The current options in the management of actinic keratosis.

Actinic keratosis is a precursor for squamous cell skin cancer. Hence, it is important to treat. For single actinic keratoses, cryo surgery is recommended. For widespread actinic keratoses, imiquimod, photodynamic therapy (PDT) or 5-FU may be used. ''One-shot'' treatments are advocated as prolonged treatment over several weeks probably diminishes patient compliance. Consequently, cryo surgery for single actinic keratoses and PDT for widespread actinic keratoses should primarily be recommended.

Bioavailability of aminolaevulinic acid and methylaminolaevulinate in basal cell carcinomas: a perfusion study using microdialysis in vivo.

BACKGROUND: Photodynamic therapy is becoming a popular treatment for superficial nonmelanoma precancerous and cancerous lesions, showing excellent cosmetic results. Nevertheless, the reported cure rates vary and the transdermal penetration of drugs has been discussed as a limiting factor, particularly for treatment of nodular basal cell carcinoma (BCC). OBJECTIVES: To investigate the transdermal penetration of aminolaevulinic acid (ALA) and methylaminolaevulinate (MAL) in BCC in vivo using a microdialysis technique. The different prodrugs were compared and the effect of curettage was studied. METHODS: Twenty patients with 27 histologically verified BCCs (13 superficial, 14 nodular) were included. All lesions were located at the front of the body (head and face excluded). The first 10 patients included were treated with MAL (13 BCCs), and the following 10 patients with ALA (14 BCCs). A light curettage was performed on every second lesion (curettage, n = 13; noncurettage, n = 14). Microdialysis catheters were inserted into the tumours at tissue depths varying from 0.4 to 1.9 mm. Dialysates were collected at 15-30-min intervals for 4 h and the interstitial concentrations of MAL and ALA were determined using high-performance liquid chromatography. RESULTS: No significant difference in interstitial drug concentration was observed between lesions treated with ALA or MAL during the 4-h measurement period. However, for the lesions with deeper catheter locations, i.e. at or below 1 mm (n = 11), drug concentrations above the detection limit were obtained in only six lesions. All but one BCC with superficial catheter location, i.e. < 1 mm (n = 16), exhibited detectable drug concentration (P = 0.026). The interstitial peak concentrations were reached within 90 min in 23 of the 27 BCCs, but were not found to be correlated with the depth of the catheters. No difference was found when comparing superficial and nodular BCCs, and the effect of curettage was found to be negligible. CONCLUSIONS: The results imply that there is no significant difference in transdermal penetration of ALA and MAL in tumour tissue. Detectable levels of drug were not obtained in almost 50% of the lesions where catheters were situated 1-1.9 mm in the lesion. Curettage was not found to affect the interstitial concentration, indicating that penetration of drug indeed might be a problem when treating BCCs thicker than 1 mm.

Bispectral fluorescence imaging of aggressive basal cell carcinoma combined with histopathological mapping: a preliminary study indicating a possible adjunct to Mohs micrographic surgery.

BACKGROUND: Fluorescence imaging is an attractive diagnostic technique for skin tumour demarcation with potential to move to clinical use. Bispectral fluorescence imaging combines skin autofluorescence with delta-aminolaevulinic acid-induced fluorescence. To evaluate the technique, fluorescence data must be compared with the histopathological extent of the tumour, which is the purpose of the current study. OBJECTIVES: To investigate the agreement between bispectral fluorescence images and the histopathological tumour boundary of ill-defined basal cell carcinomas (BCCs). After fluorescence imaging the tumours were removed using Mohs micrographic surgery (MMS) to obtain histopathological maps of the tumour boundaries. METHODS: Twelve patients with aggressive BCC of mean diameter 16 mm (range 5-32) in the face were included in the study. The patients were subjected to bispectral fluorescence imaging within the 2 months prior to MMS. The fluorescence images and histopathological maps were aligned using image warping. RESULTS: Five patients (42%) showed good agreement with the histopathological mapping and the remaining seven patients (58%) showed partial agreement. Bispectral investigation combining autofluorescence with protoporphyrin IX (PpIX) fluorescence generally yielded better agreement with the histopathological boundaries of the tumours compared with using only the PpIX fluorescence. CONCLUSIONS: In this preliminary study the fluorescence has been compared with the histopathological tumour boundaries. The result implies that the technique can be applied as a useful tool for indicating tumour boundary of aggressive BCCs. Further refinement is needed to be able to indicate the exact tumour border.

