Actinic Keratoses (AKs), also referred to as senile keratoses or solar keratoses, are benign intra-epithelial neoplasms and represent one of the most common skin disorders evaluated by dermatologists. Often associated with chronic sun exposure, individuals with AKs may present with irregular, red, scaly papules or plaques on sun-exposed regions of the body. If left untreated, AKs have the potential to evolve into invasive squamous cell carcinoma, which underscores the importance of early detection and development of a treatment plan. There are a variety of management options that are available for AKs, which will be covered in this review.
- actinic (Actinic cheilitis, solar cheilitis, actinic cheilosis, cheilitis actinic, cheilosis actinic, actinic keratosis of the lip, solar keratosis of the lip, cheilitis exfoliativa).
The pathophysiology of actinic keratoses development is complex. Excessive and cumulative UV radiation exposure from the sun can induce a number of pathologic changes to the epidermal keratinocyte through the disruption of regulatory pathways involved in cell growth and differentiation. The resulting inflammation and immunosuppression lead to the intraepidermal proliferation of dysplastic keratinocytes, which give rise to AKs.[rx][rx]
Causes of Actinic Keratoses
Actinic keratoses typically develop from the damaging effects of ultraviolet (UV) radiation to the skin accumulated over a lifetime of sun exposure. Actinic keratoses are predominantly located on chronically sun-exposed areas of the body such as the face, scalp (bald or thinning), back of the arms, and dorsal aspect of the hands, especially in older people who have accumulated decades of sun exposure.[rx] There are numerous independent risk factors associated with the development of AKs, including:
- Increased Age – AKs increasingly affect the older population due to the high cumulative lifetime exposure to the sun and inadequate sun protection.
- Male Gender – AK prevalence is higher in men compared to women.
- Fair-skinned individuals (Fitzpatrick Skin Phototypes I and II) – Pale or light-skinned individuals have less melanin pigment in the skin and tend to burn easily with sun exposure. Other characteristics of these skin phototypes may include red or blonde hair and blue or light-colored eyes.
- Geographic Location – Countries located closer to the equator demonstrate higher rates of AKs. For example, prevalence rates of AKs in Australia are close to 60% due to its proximity to the equator (in addition to its sizable White population). In contrast, the prevalence of AKs in a non-equatorial location, such as the United States, is around 20%.[rx]
- Immunosuppression – Individuals with a compromised immune system have an increased susceptibility to develop AKs, such as observed with chemotherapy, acquired immune deficiency syndrome, immunosuppressive medications (transplant medications), and leukemia.
- History of Actinic Keratosis and/or Previous Skin Malignancy – This important component of the history may indicate genetic factors associated with increased susceptibility to UV radiation as well as the chronicity of UV radiation exposure to which the individual has been exposed.[rx]
- Excessive and Chronic Sun Exposure – People with greater cumulative lifetime exposure to UV radiation from the sun are more prone to developing AKs. At-risk individuals include those with outdoor occupations (e.g., construction, farming) and outdoor activities (e.g., tennis, golf, baseball players).
Symptoms of Actinic Keratoses
The signs and symptoms of an actinic keratosis include:
- A rough, dry or scaly patch of skin, usually less than 1 inch (2.5 centimeters) in diameter
- Flat to slightly raised patch or bump on the top layer of skin
- In some cases, a hard, wartlike surface
- Color as varied as pink, red or brown
- Itching or burning in the affected area
Diagnosis of Actinic Keratoses
History and Physical
Important elements of the patient history include
- Presenting symptoms (pruritus, pain, bleeding with minor trauma) of the lesion(s), a thorough review of medical problems and medications, previous skin cancer treatments/surgery, and a thorough assessment of all risk factors as outlined above, including duration/history of sun exposure, history of sunburn, use of sunscreen, sun protection habits, and occupation.
- The physical exam involves a detailed full-body skin exam with particular attention to the number, size, distribution, and description of any suspicious skin lesions or skin pathology, especially in the sun-exposed areas of the body (head, face scalp, neck, dorsal forearms, hands). The presence of any ulceration and bleeding should be noted. AKs may appear as scaly, erythematous macules, papules, plaques, or cutaneous horns. Surrounding skin changes may indicate solar damage. AKs often are better appreciated by their rough texture on palpation as they may demonstrate differing degrees of hyperkeratosis.
