Dr Neil Shroff explores updated British Association of Dermatologists guidance on actinic keratosis and offers an overview of treatment options and considerations

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Read this article to learn more about:

  • prevalence and grading of actinic keratosis
  • topical treatments that can be prescribed in primary care
  • special sites and when to refer to secondary care.

NICE accreditation logo

The British Association of Dermatologists’ guidelines for the care of patients with actinic keratosis 2017 has been awarded the NICE Accreditation Mark.

The British Association of Dermatologists (BAD) published an updated, evidence-based guideline on actinic keratosis (AK) in January 2017.1 Accredited by NICE, the guideline covers accurate diagnosis of AK and available treatments, graded recommendations, current developments, and some health economic implications.

This article summarises the different presentations of actinic keratoses and what treatment options are suitable for each. It also considers prevalence, counselling patients, when to treat, and when to refer to secondary care, with reference to both the updated 2017 BAD1 and Primary Care Dermatology Society (PCDS) actinic keratosis guidelines.2 The PCDS guidance provides further specific information to primary care about the treatments discussed below.2

Background and prevalence

Actinic keratosis (AK) is a chronic skin condition characterised by a scaly or hyperkeratotic lesion that has the potential to be malignant. Actinic keratoses tend to occur on sun-exposed areas such as the head and neck and the back of forearms and hands. They are usually less than 1 cm in diameter and often felt as rough, gritty areas even before they become visible. Rough, white surface scale is usually present.2

One prevalence study conducted in South Wales demonstrated that approximately 23% of the population aged 60 years and over had actinic keratosis.3 Another UK study reported that 34.1% of men and 18.2% of women aged 70 years and over had actinic keratosis.4 A more recent study in Rotterdam of more than 2000 Dutch men and women with a mean age of 72 years reported a prevalence of AK in 49% of men and 28% of women.5

The above findings go some way to explaining why the condition is commonly encountered in primary care.

Actinic keratosis is a chronic skin condition characterised by a scaly or hyperkeratotic lesion …

Risk of malignant transformation

The rate of malignant transformation of AK is low, with less than 1 in 1000 AKs developing into a squamous cell carcinoma (SCC) per annum.1,6,7 However, evidence shows that AKs are a marker of excess risk for non-melanoma skin cancer.1 Mathematical models from one study predicted that for a person with an average 7.7 AKs, the probability of developing an SCC within 10 years was approximately 10%.1,6 Another prospective study followed 918 adults (mean age 61 years) with AKs and no previous history of skin cancer for 5 years; estimated incidence rates for basal cell carcinoma (BCC) and SCC were 4106 and 3198 per 100,000 person-years, respectively—higher than in the general population.1,8

Diagnosis and assessment in primary care 

In the author’s experience, most patients present with AKs due to:

  • concerns that they could be skin malignancies
  • functional problems, e.g. thickened AK catching when combing the hair
  • unsightly appearance of AK. 

Most AKs can be diagnosed and managed in the primary care setting, and most AKs can be managed with topical treatments.1 The PCDS has developed guidance incorporating new modalities of treatment (see Table 1).6

Table 1: Actinic keratosis treatments6
Generic nameGrade 1Grade 2Grade 3Field change
Small (<26 cm2)Large
Topical 3% diclofenac with HA ✓✓ ✓✓ ✓✓
5% fluorouracil (5-FU) ✓✓ ✓✓ ✓*
5% imiquimod
0.5% 5-FU+10% salicylic acid ✓✓ ✓✓
3.75% imiquimod ✓✓
0.015% ingenol mebutate—face & scalp ✓✓ ✓✓ ✘*
0.05% ingenol mebutate—trunk & limbs
Other Liquid nitrogen
Photodynamic therapy
Curettage
✓=relative recommendation ✓✓=strong recommendation ✘=not recommended in primary care
* It may be preferable to divide larger areas into smaller ones and treat them sequentially | HA=hyaluronic acid
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 Reproduced with permission.

