Actinic keratosis

Actinic keratoses (AKs) most commonly present as a white, scaly plaque of variable thickness with surrounding redness; they have a sandpaper-like texture when felt with a gloved hand. Skin nearby the lesion often shows evidence of solar damage characterized by pigmentary alterations, being yellow or pale in color with areas of hyperpigmentation; deep wrinkles, coarse texture, purpura and ecchymoses, dry skin, and scattered telangiectasias are also characteristic. Photoaging leads to an accumulation of oncogenic changes, resulting in a proliferation of mutated keratinocytes that can manifest as actinic keratoses or other neoplastic growths. The lesions are usually asymptomatic, but can be tender, itch, bleed, or produce a stinging or burning sensation. Actinic keratoses 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). Variants Actinic keratoses can have various clinical presentations, often characterized as follows: • Classic (or common): Classic actinic keratoses present as white, scaly macules, 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. • Pigmented actinic keratosis: Pigmented actinic keratoses 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. • Actinic cheilitis: When an actinic keratosis 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 actinic keratosis: Usually presents as a solitary, erythematous, scaly patch or plaque with well-defined borders. Bowenoid actinic keratoses are differentiated from Bowen's disease by degree of epithelial involvement as seen on histology. The presence of ulceration, nodularity, or bleeding should raise concern for malignancy. Specifically, clinical findings suggesting an increased risk of progression to squamous cell carcinoma can be recognized as "IDRBEU": I (induration/inflammation), D (diameter > 1 cm), R (rapid enlargement), B (bleeding), E (erythema), and U (ulceration). Actinic keratoses are usually diagnosed clinically, but because they are difficult to clinically differentiate from squamous cell carcinoma, any concerning features warrant biopsy for diagnostic confirmation. == Causes ==

The most important cause of actinic keratosis formation is solar radiation, through a variety of mechanisms. Mutation of the p53 tumor suppressor gene, induced by UV radiation, has been identified as a crucial step in actinic keratosis formation. This tumor suppressor gene, located on chromosome 17p132, allows for cell cycle arrest when DNA or RNA is damaged. Dysregulation of the p53 pathway can thus result in unchecked replication of dysplastic keratinocytes, thereby serving as a source of neoplastic growth and the development of actinic keratosis, as well as possible progression from actinic keratosis to skin cancer. Other molecular markers that have been associated with the development of actinic keratosis include the expression of p16ink4, p14, the CD95 ligand, TNF-related apoptosis-inducing ligand (TRAIL) and TRAIL receptors, and loss of heterozygosity. Similar to UV radiation, higher levels of HPV found in actinic keratoses reflect enhanced viral DNA replication. This is suspected to be related to the abnormal keratinocyte proliferation and differentiation in actinic keratoses, which facilitate an environment for HPV replication. This in turn may further stimulate the abnormal proliferation that contributes to the development of actinic keratoses and carcinogenesis. Ultraviolet radiation It is thought that ultraviolet (UV) radiation induces mutations in the keratinocytes of the epidermis, promoting the survival and proliferation of these atypical cells. Both UV-A and UV-B radiation have been implicated as causes of actinic keratoses. UV-A radiation (wavelength 320–400 nm) reaches more deeply into the skin and can lead to the generation of reactive oxygen species, which in turn can damage cell membranes, signaling proteins, and nucleic acids. UV-B radiation (wavelength 290–320 nm) causes thymidine dimer formation in DNA and RNA, leading to significant cellular mutations. In particular, mutations in the p53 tumor suppressor gene have been found in 30–50% of actinic keratosis lesion skin samples. Furthermore, the use of sunscreen (SPF 17 or higher) has been found to significantly reduce the development of actinic keratosis lesions, and also promotes the regression of existing lesions. • History of sunburn: Studies show that even a single episode of painful sunburn as a child can increase an individual's risk of developing actinic keratosis as an adult. Six or more painful sunburns over the course of a lifetime was found to be significantly associated with the likelihood of developing actinic keratosis. They may develop actinic keratosis at an earlier age or have an increased number of actinic keratosis lesions compared to immunocompetent people. • Genodermatoses: Certain genetic disorders interfere with DNA repair after sun exposure, thereby putting these individuals at higher risk for the development of actinic keratoses. Examples of such genetic disorders include xeroderma pigmentosum and Bloom syndrome. • Balding: actinic keratoses 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 actinic keratoses when compared to men with minimal or no baldness. 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 biopsy may be necessary when the keratosis is large in diameter, thick, or bleeding, in order to make sure that the lesion is not a skin cancer. Actinic keratosis may progress to invasive squamous cell carcinoma (SCC) but both diseases can present similarly upon physical exam and can be difficult to distinguish clinically. Histological examination of the lesion from a biopsy or excision may be necessary to definitively distinguish actinic keratosis from in situ or invasive SCC. The normal ordered maturation of the keratinocytes is disordered to varying degrees: there may be widening of the intracellular spaces, cytologic atypia such as abnormally large nuclei, and a mild chronic inflammatory infiltrate. It is hypothesized that the "rosette sign" corresponds histologically to the changes of orthokeratosis and parakeratosis known as the "flag sign." • Pigmented actinic keratoses: gray to brown dots or globules surrounding follicular openings, and annular-granular rhomboidal structures; often difficult to differentiate from lentigo maligna. == 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. Therefore, preventive measures for actinic keratoses 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 • Using sun protection • Applying sunscreens with SPF ratings 30 or greater that also block both UVA and UVB light, at least every 2 hours and after swimming or sweating == Management ==

