Drs Neil Shroff (left) and Stephen Kownacki explore the clinical approaches to actinic keratosis and show how most patients can be treated and managed in primary care
A n actinic keratosis is a common, sun-induced, scaly or hyperkeratotic lesion, which has the potential to become malignant. Precancerous lesions of the skin are common. Prevalence studies have demonstrated that approximately 23% of the population aged 60 years and older have actinic keratosis.1 One UK study reported that 34% of men and 18% of women over the age of 70 years had actinic keratosis.2
Although the risk of an actinic keratosis transforming into a squamous cell carcinoma (SCC) is very low, this risk increases over time and with larger numbers of lesions.
Actinic keratosis is a consequence of cumulative, long-term sun exposure, with incidence increasing with age. As a result of an aging population, the UK incidence of this condition is rising. Risk factors associated with actinic keratosis include:3
- gender—men are more affected than women
- genetic factors—individuals with fair skin, blue eyes, and blonde hair are at higher risk
- exposure to artificial ultraviolet radiation:
- used in the treatment of psoriasis and other skin conditions (e.g. ultraviolet B [UVB] and psoralen combined with ultraviolet A [PUVA])
- from use of sun beds.
Human papillomavirus acts as a co-carcinogen, especially in immunosuppressed patients. Patients who have received an organ transplant and other immunocompromised individuals have a 250-fold increased risk of developing actinic keratoses, and a 100-fold higher risk of developing invasive SCC. Actinic keratoses usually occur at an earlier age in these patient groups and become malignant at an increased rate.4
Clinical findings and types
Actinic keratotic lesions tend to occur on sun-exposed areas (e.g. the head, neck, backs of forearms, and hands). They are usually less than 1 cm in diameter and are often felt as rough, gritty areas even before they become visible; rough surface scale, usually white, is present.3
Actinic keratoses can be asymptomatic, or present with tenderness, or be cosmetically unsightly. They are divided into five main clinical types:5
- erythematous (the rough scale is more palpable than visible)
- keratotic papular
- verrucous papillomatous
- cutaneous horns (which they sometimes resemble)
In 2007, a clinical classification for grading actinic keratoses (Grade 1, 2, and 3) was developed (see Figure 1, for some examples). Actinic keratoses are graded as follows:6
- Grade 1: slightly palpable (better felt than seen)
- Grade 2: moderately thick (easily felt and seen)
- Grade 3: very thick, hyperkeratotic and/or obvious.
When to refer for specialist advice
Most patients with precancerous skin lesions can be managed by their GP or by a clinician working in the community,1 but specialist referral should be made in the situations below.
The following features are suspicious of SCC, and appropriate patients should be referred and seen in secondary care within the current 2-week rule for urgent referrals:
- induration (i.e. swelling or thickening of the skin lesion)
- a nodular lesion
- lesions on the lips.
Other reasons for referral are:
- where there is diagnostic uncertainty
- where the patient:3
- has more widespread/severe actinic damage
- is immunosuppressed, in particular post-transplantation
- is very young—consider xeroderma pigmentosum.
It should be remembered that actinic keratoses are an indication of significant sun damage and so a full examination of the skin is recommended to exclude other skin cancers, which is considered good clinical practice.
To treat or not to treat?
Opinions differ about the extent to which actinic keratoses should be treated. The European Dermatology Forum 2010 guideline recommends that all lesions should be treated, as it is impossible to predict which will progress to SCC.7
By contrast, the British Association of Dermatologists 2007 guideline advocates no treatment where there is little clinical concern and the patient is not troubled by the lesions.8 Fifteen to twenty-five percent of actinic keratoses resolve spontaneously within 12 months,9 with less than 1 in 1000 per annum developing into SCC.10 The PCDS guideline 3 provides further guidance as to whether treatment is needed and sets out the range of options.
Patient advice and information
Many patients will only need a diagnosis and explanation and advice regarding:11
- limiting sun exposure
- use of sunscreens
- use of emollients for symptomatic relief
- potential changes in lesions and what to look out for.
The daily application of sunscreen has been demonstrated to be effective in preventing the development of actinic keratosis, as well as in reducing the risk of progression to SCC.12
It is important to consider not only treatment of individual lesions in actinic keratosis, but also the sun-damaged skin in general, and affected ‘fields’ when using topical therapies. Subclinical fields of actinic keratosis may present as:3
- chronic photodamage
- several lesions.
Fields are more prone to developing into SCC and therefore treating them can minimise the risk of malignant transformation.13 The likelihood of change to SCC is increased with greater numbers of actinic keratoses, which is an important pointer towards a positive decision to treat. Treatment options can be divided into:
- ablative—treatments that physically destroy the actinic keratoses. These may be appropriate for confidently diagnosed individual hyperkeratotic lesions, especially where patients cannot or do not wish to apply creams.
