Subclinical Actinic Keratosis Research Articles

Treating the invisible: Subclinical actinic keratosis detected by imiquimod

AbstractBackgroundSkin in UV‐exposed areas may develop UV‐induced actinic damage in DNA sequences leading to proliferation of keratinocyte carcinoma, a type of non‐melanoma skin cancer. Actinic keratosis (AK) represents early‐stage in situ squamous cell carcinoma. It develops from the basal cell layer and may be present in subclinical stages, being reported as field cancerization, even before being clinically visible. Thus, we hypothesise that from the age of 50 + UV‐exposed skin features subclinical forms of AKs without visible skin lesions.ObjectivesThis study aims at clarifying the existence of the clinically invisible, early stages of AKs on chronically UV‐exposed skin without showing clinically evident features of AK.Methods46 volunteers (26 females and 20 males) aged 50+ with signs of moderate to severe UV‐damage (photodamage) applied imiquimod 3.75% creme on their entire face every night for a 2‐week period. All participants kept a diary noting onset, severity of inflammatory reactions, and unexpected side effects.ResultsMore than 90% of participants without clinical evidence of AK showed inflammatory reactions on topical treatment with imiquimod on their face demonstrating an interaction between UV‐damaged mutated keratinocytes and the topically applied immunomodifier, thus proofing the presence of subclinical AKs.ConclusionsThe action of imiquimod is not restricted to visible AK lesions, but often includes their vicinity, suggesting that neoplastic processes are frequent at a cellular level, not confined to clinically evident lesions, supporting the concept of field cancerization. Thus, subclinical AKs do exist in an early, macroscopically invisible state and may be targeted by imiquimod or 5‐FU. At this stage, AKs are being treated before diagnosis by usual clinical means, and well before potential progression to invasive squamous cell carcinoma (SCC). Eventually, imiquimod 3.75% cream could be recommended in UV‐exposed skin to prevent the presumptive development of AK and later on, early SCC.

Characterization of Permeability Barrier Dysfunction in a Murine Model of Cutaneous Field Cancerization Following Chronic UV-B Irradiation: Implications for the Pathogenesis of Skin Cancer.

Simple SummaryIn the present work, we developed an experimental preclinical model of skin with cutaneous field cancerization after chronic UV-B light exposure in an immunologically intact mouse model (SKH1 aged mice). We observed impairments in the transepidermal water loss, stratum corneum hydration, and surface pH. We also detected a marked hyperkeratotic hyperplasia of the epidermis, induction of keratinocyte hyperproliferation, incidental actinic keratosis, and in situ squamous cell carcinomas in the UV-B light-irradiated groups. In this context, the association between the permeability barrier impairment and keratinocyte hyperproliferation might be considered a new target in the management of skin with cutaneous field cancerization. As current therapeutic approaches to actinic keratosis and cutaneous field cancerization only focus on the direct antineoplastic, immunomodulatory, or photodynamic effects of approved topical drugs, this mouse model of skin with cutaneous field cancerization might be helpful for both the identification and screening of potentially new preventive strategies or treatments (e.g., skin barrier therapies).Chronic ultraviolet B (UV-B) irradiation is known to be one of the most important hazards acting on the skin and poses a risk of developing photoaging, skin with cutaneous field cancerization (CFC), actinic keratosis (AKs), and squamous cell carcinomas (SCCs). Most of the UV-B light is absorbed in the epidermis, affecting the outermost cell layers, the stratum corneum, and the stratum granulosum, which protects against this radiation and tries to maintain the permeability barrier. In the present work, we show an impairment in the transepidermal water loss, stratum corneum hydration, and surface pH after chronic UV-B light exposure in an immunologically intact mouse model (SKH1 aged mice) of skin with CFC. Macroscopic lesions of AKs and SCCs may develop synchronically or over time on the same cutaneous surface due to both the presence of subclinical AKs and in situ SCC, but also the accumulation of different mutations in keratinocytes. Focusing on skin with CFC, yet without the pathological criteria of AKs or SCC, the presence of p53 immunopositive patches (PIPs) within the epidermis is associated with these UV-B-induced mutations. Reactive epidermis to chronic UV-B exposure correlated with a marked hyperkeratotic hyperplasia, hypergranulosis, and induction of keratinocyte hyperproliferation, while expressing an upregulation of filaggrin, loricrin, and involucrin immunostaining. However, incidental AKs and in situ SCC might show neither hypergranulosis nor upregulation of differentiation markers in the upper epidermis. Despite the overexpression of filaggrin, loricrin, involucrin, lipid enzymes, and ATP-binding cassette subfamily A member 12 (ABCA12) after chronic UV-B irradiation, the permeability barrier, stratum corneum hydration, and surface pH were severely compromised in the skin with CFC. We interpret these results as an attempt to restore the permeability barrier homeostasis by the reactive epidermis, which fails due to ultrastructural losses in stratum corneum integrity, higher pH on skin surface, abundant mast cells in the dermis, and the common presence of incidental AKs and in situ SCC. As far as we know, this is the first time that the permeability barrier has been studied in the skin with CFC in a murine model of SCC induced after chronic UV-B irradiation at high doses. The impairment in the permeability barrier and the consequent keratinocyte hyperproliferation in the skin of CFC might play a role in the physiopathology of AKs and SCCs.

