Actinic Keratosis

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Practice Essentials

Actinic keratosis (AK) is an ultraviolet (UV) light–induced skin lesion that may progress to invasive squamous cell carcinoma (SCC). It is by far the most common lesion with malignant potential to arise on the skin. Actinic keratosis is seen in fair-skinned persons on skin areas that have had long-term sun exposure.[1] In Australia, the country with the highest skin cancer rate in the world, the prevalence of actinic keratosis among adults older than 40 years has been reported to range from 40-60%. In the United States, actinic keratosis represents the second most frequent reason for patients to visit a dermatologist.[2, 3]  See the image below.



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Actinic keratosis. Courtesy of Hon Pak, MD.

An actinic keratosis may follow 1 of 3 paths: It may regress, persist unchanged, or progress to invasive SCC. The percentage that progress to invasive SCC remains unknown, and estimates have varied from as low as 0.1% to as high as 10%.[4, 5]

A study by Criscione and colleagues of 7784 actinic keratoses in a high-risk population found that nearly 65% of primary SCCs and 36% of primary basal cell carcinomas arise from clinically diagnosed actinic keratoses. Furthermore, risk of progression of actinic keratosis to SCC was 0.60% at 1 year and 2.57% at 4 years, which is 6-8 times more frequent than had been reported in some prior studies.[6]  

Although it is impossible to predict which course an individual lesion will follow, most patients have many lesions, so assessing risk becomes more significant and aids in tailoring treatments. Overall, actinic keratoses can be safely and effectively eradicated, and, therefore, therapy is warranted.

Signs and symptoms

Actinic keratoses develop as follows:

The typical patient with actinic keratoses is an elderly, fair-skinned, sun-sensitive person.[10] The lesions arise in areas of long-term sun exposure, including the face and ears, and bald scalp in men, as well as the dorsal forearms and hands.[1, 11]

Patients may develop multiple lesions within a single anatomic site, to the extent that the lesions coalesce and produce confluent actinic keratosis over a relatively large area. The following variants can occur[12] :

The image below is a typical depiction of actinic keratosis.



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Erythematous, scaly lesions on the temple area, typical of actinic keratosis.

See Presentation for more detail.

Diagnosis

Histology

A skin biopsy is indicated to confirm the diagnosis and to rule out invasive SCC for suspicious or more advanced lesions (ie, those with more pronounced hyperkeratosis, increased erythema, or induration or nodularity).[13, 14] A biopsy is also indicated for recurrent lesions or those that are unresponsive to therapy.

Actinic keratosis is characterized by dysplasia and architectural disorder of the epidermis, as follows[7] :

In general, hair follicles, sebaceous glands, and apocrine and eccrine ducts are not involved.[7]

Fluorescence

Fluorescence with the use of a photosensitizing drug (methyl ester of 5-aminolevulinic acid [ALA], a precursor of protoporphyrin) commonly used in photodynamic therapy (PDT) has been described as a diagnostic tool for actinic keratosis.[15] Areas of involvement, including occult areas of abnormal skin, emit a pink fluorescence with a Wood lamp or PDT lamp.[15]

See Workup for more detail.

Management

Treatment consists of the following categories:

Pharmacologic treatment

Medications approved by the US Food and Drug Administration (FDA) for the treatment of actinic keratosis include the following[16, 17, 18] :

Photodynamic therapy

PDT uses a light-sensitizing compound that preferentially accumulates in actinic keratosis 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.[19]

Surgery

Types of surgery used in the eradication of actinic keratoses include the following[20, 21, 22] :

See Treatment and Medication for more detail.

Background

 

 

Pathophysiology

Actinic keratoses most often 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.[1] 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.[1, 23]  

Actinic keratosis frequency correlates with cumulative UV exposure.[1] Therefore, the frequency of actinic keratosis 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.[10, 1] DNA analysis of the cells within actinic keratoses shows characteristic UV-induced mutations in key genes, including TP53 and deletion of the gene coding for p16 tumor suppressor protein.[23, 24, 25]

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.[1] Usually, patients demonstrate a background of solar-damaged skin, with telangiectasias, elastosis, and pigmented lentigines.[7]

 In both histologic and molecular parameters, actinic keratoses share features with squamous cell carcinoma,[26]  and over time, a small percentage of actinic keratoses may transform into invasive squamous cell carcinoma. According to one study of almost 7000 patients, the length of time for this transformation to occur was approximately 2 years.[27]

