Actinic keratosis: Current challenges and unanswered questions.

Actinic keratoses (AK) are common skin lesions associated with chronic exposure to sun. They are believed to be precursors of malignancy as they potentially may progress to invasive squamous cell carcinomas. The goal of current therapies is to reduce the number of AK and to prevent future cancer development. This review aims at providing an overview of the hallmarks of AK and skin field cancerization. We discuss epidemiology trends, risk factors and the state of the art and evidence of the current treatments. We review key figures of AK prevalence from different countries with regard to skin cancer risk and the associated economic burden of AK. We discuss the mutational status in AK lesions and the difficulties encountered by clinicians in evaluating AK visible and invisible lesions, referring to the concept of field cancerization. Based on a systematic literature review, we further evaluate the available treatment options. The presence of subclinical skin alterations in the periphery of visible AK lesions has gained a particular attention as those non-visible lesions are known to contain the same genetic changes as those found in the AK lesions themselves, prompting the concept of 'field cancerization'. Therefore, AK treatment guidelines now recognize the importance of treating the field in patients with AK. A recent systematic literature review and network meta-analysis showed that 5-FU interventions were associated with the best efficacy and a satisfactory acceptability profile compared with other field-directed therapies used in the treatment of AK. Although AK are considered quite common, they lack an accurate descriptive definition and conclusive epidemiologic data. Limited public awareness is a barrier to early and effective treatment, including prevention strategies. While different treatment options are available, there is still a limited understanding of long-term outcomes of treatment as measured by recurrence of cancer prevention.

European consensus-based interdisciplinary guideline for diagnosis, treatment and prevention of actinic keratoses, epithelial UV-induced dysplasia and field cancerization on behalf of European Association of Dermato-Oncology, European Dermatology Forum, European Academy of Dermatology and Venereology and Union of Medical Specialists (Union Européenne des Médecins Spécialistes).

A collaboration of multidisciplinary experts from the European Association of Dermato-Oncology, the European Dermatology Forum, the European Academy of Dermatology and Venereology, and the European Union of Medical Specialists was formed to develop European recommendations on AK diagnosis and treatment, based on current literature and expert consensus. This guideline addresses the epidemiology, diagnostics, risk stratification and treatments in immunocompetent as well as immunosuppressed patients. Actinic keratoses (AK) are potential precursors of cutaneous squamous cell carcinoma (cSCC) and display typical histopathologic and immunohistochemical features of this malignancy in an early stage. They can develop into cSSC in situ and become invasive in a low percentage of cases. AK is the most frequent neoplasia in white populations, frequently occurring within a cancerous field induced by ultraviolet radiation. Since it cannot be predicted, which lesion will progress to cSCC and when treatment is usually recommended. The diagnosis of AK and field cancerization is made by clinical examination. Dermatoscopy, confocal microscopy, optical coherence tomography or line-field confocal-OCT can help in the differential diagnosis of AK and other skin neoplasms. A biopsy is indicated in clinically and/or dermatoscopically suspicious and/or treatment-refractory lesions. The choice of treatment depends on patients' and lesion characteristics. For single non-hyperkeratotic lesions, the treatment can be started upon patient's request with destructive treatments or topical treatments. For multiple lesions, field cancerization treatment is advised with topical treatments and photodynamic therapy. Preventive measures such as sun protection, self-examination and repeated field cancerization treatments of previously affected skin areas in high-risk patients are advised.

Diagnosis and therapy of actinic keratosis.

Actinic keratosis (AK) is considered a chronic and recurring in situ skin neoplasia, with a possible transformation into invasive squamous cell carcinoma (SCC). Among others, predominant risk factors for development of AK are UV-light exposure and immunosuppression. Basal epidermal keratinocyte atypia (AK I) and proliferation (PRO score) seem to drive malignant transformation, rather than clinical appearance of AK (Olsen I-III). Due to the invasiveness of punch biopsy, those histological criteria are not regularly assessed. Non-invasive imaging techniques, such as optical coherence tomography (OCT), reflectance confocal microscopy (RCM) and line-field confocal OCT (LC-OCT) are helpful to distinguish complex cases of AK, Bowen's disease, and SCC. Moreover, LC-OCT can visualize the epidermis and the papillary dermis at cellular resolution, allowing real-time PRO score assessment. The decision-making for implementation of therapy is still based on clinical risk factors, ranging from lesion- to field-targeted and ablative to non-ablative regimens, but in approximately 85% of the cases a recurrence of AK can be observed after a 1-year follow-up. The possible beneficial use of imaging techniques for a non-invasive follow-up of AK to detect recurrence or invasive progression early on should be subject to critical evaluation in further studies.

