Actinic keratosis

Actinic keratosis
Other names	Solar keratosis, senile keratosis (SK)
Actinic keratosis seen on the back of the hands
Specialty	Dermatology

Actinic keratosis (AK), sometimes called solar keratosis or senile keratosis,

Actinic keratoses characteristically appear as thick, scaly, or crusty areas that often feel dry or rough. Size commonly ranges between 2 and 6

Given the causal relationship between sun exposure and AK growth, they often appear on a background of sun-damaged skin and in areas that are commonly sun-exposed, such as the face, ears, neck, scalp, chest, backs of hands, forearms, or lips. Because sun exposure is rarely limited to a small area, most people who have an AK have more than one.[10]

If clinical examination findings are not typical of AK and the possibility of in situ or invasive

Cryotherapy is frequently used for few and well-defined lesions,^[14] but undesired skin lightening, or hypopigmentation, may occur at the treatment site.^[15] By following up with a dermatologist, AKs can be treated before they progress to skin cancer. If cancer does develop from an AK lesion, it can be caught early with close monitoring, at a time when treatment is likely to have a high cure rate.

Signs and symptoms

Actinic keratoses (AKs) most commonly present as a white, scaly

Photoaging leads to an accumulation of oncogenic changes, resulting in a proliferation of mutated keratinocytes that can manifest as AKs or other neoplastic growths.^[17] With years of sun damage, it is possible to develop multiple AKs in a single area on the skin. This condition is termed field cancerization.

The lesions are usually asymptomatic, but can be tender, itch, bleed, or produce a stinging or burning sensation.^[18] AKs are typically graded in accordance with their clinical presentation: Grade I (easily visible, slightly palpable), Grade II (easily visible, palpable), and Grade III (frankly visible and hyperkeratotic).^[19]

Variants

Actinic keratoses can have various clinical presentations, often characterized as follows:

• Classic (or common): Classic AKs present as white, scaly
  papules or plaques of various thickness, often with surrounding erythema. They are usually 2–6mm in diameter but can sometimes reach several centimeters in diameter.^[18]
• Hypertrophic (or hyperkeratotic): Hypertrophic AKs (HAKs) appears as a thicker
  scale
  or rough papule or plaque, often adherent to an erythematous base. Classic AKs can progress to become HAKs, and HAKs themselves can be difficult to distinguish from malignant lesions.
• Atrophic: Atrophic AKs lack an overlying scale, and therefore appear as a nonpalpable change in color (or macule). They are often smooth and red and are less than 10mm in diameter.
• AK with cutaneous horn: A cutaneous horn is a keratinic projection with its height at least one-half of its diameter, often conical in shape. They can be seen in the setting of actinic keratosis as a progression of an HAK, but are also present in other skin conditions.^[18] 38–40% of cutaneous horns represent AKs.^[20]
• Pigmented AK: Pigmented AKs are rare variants that often present as macules or plaques that are tan to brown in color. They can be difficult to distinguish from a
  solar lentigo or lentigo maligna.^[21]
• Actinic cheilitis: When an AK forms on the lip, it is called actinic cheilitis. This usually presents as a rough, scaly patch on the lip, often accompanied by the sensation of dry mouth and symptomatic splitting of the lips.
• Bowenoid AK: Usually presents as a solitary, erythematous, scaly patch or plaque with well-defined borders. Bowenoid AKs are differentiated from
  Bowen's disease by degree of epithelial involvement as seen on histology.^[22]

UV radiation has also been shown to cause elevated inflammatory markers such as arachidonic acid, as well as other molecules associated with inflammation.^[27] Eventually, over time these changes lead to the formation of AKs. Several predictors for increased AK risk from UV radiation have been identified:

• Extent of sun exposure: Cumulative sun exposure leads to an increased risk for development of AKs. In one U.S. study, AKs were found in 55% of fair-skinned men with high cumulative sun exposure, and in only 19% of fair-skinned men with low cumulative sun exposure in an age-matched cohort (the percents for women in this same study were 37% and 12% respectively).^[31] Furthermore, the use of sunscreen (SPF 17 or higher) has been found to significantly reduce the development of AK lesions, and also promotes the regression of existing lesions.^[32]
• History of sunburn: Studies show that even a single episode of painful sunburn as a child can increase an individual's risk of developing AK as an adult.^[33] Six or more painful sunburns over the course of a lifetime was found to be significantly associated with the likelihood of developing AK.^[33]

Skin pigmentation

Melanin is a pigment in the epidermis that functions to protect keratinocytes from the damage caused by UV radiation; it is found in higher concentrations in the epidermis of darker-skinned individuals, affording them protection against the development of AKs.

