Although the premalignant nature of AK was recognized almost 100 years ago, the name AK was not introduced until 1958. The name literally means thickened scaly growth (keratosis) caused by sunlight (actinic). These lesions are common in white populations. In the United States, AK represents the second most frequent reason for patients to visit a dermatologist. Although most do not, some of these lesions may progress to invasive squamous cell carcinoma with metastatic potential. They can be safely and effectively eradicated, and therefore therapy is warranted.
Pathophysiology: AKs arise on fair-skinned people in areas of long-term sun exposure, such as the face, ears, bald scalp, forearms, and backs of the hands. However, they may occur on any area that is repeatedly exposed to the sun, such as the back, the chest, and the legs. Long-term UV light exposure is implicated as the cause from both epidemiologic observations and molecular analysis of tumor cells. AK frequency correlates with cumulative UV exposure. Therefore, AK frequency increases with each decade of life, is greater in residents of sunny countries closer to the equator, and is greater in persons with outdoor occupations. DNA analysis of the cells within AKs shows characteristic UV-induced mutations in key genes.
Clinically, AKs range from barely perceptible rough spots of skin to elevated, hyperkeratotic plaques several centimeters in diameter. Most often, they appear as multiple discrete, flat or elevated, keratotic lesions. Lesions typically have an erythematous base covered by scale (hyperkeratosis). They are usually 3-10 mm in diameter and gradually enlarge into broader, more elevated lesions. With time, actinic keratoses may develop into invasive squamous cell carcinoma. Development of actinic keratoses may occur as early as the third or fourth decade of life in patients who live in areas of high solar radiation, are fair-skinned, and do not use sunscreen for photoprotection. Usually, patients demonstrate a background of solar-damaged skin with telangiectasias, elastosis, and pigmented lentigines.
In both histologic and molecular parameters, AKs share features with squamous cell carcinoma. AK is an epidermal lesion characterized by aggregates of atypical, pleomorphic keratinocytes at the basal layer that may extend upwards to involve the granular and cornified layers. The epidermis itself shows an abnormal architecture, with acanthosis, parakeratosis, and dyskeratoses. Cellular atypia is present, and the keratinocytes vary in size and shape. Mitotic figures are present.
This presentation may resemble Bowen disease or carcinoma in situ, and the distinction between the 2 is a matter of degree (extent of the lesion) rather than differences in individual cells. Often, marked hyperkeratosis and areas of parakeratosis with loss of the granular layer are present. A dense inflammatory infiltrate is usually present. The case has been made that AK is the earliest manifestation of squamous cell carcinoma and should be regarded as such rather than as a precancerous lesion. Others have argued that calling AK a carcinoma unduly alarms patients. Cockerell has proposed renaming the lesion keratinocytic intraepidermal neoplasia, in a nomenclature analogous to cervical and vulvar intraepithelial neoplasia.
Frequency:
- In the US: AK occurs primarily in whites, the frequency of which correlates with cumulative UV exposure. Therefore, frequency increases with age, proximity to the equator, and outdoor occupation. AKs are seen more in men than in women and have also been correlated with a high-fat diet. Overall, the rate in the United States is estimated to range from 11-26%.
- Internationally: The prevalence is highest in Australia, where a light-skinned population is common and outdoor sports are very popular activities. Overall, AK is estimated to be present in 40-50% of the Australian population older than 40 years.
Mortality/Morbidity: Lesions begin as barely perceivable rough spots of skin, better felt than seen. The early lesions feel like sandpaper. Later lesions become erythematous, scaly plaques that may enlarge to several centimeters. Lesions may remain unchanged for years, may spontaneously regress, or may progress to invasive squamous cell carcinoma. Most AKs do not progress to invasive squamous cell carcinoma; however, most invasive squamous cell carcinomas have evidence of a preexisting AK. Invasive squamous cell carcinoma may produce significant morbidity by direct extension into facial structures. In less than 10% of cases, invasive squamous cell carcinoma may metastasize, with a low 5-year survival rate.
Race: The prevalence is much higher in individuals with fair skin and blue eyes and is lower in individuals with darker skin types. It is relatively nonexistent in black skin. Patients with AKs tend to have Fitzpatrick type I or II skin, which burns and does not tan. The prevalence is reduced precipitously in persons with Fitzpatrick types III, IV, and V skin and is nonexistent in those with Fitzpatrick type VI skin.