Most patients who present in primary care will only need a diagnosis, an explanation of why they have the condition, and advice regarding:2,6

  • reducing sun exposure
  • use of sunscreens and protective clothing, e.g. a good hat for the balding scalp
  • emollient use for symptomatic relief (may actually improve cosmesis)
  • potential changes in lesions and what to look for. 

A patient information leaflet produced by BAD is available.

Patients with multiple AKs are at increased risk of non-melanoma skin cancers.1 A thorough check of the patient’s skin is required.2

Teledermatology has been shown to be effective in the diagnosis and management of AK in primary care, using the help and guidance of dermatologists.1,9

Classification of actinic keratosis

Clinically, AKs can be classified as follows, to help guide management:1

  • grade 1, mild—pink or grey marks with slight scale or are gritty to touch
  • grade 2, moderate—thicker hyperkeratosis and easily detected
  • grade 3, severe—hypertrophic, thick keratin
  • field change—confluent areas of several centimetres or more with a range of features matching any or all of the grades of AK.

Sometimes it can be difficult to differentiate grade 3 AKs from small, early SCCs.

Occasionally AK can be sore and itch.1 The term ‘field change’ is used to describe an area of skin that is involved extensively with actinic damage.2,10

See Figure 1 below for various presentations of AK.

Figure 1: Different presentations of actinic keratosis

Actinic keratosis

Actinic damage with grade 1 and 2 AKs on the forehead of a 70-year-old gentleman who has had a BCC excised previously

Actinic keratosis

Actinic damage on the balding scalp with evidence of grade 2 actinic keratoses

Actinic keratosis

Poorly differentiated SCC on the right temple with evidence of field change

Management 

Where there is little clinical concern and the patient is not troubled by the lesions, the option of no treatment can be advocated.1,2 The BAD 2016 guideline cites evidence that 25–70% of (probably grade 1 and grade 2) AKs resolve over a 1–4 year period.1

It is important to involve the patient in decisions about no treatment or, if treatment is advised, the type of treatment.

The PCDS and BAD guidelines provide further guidance as to whether treatment is needed and set out the range of options.1,2

Sun protection and sunscreen

Sunscreen has a combined emollient and photoprotective effect.1 The daily application of sunscreen has been demonstrated to be effective in preventing the development of AK, as well as reducing the risk of progression to SCC.1

When to refer to secondary care

Refer if transformation from AK into SCC is suspected. The risk of this is very low, but increases over time and with large numbers of lesions. The following features are suggestive of SCC:2

  • recent growth
  • induration (i.e. swelling or thickness of the skin lesion)
  • tenderness
  • inflammation
  • a nodular lesion
  • bleeding/ulceration/non-healing
  • lesions on the lips, where SCC can be subtle. 

Such patients should be referred and seen in secondary care within the current 2-week rule for urgent referrals. Other reasons for referral are:2

  • where there is diagnostic uncertainty
  • where the patient:
    • has more widespread/severe actinic damage
    • is immunosuppressed, e.g. following solid organ transplantation 
    • is very young (consider xeroderma pigmentosum).

Self-care

The 2017 BAD actinic keratosis guideline places some emphasis on self-care, which involves patient education, ongoing self-directed treatment regimens, recognition of risk of skin cancers, and how to mitigate the risk.1 Ideally, if patients discover new AK lesions they should consult their primary care provider before embarking on treatment.1 The guideline also emphasises that patients should be made aware of the side-effects of treatment before they start their regimen. The treatments can cause redness, scaling, crusting, and soreness during the treatment course. Poor concordance can result if patients are not made aware of these side-effects.1

Treatment 

Many factors come into play regarding treatment. These include the grade of AK, the anatomical site, previous treatments, patient preference, and immune status of the patient. 

Treatment options can be divided into:

  • topical—particularly useful for diffuse and/or widespread thinner lesions especially field change. These treatments are more likely to be relevant to primary care
  • ablative—treatment that physically destroys AKs. These treatments may be appropriate for confidently diagnosed individual hyperkeratotic lesions, especially where patients cannot or do not wish to apply creams.