Field cancerization in clinically solitary actinic keratosis: A pilot study.

Clinical studies have demonstrated that subclinical actinic keratoses (AKs) may be clinically evidenced following treatment of multiple AKs with a topical immunotherapy agent known to reveal a "field cancerization". The aim of our study was to investigate if subclinical AKs may be evidenced also in case of single AKs. Ten patients with single, solitary AKs were treated with IQ 3.75% cream applied on the lesion and on a 5 × 5 cm surrounding area once daily for two 2-week treatment cycles separated by a 2-week treatment-free period. Lesions were evaluated by clinical, dermoscopic and RCM examination. At the end of treatment, subclinical lesions were evidenced in 8 of 10 patients revealing the presence of a field cancerization. If larger studies will confirm these results, field cancerization could likely be considered also in case of solitary AKs, resulting in a different approach in terms of disease evolution and treatment.

Management Pearls on the Treatment of Actinic Keratoses and Field Cancerization.

Field cancerization (FC) is a chronic disease involving multiple clinical and subclinical actinic keratoses (AK) on large photo-exposed surfaces with multifocal areas of dysplasia and precancerous changes. Patients and treatment must be properly monitored and managed to avoid aggravation and progression of the disease. Management of actinic keratoses includes lesion-directed treatments, such as cryotherapy and field-directed therapies. Field-directed therapies may have the potential to address subclinical damage, reduce AK recurrence rates and potentially reduce the risk of squamous cell carcinoma development. Multiple studies have demonstrated the efficacy of field-directed treatments, including 5-fluorouracil, photodynamic therapy, imiquimod, chemical exfoliation with trichloroacetic acid and diclofenac gel, for multiple AK and FC. The choice of therapy should be based on multiple factors, such as efficacy, tolerability, patient risk profile, costs and cosmetic results. Management of AK includes not only treatment but also prevention. Medical devices, such as sunscreens containing liposome-encapsulated DNA repair enzymes, can repair DNA damage associated with chronic UV radiation and reduce the number of new AK lesions. Here we provide therapeutic pearls and expert opinions on the treatment of AK and FC (as monotherapy or in combination) with the overall aim to achieve better, faster, and well-tolerated clinical responses.

Digital follow-up by means of dermatoscopy and reflectance confocal microscopy of actinic keratosis treated with Imiquimod 3.75% cream.

