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Actinic keratosis
Evidence Levels: A Double-blind study B Clinical trial ≥ 20 subjects C Clinical trial < 20 subjects D Series ≥ 5 subjects E Anecdotal case reports
Actinic keratoses (AKs) are ill-defined, pink to skin-colored, scaly lesions found on chronically sun-exposed areas in light-skinned individuals. They most frequently appear on the face, ears, balding scalp, extensor forearms, and dorsal hands. AKs are a strong predictor for the development of squamous cell carcinoma (SCC) and, to a lesser extent, basal cell carcinoma. Australians have the highest reported prevalence, which approaches 60%, and in the US, AKs are the second most common reason for visits to the dermatologist.
Management Strategy
AKs are common dysplastic intraepidermal lesions that are considered to be precursors to SCC. Reports have varied as to the rates of progression to invasive SCC, from 0.025% to over 25% per year, and AKs are commonly located adjacent to SCC histologically. For these reasons, most practitioners advocate the treatment of AKs, as considerable morbidity and potential mortality can be associated with invasive disease. In 2018, Weinstock and colleagues were the first to perform a randomized trial showing that topical treatment for AKs led to a significantly reduced need for surgery for SCC.
The diagnosis of AK is primarily clinical, and because of their superficial nature, a variety of effective management approaches exist. Biopsy of suspected AKs is typically not warranted; however, in patients with a history of multiple skin cancers, immunosuppressed patients, and lesions in high-risk areas such as the lip or ear, clinicians should have a low threshold for biopsy to rule out invasive SCC. Indications for biopsy include tenderness, rapid growth or thickening of lesions, bleeding, hyperkeratosis, and failure to respond to treatment.
Prevention of AKs through sun avoidance and diligent use of broad-spectrum sunscreens and blocking agents is an important aspect of management. This has been shown to prevent the development of new AKs and reduce the incidence of non-melanoma skin cancers.
With cumulative sun exposure and advancing age, rates of AK development increase, necessitating either ablative or field treatment. Cryotherapy with liquid nitrogen is by far the most commonly employed therapeutic modality for discrete lesions because it can be performed quickly and effectively in the office setting. However, given the common appearance of AKs on a background of diffuse actinic damage, individual lesions may be poorly defined and involve large, contiguous areas requiring field treatment with topical agents such as 5-fluorouracil (5-FU) or imiquimod , or with photodynamic therapy. The advantages of field approaches are that they are non-invasive, carry little risk, and can be used for anatomically difficult or cosmetically sensitive areas. Furthermore, they address both clinically apparent as well as subclinical areas of skin in contiguous fashion. Most of these agents must be used for weeks to months, result in some degree of erythema, inflammation, and discomfort, and require adequate patient compliance.
Photodynamic therapy (PDT) with aminolevulinic acid (ALA) or methyl aminolevulinate (MAL) has continued to become more widespread, given its proven therapeutic results and excellent cosmetic outcome. PDT offers a physician-administered approach to field treatment with shorter periods of inflammation and erythema than several topical agents and, thus, higher patient satisfaction. Variations in the light dose, light source, sensitizing agent and its application time, and frequency of treatments may improve efficacy. Most recently, PDT using natural daylight to excite the chemical sensitizer has gained popularity.
Head-to-head trials of different treatment approaches are difficult to perform, as variations in treatment protocols make direct comparisons challenging. Several well-designed trials have suggested topical 5-fluorouracil as the most effective stand-alone topical agent to treat AKs. Recently, there has been a growing trend towards combination therapy , such as topical agents either before or after cryotherapy, or sequential use of multiple field modalities with differing mechanisms of action. Other approaches such as laser resurfacing , chemical peels , and dermabrasion may be considered in certain situations when lesions have failed the above treatments, or if severe photodamage is present. Finally, for recalcitrant or hyperkeratotic lesions, curettage or excision may be appropriate.
Specific Investigation
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Biopsy
Actinic keratoses and the incidence of occult squamous cell carcinoma: a clinical–histopathologic correlation
Ehrig T, Cockerell C, Piacquadio D, et al. Dermatol Surg 2006; 32: 1261–5.
Two hundred and seventy-one clinically diagnosed AKs were biopsied. Clinical diagnosis agreed with histology 91% of the time, with about 1 in 25 lesions revealing invasive SCC.
Clinical recognition of actinic keratoses in a high-risk population: how good are we?
Venna SS, Lee D, Stadecker MJ, et al. Arch Dermatol 2005; 141: 507–9.
Seventeen of 23 lesions (74%) with classic features of AK in patients with a history of previous skin cancer were confirmed histologically. Five lesions (22%) were shown to be SCC.
Actinic keratoses are typically diagnosed clinically. However, there should be a low threshold to biopsy tender, hyperkeratotic, large, or recalcitrant lesions to exclude malignancy.
A randomized controlled trial to assess sunscreen application and beta carotene supplementation in the prevention of solar keratoses
Darlington S, Williams G, Neale R, et al. Arch Dermatol 2003; 139: 451–5.
