The clinical course of actinic keratosis correlates with underlying molecular mechanisms

Abstract

Summary Background Actinic keratoses (AKs) are common premalignant skin lesions triggered by excessive ultraviolet exposure. The majority of AKs regress or persist, but some progress to squamous cell carcinomas. Biomarkers associated with their persistence, progression and regression have not been characterized. Objectives We performed skin biopsies in patients with extensive actinic damage to identify biomarkers that correlate with clinical progression and regression of AKs. Methods This was an observational study of a cohort of patients with extensive actinic damage. AKs were mapped on a clear plastic template in 26 patients at months 3, 6, 9 and 11. Biopsies were taken from randomly selected, predetermined AKs and were evaluated for p53, E‐cadherin, Snail, Slug and Twist. The study is registered at Clinicaltrials.gov: NCT00027976. Results p53 exhibited greater expression in clinically apparent AKs (histological score 2·89 ± 1·45) than in regressed AKs (0·75 ± 0·96); P < 0·01. There was also significantly less membrane E‐cadherin, the lack of which is a marker of epithelial–mesenchymal transition, in clinically apparent AKs (1·89 ± 1·81) than in sun‐exposed skin (3·07 ± 1·75); P < 0·005. The E‐cadherin transcription repressors Snail, Slug and Twist were increased in AKs compared with sun‐exposed skin. A limitation of the study is that measurement of histological biomarkers was not a primary end point. In addition, patients were allowed to apply sunscreens. Conclusions At the molecular level, loss of E‐cadherin and an increase in p53 are linked to the dynamic interplay between the persistence, progression and regression of AKs. What's already known about this topic? Actinic keratoses (AKs) are common dysplastic epidermal lesions that result from chronic and excessive ultraviolet exposure. Biomarkers associated with progression and regression of AK have not been characterized. What does this study add? Decreased E‐cadherin and increased p53, Snail, Slug and Twist (E‐cadherin transcription factors) were associated with progression from AK to nonmelanoma skin cancer. What is the translational message? Strategies targeting these molecules may be effective in reversing rising skin cancer rates. E‐cadherin, p53, Snail, Slug and Twist are potential biomarkers that may be used to assess the efficacy of existing chemopreventive agents.

The diagnostic value of p63, p16, and p53 immunohistochemistry in distinguishing seborrheic keratosis, actinic keratosis, and Bowen's disease

“…22,23 The expression of p53 also decreased in regressed AK and non-sun-exposed skin compared with sun-exposed skin and clinically apparent AK. 24 Ishida et al and our findings demonstrated that p53 stained basal keratinocytes in AK and left them unstained in BD. 25 They assumed that attenuation and disappearance of the sparing of the basal keratinocytes is a sign of tumor progression.…”

Biomarkers in melanoma and non‐melanoma skin cancer prevention and risk stratification

“…[42] There is a growing interest in the development of of E-cadherin, and these were increased in AKs compared with normal sun-exposed skin. [43] Studies are ongoing to determine genes that can differentiate high-risk AKs from more indolent lesions that will not progress into SCCs, which will facilitate the identification of benign AKs to avoid unnecessary treatment of the 95% of AKs that will not develop into malignant cancerous lesions.…”

P53 staining index and zonal staining patterns in actinic keratoses

“…Actinic keratoses (AKs) are common dysplastic epidermal lesions resulting from chronic and excessive ultraviolet exposure [ 1 ]. AKs are more common in male sex, phototypes I and II, and in old age [ 2 , 3 ].…”

“…AKs are more common in male sex, phototypes I and II, and in old age [ 2 , 3 ]. The majority of AKs persist, regress, or regress and relapse, but some progress to invasive squamous cell carcinomas (SCCs) [ 1 ]. The real risk of progression is difficult to quantify and has been variously estimated by different authors.…”