Clinical Focus on Actinic Keratosis Skin cancer in general practice: know the risk factors by Devon Phillips Skin cancer continuum: AK to SCC SCC and previous AK status Actinic keratosis (AK) has been demonstrated as the initial lesion in the disease continuum that progresses to invasive squamous cell carcinoma (SCC) with the potential for significant morbidity and death.1 Similar to the value of the fecal occult blood test for colorectal cancer and the PAP test for cervical cancer in saving thousands of lives,2 the prevention, screening and early treatment of AK has been recommended to reduce the potential for progression to nonmelanoma skin cancer (NMSC).3,4 Different studies have shown an estimated 40–80% of SSCs arose from lesions previously diagnosed on AKs.11,12 In defined high-risk populations (older males), about 65% of all primary SCCs diagnosed arose in lesions that were previously defined as AKs.13 Increased rates of nonmelanoma skin cancer The incidence of NMSC (the most frequent family of skin cancers) in Canada is projected to increase over the next several decades due to a growing and aging population, from an estimated annual average of 75,953 cases between 2000 and 2004 to 147,000 cases in 2031, representing a significant burden of treatment costs and lost productivity.5 It’s estimated that 81,300 new cases of NMSC will be diagnosed in Canada in 2012 alone6 and that 320 deaths will result from this disease in 2012.6 Redefining actinic keratosis AKs are dysplastic keratinocytic skin lesions that are caused by chronic exposure to ultraviolet (UV) radiation. The clinical significance of AK relates to the risk of malignant transformation to NMSC. Although NMSC is treatable, some lesions, particularly SCC, may become invasive and lead to death.3 Current consensus in some jurisdictions is that AK can be considered the earliest clinically recognizable manifestation of malignancy1 or an early in situ SCC.7 AK demonstrates cytologic and molecular features of malignancy. AK and SCC share genetic tumour markers and identical p53 gene mutations, are considered to be on the same disease continuum1 and share the same risk factors.8 Risk of progression from AK to NMSC In a review of 5 clinical studies, the risk of progression of AK to invasive SCC ranged between 0.025% and 16% per year for individual lesions.9 Extrapolation from these studies suggests a rate of risk of progression of AK to SCC of approximately 8%.9 Relative risk of transformation depends on a number of factors relating to the AK itself including thicknesss, grade of inflammation, degree of photo-damage in the surrounding area, as well as individual patient factors such as immune status and degree of pigmentation.10 Clinical appearance of AKs AKs appear as rough or scaly, often hyperkeratotic, flesh-coloured macules, papules, patches or plaques with discrete or diffuse borders. They can also be pigmented or erythematous and can present as plaques. The key to clinical diagnoses is often the sandpapery-like “People at increased sensation when touched.7 risk for actinic Lesions are typically 1–3 mm keratosis have fair in diameter but can be several skin, blue eyes, light centimetres in size and numerous as well as blended together. hair, tend to burn in The scaliness can often be felt the sun and not tan, before it is seen.1 and they have spent AK lesions occur on areas of a great deal of time chronically sun-exposed skin, including hands, forearms, face, out in the sun. Those bald scalp/forehead and rim of the at most risk include ears. If the patient has a history outdoor workers.” of significant tanning bed use, – Cheryl F. Rosen, MD, FRCPC, lesions could appear anywhere. Canadian Dermatology Association AK: scalp Squamous cell carcinoma AK: chest AK: forearm and hand All images have been acquired from DermNetNZ and images are published with permission from the New Zealand Dermatological Society Incorporated. Sponsorship of this Clinical Focus in Parkhurst Exchange is funded by Leo Pharma Inc. Risk factors for actinic keratosis (AK) and squamous cell carcinoma (SCC)1 Skin type Fair-skinned phenotype (with light-coloured eyes, red or blonde hair, inability to tan, tendency to sunburn, and the ability to form freckles, especially nonfacial freckles) UV light exposure Excessive or cumulative overexposure to UV radiation *Age Advancing age Occupation Outdoor vocation or hobbies Place of residence Sunbelt latitudes *History Presence of AKs or previous NMSC Gender Male, especially in early decades of life; in advanced age, gender risk is equal Anatomic distribution AK: often appears on back of hands, forearms, head, neck; SCC: frequently on head and neck Other Immunosuppression or predisposing genetic diseases such as xeroderma pigmentosum * The highest risk factors for developing AK and SCC are advancing age and the presence of AKs or a previous NMSC. Treatment The goals of treatment are to eradicate AKs and minimize their risk of progression to invasive SCC. This reduces the potential to metastasize and cause death, while achieving the best cosmetic outcome and reducing symptoms such as tenderness.14 Lesion-directed therapy (e.g. cryotherapy and other surgical therapies such as excision, laser therapy, dermabrasion, electrodessication and curettage) are used to treat single lesions but they don’t address “There are not enough dermatologists in the problem of actinic changes in the surrounding sun-damaged Canada. We need to area. To treat the whole area of enlist the help of field damage (i.e. obvious