Update on diagnosis and treatment of actinic keratosis

Actinic keratosis (AK) is a relatively common skin condition occurring due to chronic sun‐exposure, primarily affecting fair skin. Most dermatologists consider it an incipient malignancy due to its risk of full‐blown malignant transformation to squamous cell carcinoma. However, the exact risk factors remain unknown, and thus its course cannot be predicted. Therefore, all cases of AK need early diagnosis and appropriate treatment to mitigate this risk. Over the years, several noninvasive diagnostic techniques such as dermoscopy, reflectance confocal microscopy, and newer treatment modalities (lesion‐directed and field‐directed) have been introduced with their own set of advantages and disadvantages. Notably, invasive skin biopsy with histopathology remains the gold‐standard for diagnosis. Prevention is of paramount importance, highlighted by adequate sun‐protection measures. This article reviews the diagnostic and treatment modalities of AK, with their latest updates, to optimize patient management.


| MATERIALS AND METHODS
We undertook a comprehensive English literature search across multiple databases including PubMed, SCOPUS, EMBASE, MEDLINE, and Cochrane using keywords (alone and in combination) and MeSH items such as "actinic keratosis," "diagnosis," "treatment," "dermoscopy," "recent updates" to obtain several relevant articles, priority being given to prospective randomized controlled trials. We scanned all the relevant articles in the English literature and summarized them to obtain the latest information about this condition to prepare the current article. We scanned the reference of selected articles for more relevant articles.
Articles in other languages were excluded from our search.

| Diagnosis
The diagnosis of AK is mainly clinical but often there are multiple lesions with variable presentations. Both clinically apparent and subclinical AKs present on an area of chronic actinic damage thus, making clinical diagnosis difficult. Moreover, AKs may often be confused with seborrheic keratoses, Bowen disease, SCC, basal cell carcinoma, and discoid lupus erythematosus. 1 In such cases, several invasive and noninvasive diagnostic modalities may be utilized.

| CLINICAL DIAGNOSIS
AKs clinically present as single or multiple, ill-defined macule/papule/ plaque lesions, pink to red-brown in color with dry, adherent scales.
They are mostly located on the neck, face, ears, bald scalp, extensors of upper limbs, and lower lip. 4 The size of the lesion may vary from a few millimeters to a few centimeters. 4 They are usually asymptomatic but may be associated with itching, burning, bleeding, or tenderness. Larger, symptomatic lesions are at a higher risk of transformation to SCC. 1 For better understanding, a clinical classification is used to grade AK into Grades I-III. 1,4,6 (Table 1).
Despite the above, the clinical diagnosis between Grade III AK and early invasive SCC may not always be possible and is subject to individual clinical interpretation.
Recently, Schmitz and colleagues have highlighted the importance of basal (downward) growth pattern of keratinocytes on histologic examination, as they do not correlate with the classical I-III grading system. They categorized the downward growth pattern under 3 headscrowding (pro I), budding (pro II), and papillary sprouting (pro III), and opined that "downward or basal" proliferation of keratinocytes increases the risk of progression to SCC. 7 Another recent European study has considered basal proliferative AKs, along with atypical keratinocytes restricted to the lower third of epidermis to be more closely associated with invasive SCC, rather than full-thickness epidermal dysplasia. 8 Thus, it is of paramount importance to grade AKs according to the basal proliferation of keratinocytes (pro I, pro II, and pro III) in addition to the classical Grades I-III classification to evaluate their prognosis.
Even though clinical diagnosis has the advantage of being easy, inexpensive, and accessible, it is sometime insufficient alone to make the diagnosis and may often result in over or under diagnosis of AK. 4

| ROLE OF DERMOSCOPY IN DIAGNOSIS
Dermoscopy, a recent introduction to the dermatologists' armamentarium, allows 6-100 fold magnification and visualization of skin structures with polarized light and it has proven to be a boon for dermatologists especially when dealing with potentially malignant lesions like AK. 4 It's a cheap, noninvasive and easily accessible diagnostic modality which may reduce the need for subsequent invasive procedures. The sensitivity and specificity of dermoscopy for nonpigmented AK is 98% and 95%, respectively. 1,4,9 The clinical grading (Grades I-III) of AK correspond to different dermoscopy patters 9 (Table 1).
Facial AKs are a diagnostic dilemma and are dermoscopically characterized by four patterns, as follows 9 : • Erythema and pink-to-red "pseudo-network" surrounding the hair follicles, • Surface scale white-to-yellow, • Fine, linear-wavy blood vessels surrounding the hair follicles, and • Yellowish keratotic plugs in the follicular openings with or without a whitish halo.
T A B L E 1 Correlation of clinical grading of actinic keratosis, dermoscopy patterns, and reflectance confocal microscopy findings 1,4,7 Grade Clinically Dermoscopy pattern Reflectance confocal microscopy These features combined often produce a "strawberry appearance." 4,9 Less frequently, AKs may be pigmented and dermoscopically Dermoscopy may also help to predict the progression of AK to SCC when initial dotted or glomerular vessels become hairpin and linear vessels, indicating progression toward a more invasive growth. 9 Nonpolarized dermoscopy with fluid immersion is useful in such cases as it renders the keratin largely invisible, providing more information about vascular structures. Moreover, a central mass of keratin, ulceration, and red starburst pattern gives a clue toward a more aggressive lesion. 4