- Evaluation of actinic keratoses is primarily by clinical observation during the physical examination. In some cases, useful diagnostic adjuncts to the clinical exam may include dermoscopy or biopsy. On dermoscopy, non-pigmented facial AKs are characterized by a strawberry pattern and include an erythematous vessel pseudo network, prominent follicular openings, and a surrounding white halo.[rx]
- A shave or punch biopsy may be recommended in cases of diagnostic uncertainty, failure to respond to treatment, or in situations where one wants to determine whether an AK has progressed to squamous cell carcinoma.
Dermatologists often recommend treatment, long-term follow-up, and preventive strategies to reduce symptomatic actinic keratoses, as well as development and progression to squamous cell carcinoma. The average risk for malignant transformation is 8% in immunocompetent patients, with a range from 0.025% to 16%.[rx][rx][rx][rx]
Although there are a variety of options available for the treatment of AKs, the treatment mantra is the same: “no pain, no gain.” Lesion-directed therapies (e.g., cryotherapy, curettage, surgery) target individual AKs, whereas field-directed therapies (e.g., topical medications, light-based therapies, laser resurfacing) have the advantage of treating multiple, widespread, and subclinical AKs that may be within a field of chronic sun damage.
Treatment strategies should be individualized, taking into account several factors: AK’s characteristics and symptoms, patient desires/expectations, treatment availability, patient’s ability to comply with treatment regimens, tolerability of treatment side effects, and cost. Urgency is indicated when lesions are numerous, bleeding, painful, and/or rapidly growing in size. The timeline of expected side effects of blistering, erosion, crusting, burning, discomfort, pain, pruritus, erythema, and edema must be reviewed, as well as how to care for the skin as it heals, regenerates, and recovers from the treatment.[rx][rx]
No treatment is without risks. All AK treatments may result in the following potential adverse effects: pain, inflammation, healing issues, pigment changes, and scarring. Recurrence and need for more than one treatment are not uncommon. Healing may take days to weeks, depending on location and number of lesions treated. AKs that fail to respond to aggressive treatment should prompt consideration of treatment noncompliance, misdiagnosis, and possible malignant transformation to squamous cell carcinoma.
AKs are a cutaneous manifestation of repeated sun exposure. Patients diagnosed with AKs should undergo skin cancer screening. Photoprotection strategies and self-skin cancer surveillance should be reviewed with these individuals. Vitamin B3 dosed at 500 mg twice a day has been shown to reduce the number of AKs after several months of use.[rx]
Lesion-Directed Treatments: Target individual AKs
- Cryotherapy – Cryotherapy is a commonly used lesion-directed treatment modality for AKs. It involves the freezing of skin lesions through the topical application of liquid nitrogen via spray or cotton tip applicator. With excellent response rates, it is a viable treatment option for patients with only a few AKs or isolated lesions. Healing will depend on the duration of liquid nitrogen application and the number of freeze-thaw cycles.
- Curettage or Shave – Lesion removal with a curette or blade can be used for hyperkeratotic AKs that may be unresponsive to alternative treatments. Curettage or shave allows specimen collection for histopathologic evaluation. Electrodessication can be added following curettage to assist with hemostasis.
- Chemical peel – This is a medical-grade chemical peel used to destroy the top layers of skin. You cannot get this type of chemical peel at a salon or from a kit sold for home use. After a medical-grade chemical peel, the treated skin will be red, swollen, and sore. As the area heals, you will see new healthy skin.
- Curettage – If you have an extremely thick AK, this may the best treatment. During this procedure, your dermatologist first scrapes the AK from your skin, using a technique called curettage. Your dermatologist may follow this with an electrodesiccation, which heats the treated area to destroy any remaining AK cells.
- Laser resurfacing – This may be a treatment option for actinic cheilitis, a precancerous growth on the lip. It works by removing the surface layer of the skin. After treatment, the skin will feel raw and sore. When it heals in 1 or 2 weeks, you see new, healthier skin.