Actinic keratosis 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.[26] 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.[26] This presentation may resemble Bowen disease or carcinoma in situ, and the distinction between the two is a matter of degree (extent of the lesion) rather than differences in individual cells.[26]

Etiology

As the term "actinic" indicates, actinic keratoses are induced by UV light. Both epidemiologic observations and molecular biologic characteristics of the tumor cells suggest that UV light is sufficient by itself to induce actinic keratosis.[23, 25] Sensitivity to UV light is inherited; actinic keratoses occur more frequently in fair, redheaded, or blonde patients who burn frequently and tan poorly.[1] Increased sun exposure and higher-intensity exposure increase the chance of actinic keratosis development. Immunosuppression following organ transplantation dramatically increases the risk of developing actinic keratoses[28] ; however, actinic keratoses do not occur without sun exposure.

Additional studies have shown an association between cutaneous human papillomavirus and actinic keratosis.[29, 30, 31] The role of human papillomavirus in skin tumorigenesis was discovered the 1950s, and the group of known human papillomavirus types associated with skin tumorigenesis has been classified as beta-papillomavirus.[30]  

Beta-papillomavirus DNA has been identified in healthy skin and in squamous cell carcinoma, basal cell carcinoma, and actinic keratosis. A 2007 study suggested that only a small association exists between beta-papillomavirus and actinic keratosis; however, persons with beta-papillomavirus infection plus age over 60 years, fair skin, or high sun exposure had markedly higher risk for actinic keratoses than persons without the combination of beta-papillomavirus infection with any of those risk factors.[30]

Epidemiology

United States

Actinic keratosis occurs primarily in Whites, and the frequency correlates with cumulative UV exposure[1] and therefore with age, proximity to the equator, and outdoor occupation. Actinic keratoses are seen more often in men than in women and have also been correlated with a high-fat diet.[10, 32] Overall, the rate in the United States population is estimated to range from 11-26%.[3]

International

The prevalence is highest in Australia, where much of the population is light-skinned and outdoor sports are very popular activities.[33] Overall, actinic keratosis is estimated to be present in 40-60% of the Australian population older than 40 years.[3]

Although in Korea the incidence of actinic keratosis is not as high as among Whites, it has been increasing from 17.9 to 54.0 per 100,000 person-years between 2006 and 2015 with higher prevalence among older populations (1.95 per 10,000 persons in individuals in their 40s compared to 31.81 per 10,000 persons in individuals in their 80s).  Because Korea is a fast-aging society, the incidence of actinic keratosis is expected to continue to increase in the future.[34]

Race

The prevalence of actinic keratosis is much higher in individuals with fair skin and blue eyes and is lower in individuals with darker skin types.[10] Actinic keratosis is relatively nonexistent in Black skin.[35] Patients with actinic keratoses tend to have Fitzpatrick type I or II skin, which burns and does not tan.[1] 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.[35] Although the incidence of cutaneous malignancies in darker-skinned individuals is much lower than in White persons, UV exposure may still play a role in the etiology of squamous and basal cell carcinoma; screening and sun safety education should still be promoted because cutaneous malignancies in darker-skinned individuals can be very aggressive.[35]

Sex

The prevalence of actinic keratosis is higher in men than in women.[1] This is theorized to result from a greater likelihood that men have an outdoor occupation and thus have greater cumulative UV exposure.[10]

Age

One of the most important determinants of actinic keratosis risk is age, particularly in combination with other strong predictors, including cumulative sun exposure, place of birth, occupation, and skin type.[10, 1] Actinic keratoses can occur in persons aged 20-30 years, but they are more common in those aged 50 years and older.[1]

Prognosis

The prognosis for actinic keratosis is good. With continuing surveillance and treatment, these lesions can be managed individually. Lesions begin as barely perceivable rough spots of skin, better felt than seen.[7, 15] Early lesions feel like sandpaper; later lesions become erythematous, scaly plaques that may enlarge to several centimeters.[7, 1] Lesions may remain unchanged for years, may spontaneously regress, or may progress to invasive squamous cell carcinoma.[4, 5]

Most actinic keratoses do not progress to invasive squamous cell carcinoma; however, most invasive squamous cell carcinomas have evidence of a preexisting actinic keratosis.[1, 5] 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.[36, 37]  Development 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.