Shedding new light on actinic keratoses and squamous cell carcinoma in situ.

ABSTRACT: Cutaneous squamous cell carcinoma can arise from various premalignant lesions such as actinic keratosis, Bowen disease, and premalignant genital squamous cell lesions. Identification and treatment can prevent malignant transformation and death. This article describes the causes, epidemiology, and characteristics of suspicious premalignant squamous cell lesions so that clinicians can identify these lesions and refer patients for specialist treatment as appropriate.

Expert Recommendations on Facilitating Personalized Approaches to Long-term Management of Actinic Keratosis: The Personalizing Actinic Keratosis Treatment (PAKT) Project.

Actinic keratoses are pre-malignant skin lesions that require personalized care, a lack of which may result in poor treatment adherence and suboptimal outcomes. Current guidance on personalizing care is limited, notably in terms of tailoring treatment to individual patient priorities and goals and supporting shared decision-making between healthcare professionals and patients. The aim of the Personalizing Actinic Keratosis Treatment panel, comprised of 12 dermatologists, was to identify current unmet needs in care and, using a modified Delphi approach, develop recommendations to support personalized, long-term management of actinic keratoses lesions. Panellists generated recommendations by voting on consensus statements. Voting was blinded and consensus was defined as ≥ 75% voting 'agree' or 'strongly agree'. Statements that reached consensus were used to develop a clinical tool, of which, the goal was to improve understanding of disease chronicity, and the need for long-term, repeated treatment cycles. The tool highlights key decision stages across the patient journey and captures the panellist's ratings of treatment options for attributes prioritized by patients. The expert recommendations and the clinical tool can be used to facilitate patient-centric management of actinic keratoses in daily practice, encompassing patient priorities and goals to set realistic treatment expectations and improve care outcomes.

Ablative Fractional Laser Enhances Artificial or Natural Daylight Photodynamic Therapy of Actinic Field Cancerization: A Randomized and Investigator-initiated Half-side Comparative Study.

Artificial daylight photodynamic therapy is a near-painless treatment for actinic keratoses, which can be performed indoors using a controlled light dose. Daylight photodynamic therapy is approved only for treatment of grade I-II actinic keratoses. The aim of this study was to evaluate whether fractional laser pre-treatment improves the outcomes of daylight photodynamic therapy for actinic keratoses of all grades. In addition, the study compared the outcomes of artificial and natural daylight photodynamic therapy. This randomized single-blinded split-side comparative study included 60 patients with ≥ 2 actinic keratoses of the head. Fractional laser pre-treatment was assigned randomly for actinic keratoses on 1 side of the head and, subsequently, the entire treatment area was treated with artificial or natural daylight photodynamic therapy. Fractional laser-mediated daylight photodynamic therapy achieved significantly higher complete clearance (50.0% vs 30.3%, p = 0.04), partial clearance (78.6% vs 50.0%, p < 0.01) and lesion-specific clearance (86.2% vs 70.2%, p < 0.01) than daylight photodynamic therapy alone at the 6-month follow-up. No significant differences were found in the outcomes of artificial vs natural daylight photodynamic therapy or grade I lesions vs grade II-III lesions. Thus, fractional laser pre-treatment appears to significantly increase the efficacy of artificial and natural daylight photodynamic therapy, and to be suitable for treatment of actinic keratoses of all grades.

Actinic keratosis - lesions behind the mask.