- Chemotherapy. A topical cancer medicinal cream called fluorouracil is applied to the skin lesion or the entire sun-damaged area. It takes around 4 to 6 weeks to work. Usually, the skin turns red and blisters before new skin appears.
- Photodynamic therapy – A chemical is applied to the skin. Then the skin is exposed to a light that activates the chemical to destroy the abnormal skin cells. There can be burning, stinging, and changes in pigmentation of the skin.
- Chemical peel – A chemical solution is applied to the skin to cause blistering and peeling away of the actinic keratoses. Temporary redness and swelling will likely occur.
- Dermabrasion – This uses a handheld device to “sand” the skin and improve its appearance. It can be used to treat large lesions that are often too big to treat with topical treatments. It leaves the skin red and raw and can be a painful procedure. A topical numbing ointment, nerve blocks, or other pain medications are often used.
- Immunomodulator therapy – Imiquimod cream, ingenol gel, or diclofenac gel works much like fluorouracil to selectively rid the skin of abnormal cells. There may be redness, itching, swelling, crusting, and peeling
At-home treatment for actinic keratosis
If you have many AKs or AKs that you can feel but not see, your dermatologist may recommend at-home treatment.
- When you treat at home, you apply medication to your skin as directed.
- The advantage of using a medication to treat your AKs is that the medication can treat many AKs, including the ones you cannot see yet. Using this approach can reduce your risk of developing new AKs and possibly skin cancer.
- The downside of applying medication to your skin is that some patients say it’s difficult to follow the treatment plan. To be effective, you need to apply the medication as often as your dermatologist recommends. Even when the medication causes a skin reaction, which indicates that it’s working, you’ll need to keep applying the medication.
- The medications that dermatologists prescribe include the following, which have all been approved by the US. Food and Drug Administration (FDA) to treat AKs:
- 5-fluorouracil (5-FU) cream – You apply this once or twice a day for 2 to 4 weeks. It’s often a treatment option for the chest, arms, or back, but usually not the face due to the skin reaction it causes. This is not a treatment option for a woman who is pregnant. 5-FU can harm an unborn baby.
- Diclofenac sodium gel – This medication tends to cause less of a skin reaction than 5-FU, but it can still be very effective. You will need to apply it twice a day for 2 to 3 months. While using this medication, you must protect your treated skin from the sun. Your dermatologist can tell you the best way to protect your skin.
- Imiquimod cream – This can be a good option for the face because you can apply it once (or twice) a week, so you don’t get lots of redness and crusting. You may need to apply it for 12 to 16 weeks. If 12 to 16 weeks is too long, you may be able to use the medication a bit differently. You’d apply imiquimod every night for 2 weeks. For the next 2 weeks, you’d give your skin a break. Then you’d apply it again, using it every night for 2 weeks.
- Ingenol mebutate gel – This requires the shortest treatment time. To treat your face or scalp, you’d apply it for 3 days. On other parts of your body, you’d apply it for 2 days. While you apply this medication for the least amount of time, your skin will still react. For 1 or 2 weeks, you may have a reaction on your face or scalp, such as redness, swelling, crusting, or scaly skin. Reactions can last for up to 4 weeks on the other parts of your body.
Surgical excision can be considered when the diagnosis is unclear or if there is a high suspicion of squamous cell carcinoma.[rx] Surgical excision will yield tissue for histopathologic diagnosis and help guide further treatment.
- Surgical removal and biopsy The lesion may be removed and examined if there is a possibility it has become cancerous.
- Field-Directed Treatments – Treat multiple, widespread, and subclinical AKs that may be within a field of chronic sun damage
- Dermabrasion – In dermabrasion, a motorized handheld device with attached abrasive material is used to remove the superficial skin layers in areas of actinic damage.