Percutaneous absorption of the sunscreen benzophenone-3 after repeated whole-body applications, with and without ultraviolet irradiation.

BACKGROUND: Benzophenone-3 (BZ-3; 2-hydroxy-4-methoxybenzophenone, oxybenzone) is commonly used to absorb ultraviolet (UV) radiation. BZ-3 penetrates the skin and can be found in the urine. The amount varies between 0.4% and 2%. This seems to be the main metabolic pathway in rats. OBJECTIVES: To investigate the total amount of BZ-3 excreted in the urine after repeated topical whole-body applications of a sunscreen and to see if UV radiation has any effect on the amount excreted. METHODS: Twenty-five volunteers applied a commercially available sunscreen containing 4% BZ-3 morning and night for 5 days. Their urine was measured during those 5 days and during a further 5 days after the last application. They were divided into groups A (unirradiated) and B. Group B received UV radiation according to skin type: UVA between 400 and 707 J cm(-2), and UVB between 0.46 and 2.0 J cm(-2). BZ-3 in urine was analysed with a high-performance liquid chromatography method. RESULTS: The volunteers excreted 1.2-8.7% (mean 3.7%) of the total amount of BZ-3 applied. There was no significant difference between the two groups (P < 0.99, t-test). CONCLUSIONS: We show that a large amount of BZ-3 is absorbed. BZ-3 is accumulated in the body as the volunteers excreted BZ-3 5 days after the last application.

Photodynamic therapy of actinic keratosis at varying fluence rates: assessment of photobleaching, pain and primary clinical outcome.

BACKGROUND: Although photodynamic therapy (PDT) is becoming an important treatment method for skin lesions such as actinic keratosis (AK) and superficial basal cell carcinoma, there are still discussions about which fluence rate and light dose are preferable. Recent studies in rodents have shown that a low fluence rate is preferable due to depletion of oxygen at high fluence rates. However, these results have not yet been verified in humans. OBJECTIVES: The objective was to investigate the impact of fluence rate and spectral range on primary treatment outcome and bleaching rate in AK using aminolaevulinic acid PDT. In addition, the pain experienced by the patients has been monitored during treatment. PATIENTS/METHODS: Thirty-seven patients (mean age 71 years) with AK located on the head, neck and upper chest were treated with PDT, randomly allocated to four groups: two groups with narrow filter (580-650 nm) and fluence rates of 30 or 45 mW cm(-2), and two groups with broad filter (580-690 nm) and fluence rates of 50 or 75 mW cm(-2). The total cumulative light dose was 100 J cm(-2) in all treatments. Photobleaching was monitored by fluorescence imaging, and pain experienced by the patients was registered by using a visual analogue scale graded from 0 (no pain) to 10 (unbearable pain). The primary treatment outcome was evaluated at a follow-up visit after 7 weeks. RESULTS: Our data showed a significant correlation between fluence rate and initial treatment outcome, where lower fluence rate resulted in favourable treatment response. Moreover, the photobleaching dose (1/e) was found to be related to fluence rate, ranging from 4.5 +/- 1.0 J cm(-2) at 30 mW cm(-2), to 7.3 +/- 0.7 J cm(-2) at 75 mW cm(-2), indicating higher oxygen levels in tissue at lower fluence rates. After a cumulative light dose of 40 J cm(-2) no further photobleaching took place, implying that higher doses are excessive. No significant difference in pain experienced by the patients during PDT was observed in varying the fluence rate from 30 to 75 mW cm(-2). However, the pain was found to be most intense up to a cumulative light dose of 20 J cm(-2). CONCLUSIONS: Our results imply that the photobleaching rate and primary treatment outcome are dependent on fluence rate, and that a low fluence rate (30 mW cm(-2)) seems preferable when performing PDT of AK using noncoherent light sources.

