AUTHOR AND EDITOR INFORMATION

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• Follow-up
• Miscellaneous
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INTRODUCTION

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Background

Actinic keratosis (AK) is a UV light–induced lesion of the skin that may progress to invasive squamous cell carcinoma. It is by far the most common lesion with malignant potential to arise on the skin. AK is seen in fair-skinned persons in areas of long-term sun exposure, with an estimated frequency of 40-50% of the adult population older than 40 years in Australia, the country with the highest skin cancer rate in the world.

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 dyskeratosis. 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

United States

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%.

International

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.

CLINICAL

Section 3 of 11  

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• Clinical
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• Follow-up
• Miscellaneous
• Multimedia
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History

AKs are seen almost exclusively in whites, especially those with skin phototypes I and II. The incidence increases with each decade of life, and men have a slightly increased frequency of AK. AK is correlated with chronic UV exposure, such as occurs in persons with outdoor occupations.

Patients immunosuppressed following organ transplantation are at markedly increased risk of developing AKs. The lesions still arise in areas of chronic UV exposure, and they are thought to be actinically induced.

Physical

The typical patient with AKs is an elderly, fair-skinned, sun-sensitive person. The lesions arise in areas of long-term sun exposure, including the face, ears, bald scalp in men, and the dorsal forearms and hands. AKs begin as small rough spots that are easier felt than seen. They feel similar to rubbing sandpaper. With time, the lesions enlarge, usually becoming red and scaly. Most are only 3-10 mm, but they may enlarge to several centimeters.

Patients may develop multiple lesions within a single anatomic area to the extent that the lesions collide and produce confluent AK over a relatively large area. Variants may be brown (pigmented AK), lichen planus–like, or have exaggerated hyperkeratosis, producing a hornlike projection above the skin surface known as a cutaneous horn.

Causes

AKs are induced by UV light. Both epidemiologic observations and molecular biologic characteristics of the tumor cells suggest UV light is sufficient by itself to induce AK. Sensitivity to UV light is inherited. AKs occur more frequently in fair, redheaded, or blonde patients who burn frequently and tan poorly. Increased sun exposure and higher-intensity exposure increase the chance of AK development. Immunosuppression following organ transplantation dramatically increases the risk of developing AKs; however, AKs do not occur without sun exposure.

DIFFERENTIALS

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Other Problems to be Considered

• Discoid lupus erythematosus - Demonstrates dyspigmentation, dilated follicles, and atrophy
• Seborrheic keratosis - Greasy, brown crusts; sharply demarcated borders; nonerythematous base; may occur in nonexposed areas
• Bowen disease - A larger plaque with a sharp outline
• Invasive squamous cell and basal cell carcinomas - Indurated nodular lesions, more rapid growth, eroded or ulcerated surface

WORKUP

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Lab Studies

• Blood work is not indicated.

Procedures

• A skin biopsy is indicated to confirm the diagnosis and to rule out invasive squamous cell carcinoma for suspicious or more advanced lesions (ie, those with more pronounced hyperkeratosis, increased erythema, induration or nodularity).
• A biopsy is also indicated for recurrent lesions or those that are unresponsive to therapy.

Histologic Findings

AK is characterized by dysplasia and architectural disorder of the epidermis. Keratinocytes of the basal layer are abnormal and are variable in size and shape. Cellular polarity is altered, and nuclear atypia is seen. These alterations may extend upward to the granular layer, which may be thinned. Overall, the epidermis exhibits hyperkeratosis and parakeratosis, and irregular acanthosis may be present. In general, hair follicles, sebaceous glands, and apocrine and eccrine ducts are not involved.

TREATMENT

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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 a 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 or 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

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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 Category: Immunomodulators, topical

Investigation of imiquimod demonstrates it induces interferons alpha and gamma, TNF-alpha, and interleukin 12, among other cytokines. Studies using 5% cream in mice showed significant induction of interferon alpha at the site of application, occurring as early as 2 h after treatment. At 4 h after application, increases in interferon alpha mRNA levels were found, indicating an increase in transcription. Cytokine up-regulation is thought to be activated by imiquimod binding to toll-like receptor VII.

FOLLOW-UP

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Further Outpatient Care

• If the lesions do not respond to topical therapy, they can be treated with cryotherapy with liquid nitrogen spray for 5-10 seconds. Lesions become irritated, ulcerate, and slough the diseased pathology.
• A biopsy of more advanced lesions that are indurated should be performed to rule out an invasive carcinoma.

Deterrence/Prevention

• The development of these lesions is directly proportional to sun exposure. AKs can be reduced or delayed by using sunscreens and reducing sun exposure.
• • Patients should limit recreational exposure, and those who work outdoors should consider making adjustments in their work-related sun exposure.
  • For patients forced to undergo sun exposure, recommend applying a sunscreen of sun protection factor (SPF) 30 or more and wearing protective clothing daily.

Complications

• Lesions may progress into invasive squamous cell carcinomas. A biopsy should be performed on nodular, indurated, or unresponsive lesions.