Sex: The prevalence of AK is higher in men than in women. This is theorized to result from a greater likelihood that men have an outdoor occupation and thus have greater cumulative UV exposure.
Age: The frequency of AK is directly related to cumulative sun exposure. The age of occurrence is related to the skin type and the amount of sun damage. AKs can occur in patients aged 20-30 years, but they are more common in patients aged 50 years and older.
/a>Medical Care: AKs may remain unchanged, spontaneously resolve, or progress to invasive squamous cell carcinoma. The fate of any one AK is impossible to predict. Although the risk of progression of any one AK to invasive squamous cell carcinoma is small, a patient may have many lesions, and thus the risk of progression becomes significant. Therapy is generally well tolerated and simple; therefore, treatment is warranted.
- Medical management begins with educating the patient to limit sun exposure. Patients should be cautioned to avoid sun exposure from 10:00 AM to 3:00 PM as much as possible. They also must wear adequate sunscreens and protective clothing daily. One study suggested that a low-fat diet leads to fewer new AKs and greater resolution of old ones.
- Treatment consists of 2 broad categories: surgical destruction of the lesion and medical therapy. Medical therapy has the advantage of being able to treat large areas with many lesions. The disadvantages of medical therapies include lengthy courses of treatment with irritation and discomfort. Currently, the US Food and Drug Administration has approved 4 medications for the treatment of AKs. These are topical 5-fluorouracil (5-FU), 5% imiquimod cream, topical diclofenac gel, and photodynamic therapy (PDT) with topical delta-aminolevulinic acid.
- The most experience in topical therapy for AKs is with 5-FU. Several formulations are available, including a 5% cream or solution, a 2% solution, a 1% cream or solution, and, most recently, a micronized 0.5% cream. Although not well studied, efficacy among the various formulations does not seem to differ significantly.
- The most popular formulation is the 5% cream, which is applied twice daily for 1 month. During the treatment phase, the lesions become increasingly erythematous and cause discomfort; small subclinical lesions become visible. This treatment can be temporarily disfiguring, with erythematous ulcerations and crust formation. However, if the patient completes the treatment, the lesions usually heal within 2 weeks of stopping treatment, the complexion is smooth, and the AKs are improved.
- The 0.5% micronized cream was developed to increase tolerability because inflammation and discomfort can be a limiting factor in the use of topical 5-FU. The 0.5% micronized cream is applied once daily for 1 month.
- Imiquimod is a topical medication that up-regulates a variety of cytokines, which, in turn, invoke a nonspecific immune response (interferons, natural killer cells) and an specific immune response (T cells). It is applied 2-3 times a week for up to 4 months, although generally 1 month is sufficient. Reaction to the drug is idiosyncratic, with some patients barely reacting and others developing marked inflammation. Subclinical lesions previously not appreciated may become inflamed during therapy. In patients with a brisk inflammatory response, dosing is reduced to twice or even once a week, with preservation of therapeutic efficacy but increased tolerability. Experimental evidence suggests patients may develop T-cell memory after treatment with this drug and thus may be less likely to develop new AKs in the future.
- Topical diclofenac is a nonsteroidal anti-inflammatory drug. Its mechanism of action against AKs is unknown. It is effective therapy when applied twice a day for 3 months. A shorter course of therapy is dramatically less effective. Its chief advantage is that it produces little-to-no inflammation and thus is very well tolerated.
- PDT uses a light-sensitizing compound that preferentially accumulates in AK cells, where it can be activated by the appropriate wavelength of light. Delta-aminolevulinic acid is a component of the heme biosynthetic pathway that accumulates preferentially in dysplastic cells. Once inside these cells, it is enzymatically converted to protoporphyrin IX, a potent photosensitizer. With exposure to light of an appropriate wavelength, oxygen free radicals are generated and cell death results.
- Patients experience pain in the areas treated, which is similar in scope to the pain resulting from topical 5-FU. The treated lesions may become erythematous and crusted. One treatment with PDT appears to be as effective as topical 5-FU therapy.
- When used with light sources that have a cosmetic benefit by themselves, such as the pulsed dye laser of intense pulsed light devices, a cosmetic benefit may be seen from the use of topical PDT beyond that of AK eradication.