- Laser – Ablative resurfacing lasers (e.g., CO2 and erbium-YAG lasers) can be used to treat AKs by ablating the epidermis and superficial dermis.[rx]
- Chemical Peels – Chemical peels have been used to treat patients with multiple or widespread facial AKs. A chemical peel involves the topical application of a caustic agent, such as trichloroacetic acid (TCA), to remove the outer skin layers to variable depths. The depth of the peel depends on the agent used, its concentration, and the duration of application. Peels for AKs are approximately 75% effective.[rx]
- Photodynamic Therapy (PDT) – PDT involves the topical application of a photosensitizer to the treatment area and exposure to a light source of a specified wavelength, depending on the depth of skin penetration desired. The generation of reactive oxygen species leads to the destruction of atypical keratinocytes.[rx] PDT therapy is an office-based treatment. Disadvantages of conventional PDT include patient complaints of pain, extended time spent in the office during treatment sessions as well as frequent office visits for treatment. These drawbacks have prompted the development of alternative uses of PDT, including daylight photodynamic therapy, where natural daylight is used to activate the photosensitizer in place of an artificial light source. Daylight PDT reportedly has a similar lesion response rate compared to conventional PDT with the advantages of less patient discomfort and added convenience of treatment outside of the office setting.[rx][rx][rx]
- Topical Medications – There are several FDA-approved topical medications for the treatment of AKs. Because the patient at home can apply these medications, patient education is imperative to obtain a favorable outcome and compliance with recommended treatment. The timeline of expected side effects of blistering, erosion, crusting, burning, discomfort, pain, pruritus, erythema, and edema must be reviewed, as well as how to care for the skin at home as it heals and recovers from the field treatment. Numerous treatment regimens have been reported for each of the drugs.[rx][rx]
- 5-Fluorouracil (5-FU) – 5-FU is an FDA-approved topical medication and applied one to two times per day for several weeks. 5-FU, a pyrimidine analog, acts by blocking DNA synthesis and disrupting cell division, providing some of the most effective treatment for AKs.
- Imiquimod (IMQ) – IMQ is an FDA-approved treatment for AKs. IMQ functions to augment the patient’s immune response at the site of medicine application.[rx] It is typically indicated in limited areas of the face and scalp over several weeks.
- Diclofenac Sodium (DFS) – DFS gel is a topical, non-steroidal, anti-inflammatory FDA-approved drug for AK treatment. The treatment regimen involves application two times per day over a course of two to three months. DFS treatment appears to be better tolerated by patients compared to 5-FU because of milder adverse skin effects.[rx][rx]
- Ingenol mebutate (IM) – IM is obtained from the Euphorbia peplus plant and is FDA-approved for the treatment of AKs. The mechanism of action involves rapid induction of keratinocyte cell death within a few hours and an inflammatory response over the ensuing days, which is immunostimulatory. An advantage of IM treatment is that the duration of therapy is only a couple of days, thus significantly shorter than the other topical drug treatments.[rx][rx]
- The use of curettage under local anesthesia for treatment of actinic keratoses can be performed in isolation or in association with electrodesiccation, which appears to increase the resolution of potential remaining dysplastic cells and also to achieve hemostasis. An alternative to electrodesiccation is cryotherapy.[rx] As a monotherapy, a curettage is especially indicated for patients with few lesions, especially hyperkeratotic actinic keratoses. The method is frequently used in the setting of patients with large clinical variability of keratoses as a complementary therapy for lesions resistant to field cancerization therapy, in addition to allowing the collection of material for histopathological analysis.[rx]
- Disadvantages regarding the method include the need for local anesthesia, the healing time, which can be prolonged when lesions are treated especially in the lower limbs, and the risk of dyspigmentation symptoms in the treated area.[rx, rx] Although curettage is widely performed in daily practice, the lack of randomized clinical trials evaluating the subject results in a low degree of the recommendation of the procedure for actinic keratoses treatment.[rx]
- Lasers induce coagulative necrosis, ablation, and hyperthermia, which lead to lesional destruction. A single session of non-fractional CO2 laser could be used to remove superficial lesions on the epidermis, such as actinic keratoses. The 10,600 nm CO2 non-fractional laser has a wavelength absorbed by water, resulting in non-specific tissue destruction. Therefore, the non-fractional CO2 laser can be used for field cancerization treatment or for localized lesion destruction.
