Ilya Shoimer, BSc; Nathan Rosen, MD; Channy Muhn, MD
Division of Dermatology, Department of Medicine, McMaster University, Hamilton, ON, Canada
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 skin conditions seen by dermatologists, preceded only by acne vulgaris and dermatitis.1 AKs are clinically relevant lesions due to their potential to evolve into invasive squamous cell carcinoma (SCC).2 Additionally, they are considered a risk factor for the subsequent development of melanoma and non-melanoma skin cancer. There are numerous treatments available for managing AKs including those broadly categorized as destructive, topical field, and procedural field therapies. The recent introduction of imiquimod 3.75%, approved for the treatment AKs on the face and scalp, widens the therapeutic arsenal.
Prevalence and Risk Factors
- In the northern hemisphere, it is estimated that between 11-25% of adults have at least one AK.3
- These lesions are most commonly seen in the older fair-skinned population or in individuals classified under Fitzpatrick skin phototypes I-III.
- Cumulative ultraviolet (UV) radiation exposure and older age are the most important contributing risk factors.
- Immunocompromised individuals or those with certain genetic syndromes (e.g., xeroderma pigmentosum and albinism) are at greater risk.
- UV radiation is involved in the pathogenesis of AKs through inducing cellular DNA mutations in the skin, which may affect cell proliferation genes (e.g., p53 and ras) or prompt evasion of apoptosis.2
- Disruption of one of these genes may lead to 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 inherent repair mechanisms. However, additional UV light exposure may induce further DNA mutations resulting in the development of invasive SCC.
- AKs typically manifest as small (1-3mm), erythematous, scaly papules with a hyperkeratotic texture.
- 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 (e.g., telangiectasia, blotchy hyperpigmentation, and yellow discolouration of the skin).4
- The clinical variants of AKs include the cutaneous horn, lichen planus-like keratosis, pigmented actinic keratosis, and actinic cheilitis.4,5
- The natural history of AKs is variable and unpredictable; a 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
- Over several years, these lesions can progress, becoming thicker and developing into a hypertrophic AK, Bowenâ€™s disease (SCC in situ), or an invasive SCC.
- The stages of this biologic continuum are clinically indistinguishable, therefore, a biopsy should be performed if a SCC is suspected.
- A presentation that includes pain, pruritus, induration, larger size, rapid growth, ulceration, bleeding, or resistance to treatment may point towards a more sinister pathology (i.e., SCC).4,5
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. Therapeutic choices are guided by efficacy, adverse effects, cosmetic results, and patient adherence.
The most common therapies for individual AKs work destructively by physically removing the lesion. These modalities should be considered first-line 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.
Cryotherapy is the most frequently utilized technique, with liquid nitrogen being the most commonly applied 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, limited in number, or for patients who are nonadherent to topical regimes.7
- Reported cure rates range from 39-83%.8
- Treatments are generally well-tolerated and do not require local anesthetic, but the procedure can be painful and result in 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.
- 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, and dyspigmentation, as well as anesthetic related side-effects.
Topical Field Therapy
Commonly, physicians are faced with patients who are covered in actinic damage, a clinical scenario now described as field cancerization, which includes both clinical and subclinical lesions within a given anatomical region.9 For these patients, a different therapeutic approach, known as field therapy, is needed for the clearance of both clinically visible and subclinical AKs within the treatment area.
Topical 5-fluorouracil (5-FU)
The antimetabolite 5-FU was the first approved agent for topical field therapy. Discovered serendipitously whenAKs 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, which 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 skin tissue.
- The average cure rate is 62.5%,11 but for optimal results full patient adherence is necessary. Recommended dosing is twice-daily for 3 weeks.
- There is evidence showing concurrent treatment with topical tretinoin enhances the effectiveness of 5-FU.12
- It is common for all patients undergoing successful treatment with 5-FU to experience inflammation, erythema, and erosions.
- Common side-effects include pain, pruritus, photo- sensitivity, and burning at the site of application.
- 5-FU can worsen preexisting cutaneous conditions (e.g., melasma or acne rosacea), as such, use should be avoided in these patients.7
Diclofenac 3% gel is a nonsteroidal anti-inflammatory drug, which 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 tumours 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 on long-term therapy.
Topical 5% imiquimod cream 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 used off-label for Bowen’s disease, invasive SCC, lentigo maligna, molluscum contagiosum, keloid scars, and others.14 Imiquimod acts as a toll-like receptor-7 agonist, which results in modification of the immune response and stimulation of apoptosis, thereby disrupting tumour proliferation.15 Stockfleth et al.16 demonstrated that 84% of treated AKs showed clinical clearance with one 12-week cycle of 5% imiquimod therapy.
- Common localized irritation coupled with its long duration of treatment (twice-weekly for 16 weeks) can discourage patient adherence.
- Treatment should be applied to both the lesion and surrounding tissue to target subclinical AKs.
- Rare systemic effects include fatigue, flu-like symptoms, headaches, myalgias, and angioedema.
In December 2009, Health Canada approved the use of imiquimod 3.75% 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%.17,18
- In the trial by Swanson et al.,17 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 experienced complete clearance.
- These efficacy data rival those achieved using imiquimod 5% twice-weekly for 16 weeks, but with the advantage of signif icantly improved patient tolerance.
- 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 >90%.17,18
- Overall, the newly approved formulation of imiquimod 3.75% is a reasonable alternative to imiquimod 5%, as it demonstrated comparable efficacy, but with a much more simplified, shorter dosing regimen.
- 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 favour an improved 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)
PDT is a procedural field therapy that utilizes topical 5-aminolevulinic acid (ALA) or methyl aminolevulinate 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).19 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.19
- PDT is effective for the treatment of multiple and diffuse AKs, and the cosmetic results are generally excellent.
- PDT is not suited for treating thicker or deeper AKs19 and is generally reserved for patients who exhibit an inadqueate response to topical field therapy or cryosurgery.
- Patients may experience erythema, edema, and a burning sensation during 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. Family physicians can play an important role in encouraging patients to wear broad-based sunscreens, wide-brimmed hat, protective eyewear, and avoiding the sun during peak hours, which may prevent recurrence or limit the progression of AKs. Furthermore, patients are well-served by offering education on the potential side-effects and expected onset of action of topical field therapies.
- 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, 1990Â–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):S8Â–10 (2000 Jan).
- Duncan KO, Geisse JK, Leffell DJ. Chapter 113. Epithelial Precancerous Lesions. In: Wolff K, Goldsmith LA, Katz SI, et al. (eds.) Fitzpatrick’s Dermatology in General Medicine: 7th edition. New York, USA: McGraw-Hill Companies (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 SlaughterÂ’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).
- 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):57-58 (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):162Â–70 (2003 Sep).