I. Shoimer, BSc; N. Rosen, MD; C. Muhn, MD
Division of Dermatology, Department of Medicine, McMaster University, Hamilton, ON, Canada
An actinic keratosis (AK) is a pre-malignant cutaneous lesion that frequently manifests in sun-exposed areas of the skin as a small, rough, scaly erythematous papule. They are one of the most common presenting complaints for dermatologists. AKs should be treated due to their potential to progress into a squamous cell carcinoma (SCC). There are numerous treatments available for managing AKs including those broadly categorized as destructive, topical field, and procedural field therapies. The topical field therapies include 5-fluorouracil, imiquimod, and diclofenac gel. Recently, imiquimod 3.75% (Zyclara™) has been approved for the treatment of AKs on the face and scalp. It is a reasonable alternative to imiquimod 5%, as the approved indication includes a larger surface area for treatment, shorter duration course, and the potential for less severe local skin reactions. There is no widely accepted algorithm for the treatment of AKs, as comparative data is unavailable between all approaches. Therapy choices are guided by efficacy, adverse effects, cosmetic results, and patient compliance.
actinic keratosis, imiquimod, squamous cell carcinoma, skin cancer, Zyclara™
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).
In the northern hemisphere, 11-25% of adults are believed to have at least one AK.3 These lesions are most commonly seen in the older fair-skinned population (Fitzpatrick skin phototypes I-III). Cumulative ultraviolet (UV) radiation exposure and older age are the most important risk factors for this condition. Individuals who are immunocompromised or have certain genetic syndromes, such as xeroderma pigmentosum and albinism, are at greater risk.
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.
AKs typically manifest as small (1-3mm) erythematous scaly papules with a hyperkeratotic texture. As such, they are best identified with touch rather than visual inspection alone. AKs are characteristically distributed in sun-exposed areas, including the face, bald scalp, ears, neck, anterior chest, dorsal forearms, and dorsal hands. Surrounding areas may show evidence of solar elastosis, such as telangiectasia, blotchy hyperpigmentation, and yellow discoloration of the skin.4 The clinical variants of actinic keratosis include the cutaneous horn, lichen planus-like keratosis, pigmented actinic keratosis, and actinic cheilitis.4,5 Over several years, these lesions can progress, becoming thicker and developing into a hypertrophic AK, Bowen’s disease (SCC in situ), or an invasive SCC. Unfortunately, the stages of this biologic continuum are clinically indistinguishable and a biopsy should be performed if a SCC is suspected. However, a presentation that includes pain, pruritus, induration, larger size, rapid growth, ulceration, bleeding, or resistance to treatment may point towards a more sinister pathology
The natural history of AKs is variable and unpredictable. The lesion can follow one of three paths: it can persist, regress, or transform into an invasive SCC. It is impossible to predict which path any given AK may take. The risk of a single lesion progressing from an AK to a SCC ranges from 0.025-16% per year.6 Nonetheless, it is recommended that all AKs be treated as there are no reliable clinical predictors to discern an AK from a SCC. If a SCC is missed, it may become locally invasive and destructive; these lesions are capable of metastases resulting in death.
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.
Recently, regulatory approval was granted by Health Canada in December 2009 and by the US FDA in March 2010 to imiquimod 3.75% (Zyclara™) for the treatment of AKs on the face or balding scalp. Two identical placebo-controlled trials have evaluated the safety and efficacy of imiquimod 3.75%.18,19 In the trial by Swanson et al.,18 creams were applied daily to the entire face or balding scalp for two 2-week treatment cycles, separated by a 2-week interval without treatment. Patients applying imiquimod 3.75% achieved a median lesion reduction of 82%, while just over one-third demonstrated complete clearance. These efficacy data rival those achieved using imiquimod 5% twice-weekly for 16 weeks, with the advantage of significantly improved patient tolerance exhibited by the lower dosage. The therapy was found to be safe and did not result in any serious adverse events. Erythema was observed in most patients, with about 25% developing severe erythema. However, no patients withdrew from the study as a result of this; compliance rates were noted to be greater than 90%.18,19 Overall, the newly approved imiquimod 3.75% is a reasonable alternative to imiquimod 5%, as it demonstrates comparable efficacy, allows for a much simplified, shorter dosing regimen, and seemingly yields less severe adverse effects. Additionally, imiquimod 3.75% is approved for the treatment of a larger surface area of up to 200cm2, compared with 25cm2 for the 5% formulation, and thus, is able to target more AKs.
