Actinic keratoses (AKs) are common cutaneous lesions that occur on sun-exposed areas particularly in blond or red-haired, fair-skinned individuals with green or blue eyes. They of course can occur in patients that do not possess these phenotypic features and relate most directly to cumulative sun exposure.  AKs represent the initial intraepidermal manifestation of abnormal proliferation of keratinocytes with the possibility of progression to squamous cell carcinoma in situ (SCC in situ) and invasive squamous cell carcinoma (SCC).

Clinically, AKs have three possible behavioral patterns: spontaneous regression, persistence, or progression into invasive SCC.   The risk of progression of AK to SCC has been calculated to be between 0.025 and 16% per year and the calculated lifetime risk of malignant transformation for a patient with AKs followed for a period of 10 years ranges from 6.1 to 10.2%.  The long-term risk of development of invasive SCC in patients with multiple AKs has been estimated to be as high as 10%.  Approximately 60-65% of SCCs arise from prior AKs.  Spontaneous regression has been reported in as high as 25.9% of AKs over a 12-month period, although a 15% recurrence rate was noted at follow-up.

Pathogenesis

Factors linked to pathogenesis of AKs include

• exposure to ultraviolet B (UVB) light; UVB causes mutations of the tumor suppressor gene (TSG) p53
• genetic DNA instability (i.e. xeroderma pigmentosum) or melanin deficiency (albinism)
• older age
• male gender
• anatomical location; over 80% of AKs are located on the head and neck, dorsal forearms and hands
• history of immunosuppression; solid organ transplant patients are at significantly increased risk.

Clinical Features

AKs are red, pink, or brown papules with a scaly (hyperkeratotic) surface.  They occur on sun-exposed areas and are especially common on the balding scalp, forehead, face, dorsal forearms and hands.   Subclinical (non-visible) AKs are estimated to occur up to 10 times more often than clinically visible AKs, particularly on sun-exposed skin.

Treatment

Prevention of disease is always superior and preferable to the need for treatment. Effective preventative measures include avoidance of excessive sun exposure (use of broad-brimmed hats, sun-protective clothing and sunscreen), patient education, and regular self-examinations to detect the earliest signs of malignant transformation.

Due to their low but real potential to develop into invasive SCC, AK therapy is generally recommended.  The management options for AKs should be chosen depending on whether a lesion-directed or a field-directed therapy is preferred.  Lesion-directed therapy, including ablative and surgical procedures, is reserved for selected cases where only a few clinically visible AKs are present.  Field-directed therapy, including ablative, non-ablative and topical treatments, offers the advantage of treating both clinically evident and subclinical lesions that may progress to visible AKs.

Lesion-directed treatment

Cryotherapy is the most commonly used lesion-directed treatment modality.  Clearance rates range from 39 to 98.8%.  In a large, multi-center Australian study evaluating the efficacy of cryotherapy for the treatment of AKs on the face and scalp, of the 89 patients and 421 lesions in the intended-to-treat population, there was an average of 67.2% lesion response rate per patient.  Cryotherapy treatment was associated with “good” and “excellent” cosmetic outcomes in 94% of the lesions.

Other lesion-directed treatment options include electrodessication and curettage (ED&C) and surgical excision.  Treatment with ED&C may require two or three cycles.  High cure rates and good cosmetic outcome have been reported.  C&D should be generally avoided in recurrent lesions, punch-biopsied lesions and hair bearing sites. 

Field-directed treatment

Field-directed treatment modalities include topical pharmacologic therapies including imiquimod, 5-FU and diclofenac, ablative and nonablative laser resurfacing, PDT, dermabrasion and deep and medium-depth chemical peels.

Retinoids

In a double-blind, randomized clinical trial 25 patients applied topical all-trans-retinoic acid (tretinoin) 0.05% cream twice daily for 16 weeks resulting in a 30.3% reduction in the number of AKs compared with baseline.

Imiquimod (Aldara, Zyclara)

The manufacturer-recommended standard imiquimod treatment protocol for AKs is twice weekly for sixteen weeks.  Other treatment protocols (three times a week for four weeks followed by a 4 week rest and an additional 4 weeks of treatment if remaining lesions are still present; two to three times a week for 16 weeks) have been reported.  Clearance rates with imiquimod range from 45 to 85%.  Reported recurrence rates are 10 and 16% within 1 year and 18 months of treatment respectively.

Common reported side effects of imiquimod therapy included site reactions (edema, erythema, vesicles and erosions/ulcerations), fatigue, headache, diarrhea, nausea and leucopenia.  No serious adverse events were reported.

5-FU (Efudex and Carac)

Manufacturer-recommended 5-FU treatment protocol for AKs is twice daily for 2-4 weeks.  Other protocols proposed in the literature include 5% 5-FU (Efudex) once to twice daily for 2-7 weeks; 5% 5-FU once daily, one day per week for 12 weeks; and 0.5% 5-FU (Carac) once or twice daily for 1-4 weeks.  The literature reported rates of AK resolution with 5-FU that reach 89% with twice weekly application for 16 weeks, albeit recurrence rates of up to 55% have been reported.  In addition, low compliance, due to adverse effects of medication, is associated with significant treatment failure rates.

Diclofenac

Efficacy of topically applied 3% diclofenac gel in 2.5% hyaluronic acid vehicle gel vs. vehicle was addressed in a multicenter, randomized, double-blind, placebo-controlled study of 195 patients.  Treatment with 3% diclofenac gel twice daily for 30-90 days resulted in an improvement of 59% compared with 31% with placebo.

Photodynamic Therapy (PDT) (LINK)

PDT with ALA (dALA or δ-ALA or 5ala or 5-aminolevulinic acid) activated by either blue or red light showed reported overall clearance values for AKs of 80% and 60%, respectively.   Response rates vary with duration of ALA incubation and thickness of AK lesions.  In a study of 243 patients with total of 1403 AKs on scalp and face, were treated with ALA (incubation time 1-18 hrs) and exposure to blue light.  At 8 weeks, 30% of patients with partial response were retreated.  At 12 weeks, 91% lesion clearance rate was reported.  Discomfort was the most commonly reported adverse event. Satisfaction with the cosmetic outcomes for PDT was 96%.