Dr Gillian Kyei GPwER Bromley Community Dermatology Service Actinic Keratosis Dr Gillian Kyei GPwER Bromley Community Dermatology Service

Introduction What is an Actinic Keratosis (AK)? Why is AK important? How do I diagnose AK? To manage in primary care or refer? To treat or not to treat? What treatments can help? Are there any special considerations?

Mr V Fair, 65 years old “I have red, dry patches on my face and arms doctor. They have been there for months. I saw another GP who gave me some steroid cream but it didn’t work” “I tan after a while in the sun but I burn first. I love my sunny holidays but I’m not good with suncream.” Fitzpatrick Type 2 skin Other history: Never had a skin cancer. Otherwise completely well with no regular medication.

What is an Actinic Keratosis? Scaly, erythematous lesions Premalignant (risk of SCC) Low potential for invasive malignancy Can spontaneously regress Sites with chronic UV exposure Face, ears, scalp Dorsum of hands, forearms Lower legs More common with increasing age, fair skin, immunosuppression Point-prevalence studies demonstrate that lesions regress and relapse over time (this is probably relevant in the case of grade 1 and 2 lesions). Figures range between 25% and 70% for apparent resolution of AKs over a period of 1–4 years.

What is an Actinic Keratosis? Normal Skin Top layer of keratin (horny epidermis) Rest of the epidermis Dermis Actinic Keratosis Pathophysiology[1] The condition is caused by UV-induced DNA damage within the skin. Cells within AKs show characteristic UV-induced gene mutations. Human papillomaviruses (HPVs) have been implicated as co-carcinogens in the pathogenesis[2]. Histologically AKs share features with SCC. AK is an epidermal lesion characterised by: Collections of atypical, pleomorphic keratinocytes in the basal layer which can extend to the upper granular and cornified layers. The epidermis being abnormal in architecture, with acanthosis, parakeratosis and dyskeratoses. Cellular atypia is present with keratinocytes varying in size and shape. Mitotic figures being present. Limitation to within the epidermis only. AKs can resolve spontaneously, stay stable, or progress to Bowen's disease (carcinoma in situ) or to SCC. They can be distinguished more by the degree of cellular change and the extent of the lesions rather than differences in the features of individual cells. AK is considered by some to be the earliest manifestation of SCC[2]. Lots of top layer skin (hyperkeratosis) Epithelial dysplasia Normal dermis

How Do I Diagnose AK? Scaly, red lesions Location: sun-exposed sites Asymptomatic (usually) Grades of Severity: 1 to 3 and “field change” Field change refers to areas of skin that have multiple AK associated with a background of erythema, telangiectasia and other changes seen in sun-damaged skin. These areas are probably more at risk of developing SCC, especially if left untreated and, as such, it is recommended that they should be treated more vigorously. As such, the treatments should be applied to the whole area of field change and not just the individual lesions.

How Do I Diagnose AK? Field change: Large areas of multiple AKs on a background of erythema and sun damage Grade III: : Very thick hyperkeratosis. IS IT AN SCC? Grade II: : Moderately thick hyperkeratosis on background of erythema that are easily felt and seen Grade I: Flat, pink macule often easier felt than seen. Scale and pigmentation may be present AK Variants Erythematous Pigmented Hypertrophic / Bowenoid (thick areas of scale) Cutaneous horn Lichenoid (smooth, shiny, mainly in areas of friction) Actinic cheilitis (lips)

How Do I Diagnose AK? Dermoscopy ​A red pseudonetwork Strawberry-like appearance Structures may not be visible if there is a lot of scale

Why are Actinic Keratoses Important? AK is a risk marker for skin cancer an individual with average 7.7 AKs has 10% probability of developing SCC within 10 years full-body skin examination more likely to reveal a skin cancer in patients with AK Full body exam revealed BCC, SCC or melanoma in 4% individuals with AK (n=2061) High prevalence >23% UK population aged 60 and above have AK Re: Rotterdam study full body skin examination fact: Flohil SC, van der Leest RJ, Dowlatshahi EA et al. Prevalence of actinic keratosis and its risk factors in the general population: the Rotterdam Study. J Invest Dermatol 2013; 133:1971–8. Mathematical model estimate for 7.7 AK fact: Dodson JM, DeSpain J, Hewett JE et al. Malignant potential of actinic keratoses and the controversy over treatment. A patientoriented perspective. Arch Dermatol 1991; 127:1029–31.

