1. Epidemiology and aetiology
Actinic keratoses (AKs) are one of the most common sunlight-induced skin lesions. Although often thought of as a cosmetic problem, the importance of AK lies in their risk of progression to squamous cell carcinoma (SCC); some experts consider these precursor lesions to SCC. Estimates suggest that one in six people develop AK lesions during their lifetime; 34 per cent of men over the age of 70 in the UK have at least one AK lesion. Estimates vary for the risk of progression of a single AK to invasive SCC.
The main risk factors in the development of AK are cumulative ultraviolet light exposure and skin phenotype. AK is more prevalent in skin types I and II, that is, fair-skinned individuals with red or blond hair, who burn easily in the sun but tan poorly.
Immunosuppressed patients are at particularly high risk of developing AK. Compared with the non-transplant population, transplant recipients have a 250-fold risk of developing an AK.
Areas of damage
AKs usually arise in areas of extensive actinic field damage, in which a cascade of genetic damage occurs at different stages at multiple sites, ranging from sub-clinical changes, AK lesions, in situ SCC and finally invasive SCC.
A number of mechanisms are known to play a key role in this cascade, including reduced apoptosis, increased cell proliferation, modification of the ras oncogene, magnified cyclo-oxygenase (COX) expression, p53 mutation and diminished immune response. Gene expression profiling of AK lesions has revealed prevention of certain normal anti-cancer processes. In normal skin, DNA damage stimulates repair mechanisms that up-regulate tumour suppressor genes including p53, ras and p16. In early AK lesions, however, the p53 gene has been shown to mutate into a new form that initiates the AK-SCC cascade: even early, mild AK stage I lesions harbour p53 gene mutations. There is evidence of ras mutations in stage II and in stage III p16 mutations are also found. Research is under way to establish the extent of the gene mutations present in SCC. The COX-2 pathway plays an important role in the AK-SCC cascade and it is hoped that by inhibiting this pathway it may be possible to prevent the progression of early AK lesions to invasive SCC.
2. Making a diagnosis
The diagnosis and management of AK in primary care has been recently described in NICE guidelines and in the Primary Care Dermatology Society protocol.
AKs are most often detected on sun exposed sites including the face, neck, hands, forearms, ears and scalps of elderly bald men.
The lesions present as skin-coloured or erythematous patches that later develop a rough white scale or crust. There is a wide variability in their shape (flat, circular or irregular) and size (measuring a few millimetres to centimetres).
Multiple lesions are frequent, but even isolated lesions arise on a background of a wider actinic field change in which there are other sub-clinical lesions. Failure to recognise and treat these lesions often results in clinical recurrence. This is an essential point in these patients’ management.
Diagnosis is primarily clinical and histology is rarely required. However, hypertrophic or ulcerated lesions carry higher risk and invasive SCC should be excluded.
Hypertrophic or hyperkeratotic AK are thickened red scaly lesions with or without cutaneous horn. They can mimic SCC, viral warts, irritated seborrhoeic keratoses and basal cell carcinoma (BCC), especially when on the trunk.
Lichenoid AK have a pink and pearly appearance and may be mistaken for a BCC.
Proliferative AK are erythematous macules with poorly defined borders. They grow around hair follicles to the level of the sebaceous glands and tend to be greater than 1cm in diameter. They frequently recur following treatment with liquid nitrogen and it may be difficult to differentiate between them and SCC.
Pigmented AK can mimic lentigo maligna and pigmented BCC.
Actinic cheilitis usually affects patients over 50 years of age; its frequency increases with age. It occurs on the vermilion of the lower lip because of more direct sunlight exposure to this site. The normal demarcation between the vermilion zone and the skin of the lip becomes blurred or disappears. As the lesion progresses, rough, scaly areas develop on the drier portions of the vermilion.
This condition has a relatively high potential for transformation into SCC (6-10 per cent).
Actinic conjunctivitis can also progress to SCC of the conjunctiva.
AK should be differentiated from warty brown seborrhoeic keratoses, which increase in number and size with age but also occur on non-sun exposed areas of the body and are not premalignant.
3. Topical treatment options
Patients with flat or barely palpable lesions on a background of sun-damaged skin should be given strict sun avoidance advice and sunscreens recommended.
Topical moisturisers can help smooth the roughened skin and improve cosmetic appearance.
Isolated lesions can be treated with curettage or cryotherapy. Patients should be advised about post-cryotherapy or curettage sequelae, including the development of a local inflammatory blister with cryotherapy and the risks of infection and hypopigmented scarring at the site of surgery.
There are a number of topical treatment options. Multiple palpable AKs can be treated with topical diclofenac sodium or 5-fluorouracil.
Diclofenac gel should be applied twice daily for 60-90 days; 5-fluorouracil should be applied over a four-week treatment period. Application regimens for 5-fluorouracil vary depending on physician and patient preference.
Patients should be warned about the risk of developing an inflammatory reaction at the application site with both treatments.
This is especially true with 5-fluorouracil, which can lead to the significant erythema and inflammation.
Topical steroids can be used to settle the reaction. It is equally important to make patients aware that generation of an inflammatory reaction is essential for the drug to exert its effect. As a result of its easy application and lack of severe inflammatory effects, diclofenac is now widely used in primary care.
Imiquimod is an immune response modifier that is now established as an effective treatment for AK.
Although application three times weekly for four weeks is recommended by the manufacturer, treatment schedules vary from two to three applications per week for seven to 16 weeks, as tolerated. Side-effects are similar to 5-fluorouracil and the cream is generally well tolerated.
Another treatment for AK is photodynamic therapy (PDT), which offers excellent cosmetic results. A study showed PDT as an attractive single treatment for AK, with comparable efficacy and superior cosmetic outcomes compared with cryotherapy.
Large inflamed, ulcerated, hypertrophic, treatment-resistant and atypical AKs and those arising in the setting of immunosuppression should be considered for referral.
Solar skin damage and its sequelae have significant cost and time implications, especially in primary care.