INTRODUCTION: Actinic keratoses (AKs) are common skin lesions that arise in skin areas chronically exposed to ultraviolet (UV) radiation. They may progress to squamous cell carcinomas in 16% of cases within 1 year. Clinically, they present as erythematous scaly plaques and mainly affect face, neck, chest, back of the hands, shoulders and scalp. Cumulative exposure to UV radiation is the main risk factor. Other factors are advanced age, outdoor activities, geographic characteristics, exposure to artificial UV radiation and chronic skin inflammation. Many of these factors are often present in rural populations where agriculture remains important. METHODS/RESULTS: This presentation present the case of a 67-year-old male patient, who went to his Family Doctor for odynophagia with 2 days of evolution. He had hypertrophied and erythematous tonsils with purulent exudate and was medicated with amoxicillin-clavulanic acid 875+125 mg for 8 days with improvement of symptoms. To perform the observation of the oropharynx, he was asked to remove his face mask, which revealed an erythematous scaly lesion in the left malar region, suggestive of actinic keratosis. He was referred to Dermatology where cryotherapy of the lesion was performed with a favourable evolution without relapses. DISCUSSION: AKs are pre-malignant lesions. Rural populations are particularly at risk for their development. It is therefore essential to raise awareness for the use of protective measures as well as to investigate lesions already established. This case seeks to alert for the fact that the use of masks due to COVID-19 pandemic can hide pre-malignant lesions of the face with a consequent delay in diagnosis and treatment.

Efficacy Assessment of the High-Frequency High-Intensity Focused Ultrasound as a New Treatment for Actinic Keratosis.

BACKGROUND: Actinic keratosis (AK) is the most common precancerous cutaneous lesion, with risk of progression to cutaneous squamous cell carcinoma. In the current study, we evaluated the efficacy of 20-MHz high-intensity focused ultrasound (HIFU), as a new treatment modality for AK. MATERIALS AND METHODS: Patients with AK lesions (grades I-III) treated with HIFU were included in the study. The clinical assessment was performed 3 months after therapy. RESULTS: Twenty-one patients (14 men, 7 women) with 108 AK lesions (grades I-III) were included in the current study. Ages ranged from 62 to 85 years (mean 72.6 years). Clinically complete resolution of the actinic damage in the treated area was detected in 72.2% of lesions. Furthermore, 28 lesions (26%) showed a reduction of the AK grade, or partial response, after the therapy. Most of the patients experienced annoying but short pain during the procedure. However, late adverse effects of the therapy, such as hypopigmentation, hyperpigmentation and erythema were reported only in a small portion of the lesions. CONCLUSIONS: 20-MHz HIFU could be an effective and safe alternative treatment for AK.

Classifying Actinic Keratosis: What the Reality of Everyday Clinical Practice Shows Us.

Difficulties faced by clinicians in routine clinical practice when selecting the appropriate treatment for patients with actinic keratosis (AK) include: the independent evaluation of AK lesions, the absence of a standardized definition of field cancerization (FC), and the lack of a reproducible classification to grade the entire AK-affected area. Moreover, to assess the severity of AK, most guidelines rely on lesion count, which is often not reproducible among specialists. The present work has 2 main objectives: first, to review and highlight some of the issues clinicians tackle when classifying and monitoring AK lesions and the status of FC, looking in more detail at some of the most commonly used clinical scales for classifying AK lesions. Second, we pose questions that we encounter in daily clinical practice, and whose answers or comments help to deal with cases of AK, facilitating the work of clinicians: How should we approach AK diagnosis? How do the challenges of clinical studies on the evaluation of treatment efficacy translate into clinical practice? We review the literature on the clinical classifications and management of AK, and propose how to guide the diagnosis, management, and monitoring of patients with AK. J Drugs Dermatol. 2022;21(8):845-849. doi:10.36849/JDD.6704.

Advances and Considerations in the Management of Actinic Keratosis: An Expert Consensus Panel Report.