Topical methyl aminolaevulinate photodynamic therapy in patients with basal cell carcinoma prone to complications and poor cosmetic outcome with conventional treatment.

BACKGROUND: Conventional treatment of basal cell carcinoma (BCC) causes morbidity and/or disfigurement in some patients because of the location (e.g. mid-face) and size of the lesion. OBJECTIVES: Following reports that such difficult-to-treat BCC lesions have been treated successfully with topical methyl aminolaevulinate (MAL) photodynamic therapy (PDT), a multicentre study was performed to determine the response of such BCC to MAL-PDT. METHODS: An open, uncontrolled, prospective, multicentre study was conducted comprising patients with superficial and/or nodular BCC who were at risk of complications, poor cosmetic outcome, disfigurement and/or recurrence using conventional therapy. Patients were given one or two cycles within 3 months of topical MAL-PDT, each consisting of two treatments 1 week apart. Tumour response was assessed clinically at 3 months after the last PDT, with histological confirmation of all lesions in clinical remission. The cosmetic outcome was rated. Patients with a BCC in remission will be followed up for 5 years for recurrence, of which the 24-month follow-up is reported here. Ninety-four patients with 123 lesions were enrolled and treated with MAL-PDT at nine European primary care and referral university hospitals. An independent blinded study review board (SRB) retrospectively excluded nine patients and a total of 15 lesions from the efficacy analysis, for not having a difficult-to-treat BCC according to the protocol. RESULTS: The lesion remission rate at 3 months was 92% (45 of 49) for superficial BCC, 87% (45 of 52) for nodular BCC, and 57% (four of seven) for mixed BCC, as assessed by clinical examination, and 85% (40 of 47), 75% (38 of 51), and 43% (three of seven), respectively, as assessed by histological examination and verified by the SRB. At 24 months after treatment, the overall lesion recurrence rate was 18% (12 of 66). The cosmetic outcome was graded as excellent or good by the investigators in 76% of the cases after 3 months follow-up, rising to 85% at 12 months follow-up, and 94% at 24 months follow-up. CONCLUSIONS: Topical MAL-PDT is effective in treating BCC at risk of complications and poor cosmetic outcome using conventional therapy. MAL-PDT preserves the skin and shows favourable cosmetic results.

A spectroscopic study of the photobleaching of protoporphyrin IX in solution.

Photodynamic therapy (PDT) has developed into an important new clinical treatment for cancer during the past 30 years. The method is non-invasive and based on the photochemical activity of a photosensitising agent present in cells and tissues. In so-called ALA-PDT, protoporphyrin IX (Pp IX) is induced from aminolaevulinic acid (ALA) applied topically or systemically. It has been shown that Pp IX is photodegraded by a photo-oxidation process and that its photoproducts have a characteristic absorption band around 670 nm, as observed both in solution and in cells incubated with ALA. In this study, the involvement of oxygen in the photobleaching process was verified by studying the effect of oxygen depletion using the freeze-pump-thaw (FPT) method. A solution of Pp IX in dimethylformamide (DMF) was exposed to light in the wavelength region 600-700 nm (peak centred at 620 (+/-25) nm) both in the presence and in the absence of oxygen. The bleaching process was observed by absorbance and fluorescence measurements. Photobleaching was observed in the presence of oxygen, as verified by the build-up of a photoproduct absorbing at 670 nm. When the sample was deoxygenated with the FPT method, the photoproduct absorption peak at 670 nm was missing. These results confirm that the formation of photoprotopor-phyrin is a photo-oxidation process and that no photobleaching takes place in the absence of oxygen. When comparing our results to the studies carried out by N(2) bubbling, the N(2) bubbling seems to be insufficient to remove the oxygen completely from the solution.

Percutaneous absorption of benzophenone-3, a common component of topical sunscreens.

