Actinic Keratosis
Katrine Togsverd-Bo
Merete Haedersdal
BACKGROUND
Actinic keratoses (AKs) are common epidermal dysplastic lesions that typically present as scaly or keratotic macules or papules with a diffuse erythematous base in fair-skinned individuals at increasing age. Resulting from chronic exposure to ultraviolet radiation (UVR), AKs are predominantly located in sun-exposed skin such as the face, scalp, and dorsal arms and hands.
The incidence of AKs increases with patient age, and it is recognized as the most frequent dermatologic diagnosis in patients above 60 years of age. Studies find prevalence rates in patients above 60 years ranging between 19% and 25% in the United States and 23% in a UK population,1,2 whereas the highest prevalence of AKs is reported in Australia with up to 60% of patients having AKs.3 In men aged 65 to 74 years, a study found AK prevalence rates at 55% and 19% in patients with high and low sun exposure, respectively, and reflects an increased incidence of AKs in patients with high cumulative UVR exposure.4
AKs are premalignant intraepidermal keratinocyte neoplasia that can progress into invasive squamous cell carcinoma (SCC).5
The reported risk of each AK undergoing malignant transformation to SCC varies considerably and ranges from 0.025% to up to 2% per year, although the majority of studies that also include larger patient sets find transformation rates between 0.075% and 0.96% per year. The risk of SCC development is significantly greater in immunosuppressed organ transplant recipients (OTRs) and in patients with field cancerization, comprising photodamaged skin with multiple AKs, subclinical nonvisible lesions, and previous keratinocyte cancers.6,7 A patient with typical field cancerized skin is illustrated in Figure 5.1.1.
PRESENTATION
AKs present as scaly or keratotic macules or papules with a diffuse erythematous base in fair-skinned individuals at increasing age. They are distributed on
sun-exposed skin, and patients will often complain of red patches that are irritated or flaky.
sun-exposed skin, and patients will often complain of red patches that are irritated or flaky.
 FIGURE 5.1.1 Patient with field cancerization on the chest visualizing multiple actinic keratoses, several scars from curettage and hypopigmentation following cryotherapy. |
DIAGNOSIS
Clinical Diagnosis
AKs appear in photodamaged skin as rough erythematous lesions with various degrees of white-yellow scales (Figures 5.1.1 and 5.1.2). Each lesion can range in size from few millimeters to larger, confluent patches up to several centimeters in diameter. Although mostly asymptomatic, AKs may cause occasional itching, stinging, or even a burning sensation when exposed to sunlight.
Early signs of AK typically involve slight erythema with subtle scaling or may present as rough, slightly scaling lesions with indistinct borders (Figure 5.1.2B). Advanced AKs are usually thicker, well defined with more visible hyperkeratosis that may evolve into thick scales (Figure 5.1.2C). On clinical examination, visual inspection is preferably accompanied with simultaneous palpation to detect less apparent lesions. Actinic cheilitis is used to describe AKs on the lower vermilion lip. Clinically, actinic cheilitis may be well-defined plaques with scale or diffuse, scaling lesions that may affect large areas of the lower lip. As invasive SCCs occurring on the lips are associated with greater risk of metastasis, a biopsy should be performed if the clinical appearance is uncertain.
Histopathology
AKs are intraepidermal dysplasia with various degrees of keratinocyte atypia. The earliest changes originate from the basal layer of the interfollicular epidermis characterized by hyperchromatic and pleomorphic nuclei with alteration of the nuclear to cytoplasmatic ratio.8 These changes are visible in both AKs and field cancerized skin and usually occur together with solar elastosis, parakeratotic areas, and a lymphocytic infiltrate in the dermis.9
AKs can be graded into World Health Organization-defined histological subtypes: hyperkeratotic, pigmented, lichenoid, atrophic, Bowenoid, and actinic cheilitis.10
Hyperkeratotic AKs are easily identified as hyperkeratotic plaques or papules with thick yellow or white scales. Histologically, acanthosis and hyperkeratosis are prominent.
Pigmented AKs have a hyperpigmented or reticulated appearance that may be difficult to distinguish from seborrheic keratoses as the erythema may be less pronounced. The pigmented appearance results from increased melanin pigmentation in the epidermis.
Lichenoid AKs are histologically characterized by keratinocyte apoptosis, a bandlike infiltrate of lymphocytes in the papillary dermis and vacuolar alteration at the dermoepidermal junction.
