Actinic keratoses

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Actinic keratoses

Sherrif F. Ibrahim and Marc D. Brown

Evidence Levels:  A Double-blind study  B Clinical trial ≥ 20 subjects  C Clinical trial < 20 subjects  D Series ≥ 5 subjects  E Anecdotal case reports

image

Actinic keratoses (AK) are ill-defined pink to skin-colored, scaly papules 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

Actinic keratoses are common dysplastic intra-epidermal 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. However, there have been no randomized controlled studies demonstrating a reduction in the frequency of SCC with treatment of AKs.

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 topical treatment. Cryotherapy with liquid nitrogen is by far the most commonly employed therapeutic modality 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. The latter has recently been shown to have high rates of treatment success with durable results and has become an accepted first-line therapy with a newer 3.75% formulation recently introduced. A novel agent, ingenol mebutate, is derived from the Euphorbia peplus plant and has been approved as an additional topical agent for the field treatment of AKs. The advantages of topical approaches are that they are patient-administered, non-invasive, carry little risk of scarring or pigmentary change, and can be used for anatomically difficult or cosmetically sensitive areas. However, these agents require adequate patient compliance and are often accompanied by prolonged erythema lasting several weeks. 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 many studies indicate higher patient satisfaction. Variations in the light dose, light source, sensitizing agent and its application time, and frequency of treatments may improve efficacy. Head-to-head trials of different treatment approaches are difficult to perform, as variations in treatment protocols make direct comparisons challenging. Recently, there has been a growing trend towards combination therapy, such as topical agents either before or after cryotherapy, or sequential use of multiple topical modalities with varying 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 investigations

In selected cases:

First-line therapies

imageSunscreens A
imageCryosurgery B
imageTopical 5-FU A
imageImiquimod A
imagePhotodynamic therapy A

Effect of a 1 week treatment with 0.5% topical fluorouracil on occurrence of actinic keratosis after cryosurgery.

Jorizzo J, Weiss J, Furst K, VandePol C, Levy SF. Arch Dermatol 2004; 140: 813–16.

This study demonstrates that there is a role for the combination of therapeutic modalities in the treatment of AKs. In this prospective, double-blind, randomized controlled trial, 144 patients, each with at least five AKs on the face, were randomized to receive 1 week of treatment with 0.5% 5-FU cream daily for 7 days or placebo cream. Patients were then treated with single freeze–thaw cycle cryotherapy using liquid nitrogen, with a thaw time of 10 seconds. These patients were then followed up at 4 weeks and 6 months. The authors found that, at 4 weeks, 16.7% of patients in the 5-FU group were completely clear of lesions, compared to 0% in the vehicle group (p<0.001). At 6 months post-treatment, 30% of patients in the 5-FU group were clear of lesions, compared to 7.7% of patients in the vehicle group (p<0.001).

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, Mann I, Sterry W, Stockfleth E. 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.

Multicentre intraindividual randomized trial of topical methyl aminolaevulinate–photodynamic therapy vs. cryotherapy for multiple actinic keratoses on the extremities.

Kaufmann R, Spelman L, Weightman W, Reifenberger J, Szeimies RM, Verhaeghe E, et al. Br J Dermatol 2008; 158: 994–9.

This was another intra-individual trial that treated one side of the body (non-face/scalp) with a single course of PDT and the other with cryotherapy. For the 1343 lesions treated, both treatment modalities had high efficacy rates at 24 weeks, although cryosurgery performed better (78% for PDT and 88% for cryosurgery). Investigator and patient assessment of cosmetic outcome was much higher for PDT than for cryosurgery (79% vs 56% of lesions having ‘excellent cosmetic outcome’ based on investigator evaluation, 50% vs 22% based on patient evaluation).

Photodynamic therapy with aminolevulinic acid topical solution and visible blue light in the treatment of multiple actinic keratoses of the face and scalp: investigator-blinded, phase 3, multicenter trials.

Piacquadio DJ, Chen DM, Farber HF, Fowler JF Jr, Glazer SD, Goodman JJ, et al. Arch Dermatol 2004; 140: 41–6.

In this randomized, placebo-controlled study 243 patients were randomized to receive vehicle or ALA followed by PDT within 14–18 hours. Clinical response rate was based on complete clearing of 75% of lesions measured at weeks 8 and 12. Of the PDT-treated group, 77% had a complete response by week 8 and 89% by week 12. This compared to 18% and 13% for the placebo group. Most patients experienced erythema and edema at the treated sites, which improved within 4 weeks of therapy. Stinging, burning, or pain occurred during the treatments, but resolved within 24 hours.

Second-line therapies

imageTopical adapalene A
imageTopical diclofenac A
imageTopical ingenol mebutate A

Randomized, double-blind, double-dummy, vehicle-controlled study of ingenol mebutate gel 0.025% and 0.05% for actinic keratosis.