Patients with extensive involvement unresponsive to cryosurgery and topical therapy may benefit from skin resurfacing by dermabrasion,[22] chemical peeling, or laser resurfacing.[21]

Patient Education

Instruct patients to practice sun safety, such as the use of sunscreen and protective clothing, and to limit outdoor activity from 10 AM to 3 PM.[38]  

History

Actinic keratoses are seen almost exclusively in persons with lighter skin, especially those with skin phototypes (Fitzpatrick) I and II.[10] The incidence increases with each decade of life, and men have a slightly increased frequency of actinic keratosis.[10, 3] Actinic keratosis frequency correlates with long-term ultraviolet (UV) light exposure, such as occurs in persons with outdoor occupations.[10]

Patients who are immunosuppressed following organ transplantation are at markedly increased risk of developing actinic keratoses.[28] The lesions still arise in areas of long-term exposure,[11, 27, 39] and they are thought to be actinically induced—but with normal immune surveillance compromised, they occur with increased frequency and growth rate.

Physical Examination

The typical patient with actinic keratoses is an elderly, fair-skinned, sun-sensitive person.[10] The lesions arise in areas of long-term sun exposure, including the face, ears, bald scalp in men, and the dorsal forearms and hands.[1, 11] Actinic keratoses begin as small rough spots that are easier felt than seen, often described as being similar to rubbing sandpaper.[7] With time, the lesions enlarge, usually becoming red and scaly; most are only 3-10 mm, but they may enlarge to several centimeters.[7, 8, 9] Note the images below.



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Actinic keratosis. Courtesy of Hon Pak, MD.



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Erythematous, scaly lesions on the temple area, typical of actinic keratosis.

Multiple lesions may develop within a single anatomic site, to the extent that the lesions coalesce and produce confluent actinic keratosis over a relatively large area. Variants may be pigmented, atrophic, bowenoid, lichen planus–like, or hypertrophic.  

Procedures

A skin biopsy is usually unnecessary for diagnosing actinic keratosis, provided the clinical findings are characteristic.[40, 41]  However, biopsy is indicated for suspicious or more advanced lesions (ie, those with more pronounced hyperkeratosis, increased erythema, induration, or nodularity), to rule out invasive squamous cell carcinoma.[13, 14] A biopsy is also indicated for recurrent lesions or those that are unresponsive to therapy.

Fluorescence with the use of a photosensitizing drug (methyl ester of 5-aminolevulinic acid [ALA], a precursor of protoporphyrin) commonly used in photodynamic therapy (PDT) has been described as a diagnostic tool for actinic keratosis.[15] Areas of involvement, including occult areas of abnormal skin, emit a pink fluorescence with a Wood lamp or photodynamic therapy lamp.[15]

Histologic Findings

Actinic keratosis is characterized by dysplasia and architectural disorder of the epidermis.[7] Keratinocytes of the basal layer are abnormal and are variable in size and shape; cellular polarity is altered, and nuclear atypia is seen.[7] 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.[7] In general, hair follicles, sebaceous glands, and apocrine and eccrine ducts are not involved.[7]

Imaging Studies

Advances in noninvasive technologies have idenitified features of actinic kerosis. Dermoscopy is in routine clnical use but newer techniques, such as reflectance confocal microscopy and optical coherence microscopy, have been used to assess actinic keratoses.[42]

Approach Considerations

Actinic keratoses may remain unchanged, spontaneously resolve, or progress to invasive squamous cell carcinoma.[7]  The fate of any one actinic keratosis is impossible to predict. Although the risk of progression of any one actinic keratosis to invasive squamous cell carcinoma is small (at most approximately 10%),[4]  a patient may have many lesions, and thus the risk of progression becomes significant. Additionally, actinic keratoses can be clinically indistinguishable from more serious cutaneous malignancies, including squamous cell carcinoma and lentigo maligna.[43, 44] Therapy is generally well tolerated and simple; therefore, treatment of all actinic keratoses is warranted.

Selection of treatment is generally based on the number of lesions present and the efficacy of the treatment.[45] Additional variables to consider include persistence of the lesion(s), age of the patient, history of skin cancer, and tolerability of the treatment modality.[4] Treatment consists of 2 broad categories: surgical destruction of the lesion and medical therapy.

