CUSTOM DERMATOLOGY SEARCH:
Current Management of Actinic Keratoses
I. Shoimer, BSc; N. Rosen, MD; C. Muhn, MD
Actinic keratoses (AKs), or solar keratoses, are pre-malignant cutaneous lesions that predominantly manifest in sun-exposed areas. They are one of the most common pathologies seen by dermatologists, preceded only by acne vulgaris and dermatitis as more frequent complaints.1 AKs are clinically relevant lesions due to their potential to progress into a squamous cell carcinoma (SCC).2 Additionally, they are considered a risk factor for the subsequent development of melanoma and non-melanoma skin cancer (NMSC).
Grossman and Leffell2 explain that UV radiation is involved in the pathogenesis of AKs through inducing cellular DNA mutations in the skin, which may affect cell proliferation genes, such as p53 and ras, or prompt evasion of apoptosis. Disruption of one of these genes may lead to the formation of atypical keratinocytes in the basal layer and development of an AK; all of these histopathologic changes are limited to the epidermis. The absence of further UV light exposure may result in resolution through repair mechanisms. However, additional UV light exposure may induce further DNA mutations, resulting in the development of an invasive SCC.
The most common therapies for individual AKs work destructively by physically removing the lesion. These should always be considered for isolated lesions or early presentations of AKs. Destructive therapies include liquid nitrogen cryotherapy, curettage with or without electrodessication, and shave excision. The main advantages of these procedures are that they are quick, procedurally simple, and provide adequate clearance of abnormal tissue. A major limitation of such targeted approaches is that they fail to address field cancerization.
Cryotherapy is the most commonly utilized technique, with liquid nitrogen being the most frequently selected cryogen. Applying cryotherapy to the affected area lowers the skin to temperatures that destroy atypical AK cells.7 This technique is ideal if lesions are scattered or limited in number, or for patients who are non-compliant with topical regimes.7 Reported cure rates range from 39-83%.8 Cryotherapy is advantageous in that it is generally well-tolerated and does not require local anesthetic, but downsides include pain during the procedure and frequent permanent hypopigmentation. Potential side-effects include blisters, scarring, textural skin changes, infection, and hyperpigmentation.
Curettage and Shave Excision
Curettage consists of using a curette to mechanically remove atypical cells. A shave excision using a surgical blade is another technique. These may be followed by electrocautery, which will destroy additional atypical cell layers as well as provide hemostasis. There are no studies documenting cure rates with these treatment modalities. These techniques are most appropriate for treating individual AKs, cases where a biopsy is required to rule out frank carcinoma, or for hypertrophic AKs that are refractory to other treatments. Potential side-effects include infection, scarring, anesthetic related side-effects, and dyspigmentation.
Topical Field Therapy
Commonly, physicians are faced with patients who are covered in actinic damage, a clinical scenario now described as field cancerization. This describes both clinical and subclinical lesions within a given anatomical region.9 For these patients, a different therapeutic approach, known as field therapy, is needed. The goal of field therapy is the eradication of both the clinically visible and subclinical AKs within the treatment area.
The antimetabolite 5-fluorouracil (5-FU) was the first approved topical field therapy. Discovered serendipitously when AKs were noted to become inflamed and subsequently resolved in patients receiving systemic 5-FU as a chemotherapeutic agent, it was eventually designed into an effective topical formulation. It acts as a thymidylate synthase inhibitor by blocking a methylation reaction; this in turn disrupts DNA and RNA synthesis and effectively stops the growth of the rapidly proliferating or cancerous cells.10 As such, 5-FU preferentially targets the atypical cells over normal cutaneous tissue. The average cure rate is 62.5%,11 but for optimal results full patient adherence is necessary. Interestingly, there is evidence showing concurrent treatment with topical tretinoin enhances the effectiveness of 5-FU.12 All patients undergoing successful treatment should experience erythema, inflammation, and erosions. Commonly experienced side-effects include pain, pruritus, photosensitivity, and burning at the site of application. Additionally, topical 5-FU can exacerbate other pre-existing cutaneous conditions, such as melasma or acne rosacea; therefore, use should be avoided in these cases.7
Diclofenac 3% gel is a nonsteroidal anti-inflammatory drug that is believed to exert its effects through the inhibition of cyclooxygenase (COX), especially COX-2. The production of prostaglandins is thought to suppress the immune system, thereby allowing tumors to form.13 Without COX, prostaglandin production is reduced and the cascade is disrupted.13 Despite the more rigorous treatment regimen (twice-daily for 90 days), only mild to moderate local skin reactions are noted. Though rare, drug-induced hepatotoxicity reports have surfaced, consequently transaminases should be measured periodically in patients receiving long-term therapy.14
Topical 5% imiquimod cream (Aldara®) was originally indicated as a treatment for genital and perianal warts; additional approved indications for treating AKs and superficial basal cell carcinomas followed. It is also used off label for treating Bowen’s disease, invasive SCC, lentigo maligna, molluscum contagiosum, keloid scars, and others.15 Imiquimod acts as a toll-like receptor-7 agonist, which results in modification of the immune response and stimulation of apoptosis, thereby disrupting tumor proliferation.16 Stockfleth et al.17 demonstrated that 84% of treated AKs showed clinical clearance with one 12-week cycle of 5% imiquimod therapy. As with 5-FU, local irritant reactions are common. Coupled with its long duration of application (twice-weekly for 16 weeks), treatment adherence may be challenging with this agent. Administration to both the lesion and surrounding tissue targets both visible and subclinical AKs. Systemic effects, such as fatigue, flu-like symptoms, headaches, myalgias, and angioedema are rare.
Procedural Field Therapy
Procedural field therapies may be an appropriate option for patients who require minimal down time, are unlikely to adhere to a topical approach, have AKs resistant to topical therapy, or favor an optimal cosmetic result. Treatment options for procedural field therapy include photodynamic therapy, manual dermabrasion, laser resurfacing, cryopeeling, and chemical peels. Each of these techniques treats AKs by destroying the superficial layers of the skin through physical or chemical means.
Photodynamic therapy (PDT) is a procedural field therapy that utilizes topical 5-aminolevulinic acid (ALA) or methyl aminolevulinate (Metvix®/Metvixia®) to target AKs. These molecules preferentially find their way into the hyperproliferating cells, which lack normal cell to cell adhesion junctions, and are converted intracellularly to protoporphyrin IX (PpIX).20 This photosensitizer is then exposed to blue or red light, which corresponds to the peaks in the absorption spectrum of PpIX, resulting in a phototoxic reaction that destroys the abnormal cell.20 PDT is effective for the treatment of multiple and diffuse AKs, and the cosmetic results are generally excellent. However, it is not ideal for treating thicker or deeper AKs20 and is generally reserved for patients who exhibit an inadequate response to topical field therapy or cryosurgery. Patients may experience erythema, edema, and a burning sensation during the light therapy.
There is no widely accepted algorithm for the treatment of AKs. Often several different treatment regiments must be employed to manage AKs, especially with widespread or resistant cases. As always, the best way to manage AKs is prevention by avoiding exposure to significant or unnecessary UV radiation. Encouraging patients to wear broad-based sunscreens, wide-brimmed hat, sunglasses, and avoiding the sun during peak hours may prevent recurrence or limit the progression of AKs.
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Last modified: Tuesday, 15-Dec-2015 15:40:11 MST