There are a variety of treatment options for actinic keratosis depending on the patient and the clinical characteristics of the lesion. Actinic keratoses 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. Medication Topical medications are often recommended for areas where multiple or ill-defined actinic keratoses are present, as the medication can easily be used to treat a relatively large area. This in turn prevents the proliferation of dysplastic cells in AK. Topical 5-FU is the most utilized treatment for AK, and often results in effective removal of the lesion. Overall, there is a 50% efficacy rate resulting in 100% clearance of actinic keratoses treated with topical 5-FU. 5-FU may be up to 90% effective in treating non-hyperkeratotic lesions. While topical 5-FU is a widely used and cost-effective treatment for actinic keratoses and is generally well tolerated, its potential side-effects can include: pain, crusting, redness, and local swelling. These adverse effects can be mitigated or minimized by reducing the frequency of application or taking breaks between uses. Imiquimod cream Imiquimod is a topical immune-enhancing agent licensed for the treatment of genital warts. The Imiquimod 3.75% cream has been validated in a treatment regimen consisting of daily application to entire face and scalp for two 2-week treatment cycles, with a complete clearance rate of 36%. 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. Treatment with the 0.015% gel was found to completely clear 57% of AK, while the 0.05% gel had a 34% clearance rate. Advantages of ingenol mebutate treatment include the short duration of therapy and a low recurrence rate. Ingenol mebutate has been withdrawn from the market worldwide since 2020 following safety concerns regarding an increased risk of skin cancer (squamous cell carcinoma) compared to other treatment options. Diclofenac sodium gel Topical diclofenac sodium gel is a nonsteroidal anti-inflammatory drug that is thought to work in the treatment of actinic keratosis through its inhibition of the arachidonic acid pathway, thereby limiting the production of prostaglandins which are thought to be involved in the development of UVB-induced skin cancers. Common side effects include dryness, itching, redness, and rash at the site of application. Treatment with adapalene gel daily for 4 weeks, and then twice daily thereafter for a total of nine months led to a significant but modest reduction in the number of actinic keratoses compared to placebo; it demonstrated the additional advantage of improving the appearance of photodamaged skin. Topical tretinoin is ineffective as treatment for reducing the number of actinic keratoses. Acitretin is a viable treatment option for organ transplant patients according to expert opinion. 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. Procedures Cryotherapy Liquid nitrogen (−195.8 °C) is the most commonly used destructive therapy for the treatment of actinic keratosis in the United States. It is a well-tolerated office procedure that does not require anesthesia. Cryotherapy is particularly indicated for cases where there are fewer than 15 thin, well-demarcated lesions. Treatment with both cryotherapy and field treatment can be considered for these more advanced lesions. Photodynamic therapy one week after exposure. Patient has light skin, blue eyes. Actinic keratoses are one of the most common dermatologic lesions for which photodynamic therapy, including topical methyl aminolevulinate (MAL) or 5-aminolevulinic acid (5-ALA), is indicated. Treatment begins with preparation of the lesion, which includes scraping away scales and crusts using a dermal curette. A thick layer of topical MAL or 5-ALA cream is applied to the lesion and a small area surrounding the lesion, which is then covered with an occlusive dressing and left for a period of time. During this time the photosensitizer accumulates in the target cells within the actinic keratosis lesion. The dressings are then removed and the lesion is treated with light at a specified wavelength. 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. 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, and seems to result in superior cosmetic outcomes when compared to cryotherapy or 5-FU treatment. Photodynamic therapy can be particularly effective in treating areas with multiple actinic keratosis lesions. Surgical techniques • Surgical excision is a rarely utilized technique for actinic keratosis treatment. • Shave excision and curettage (sometimes followed by electrodesiccation when deemed appropriate by the physician Laser therapy Laser therapy using carbon dioxide () or erbium:yttrium aluminum garnet (Er:YAG) lasers is a treatment approach being utilized with increased frequency, and sometimes in conjunction with computer scanning technology. Laser therapy has not been extensively studied, but evidence suggests it may be effective in cases involving multiple actinic keratoses refractive to medical therapy, or actinic keratoses located in cosmetically sensitive locations such as the face. The laser has been recommended for extensive actinic cheilitis that has not responded to 5-FU. It can be achieved with 35% to 50% trichloroacetic acid (TCA) alone or at 35% in combination with Jessner's solution in a once-daily application for a minimum of 3 weeks; 70% glycolic acid (α-hydroxy acid); or solid . When compared to treatment with 5-FU, chemical peels have demonstrated similar efficacy and increased ease of use with similar morbidity. Chemical peels must be performed in a controlled clinic environment and are recommended only for individuals who are able to comply with follow-up precautions, including avoidance of sun exposure. Furthermore, they should be avoided in individuals with a history of HSV infection or keloids, and in those who are immunosuppressed or who are taking photosensitizing medications. == Prognosis ==