Imiquimod 3.75% cream (Zyclara® Meda, Stockholm, Sweden) is a new field-directed therapy for actinic keratosis (AK). The aim is to evaluate efficacy and the morphologic dynamic changes induced by this treatment by means of dermatoscopy and reflectance confocal microscopy (RCM) of imiquimod 3.75% cream for the treatment of AKs of the face or scalp and to evaluate. Thirty-two patients were treated with Imiquimod 3.75% cream. Demographic parameters, AK-FAS and AKASI scores and side-effects were collected. RCM and dermatoscopy on one target AKs were performed at each visit. We collected images at baseline (T0), after 1week from the end of the first 2-week cycle (T1), after 1week from the end of the entire treatment (T2) and 2months after the end of treatment (T3). One target representative AK in the selected area of treatment of each patient was analysed. All dermoscopic and confocal parameters were reduced 2months after the end of the therapy (T3) with a substantial reduction of AKASI and AK-FAS scores, and 17 cases (54.8%) were completely solved. Confocal microscopic analysis showed a reduction of keratinocytes disarray in 77.4% of cases; none showed crusts and parakeratosis. Inflammation was considerably decreased and was observed only in 12.9% of patients at the last visit. This improvement was not assessed on dermatoscopy because of inflammation and background erythema, which adversely influenced the assessments. LSRs were observed in almost all the patients during treatment being more severe after the first cycle of treatment (T1). Imiquimod 3.75% cream is effective in treating clinical and subclinical AKs with an easy management of side-effects. Dermatoscopy and mostly RCM allow non-invasive monitoring of treatment response invivo.

The conventional protocol vs. a protocol including illumination with a fabric-based biophotonic device (the Phosistos protocol) in photodynamic therapy for actinic keratosis: a randomized, controlled, noninferiority clinical study.

Topical photodynamic therapy (PDT) using methyl aminolaevulinate is a noninvasive treatment option suitable to treat clinical and subclinical actinic keratosis (AK) over a large area (field cancerization). The most widely used, conventional protocol in Europe includes illumination with a red-light lamp. This illumination commonly causes pain, and patients often cannot complete the treatment. The aims of this paper are twofold. The first aim is to introduce a novel protocol, the Phosistos protocol (P-PDT), which includes illumination with a fabric-based biophotonic device. The second and major aim is to assess the noninferiority, in terms of efficacy for PDT of AK, of P-PDT compared with the conventional protocol (C-PDT). A randomized, controlled, multicentre, intraindividual clinical study was conducted. Forty-six patients with grade I-II AK of the forehead and scalp were treated with P-PDT on one area (280 AK lesions) and with C-PDT on the contralateral area (280 AK lesions). The primary end point was the lesion complete response (CR) rate at 3 months, with an absolute noninferiority margin of -10%. Secondary end points included pain scores, incidence of adverse effects and cosmetic outcome. Three months following treatment, the lesion CR rate of P-PDT was noninferior to that of C-PDT (79·3% vs. 80·7%, respectively; absolute difference -1·6%; one-sided 95% confidence interval -4·5% to infinity). The noninferiority of P-PDT to C-PDT in terms of the lesion CR rate remained at the 6-month follow-up (94·2% vs. 94·9%, respectively; absolute difference -0·6%; one-sided 95% confidence interval -2·7% to infinity). Moreover, the pain score at the end of illumination was significantly lower for P-PDT than for C-PDT (mean ± SD 0·3 ± 0·6 vs. 7·4 ± 2·3; P < 0·001). P-PDT is noninferior to C-PDT in terms of efficacy for treating AK of the forehead and scalp and resulted in much lower pain scores and fewer adverse effects. What's already known about this topic? Topical photodynamic therapy using methyl aminolaevulinate is effective for treating actinic keratosis. In Europe, the conventional protocol involves illumination with a red-light lamp. Unfortunately, pain is often experienced by patients undergoing this protocol. An alternative protocol that uses daylight illumination has recently been shown to be as effective as the conventional protocol while being nearly painless. However, this alternative protocol can be conducted only in suitable weather conditions. What does this study add? The Phosistos protocol is demonstrated to be as effective as the conventional protocol, nearly as painless as the daylight protocols and suitable year round for treatment of actinic keratosis.

