlation between MCI and skin types II‐VI in both exposed (r = 0.95, P< 0.00l) and unexposed areas (r = 0.89, P< 0.005). Image analysis also demonstrated that the number of melanin granules in surface corneocytes was significantly higher in the exposed area compared with the unexposed area, for skin types II, III, IV, V and VI. Melanin cap‐like structures were also observed in exposed corneocytes and heavily pigmented skin contained larger melanin particles than fairer skin. The results indicate that an individuals skin phototype and melanin content, assessed by image analysis, have a significant correlation.

Modulation of ultraviolet (UV) transmission by emollients: relevance to narrowband UVB phototherapy and psoralen plus UVA photochemotherapy.

Background  Patients with psoriasis undergoing or about to undergo ultraviolet (UV) phototherapy and photochemotherapy often have thick scale on their plaques which can prevent the penetration of UV radiation. Emollients are used to moisturize the skin and to prevent or reduce some of the milder side‐effects (‘dryness’, itching) sometimes experienced during UV therapy. However, emollients can alter the UV transmission of skin and thus may alter the clinical effects of phototherapy and photochemotherapy.