AK family physicians to as well as subclinical disease/ diagnose and treat invisible lesions), topical treatactinic keratoses.” ment or photodynamic therapy – Cheryl F. Rosen, MD, FRCPC, Canadian is recommended.10 Dermatology Association Follow-up and prevention A 5-minute skin examination by physicians (perhaps as part of the annual physical checkup) to screen and monitor for the development of AKs is vital, especially in high-risk patients.8 In addition, primary care physicians should educate patients about skin self-examination to detect the signs of malignant transformation and to report any suspicious moles or plaques.14 NMSC prevention strategies 6,14 Field cancerization AKs may present on a patient as a few detectable lesions. In addition to these, there are subclinical (invisible) AKs that are estimated to occur up to 10 times more often than visible AKs because all unprotected skin receives UV radiation from the sun.14 The phenomenon of clinical and subclinical AK lesions occurring in photo-damaged skin is called field cancerization. A field of change can be up to 7 cm around the primary lesions, resulting in lesions that are genetically similar.10 The presence of whole actinically damaged fields demands treatment modalities that are able to target and clear all lesions within the affected area, in order to reduce the risk of developing local recurrence, further AK and second tumours. 10,15 No technology or tests exist to determine which individual AK lesions will resolve spontaneously, remain stable or progress to invasive skin cancer.1 In one study, 82.4% of SCC cases were found to have concomitant AK giving rise to and/or in close proximity to SCC.16 Avoid excessive sun exposure (particularly between 11 a.m. and 2 p.m.), or any time of day the UV index is ≥ 3. Wear protective clothing (e.g. wide-brimmed hats) and sunglasses (wraparound is best) with 100% UV protection. Avoid artificial UV light such as tanning beds and sun lamps. Apply generous amounts of sunscreen with at least 30 SPF 3 or 4 times a day (if outdoors). Take extra care to practise good sun protection technique when participating in outdoor sports (e.g. swimming, skiing, snowboarding) because UV rays from the sun can be reflected by water, sand, pavement, snow and ice. Check “hard-to-see” places such as the back, back of the neck, legs and ears for any change in a birthmark or a mole that changes shape, colour, size or surface, or any new growth on the skin — pale, pearly nodules that may grow larger and crust, or red, scaly, sharply defined patches, any sore that doesn’t heal, and any patch of skin that bleeds, oozes, swells, itches or becomes red and bumpy. References 1. Oppel T, Korting HC. Actinic keratosis: the key event in the evolution from photoaged skin to squamous cell carcinoma. Skin Pharmacol Physiol 2004;17:67-76. 2. Canada Cancer Statistics 2012. www.cancer.ca/Canada-wide/About%20us/ Media%20centre/CW-Media%20releases/CW-2012/Canadian%20Cancer%20 Statistics%202012.aspx?sc_lang=en#ixzz1uPEMbjMS. Accessed May 9, 2012. 3. Cohen JL. Actinic keratosis treatment as a key component of preventive strategies for nonmelanoma skin cancer. J Clin Aesthet Dermatol 2010;3:39-44. 4. Carpenter PM, Linden KG, McLaren CE, et al. Nuclear morphometry and molecular biomarkers of actinic keratosis, sun-damaged and nonexposed skin. Cancer Epidemiol Biomakers Prev 2004;13:1996-2002. 5. National Skin Cancer Prevention Committee. The economic burden of skin cancer in Canada: current and projected. February 26, 2012, pages 1, 42. www.partnership againstcancer.ca/wp-content/uploads/Economic-Burden-of-Skin-Cancer-in-CanadaReport-Final1.pdf 6. Canadian Cancer Society. Non-melanoma skin cancer overview (http://info.cancer. ca/cce-ecc/default.aspx?Lang=E&toc=47). Accessed May 9, 2012. 7. Anwar J, Wrone DA, Kimiyai-Asadi A, Alam M. The development of actinic keratosis into invasive squamous cell carcinoma: evidence and evolving classification schemes. Clinics Dermatol 2004;22:189-196. 8. Berman B, Bienstock L, Kuritzky L et al. Actinic keratosis: sequelae and treatments. Recommendations from a consensus panel. Supplement to the Journal of Family Practice 2006: 1-8. www.jfponline.com/uploadedFiles/Journal_Site_Files/Journal_of_Family_ Practice/supplement_archive/Suppl_AK.pdf. Accessed May 6, 2012. 9. Glogau RG. The risk of progression to invasive disease. J Am Acad Dermatol 2000;42 (1) Suppl 1:S23-24. 10. Valve M, Ortonne J-P, Birch-Machine MA, Gupta G. Management of field change in actinic keratosis. British J Derm 2007;157 (suppl 2):21-24. 11. Marks R, Rennie G, Selwood TS. Malignant transformation of solar keratosis to squamous cell carcinoma. Lancet 1988;33 (8589):795-797. 12. Feldman SR, Fleischer AB. Progression of actinic keratosis to squamous cell carcinoma revisited: clinical and treatment implications. Cutis 2011;Apr;87(4):201-7. 13. Criscione VD et al. Actinic keratosis. Natural history of malignant transformation in the veterans affairs topical tretinoin chemoprevention trial. Cancer 2009;115:2523-30. 14. Berman B, Amini S, Valins W, Block S. Pharmacotherapy of actinic keratosis. Expert Opin Pharmacother 2009:10(18):3015-3031. 15. Ulrich M, Drecoll U, Stockfleth E. Emerging drugs for actinic keratosis. Expert Opin Emerging Drugs 2010;15(4):545-555. 16. Mittelbronn MA, Mullins DL, Ramos-Caro FA, Flowers FP. Frequency of pre-exisiting actinic keratosis in cutaneous squamous carcinoma. Int J Dermatol 1998;37:677-681. Sponsorship of this Clinical Focus in Parkhurst Exchange is funded by Leo Pharma Inc.