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.
- Salasche SJ. Epidemiology of actinic keratoses and squamous cell carcinoma. J Am Acad Dermatol 42(1 Pt 2):S4-7 (2000 Jan).
- Grossman D, Leffell DJ. The molecular basis of nonmelanoma skin cancer. Arch Dermatol 133(10):1263-70 (1997 Oct).
- Gupta AK, Cooper EA, Feldman SR, et al. A survey of office visits for actinic keratosis as reported by NAMCS, 1990–1999. National Ambulatory Medical Care Survey. Cutis 70(2 Suppl):S8-13 (2002 Aug).
- Moy RL. Clinical presentation of actinic keratoses and squamous cell carcinoma. J Am Acad Dermatol 42(1 Pt 2):S8-10 (2000 Jan).
- Duncan Karynne O, Geisse John K, Leffell David J. Chapter 113. Epithelial precancerous lesions. In: Wolff K, Goldsmith LA, Katz SI, et al. (eds). Fitzpatrick’s dermatology in general medicine: 7th ed. New York: McGraw-Hill Companies, p1007-25 (2008).
- Glogau RG. The risk of progression to invasive disease. J Am Acad Dermatol 42(1 Pt 2):S23-4 (2000 Jan).
- Dinehart SM. The treatment of actinic keratoses. J Am Acad Dermatol 42 (1 Pt 2):S25-8 (2000 Jan).
- Thai KE, Fergin P, Freeman M, et al. A prospective study of the use of cryosurgery for the treatment of actinic keratoses. Int J Dermatol 43(9):687-92 (2004 Sep).
- Braakhuis BJ, Tabor MP, Kummer JA, et al. A genetic explanation of Slaughter’s concept of field cancerization: evidence and clinical implications. Cancer Res 63(8):1727-30 (2003 Apr 15).
- Eaglstein WH,Weinstein GD, Frost P. Fluorouracil: mechanism of action in human skin and actinic keratoses, I: effect on DNA synthesis in vivo. Arch Dermatol 101(2):132-9 (1970 Feb).
- Gupta AK. The management of actinic keratoses in the United States with topical fluorouracil: a pharmacoeconomic evaluation. Cutis 70(2 Suppl):30-6 (2002 Aug).
- Bercovitch L. Topical chemotherapy of actinic keratoses of the upper extremity with tretinoin and 5-fluorouracil: a double-blind controlled study. Br J Dermatol 116(4):549-52 (1987 Apr).
- Stockfleth E, Kerl H; Guideline Subcommittee of the European Dermatology Forum. Guidelines for the management of actinic keratoses. Eur J Dermatol 16(6):599-606 (2006 Nov-Dec).
- US FDA 2009 safety alerts for human medical products: Voltaren gel (diclofenac sodium topical gel) 1% – hepatic effects labeling changes (issued December 4, 2009).
- Ganjian S, Ourian AJ, Shamtoub G, et al. Off-label indications for imiquimod. Dermatology Online Journal 15(5):4 (2009 May).
- Dummer R, Urosevic M, Kempf W, et al. Imiquimod in basal cell carcinoma: how does it work? Br J Dermatol 149(suppl 66):57-8 (2003 Nov).
- Stockfleth E, Meyer T, Benninghoff B, et al. A randomized, double-blind, vehicle controlled study to assess 5% imiquimod cream for the treatment of multiple actinic keratoses. Arch Dermatol 138(11):1498-502 (2002 Nov).
- Swanson N, Abramovits W, Berman B, et al. Imiquimod 2.5% and 3.75% for the treatment of actinic keratoses: results of 2 placebo-controlled studies of daily application to the face and balding scalp for two 2-week cycles. J Am Acad Dermatol 62(4):582-90 (2010 Apr).
- Hanke CW, Beer KR, Stockfleth E, et al. Imiquimod 2.5% and 3.75% for the treatment of actinic keratoses: results of 2 placebo-controlled studies of daily application to the face and balding scalp for two 3-week cycles. J Am Acad Dermatol 62(4):573-81 (2010 Apr).
- Silapunt S, Goldberg LH, Alam M. Topical and light-based treatments for actinic keratoses. Semin Cutan Med Surg 22(3):162–70 (2003 Sep).