Topical treatments

Consult the summary of product characteristics for further information about all treatments described below.

5-fluorouracil (5-FU)

The topical chemotherapeutic agent 5-fluorouracil (5-FU) was used in the treatment of AK as early as 1962.11 It works by the inhibition of thymidylate synthetase, which is needed for deoxyribonucleic acid (DNA) and ribonucleic acid (RNA).1 This results in apoptosis of the dysplastic skin. It is used twice daily for 3–4 weeks,1 and is suitable for grade 1 and 2 lesions. The treatment is widely used, flexible, and is low-cost. It can be used not only for lesion-directed treatment but also to treat field damage.1 Treatment can cause soreness, itching, redness, ulceration, and crusting (see Figure 2).1,12 It is important that patients are warned of these side-effects, which can be lessened by reducing the frequency of application or having short breaks. It is also important be aware of treating poor healing sites such as the lower leg where gentler regimens may be necessary to reduce ulceration.

Efudix reaction crop

Figure 2: Typical 5-fluorouracil reaction half way into treatment

5-fluorouracil 0.5% and salicylic acid 10%

5-fluorouracil 0.5% and 10% salicylic acid is a newer preparation that acts in a similar way to 5-FU with the added benefit of salicylic acid, which appears to act as a keratolytic.1 It is useful for lesion-directed therapy and thicker AKs (grade 1 or 2). Daily application to the lesion is with a brush soaked in the topical agent; the film caused by the solution is peeled off the following day.13 The treatment is used for 6–12 weeks and it can be used to treat an area up to 5 cm by 5 cm, or 10 AKs.1,13 Complete healing of the lesion(s) or optimal therapeutic effect may not be evident for up to 8 weeks after treatment cessation.1,13 About 50% of patients discontinue treatment at 6 weeks because of the disappearance of the AK.1

Imiquimod 5%

Imiquimod 5% is an immune-response modifier and cytokine inducer. This topical agent upregulates cell-mediated immunity, which is effective against viruses and tumours.11 In the UK it is licensed for non-hyperkeratotic, non-hypertrophic AKs on the face or scalp in immunocompetent adults when the size or number of lesions limits the efficacy and/or acceptability of cryotherapy and other topical treatments are not considered appropriate.1,14 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. 1,14 A meta-analysis from five randomised controlled trials, where imiquimod 5% cream was used two to three times a week for 12–16 weeks, showed a 50% complete clearance rate.1 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.1,11,14

A weaker strength of imiquimod (3.75%) is available for treating AKs of the face and scalp using a simplified daily dosage regimen (2 weeks on, 2 weeks off, and another 2 weeks on).1,15 In the author’s experience, there appear to be less severe side-effects with this product compared with the 5% formulation, and this places it in the application of field-directed therapies.

Diclofenac gel 

Topical diclofenac gel 3% in 2.5% hyaluronic gel is used twice daily for 60–90 days and again can be used for lesion and field-based treatment. Normally an amount of gel the size of a pea (0.5 g) is used on a 5 cm by 5 cm lesion site; a maximum of 8 g daily should not be exceeded.1,16 It is thought to work by inhibition of the cyclo-oxygenase pathway leading to reduced prostaglandin E2 synthesis, thereby reducing angiogenesis and cellular proliferation. The advantages, despite the long treatment period, are that it usually causes less irritation and inflammation of the skin compared with 5-FU or imiquimod cream.1

Ingenol mebutate

Extracted from the plant sap of Euphorbia peplus, ingenol mebutate is indicated for the treatment of non-hyperkeratotic and non-hypertrophic AKs in adults (grades 1 and 2).1,17,18 It is licensed to cover a skin surface area of 5 cm by 5 cm. It works by the disruption of mitochondrial membranes resulting in damage and death of host cells and promotion of cell-specific antibodies with cell-medicated toxicity.1 Two formulations exist:1,17,18

  • 150 mcg/g applied to the face or scalp once daily for 3 days
  • 500 mcg/g applied to the the trunk and extremities once daily for 2 days.

