genetic syndromes with increased sensitivity to UV radiation (either from melanin deficiency or chromosomal instability), such as albinism, xeroderma pigmentosum, Bloom syndrome, Cockayne syndrome, and poikiloderma congenitale.6 The presence of cutaneous human papilloma virus has also been implicated in the development of AKs, possibly as an oncogenic cofactor or result of true infection.10
Excessive and cumulative exposure to UV radiation induces genetic damage, inflammation, immunosuppression (loss of tumor surveillance), and mutagenesis in epidermal keratinocytes, which eventually gives rise to AKs through clonal expansion.11,12 UV light promotes the production of arachidonic acid, pro-inflammatory cytokines, adhesion molecules, and mast cell-derived mediators.11 The majority of UV exposure occurs from UVA (320–400 nm), which penetrates the skin more deeply than UVB (290–320 nm). UVA produces reactive oxygen species (ROS), such as superoxide anions, hydroxyl radicals, and hydrogen peroxide. These ROS trigger oxidative damage in nucleic acids, membrane lipids, and proteins, thereby disrupting normal cellular signal transduction pathways and causing abnormal proliferation. The effects of UVA also result in 8-hydroxyguanine adducts, leading to signature transitions of thymine (T) -> guanine (G).12,13 UVB produces cytosine (C)-containing cyclobutane pyrimidine dimers and pyrimidine-pyrimidone 6-4 photoproducts that result in signature transitions of C -> T and CC -> TT.11,13 This generation of DNA photoproducts disrupts normal replication and transcriptional processes.The most significant UV-induced mutations occur in tumor suppression genes. The initial mutation serves as a pivotal event that increases susceptibility to the accumulation of mutations in additional tumor suppressor genes and proto-oncogenes, thereby facilitating the unrestrained proliferation of neoplastic keratinocytes.11 Some mutations implicated in the development of AK and the progression to SCC include RAS oncogenes, C-MYC proto-oncogenes, as well as the tumor suppressor genes p16 (INK4a), p14 (ARF), and p15 (INK4b).14 In particular, mutations in the p53 tumor suppressor gene are commonly present in AKs, SSCs, and normal perilesional skin from sun-exposed sites.15-17 This evidence suggests that the p53 mutation is an early step in AK development. Under normal conditions, the p53 gene is activated by DNA damage to arrest the cell cycle and allow for the repair of damaged DNA. In the event of irreparable damage, p53 also triggers apoptosis of keratinocytes with premalignant or malignant properties in order to prevent clonal expansion.11,13 The protective role of the p53 gene in preventing carcinogenesis by UV radiation was demonstrated in p53-heterozygous mice, who showed increased susceptibility to skin cancer, an effect that was even further exaggerated in p53-homozygous knockout mice.18 It has also been shown that UVB-induced point mutations lead to p53 inactivation, compromising the gene’s tumor suppressive functions and creating genetically compromised keratinocytes.11,12
EVOLUTION TO SQUAMOUS CELL CARCINOMA
Actinic keratoses may regress spontaneously, remain stable, or progress to invasive SCC.19,20 Approximately 26% of lesions regress, although the mechanism of regression is not well understood.19 Anywhere between 0.025% and 16% of AKs can transform to invasive SCC.21 Extrapolation studies suggest the overall risk of progression is approximately 8%, although the likelihood varies with age, gender, chronic UV exposure, and location of AKs.22,23 Given the variable reporting on the risk of transformation, the decision to treat should be made in the context of individual risk factors.21 Histological evidence endorses a strong association between AK and SCC. In a review of 165 SCC cases, 80% of SCC were found to be contiguous with or arise in close proximity of AKs.24 A review of 1011 cases of SCC found that 97.2% of SCCs contained SCC in situ at the periphery or within the confines of the SCC itself.25 The authors suggested that had all specimens been removed with adequate margins, 100% of specimens would contain evidence of SCC in situ, demonstrating the histopathological progression of AK to SCC.While it is not possible to accurately predict which AK lesions will progress to SCC, certain clinical parameters may indicate an increased risk of malignancy. In a systematic review of studies of malignant transformation of AK to SCC, predictive factors included induration/inflammation, diameter greater than 1 cm, rapid enlargement, bleeding, erythema, and ulceration.26 In lesions that develop palpability, induration, or ulceration, biopsy is commonly indicated to rule out malignant transformation.27
A wide range of management options exist for AKs. Therapies can be broadly divided according to the number of lesions targeted: destructive and surgical therapies that target individual lesions, and field treatments that target widespread lesions.
Cryosurgery with liquid nitrogen remains a preferred treatment for isolated AK lesions. With cryosurgery, liquid nitrogen at -196°C is applied to the affected lesion using either a spray device or cotton tip applicator. The cold temperatures lead to intracellular and extracellular ice crystal formation, which damage AK cells through cryolysis, vascular stasis, and apoptosis.28