Untreated actinic keratoses follow one of three paths: they can either persist as actinic keratoses, regress, or progress to invasive skin cancer, as actinic keratosis lesions are considered to be on the same continuum with squamous cell carcinoma (SCC). Despite this low rate of progression, studies suggest that a full 60% of SCCs arise from pre-existing actinic keratoses, reinforcing the idea that these lesions are closely related. Clinical course Given the aforementioned differering clinical outcomes, it is difficult to predict the clinical course of any given actinic keratosis. Actinic keratosis 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 actinic keratosis will advance to become squamous cell carcinoma, it has been noted that squamous cell carcinomas originate in lesions formerly diagnosed as actinic keratoses with frequencies reported between 65 and 97%. == Epidemiology ==

Actinic keratosis is very common, with an estimated 14% of dermatology visits related to actinic keratoses. It is seen more often in fair-skinned individuals, Other factors such as exposure to ultraviolet (UV) radiation, certain phenotypic features, and immunosuppression can also contribute to the development of actinic keratoses. Men are more likely to develop actinic keratosis than women, and the risk of developing actinic keratosis 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 actinic keratosis compared to 68% of women ages 60–69, and 10% of men ages 20–29 develop actinic keratosis compared to 79% of men ages 60–69. 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 actinic keratosis. Much of the literature on actinic keratosis comes from Australia, where the prevalence of actinic keratosis is estimated at 40–50% in adults over 40, == Research ==

Research implicating human papillomavirus (HPV) in the development of actinic keratoses suggests that HPV prevention might in turn help prevent development of actinic keratoses, as UV-induced mutations and oncogenic transformation are likely facilitated in cases of active HPV infection. 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. Diagnostically, researchers are investigating the role of novel biomarkers to assist in determining which actinic keratoses are more likely to develop into cutaneous or metastatic SCC. Upregulation of matrix metalloproteinases (MMP) is seen in many different types of cancers, and the expression and production of MMP-7 in particular has been found to be elevated in SCC specifically. The role of serin peptidase inhibitors (Serpins) is also being investigated. SerpinA1 was found to be elevated in the keratinocytes of SCC cell lines, and SerpinA1 upregulation was correlated with SCC tumor progression in vivo. Afamelanotide is a drug that induces the production of melanin by melanocytes to act as a protective factor against UVB radiation. It is being studied to determine its efficacy in preventing actinic keratoses 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 being investigated for potential use in the treatment and prevention of actinic keratoses. == References ==