Actinic Keratosis

Etiology

Actinic keratoses primarily arise due to the cumulative effects of ultraviolet (UV) radiation on the skin, which occurs over an individual's lifetime of sun exposure.[1]

Epidemiology

Actinic keratoses predominantly appear on chronically sun-exposed body areas, particularly in older individuals who have experienced decades of sun exposure.[2] Common locations for actinic keratoses include the face, scalp (bald or thinning hair), back of the arms, and dorsal aspect of the hands. The development of actinic keratosis is influenced by various independent risk factors, which may include:

• Increased age: Actinic keratosis increasingly affect the older population due to the high cumulative lifetime exposure to the sun and inadequate sun protection measures.[3]

• Male gender: The prevalence of actinic keratosis 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 their skin, which makes them more susceptible to sunburns and the damaging effects of IV radiation. Typical characteristics of individuals with these skin phototypes may include red or blonde hair and blue or light-colored eyes.[4]

• Geographic location: Countries located closer to the equator demonstrate higher rates of actinic keratosis. For example, prevalence rates of actinic keratosis 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 actinic keratosis in a non-equatorial location, such as the United States, is around 20%.[2]

• Immunosuppression: Individuals with a compromised immune system, such as those undergoing chemotherapy, individuals with acquired immune deficiency syndrome (AIDS), recipients of immunosuppressive medications (commonly used after organ transplantation), or individuals with leukemia, are more susceptible to developing actinic keratosis.[5][6]

• History of actinic keratosis or previous skin malignancy: This vital component of the history may indicate genetic factors associated with increased susceptibility to UV radiation and the prolonged exposure to UV radiation that the individual has experienced.[7]

• Excessive and chronic sun exposure: Individuals who have accumulated a greater lifetime exposure to UV radiation from the sun are more prone to developing actinic keratosis. At-risk individuals include outdoor occupations (eg, construction, farming) and outdoor activities (eg, tennis, golf, baseball players).[8]

Pathophysiology

The pathophysiology of actinic keratosis development is complex. Excessive and cumulative UV radiation exposure from the sun can trigger pathological changes in the epidermal keratinocytes by disrupting regulatory pathways involved in cell growth and differentiation.[9] This disruption leads to inflammation and immunosuppression, contributing to the intraepidermal proliferation of dysplastic keratinocytes, the precursors of actinic keratosis.[10][11]

Histopathology

The primary histopathologic feature of actinic keratosis is the presence of atypical keratinocytes within sun-damaged skin that is limited to the lower third of the epidermis.[10][12]

History and Physical

The following elements of the patient's history are important when evaluating a patient with actinic keratosis including:[13]

• Presenting symptoms: Inquire about any symptoms associated with the lesions, such as pruritus (itching), pain, or bleeding with minor trauma. These symptoms may indicate an increased risk of invasive squamous cell carcinoma progression.
• Medical history and medications: Perform a comprehensive review of the patient's medical problems and medications. Certain medical conditions and medications, such as immunosuppressive therapies, can increase the risk of actinic keratosis.
• Previous skin cancer treatments or surgery: Determine if the patient has a history of prior skin cancer treatments or surgeries. This information is relevant in assessing the patient's overall risk profile and the potential need for more aggressive management.
• Assessment of risk factors: Conduct a thorough assessment of all the risk factors associated with actinic keratosis, as mentioned earlier. This includes evaluating the duration and history of sun exposure, past occurrences of sunburn, regular use of sunscreen, sun protection habits, and the patient's occupation, especially if it involves prolonged outdoor activities.

The physical examination involves a detailed full-body skin assessment with particular attention to the number, size, distribution, and characteristics of suspicious skin lesions or skin pathology. The focus is mainly on the sun-exposed areas of the body, including the head, face, scalp, neck, dorsal forearms, and hands. The presence of any ulceration and bleeding should be noted.

Actinic keratosis can present in various forms, such as scaly, erythematous macules, papules, plaques, or cutaneous horns. Surrounding skin may exhibit solar damage, such as wrinkling, mottled pigmentation, or telangiectasias. On palpation, actinic keratoses are often appreciated by their rough texture due to varying degrees of hyperkeratosis.

Evaluation

The evaluation of actinic keratosis is primarily based on clinical observation during the physical examination. However, additional diagnostic techniques such as dermoscopy or biopsy may provide valuable information in certain cases.