Medical management begins with educating the patient to limit sun exposure. Patients should be cautioned to avoid sun exposure from 10 AM to 3 PM as much as possible. They also must apply adequate sunscreens and wear protective clothing daily.[38]

Medical Care

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. The US Food and Drug Administration (FDA) has approved the following medications for the treatment of actinic keratoses[16, 17, 18, 46] :

Ingenol mebutate topical was approved by the FDA in 2012 for treatment of actinic keratosis. However, the manufacturer withdrew the medication from worldwide markets in 2020 due to an increased risk of squamous cell carcinoma and other nonmelanoma skin malignancies associated with use of the drug.[47]

5-Fluorouracil

The most experience in topical therapy for actinic keratoses is with 5-FU, which inhibits thymidylate synthetase and causes cell death in actively proliferating cells.[48] 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.[16] Although not well studied, efficacy among the various formulations does not seem to differ significantly.[49, 50]

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; in addition, 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 actinic keratoses 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.

Usage of the 0.5% micronized cream 1 week prior to cryosurgery has also been shown to produce complete lesion clearance in a higher number of patients compared with cryosurgery alone (32.4% and 15%, respectively).[51] Note the images below.



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Actinic keratosis during treatment with topical 5-fluorouracil. Courtesy of Hon Pak, MD.



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Actinic keratosis right after treatment with topical 5-fluorouracil. Courtesy of Hon Pak, MD.

Imiquimod

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.[52] 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.

Two newer formulations of imiquimod (2.5% and 3.75%) were studied and found to be effective in clearing actinic keratoses (25% and 34% clearance, respectively), with a more intuitive daily dosing schedule. Although not as effective as 5% imiquimod, the newer formulations cause less irritation, promoting better compliance.[53] Experimental evidence suggests patients may develop T-cell memory after treatment with this drug and thus may be less likely to develop new actinic keratoses in the future. Imiquimod 5% cream has also been shown to be safe and effective in transplant patients.[54, 55]

Topical diclofenac sodium 3% gel

Topical diclofenac sodium 3% gel is a nonsteroidal anti-inflammatory drug approved by the FDA for the treatment of actinic keratosis. Its mechanism of action against actinic keratoses is unknown. It is effective when applied twice a day for 3 months. A shorter course of therapy is dramatically less effective. The chief advantage of diclofenac is that it produces little to no inflammation and thus is very well tolerated. Diclofenac therapy after cryosurgery has also been shown to produce complete lesion clearance in a higher number of patients compared with cryosurgery alone (64% vs 32%, respectively).[56]  American Academy of Dermatology guidelines conditionally recommend diclofenac for topical therapy.[57]

Tirbanibulin topical

Tirbanibulin topical is a novel microtubule inhibitor approved by the FDA in 2020 for the treatment of actinic keratosis. It exerts its effect by inhibiting tubulin microfilament polymerization and interference with Src kinase.[58] In 2022, the American Academy of Dermatology added topical tirbanibulin to its list of agents strongly recommended for topical therapy field treatment, joining 5-fluorouracil and imiquimod.[57]

Approval was based on two phase 3 clinical trials (AK003 and AK004) that evaluated the safety and efficacy of tirbanibulin topical in adults (N = 702) with facial or scalp actinic keratosis. Compared with the placebo group, the tirbanibulin-treated group achieved a higher percentage of complete clearance of actinic keratosis at Day 57 (44% vs 5% in AK003, 54% vs 13% in AK004). Rates of partial clearance were also higher with tirbanibulin than with placebo (68% vs 16% in AK003, 76% vs 20% in AK004).[46]

Photodynamic therapy

Photodynamic therapy (PDT) uses a light-sensitizing compound that preferentially accumulates in actinic keratosis 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.[19]

Patients experience pain in the treated areas, 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.[59]

A meta-analysis and systematic review of PDT versus cryotherapy found that PDT had a 14% better chance of complete lesion clearance at 3 months for thin actinic keratoses on the face and scalp compared with cryotherapy.[60]

Immunosuppressed patients may also benefit from PDT in the prevention of nonmelanoma skin cancers.[61]

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 actinic keratosis eradication. Compared with other destructive therapeutic options such as cryotherapy, PDT may offer better cosmetic results and higher patient preference.[61, 62]

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.[61, 63]

