INTRODUCTION
Actinic keratosis (AK) exemplifies the oncologic concept of field cancerization of the skin.1,2 This represents a step within a continuum from photodamage to early, subclinical actinic keratinocyte dysplasia, clinical visible actinic keratinocyte dysplasia (in situ squamous cell carcinoma), and ultimately, however rarely observed, invasive squamous cell carcinoma. Hence, treatment of AK should not be limited to the destruction of single lesions, but rather include the entire area of actinic damage (subclinical and clinical) in order to achieve clearance of the entire oncological spectrum. AK is a very common disease, with an estimated 60% of the population above 40 years of age being affected.3 As AK mostly occurs in the background of actinically damaged skin, topical treatment addressing actinic field cancerization is recommended.4,5 Several treatment options are available.5 Recently ingenol mebutate gel has been approved for the field treatment of AK in concentrations of 0.05% applied for two days for trunk or extremities and 0.015% applied for three days for face or scalp, with a reported median reduction in AK lesions of 75% and 83%, respectively.6 The current knowledge regarding the mode of action of ingenol mebutate is based on pre-clinical studies. Topically applied to human reconstructed skin, ingenol mebutate accumulates in the epidermis in concentrations up to 300 μM, inducing cell death restrictive to the epidermis. Furthermore, the cell death induced is suggestive of being selective for rapidly dividing cells being cancer cells>atypical cells>proliferative cells>differentiated cells.7 In the dermis, however, low concentrations of ingenol mebutate in the range of 15–40 μM are accumulated. At this concentration range, ingenol mebutate is likely to cause a potent activation of protein kinase-C isoforms.7,8 This specific PKC-activation has been shown to induce a specific cytokine and chemokine production and release (eg, interleukin-8, tumor necrosis factor-α, interleukin-6, interleukin-1β) as well as vascular endothelial activation (ICAM1 and E-selectin).9 Furthermore, studies in mice have shown that solid tumors topically treated with ingenol mebutate induced a local infiltration of mostly neutrophils , and played a key role, mutually together with the cell death, for the effectiveness in clearing cancer cells.10 Interestingly, field treatment with ingenol mebutate gel in severe photo-damaged skin in mice resulted in reduction of p53 patches.11 This suggest an efficacy of ingenol mebutate in early keratinocyte dysplasia and the potential to clear subclinical AK (SC-AK). Nevertheless, the mechanism of action of ingenol mebutate in actinic fields in humans remained largely unclear.