Fair-skinned individuals have a significantly increased risk of developing AKs when compared to olive-skinned individuals (odds ratios of 14.1 and 6.5, respectively),^[33] and AKs are uncommon in dark-skinned people of African descent.^[31] Other phenotypic features seen in fair-skinned individuals that are associated with an increased propensity to develop AKs include:^[31]

• Freckling
• Light hair and eye color
• Propensity to sunburn
• Inability to tan

Other risk factors

• Immunosuppression: People with a compromised immune system from medical conditions (such as AIDS) or immunosuppressive therapy (such as chronic immunosuppression after organ transplantation, or chemotherapy for cancer) are at increased risk for developing AKs.^[34] They may develop AK at an earlier age or have an increased number of AK lesions compared to immunocompetent people.^[35]
• Human papillomavirus (HPV): The role of HPV in the development of AK remains unclear, but evidence suggests that infection with the betapapillomavirus type of HPV may be associated with an increased likelihood of AK.^[36]
• Genodermatoses: Certain genetic disorders interfere with DNA repair after sun exposure, thereby putting these individuals at higher risk for the development of AKs. Examples of such genetic disorders include xeroderma pigmentosum and Bloom syndrome
  .
• Balding: AKs are commonly found on the scalps of balding men. The degree of baldness seems to be a risk factor for lesion development, as men with severe baldness were found to be seven times more likely to have 10 or more AKs when compared to men with minimal or no baldness.[37] This observation can be explained by an absence of hair causing a larger proportion of scalp to be exposed to UV radiation if other sun protection measures are not taken.

Diagnosis

Physicians usually diagnose actinic keratosis by doing a thorough physical examination, through a combination of visual observation and touch. However a

On histologic examination, actinic keratoses usually show a collection of atypical keratinocytes with hyperpigmented or pleomorphic nuclei, extending to the

Specific findings depend on the clinical variant and particular lesion characteristics. The seven major histopathologic variants are all characterized by atypical keratinocytic proliferation beginning in the basal layer and confined to the epidermis; they include:[39]

• Hypertrophic: Notable for marked hyperkeratosis, often with evident parakeratosis.^[39] Keratinocytes in the stratum malphigii may show a loss of polarity, pleomorphism, and anaplasia.^[25] Some irregular downward proliferation into the uppermost dermis may be observed, but does not represent frank invasion.^[25]
• Atrophic: With slight hyperkeratosis and overall atrophic changes to the epidermis; the basal layer shows cells with large, hyperchromatic nuclei in close proximity to each other. These cells have been observed to proliferate into the dermis as buds and duct-like structures.^[25]
• Lichenoid: Demonstrate a band-like lymphocytic infiltrate in the papillary dermis, directly beneath the dermal-epidermal junction.^[39]
• Achantholytic: Intercellular clefts or lacunae in the lowermost epidermal layer that result from anaplastic changes; these produce dyskeratotic cells with disrupted intercellular bridges.
• Bowenoid: This term is controversial and usually refers to full-thickness atypia, microscopically indistinguishable from Bowen's Disease.^[25] However most dermatologists and pathologists will use it in reference to tissue samples that are notable for small foci of atypia that involve the full thickness of the epidermis, in the background of a lesion that is otherwise consistent with an AK.^[39]
• Epidermolytic: With granular degeneration.^[25]
• Pigmented: Show pigmentation in the basal layer of the epidermis, similar to a solar lentigo.^[39]

Dermoscopy

Dermoscopy is a noninvasive technique utilizing a handheld magnifying device coupled with a transilluminating lift. It is often used in the evaluation of cutaneous lesions but lacks the definitive diagnostic ability of biopsy-based tissue diagnosis. Histopathologic exam remains the gold standard.

Polarized contact dermoscopy of AKs occasionally reveals a "rosette sign," described as four white points arranged in a clover pattern, often localized to within a follicular opening.^[41] It is hypothesized that the "rosette sign" corresponds histologically to the changes of orthokeratosis and parakeratosis known as the "flag sign."^[41]

• Non-pigmented AKs: linear or wavy vascular patterning, or a "strawberry pattern," described as unfocused vessels between hair follicles, with white-haloed follicular openings.^[42]
• Pigmented AKs: gray to brown dots or globules surrounding follicular openings, and annular-granular rhomboidal structures; often difficult to differentiate from lentigo maligna.^[43]

Prevention

Ultraviolet radiation is believed to contribute to the development of actinic keratoses by inducing mutations in epidermal keratinocytes, leading to proliferation of atypical cells.^[44] Therefore, preventive measures for AKs are targeted at limiting exposure to solar radiation, including:

• Limiting extent of sun exposure
  • Avoid sun exposure during noontime hours between 10:00 AM and 2:00 PM when UV light is most powerful
  • Minimize all time in the sun, since UV exposure occurs even in the winter and on cloudy days^[45]
• Using sun protection
  • Applying sunscreens with
    UVB light, at least every 2 hours and after swimming or sweating^[45]
  • Applying sunscreen at least 15 minutes before going outside, as this allows time for the sunscreen to be absorbed appropriately by the skin[45]
  • Wearing sun protective clothing such as hats, sunglasses, long-sleeved shirts, long skirts, or trousers. “Consider taking 10 micrograms of vitamin D a day if you always cover up outdoors. This is because you may not get enough vitamin D from sunlight.”^[46]

Recent research implicating human papillomavirus (HPV) in the development of AKs suggests that HPV prevention might in turn help prevent development of AKs, as UV-induced mutations and oncogenic transformation are likely facilitated in cases of active HPV infection.^[29] A key component of HPV prevention includes vaccination, and the CDC currently recommends routine vaccination in all children at age 11 or 12.^[47]

There are some data that in individuals with a history of non-melanoma skin cancer, a low-fat diet can serve as a preventative measure against future actinic keratoses.^[38]

Management

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There are a variety of treatment options for AK depending on the patient and the clinical characteristics of the lesion. AKs show a wide range of features, which guide decision-making in choosing treatment. As there are multiple effective treatments, patient preference and lifestyle are also factors that physicians consider when determining the management plan for actinic keratosis.^[48] Regular follow-up is advisable after any treatment to make sure no new lesions have developed and that old ones are not progressing. Adding topical treatment after a procedure may improve outcomes.^[49]

Medication

Topical medications are often recommended for areas where multiple or ill-defined AKs are present, as the medication can easily be used to treat a relatively large area.^[48]

Fluorouracil cream

Topical

While the clearance rate observed with the Imiquimod 3.75% cream was lower than that observed with the 5% cream (36 and 50 percent, respectively), there are lower reported rates of adverse reactions with the 3.75% cream: 19% of individuals using Imiquimod 3.75% cream reported adverse reactions including local erythema, scabbing, and flaking at the application site, while nearly a third of individuals using the 5% cream reported the same types of reactions with Imiquimod treatment.[58]^[59] However, it is ultimately difficult to compare the efficacy of the different strength creams directly, as current study data varies in methodology (e.g. duration and frequency of treatment, and amount of skin surface area covered).

Ingenol mebutate gel

Ingenol mebutate is a newer treatment for AK used in Europe and the United States. It works in two ways, first by disrupting cell membranes and mitochondria resulting cell death, and then by inducing antibody-dependent cellular cytotoxicity to eliminate remaining tumor cells.^[60] A 3-day treatment course with the 0.015% gel is recommended for the scalp and face, while a 2-day treatment course with the 0.05% gel is recommended for the trunk and extremities.^[61] Treatment with the 0.015% gel was found to completely clear 57% of AK, while the 0.05% gel had a 34% clearance rate.^[62] Advantages of ingenol mebutate treatment include the short duration of therapy and a low recurrence rate.^[63] Local skin reactions including pain, itching and redness can be expected during treatment with ingenol mebutate. This treatment was derived from the petty spurge, Euphorbia peplus which has been used as a traditional remedy for keratosis.

Diclofenac sodium gel

Topical

Topical tretinoin is ineffective as treatment for reducing the number of AKs.^[25] For secondary prevention of AK, systemic, low-dose acitretin was found to be safe, well tolerated and moderately effective in chemoprophylaxis for skin cancers in kidney transplant patients.^[67] Acitretin is a viable treatment option for organ transplant patients according to expert opinion.^[48]

Tirbanibulin

Tirbanibulin (Klisyri) was approved for medical use in the United States in December 2020, for the treatment of actinic keratosis on the face or scalp.^{[68][69][70][71]}

Procedures

Cryotherapy

Liquid nitrogen (−195.8 °C) is the most commonly used destructive therapy for the treatment of AK in the United States.^[72] It is a well-tolerated office procedure that does not require anesthesia.^[73]

Cryotherapy is particularly indicated for cases where there are fewer than 15 thin, well-demarcated lesions.^[72] Caution is encouraged for thicker, more hyperkeratotic lesions, as dysplastic cells may evade treatment.^[57] Treatment with both cryotherapy and field treatment can be considered for these more advanced lesions.^[57] Cryotherapy is generally performed using an open-spray technique, wherein the AK is sprayed for several seconds.^[25]

The process can be repeated multiple times in one office visit, as tolerated. Cure rates from 67 to 99 percent have been reported,^[74][15] depending on freeze time and lesion characteristics. Disadvantages include discomfort during and after the procedure; blistering, scarring and redness; hypo- or hyperpigmentation; and destruction of healthy tissue.^[75]