Benzophenone-3 (BZ-3) is a commonly used, chemical UV-absorber. It has been used for many years to protect against UV-radiation. Previous studies have shown that BZ-3 penetrates the skin, and it can be found in urine, faeces, and blood. In this study we examined the percutaneous absorption of BZ-3. The amount of BZ-3 absorbed was measured in urine, as experimental studies in the rat have shown that urine is the major route of excretion. Eleven volunteers applied the recommended amount of a commercially available sunscreen and urine samples were collected during a 48-h period after application. The average total amount excreted was 11 mg, median 9.8 mg, which is approximately 0.4% of the applied amount of BZ-3. Some of the volunteers still excreted BZ-3 48 h after application. It is evident that BZ-3 undergoes conjugation in the body to make it water soluble. However, we do not know at what age the ability to conjugate is fully developed, and therefore for children physical filters such as titanium dioxide and/or zinc oxide might still be considered a more appropriate sunscreen component.

Pain caused by photodynamic therapy of skin cancer.

Pain resulting from photodynamic therapy (PDT) of skin cancer was investigated. The study included 69 lesions (60 patients) with different types of skin tumours or precursors. Protoporphyrin IX, which is produced by the topical application of delta-aminolevulinic acid, was used as a photosensitizing agent. Twenty-three of the lesions (19 patients) were examined with a fluorescence imaging system which demarcates the tumour area from the healthy skin and visualizes the contrast between the fluorescence from healthy skin and that from the tumour. EMLA is used on all patients as part of our routine PDT protocol but despite this the major side-effect of PDT is pain during treatment. There is a large variation in pain intensity experienced by the patients, as measured by a visual analogue scale (VAS). Patients with actinic keratoses experienced more pain than those with Bowen's disease or basal cell carcinoma. The mean VAS score was higher when treating lesions located on the head than when treating lesions on the torso or the extremities. Also, treatment of large skin areas resulted in more pain than treatment of small areas, and men experienced more pain than women. The pain experienced by the patients did not correlate with treatment dose, Fitzpatrick skin type, age or fluorescence intensity.

Mohs' micrographic surgery for basal cell carcinomas on the eyelids and medial canthal area. I. Characteristics of the tumours and details of the procedure.

PURPOSE: To analyse the characteristics of eyelid basal cell carcinomas excised using Mohs' micrographic technique. METHODS: Sixty-six eyelid basal cell carcinomas were excised using Mohs' micrographic technique. The tumours were classified into four subtypes; morpheiform, intermediate, nodular/micronodular and superficial. Data on previous treatment of the tumours were retrieved. RESULTS: Thirty-two tumours (48%) were primary, 8 tumours (12%) were incompletely excised using conventional excision surgery and 26 tumours (39%) were recurrent. Nineteen of the 26 (73%) recurrent tumours and 14 of the 32 (44%) primary tumours were nodular/micronodular. To achieve radical excision, superficial tumours needed an average of 2.0, nodular/micronodular 2.5, intermediate 2.0 and morpheiform tumours 2.9 excisions. CONCLUSIONS: Eyelid basal cell carcinomas with ill-defined borders or recurrent tumours are well suited for Mohs' micrographic surgery. The extensions of the tumours are difficult to determine even in some less aggressive subtypes such as superficial and nodular/micronodular basal cell carcinomas.

Mohs' micrographic surgery for basal cell carcinomas on the eyelids and medial canthal area. II. Reconstruction and follow-up.

PURPOSE: To report our experience of reconstruction and follow-up of eyelid basal cell carcinomas treated with Mohs' micrographic technique. METHODS: Sixty-four periocular basal cell carcinomas, with a high risk of recurrence in one or more aspects with regard to location, size, morphology or prior treatment, were excised using Mohs' micrographic technique. All ensuing defects were repaired. The cases were followed prospectively for up to ten years. All complications and interventions were documented during the follow-up period. RESULTS: The average size of the defect before repair was 21 mm (range 5-45 mm). The mean follow-up time was 49 months (range 3-120). The recurrence rate was 5% (3 of 64 cases). The three recurrences occurred after one, four and six years, respectively. CONCLUSIONS: The recurrence rate of high risk tumours reported in this study was less than reported with other modes of treatment and comparable with that in other studies using Mohs' micrographic technique.

Delta-aminolevulinic acid in superficial basal cell carcinomas and normal skin-a microdialysis and perfusion study.