Action for all AK patients: Advise sun protection Undress patient for full skin examination Discuss the risk of skin cancer and how to recognise change Give leaflets (BAD, Dermnet NZ)

To Treat or To Refer? AK Guidelines (BAD, 2017) recommend management of AK in primary care Refer when: Higher risk patient History of skin cancer/extensive UV damage Long-term immunosuppressed/young patients Multiple or relapsing AKs Treatment failure RED FLAGS for SCC (2WW): Bleeding/Ulceration Painful/Tender Rapidly growing Thickened “with substance”/firm, fleshy base/indurated Lip lesions

To Treat or Not to Treat? You do not have to treat all patients (Grades I-II) Spontaneous regression, low malignant potential Side-effects of treatment Consider patient preference, general health, extent of lesions, risk factors for skin cancer Hypertrophic AK (Grade III) and Field Change - treat Emollient may be useful The natural history of individual lesions suggests that treatment is not universally required on the basis of preventing progression into SCC.15 An indirect benefit of treatment is the demonstration of lesions not responding to normal therapy, which may represent a subgroup with higher malignant potential. There is a body of professional opinion that believes AKs are part of a spectrum that includes SCC in situ, and that prevention of SCC is therefore the reason for therapy.31 A Cochrane review of treatment of AK did not find any evidence that treatment of AK resulted in reduction in presentation of invasive SCC.32 There is inadequate evidence to justify treatment of all AKs to try to prevent malignant change. The number and severity of actinic keratoses can also be reduced by taking nicotinamide (vitamin B3) 500 mg twice daily.

What Treatments Can Help? Topical treatments (remove defective epidermis) Diclofenac gel (Solaraze) 5-Fluorouracil (Efudix) 5-Fluorouracil with salicylic acid (Actikerall) Imiquimod (Aldara, Zyclara) Ingenol mebutate (Picato) Cryotherapy (community dermatology service) Curettage and cautery (community dermatology service) Photodynamic therapy, PDT (secondary care) Treatment of an actinic keratosis requires removal of the defective skin cells. Epidermis regenerates from surrounding or follicular keratinocytes that have escaped sun damage.

Solaraze (Diclofenac gel) BD for 12 weeks. Review 4 weeks after completion. Advantages Generally well-tolerated, side-effects less harsh May be useful for thinner AKs and for field change Disadvantages Less efficacious than other topical treatments Requires commitment to long course

Efudix (5% 5-fluorouracil) OD-BD for 4 weeks. Area up to 23x23cm2. Review after 3 months. Most efficacious topical treatment (Cochrane meta-analysis) Harsh side-effects expected during treatment and for 2-3 weeks afterwards Redness, oozing, crusting, soreness, photosensitivity Prepare patient For Adult  Apply 1–2 times a day for 3–4 weeks (usual duration of initial therapy), apply thinly to the affected area, maximum area of skin 500 cm2 (e.g. 23 cm × 23 cm) treated at one time, alternative regimens may be used in some settings. 5-Fluorouracil is a cytotoxic agent. The cream formulation is applied once or twice daily for 2 to 8 weeks. 5-fluorouracil cream is sometimes combined with salicylic acid. Its effect may be enhanced by calcipotriol ointment. Complete clearance of lesions can be delayed several weeks beyond completion of topical therapies

