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Home , Actinic keratosis, Cryosurgery, Erythema, Sunburn

 CLINICAL PRACTICE Actinic keratoses Update

Actinic keratoses (AK) commonly occur in the caucasian population living in environments of high levels of exposure, and are considered to be a marker for chronic sun damage. This article reviews the epidemiology, pathogenesis, and current debate on AK as precancerous lesions. The various treatment options for AK, including combination therapy, are also discussed.

Alvin Chia MBBS, is Research Fellow, St Actinic keratoses (AK), or solar keratoses commonly 1% over 10 years,8 with some estimates as high as 10% George & Cancer Centre, Kogarah, New occur in the caucasian population living in environments over 10 years.9 Conversely, AK may regress spontaneously South Wales. alvin_chia74@ with high levels of sun exposure. They overwhelmingly or remain stable.10 The relative risk for SCC increases for yahoo.com.au occur on sun exposed areas of fair skinned individuals those with more than five AK.11 Gilberto Moreno and are a marker for chronic sun damage. Actinic keratoses have historically been considered MD, is Resident Medical premalignant, but recent publications have advocated that Officer, Royal North Shore Epidemiology AK be considered ‘cancerous’.12,13 Actinic keratoses share Hospital, St Leonards, New Cumulative sun exposure is the single most important cause many similar molecular and histological features with SCC South Wales. of AK.1 The prevalence of AK in the Australian caucasian and it can sometimes be difficult to distinguish between Adrian Lim population over 40 years of age is 40–50%.2 The incidence of the two clinically. Some clinicians14 are concerned about FRACGP, FACD, is a dermatologist, St George AK rises with age, increasing from less than 10% in the third the ramifications of a ‘cancer’ diagnosis for the patient Dermatology & decade of life to more than 80% in the seventh decade.3,4 and the care system. These include the patient’s Centre, Kogarah, New South The most important factor determining susceptibility to emotional distress associated with the diagnosis of ‘cancer’ Wales. (UV) damage is the skin phenotype. and also increased health care costs. AK may be regarded Stephen Shumack Individuals with fair skin who easily (Fitzpatrick type as an early clinical manifestation on a biological spectrum FACD, is a dermatologist, I and II) and have difficulty tanning, are most at risk. that has invasive SCC at the other end. Actinic keratoses Royal North Shore Hospital, An Australian population based survey has demonstrated are nevertheless considered a relatively late event on the St Leonards, and St George Dermatology & Skin Cancer 2 that individuals with AK have on average 6–8 lesions. The carcinogenesis pathway as it requires substantial UV damage Centre, Kogarah, New South upper limbs and head/neck region account for more than to the skin for AK to occur. Wales. 80% of all AK, with the back of the hands and forearm being the most commonly affected. Treatment Treatment of AK needs to be discussed with patients for Pathogenesis several reasons. Patients should realise that there is a Ultraviolet radiation damages the DNA of low rate of transformation of AK to SCC. Despite this, the with repeated exposure. It has been suggested that AK will presence of AK indicates that they have a higher risk for more likely progress to invasive squamous skin cancers compared to the general population, and would (SCC) if mutations occur in p16(INK4a).5 Ultraviolet radiation therefore need to be screened and checked on a regular also gives rise to AK through interference of the skin’s basis. Ultimately, most patients want their AK treated, .6,7 A decrease in cellular immunity allows either for their malignant potential, or other reasons such some DNA damaged keratinocytes to escape , as cosmesis and symptomatic relief. The discussion should which may lead to the growth of atypical clones. These also include advice on reducing or preventing further sun molecular changes are part of a multistep process that leads damage by ensuring appropriate outdoor and the to the development of AK and SCCs. This process may be use of . It has been shown that regular use of accelerated in immunocompromised patients. not only prevents the development of AK, but also hastens the remission of existing AK.15 Relationship with SCC Lesion specific therapy Actinic keratoses can progress to, but are by no means an obligate precursor of, SCC. The risk of progression is Lesion specific therapies, such as , are estimated as 0.075–0.096% per lesion per year, or around widely considered the most practical and effective

