Solar Keratosis (Actinic keratosis) and its topical Treatment options

Solar or actinic keratosis is a skin condition in which pigmented lesions appear on skin, often more prevalent in those with paler skin. This form of keratosis is associated with damage caused by exposure to UV radiation (i.e. sunlight), and results in irregular, brownish or reddish 'scaly' lesions on skin, which may also be accompanied by reddened borders, indicating excessive sun damage. These lesions may be a precursor of a form of skin cancer known as in situ squamous-cell carcinoma (SCC). It may be for this reason that solar keratosis is regarded as the most common type of (potentially) malignant skin lesion.

The prevalence of solar keratosis may depend on a couple of factors:

• Geographical location, i.e. it may be more common in parts of the world commonly linked to prolonged periods of sunlight exposure.
• Age. For example, up to 50% of Australians aged 40 years or more are reported to have developed solar keratosis.

Solar keratoses typically develop in areas more likely (for most demographics) to be exposed to the sun when outdoors such as face, neck, scalp, back of hands, forearms and legs. 

Mechanisms of Solar/Actinic Keratosis Development

Solar keratosis begins at the cellular level (in epidermal keratinocytes, or skin cells in the uppermost layer of skin) when the DNA in the cells sustain damage (or mutate) as a result of the deleterious actions of UV radiation. This results in aberrations in these cells that allow them to resist cell death, a natural process that ensures new cells develop, function, differentiate, and then make way for new ones, and is the basis of tissue health and healing. This process is called transformation, and may cause the formation of benign growths such as solar keratoses over time. This in turn may lead to the growth becoming malignant, i.e. developing into skin cancer. Skin keratosis that has reached the stage of malignancy is known as Bowen's disease. This in turn may develop into full-blown squamous-cell carcinoma. Keratosis, and its progression to full malignancy, is associated with a number of risk factors. These may include:

• Caucasian ancestry and advancing age, as mentioned above
• Co-infection of skin with the human papilloma virus. This has become associated with malignancy in solar keratosis. A protein that makes up the HPV virus may act to reduce a protein involved in the promotion of normal cell death.
• Inflammation: This contributes to the probability of transformation and benign growth formation
• Immunosuppression: This may also affect the risk of mutation and transformation
• Location of the lesion: This may influence the progression to malignant carcinoma
• Numbers of abnormal (i.e. mutated) skin cells in the epidermis; generally, a higher number of these increases the risk of malignancy
• Male gender
• Size (in diameter) of the lesion: This may also determine eventual malignancy

Once solar keratosis has developed, it tends to follow one of three main outcomes. These are:

• Remission: This is the spontaneous resolution of keratotic lesions, a relatively common outcome
• Stability, i.e. remaining at a consistent size and shape without further complications (e.g. metastasis)
• Progression to full squamous-cell carcinoma

A patient may have one or more keratotic lesions; the average number of these is six to eight per patient. Lesions may be relatively large and noticeable, measuring 5mm in diameter or more.

Treatment for solar keratosis

Treatment for solar keratosis, or lesions that have progressed to malignancy, may require surgical procedures to remove these growths. These may include techniques such as:

• Cryotherapy
• Curettage
• Dermabrasion
• Excision
• Laser resurfacing

These therapies may be associated with adverse events such as infection, pain, burning and stinging sensations in the skin targeted, redness, scarring and other disfigurements.

Cryotherapy (the application of liquid nitrogen to lesions to freeze them and separate them from the dermis below) is accurate and safe in most cases, but is also associated with some adverse events such as pigment changes in the targeted skin due to the increased susceptibility of melanocytes (pigment-producing cells) to freezing. Reduced pigmentation as a result of cryotherapy may occur in approximately 29% of cases, whereas paradoxical hyperpigmentation may occur in up to 6%.

Dermabrasion and laser resurfacing are also more likely to be associated with scarring, as they can cover a wider area. Most surgical treatments are regarded as most suitable and effective in cases of singular lesions, or clusters of small lesions. Larger lesions and groups of lesions are generally targeted with 'field-directed' treatments. These are typically topical formations, which can cover larger areas, containing drugs that can act to interfere with the mechanisms of transformation and mutation.

Topical Treatments for solar keratosis

5-Fluorouracil

This is a standard treatment for solar keratosis. It is an analogue of one of the 'building blocks' of genetic material. It can interrupt the synthesis of DNA, and therefore can stop the propagation of UV-induced mutations in affected skin cells. Chemowrapping with 5% 5-fluoruracil may be an alternative treatment for extensive lesions and/or carcinoma, particularly for those who may find surgery less tolerable, e.g. more senior patients.