Dermoscopy can reveal characteristic features. Nonpigmented facial actinic keratoses may exhibit a “strawberry pattern.” This pattern includes an erythematous vessel pseudo network, prominent follicular openings, and a surrounding white halo.[7] 

In certain circumstances, a biopsy may be necessary to confirm the diagnosis of actinic keratosis. A biopsy is typically reserved for individuals who fail to respond to treatment or in situations where one wants to determine whether an AK has progressed to squamous cell carcinoma.[14]

Treatment / Management

Dermatologists often recommend treatment, long-term follow-up, and preventive strategies to reduce symptomatic actinic keratosis and minimize the risk of their progression to squamous cell carcinoma. The average risk of malignant transformation in immunocompetent patients is 8%, although it can vary between individuals, ranging from 0.025% to 16%.[10][15](B3)

Treatment options for actinic keratosis can be categorized into lesion- and field-directed therapies. The treatment mantra often associated with actinic keratosis is "no pain, no gain," implying that effective treatment may involve some discomfort or side effects.

Lesion-directed therapies focus on treating individual actinic keratoses. Standard options include cryotherapy, curettage, or surgical excision. These therapies are effective for targeting specific visible lesions.

On the other hand, field-directed therapies offer the advantage of treating multiple, widespread, and subclinical actinic keratosis within an area of chronic sun damage. These therapies aim to treat the entire affected field of skin rather than individual lesions. Field-directed therapies can include topical medications (chemotherapy creams or immunomodulators), light-based therapies like photodynamic therapy (PDT), or laser resurfacing. These treatments effectively address visible actinic keratoses and subclinical lesions that may not be visible to the naked eye.

Treatment strategies should be individualized, considering several factors that include the characteristics and symptoms of the lesions, patient preferences and expectations, treatment availability, patient compliance with treatment regimens, tolerability of adverse effects, and cost considerations. 

When determining the urgency of treatment, specific indications warrant prompt intervention. These include numerous lesions, bleeding, pain, and rapid growth of the lesions. In such cases, immediate attention is required to prevent potential complications.

Having a discussion with patients about the anticipated timeline of treatment adverse effects, which may include blistering, erosion, crusting, burning, discomfort, pain, pruritus, erythema, and edema, is crucial. Patients should be informed about the expected course of healing, regeneration, and recovery following treatment.[16][17] Additionally, instructions on how to care for the skin during the healing process should be provided.

Recognizing that no treatment for actinic keratosis is entirely risk-free is essential. Each treatment modality carries its potential adverse effects. Some common possible adverse effects include pain, inflammation, healing issues, pigment changes, and scarring.

Recurrence of actinic keratosis and the need for multiple treatments are common occurrences. The healing process may range from days to weeks, depending on the location and number of lesions treated. In cases where actinic keratosis fails to respond to aggressive treatment, further investigation is warranted. Potential reasons for treatment failure include noncompliance with the prescribed treatment regimen, misdiagnosis, or, in rare instances, the possibility of malignant transformation to squamous cell carcinoma.

Actinic keratoses are a cutaneous manifestation of repeated sun exposure. Patients diagnosed with actinic keratosis should undergo regular skin cancer screening. Patients should be educated about photoprotection strategies and self-skin cancer surveillance. Additionally, vitamin B3 (niacinamide) has shown promise in reducing the number of actinic keratoses. Studies have demonstrated that a daily dosage of 500 mg of vitamin B3 taken twice a day can reduce AKs after several months of use.[18] (A1)

Lesion-Directed Treatments: Target individual actinic keratoses.`

• Cryotherapy: Cryotherapy is a commonly used lesion-directed treatment modality for AKs. It involves freezing skin lesions through 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 actinic keratoses 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 actinic keratoses that may be unresponsive to alternative treatments. Curettage or shave allows specimen collection for histopathologic evaluation. Electrodessication can be applied following curettage to assist with hemostasis. 

• Surgery: Surgical excision can be considered when the diagnosis is unclear or if there is a high suspicion of squamous cell carcinoma.[19] Surgical excision will yield tissue for histopathologic diagnosis and help guide further treatment.

Field-Directed Treatments: Treat multiple, widespread, and subclinical actinic keratoses that may be within an area of chronic sun damage

• Dermabrasion: Dermabrasion involves the mechanical removal of the superficial layers of the skin in areas affected by actinic damage. During dermabrasion, a motorized handheld device with attached abrasive material removes the superficial skin layers in areas of actinic damage. 