The importance of treating the field in actinic keratosis.

Actinic keratoses (AKs) are intraepithelial atypical proliferations of keratinocytes that develop in skin that has undergone long-term exposure to ultraviolet radiation. Given the ageing population and an increasing prevalence of AK, the socio-economic burden of AK is likely to rise over the coming years. Areas of subclinical (non-visible) sun damage in the periphery of visible AK lesions contain the same genetic changes as those found in the lesions themselves, and are known as areas of field cancerization. AK lesions and the field are associated with an increased risk of skin cancer, including invasive squamous cell carcinoma. Although effective in clearing visible AK, lesion-directed therapies do not address field cancerization and can lead to high recurrence rates. In contrast, field-directed therapies, such as ingenol mebutate, imiquimod and diclofenac, can clear both visible and subclinical AK lesions and reduce the development of new lesions in the treated field. Additionally, preclinical studies suggest that field therapy may prevent or delay the recurrence of non-melanoma skin cancer. AK treatment guidelines now recognize the importance of treating the field in patients with AK, and adaptation of treatment guidelines into clinical practice is warranted. Physician and patient education around the consequences of leaving the field of cancerization untreated is necessary in order to reduce the increasing burden associated with AK.

Low-Dose 0.5% 5-Fluorouracil/10% Salicylic Acid Topical Solution in the Treatment of Actinic Keratoses.

Actinic keratosis (AK) lesions have the potential to develop into invasive squamous cell carcinomas (SCCs), and approaches to treatment are evolving to try to reduce the burden of SCC. To present the published clinical research surrounding the use of 0.5% 5-fluorouracil with 10% salicylic acid (low-dose 5-FU/SA) for the treatment of hyperkeratotic AKs. A review of published clinical evidence for low-dose 5-FU/SA for the treatment of AKs. The articles were selected following a MEDLINE database search of the combined terms fluorouracil, salicylic acid and actinic keratosis which represent the peer review publications of clinical studies that primarily investigate the use of Actikerall in AK. Combining low-dose 5-FU with keratolytic SA is associated with high rates of histologic clearance, reduction in lesion number/area, and sustained clinical response in clinical study and the clinical practice setting. Low-dose 5-FU/SA has also been evaluated using imaging to detect the progression of subclinical AK lesions through a course of the field-directed treatment. Low-dose 5-FU/SA is an effective and well-tolerated treatment option licensed for the lesion-directed treatment of mild-to-moderate hyperkeratotic AK lesions.

Treatment monitoring of 0.5% 5-fluorouracil and 10% salicylic acid in clinical and subclinical actinic keratoses with the combination of optical coherence tomography and reflectance confocal microscopy.

Reflectance confocal microscopy (RCM) and high-definition optical coherence tomography (HD-OCT) allow the observation in vivo of dynamic changes in response to non-surgical treatment of actinic keratosis and field of cancerisation. To non-invasively assess the pharmacodynamic changes induced by treatment with low dose 5-fluorouracil and 10% salicylic acid by means of RCM and high-definition OCT in field cancerization and actinic keratosis. Twenty patients aged >50 years with diagnosis of actinic keratosis on the head and face and indication for treatment with 0.5% 5-fluorouracil and 10% salicylic acid were enrolled. An area of 25 cm² including visible type I and II AK and subclinical AK was treated once daily during 6 weeks and examination was performed with RCM and HD-OCT before treatment and 2 weeks after the end of treatment High-definition optical coherence tomography results at baseline of mean thickness of the stratum corneum and epidermis were in AK 10.4 (SD = 4.99) and 43.3 (SD = 24.01) μm respectively and in subclinical AK 3.7 (SD = 2.15) and 30.05 (SD = 16.85) μm. At week 8 (2 weeks after the end of treatment) measurements of stratum corneum and epidermis were significantly reduced in AK and subclinical AK for stratum corneum and epidermis. In RCM at week 8 scaling, detached corneocytes, atypical honeycomb, round nucleated cells in the spinosum granulosum layer, round vessels (dermal papillae), inflammatory cells and total AK score were significantly reduced in AK and subclinical AK. Evaluation of AK and subclinical AK by RCM and HD-OCT showed objective improvement after treatment with 5-fluorouracil and 10% salicylic acid. These methods allowed the study of dynamic changes in the tissue at a subclinical level.