BACKGROUND: Actinic Keratosis (AK) is a potentially pre-malignant tumor with a poorly defined risk of progression to invasive squamous cell carcinoma (SCC). Because of the typical need for recurrent cycles of AK treatment, outcomes can be limited by both therapeutic efficacy and patient adherence. OBJECTIVE: To synthesize the available and most current literature into overarching principles to provide guidance on the management of AKs, improving patient experiences and treatment outcomes. METHODS: A systematic review querying epidemiology, natural history, prognosis, management of AKs as well as the mechanism of action of and adherence to current AK therapy was conducted. After reviewing the literature, an expert consensus panel consisting of 10 expert dermatologists and dermatopathologists used a modified Delphi process to develop statements regarding the pathogenesis and management of AKs. Final statements were only adopted with a supermajority vote (≥7/10). RESULTS: The panel developed 7 consensus statements regarding AKs pathogenesis and management. CONCLUSION: The poorly defined risk for AK progression into invasive SCC without universally accepted clinical-histopathological factors highlights the importance of long-term efficacious treatment. To effectively counsel and treat patients with actinic keratoses, dermatologists must understand how newer therapeutic approaches with mechanisms of action that have more rapid onset of action, shorter treatment courses, and less intense local skin reaction (LSRs) may promote adherence and improve long-term outcomes. J Drugs Dermatol. 2021;20(8):888-893. doi:10.36849/JDD.6078 THIS ARTICLE HAD BEEN MADE AVAILABLE FREE OF CHARGE. PLEASE SCROLL DOWN TO ACCESS THE FULL fTEXT OF THIS ARTICLE WITHOUT LOGGING IN. NO PURCHASE NECESSARY. PLEASE CONTACT THE PUBLISHER WITH ANY QUESTIONS.

Ingenol Mebutate and the Treatment of Actinic Keratosis.

Actinic keratoses (AKs) are common skin lesions association with increased exposure to ultraviolet radiation; these lesions have the potential to transform into squamous cell carcinomas (SCCs).1.

Comparison of Grenz ray and photodynamic therapy for field treatment of actinic keratoses on the forearm: A case series.

BACKGROUND: Actinic Keratosis is an intraepidermal neoplasm that represents the second most common reason for dermatologic visits in the United States. Sustained clearance with existing therapies is highly variable. OBJECTIVE: To assess the effects of combination and monotherapy with photodynamic therapy (PDT), grenz ray therapy, and PDT with microneedling (microchannel skin system) for actinic damage of the dorsal forearms and hands. METHODS: Full ethics approval was obtained through a Human Subjects Committee. Four patients with diffuse actinic field damage on their forearms and hands were recruited for the study. The dorsal forearm and hand from the elbow to the metacarpophalangeal joint were divided into four equal sections. Section 1 was treated with PDT. Section 2 was treated with grenz ray. Section 3 was treated with PDT plus microneedling. Section 4 was treated with grenz ray and PDT with microneedling. Lesion counts were recorded with transparent grids, photographed and evaluated by the same investigator at baseline, 1, 2, 3 and 6 months. RESULTS: At month 6 post treatment, lesion counts, as a per cent reduction from baseline, were 91.7% in section 1 (PDT); 97.3% in section 2 (grenz ray); 92.9% in section 3 (PDT + microneedle); and 93.9% in section 4 (grenz ray + PDT + microneedle). CONCLUSION: The greatest reduction occurred in the grenz ray monotherapy section and the second greatest reduction in the grenz ray, PDT, microneedling section. Further research on the efficacy of grenz ray therapy for field treatment of actinic keratosis of the forearms and hands is needed.

A review of actinic keratosis, skin field cancerisation and the efficacy of topical therapies.

While a wide range of treatments exist for actinic keratosis and skin field cancerisation, the long-term benefits of the most common topical therapies are poorly defined. This report reviews the efficacy of the most commonly used topical therapies to treat regional or field lesions. Limited clinical and histopathological data are available on clearance rates at 12 months post-treatment for the most commonly used agents, with varied outcome measures making any comparison difficult. In general, total field clearance rates at 12 months are suboptimal for the most commonly employed agents. Given the increasing incidence of actinic keratosis and skin field cancerisation due to an ageing population, further research into the efficacy of therapies is critical to guide treatment choice.

[Decision criteria and patient characteristics for patient-oriented treatment of field cancerization : Standardized algorithm for personalized treatment concepts]. / Entscheidungskriterien und Patientencharakteristika zur patientenorientierten Therapie der Feldkanzerisierung : Ein standardisierter Bewertungsalgorithmus für individuelle Behandlungskonzepte.

