Field Cancerization Therapies for Management of Actinic Keratosis: A Narrative Review

Abstract

Actinic keratoses (AKs) are atypical, precancerous proliferations of keratinocytes that develop because of chronic exposure to ultraviolet (UV) radiation. Treatment of AK can be lesion-directed or field-directed. Field cancerization theory postulates that the skin surrounding AK is also at increased risk for possible malignant transformation since it has been exposed to the same chronic UV light. Field-directed therapies thus have the potential to address subclinical damage, reduce AK recurrence rates, and potentially reduce the risk of squamous cell carcinoma (SCC) development. Published clinical studies have found lesion clearance rates ranging from 81 to 91% for photodynamic therapy (PDT) with either aminolevulinic acid (ALA) or methylaminolevulinate (MAL). Clinical studies have also been published on various topical treatments. Complete clinical clearance (CCC) was significantly higher in patients treated with a combination of 5-fluorouracil and salicylic acid (5-FU-SA) than in the vehicle group across multiple studies, and CCC ranged between 46 and 48% following treatment with imiquimod. Additionally, treatment with diclofenac sodium (DFS) found reduction in lesion sizes to range from 67 to 75%. Reported results have been similar for another non-steroidal anti-inflammatory drug (NSAID), piroxicam, which has more cyclooxygenase (COX)-1 activity than DFS. Active treatments with ingenol mebutate were also significantly more effective than vehicle at clearing AK lesions. All treatments resulted in mild, localized skin reactions. PDT using conventional light sources was associated with increased severity of pain and/or discomfort, while PDT using daylight as the light source was associated with less pain and occasionally no pain at all. Though no widely accepted algorithm for the treatment of AKs exists, field-directed therapy can be particularly useful for treating photo-exposed areas containing multiple AKs. Additional research with more direct comparisons between these field-directed therapies will help clinicians determine the best therapeutic approach. Here, we provide a balanced and comprehensive narrative review of the literature, considering both light-based and topical therapies with a focus on their field-therapy aspects, and propose a therapeutic algorithm for selecting an appropriate treatment in the clinical setting.

Clinical features and outcome of dermal squamous cell carcinoma in 193 dogs (1987‐2017)

“…This process, sometimes called “field cancerization,” could explain why SCCs accompanied by actinic change may be less discrete . Some of these characteristics are shared with human dermal SCC where clear predispositions also exist for sun‐exposed regions such as the head and neck, people with fair skin, as well as a propensity for actinically associated field cancerization . This study documented an association of actinic change with younger dogs, however, the risk in people for developing dermal SCC increases with age, with a median age of onset in one study of 73 years and a male predisposition .…”

“…46 Some of these characteristics are shared with human dermal SCC where clear predispositions also exist for sun-exposed regions such as the head and neck, people with fair skin, as well as a propensity for actinically associated field cancerization. 18,47 This study documented an association of actinic change with younger dogs, however, the risk in people for developing dermal SCC increases with age, with a median age of onset in one study of 73 years and a male predisposition. 18 Ultimately, it is unknown what might explain this divergence in age between species, but some dogs may live outside or have minimal to no protection from solar UV exposure, thus accumulating solar damage within a shorter time span.…”

Ingenol mebutate‐mediated reduction in p53‐positive keratinocytes in skin cancerization field directly correlates with clinical response in patients with multiple actinic keratoses

“…16,17,[20][21][22][23] It is commonly believed that chronic UV radiation exposure represents the crucial risk factor for NMSC, 1 being responsible of several mutations on p53 suppressor gene, typically involved in the apoptosis of DNA-damaged keratinocytes. 16,17,[20][21][22][23] It is commonly believed that chronic UV radiation exposure represents the crucial risk factor for NMSC, 1 being responsible of several mutations on p53 suppressor gene, typically involved in the apoptosis of DNA-damaged keratinocytes.…”

“…4-7 UVdamaged keratinocytes, with mutated p53, replicate and form the so-called 'p53 patches' in skin, 4,8,9 which might develop in AK, 7,10 and later on in NMSC. 22 Among field therapy drugs, ingenol mebutate was able to reduce AKs with quite rapid resolution of local reaction, with the shortest duration of treatment and the possibility of self-application which strongly improve patients' quality of life. 22 Among field therapy drugs, ingenol mebutate was able to reduce AKs with quite rapid resolution of local reaction, with the shortest duration of treatment and the possibility of self-application which strongly improve patients' quality of life.…”

“…22 Among field therapy drugs, ingenol mebutate was able to reduce AKs with quite rapid resolution of local reaction, with the shortest duration of treatment and the possibility of self-application which strongly improve patients' quality of life. 18,22 Beside the first, rapid cytotoxic action on mitochondrial membranes, responsible of cell death by necrosis 24 and clinically characterized by a transient and self-healing LSR, an important inflammatory response occurs after 24 h, predominantly involving polymorphonuclear neutrophils 24,25 and pro-inflammatory cytokines release from cells undergone drug-induced necrosis, which in turn activate endothelial cells and improve the transmigration of recruited neutrophils into treatment site. 18,22 Beside the first, rapid cytotoxic action on mitochondrial membranes, responsible of cell death by necrosis 24 and clinically characterized by a transient and self-healing LSR, an important inflammatory response occurs after 24 h, predominantly involving polymorphonuclear neutrophils 24,25 and pro-inflammatory cytokines release from cells undergone drug-induced necrosis, which in turn activate endothelial cells and improve the transmigration of recruited neutrophils into treatment site.…”