- topical—particularly useful for diffuse and/or widespread thinner lesions, especially field treatments.
Although all modalities of actinic keratosis treatment can be delivered in primary care, photodynamic therapy (see below) needs economy of scale, making it more suitable for a GP with special interest, or secondary care, clinic. Cryotherapy using liquid nitrogen is less popular in GP surgeries because of health and safety requirements.
An effective option for field-directed treatment is photodynamic therapy (PDT).3 This involves the application of a photosensitising cream, either 5-aminolaevulinic acid (ALA) or methyl aminolaevulinic acid (MAL), in combination with an activating wavelength of light. The resulting cytotoxic reaction leads to cell death at the skin surface. This treatment is useful for areas of extensive field damage and multiple actinic keratoses (e.g. such as on the bald scalp, or lower legs) that are prone to poor wound-healing.14
Photodynamic therapy has similar efficacy rates to cryotherapy and 5-fluorouracil (5-FU) (see below). However, patients have rated cosmetic outcome and satisfaction more highly for PDT than for cryotherapy.15 New treatment modalities have been developed using portable, disposable light sources so that patients can remain ambulatory while receiving PDT; this reduces health practitioner time and offers wider availability of the treatment to patients.
Despite its advantages, PDT is limited by the high costs of the light source and photosensitising cream, which increase the tariff costs for the procedure. Additionally, there may be considerable pain in the affected area during and after treatment.
Cryotherapy using liquid nitrogen is a simple, effective technique for treating uncomplicated, solitary actinic keratoses.3 A 5-second freeze, in a single or double dose, is usually sufficient. Cryotherapy is quick, convenient, and easy to administer in an outpatient clinic. However, this technique is not without its problems, as the patient can experience pain during the procedure, and blistering and hypopigmented scarring can occur afterwards. A randomised controlled trial showed complete response rates to cycles of cryotherapy in 75% of actinic keratoses after 3 months, compared with in 69% of lesions after a single session of PDT.16
Other ablative options include surgical excision of actinic keratoses where SCC is suspected. This ensures a correct clinical diagnosis (through biopsy) and simultaneously treats the patient effectively.
Where topical choices are contraindicated, curettage and cautery, and shave biopsy, are also effective therapies for larger actinic keratoses.3 Shave biopsy often makes interpretation of the pathology easier because the architecture of the specimen is preserved.
Ablative treatments that are rarely used include laser treatments using carbon dioxide, chemical peels, and dermabrasion. These are more likely to be used outside the UK due to their expense and to safety legislation.
As a result of the increasing incidence of actinic keratosis, a number of topical therapies have evolved, which can be used in primary care.3 A summary of these treatments is given below.
Topical diclofenac gel 3% in hyaluronate
Topical diclofenac gel 3% in hyaluronate used twice daily for 60 days results in a 64% reduction of targeted lesions versus 34% with placebo.17 This agent has moderate efficacy and is well tolerated, with few side-effects. Its mechanism of action is to inhibit cyclo-oxygenase-2 (COX-2), reducing angiogenesis and cellular proliferation.18 The benefits, despite the long treatment period, are less irritation and inflammation of the skin than with other topical agents.18
The topical chemotherapeutic agent, 5-FU, has been used in the treatment of actinic keratosis since 1962. It works by disrupting deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) synthesis, which results in apoptosis of the dyplastic skin. It is used twice daily for 3–4 weeks.19,20 When used twice daily for 3 weeks, 5-FU has demonstrated a 70% decrease in size of the area treated,21 though there are recurrence rates of 55%.22 Treatment can cause a vigorous inflammatory reaction, which leads to pain, itching, and even ulceration with scarring. It is vital that patients are counselled in advance about the side-effects they should expect, so they are more likely to comply with treatment. Although less intensive treatment regimens have been used, which provoke fewer severe side-effects (for example, 5-FU application twice-weekly for 10 weeks), their efficacy is debatable, in the authors’ experience.