American Academy of Dermatology guidelines conditionally recommend PDT, to include aminolevulinic acid (ALA)–red light PDT, ALA-daylight PDT, or ALA-blue light PDT. The recommended incubation time for ALA-red light PDT is 1-4 hours. Daylight PDT is less painful but equally effective compared with ALA-red light PDT. ALA-red light PDT is preferred over trichloroacetic acid peel.[57] Conditional recommendations were issued against the following:

Another photosensitizing agent approved in the use of PDT is methyl-5-aminolaevulinate (MAL). Comparison studies between ALA and MAL are not currently decisive. A study investigating the clinical efficacy of ALA-PDT versus MAL-PDT in the treatment of actinic keratosis, Bowen disease, nodular basal cell carcinoma, and superficial basal cell carcinoma found no statistically significant differences in treatment outcomes using either of these agents.[64]  

However, a randomized, multicenter, observer-blind, placebo-controlled trial comparing the efficacy of BF-200 ALA versus MAL cream in the treatment of actinic keratoses lesions demonstrated that PDT with BF-200 ALA was superior to the MAL cream regarding complete clearance of lesions. Six- and 12-month follow-up studies substantiated the efficacy of PDT with BF-200 ALA and the lower recurrence rates of lesions with BF-200 ALA treatment versus MAL treatment.[65, 66] On the other hand, MAL-PDT was found to be less painful than ALA-PDT in a retrospective single-center study of 173 patients.[67]

Other therapies

Resiquimod is a topical immune-response modifier that works directly on both Toll-like receptor 7 (TLR7) and TLR8, resulting in the activation of myeloid and plasmacytoid dendritic cells. Like imiquimod, resiquimod belongs to the class of imidazoquinolines, but it induces more interleukin-12 (IL-12) and achieves a higher potency (10-100 times) than imiquimod. It has been studied at concentrations of 0.01, 0.03, 0.06, or 0.1%, with efficacy reported when applied three times weekly for four weeks. However, high rates of adverse effects have been reported at higher doses.[68, 69]

Piroxicam is a nonsteroidal anti-inflammatory drug and cyclooxygenase-1 inhibitor. It is administered in a topical formation of 0.8% combined with a broad-spectrum sunscreen. A number of small studies have shown efficacy with minimal adverse effects.[70, 71]  Large controlled studies are needed to compare its efficacy with that of standard treatments.[71]

Potassium hydroxide 5% solution has been proposed as a less expensive alternative to 5-FU. In a small study of 23 patients, outcomes after 3 months were similar, with no significant difference in recurrence rates.[72]  An ongoing, three-armed, randomized, double-blind phase 3 study in Germany is evaluating the efficacy and tolerability of 5% potassium hydroxide versus 3% diclofenac gel and placebo (NCT04552327).

 

Surgical Care

The goal of surgical therapy is complete eradication of actinic keratoses, usually by physical destruction, with limited to no damage to surrounding healthy tissue. When the diagnosis is unclear and an 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. 

Cryosurefery has been shown to produce an overall clearance rate of 67-88%.[62, 73]  American Academy of Dermatology guidelines strongly recommend cryosurgery for actinic keratosis, and conditionally recommend it over carbon dioxide laser surgery.[40]

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 leave a scar.

Cosmetic resurfacing procedures, in which the entire epidermis is removed, sometimes with some portion of the dermis, are effective for actinic keratosis eradication. Cosmetic resurfacing procedures include medium and deep chemical peels, dermabrasion, and ablative laser resurfacing.[20, 21, 22] All of those 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 actinic keratosis therapy.

Diet

One study has suggested that a low-fat diet in humans leads to greater resolution of existent actinic keratoses and the development of fewer new ones during the study period.[32]  However, dietary changes are not routinely recommended.

Prevention

The development of these lesions is directly proportional to sun exposure. Actinic keratoses can be reduced or delayed by using sunscreens and reducing sun exposure.[38] Patients should limit recreational exposure, and those who work outdoors should consider making adjustments in their work-related sun exposure. For patients who must undergo sun exposure, recommend applying a sunscreen with sun protection factor (SPF) 30 or more and wearing protective clothing daily.[38]

Long-Term Monitoring

If the lesions do not respond to topical therapy, they can be treated with cryotherapy with liquid nitrogen spray for 5-20 seconds.[73] Lesions become irritated and ulcerate, and eventually are sloughed from healthy skin.[73]

A biopsy of more advanced lesions that are indurated should be performed to rule out an invasive carcinoma.[14]

Medication Summary

The goals of pharmacotherapy are to reduce morbidity and to prevent complications. Several topical agents are available.