- For localized lesions, complete lesion clearance results in the first months are similar to those obtained with cryotherapy (72.8% in the laser group vs. 78% for cryotherapy); however, in long-term follow-up, lesions treated with CO2 laser present lower sustained response rates: only 37% of the patients treated with laser remain without lesions vs. 66.8% of those treated with cryotherapy.[rx] Furthermore, because the technique is operator-dependent, different levels of expertise with the technique may influence the results.[rx] In addition, there is a risk of secondary infection, esthetical scars, and dyschromia.
- Because of the increased risk of infection in immunosuppressed patients, the CO2 laser is not recommended for the treatment of field cancerization and should be used only for localized lesions in these patients.[rx] Although the use of CO2 laser can be considered as an option for actinic keratoses treatment, the degree of recommendation for its use in immunocompetent patients is weak.[rx]
One of the first studies to report the benefits of topical retinoids for patients with actinic keratoses dates back to 1970, a case series of 60 patients that reported benefits of tretinoin use at 0.1–0.3%, for a reduction in actinic keratoses scores of about 50%.[rx] Subsequent studies have shown that tretinoin at a lower concentration (0.05%) was not as effective, with a maximum reduction in the number of actinic keratoses of 45%.[rx], [rx] However, despite these initial positive results, more recent studies evaluating the use of topical retinoids in a larger sample (>1000 individuals) have not been able to demonstrate their efficacy in reducing the occurrence of SCC and basal cell carcinoma (BCC) in patients at risk; besides, no benefit in reducing the number of actinic keratoses was observed.[rx], rx]
Some studies have described the effect of serial peelings with glycolic acid, trichloroacetic acid (TCA), and salicylic acid in animal models previously exposed to UV radiation; they observed reduction of mutated p53 and expression of COX-2 mRNA, demonstrating a possible role in tumor prevention.[rx], [rx], [rx] In humans, there are few studies with a high level of evidence on the subject. A split-face study including 15 patients with facial actinic keratoses a single session of Jessner’s peel plus TCA 35% achieved similar effectiveness to the use of 5-FU twice daily for three weeks.[rx] There was a reduction of 75% in the total number of lesions in both groups, in addition to a similar reduction between treatments in keratinocytes atypia, parakeratosis, hyperkeratosis, and inflammation in the histopathological analysis.
More recently, the association of glycolic acid or Jessner’s peel with 5-FU 5% at fortnightly intervals demonstrated effectiveness for treatment of field cancerization[rx]; 31 patients were submitted to the sessions until complete lesion remission or until completing ten sessions. The treatment was effective and showed good tolerability; moreover, only five patients presented relapses after 36 months of follow-up.
Oral retinoids, synthetic derivatives of vitamin A, are used for chemoprevention of NMSC in high-risk patients for both immunocompetent and immunosuppressed patients, including patients with genodermatoses, such as xeroderma pigmentosum.[rx, 2rx, rx] The main medications described in the studies are acitretin, etretinate, and isotretinoin; among them, acitretin has the greatest degree of evidence regarding its protective effect.[rx] Several mechanisms of action are proposed to explain the chemopreventive effect of retinoids, including immunomodulation, apoptosis, promotion of cell differentiation, and inhibition of keratinization and cell proliferation.[rx] The first randomized clinical trial evaluating the use of 5 mg etretinate three times a week in 100 patients with actinic keratoses for a period of two months observed complete or partial remission of actinic keratoses in 84% of the treated patients (37 of 44 patients) vs. 5% (2 of 42 patients) in the placebo group.[rx]
Another clinical trial with acitretin 30 mg daily for six months in 44 transplant recipients patients observed a 13.4% reduction in actinic keratoses in the treated group vs. an increase of 28.2% in the number of actinic keratoses in the placebo group.[rx] In addition, there was a reduction in the appearance of new SCCs in the acitretin group: only two of the 19 patients in the intervention group (11%) developed SCCs vs. nine of the 19 patients of the placebo group (47%) (the relative risk reduction of developing SCCs was of 78% for patients taking acitretin).[rx, rx] Smit et al. evaluated the use of acitretin 0.4 mg/kg/day for three months in 33 renal transplant recipients and performed the histological and immunohistochemical analysis; modifications observed in actinic keratoses were the reduction of an epidermal thickness (p < 0.002) and normalization of the K10 keratinization pattern (p < 0.02). However, there was no change in cell proliferation, which could explain the early recurrence of actinic keratoses after acitretin discontinuation.[rx] Data on the optimal dose and duration of treatment are not defined in the literature.[rx]
Nicotinamide, the amide form of vitamin B3, is a cofactor for ATP production that prevents ATP depletion and glycolytic blockade induced by UV radiation, and thus assists in DNA repair. In addition, nicotinamide reduces UV-induced immunosuppression without altering basal immunity. Studies for the prevention of actinic keratoses are sparse, and its use for this purpose is still debated.