Impetigo After Actinic Keratosis Treatment With Ingenol Mebutate Gel: An Important Complication

Field therapy is a popular and important treatment for actinic keratosis. These agents have unique benefits as well as side effects. Dermatologists and others prescribing topical treatment for actinic keratosis should be aware of several important side effects. One of the most important side effects is the development of impetigo on the treated skin. We present a case of a patient who developed impetigo after applying ingenol mebutate gel for treatment of actinic keratosis. Impetigo is a not uncommon, but important complication of topical therapy for actinic keratosis. Prompt diagnosis and treatment can prevent unnecessary morbidity. Topical pharmacotherapy for treatment of actinic keratosis (AK) is an alternative preferred by some dermatologists over lesion-directed modalities because the former allows for coverage of subclinical AKs (so called “field treatment”). There are several options for dermatologists and patients considering field treatment with a topical agent. Traditionally 5-fluorouracil (5-FU) has been used, but this requires consistent daily to twice daily application for up to four weeks. In comparison, ingenol mebutate (IM) requires only once daily applications for two or three days. Such a schedule allows for enhanced patient adherence. Furthermore, a recent prospective randomized trial confirmed that the local skin reaction (LSR) of patients treated with IM is more short lived compared to those treated with 5-FU (1). Topical pharmacotherapy agents are generally well tolerated. Nearly all patients receiving topical pharmacotherapy for AKs notice erythema and discomfort at the site of treatment. In a multicenter, randomized, doubleblind study, pain and pruritus were found to be the most commonly reported adverse events with IM use (2). A 70-year-old Caucasian male with prior non-melanoma skin cancer history presented with three erythematous macules with adherent scale on the lip and forehead. These were clinically determined to be AKs and were treated with combination cryotherapy and field treatment of the face with IM 0.015% gel for three days. The patient returned four weeks later with bright erythema and honey-colored crust of the upper and lower lip (Figure 1). A bacterial culture was collected and at that time the patient was treated empirically with mupirocin and cephalexin. The bacterial culture subsequently revealed pan-sensitive staphylococcus aureus and the patient rapidly improved. Impetigo during treatment with 5-FU for AK is not uncommon and is presumably a result of a compromised skin barrier. Reasonably, the incidence of impetigo could be expected to be higher in patients receiving 5-FU compared to IM as the LSR is more persistent in the former (1). In a study of 162 patients receiving IM, only one patient developed impetigo (3). Prompt recognition and treatment of this condition is essential to prevent unnecessary morbidity. While IM has a preferable treatment schedule and duration of LSR, it nevertheless can result in the adverse effects like impetigo that are assumed to be more characteristic of 5-FU.

Monitoring Treatment of Field Cancerisation with 3% Diclofenac Sodium 2.5% Hyaluronic Acid by Reflectance Confocal Microscopy: A Histologic Correlation

Visual inspection may fail to accurately evaluate field cancerisation (subclinical actinic keratoses [AKs]). We aimed to describe field cancerisation by confocal reflectance microscopy and changes induced by the application of 3% diclofenac sodium gel in 2.5% hyaluronic acid. Fourteen male patients, > 50 years old, with AKs on the bald scalp were included. Clinical examination, confocal microscopy and histological study of clinically visible lesions and "normal appearing" adjacent skin before and after treatment was completed. Reflectance confocal microscopy showed a decrease in scaling (p = 0.001) and atypia of the honeycomb pattern (p = 0.001) at 2 weeks of treatment. Changes in parakeratosis, inflammation and dermal collagen remodelling were also observed. Histology correlated with confocal features in AK and subclinical AK. Reflectance confocal microscopy was useful in the evaluation of field cancerisation and monitoring of treatment response. A rapid improvement in epidermal atypia was observed.