Prognosis

• The prognosis is good. With continuing surveillance and treatment, these lesions can be managed individually. The opportunity for them to develop into invasive squamous cell carcinomas can be prevented by aggressive therapy and sun protection. However, the prognosis in a person with long-term exposure is more guarded because of the multitude of their lesions. Some lesions may progress and develop into invasive squamous cell carcinomas. Patients with extensive involvement unresponsive to cryosurgery and topical therapy may benefit from skin resurfacing by dermabrasion, chemical peeling, or laser resurfacing.

Patient Education

• Encourage patients to wear sunscreens, to limit sun exposure, and to adjust their hobby or profession to decrease sun exposure.
• For excellent patient education resources, see eMedicine's Skin, Hair, and Nails Center. Also, see eMedicine's patient education article Skin Cancer.

MISCELLANEOUS

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Medical/Legal Pitfalls

• A lesion that is observed by the physician over the long term and is allowed to progress to an invasive squamous cell carcinoma that may become metastatic and cause a fatality can lead to a medicolegal pitfall. However, metastasis is unlikely except in neglected, large tumors, so in general, a dangerous invasive squamous cell carcinoma will be obvious. As always, biopsy should be performed on enlarging nodular lesions.

MULTIMEDIA

Section 10 of 11  

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• Miscellaneous
• Multimedia
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Media file 1:  Courtesy of Hon Pak, MD, and reviewed by Ross Levy, MD.
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Media file 2:  Actinic keratosis during treatment with topical 5-fluorouracil. Courtesy of Hon Pak, MD, and reviewed by Ross Levy, MD.
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Media file 3:  Actinic keratosis right after treatment with topical 5-fluorouracil. Courtesy of Hon Pak, MD, and reviewed by Ross Levy, MD.
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Media file 4:  Erythematous, scaly lesions on the temple area, typical of actinic keratosis.
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REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
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• Differentials
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• Ackerman AB. Opposing views of 2 academies about the nature of solar keratosis. Cutis. May 2003;71(5):391-5. [Medline].
• American Academy of Dermatology. Actinic keratoses: scientific evaluation and public health implications. Proceedings of a conference. January 27, 1999. J Am Acad Dermatol. Jan 2000;42(1 Pt 2):1-30. [Medline].
• Cockerell CJ. Histopathology of incipient intraepidermal squamous cell carcinoma("actinic keratosis"). J Am Acad Dermatol. Jan 2000;42(1 Pt 2):11-7. [Medline].
• Cohn BA. From sunlight to actinic keratosis to squamous cell carcinoma. J Am Acad Dermatol. Jan 2000;42(1 Pt 1):143-4. [Medline].
• Drake LA, Ceilley RI, Cornelison RL, et al. Guidelines of care for actinic keratoses. Committee on Guidelines of Care. J Am Acad Dermatol. Jan 1995;32(1):95-8. [Medline].
• Feldman SR, Fleischer AB Jr, Williford PM, Jorizzo JL. Destructive procedures are the standard of care for treatment of actinic keratoses. J Am Acad Dermatol. Jan 1999;40(1):43-7. [Medline].
• Glogau RG. The risk of progression to invasive disease. J Am Acad Dermatol. Jan 2000;42(1 Pt 2):23-4. [Medline].
• Kurwa HA, Yong-Gee SA, Seed PT, et al. A randomized paired comparison of photodynamic therapy and topical 5-fluorouracil in the treatment of actinic keratoses. J Am Acad Dermatol. Sep 1999;41(3 Pt 1):414-8. [Medline].
• Leffell DJ. The scientific basis of skin cancer. J Am Acad Dermatol. Jan 2000;42(1 Pt 2):18-22. [Medline].
• Marks R, Rennie G, Selwood TS. Malignant transformation of solar keratoses to squamous cell carcinoma. Lancet. Apr 9 1988;1(8589):795-7. [Medline].
• Moy RL. Clinical presentation of actinic keratoses and squamous cell carcinoma. J Am Acad Dermatol. Jan 2000;42(1 Pt 2):8-10. [Medline].
• Salasche SJ. Epidemiology of actinic keratoses and squamous cell carcinoma. J Am Acad Dermatol. Jan 2000;42(1 Pt 2):4-7. [Medline].
• Spencer JM, Hazan C, Hsiung SH, Robins P. Therapeutic decision making in the therapy of actinic keratoses. J Drugs Dermatol. May-Jun 2005;4(3):296-301. [Medline].
• Thai KE, Fergin P, Freeman M, et al. A prospective study of the use of cryosurgery for the treatment of actinic keratoses. Int J Dermatol. Sep 2004;43(9):687-92. [Medline].
• Tutrone WD, Saini R, Caglar S, et al. Topical therapy for actinic keratoses, II: Diclofenac, colchicine, and retinoids. Cutis. May 2003;71(5):373-9. [Medline].
• Tutrone WD, Saini R, Caglar S, et al. Topical therapy for actinic keratoses, I: 5-Fluorouracil and imiquimod. Cutis. May 2003;71(5):365-70. [Medline].
• Winton GB, Salasche SJ. Dermabrasion of the scalp as a treatment for actinic damage. J Am Acad Dermatol. Apr 1986;14(4):661-8. [Medline].

Article Last Updated: Oct 2, 2006