The use of nicotinamide as a chemoprotective agent to reduce the appearance of new lesions of NMSC and actinic keratoses in high-risk patients, a 1 g daily dose of the medication divided into two doses, was considered effective. After 12 months of follow-up, the rates of onset of new lesions in the patients receiving nicotinamide were 23% lower compared to the placebo group (p = 0.02), with reduction of both new basal cell carcinomas (20% reduction) and SCCs (30% reduction), as well as actinic keratoses (13%). The protective effect was maintained only during the use of the medication, which presented a good safety profile. However, subsequent studies are needed to confirm the reproducibility of the beneficial effects found, as well as the appropriate treatment duration.[rx]
All patients with actinic keratosis should be advised regarding physical photoprotection and the use of sunscreens as an adjuvant to the treatment, and to prevent the onset of new lesions, regardless of the type of treatment proposed.[rx, rx] Regular use of sunscreen with a sun protection factor (SPF) over 15 reduces the development of new actinic keratoses in immunocompetent patients, ranging from a 50% reduction in the number of new lesions in one year (study using SPF 29) and 37% in two years (study using SPF 16) (p < 0.05).[rx, rx] In addition, patients who benefit the most from sunscreen use to slow the development of new actinic keratoses include young patients who have not had previous NMSC and those who tan after sunbathing (phototypes ≥III).[rx] For immunocompromised patients, a case-control study with 120 immunosuppressed patients followed for 24 months observed that the use of broad-spectrum SPF 50 sunscreen significantly reduced the appearance of new lesions in the intervention group (p < 0.05).[rx] Moreover, the effect of daily sunscreen use on spontaneous regression of actinic keratoses is also observed in both immunocompetent and immunosuppressed patients; this regression is higher than that observed in the lesions of patients who do not use sunscreen.[rx, rx, rx, rx] In addition, daily use of sunscreen reduces the incidence of new SCCs (p < 0.01).[rx, rx]
Prevention of actinic keratoses is important because the condition can precede cancer or be an early form of skin cancer. Sun safety is necessary to help prevent development and recurrence of actinic keratosis patches and spots.
Take these steps to protect your skin from the sun:
- Limit your time in the sun – Especially avoid time in the sun between 10 a.m. and 2 p.m. And avoid staying in the sun so long that you get sunburn or a suntan. Both result in skin damage that can increase your risk of developing actinic keratoses and skin cancer. Sun exposure accumulated over time may also cause actinic keratoses.
- Use sunscreen. Daily use of sunscreen reduces the development of actinic keratoses. Before spending time outdoors, apply a broad-spectrum sunscreen with a sun protection factor (SPF) of at least 30. The American Academy of Dermatology recommends using a broad-spectrum, water-resistant sunscreen with an SPF of at least 30. Use sunscreen on all exposed skin, and use lip balm with sunscreen on your lips. Apply sunscreen 15 minutes before sun exposure and reapply it every two hours — or more often if you’re swimming or perspiring.
- Cover up – For extra protection from the sun, wear tightly woven clothing that covers your arms and legs. Also wear a broad-brimmed hat, which provides more protection than does a baseball cap or golf visor. You might also consider wearing clothing or outdoor gear specially designed to provide sun protection.
- Avoid tanning beds – The UV exposure from a tanning bed can cause just as much skin damage as a tan acquired from the sun.
- Check your skin regularly and report changes to your doctor – Examine your skin regularly, looking for the development of new skin growths or changes in existing moles, freckles, bumps and birthmarks. With the help of mirrors, check your face, neck, ears and scalp. Examine the tops and undersides of your arms and hands.
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