Lmax and imiquimod 3.75% in daily clinical practice.

Lmax, the maximum lesion count during treatment, is a new concept for evaluating the efficacy of field-directed treatments for actinic keratosis (AK) against clinical and subclinical lesions. Imiquimod 3.75% is a field-directed AK treatment, which can detect and clear clinical and subclinical lesions across an entire sun-exposed field such as the full face or balding scalp. To evaluate the importance of integrating Lmax into daily clinical practice by describing the clinical features and outcomes obtained in the first 10 patients who were treated with imiquimod 3.75% in a UK dermatology department. Ten AK patients were treated with imiquimod 3.75% in two 2-week treatment cycles separated by a 2-week treatment-free interval. Lesions were counted before, during and 2 months after treatment was completed. Patients compared the imiquimod 3.75% regimen with their previous AK therapies in terms of treatment duration and side-effect profile. All 10 patients in this cohort had used two or more prior AK treatments including 5-flurouracil, diclofenac, imiquimod 5% and photodynamic therapy. The patients had a median of 10 AK lesions on clinical presentation and a median Lmax of 14. The median lesion count was zero 2 months after treatment was completed. All patients thought that imiquimod 3.75% was easy-to-use and that the duration of treatment was better than that of previous AK therapies. Seven of the patients considered the side-effect profile of imiquimod 3.75% to be better than that of their prior AK treatments. Imiquimod 3.75% in daily clinical practice enables dermatologists to detect and clear clinical and subclinical AK lesions across a large sun-exposed area. Patients generally find imiquimod 3.75% easy-to-use with a better side-effect profile than other AK treatments.

Ingenol mebutate: a novel treatment for actinic keratosis

A novel, topically applied, short course therapy for actinic keratoses (AK) is now widely licensed following first approval in the USA in 2012. The active agent, ingenol mebutate, is a naturally occurring diterpenoid found in the plant Euphorbia peplus. AK, the most common premalignant dermatological pathology, is increasing in prevalence with increased UV radiation exposure and aging populations, and has the potential to progress to malignant disease. Various treatment modalities exist for AK and the choice for the clinician and patient is now extended with this novel treatment, which requires topical application for only 2 or 3 days, and has cosmetic and tissue-sparing advantages. Ingenol mebutate gel is used as a field-directed therapy, thereby potentially reducing perilesional subclinical AK.

Evidence for field cancerisation treatment of actinic keratoses with topical diclofenac in hyaluronic acid

Actinic keratosis (AK) is a common skin disease seen in daily practice. It is associated with a risk of progression to invasive squamous cell carcinoma and can be regarded as a marker of increased risk for non-melanoma skin cancer. The use of a field-directed treatment approach reflects the need to initiate early treatment over an affected area to prevent tumour development and local recurrence. Candidate field-directed treatments require a mechanism of action compatible with an effect on field cancerisation, immediate and long-term efficacy against visible lesions and efficacy against subclinical AK. Applicability to large treatment areas, tolerability compatible with long-term use, utility in organ transplant patients and, ideally, evidence of extended long-term activity may also be desirable. We review the evidence of a role for topical diclofenac sodium 3% administered in a 2.5% hyaluronic acid gel (diclofenac/HA) as field-directed treatment. Diclofenac/HA directly targets AK pathophysiology through multiple mechanisms, including induction of apoptosis, inhibition of angiogenesis and reduced inflammation. Clearance of visible field cancerisation is safely and rapidly achieved with a 90-day treatment course in patients with affected areas of up to 50 cm(2) and is associated with a ≥75% reduction in target lesion number score in 85% and 91% of patients, respectively, at 30 days and 1 year post-treatment. Following treatment of AK in high-risk transplant patients, 45% remained free of lesions in the treatment area at 2 years post-treatment. We conclude that diclofenac/HA fulfils most criteria necessary to be considered an appropriate candidate for a field-directed treatment in AK.