Delta-aminolevulinic acid (ALA) is used for photodynamic therapy of basal cell carcinoma (BCC) as it is converted to protoporphyrin IX in tumour tissue. During illumination with 635 nm light a photochemical reaction takes place, singlet oxygen is generated and the tumour destroyed. In this study we used the microdialysis technique to quantify the concentration of ALA at a certain depth in tumour and healthy skin. The penetration ability of ALA was investigated as a function of time in BCCs (n = 14) and in normal skin (n = 4) after topical application. The microdialysis catheters were inserted intracutaneously and the depth position recorded by means of ultrasound. Microdialysate sample concentrations of amino acids and ALA were determined by high performance ion-exchange chromatography. A laser Doppler perfusion imager measured perfusion in the BCCs. The data show that the average depth of the microdialysis catheters was 0.5 mm. The interstitial ALA concentration in the BCCs increased from 0 to 3.1 mmol/L 15 min after application of ALA, whereas no measurable amounts of ALA were found in healthy skin. The blood perfusion was 2.5-fold increased in the BCCs. The interstitial levels of amino acids were not significantly changed during the ALA treatment. In summary, we found that ALA rapidly penetrates tumour skin. We conclude that microdialysis seems to be well suited for pharmacodynamic studies of ALA in skin.

Experimental Candida albicans lesions in healthy humans: dependence on skin pH.

The addition of suspensions of Candida albicans cells under occlusion to the left and right forearms, buffered at 2 different pH levels (6.0 and 4.5), resulted after 24 h in unilateral or bilateral lesions in 14 of 15 volunteers. The resulting skin-surface pH was 5.7+/-0.3 and 5.1+/-0.2, respectively. The lesions were more pronounced on the arm with the higher pH in all 14 subjects who reacted. In 11 cases, reactions occurred only on the arm with the higher pH. The pH-induced results are not due to inhibited growth of C. albicans. They may be due to a pH dependence of the yeast's virulence capacity and/or a modulation of the host's defence ability. The use of skin-occlusive products (e.g. dressings, diapers and panty liners) is known to raise skin pH and is associated with skin infections of C. albicans. An acidic buffer incorporated in such products could be a preventive measure for Candida-induced skin rash.

Changes in ultraviolet absorption of sunscreens after ultraviolet irradiation.

The incidence of skin cancer is increasing rapidly and sunscreens have been recommended in order to reduce damage from sunlight. In this investigation we have studied the change in the absorption spectrum of some photoactive organic species in sunscreens after ultraviolet A and ultraviolet B irradiation in a dose normally encountered during a full day in the sun. Samples of a number of photoactive compounds commonly used in sunscreens were irradiated with ultraviolet A and ultraviolet B light. A UVASUN 2000 MUTZHAS sunlamp was used for ultraviolet A irradiation and an Esshå Corona mini, equipped with two Philips TL12 20 W lamps, was used as the ultraviolet B source. The ultraviolet A dose was 100 J per cm2. The ultraviolet B dose corresponded to 20 minimal erythema doses. The absorption spectra of the compounds were recorded before and after irradiation. The absorbance of 2-ethylhexyl 4-methoxycinnamate was reduced significantly, whereas 3-(4-methylbenzyliden)camphor seemed to be rather stable. The benzophenones studied seemed to be relatively stable. In the case of 4-tert. butyl-4'-methoxy-dibenzoylmethane there was a rapid decrease in the ultraviolet A absorption leading to unsatisfactory protection in the ultraviolet A region. 4-Isopropyl-dibenzoylmethane also lost most of its ultraviolet protective capacity after irradiation with ultraviolet A. Ultraviolet B seemed to have a minor effect on all the samples. It is important for the clinician not only to know the initial absorption spectrum in the ultraviolet region for a specific sunscreen substance, but also whether it is altered during irradiation and in what way. This study including gas chromatography and mass spectrometry analysis indicates that some of the photoactive organic species commonly used today in sunscreens are unstable following ultraviolet irradiation.

Five-year results of Mohs' micrographic surgery for aggressive facial basal cell carcinoma in Sweden.