| FLUORESCENT TECHNIQUES
The topical application of aminolevulinic acid (ALA) and the methyl ester of ALA (MAL) associated with photodynamic therapy does not only serve as a therapeutic modality but also helps in diagnosis.   Broadly, the treatment for AK can be divided into general measures and specific measures. The latter can be categorized under 2 heads-lesion-directed and field-directed therapies 1,16-22 (Table 2).
Lesion-directed treatments involve ablative procedures that remove atypical keratinocytes from the lesions, whereas, Field-directed treatment involves use of medications that target clinically visible as well as subclinical lesions within a field of chronic sun-damaged skin, that is, "field cancerization." 1

| GENERAL MEASURES
As chronic sun-exposure (ultraviolet rays) form the backbone of AK pathogenesis, strict sun-protection measures from an early age are of paramount importance to prevent the occurrence of this disorder and its malignant transformation. Commonly employed sun-protection measures include regular use of sunscreens (at least SPF 30), umbrellas, full-sleeved clothing, sunglasses, and shade-seeking behavior.
Another critical measure is providing adequate information about this disease and its consequences, along with its preventive strategies to the common public in simple language, using mass media such as television, radio, and educational programs. Liquid nitrogen is the preferred agent. It can be applied with a cotton tip applicator or a spray involving 1 mm area of the surrounding normal skin using a single freeze-thaw cycle between 5 and 40 s. 16 The response to cryosurgery depends on the duration of freezing and it is approximately 98%. 1 Pretreatment of the area with 5-FU or 3% diclofenac gel can increase the efficacy of cryotherapy. 1,16 Also, post cryotherapy application of 5% imiquimod helps in better removal and destruction of clinical/subclinical and total AKs. 17 Cryotherapy has the advantage of being a rapid technique with good efficacy, not requiring anesthesia, or hospital admission. Minor adverse effects like erythema, pain, blistering, and hypochromia may be seen.

| LASER THERAPY
Laser therapy is one of the most effective treatment modalities available as it physically removes the lesion of AK. Additionally, there is resurfacing of skin, thus serving as a prophylaxis against future AK lesions. Commonly used lasers are ablative lasers like CO2 and erbium yttrium aluminum garnet that ablate the epidermis and superficial dermis, or non-ablative fractional lasers like erbium glass systems that create a controlled coagulation of tiny columns of skin, leaving the surrounding skin undamaged. 16,17 The response rate to laser treatment is 90% in case of AKs with a recurrence rate of 10%-15% at 6 months. 1 Lasers can be combined with other topical treatments to improve the efficacy. The response rate of lasers and cryotherapy is almost similar (71.6% for cryotherapy vs. 65.3% for laser ablation) but the stability of patients at 1 year is more for cryotherapy as compared to lasers (66.8% for cryotherapy vs. 37% for laser ablation). 17,23 Laser has the advantage of being a rapid and effective modality of treatment but restricted availability, high cost, and a steep learning curve serve as disadvantages. 18

| CURETTAGE
Curettage is used for hyperkeratotic AK or lesions that are refractory to other treatments. 16 Post-curretage electrodessication may help with hemostasis and for defining the lesion margins.
It allows collection of sample for histopathological examination (HPE) but has the drawback of requiring anesthesia and risk of scarring. [17][18][19]23   with a keratolytic like 10% salicylic acid can be used topically once daily for 12 weeks. 21,22 It is an easy, inexpensive treatment but may be associated with side effects like erythema, burning, inflammation, pruritus, and erosions. 20 Systemic toxicity like headache, insomnia, irritability, thrombocytopenia, leucocytosis, neurotoxicity is seen in patients with dihydropyrimidine dehydrogenase deficiency. Not recommended in pregnant females as it may lead to birth defects and miscarriage.

| TOPICAL DICLOFENAC
Diclofenac is a nonsteroidal anti-inflammatory drug, that inhibits the activity of cyclooxygenase (COX), UV-induced pro-inflammatory cytokines, inhibits tumor cell proliferation and angiogenesis and induces metalloproteinases. 19 Recurrence rate at 12 months of follow-up was 20% with ALA-PDT and 34% with MAL-PDT be applied topically twice daily for 2-3 months and has a clearance rate of 58% after 1 month. 1,21 It is a cheap, easy, and well-tolerated treatment modality. It should be avoided in aspirin-sensitive patients, long duration of treatment and side effects like erythema, pruritus, dryness are some of the drawbacks.