Eruptive purpuric papules on the arms; a case of chemotherapy-induced inflammation of actinic keratoses and review of the literature

Chemotherapy-induced inflammation of actinic keratosis can present in patients with subclinical actinic keratoses that become erythematous and pruritic within weeks of initiating systemic chemotherapy. The reaction is limited to sun-exposed areas and, classically, histologic findings of parakeratosis and epidermal necrosis with keratinocyte nuclear pleomorphism are present. Exuberant reactions with extensive epidermal necrosis may lead to subepidermal vesiculation. We report a case of a 67-year-old man with a history of chronic hepatitis B virus infection and recently diagnosed squamous cell carcinoma of the lung who was noted to have progressive asymptomatic violaceous papules on the extensor forearms and distal upper arms while hospitalized for possible sepsis following initiation of chemotherapy. A dermatology consulatation was requested to rule out possible vasculitis. It is important to recognize chemotherapy-induced inflammation of actinic keratoses in predisposed patients; it may be managed successfully with topical corticosteroids and does not necessitate discontinuation of the offending chemotherapeutic agent.

Visualization and treatment of subclinical actinic keratoses with topical imiquimod 5% cream: an observational study.

Background. Imiquimod 5% is licensed for the treatment of external genital warts, superficial basal cell carcinoma, and actinic keratosis (AK) and is being used experimentally in various other dermato-oncological conditions. Objective. This observational study shall show that nonmelanoma skin cancer can be detected at its earliest subclinical stage by its reaction with imiquimod and can be cleared by finishing the course of treatment. Material and Methods. In this single arm trial 15 patients with chronically sun-exposed skin who had no clinical evidence of AK were treated with 5% imiquimod cream on the face or scalp for 4 weeks three times per week. Results. During treatment, all patients developed multiple areas with mild to moderate inflammatory skin reactions, such as erythema, induration, and scaling. Biopsies obtained from 12 patients prior to treatment revealed no malignancies. However, in cases with more pronounced inflammation during treatment, targeted biopsies indicated very early malignant alterations. Conclusion. Topical imiquimod treatment of chronically sun-exposed skin without overt clinical signs of AK is able to detect subclinical actinic keratoses (SAK) and to completely clear the lesions, even before they can be clinically diagnosed as AK. In such patients, imiquimod might be able to prevent the evolution of SCC.

Optimal treatment of actinic keratosis

Optimal treatment of actinic keratosis Gary GoldenbergMount Sinai School of Medicine, New York, NY, USA We read with interest the review by Uhlenhake on treatments for actinic keratosis (AK).1 The author presents a summary of the various AK treatment options used to reduce the risk of progression to invasive squamous cell carcinoma. The article includes a table (Table 1) comparing advantages and side effects of these options.Patient-administered topical treatments are an important strategy for treating confluent AKs and areas of sun-damaged skin that may contain subclinical AKs. Rates of complete and partial clearance are similar across the topical agents (fluorouracil, imiquimod, diclofenac, and ingenol mebutate). It is noteworthy that the uniquely brief regimen for ingenol mebutate, 2 to 3 days, produced clearance rates similar to those with the other agents, which have treatment regimens of several weeks.1View original paper by Uhlenhake.