Atrophic AKs may be used to describe erythematous lesions with minimal hyperkeratosis and histological atrophic epidermis.
Bowenoid AKs or Bowen disease equivalents SCC in situ and is histologically different from AK including full-thickness atypia of the epidermis with more pronounced dysplastic changes that resembles invasive SCC.
The keratinocyte atypia can progress from the basal layer to comprise the full epidermal thickness. The severity of atypia has traditionally been categorized as a 3-stage classification based on the thickness of keratinocyte atypia in the epidermis, labeled keratinocyte intraepithelial neoplasia (KIN). Hence, in KIN I, keratinocyte atypia involves the lower third; in KIN II, atypia involvement reaches the 2 lower thirds, and in KIN III, atypical keratinocytes extend to the upper layers. Traditionally, progression from AK to SCC has been considered to follow the “classical pathway” involving complete transformation of the entire epidermis, ie, from KIN I to KIN II to KIN III. However, histologically stage KIN I AKs have shown to be common precursors of SCC. This pathway is described as the “differentiation pathway.”11 In this pathway, invasion can occur directly from AKs with involvement limited to the basal layer. Correspondingly, studies have found no association between KIN grade and the
clinical thickness of hyperkeratosis of each AK.12 These findings suggest that KIN grade alone cannot predict transformation of an AK into SCC and that SCC may directly develop from clinically normal skin with field cancerization.
clinical thickness of hyperkeratosis of each AK.12 These findings suggest that KIN grade alone cannot predict transformation of an AK into SCC and that SCC may directly develop from clinically normal skin with field cancerization.
 FIGURE 5.1.2 Actinic keratoses in the face of a patient with Fitzpatrick skin type I (A). The patient has both grades 1 and 2 AKs (B) as well as hyperkeratotic AKs (C). |
Subtypes
AKs may be clinically graded according to the level of hyperkeratosis as lesions that are slightly palpable (more easily felt than seen, grade 1), moderately thick (easily felt and seen, grade 2) and thick, hyperkeratotic lesions (grade 3).13 AKs with thick hyperkeratotic scales may be difficult to distinguish from SCC, but rapid growth, ulceration, and tenderness upon palpation are associated with progression into invasive SCC. In these cases, a biopsy for histological clarification is warranted.
PATHOGENESIS
Chronic exposure to UVR results in photoaging and skin cancer development. The main source of UVR is solar UVR, consisting of UVB (280-320 nm) and UVA (320-400 nm). For AK and SCC development, studies suggest a strong, positive association with accumulated UVR exposure, whereas exposure patterns are considered of less importance.14 UVR exposure induces direct formation of photoproducts as well as indirect oxidative damage that both result in structural damage to skin DNA and RNA.15 If the photoproducts are not repaired, they may induce transition-type mutation such as cytosine to thymine (C → T) in tumor suppressor genes, including p53, p16INK4a, p14ARF, and PTEN.16 Accumulated mutations in tumor suppressor genes, especially p53, are typically detected in photodamaged skin and may result in dysplastic transformation, proliferation of atypical keratinocytes, and development of AKs and invasive SCC.17,18
The major risk factors for AK development are male sex, age >70 years, baldness, photodamaged skin, and a high cumulative UVR exposure from sun exposure or tanning beds.19 Individuals with fair skin types, including Fitzpatrick skin types I and II, possess a higher risk of AK development as these patients are more sensitive to UVR exposure owing to a lower constitutive skin pigmentation. Other risk factors include history of smoking and outdoor
work, whereas the number of nevi has not been related to AK prevalence.20 Furthermore, studies have found that coexisting infection with human papilloma virus (HPV) is associated with AK and SCC initiation, although the exact mechanism is not fully established.21,22
work, whereas the number of nevi has not been related to AK prevalence.20 Furthermore, studies have found that coexisting infection with human papilloma virus (HPV) is associated with AK and SCC initiation, although the exact mechanism is not fully established.21,22
A few genetic syndromes are associated with an increased risk of AK and SCC development, including xeroderma pigmentosum, oculocutaneous albinism, and epidermodysplasia verruciformis. In xeroderma pigmentosum, defects in the DNA repair mechanism, nucleotide excision repair, greatly accelerate UVR-induced AK and SCC development. In albinism and epidermodysplasia verruciformis, SCC development occurs from lack of pigmentation and widespread colonization with multiple oncogenic HPV types, respectively.