“My Efudex Experience” Treatment Day 5

“My Efudex Experience” Treatment Day 18

“My Efudex Experience” Treatment Day 30

“My Efudex Experience” Healing Day 6

“My Efudex Experience” Healing Day 36

“My Efudex Experience” Four years later

Efudix (5% 5-fluorouracil) OD-BD for 4 weeks. Area up to 23x23cm2. Review after 3 months. Most efficacious topical treatment (Cochrane meta-analysis) Harsh side-effects expected Redness, oozing, crusting, soreness, photosensitivity Prepare patient Consider breaks in treatment/applying over small area first Consider hydrocortisone 1% or Eumovate cream after treatment has finished Consider pulsed treatment regimes (less effective) e.g 1 day a week for 12 weeks Contraindications Dihydropyrimidine dehydrogenase (DPD) deficiency Pregnancy/lactation For Adult  Apply 1–2 times a day for 3–4 weeks (usual duration of initial therapy), apply thinly to the affected area, maximum area of skin 500 cm2 (e.g. 23 cm × 23 cm) treated at one time, alternative regimens may be used in some settings. 5-Fluorouracil is a cytotoxic agent. The cream formulation is applied once or twice daily for 2 to 8 weeks. 5-fluorouracil cream is sometimes combined with salicylic acid. Its effect may be enhanced by calcipotriol ointment. Complete clearance of lesions can be delayed several weeks beyond completion of topical therapies

Other Topical Treatments Aldara (5% imiquimod) Apply three times a week for 4 weeks Side-effects similar to Efudix and possible flu-like symptoms Picato (Ingenol mebutate) Data less convincing regarding efficacy Expensive 2-3 day application only Consider where long term application is impractical Actikerall (5FU and salicylic acid) Field change, below knee AK, hands and forearm AK Ingenol mebutate (Picato) A 2015 update from the US Food and Drug Administration highlights the risks of severe adverse reactions, with local and systemic allergic features and herpes zoster infection. Within the update they emphasize the need ‘to avoid applying the gel in, near, and around the mouth, lips and eye area Clobetasol propionate, used twice daily for 4 days post-treatment, did not alleviate the symptoms or efficacy of ingenol mebutate.99 This may be relevant to other treatments causing soreness. Retinoids A range of older trials demonstrate a modest benefit with the use of topical retinoids in AK.100 They may lend some additional benefit with respect to improvement in lentigines and reduced wrinkles. Their use is usually sustained rather than based on a limited course of treatment.

PCDS Actinic Keratosis Guidance

PCDS Actinic Keratosis Guidance

Special considerations Periocular AK Risk: conjunctivitis, preseptal cellulitis with Efudix/Aldara on eyelids Low threshold to refer Ear AK The risk of SCC metastasis is higher on the ear, consider histology for thick AKs Forearms & hands AK May need prolonged treatment, more resistant than face/scalp Actikerall or curettage can be useful Below the knee AK Risk of treatment complications (nonhealing, soft-tissue infection) Flexible regimens and heightened supervision Elevation and compression for some Avoid cryotherapy in gaiter area Actikerall, PDT and curettage most highly recommended in BAD Guidelines liquid nitrogen is used with a contact probe, ensuring that cold vapour does not damage the eye 14 patients treating periocular skin with 5-FU 5% twice daily for 2 weeks, antibiotic ointment was coprescribed and used until the area had healed.163 Six of the 14 AKs were on the upper eyelid and nine abutted a lid margin. Five patients required a second course of treatment, but overall clearance was complete in all cases and remained so for a mean follow-up period of 38 months. A retrospective study of the use of imiquimod 5% cream for a range of periocular actinic lesions identified 47 patients mainly with AK, mainly on the lower lid.164 Conjunctivitis occurred in 15 and six had ocular stinging, with conjunctivitis in three for over 2 weeks. Antibiotics were needed in three, for preseptal cellulitis in two of them. Nine patients discontinued imiquimod due to ocular irritation and conjunctivitis, of whom four patients recommenced and finished the treatment after a rest period. At a mean follow-up of 16 weeks, 34 (72%) patients had clinical clearance of the periocular lesions and no patient had any residual ophthalmic side-effects from imiquimod.

Special considerations Aldara and Picato dispensed in aliquot packages that are single-treatment doses Tightly defines cost per course of treatment Efudix comes in a tube Only 31% use the contents of a tube in a single course of treatment More flexibility

Summary AK is common Important risk factor for developing skin cancer Treatment is not always needed but vigilance is required In primary care, Efudix is an effective option but needs appropriate counselling Beware of red flags for SCC, 2WW if concerned including high risk background, bleeding, ulceration, tenderness, rapid growth, thickened