In this Australian study, 1621 adults were randomized to either daily use of sunscreen or application at their usual discretionary rate. There was a 24% reduction in AKs in the daily use group.
Reduction of solar keratoses by regular sunscreen use
Thompson SC, Jolley D, Marks R. N Engl J Med 1993; 14: 1147–51.
In a 6-month randomized, placebo-controlled trial of 588 patients in Australia, SPF 17 sunscreen applied daily was found to both reduce the development of new AKs and increase the remission of existing AKs in comparison to a vehicle cream.
A prospective study of the use of cryosurgery for the treatment of actinic keratoses
Thai K, Fergin P, Freeman M, et al. Int J Dermatol 2004; 43: 687–92.
In this prospective multicenter study, 90 patients with 421 AKs on the face and scalp were treated with cryotherapy with a single freeze–thaw cycle using different freeze times. The patients were reviewed 3 months later. Overall, the complete response (CR) rate was 67.2%, varying from 39% for freeze times less than 5 s to 83% for times longer than 20 s. The authors also found that hypopigmentation was present in 29% of CR lesions. Patients rated cosmetic outcomes as good to excellent for 94% of CR lesions.
Chemoprevention of basal and squamous cell carcinoma with a single course of fluorouracil, 5%, cream: a randomized clinical trial
Weinstock MA, Thwin SS, Siegel JA, et al. JAMA Dermatol 2018 1; 154: 167–74.
In this randomized trial, 932 patients with a prior history of non-melanoma skin cancer received either 5-FU cream or vehicle twice daily for 2–4 weeks. There was a significantly reduced need for surgery to address SCC in the treatment arm.
Effective treatment of actinic keratosis with 0.5% fluorouracil cream for 1, 2 or 4 weeks
Weiss J, Menter A, Hevia O, et al. Cutis 2002; 70: 22–9.
In this randomized, double-blind, parallel-group vehicle-controlled study, 177 patients with at least five AKs were treated with topical 0.5% 5-FU cream daily for 1, 2, or 4 weeks. In patients who were treated for 4 weeks, complete clearance of lesions was observed in 47.5%, compared with 26% who were treated for 1 week ( p <0.001 vs vehicle). Moderate-to-severe irritation of the skin was noted in 90% of these patients.
Imiquimod 5% cream for the treatment of actinic keratosis: results from two phase III, randomized, double-blind, parallel group, vehicle-controlled trials
Lebwohl M, Dinehart S, Whiting D, et al. J Am Acad Dermatol 2004; 50: 714–21.
In this report of two phase III double-blind, vehicle-controlled studies, 436 subjects at 24 centers in the US were randomized to either 5% imiquimod or vehicle applied once daily, two days per week, for 16 weeks. The complete clearance rate for the treated arm was 45%, as opposed to 3.2% for the vehicle group. The median percent reduction in AK lesions was 83% for the treated group and 0% for the vehicle group, indicating that a reduced frequency of imiquimod application is quite effective.
Imiquimod 2.5% and 3.75% for the treatment of actinic keratoses: results of two placebo-controlled studies of daily application to the face and balding scalp for two 3-week cycles
Hanke CW, Beer KR, Stockfleth E, et al. J Am Acad Dermatol 2010; 62: 573–81.
Imiquimod 2.5% and 3.75% for the treatment of actinic keratoses: results of two placebo-controlled studies of daily application to the face and balding scalp for two 2-week cycles
Swanson N, Abramovits A, Berman B, et al. J Am Acad Dermatol 2010; 62: 582–90.
These two back-to-back reports demonstrate the efficacy and tolerability of lower concentration formulations of imiquimod as well as alternate dosing schedules. Interestingly, the results were essentially identical for two 3-week cycles as they were for two 2-week cycles, with the 3.75% strength imiquimod proving superior to the 2.5% in both studies and slightly less efficacious than previous studies that have investigated 5% imiquimod used twice weekly for 16 weeks.
A randomised study of topical 5% imiquimod vs. topical 5-fluorouracil vs. cryosurgery in immunocompetent patients with actinic keratoses: a comparison of clinical and histological outcomes including 1-year follow-up
Krawtchenko N, Roewert-Huber J, Ulrich M, et al. Br J Dermatol 2007; 157 Suppl 2: 34–40.
This study compared the baseline and 1-year follow-up rates of clinical clearance, histological clearance, and cosmetic outcomes of imiquimod, 5-FU, and cryosurgery for the treatment of AKs. Patients were randomized to one of the three treatment groups. Clinical clearance was achieved in 68% of those treated with cryosurgery, 96% with 5-FU, and 85% with imiquimod. Histological clearance rate was 32% for cryosurgery, 67% for 5-FU, and 73% for imiquimod. The 1-year sustained clearance rate was 28% for cryosurgery, 54% for 5-FU, and 73% for imiquimod. The patients treated with imiquimod were also judged to have superior cosmetic outcomes.
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