Fluorouracil topical (Fluoroplex, Carac, Efudex, Tolak)

Clinical Context:  Fluorouracil topical is used topically for the management of actinic keratoses. It 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.

Class Summary

The drug of choice is topical 5-FU lotion or cream, which inhibits cell growth and proliferation.

Imiquimod (Aldara, Zyclara)

Clinical Context:  Imiquimod is an immune response modifier thought to produce a nonspecific anti–actinic keratosis response, interferon, natural killer cells, and a specific immune response (cytotoxic T cells). It is indicated for clinically typical, nonhyperkeratotic, nonhypertrophic actinic keratoses on the face or scalp.

Class Summary

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 hours after treatment. At 4 hours 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.

Aminolevulinic acid topical (Ameluz, Levulan Kerastick)

Clinical Context:  This agent is a porphyrin precursor used in photodynamic therapy (PDT) for actinic keratoses. When used with PDT, accumulation of photoactive porphyrins in the lesion produces a photodynamic reaction that results in a cytotoxic process. The 20% solution (Levulan Kerastick) is used with blue light illumination; the 10% solution (Ameluz) is used with red light illumination. 

Topical solution 20% is intended for direct application to individual lesions diagnosed as actinic keratosis and not to perilesional skin. Application should involve either scalp or face lesions, but not both simultaneously. Application of the solution is followed by illumination with blue light 14-18 hours later; treatment may be repeated every 8 weeks. Recommended treatment frequency is 1 application and 1 dose of illumination per treatment site per treatment session. Each Levulan Kerastick should be used for only one patient.

Topical solution 10% is to be applied 1 mm thick to actinic keratosis and to approximately 5 mm of surrounding skin. Application area should not exceed 20 cm2 and 2 g at one time. After covering with a light-blocking occlusive dressing for 3 hours, remove the dressing, wipe off the remaining gel, and follow with red light illumination.

Class Summary

Topical photosensitizing agents are administered in combination with PDT.

Diclofenac topical (Flector Transdermal Patch, Licart, Pennsaid topical solution)

Clinical Context:  Diclofenac topical is designated chemically as 2-[(2,6-dichlorophenyl) amino] benzeneacetic acid, monosodium salt, with an empirical formula of C14 H10 Cl2 NO2 Na. It is one of a series of phenylacetic acids that has demonstrated anti-inflammatory and analgesic properties in pharmacological studies. It is believed to inhibit the enzyme cyclooxygenase, which is essential in the biosynthesis of prostaglandins. Diclofenac topical can cause hepatotoxicity; hence, liver enzyme levels should be monitored in first 8 weeks of treatment.

It is used topically as a keratolytic agent to treat actinic keratoses.

Tirbanibulin topical (Klisyri)

Clinical Context:  Tirbanibulin topical is a novel, first-in-class microtubule inhibitor that inhibits tubulin polymerization and Src kinase signalling. It is indicated for the topical treatment of actinic keratosis of the face or scalp. 