• Laser: Ablative resurfacing lasers (eg, CO2 and erbium-YAG lasers) can treat actinic keratosis by ablating the epidermis and superficial dermis.[17] 

• Chemical peels: Chemical peels have been used to treat patients with multiple or widespread facial actinic keratosis. 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 can be adjusted based on the specific agent used, its concentration, and the duration of application. The effectiveness of chemical peels for AKs is approximately 75%.[17] 

• Photodynamic therapy (PDT): PDT involves the topical application of a photosensitizer to the treatment area, followed by exposure to a light source of a specified wavelength, depending on the desired skin penetration depth. This light activates the photosensitizer, generating reactive oxygen species that selectively destroy atypical keratinocytes.[10] PDT therapy is performed in an office-based setting. Disadvantages of conventional PDT include patients experiencing pain during the treatment, requiring an extended period in the office during treatment sessions, and frequent office visits or treatment. These drawbacks have prompted the development of alternative uses of PDT, including daylight photodynamic therapy, where natural daylight activates the photosensitizer instead of an artificial light source. Daylight PDT reportedly has a similar lesion response rate to conventional PDT but with the advantages of reduced patient discomfort and the convenience of treatment outside of the office setting.[7][11][20] 

• Topical medications: There are several FDA-approved topical medications for treating actinic keratosis. The patient can apply these medications at home, making patient education crucial for achieving positive outcomes and ensuring compliance with the recommended treatment plan. The timeline of expected side effects of blistering, erosion, crusting, burning, discomfort, pain, pruritus, erythema, and edema must be reviewed. Additionally, patients should be educated on proper at-home care for the skin as it heals and recovers from the treatment. Numerous treatment regimens have been reported for each of the FDA-approved medications.[16][17] 
  • 5-Fluorouracil (5-FU): 5-FU is an FDA-approved topical medication applied 1 to 2 times daily for several weeks. 5-FU, a pyrimidine analog, inhibits DNA synthesis and disrupts cell division. This mechanism of action makes it one of the most effective treatments for actinic keratosis.
  • Imiquimod (IMQ): IMQ is an FDA-approved treatment for actinic keratosis. IMQ functions to augment the patient's immune response at the site of medicine application.[16] It is typically indicated for use on limited face and scalp areas over several weeks.
  • Diclofenac Sodium (DFS): DFS gel is a topical, non-steroidal, anti-inflammatory FDA-approved drug for actinic keratosis treatment. The treatment regimen involves application 2 times per day for 2 to 3 months. DFS gel is generally better tolerated by patients than 5-FU because of milder adverse skin effects.[10][16] 
  • Ingenol mebutate (IM): IM is derived from the Euphorbia peplus plant and is FDA-approved for treating actinic keratosis. The mechanism of action involves the rapid induction of keratinocyte cell death within a few hours of application. This cell death triggers an inflammatory response over the following days, which also has immunostimulatory effects. An advantage of IM treatment is that the duration of therapy is only a couple of days, thus significantly shorter than other topical medications used for actinic keratosis.[10][16]

Differential Diagnosis

Clinical variants of actinic keratosis include hyperkeratotic actinic keratosis, atrophic actinic keratosis, actinic cheilitis, pigmented actinic keratosis, lichenoid AK, and cutaneous horn.[7]  

The diagnosis of actinic keratosis is primarily made through clinical evaluation, relying on the characteristic appearance and location of the lesions. Other skin lesions in the differential diagnosis include solar lentigo, seborrheic keratosis, verruca vulgaris, verruca plana, discoid lupus erythematosus, and squamous cell carcinoma.[2]

Prognosis

Actinic keratosis can exhibit erratic behavior over time. Some actinic keratoses may spontaneously regress, though the mechanisms behind this regression are not fully understood and are an area of ongoing research.[21]

On the other hand, some actinic keratoses may remain stable, showing little change in size or appearance over time. However, it is essential to note that actinic keratoses have the potential to progress and evolve into invasive squamous cell carcinoma (SCC), a type of skin cancer.[10] Most squamous cell carcinomas develop from preexisting actinic keratoses or with areas that contain actinic keratoses.[2]

Complications

While there are various treatment options for actinic keratoses, no treatment option is without risks. Actinic keratosis treatments may have potential adverse effects such as pain, inflammation, healing issues, pigment changes, and scarring.[22] Possible complications also include actinic keratosis recurrence or transformation to squamous cell carcinoma.