likely to be detected in that area. if a shave biopsy is performed, it should extend through to the level of the dermis in order to provide sufficient tissue for diagnosis; ideally, it would extend to the mid-reticular dermis. punch biopsy usually extends to the subcutaneous fat when the entire length of the punch blade is utilized. histopathology normal skin (left) and actinic keratosis (right) with the defining characteristic of atypical basal keratinocytes that do not involve the full thickness of the epidermis. actinic keratosis, atrophic form on histologic examination, actinic keratoses usually show a collection of atypical keratinocytes with hyperpigmented or pleomorphic nuclei, extending to the basal layer of the epidermis. a "flag sign" is often described, referring to alternating areas of orthokeratosis and parakeratosis. epidermal thickening and surrounding areas of sun-damaged skin are often seen. the normal ordered maturation of the keratinocytes is disordered to varying degrees: there may be widening of the intracellular spaces, cytologic atypia such as abnormally large nuclei, and a mild chronic inflammatory infiltrate. specific findings depend on the clinical variant and particular lesion characteristics. the seven major histopathologic variants are all characterized by atypical keratinocytic proliferation beginning in the basal layer and confined to the epidermis; they include: hypertrophic: notable for marked hyperkeratosis, often with evident parakeratosis. keratinocytes in the stratum malphigii may show a loss of polarity, pleomorphism, and anaplasia. some irregular downward proliferation into the uppermost dermis may be observed, but does not represent frank invasion. atrophic: with slight hyperkeratosis and overall atrophic changes to the epidermis; the basal layer shows cells with large, hyperchromatic nuclei in close proximity to each other. these cells have been observed to proliferate into the dermis as buds and duct-like structures. lichenoid: demonstrate a band-like lymphocytic infiltrate in the papillary dermis, directly beneath the dermal-epidermal junction. achantholytic: intercellular clefts or lacunae in the lowermost epidermal layer that result from anaplastic changes; these produce dyskeratotic cells with disrupted intercellular bridges. bowenoid: this term is controversial and usually refers to full-thickness atypia, microscopically indistinguishable from bowen's disease. however most dermatologists and pathologists will use it in reference to tissue samples that are notable for small foci of atypia that involve the full thickness of the epidermis, in the background of a lesion that is otherwise consistent with an ak. epidermolytic: with granular degeneration. pigmented: show pigmentation in the basal layer of the epidermis, similar to a solar lentigo. dermoscopy dermoscopy is a noninvasive technique utilizing a handheld magnifying device coupled with a transilluminating lift. it is often used in the evaluation of cutaneous lesions but lacks the definitive diagnostic ability of biopsy-based tissue diagnosis. histopathologic exam remains the gold standard. polarized contact dermoscopy of aks occasionally reveals a "rosette sign," described as four white points arranged in a clover pattern, often localized to within a follicular opening. it is hypothesized that the "rosette sign" corresponds histologically to the changes of orthokeratosis and parakeratosis known as the "flag sign." non-pigmented aks: linear or wavy vascular patterning, or a "strawberry pattern," described as unfocused vessels between hair follicles, with white-haloed follicular openings. pigmented aks: gray to brown dots or globules surrounding follicular openings, and annular-granular rhomboidal structures; often difficult to differentiate from lentigo maligna. prevention ultraviolet radiation is believed to contribute to the development of actinic keratoses by inducing mutations in epidermal keratinocytes, leading to proliferation of atypical cells. therefore, preventive measures for aks are targeted at limiting exposure to solar radiation, including: limiting extent of sun exposure avoid sun exposure during noontime hours between 10:00 am and 2:00 pm when uv light is most powerful minimize all time in the sun, since uv exposure occurs even in the winter and on cloudy days using sun protection applying sunscreens with spf ratings 30 or greater that also block both uva and uvb light, at least every 2 hours and after swimming or sweating applying sunscreen at least 15 minutes before going outside, as this allows time for the sunscreen to be absorbed appropriately by the skin wearing sun protective clothing such as hats, sunglasses, long-sleeved shirts, long skirts, or trousers recent research implicating human papillomavirus (hpv) in the development of aks suggests that hpv prevention might in turn help prevent development of aks, as uv-induced mutations and oncogenic transformation are likely facilitated in cases of active hpv infection. a key component of hpv prevention includes vaccination, and the cdc currently recommends routine vaccination in all children at age 11 or 12. there are some data that in individuals with a history of non-melanoma skin cancer, a low-fat diet can serve as a preventative measure against future actinic keratoses. management there are a variety of treatment options for ak depending on the patient and the clinical characteristics of the lesion. aks show a wide range of features, which guide decision-making in choosing treatment. as there are multiple effective treatments, patient preference and lifestyle are also factors that physicians consider when determining the management plan for actinic keratosis. regular follow-up is advisable after any treatment to make sure no new lesions have developed and that old ones are not progressing. adding topical treatment after a procedure may improve outcomes. medication topical medications are often recommended for areas where multiple or ill-defined aks are present, as the medication can easily be used to treat a relatively large area. fluorouracil cream topical fluorouracil (5-fu) destroys aks by blocking methylation of thymidylate synthetase, thereby interrupting dna and rna synthesis. this in turn prevents the proliferation of dysplastic cells in ak. topical 5-fu is the most utilized treatment for ak, and often results in effective removal of the lesion. overall, there is a 50% efficacy rate resulting in 100% clearance of aks treated with topical 5-fu. 5-fu may be up to 90% effective in treating non-hyperkeratotic lesions. while topical 5-fu is a widely used and cost-effective treatment for aks and is generally well tolerated, its potential side-effects can include: pain, crusting, redness, and local swelling. these adverse effects can be