The Paradigm Shift in Treating Actinic Keratosis: A Comprehensive Strategy

December 2012 | Volume 11 | Issue 12 | Original Article | 1462 | Copyright © December 2012

Actinic keratoses (AKs) are cutaneous areas of atypical squamous transformation that are considered to be an early step in the continuum of transformation from normal skin to invasive and metastatic cutaneous squamous cell carcinoma (SCC). Enhanced understanding of the pathophysiologic changes leading from AK to malignancy, combined with an increasing global prevalence of AK, has led to a new focus on the importance of combining local tretments that remove individual lesions with topical or procedural field therapies that treat the entire actinically damaged field — also known as field cancerization — which is important because it is impossible to predict which AK lesions will progress to SCC. Currently available topical field therapies include 5-fluorouracil cream (5%, 1%, 0.5%), imiquimod cream (5% and 3.75%), diclofenac sodium gel 3% with 2.5% hyaluronic gel, and ingenol mebutate gel (0.05% and 0.015%). Photodynamic therapy is a procedural field therapy. Important considerations when developing a comprehensive treatment plan include patient risk factors; the number and location of AK lesions; strategies for minimizing sun exposure; and the mechanism of action, clearance rate, adverse effect profile, and application of local and topical therapies.

J Drugs Dermatol 2012;11(12):1462-1467.


Pathophysiology of AK: Progression from Normal Skin to Keratinocyte Cancers

Actinic keratoses (AKs) are intraepidermal cutaneous areas of atypical squamous transformation that develop as a result of excessive exposure to ultraviolet (UV) radiation on sun-exposed skin (eg, face, scalp, neck, extremities).1 Histologically, AKs are defined by dysplasia and consist of keratinocytes with irregular, enlarged hyperchromatic nuclei. Actinic keratoses are characterized by disorganized growth, which disrupts differentiation and leads to a thickened stratum corneum with retained nuclei.2
The most current pathophysiologic evidence is consistent with the multistep model of carcinogenesis, supporting the theory that AK is a step in the continuum of transformation from normal skin to AK to invasive cutaneous squamous cell carcinoma (cSCC) to metastatic SCC.2 Based on this model, a single genetic mutation may lead to development of a precursor lesion with a high level of genetic instability or loss of cell cycle control. Additional mutations in other driver oncogenes allow emergence of additional neoplastic properties, progressing through the following stages: sun-damaged epidermis, with individual disordered keratinocytes; AK, spontaneously regressing keratinized patches with abnormal cell differentiation and proliferation; carcinoma in situ; cSCC; and metastasis.2
The initial mechanism leading to genomic instability in keratinocytes is thought to be UVB-induced inactivation of p53, a protein that prevents normally uncontrolled cell division after chromosomal damage and thereby stops precancerous cells.2 Mutations of p53 are found in more than 90% of human cSCCs, indicating that dysplastic lesions have acquired the initial genetic mutations before transforming to cSCCs.2 If the normal response is decreased in only a single cell, UV exposure may select for clonal expansion of the p53-mutated cell into the AK. It is important to realize that sunlight can act twice—as a tumor initiator and as a tumor promoter—underscoring the importance of sun protection in the initial prevention and ongoing management of AK.3 In addition, consideration of the mechanisms of action (MOAs) of topical field therapies for AK is becoming important when selecting a treatment approach.4
The rate of progression from AK to cSCC is estimated between 0.025% and 16% per year for an individual lesion.5 The typical person with AK has 6 to 8 lesions; an individual with multiple AKs therefore has an annual risk of developing invasive cSCC between 0.15% and 80%.2 Results of the Department of Veterans Affairs Topical Tretinoin Chemoprevention Trial, which included a population at high risk for AK, showed that approximately 65% of all primary cSCCs and 36% of all primary basal cell carcinomas (BCCs) originated from lesions previously diagnosed as AKs. The majority of AKs regressed during the study—55% and 70% were not present at 1 and 5 years, respectively.6 Importantly, even a low yearly rate of transformation of a single AK lesion into an SCC can translate into an increased risk in patients with multiple AKs, especially when considered over a long period of time.7 Overall, these results support current thinking "that AKs may play a greater role in the overall burden of keratinocyte carcinomas than previously documented."6