5-FU 0.5% + salicylic acid 10%
Another topical product for the treatment of actinic keratoses is 5-FU 0.5% + salicylic acid 10% solution. This is used for the treatment of moderately thick, hyperkeratotic actinic keratosis in immunocompetent patients.19,20 It has been shown to be superior to diclofenac for complete clearance of lesions, as confirmed by histology.23 It is applied once daily, usually for 8–12 weeks, and the film caused by the solution is peeled off the following day. Complete healing of the lesion(s) or optimal therapeutic effect may not be evident for up to 8 weeks after treatment cessation. It can be used to treat an area up to 5 cm x 5 cm, or 10 actinic keratoses.19, 20, 23
Imiquimod 5% was first approved in 1997, for the treatment of external genital warts. It is an immune response modifier and cytokine inducer. This topical agent up-regulates cell-mediated immunity, which is effective against viruses and tumours. It is applied three times a week for 4 weeks with a 4-week break, followed by (if necessary) another 4-week course of treatment.19
One study showed that complete clearance of all lesions was achieved in 47% of people treated three times a week for 16 weeks with imiquimod, compared with 7.2% of the people who received a placebo.24
Imiquimod has a similar side-effect profile to 5-FU, but can also cause flu-like symptoms (fever, myalgia, and arthralgia)because of increased levels of interferon.25
Imiquimod 3.75% is now also available for treating actinic keratosis of the face and scalp using a simplified daily dosage regime (2 weeks on, 2 weeks off, and another 2 weeks on).19,20 There appear to be less severe side-effects in the authors’ experience, compared with the 5% formulation, and as the whole scalp or face can be treated at one time, it offers another treatment option.
Ingenol mebutate is another recent product, derived from the plant Euphorbia peplus, and offers a much shorter treatment regimen. Two formulations exist:19,20
- a 150 µg/g gel applied to the face or scalp once daily for 3 days
- 500 µg/g gel applied to the trunk or extremities once daily for 2 days.
The benefit of the short treatment regimen is that:
- skin reactions, which are often significant, can resolve far more quickly than with other treatments
- it is useful where compliance may be an issue.
Ingenol mebutate is indicated for the treatment of non-hyperkeratotic and non-hypertrophic actinic keratosis in adults.20 Four phase III trials have demonstrated the efficacy of ingenol mebutate versus placebo in terms of complete clearance of actinic keratotic lesions.26 The mechanism of action has not been fully elucidated but ingenol mebutate is thought to work in two ways, by:27,28
- induction of local lesion cell death
- promoting an inflammatory response characterised by infiltration of immunocompetent cells.
This article (and the PCDS actinic keratosis pathway guidance3) has been written to help clinicians answer the four main issues posed by actinic keratoses in clinical practice:
- diagnosis (and exclusion of SCC)
- whether to treat
- therapeutic options
- lesion or field.
Controversy about the need to treat all actinic keratoses, and about whether we should treat the ‘field’ rather than just individual lesions, divides the dermatological community.
In Europe and the US, there is a strong feeling that all actinic keratoses are pre-malignant and should therefore be eradicated whenever they appear. In the UK, opinions are more weighted towards treatment only when lesions are numerous, more severe, and influenced by the patient’s wishes. To treat all lesions (in the authors’ opinion) would not only be prohibitively expensive, but would also cause significant unnecessary morbidity.
There is a place for all modalities of treatment, since every patient is different and has unique circumstances and tolerances. It falls mainly to GPs to develop the therapeutic choices which suit their patient.
One area that may become more prevalent in secondary care is the practice of eradicating significant actinic keratoses and field change before transplant surgery, since patients will be at much higher risk of malignant change when taking immunosuppressant therapy.29
- In most cases, actinic keratosis can be treated in primary care
- Local formularies should identify preferred topical therapies and include patient information leaflets to support their use
- Commissioners can consider local community GPwSI and specialist nurse services to help manage this condition and to undertake cautery and photodynamic therapy; this may be cheaper than PbR tariff costs
- Commissioners, in association with colleagues in public health, should consider public information campaigns about safe sun exposure and the identification of actinic damage and possible skin cancer.
GPwSI=GP with a Special Interest
- National Collaborating Centre for Cancer. Improving outcomes for people with skin tumours including melanoma—the manual. NICE, 2006. Available at: www.nice.org.uk/nicemedia/live/10901/28906/28906.pdf
- Memon A, Tomenson J, Bothwell J,
Friedmann P. Prevalence of solar damage and actinic keratosis in a Merseyside population.
Br J Dermatol 2000; 142 (6): 1154–1159.
- Primary Care Dermatology Society. Actinic (solar) keratosis primary care treatment pathway. Available at: www.pcds.org.uk/ee/images/uploads/general/Actinic_(Solar)_Keratosis_Primary_Care_Treatment_Pathway.pdf
- Berg D, Otley C. Skin cancer in organ transplant recipients: epidemiology, pathogenesis, and management.J Am Acad Dermatol 2002; 47 (1): 1–17
- Moy R. Clinical presentation of actinic keratoses and squamous cell carcinoma. J Am Acad Dermatol 2000; 42 (1 Pt 2): 8–10.
- Röwert-Huber J, Patel M, Forschner T et al. Actinic keratosis is an early in situ squamous cell carcinoma: a proposal for reclassification. Br J Dermatol 2007; 156 (Suppl 3): 8–12.