| IMIQUIMOD
Imiquimod is a synthetic immunomodulatory drug and is a toll-likereceptor-7 (TLR-7) agonist. It stimulates the release of tumor necrosis factor-alfa (TNF-a), interferon alpha and gamma (IFN-a and IFN-c), and interleukin-12 (IL12) thus, regulating the activation of macrophages, natural killer cells, dendritic cells, and cytotoxic T-cells. 1,20 It also plays a role in gene modulation and has antiviral and antitumoral potency.
Imiquimod is available as 2.5%, 3.75%, and 5% cream. 21  Imiquimod is easy and accessible treatment option for AK but long-term therapy may be associated with side effects like erythema, weeping, erosions, pruritus, upper respiratory tract infections and influenza-like symptoms. 22 This modality provides the most cosmetically acceptable results.

| INGENOL MEBUTATE
Ingenolmebutate is a novel topical drug obtained from the latex sap of plant Euphorbia peplus. On topical application it uses P-glycoprotein drug transport to go through the stratum corneum and exerts action on the dermis and hypodermis. It acts via three different mechanisms 19 : • Tumor ablation (rapid disruption of plasma membrane and mitochondrial swelling, leading to cell death due to primary necrosis)by release of inflammatory cytokines.
• Neutrophil infiltration leading to acute inflammation.
• Last, tumor-reactive antibodies are induced and antibodydependent neutrophil cytotoxicity eliminates residual cancer cells thus, preventing relapses.
Ingenolmebutate is a protein kinase C pathway activator and targets the sub-epidermal tumor vasculature. It slows cell proliferation, enhances differentiation of undifferentiated cells, induces cell cycle arrest, promotes apoptosis of caspases, phosphorylation of signaling molecules and increases stability of p53. 19,21,22 Ingenolmebutate was approved by the US. FDA for treatment of non-hypertrophic/non-hyperkeratotic AK in 2012. It is available in a gel formulation of 0.015% for face and 0.05% for body. It has to be applied once daily for 2 consecutive days for body lesions and 3 consecutive days for lesions on the face. It has a very rapid action and requires only 2-3 days of treatment. 21 Common side effects are application-site reactions like pain, pruritus, inflammation, infection, and systemic effects like periorbital edema, nasopharyngitis, and headache. Dryness, scabbing, and erythema resolve on its own in a month. Treatment of periocular area should be avoided due to risk of mild epithelial keratoconjunctivitis to severe. 21 Safety in pregnant females and children less than 18 years of age has not been established.
Notably, Ingenol Mebutate has been withdrawn from the market and its use has been suspended by the European Medicines Agency (EMA) over concerns of increased risk for skin malignancy, which outweighed its possible benefits, as on April 2020. 24

| TIRBANIBULIN
Tirbanibulin is the newest topical treatment that has completed its The effectiveness of chemical peels in AK is 75%, with 25%-35% relapse rate within 1 year. 19,21 Combination treatment like 5FU with 70% glycolic acid or Jessner's peel has better efficacy than chemical peels alone. 1 Chemical peels offer an easy, inexpensive, easily accessible treatment modality with minor drawbacks like erythema, inflammation, pigmentation, and scarring.

| TOPICAL AND ORAL RETINOIDS
Retinoids act in AK through their mechanism of action on pathway of oxidative stress and cell differentiation. 2

| PHOTODYNAMIC THERAPY (PDT)
PDT is a local field-directed treatment of AK based on the principle of photosensitization, photochemical reactions and generation of reactive oxygen species leading to cell death.
The mechanism of action of PDT is as follows 1,21,22 : • Application of topical photosensitizer compounds like 5aminolevulinic acid (ALA) or methyl aminolevulinate (MAL) for 3 h.
These compounds are captures by premalignant lesions.
• Irradiation by wavelength of specific absorption spectrum leads to activation of photochemical mechanisms

| PIROXICAM
Piroxicam is a nonselective nonsteroidal anti-inflammatory agent that blocks the activity of COX-1 and COX-2. 1% piroxicam gel was topically applied twice daily on AKs for 12 weeks. Changes were evaluated using AKESA (erythema, scale, and atrophy on a target lesion) scoring system. 29 There was regression of 48% lesions at the end of 12 weeks. 29 Minor side effects like pruritus, erythema, and xerosis were seen during the course of treatment. Hypertensive patients on thiazide diuretics are at higher risk of SCC and AK due to the photosensitizing property of thiazides. 0.8% topical piroxicam and sunscreen 50+ has been used as a combination therapy for AKs. 30 There was significant reduction in lesion count with the improvement of field cancerization. 30

| CONCLUSION
AK is a relatively common pre-malignant skin lesion, which can progress to squamous cell carcinoma, although the risk cannot be predicted beforehand. Thus, early diagnosis and appropriate treatment should be our primary aim for all patients with AK.
Besides, cosmetic disfigurement is also present, which seem to be the main reason for dermatologic consultation. Over the years several noninvasive diagnostic modalities have become popular ranging from dermoscopy to confocal microscopy. Dermoscopy is not as effective for AK compared to melanoma or basal cell carcinoma, while confocal microscopy is limited by its shallow pe-

DISCLAIMER
We confirm that the manuscript has been read and approved by all the authors, that the requirements for authorship as stated earlier in this document have been met and that each author believes that the manuscript represents honest work.