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treatment options for AK. Other lesion specific during treatment. Noncompliance is an issue with available PDT sensitisers.24 PDT with Metvix has options include curettage (alone or with this treatment because of the significant side been reported to achieve 100% clearance in up electrodessication/cautery) and shave excision. effects such as , itching, burning and to 82% of patients and an efficacy of 90% for Adverse reactions include changes crusting. Although temporary, the side effects individual AK lesions.25 The phototoxic reactions (usually hypopigmentation), scarring, poor wound can be unpleasant and may cause discomfort and also cause adverse events such as erythema, healing and rarely, nerve damage. Hence, they short term disfigurement. Side effects usually stinging, itching, oedema and exudation. The may not be as useful in cosmetically sensitive begin after the first week and can persist for up to associated with such reactions may be areas or in regions with large numbers of AK. 2 weeks following the treatment period. Pulsed 5- severe enough to require local anaesthesia, Cryotherapy using liquid is most FU therapy has been advocated by some as a way especially during the illumination process. commonly used to treat AK. This method destroys of obtaining the same efficacy but with reduced Healing time is often less than 10 days. Patient the keratinocytes through freezing, while mostly AR.20 This has yet to be universally accepted satisfaction levels are high with regards to the preserving important dermal structures such as in clinical practice, and therefore pulsed 5-FU cosmetic outcome.25 blood vessels, nerves and collagen due to their therapy is not commonly used as a treatment for higher resistance to cold. This ranges from the AK in Australia. 83% reported for freezing times longer than Imiquimod is an immune response modifier that 20 seconds, to 39% for 5 seconds or less of targets both innate and acquired immunity. It acts freezing.16 Hypopigmentation is a recognised Diclofenac is a nonsteroidal anti-inflammatory largely by triggering the expression of a range of sequelae with cryotherapy because the drug that can be suspended in gel including interferon alpha, gamma and in the are also susceptible for topical treatment of AK. The exact mechanism interleukin.12 Imiquimod has the ability to induce to freezing injury. of the drug is not established but is likely to be apoptosis in tumour cells and thus decrease Curettage is another lesion specific technique related to the inhibition of the COX-2 enzyme21 tumour development.26 for AK that is quick and convenient to perform leading to decreased levels of prostaglandins Five precent imiquimod was found to be but requires local anaesthesia. Bleeding can be and prostacyclines, mediators that are involved in effective and well tolerated for the treatment controlled by aluminium chloride, silver nitrate, carcinogenesis. Diclofenac achieved a 100% AK of multiple AK when used twice per week for or electrodessication. Another advantage of clearance in 50% of the patients after 3 months a total of 16 weeks as reported in a recent curettage over cryotherapy is the availability of of twice per day application compared to placebo pivotal phase III study.27 More than 41% of tissue for histological examination, particularly gel.22 This relatively long treatment duration is imiquimod treated patients achieved complete when SCC is suspected. Scarring occurs more a disadvantage and reduces compliance, but a clearance, while the median percent reduction commonly than with cryotherapy. shorter treatment period is reported to have lower in AK numbers was 83%. A three times per efficacy, probably due to the delayed onset of week treatment regimen for 16 weeks has also Field therapy action.22 The advantage of diclofenac treatment been shown to be effective (48–57% complete Field therapy is treatment of an entire field (eg. is its higher tolerability due to limited local clearance).28,29 With the aim of decreasing local forehead, cheek) that is marked by the presence and irritation. Side effects and local skin reactions, which can be quite variable in of visible AK. It is increasingly accepted as reactions may include contact , dry severity, smaller studies of cycle therapy have another modality of treatment as it treats not only skin, pruritus and .23 been performed.30,31 In these studies, imiquimod visible AK but the expanded clones of dysplastic was applied 2–3 times a week for 3–4 weeks PDT cells at the subclinical and cellular level in that and this was repeated after a rest period of 4 region of UV damaged skin.17 Most field therapy This treatment modality involves the application weeks in those with residual lesions. A complete agents used these days have good tolerability and of a pre-photosensitiser to the area of the clearance rate was achieved in up to 82% of efficacy, and excellent cosmetic outcome. These skin being treated. An incubation period (1–3 treatment sites. The rest period also allows the include 5- (5-FU), diclofenac, PDT/ALA, hours) is necessary for it to be preferentially physician to assess the need for another ‘cycle’ and imiquimod. accumulated in dysplastic and malignant cells, of treatment as the therapeutic effect continues where it is converted enzymatically to the potent while inflammation subsides. 