The use of 7 days of topical 5-fluorouracil to diagnose subclinical actinic keratosis that remain 3 months after 3 different actinic keratosis treatment protocols

The use of 7 days of topical 5-fluorouracil to diagnose subclinical actinic keratosis that remain 3 months after 3 different actinic keratosis treatment protocols

Ingenol Mebutate Gel for Actinic Keratosis

BackgroundActinic keratosis is a common precursor to sun-related squamous-cell carcinoma. Treating actinic keratoses and the surrounding skin area (i.e., field therapy) can eradicate clinical and subclinical actinic keratoses. Topical field therapy currently requires weeks or months of treatment. We investigated the efficacy and safety of a new topical field therapy for actinic keratosis, ingenol mebutate gel (0.015% for face and scalp and 0.05% for trunk and extremities).MethodsIn four multicenter, randomized, double-blind studies, we randomly assigned patients with actinic keratoses on the face or scalp or on the trunk or extremities to receive ingenol mebutate or placebo (vehicle), self-applied to a 25-cm2 contiguous field once daily for 3 consecutive days for lesions on the face or scalp or for 2 consecutive days for the trunk or extremities. Complete clearance (primary outcome) was assessed at 57 days, and local reactions were quantitatively measured.ResultsIn a pooled analysis of the two trials involving the face and scalp, the rate of complete clearance was higher with ingenol mebutate than with placebo (42.2% vs. 3.7%, P<0.001). Local reactions peaked at day 4, with a mean maximum composite score of 9.1 on the local-skin-response scale (which ranges from 0 to 4 for six types of reaction, yielding a composite score of 0 to 24, with higher numbers indicating more severe reactions), rapidly decreased by day 8, and continued to decrease, approaching baseline scores by day 29. In a pooled analysis of the two trials involving the trunk and extremities, the rate of complete clearance was also higher with ingenol mebutate than with placebo (34.1% vs. 4.7%, P<0.001). Local skin reactions peaked between days 3 and 8 and declined rapidly, approaching baseline by day 29, with a mean maximum score of 6.8. Adverse events were generally mild to moderate in intensity and resolved without sequelae.ConclusionsIngenol mebutate gel applied topically for 2 to 3 days is effective for field treatment of actinic keratoses. (Funded by LEO Pharma; ClinicalTrials.gov numbers, NCT00742391, NCT00916006, NCT00915551, and NCT00942604.)

Effectiveness of cross polarized light and fluorescence diagnosis for detection of sub‐clinical and clinical actinic keratosis during imiquimod treatment

During treatment of actinic keratosis (AK) lesions with imiquimod sub-clinical lesions often become visible. It is, however, unclear whether these sub-clinical lesions would be detectable beforehand. The aim of this pilot study was to compare two techniques, cross polarized light photography (CPL) and fluorescence diagnosis (FD) using methyllevulinic acid and illumination with Wood's lamp for their ability to detect sub-clinical lesions. These findings were also compared with biopsy results taken before and after treatment with imiquimod 5% cream or vehicle. Twelve patients with at least five clinically visible AK lesions in a single contiguous 20 cm(2) area on the head were recruited. Patient eligibility was determined at the screening visit, when they were randomized to treatment. The randomization was 3:1, active to vehicle (nine treated with imiquimod, three with vehicle cream) for a total duration of 24 weeks (six clinic visits). Patients were assessed for baseline AK lesion counts (clinical and sub-clinical) at the screening visit and final counts at week 20. The number of clinically observed AK lesions was significantly lower at week 12 and week 20 compared with baseline following imiquimod treatment versus vehicle. The number of counted lesions were significantly higher using the CPL method compared with clinical counting with imiquimod treatment at baseline (8.3 +/- 3.4 vs 5.8 +/- 1.3; P = 0.027) and week 20 (4.8 +/- 2.4 vs 3.0 +/- 1.7; P = 0.02) but not in the vehicle group. The FD lesion counting method did not show a significant increase in the number of detected lesions compared with clinical analysis in the imiquimod and placebo groups but when comparisons were performed using pooled data (treatments and visits combined) the results were significant. The number of sub-clinical and clinical AK lesions detected during treatment with imiquimod can be better demonstrated using the methods of CPL and FD, but statistical significance was reached only using the CPL method. This is only a preliminary study with a small number of patients and as a result it is difficult to conclude both statistical and clinical significance. However, results were encouraging and indicate that larger studies are needed to demonstrate the relevance of these two new methods for improved detection of clinical and especially sub-clinical AK lesions.