Photodynamic therapy

AKs are one of the most common dermatologic lesions for which

Multiple treatment regimens using different photosensitizers, incubation times, light sources, and pretreatment regimens have been studied and suggest that longer incubation times lead to higher rates of lesion clearance.[77] Photodynamic therapy is gaining in popularity. It has been found to have a 14% higher likelihood of achieving complete lesion clearance at 3 months compared to cryotherapy,^[78] and seems to result in superior cosmetic outcomes when compared to cryotherapy or 5-FU treatment.^[79] Photodynamic therapy can be particularly effective in treating areas with multiple AK lesions.^[80]

Surgical techniques

• Surgical excision: Excision should be reserved for cases when the AK is a thick, horny papule, or when deeper invasion is suspected and histopathologic diagnosis is necessary.^[25]
  It is a rarely utilized technique for AK treatment.
• Shave excision and curettage (sometimes followed by electrodesiccation when deemed appropriate by the physician^[81][72]): This technique is often used for treatment of AKs, and particularly for lesions appearing more similar to squamous cell carcinoma, or those that are unresponsive to other treatments.^[72] The surface of the lesion can be scraped away using a scalpel, or the base can be removed with a curette. Tissue can be evaluated histopathologically under the microscope, but specimens acquired using this technique are not often adequate to determine whether a lesion is invasive or intraepidermal.
• procedural sedation and anesthetic, necessitating a hospital stay. One-year clearance rates with dermabrasion treatment are as high as 96%, but diminish drastically to 54% at five years.^[82]

Untreated AKs follow one of three paths: they can either persist as AKs, regress, or progress to invasive skin cancer, as AK lesions are considered to be on the same continuum with

• Progression: The overall risk of an AK turning into invasive cancer is low. In average-risk individuals, likelihood of an AK lesion progressing to SCC is less than 1% per year.[88]^[89] Despite this low rate of progression, studies suggest that a full 60% of SCCs arise from pre-existing AKs, reinforcing the idea that these lesions are closely related.^[88][89]
• Regression: Reported regression rates for single AK lesions have ranged between 15 and 63% after one year.^[90]
• Recurrence: Recurrence rates after 1 year for single AK lesions that have regressed range between 15 and 53%.^[90]

Clinical course

Given the aforementioned differering clinical outcomes, it is difficult to predict the clinical course of any given actinic keratosis. AK lesions may also come and go—in a cycle of appearing on the skin, remaining for months, and then disappearing. Often they will reappear in a few weeks or months, particularly after unprotected sun exposure. Left untreated, there is a chance that the lesion will advance to become invasive. Although it is difficult to predict whether an AK will advance to become squamous cell carcinoma, it has been noted that squamous cell carcinomas originate in lesions formerly diagnosed as AKs with frequencies reported between 65 and 97%.^[17]

Epidemiology

Actinic keratosis is very common, with an estimated 14% of dermatology visits related to AKs.^[91] It is seen more often in fair-skinned individuals,^[33] and rates vary with geographical location and age.^[92] Other factors such as exposure to ultraviolet (UV) radiation,^[93] certain phenotypic features, and immunosuppression can also contribute to the development of AKs.

Men are more likely to develop AK than women, and the risk of developing AK lesions increases with age. These findings have been observed in multiple studies, with numbers from one study suggesting that approximately 5% of women ages 20–29 develop AK compared to 68% of women ages 60–69, and 10% of men ages 20–29 develop AK compared to 79% of men ages 60–69.^[94]

Geography seems to play a role in the sense that individuals living in locations where they are exposed to more UV radiation throughout their lifetime have a significantly higher risk of developing AK. Much of the literature on AK comes from Australia, where the prevalence of AK is estimated at 40–50% in adults over 40,^[94] as compared to the United States and Europe, where prevalence is estimated at under 11–38% in adults.^[37][93] One study found that those who immigrated to Australia after age 20 had fewer AKs than native Australians in all age groups.^[95]

Research

Diagnostically, researchers are investigating the role of novel biomarkers to assist in determining which AKs are more likely to develop into cutaneous or metastatic SCC. Upregulation of

In terms of treatment, a number of medications are being studied. Resiquimod is a TLR 7/8 agonist that works similarly to imiquimod, but is 10 to 100 times more potent; when used to treat AK lesions, complete response rates have range from 40 to 74%.[97] Afamelanotide is a drug that induces the production of melanin by melanocytes to act as a protective factor against UVB radiation.^[98] It is being studied to determine its efficacy in preventing AKs in organ transplant patients who are on immunosuppressive therapy. Epidermal growth factor receptor (EGFR) inhibitors such as gefitinib, and anti-EGFR antibodies such as cetuximab are used in the treatment of various types of cancers, and are currently being investigated for potential use in the treatment and prevention of AKs.^[99]

References