What is the role of fluorescence in the diagnosis of actinic keratosis?What is actinic keratosis?What are the signs and symptoms of actinic keratosis?How are the lesions of actinic keratosis characterized?What is the role of skin biopsy in the diagnosis of actinic keratosis?How is actinic keratosis characterized?What are the treatment options for actinic keratosis?Which medications are FDA approved for the treatment of actinic keratosis?What is the role of photodynamic therapy in the treatment of actinic keratosis?What are the surgical options for eradication of actinic keratosis?What is actinic keratosis?What is the pathophysiology of actinic keratosis?What causes actinic keratosis?What is the prevalence of actinic keratosis in the US?What is the global prevalence of actinic keratosis?What are the racial predilections in prevalence of actinic keratosis?What is the sexual predilection in prevalence of actinic keratosis?Which age groups have the highest prevalence of actinic keratosis?What is the prognosis of actinic keratosis?What is included in patient education about actinic keratosis?Which clinical history findings are characteristic of actinic keratosis?Which physical findings are characteristic of actinic keratosis?What are complications of actinic keratosis?Which conditions should be included in the differential diagnosis of actinic keratosis?What are the differential diagnoses for Actinic Keratosis?What is the role of lab tests in the workup of actinic keratosis?What is the role of skin biopsy in the workup of actinic keratosis?What is the role of florescence in the workup of actinic keratosis?Which histologic findings are characteristic of actinic keratosis?What is the role of tirbanibulin topical (Klisyri) in the treatment of actinic keratosis?What are the treatment options for actinic keratosis?What is the role of 5-fluorouracil (5-FU) in the treatment of actinic keratosis?What is the role of imiquimod in the treatment of actinic keratosis?What is the role of ingenol mebutate gel (Picato) in the treatment of actinic keratosis?What is the role of topical diclofenac sodium 3% gel in the treatment of actinic keratosis?What is the role of photodynamic therapy in the treatment of actinic keratosis?What is the role of surgery in the treatment of actinic keratosis?What is the role of dietary modification in the treatment of actinic keratosis?Which activity modifications are used in the treatment of actinic keratosis?How is actinic keratosis prevented?What is included in the long-term monitoring of patients with actinic keratosis?What are goals of drug treatment for actinic keratosis?Which medications in the drug class Nonsteroidal Anti-inflammatory Drug, Topical are used in the treatment of Actinic Keratosis?Which medications in the drug class Photosensitizing Agent, Topical are used in the treatment of Actinic Keratosis?Which medications in the drug class Immunomodulator, Topical are used in the treatment of Actinic Keratosis?Which medications in the drug class Antineoplastic Agent, Topical are used in the treatment of Actinic Keratosis?Which medications in the drug class Microtubule inhibitor are used in the treatment of Actinic Keratosis?

Author

Edward J Zabawski, Jr, DO, MBA, Adjunct Assistant Professor, Clinical Sciences

Disclosure: Nothing to disclose.

Chief Editor

William D James, MD, Emeritus Professor, Department of Dermatology, University of Pennsylvania School of Medicine

Disclosure: Received income in an amount equal to or greater than $250 from: Elsevier<br/>Served as a speaker for various universities, dermatology societies, and dermatology departments.

Additional Contributors

James M Spencer, MD, Professor of Clinical Dermatology, Mount Sinai School of Medicine; Private Practice, Spencer Dermatology

Disclosure: Received grant/research funds from Genentech for independent contractor; Received grant/research funds from DUSA for independent contractor; Received honoraria from Leo Pharmicuticals for review panel membership.

Kelly M Cordoro, MD, Assistant Professor of Clinical Dermatology and Pediatrics, Department of Dermatology, University of California, San Francisco School of Medicine

Disclosure: Nothing to disclose.

Laura Jordan, DO, MA, MS, MLS, Dermatology-Focus Traditional Rotating Intern, UH Regional Hospitals

Disclosure: Nothing to disclose.

Michelle Henry, MD, Fellow in Procedural Dermatology, Department of Dermatology, Lahey Clinic, Harvard Medical School

Disclosure: Nothing to disclose.

Acknowledgements

Amy Lynn Basile, DO, MPH Sun Coast Hospital/Largo Medical Center, Largo, Florida

Disclosure: Nothing to disclose.

Mary Farley, MD Dermatologic Surgeon/Mohs Surgeon, Anne Arundel Surgery Center

Disclosure: Nothing to disclose.

James Fulton Jr, MD, PhD Medical Director, Fulton Skin Institute

Disclosure: Nothing to disclose.

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Actinic keratosis. Courtesy of Hon Pak, MD.

Erythematous, scaly lesions on the temple area, typical of actinic keratosis.

Actinic keratosis. Courtesy of Hon Pak, MD.

Erythematous, scaly lesions on the temple area, typical of actinic keratosis.

Actinic keratosis during treatment with topical 5-fluorouracil. Courtesy of Hon Pak, MD.

Actinic keratosis right after treatment with topical 5-fluorouracil. Courtesy of Hon Pak, MD.

Actinic keratosis. Courtesy of Hon Pak, MD.

Actinic keratosis during treatment with topical 5-fluorouracil. Courtesy of Hon Pak, MD.

Actinic keratosis right after treatment with topical 5-fluorouracil. Courtesy of Hon Pak, MD.

Erythematous, scaly lesions on the temple area, typical of actinic keratosis.