Organ Transplant Recipients
Immunosuppressed solid organ transplant recipients have an especially increased risk of AK and SCC development that is up to 40 to 250 times greater than that in the general population. The continuous immunosuppression reduces the repair mechanism of UVR-induced DNA damage and potentiates the carcinogenic effects of UVR.23 Specifically, azathioprine and other thiopurines have been recognized as DNA photosensitizers in immunosuppressant treatment and are associated with an increased risk of AK and SCC occurrence in patients with hematologic malignancies, inflammatory bowel disease, and rheumatic diseases.24 As a consequence, transplant recipients experience onset of AKs earlier in life and usually develop multiple lesions compared with age-matched immunocompetent patients.25 Transplant recipients are prone to develop numerous AK lesions in sun-exposed areas, which can, in conjunction with SCC, cause significant morbidity among patients. The prevalence of AKs increases significantly with increasing time after transplantation corresponding to longer duration of immunosuppressant therapy. Furthermore, patients receiving thoracic organ transplantation have a higher risk of SCCs because of higher immunosuppressive load. Daily use of sun screen, regular cutaneous screening visits, and aggressive treatment of AKs are important assets to prevent SCC development in these high-risk patients.
Natural Development of AKs
If left untreated, AKs have the potential to undergo 1 of 3 scenarios: (1) undergo spontaneous remission, (2) remain stable, or (3) progress into invasive SCC with the potential to metastasize.
Spontaneous regression of single AK lesions was reported to be 20% to 30% per year in a review, whereas one study found that up to 63% of AKs spontaneously resolved.26 However, in field cancerized skin, spontaneous regression of a complete AK-field was observed in only 0% to 7% of patients and 57% of AKs recurred following spontaneous clearance.26 These data indicate that inadequately treated AKs are dynamic but act as a chronic condition with low chance of sustained spontaneous regression, especially in field cancerized skin.26,27
The risk of an AK evolving into invasive SCC has, in prospective studies, been reported at rates of 0.075% to 0.96% per year.28 Over a 10-year period, SCC development has been reported up to 13% to 16% in patients with untreated AKs. The risk of SCC transformation seems higher in patients with clinical hyperkeratotic AK.29 The transformation from AK to SCC may be associated with a period of rapid inflammation, which subsides upon SCC development that may be caused by SCC-mediated suppression of the immune system’s tumor response.27 Additionally, AKs have been associated with an increased overall risk of skin cancer, including melanomas, possibly because AK indicates a previous or current extensive sun exposure.
TREATMENT
The choice of AK treatment should be individualized as it depends on patient preference, treatment site, type of AKs, and skin photodamage. In general, treatments of AKs consist of lesion-directed destructive treatments or field treatment with a topical medication that reverses skin dysplasia, relieves local symptoms, and improves appearance (Algorithm 5.1.1). AKs have considerable cosmetic implications as >80% appear on visible skin areas and may lower patient’s skin-related quality of life. The cosmetic result following AK treatment is therefore of major significance in most patients.
Medical
Medical treatments of AK include preventive measures and topical medication therapy.
 ALGORITHM 5.1.1 Treatment algorithm for actinic keratosis. 5-FU, 5-fluorouracil; ALA, aminolevulinic acid; alt, alternate; CO2, carbon dioxide laser; Er:YAG, erbium yttrium aluminum garnet laser; MAL, methyl aminolevulinic acid; PDT, photodynamic therapy. (Courtesy of Macrene Alexiades, MD, PhD.) |
Preventive Interventions
To prevent further actinic damage, education in photoprotection from UVR exposure is an essential and integral part of treatment of patients with AK. Photoprotection relies on behavioral modifications, clothing, and application of sunscreen and has been well documented to prevent further photodamage and AK development.30
A prospective study in high-risk OTRs found that daily use of sunscreen resulted in a significant reduction of AK and SCC development over a 2-year period.31 This shows that consistent use of photoprotection measures can prevent further development of AKs and invasive carcinomas.
Primary prevention of AKs with topical treatments has been assessed only for methyl aminolevulinate (MAL)-photodynamic therapy (PDT). In a split-side study on OTRs, 2 MAL-PDT treatments per year for 5 years showed a significant delay in the onset of AK.32 More recent epidemiologic studies indicate that oral intake of niacin is negatively associated with SCC development, although the preventative effect on AKs is unknown.33
TABLE 5.1.1 Overview of Topical Field Therapies for Actinic Keratoses (AKs)a | ||||||||||||||||||||||||||||||||||||
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