However, 5-fluoruracil may be associated with adverse events, including inflammation and ulcerative skin damage, particularly in formulations with higher concentrations (e.g. 5%). Therefore, treatments with lower concentrations (e.g. 0.5%) have also been approved for application in cases of solar keratosis. 

Diclofenac

This is a nonsteroidal anti-inflammatory drug (NSAID) typically available in a 3% gel when used to treat solar keratosis. Diclofenac reduces inflammation (as the name suggests) and also has anti-tumour properties. A review of three trials (including 364 patients) that randomised patients to this gel or the gel vehicle without diclofenac found that the 'treatment' groups had a clearance rate of nearly 40% compared to approximately 12% in the placebo group.

Adverse events associated with diclofenac may include itching, skin dryness and contact dermatitis.

Imiquimod

This is a drug that modulates the immune response and promotes cell death. Therefore, it may inhibit the proliferation and survival of malignant skin cells.

A review of ten trials comparing imiquimod with 5-fluoruracil found that this treatment was associated with a rate of efficacy of 70%, compared to 52% for 5-fluoruracil. A study incorporating two identical trials randomised a total of 490 adult patients with five to 20 lesions to 2.5% imiquimod, 3.75% imiquimod or placebo. Complete clearance rates were 34% for the 3.75% imiquimod group, 25% for the 2.5% imiquimod group and 5.5% for the placebo group.

Imiquimod may result in increases in inflammation, which may cause adverse events such as discomfort and redness. These adverse effects are considered necessary for an effective treatment, as the treatment requires that the area be involved with a level of cellular death to achieve clearance.

References

1. Roewert-Huber J, Stockfleth E, Kerl H. Pathology and pathobiology of actinic (solar) keratosis - an update. The British journal of dermatology. 2007;157 Suppl 2:18-20.
2. Dodds A, Chia A, Shumack S. Actinic Keratosis: Rationale and Management. Dermatology and Therapy. 2014;4(1):11-31.
3. Berman B, Cockerell CJ. Pathobiology of actinic keratosis: ultraviolet-dependent keratinocyte proliferation. Journal of the American Academy of Dermatology. 2013;68(1 Suppl 1):S10-19.
4. Schmitt AR, Bordeaux JS. Solar keratoses: photodynamic therapy, cryotherapy, 5-fluorouracil, imiquimod, diclofenac, or what? Facts and controversies. Clinics in dermatology. 2013;31(6):712-717.
5. Ratushny V, Gober MD, Hick R, Ridky TW, Seykora JT. From keratinocyte to cancer: the pathogenesis and modeling of cutaneous squamous cell carcinoma. The Journal of Clinical Investigation. 2012;122(2):464-472.
6. Thai KE, Fergin P, Freeman M, et al. A prospective study of the use of cryosurgery for the treatment of actinic keratoses. International journal of dermatology. 2004;43(9):687-692.
7. Hantash BM, Stewart DB, Cooper ZA, Rehmus WE, Koch RJ, Swetter SM. Facial resurfacing for nonmelanoma skin cancer prophylaxis. Archives of dermatology. 2006;142(8):976-982.
8. Pirard D, Vereecken P, Melot C, Heenen M. Three percent diclofenac in 2.5% hyaluronan gel in the treatment of actinic keratoses: a meta-analysis of the recent studies. Archives of dermatological research. 2005;297(5):185-189.
9. Gupta AK, Weiss JS, Jorizzo JL. 5-fluorouracil 0.5% cream for multiple actinic or solar keratoses of the face and anterior scalp. Skin therapy letter. 2001;6(9):1-4.
10. Kaur RR, Alikhan A, Maibach HI. Comparison of topical 5-fluorouracil formulations in actinic keratosis treatment. The Journal of dermatological treatment. 2010;21(5):267-271.
11. Pirard D, Vereecken P, Melot C, Heenen M. Three percent diclofenac in 2.5% hyaluronan gel in the treatment of actinic keratoses: a meta-analysis of the recent studies. Archives of dermatological research. 2005;297(5):185-189.
12. Gebauer K, Brown P, Varigos G. Topical diclofenac in hyaluronan gel for the treatment of solar keratoses. The Australasian journal of dermatology. 2003;44(1):40-43.
13. Gupta AK, Davey V, McPhail H. Evaluation of the effectiveness of imiquimod and 5-fluorouracil for the treatment of actinic keratosis: Critical review and meta-analysis of efficacy studies. Journal of cutaneous medicine and surgery. 2005;9(5):209-214.
14. Hanke CW, Beer KR, Stockfleth E, Wu J, Rosen T, Levy S. Imiquimod 2.5% and 3.75% for the treatment of actinic keratoses: results of two placebo-controlled studies of daily application to the face and balding scalp for two 3-week cycles. Journal of the American Academy of Dermatology. 2010;62(4):573-581.