5-fluorouracil photosensitiser protoporphyrin IX. The area is then Combining therapies Topical 5-FU has been an established treatment exposed to a light source, leading to preferential for AK for several decades.18 It interferes with tumour cell death. This is due to the generation The different therapies mentioned above can DNA synthesis by blocking the conversion of of resulting in oxidative often be combined. These benefits include deoxyuradilic acid to thymidylic acid.19 5- cell damage. Methyl 5-aminolevulinate (Metvix) is higher efficacy with limited local side effects and fluorouracil has generally been viewed as effective the most commonly applied agent as it has better better cosmetic results. The published evidence for AK and it’s efficacy is dependent on the degree penetration capabilities and higher selectivity for supporting the use of combination therapy is of inflammation, erosion and ulceration elicited abnormal cells compared to other commercially scant. Despite this, the wider availability of

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different classes of therapy for AK will likely or holiday, in climates with high levels of sun 2003;149:37–9. 18. Dillaha CJ, Jansen GT, Honeycutt WM, et al. Further studies prompt an increase in clinicians combining the exposure. Although there is ongoing debate with topical 5–fluorouracil. Arch Dermatol 1965;92:410–7. benefits of various treatments. One example about whether AK are malignant or premalignant, 19. Eaglstein WH, Weinstein GD, Frost P. Fluorouracil: mecha- would be the use of a field therapy combined the rate of transformation to SCC is low. nism of action in and actinic keratoses I: Effect on DNA synthesis in vivo. Arch Dermatol 1970;101:132–9. with cryotherapy. Field therapies may treat Nevertheless, AK remains a useful marker for 20. Labandeira J, Pereiro M Jr, Valdes F et al. Intermittent subclinical lesions not treated by cryotherapy, SCC risk. Field and lesion targeted therapies serve topical 5-fluorouracil is effective without significant irrita- tion in the treatment of actinic keratoses but prolongs while cryotherapy or curettage can treat different clinical scenarios but are increasingly treatment duration. Dermatol Surg 2004;30:517–20. hyperkeratotic lesions that may not respond well combined for optimal management of both 21. Higashi Y, Kanekura T, Kanzaki T. Enhanced expression of cyclooxygenase (COX)-2 in human skin epidermal cancer to field therapy. immunocompetent and immunosuppressed cells: Evidence for growth suppression by inhibiting COX-2 The number, location and character (eg. patients. Established and newer field treatment expression. Int J Cancer 2000;86:667–1. 22. Nelson C, Rigel D, Smoth S, et al. Phase IV, open label hypertrophic, lichenoid) of AK will influence the methods are additionally useful for subclinical assessment of the treatment of actinic with 3% choice of therapy. Multiple AK on diffusely sun lesions with the added benefit of a potentially diclofenac sodium topical gel (Solaraze). J Drugs Dermatol damaged skin may benefit from field therapy superior cosmetic outcome. 2004;3:401–7. 23. Gebauer K, Brown P, Varigos G. Topical diclofenac in hyal- while lesion specific therapy might suffice for Conflict of interest: none declared. uron gel for the treatment of solar keratoses. Australas J fewer or solitary lesions. The accessibility to Dermatol 2003;44:40–3. References 24. Fritsch C, Homey B, Stahl W, et al. Preferential relative clinic visits and anticipated compliance would 1. Kennedy C, Bajdik C, Willemze R, et al. The influence of porphyrin enrichment in solar keratoses upon topical be additional considerations. Cosmetic outcome painful and lifetime sun exposure on the risk of application of delta- methylester. Photochem Photobiol 1998;68:218–21. may influence choice of treatment, particularly in actinic keratoses, seborrheic , melanocytic nevi, atypi- cal nevi, and skin cancer. J Inv Dermatol 2003;120:1087–93. 25. Pariser D, Lowe N, Stewart D, et al. younger patients. 2. Marks R. Epidemiology of non- skin cancer and with topical for : solar keratoses in Australia: a tale of self immolation in results of a prospective randomised multicenter trial. J Immunocompromised patient Elysian fields. Australas J Dermatol 1997;38(Suppl 1):S26–9. Am Acad Dermatol 2003;48:227–32. 