The benefit of the short treatment regimen is that most skin reactions which involve redness, scabbing, pustulation, and pain resolve within 28 days.1 It can also be useful when compliance may be an issue.

Pooled data from two trials of treatment using the 150 mcg/g regimen followed successfully treated patients for 12 months. There was relapse on head and neck in just over one-half the patients in the following year. Specific sites such as the back of the hands are less likely to clear completely, with 18.5% clearance reported versus 0% for placebo. The US Food and Drug Administration highlights the risk of severe reactions with local and systemic allergic features and herpes zoster infection. In their update they state the need ‘to avoid applying the gel in, near, and around the mouth, lips and eye area’.1

Ablative treatments 

Photodynamic therapy (PDT)

Photodynamic therapy (PDT) is an effective option for field-directed treatment.1,2 It 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.1 The treatment is useful for areas of extensive field damage and multiple AKs (e.g. the bald scalp or lower legs) that are prone to poor healing. Photodynamic therapy has similar efficacy rates to cryotherapy and 5% fluorouracil (5-FU).1 However, patients have rated cosmetic outcome and satisfaction more highly for PDT than for cryotherapy.19 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 a wider availability of treatment to the patients. Another new modality is the concept of daylight PDT, which involves the application of MAL to the skin without occlusion, and then exposure to ambient daylight. Sunscreen is applied 15 minutes before MAL, then 30 minutes later the patient spends 2 hours outdoors. This treatment has been useful in grade 1 and 2 lesions on the face and scalp, with clearance rates of 70–89% reported. European studies show that daylight PDT can be performed in all weather conditions, but temperatures above 10°C are advised for patient comfort.1

Cryotherapy

Cryotherapy (or cryosurgery) using liquid nitrogen has been a longstay in the treatment of solitary, uncomplicated AK. A single or double freeze-thaw cycle, with 5 seconds per freeze, is usually sufficient. Treatment can be carried out in primary care provided that a diagnosis of AK (and not SCC) is certain and that the practitioner has the right equipment and storage facilities for liquid nitrogen.

Cryotherapy is quick, efficient, and easy to administer. Patients should be warned about pain that arises during treatment and the side-effects that arise afterwards, including blistering, ulceration, and scarring as well pigment changes in the skin.1 Additionally, care must be taken on certain anatomical sites such as the back of the hands where prolonged use can lead to the exposure of nerves and tendons, as well the lower legs where poor healing and chronic ulceration may be a problem.1 The relationship between duration of the freeze and AK clearance has been examined in a three-dose study of untreated actinic keratoses greater than 5 mm in diameter on the face and scalp, with 12-month follow up after cryosurgery. A treatment duration of less than 5 seconds showed 39% cure, 5–20 seconds 69% cure, and over 20 seconds 83% cure. A randomised study comparing cryosurgery with PDT in 193 patients at 3 months indicated an overall 75% response rate for cryosurgery compared with 69% in those treated with PDT.1

Cryotherapy (or cryosurgery) using liquid nitrogen has been a longstay in the treatment of solitary, uncomplicated AK

Surgery

No trials exist about the use of surgery in the management of AK. Surgery is a useful modality of treatment for ‘isolated, thicker lesions, especially where SCC is suspected, as it can ensure a correct clinical diagnosis (through biopsy) and simultaneously treat the patient effectively.1

Where topical treatments are ineffective, curettage and cautery, shave biopsy, or formal excision may be deployed for larger AKs.1 Shave biopsy often makes interpretation of the pathology easier because the architecture of the specimen is preserved. Surgical treatments may be carried out in primary care by approved doctors. 

It is essential that any specimen obtained is sent for histology to exclude the possibility of SCC.

Laser treatment

Finally, other ablative treatments that are rarely given include laser treatments using carbon dioxide, chemical peels, and dermabrasion.1 These are more likely to be used outside the UK due to their risk of long-term side-effects, expense, and safety legislation.