BACKGROUND: Actinic keratosis (AK), which frequently affects larger skin areas (field cancerization), is characterized by chronic course. Weighing therapy-specific advantages and disadvantages of field-oriented therapy for individual patients is challenging. OBJECTIVES: The main objective was the development of patient-oriented decision criteria for the pragmatic classification of field-directed AK treatment options in patients with a predisposition for field cancerization (patient types 1-3). MATERIALS AND METHODS: The development of the decision criteria and patient typology was based on a nominal respectively structured multilevel group process. The developed algorithm was then subsequently applied for the systematic evaluation of field-directed AK therapies. RESULTS: Patient-relevant criteria for the treatment decision included (among others): effectiveness, selectivity, safety, duration of therapy, cosmesis, patient preference and comorbidities. With regard to the decision criteria and patient types in which field therapy was the treatment of choice, daylight photodynamic therapy notably met the requirement profile. CONCLUSION: The definition of patient-relevant and therapy-related decision criteria in AK field therapy allows a systematic yet practice-oriented approach to classify specific treatment options and to derive individual treatment decisions.

A feasibility study of microwave therapy for precancerous actinic keratosis.

BACKGROUND: Actinic keratosis (AK) is a common premalignant skin lesion that can progress to cutaneous squamous cell carcinoma (cSCC). Microwave therapy is an established cancer treatment and has been used for plantar viral warts. OBJECTIVES: To evaluate the efficacy and feasibility of microwave as a treatment for AK. METHODS: Stage I was a dose-setting study, in which seven participants had the dielectric properties of 12 thick and 22 thin AKs assessed for optimization of the microwave dose used for treatment in Stage II. Stage II was a randomized, internally controlled trial evaluating 179 AKs in 11 patients (93 treated, 86 untreated controls) on the scalp/forehead or dorsal hand. Participants received one treatment initially and a repeat treatment to unresolved AKs at week 4. The response was assessed at six visits over 4 months. The primary outcome was partial or complete resolution of the treated AKs. RESULTS: A significantly higher proportion of treated AK areas responded than untreated (90% vs. 15%; P < 0·001). Thin AKs were more responsive than thick AKs. The site did not affect efficacy. Pain was severe, but brief (80% reported pain lasting 'a few seconds only'). Adverse effects were minimal (erythema, n = 6; flaking, n = 3; itch, n = 3). All participants who would chose microwave therapy over their current treatment cited the shorter discomfort period. CONCLUSIONS: Microwave therapy is a portable, safe and effective treatment for AK. An easy-to-deliver, acceptable therapy for AK is attractive as a prevention strategy. While these results are promising, a larger randomized controlled trial is needed against an effective comparator to confirm clinical efficacy and patient acceptability. What is already known about this topic? Actinic keratoses (AKs) are common precancerous skin lesions. Successful treatment of AK can prevent cutaneous squamous cell carcinoma (cSCC). Most topical therapies for AK require repeated application over weeks and drive local skin inflammation, leading to poor compliance. An easy-to-deliver and effective treatment for AK, suitable for use in primary care, could reduce cSCC. What does this study add? Microwave therapy is a feasible, effective treatment for AK. Ninety per cent of treated AKs showed full or partial resolution at 120 days post-treatment. Microwave therapy was painful, but the pain was short-lived (seconds) and this short discomfort period was cited as the main reason that microwave was preferred to their current treatment.

Actinic keratosis: where do we stand and where is the future going to take us?

Introduction: Actinic keratosis (AK) is a chronic disease which is mainly located across areas of sun-exposed skin. Clinical and subclinical lesions coexist across a large area resulting in a field cancerization. As these lesions have the potential to transform into invasive squamous cell carcinoma (iSCC), treatment is crucial. With global prevalence increasing, AK is expected to be the most common in situ carcinoma of the skin.Areas covered: In this article, we cover the established algorithm of treating AK and give an insight into the drugs under development. There are six compounds under development covering different treatment angles, from Sinecatechin a Polyphenon E which targets the link between HPV infection and development of AK, over Tirbanibulin which targets the SRC proto-oncogene and fast proliferating cells, to Tuvatexib a small-molecule dual VDAC/HK2 modulator that has shown that it can compete with the established therapies.Expert opinion: These new treatment options are moving us further toward a more individually tailored treatment for each patient considering his abilities, the size and location of his lesions but also the genetic bases as well as individual risk of transforming into a iSCC and possibly other factors contributing to each patients individual AK lesions.

Field cancerization: Treatment.