3. Frost CA, Green AC. Epidemiology of solar keratoses. Br J 26. Meyer T, Nindl I, Schmook T, et al. Induction of apoptosis Immunocompromised patients are at an Dermatol 1994;151:455–64. by toll-like receptor-7 agonist in tissue cultures. Br J 4. Green A, Beardmore G, Hart V, et al. Skin cancer in Dermatol 2003;149(Supp 66):9–13. increased risk of developing AK. These include a Queensland population. J Am Acad Dermatol 27. Lebwohl M, Dinehart S, Whiting D, et al. Imiquimod organ transplant recipients who are on 1988;19:129–38. 5% for the treatment of actinic keratosis: results 5. Mortier L, Marchetti P, Delaporte E, et al. Progression from two phase III, randomised, double blind, parallel immunosuppressive therapy. Transplant recipients of actinic keratosis to of the group, vehicle controlled trials. J Am Acad Dermatol are up to 250 times more likely to develop AK.32 skin correlates with deletion of the 9p21 region encod- 2004;50:714–21. 28. Korman N, Moy R, Ling M, et al. Dosing with 5% imiqui- Imiquimod and other field therapies have been ing the p16(INK4a) tumour suppressor. Cancer Lett 2002;176:205–14. mod cream 3 times per week for the treatment of actinic used in these immunocompromised patients 6. Simon JC, Tigelaar RE, Bergstresser PR, et al. UVB radia- keratosis: results of two phase 3, randomised, double blind, parallel group, vehicle controlled trials. Arch with good results.33 Imiquimod is generally tion converts LC from immunogenic to tolerogenic antigen presenting cells: induction of specific clonal anergy in CD4+ Dermatol 2005;141:467–73. thought to be safe in immunocompromised T helper 1 cells. J Immunol 1991;146:485–91. 29. Szeimies R-M, Gerritsen M-J, Gupta G, et al. Imiquimod patients.33 7. Yoshikawa T, Rae V, Bruins-Slot W, et al. Susceptibility to 5% cream for the treatment of actinic keratosis: results effect of UVB radiation on induction of contact hypersen- from a phase III, randomised, double blind, vehicle con- trolled, clinical trial with . J Am Acad Dermatol Other treatments sitivity as a risk factor for skin cancer in humans. J Invest Dermatol 1990;95:530–6. 2004;51:547–55. 8. Marks R, Rennie G, Selwood TS. Malignant transforma- 30. Salasche S, Levine N, Morrison L. Cycle therapy of actinic Other treatments less commonly used to treat tion of solar keratosis to squamous cell carcinoma. Lancet keratoses of the face and with 5% topical imiqui- AK include chemical peels, laser resurfacing and 1998;1:795–7. mod cream: an open label trial. J Am Acad Dematol 2002;47:571–7. . Medium depth peels are used 9. Glogau RG. The risk of progression to invasive disease. J Am Acad Dermatol 2000;42(1 Pt 2):23–4. 31. Chen K, Yap L, Marks R, et al. Short course therapy with either alone or as an adjunct for the treatment 10. Marks R, Foley P, Goodman G, et al. Spontaneous remission imiquimod 5% cream for solar keratoses: a randomised controlled trial. Australas J Dermatol 2003;44:250–5. of AK, especially in the head and neck areas. of solar keratosis: the case for conservative management. Br J Dermatol 1986;115:649–55. 32. Euvrard S, Kanitakis J, Pouteil-Noble C, et al. Comparative Chemical agents used for peels include glycolic 11. Green A, Battistutta D. Incidence and determinants of epidemiologic study on premalignant and malignant acid, trichloroacetic acid, and salicylic acid. Laser skin cancer in a high Australian population. Int J Cance epithelial cutaneous lesions developing after kidney 1990;15:356–61. and heart transplantation. J Am Acad Dermatol resurfacing and dermabrasion are techniques 12. Lober B, Lober C, Accola J. Actinic keratosis is squamous 1995;33:222–9. that work by physical destruction of AK and cell carcinoma. J Am Acad Dermatol 2000;43:881–2. 33. Ulrich C, Busch JO, Meyer T, et al. Successful treatment 13. Heaphy MR Jr, Ackerman AB. The nature of solar kerato- of multiple actinic keratoses in organ transplant patients removes outer epidermal layers. They generally sis: a critical review in historical perspective. J Am Acad with topical 5% imiquimod: a report of six cases. Br J have a good cosmetic outcome. A novel therapy Dermatol 2000;43:138–50. Dermatol 2006;155:451–4. 34. Ogbourne S, Suhrbier A, Jones B, et al. Antitumor activity being trialled at present is the use of 3-ingenyl 14. Marks R. Who benefits from calling a solar keratosis a squamous cell carcinoma? Br J Dermatol 2006;155:23–6. of 3-ingenyl angelate: plasma membrane and mitochon- angelate (extract of peplus plant) 15. Thompson SC, Jolley D, Marks R. Reduction of solar drial disruption and necrotic cell death. Cancer Res 2004;64:2833–9. to treat AK.34 keratoses by regular sunscreen use. N Engl J Med 1993;329:1147–51. 16. Thai KE, Fergin P, Freeman M, et al. A prospective study of Conclusion the use of for the treatment of actinic kerato- ses. Int J Dermatol 2004;43:687–92. Actinic keratosis is a common dermatological 17. Tran H, Chen K, Shumack S. Summary of actinic kera- CORRESPONDENCE email: [email protected] problem in caucasian populations that live, tosis studies with imiquimod 5% cream. Br J Dermatol

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