Anderson L, Schmieder GJ, Werschler WP, Tschen EH, Ling MR, Stough DB, Katsamas J. J Am Acad Dermatol 2009; 60: 934–43.

A total of 222 patients from 22 US centers with non-facial AKs were randomized to receive vehicle for 3 days, 0.025% ingenol mebutate (IM) gel for 3 days, vehicle for 1 day followed by 0.05% IM gel for 2 days, or 0.05% IM gel for 3 days. Partial clearance rate (>75% reduction in baseline AKs) as well as complete clearance rate was statistically significantly higher in all three treatment groups over baseline and these results were dose-dependent. Partial and complete clearance rates were 28%/20% for the 0.025% × 3 days group, 34%/24% for the 0.05% × 2 days group, and 43%/31% for the 0.05% × 3 days cohort. The most common local skin responses seen in all groups included erythema, scaling, crusting, swelling, erosion/ulceration, vesiculation, and pigmentary changes and were largely resolved by day 15. Patient satisfaction was high.

Third-line therapies

imageCurettage E
imageExcision E
imageLaser resurfacing B
imageChemical peels D
imageDermabrasion D

Long-term efficacy and safety of Jessner’s solution and 35% trichloroacetic acid vs 5% fluorouracil in the treatment of widespread facial actinic keratoses.

Witheiler DD, Lawrence N, Cox SE, Cruz C, Cockerell CJ, Freemen RG. Dermatol Surg 1997; 23: 191–6.

In this prospective study, 15 patients with severe facial AKs were treated on one side of the face with a single application of Jessner’s solution – a medium-depth chemical peel – and the other side with twice-daily applications of topical 5-FU 5% for 3 weeks. The authors found that both treatments resulted in a similar reduction of AKs at 12 months, with an increase in the number of AKs in both groups from 12 to 32 months. The authors concluded that both treatments were similarly efficacious in the treatment of AK, and that re-treatment for recurrences might be necessary after 12 months.

Dermabrasion for prophylaxis and treatment of actinic keratoses.

Coleman WP, Yardborough JM, Mandy SH. Dermatol Surg 1996; 22: 17–21.

In this retrospective study, 23 patients who had undergone dermabrasion for facial AKs were followed for 2 to 5 years. The authors found that the benefits of dermabrasion diminished with time: 1 year post dermabrasion, 22 patients remained clear of AKs. Of 13 patients who were followed up for 5 years, seven remained clear. The authors concluded that dermabrasion provided long-term clearance of AKs in some patients.

Recalcitrant treatment-resistant AKs may be treated with physically destructive approaches that include curettage and surgical excision. Both techniques enable tissue to be obtained for the purposes of histological analysis. Surgical excision is particularly useful in lesions suspected of being SCC because this technique enables the clinician to treat the lesion and establish the diagnosis. Widespread, extensive AKs may benefit from field treatments of a destructive nature. These include ablative laser resurfacing, dermabrasion, and chemical peels.

[/level-membership-for-dermatology-category][not-level-membership-for-dermatology-category]

Actinic keratoses

Sherrif F. Ibrahim and Marc D. Brown

Evidence Levels:  A Double-blind study  B Clinical trial ≥ 20 subjects  C Clinical trial < 20 subjects  D Series ≥ 5 subjects  E Anecdotal case reports

image

Actinic keratoses (AK) are ill-defined pink to skin-colored, scaly papules 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

Actinic keratoses are common dysplastic intra-epidermal 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. However, there have been no randomized controlled studies demonstrating a reduction in the frequency of SCC with treatment of AKs.

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 topical treatment. Cryotherapy with liquid nitrogen is by far the most commonly employed therapeutic modality 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. The latter has recently been shown to have high rates of treatment success with durable results and has become an accepted first-line therapy with a newer 3.75% formulation recently introduced. A novel agent, ingenol mebutate, is derived from the Euphorbia peplus plant and has been approved as an additional topical agent for the field treatment of AKs. The advantages of topical approaches are that they are patient-administered, non-invasive, carry little risk of scarring or pigmentary change, and can be used for anatomically difficult or cosmetically sensitive areas. However, these agents require adequate patient compliance and are often accompanied by prolonged erythema lasting several weeks. 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 many studies indicate higher patient satisfaction. Variations in the light dose, light source, sensitizing agent and its application time, and frequency of treatments may improve efficacy. Head-to-head trials of different treatment approaches are difficult to perform, as variations in treatment protocols make direct comparisons challenging. Recently, there has been a growing trend towards combination therapy, such as topical agents either before or after cryotherapy, or sequential use of multiple topical modalities with varying 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 investigations

In selected cases:

First-line therapies

imageSunscreens A
imageCryosurgery B
imageTopical 5-FU A
imageImiquimod A
imagePhotodynamic therapy A

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