The goal of field cancerization treatment is to reduce the risk of developing keratinocyte carcinoma. Selecting the appropriate therapy depends on the degree of field cancerization and the number of invasive cutaneous squamous cell carcinomas. Other considerations include treatment efficacy, cost, side effects, and patient preference. Field therapies are preferred because they address clinically visible disease and subclinical atypia. However, lesion-directed therapies are useful for lesions that are more difficult to treat or those where a histologic diagnosis is required. Patients with extensive field cancerization benefit from a combination of field-directed and lesion-directed treatments. The second article in this continuing medical education series provides a framework to guide evidence-based decision making for field cancerization treatment.

High-frequency (20 MHz) high-intensity focused ultrasound: New Treatment of actinic keratosis, basal cell carcinoma, and Kaposi sarcoma. An open-label exploratory study.

BACKGROUND: Skin cancer is common, growing, challenging, and in need of progress in early-stage treatment. 20 MHz high-intensity focused ultrasound (HIFU) is new and applied to actinic keratosis (AK) and skin cancers for the first time. HIFU of lower frequency is already used in the treatment of internal cancers. MATERIALS AND METHODS: Eight patients with 201 AK lesions, one patient with 7 basal cell carcinomas (reoccurrences after PDT), and one patient with 7 Kaposi sarcoma lesions (4 treated with radiotherapy in the past) were given 1-3 HIFU treatments. Twenty megahertz HIFU was dosed as 150 ms at 0.6-1.2 J/shot applied to target lesions. Probes with different target depths were available. The preferred shot energy and focal depth in AK were 0.9 J and 1.3 mm. A "Sandwich" strategy with HIFU applied in two depths were tried in cancers. The follow-up period was 3-6 months. RESULTS: All AK cleared except 5, giving a cure rate of 97%. Post-treatment lesion healed in 1-2 weeks with no scar. VAS pain was from 1 to 8, and in any case less than experienced with previous PDT. In both basal cell carcinoma (BCC) and sarcoma, healing was confirmed by histological verification. DISCUSSION/CONCLUSION: 20 MHz HIFU was an effective and safe treatment of AK. This new treatment, applicable to any anatomical site, has promising advantages relative to PDT and has the potential to replace or supplement PDT in future. Case-observations indicated that HIFU can be useful in skin cancers as well.

Reflectance confocal microscopy in actinic keratosis-Comparison of efficacy between cryotherapy protocols.

BACKGROUND: Actinic keratosis (AK) incidence is increasing. Due to the risk of progression to squamous cell carcinoma, early detection and treatment are essential. The method stated in the European Consensus is cryotherapy, but there is no standard protocol defined for better results. OBJECTIVES: To compare two different cryotherapy protocols for AK using reflectance confocal microscopy (RCM) as a noninvasive imaging method for evaluation. METHODS: A self-controlled clinical trial was proposed to compare the efficacy of cryotherapy in two different application protocols. Grade II AKs in the forearms were submitted to freezing and thawing time of 10 seconds for 1 cycle (group A) or 2 cycles (group B). At baseline and 4 weeks after treatment, the same dermatologists assessed RCM evaluation (thickness of horny layer, parakeratosis, dyskeratosis, atypia in spinous layer, fibrosis, and presence of inflammatory cells in epidermis and dermis). RESULTS: We examined 24 AK lesions in each group. Statistical evaluation of the results evidenced superior response after 2 cycles of cryotherapy in parakeratosis and number of inflammatory cells in epidermis. CONCLUSION: Both protocols are effective in clearing clinical AK. Two cycles are not generating more side effects (fibrosis) and could reduce the risk of recurrence (better "clearance" of parakeratosis).

The more the better? An appraisal of combination therapies for actinic keratosis.

Actinic keratoses (AK) are common precancerous lesions of the skin. Numerous interventions exist for the treatment of AK, including lesion- and field-directed approaches. In daily practice, different treatment modalities are often combined to maximize clearance rates. However, whether a combination therapy is preferable to monotherapy in terms of efficacy and safety has been subject of intense debate. In this review, we summarize the current knowledge on the efficacy and safety of local combination therapies for the treatment of patients with AK. Combination approaches of cryosurgery followed by photodynamic therapy (PDT), laser-assisted PDT, PDT in combination with topical interventions and microneedling-assisted PDT have shown slightly better efficacy results with similar tolerability compared to the respective monotherapy. However, the individual usage of combination therapies should be checked on a case-by-case basis and take into account individual patient- and lesion-specific aspects as more resources are needed and because the individual monotherapies are already highly effective.