Other considerations

Immunosuppressed patients

The risk of developing SCC is likely to be higher for immunosuppressed patients than in the normal population, and so there is a greater need to treat AK in this patient group.1 Within a large group of renal transplant patients, nearly one-third were found to have AKs. Half of these AKs were solitary AKs and half were within an area of field damage. In the following year, the rate of development of SCC associated with solitary AK was 7%, in comparison with 21% of those with field change, most of which (11 of 15) arose within the field.20

Anecdotal evidence suggests that treatments for AK in transplanted patients are less effective than for the normal population, either because the lesions are more proliferative and usually thicker, or because the new lesions appear rapidly in the treated site.1

Special sites

The 2017 BAD guidance discusses treating AK in special sites, such as periocular sites, which may be awkward for topical therapies and pose a risk of adverse events to the eye. The guideline states that: ‘Periocular AK needs careful assessment in secondary care.’ 

If SCC arises on the ears, which are common sites for AK presentation, it carries a higher risk for metastasis.1 The BAD 2017 guideline recommends early attention to treatment as well as preventative measures such as sunscreens and wearing a broad-brimmed hat. Grade 3 AKs on the ear may need to be treated with curettage and cautery in order to obtain histology and reduce the risk of missing SCC.1

The legs in the elderly should be accorded more flexible regimens to avoid ulceration; less destructive therapies such as PDT should be offered.1

With regard to the hands, treatments may need to be prolonged as these areas are more resistant than the head and neck areas.1

Conclusion

Actinic keratosis is a chronic skin condition that is a marker of sun damage. The risk of transformation into SCC is low. Most AKs can be treated in primary care with topical treatments. It is worth trying to classify AKs into grades 1–3, which will help direct management. It is also useful to consider that treatment is not always required, and if it is, patients should be encouraged to participate in their treatment. Self-care measures should be recommended, including sun exposure education, and use of clothing and sunscreens. When there is a suspicion that an AK is transforming into SCC, patients should be referred expediently along the 2-week wait pathway—this is particularly important in patients who are immunosuppressed and are therefore at increased risk of SCC.

Most AKs can be treated in primary care with topical treatments

Key points

  • Actinic keratosis is a common, chronic skin condition that is prevalent in the elderly population. It should be treated in primary care with the variety of topical therapies available
  • Patients should be encouraged to self-care in relation to prevention and recognition of which AKs could be transforming into SCC. They should be reassured that AK rarely turns into SCC
  • A multitude of ways to treat AK exist, including:
    • limiting UV exposure; use of emollient for symptomatic relief
    • topical treatments
    • ablative/surgical treatments

Each treatment has its own pros and cons

  • Patients should be:
    • involved and empowered in decision-making about management of their AK
    • counselled about side-effects of treatment; this could be in the form of pictures demonstrating various topical reactions. The patient is more likely to concord with treatment if they have been warned about side-effects
  • The role of primary care in the management of AK is to:
    • educate the patient and manage expectations
    • encourage treatment in the community
    • consider the lesions as markers of solar damage and therefore possible skin cancer
    • refer patients promptly if AK is transforming into SCC: this is vitally important for ‘at risk’ patients, e.g. the immunosuppressed or those with conditions such as xeroderma pigmentosa.

AK=actinic keratosis, SCC=squamous cell carcinoma; UV=ultraviolet

GP commissioning take home messages for England

written by Dr David Jenner, GP, Cullompton, Devon

  • Actinic keratosis is a common condition, and commissioners should provide support so that it can be managed in primary care thereby avoiding unnecessary specialist referral
  • Clear pathways for the treatment of AK should be established and agreed with specialist providers and be readily accessible via websites or mobile apps for reference
  • Local formularies should identify the various topical treatments available, discuss their advantages and disadvantages, and develop printable application guidance sheets for patients
  • Although conversion from AK to squamous cell carcinoma is rare, clear indications and routes for referral to specialist opinion should be identified in the pathways.

AK=actinic keratosis