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 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. There are numerous independent risk factors associated with the development of AKs, including:
AKs increasingly affect the older population due to the high cumulative lifetime exposure to the sun and inadequate sun protection.
AK prevalence is higher in men compared to women.
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.
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%.
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.
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.
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).
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.
The primary histopathologic feature of actinic keratoses is atypical keratinocytes in sun-damaged skin that is limited to the lower third of the epidermis.
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.
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 clinical exam may include dermoscopy or biopsy. On dermoscopy, non-pigmented facial AKs are characterized by a “strawberry pattern” and include an erythematous vessel pseudonetwork, prominent follicular openings, and a surrounding white halo.
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%.
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 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.
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.
Lesion-Directed Treatments: Target individual AKs
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.
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.
Surgical excision can be considered when the diagnosis is unclear or if there is a high suspicion of squamous cell carcinoma. Surgical excision will yield tissue for histopathologic diagnosis and help guide further treatment.
Field-Directed Treatments: Treat multiple, widespread, and subclinical AKs that may be within a field of chronic sun damage
In dermabrasion, a motorized handheld device with attached abrasive material is used to remove the superficial skin layers in areas of actinic damage.
Ablative resurfacing lasers (e.g., CO2 and erbium-YAG lasers) can be used to treat AKs by ablating the epidermis and superficial dermis.
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.
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. 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.
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.
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.
IMQ is an FDA-approved treatment for AKs. IMQ functions to augment the patient’s immune response at the site of medicine application. 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.
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.
Clinical variants of actinic keratoses include: hyperkeratotic AK, atrophic AK, actinic cheilitis, pigmented AK, lichenoid AK, and cutaneous horn.
The diagnosis of AK is primarily a clinical diagnosis. Other skin lesions considered in the differential include solar lentigo, seborrheic keratosis, verruca vulgaris, verruca plana, discoid lupus erythematosus, and squamous cell carcinoma.
Although there is a myriad of treatment options for AKs, there is no treatment option without some inherent risk. Actinic keratoses treatments may result in the following potential adverse effects: pain, inflammation, healing issues, pigment changes, and scarring. Potential complications also include AK recurrence or transformation to squamous cell carcinoma.
Patients need to be appropriately educated about the importance of preventative strategies to reduce the risk of actinic keratoses development and progression including minimizing/avoiding sun exposure (especially at peak hours), the use of sun-protective clothing, wide-brimmed hats, and the judicious use of sunscreen to cover sun-exposed areas of the body and face.
An interprofessional team that provides a holistic and integrated approach to Actinic keratoses can help achieve the best possible outcomes. To date, there is no superior or best treatment approach for AKs. The choice of treatment is tailored to symptoms, lesion number, compliance, and desired results. If the number of AKs is few, then lesion-directed treatment may be considered by the general practitioner. If the lesions are unresponsive to treatment by the general practitioner, consultation with a dermatologist may be considered. If AKs are numerous or rapidly evolving, and malignant transformation is a diagnostic possibility, referral to skin cancer specialists should be made for evaluation and treatment recommendations.
If noncompliance with self-administered topical medications is of concern, the patient's social support network should be reviewed. Consultation with a social worker and community nurses who can monitor the patient and make referrals as needed may be necessary to optimize patient outcomes. Collaboration, shared decision making, and communication are key elements for a good outcome. Through interprofessional care, the prognosis and outcome of AKs may be better when AKs are identified and managed before they undergo malignant transformation to squamous cell carcinoma.
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