Mohs' micrographic surgery of facial basal cell carcinoma ensures a high cure rate with maximal preservation of healthy tissue. Using precise margin control, this procedure allows complete examination of all margins of tissue removed. Due to the insufficient facilities for Mohs' micrographic surgery in Sweden, only the most aggressive tumours are referred for this procedure, which could increase the risk of recurrences. We have operated on 228 basal cell carcinomas, 87 primary and 141 recurrent tumours, over the period 1983 to 1992. The tumours were located on the face and all patients were followed for 5 years after surgery. The recurrence rate was 6.5% for primary and 10% for recurrent basal cell carcinomas. After 12 months the functional and cosmetic results were evaluated, showing good or satisfactory results in 93% of cases. Mohs' surgery is an underused but still efficacious technique in Sweden and should be recommended to other centres.

PUVA and cancer risk: the Swedish follow-up study.

There is concern about the long-term carcinogenic effects of psoralen and ultraviolet A radiation (PUVA) for treatment of skin disorders. Many authors have found an increased risk for cutaneous squamous cell carcinoma (SCC). Except in anecdotal reports, malignant melanoma had not been observed in patients treated with PUVA until recently. In the U.S.A., a 16-centre prospective study of 1380 patients showed for the first time that there might also be an increased risk for malignant melanoma in patients treated with high cumulative dosages of PUVA. We have therefore followed up the Swedish PUVA cohort until 1994. This cohort had previously been followed up until 1985. Information from 4799 Swedish patients (2343 men, 2456 women) who had received PUVA between 1974 and 1985 was linked to the compulsory Swedish Cancer Registry in order to identify individuals with cancer. The average follow-up period was 15.9 years for men and 16.2 for women. We did not find any increased risk for malignant melanoma in our total cohort of 4799 patients treated with PUVA or in a subcohort comprising 1867 patients followed for 15-21 years. For cutaneous SCC there was an increase in the risk: the relative risk was 5.6 (95% confidence interval, CI 4. 4-7.1) for men and 3.6 (95% CI 2.1-5.8) for women. Significant (P < 0.05) increases were also found in the incidence of respiratory cancer in men and women and of kidney cancer in women. In conclusion, we did not find any increased risk for malignant melanoma in our patients treated with high doses of PUVA and followed up for a long time. We confirm previous reports of an increase in the incidence of cutaneous SCC in patients treated with PUVA, and recommend that patients should be carefully selected for PUVA and rigorously followed up.

In vivo detection of basal cell carcinoma using imaging spectroscopy.

Photodynamic therapy has become an interesting alternative to conventional therapy for basal cell carcinomas. Delta-aminolevulinic acid is a precursor in the biosynthesis of protoporphyrin IX that accumulates to a large extent in tumour tissue. We have compared in vivo protoporphyrin IX fluorescence with the extent of basal cell carcinomas on the face, trunk and thigh determined by histological mapping in 30 lesions in 22 patients. A new non-laser based set-up was used to record the fluorescence images. Delta-aminolevulinic acid was applied for 4 h inducing high concentrations of protoporphyrin IX. Routine vertical histological sections and Mohs micrographic surgery were used to map the extent of the tumours. In 50% of lesions we found a good correlation between the fluorescence imaging and histological mapping. In 23% the correlation was partial. In the other lesions we found no correlation at all. This method may be used to delineate basal cell carcinomas more accurately than current methods.

Basal cell carcinoma of the eyelids and solar ultraviolet radiation exposure.

AIMS: To compare the distribution of eyelid basal cell carcinoma (BCC) with the relative ultraviolet radiation (UVR) exposure to different sites on the eyelids. METHODS: The location of BCC on the eyelids was allocated to one of seven regions. The UVR exposure was recorded with a polymer film attached to the eyelids at seven sites in a manikin and in human subjects. RESULTS: Localisation of the 329 tumours was mainly on the lower eyelids (225 tumours), and the medial canthal regions (87 tumours). There was no association between UVR doses at the seven sites of the eyelids and the location of BCCs. The UVR exposure was similar on the upper and lower eyelids, while the number of tumours on the lower eyelids outnumbered the upper lids by a factor of 13 (17 upper, 225 lower) CONCLUSION: UVR exposure only partially explains the aetiology of periorbital BCC.