- An unknown parameter in the use of topical PDT is the optimal incubation time following application of the topical aminolevulinic acid before light exposure. A second unknown parameter is the optimal light source to use for this treatment. Ongoing studies are addressing these issues.
Surgical Care: The goal of surgical therapy is complete eradication of the AKs, usually by physical destruction, with limited-to-no damage to surrounding normal tissue. When the diagnosis is unclear and invasive tumor is possible, biopsy is indicated. However, biopsy generally leaves a scar.
- Cryosurgery refers to use of a cryogen to lower the temperature of the skin and produce cell death. The most common cryogen used is liquid nitrogen, with a temperature of -195.8°C. Keratinocytes die when exposed to approximately -40 to -50°C. Other structures in the skin, such as collagen, blood vessels, and nerves, are more resistant to the lethal effects of cold than keratinocytes. Melanocytes are more sensitive than keratinocytes; thus, cryosurgery often leaves white spots. This technique has not been studied in a scientific fashion until recently, when it was demonstrated to produce an overall clearance rate of 67%.
- Lesions suggestive of invasive cancer may be treated with curettage, shave excision, or conventional excision, all of which provide a sample for histologic evaluation. These treatments require local anesthesia, produce a wound that requires time to heal, and are likely to scar.
- Cosmetic resurfacing procedures, in which the entire epidermis is removed, sometimes with some portion of the dermis, are effective for AK eradication. Cosmetic resurfacing procedures include medium and deep chemical peels, dermabrasion, and ablative laser resurfacing. All of these are cosmetic procedures unlikely to be covered by insurance, all carry the risk of scarring and infection, and all require experience and expertise on the part of the dermatologic surgeon. They are highly unlikely to be performed solely for AK therapy.
Diet: One study suggested that a low-fat diet in humans leads to greater resolution of existent AKs and the development of fewer new ones during the study period.
Activity: Instruct patients to practice sun safety, such as the use of sunscreen and protective clothing, and to limit outdoor activity from 10:00 AM to 3:00 PM.Medication
The goals of pharmacotherapy are to reduce morbidity and to prevent complications.
Drug Category: Antineoplastic agents -- DOC is topical 5-FU lotion or cream, which inhibits cell growth and proliferation.
| Drug Name | Fluorouracil (Fluoroplex, Carac, Efudex) -- Used topically for management of AKs. Interferes with DNA synthesis by blocking methylation of deoxyuridylic acid via inhibition of thymidylate synthetase and, subsequently, cell proliferation. For lesions on bald scalp or extremities, longer treatment is often necessary. |
|---|---|
| Adult Dose | Apply topically to affected areas bid for approximately 2-6 wk (has been used as long as 12 wk in some cases) |
| Pediatric Dose | Not established |
| Contraindications | Documented hypersensitivity; pregnancy |
| Interactions | None reported |
| Pregnancy | X - Contraindicated in pregnancy |
| Precautions | Inflammatory reactions may occur with occlusive dressings; porous gauze dressing may be applied for cosmetic reasons, without an increase in reaction; patients should expect inflammatory reaction with crusting; application to mucous membranes may cause increased inflammation and ulceration; exposure to UV rays (ie, sunlight) may increase intensity of the reaction |
| Drug Name | Imiquimod (Aldara) -- Immune response modifier thought to produce a nonspecific anti-AK response (interferon, natural killer cells) and a specific immune response (cytotoxic T cells). Indicated to treat clinically typical, nonhyperkeratotic, nonhypertrophic AKs on the face or scalp. |
|---|---|
| Adult Dose | Apply no more than 1 packet to defined area of face or scalp 2 times/wk hs for 16 wk; apply to dry skin (at least 10 min after washing face) and leave on for approximately 8 h; then, wash area with mild soap and water |
| Pediatric Dose | Not established |
| Contraindications | Documented hypersensitivity |
| Interactions | None reported |
| Pregnancy | C - Safety for use during pregnancy has not been established. |
| Precautions | Avoid exposure to sunlight or artificial tanning devices; regular use of sunscreen is encouraged; avoid contact with lips, eyes, or nostrils; common adverse effects include erythema, edema, vesicles, erosion or ulceration, weeping, exudate, flaking, scaling, dryness, and scabbing, or crusting |
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