- Stockfleth E, Terhorst D, Braathen L et al on behalf of the European Dermatology Forum. Guideline on actinic keratoses. Berlin, 2010. Available at: www.euroderm.org/images/stories/guidelines/guideline_Management_Actinic_Keratoses-update2011.pdf
- de Berker D, McGregor J, Hughes B on behalf of the British Association of Dermatologists Therapy Guidelines and Audit Subcommittee. Guidelines for the management of actinic keratoses. Br J Dermatol 2007; 156 (2): 222–230.
- Marks R, Foley P, Goodman G et al. Spontaneous remission of solar keratoses: the case for conservative management. Br J Dermatol 1986; 155 (6): 649–655.
- Harvey I, Franklel S, Marks R et al. Non-melanoma skin cancer and solar keratoses. I. Methods and descriptive results of the South Wales Skin Cancer Study. Br J Cancer 1996; 74 (8): 1302–1307.
- Primary Care Dermatology Society website. Actinic keratosis (syn. solar keratosis). www.pcds.org.uk/clinical-guidance/actinic-keratosis-syn.-solar-keratosis (accessed 11 October 2013).
- Thompson S, Jolley D, Marks R. Reduction of solar keratoses by regular sunscreen use. N Engl J Med 1993; 329 (16): 1147–1151.
- Quaedvlieg P, Tirsi E, Thissen M et al. Actinic keratosis: how to differentiate the good from the bad ones? Eur J Dermatol 2006; 16 (4): 335–339.
- Morton C, Brown S, Collins S et al. Guidelines for topical photodynamic therapy: report of a workshop of the British Photodermatology Group. Br J Dermatol 2002; 146 (4): 552–567.
- Morton C, Campbell S, Gupta G et al. Intraindividual, right-left comparison of topical methyl aminolaevulinate—photodynamic therapy and cryotherapy in subjects with actinic keratoses: a multicentre, randomized controlled study. Br J Dermatol 2006; 155 (5): 1029–1036.
- Szeimies R, Karrer S, Radakovic-Fijan S et al. Photodynamic therapy using topical methyl 5-aminolevulinate compared with cryotherapy for actinic keratosis: a prospective, randomized study. J Am Acad Dermatol 2002; 47 (2): 258–262.
- Rivers J, Arlette J, Shear N et al. Topical treatment of actinic keratoses with 3.0% diclofenac in 2.5% hyaluronan gel.
Br J Dermatol 2002; 146 (1): 94–100.
- Martin G, Stockfleth E. Diclofenac sodium 3% gel for the management of actinic keratosis: 10+ years of cumulative evidence of efficacy and safety. J Drugs Dermatol 2012; 11 (5): 600–608.
- British National Formulary website. www.bnf.org/bnf/index.htm (accessed 2 October 2013).
- MIMS website. www.mims.co.uk (accessed
2 October 2013).
- Kurwa H, Yong-Gee S, Seed P et al. A randomized paired comparison of photodynamic therapy and topical 5-fluorouracil in the treatment of actinic keratoses. J Am Acad Dermatol 1999; 41 3 Pt 1): 414–418.
- Krawtchenko N, Roewert-Huber J, Ulrich M et al. A randomised study of topical 5% imiquimod vs. topical 5-fluorouracil vs cryosurgery in immunocompetent patients with actinic keratoses: a comparison of clinical and histological outcomes including 1-year follow-up. Br J Dermatol 2007; 157 (Suppl. 2): 34–40
- Stockfleth E, Kerl H, Zwingers T, Willers C. Low-dose 5-fluorouracil in combination with salicylic acid as a new lesion-directed option to treat topically actinic keratoses: histological and clinical study results. Br J Dermatol 2011; 165 (5): 1101–1108.
- Korman N, Moy R, Ling M et al. Dosing with 5% imiquimod cream 3 times per week for the treatment of actinic keratosis: results of two phase 3, randomized, double-blind, parallel-group, vehicle-controlled trials. Arch Dermatol 2005; 141 (4): 467–473.
- Gaspari A, Sauder D. Immunotherapy of basal cell carcinoma: evolving approaches. Dermatol Surg 2003; 29 (10): 1027–1034 .
- Lebwohl M, Swanson N, Anderson L et al. Ingenol mebutate gel for actinic keratosis. N Engl J Med 2012; 366 (11): 1010–1019.
- Berman B. New developments in the treatment of actinic keratosis: focus on ingenol mebutate gel. Clin Cosmetic Investig Dermatol 2012; 5: 111–122.
- Rosen R, Gupta A, Tyring S. Dual mechanism of action of ingenol mebutate gel for topical treatment of actinic keratoses: rapid lesion necrosis followed by lesion-specific immune response. J Am Acad Dermatol 2012; 66 (3): 486–493.
- Professor E Stockfleth. Personal communication. G