mitigated or minimized by reducing the frequency of application or taking breaks between uses. the most commonly used application regimen consists of applying a layer of topical cream to the lesion twice a day after washing; duration of treatment is typically 2–4 weeks to thinner skin like the cheeks and up to 8 weeks for the arms; treatment of up to 8 weeks has demonstrated a higher cure rate. imiquimod cream imiquimod is a topical immune-enhancing agent licensed for the treatment of genital warts. imiquimod stimulates the immune system through the release and up-regulation of cytokines. treatment with imiquimod cream applied 2–3 times per week for 12 to 16 weeks was found to result in complete resolution of aks in 50% of people, compared to 5% of controls. the imiquimod 3.75% cream has been validated in a treatment regimen consisting of daily application to entire face and scalp for two 2-week treatment cycles, with a complete clearance rate of 36%. while the clearance rate observed with the imiquimod 3.75% cream was lower than that observed with the 5% cream (36 and 50 percent, respectively), there are lower reported rates of adverse reactions with the 3.75% cream: 19% of individuals using imiquimod 3.75% cream reported adverse reactions including local erythema, scabbing, and flaking at the application site, while nearly a third of individuals using the 5% cream reported the same types of reactions with imiquimod treatment. however, it is ultimately difficult to compare the efficacy of the different strength creams directly, as current study data varies in methodology (e.g. duration and frequency of treatment, and amount of skin surface area covered). ingenol mebutate gel ingenol mebutate is a newer treatment for ak used in europe and the united states. it works in two ways, first by disrupting cell membranes and mitochondria resulting cell death, and then by inducing antibody-dependent cellular cytotoxicity to eliminate remaining tumor cells. a 3-day treatment course with the 0.015% gel is recommended for the scalp and face, while a 2-day treatment course with the 0.05% gel is recommended for the trunk and extremities. treatment with the 0.015% gel was found to completely clear 57% of ak, while the 0.05% gel had a 34% clearance rate. advantages of ingenol mebutate treatment include the short duration of therapy and a low recurrence rate. local skin reactions including pain, itching and redness can be expected during treatment with ingenol mebutate. this treatment was derived from the petty spurge, euphorbia peplus which has been used as a traditional remedy for keratosis. diclofenac sodium gel topical diclofenac sodium gel is a nonsteroidal anti-inflammatory drug that is thought to work in the treatment of ak through its inhibition of the arachidonic acid pathway, thereby limiting the production of prostaglandins which are thought to be involved in the development of uvb-induced skin cancers. recommended duration of therapy is 60 to 90 days with twice daily application. treatment of facial ak with diclofenac gel led to complete lesion resolution in 40% of cases. common side effects include dryness, itching, redness, and rash at the site of application. retinoids topical retinoids have been studied in the treatment of ak with modest results, and the american academy of dermatology does not currently recommend this as first-line therapy. treatment with adapalene gel daily for 4 weeks, and then twice daily thereafter for a total of nine months led to a significant but modest reduction in the number aks compared to placebo; it demonstrated the additional advantage of improving the appearance of photodamaged skin. topical tretinoin is ineffective as treatment for reducing the number of aks. for secondary prevention of ak, systemic, low-dose acitretin was found to be safe, well tolerated and moderately effective in chemoprophylaxis for skin cancers in kidney transplant patients. acitretin is a viable treatment option for organ transplant patients according to expert opinion. tirbanibulin tirbanibulin (klisyri) was approved for medical use in the united states in december 2020, for the treatment of actinic keratosis on the face or scalp. cryotherapy cryosurgery instrument used to treat actinic keratoses liquid nitrogen (−195.8 °c) is the most commonly used destructive therapy for the treatment of ak in the united states. it is a well-tolerated office procedure that does not require anesthesia. cryotherapy is particularly indicated for cases where there are fewer than 15 thin, well-demarcated lesions. caution is encouraged for thicker, more hyperkeratotic lesions, as dysplastic cells may evade treatment. treatment with both cryotherapy and field treatment can be considered for these more advanced lesions. cryotherapy is generally performed using an open-spray technique, wherein the ak is sprayed for several seconds. the process can be repeated multiple times in one office visit, as tolerated. cure rates from 67 to 99 percent have been reported, depending on freeze time and lesion characteristics. disadvantages include discomfort during and after the procedure; blistering, scarring and redness; hypo- or hyperpigmentation; and destruction of healthy tissue. photodynamic therapy interim result of phototherapy for actinic keratosis with methyl aminolevulinate one week after exposure. patient has light skin, blue eyes. aks are one of the most common dermatologic lesions for which photodynamic therapy, including topical methyl aminolevulinate (mal) or 5-aminolevulinic acid (5-ala), is indicated. treatment begins with preparation of the lesion, which includes scraping away scales and crusts using a dermal curette. a thick layer of topical mal or 5-ala cream is applied to the lesion and a small area surrounding the lesion, which is then covered with an occlusive dressing and left for a period of time. during this time the photosensitizer accumulates in the target cells within the ak lesion. the dressings are then removed and the lesion is treated with light at a specified wavelength. multiple treatment regimens using different photosensitizers, incubation times, light sources, and pretreatment regimens have been studied and suggest that longer incubation times lead to higher rates of lesion clearance. photodynamic therapy is gaining in popularity. it has been found to have a 14% higher likelihood of achieving complete lesion clearance at 3 months compared to cryotherapy, and seems to result in superior cosmetic outcomes when compared to cryotherapy or 5-fu treatment. photodynamic therapy can be particularly effective in treating areas with multiple ak lesions. surgical techniques surgical excision: excision should be reserved for cases when the ak is a thick, horny papule, or when deeper invasion is suspected and histopathologic