The prevalence of actinic keratosis (AK) is difficult to estimate because case registers have not been established and few studies have focused specifically on prevalence. Available epidemiologic data indicate a high prevalence of the condition in populations with certain skin phototypes (I to III) as well as a rise in the number of cases in recent decades.1–6 In the United Kingdom, a prevalence of 15% in men and 6% in women has been documented.7 Estimates vary considerably from one country to another and according to the age of the population studied. The UK study found rates over 34% in age groups over 70 years. A European guideline on this disease8 concluded that AK is increasing in prevalence; it affects millions of patients worldwide and is becoming the most common in situ carcinoma in humans.

The European guideline8 begins by summarizing available evidence on the etiology and pathogenesis of AK as well as the histopathology and clinical manifestations of the disease; it also reviews the wide range of treatment options available. This document should be used to orient decision-making even though specific recommendations were not formulated in it. The aim of the present article is to facilitate greater consistency in making decisions about the management of symptoms and treatment of AK. The emphasis is on the importance of early diagnosis and treatment of lesions to prevent their progression to invasive squamous cell carcinoma (SCC).

The basis for this consensus paper is the 2011 European guideline8 and its adaptation to the Spanish context through structured, participatory consensus building among experts, who are the drafters of the recommendations and authors of the paper.

The working group consisted of 7 specialists and 1 primary care physician who attend patients in different Spanish health care facilities. The group first made a technical translation of the European guideline8 in order to subject it to critical reading focused on the objectives the group prioritized. The information in the guideline was then synthesized to establish recommendations applicable to Spain. The experts also conducted a further review of the literature published after the guideline appeared. They then incorporated evidence from the new literature and drafted preliminary recommendations for the evaluation and treatment of AK, also providing additional general and conceptual reflections on the disease.

The first draft of this paper was debated and revised in a structured meeting in which all members of the expert working group participated. Once the experts approved the draft, each recommendation was graded and classified according to level of evidence using the criteria of the Scottish Intercollegiate Guidelines Network9 (Table 1) and the National Institute for Clinical Excellence10 in the case of evidence for diagnostic tests (Table 2). The final manuscript was approved by all participants.

Diagnosis of AK is mainly clinical. However, histopathologic confirmation may be required to distinguish AKs from other lesions and is especially necessary when there may be dermal invasion and, therefore, transformation to invasive SCC. Although there are no clear clinical signs to indicate progression to invasive disease, this possibility should be suspected, at least initially, when a lesion appears inflamed, indurated, ulcerated or large (> 2 cm). Other signs of possible progression are bleeding, rapid growth, lack of response to appropriate treatment, or recurrence after successful treatment. To distinguish AK from other possible lesions when the clinical diagnosis is doubtful, and whenever there is suspicion of transformation to invasive SCC, the lesion should be biopsied (level of evidence 4, grade D recommendation).

Several diagnostic tools have proven useful for differential diagnosis. Dermoscopy can help distinguish AK from superficial basal cell carcinoma, or differentiate between pigmented AK and lentigo maligna or pigmented basal cell carcinoma. Confocal scanning laser microscopy has been reported to have good diagnostic sensitivity and specificity,30 but at least in Spain, this tool is available in few hospitals and so is currently used more for research than routine clinical care. Photodynamic therapy (PDT) adapted for diagnosis provides another method. While the efficacy of this resource has not been fully confirmed, it seems it can help identify the limits of field cancerization.31 However, PDT is not available in all centers and so trying this approach would require investment.

The natural history of AKs may proceed in any of 3 ways. They may regress spontaneously, remain AKs, or progress to invasive SCC. As the course they will take cannot be predicted, treatment is advisable. In 1977, Harvey et al.3 reported a rate of spontaneous regression between 15% and 55% for AK within the year. The percentage of AKs that become invasive SCCs has been the focus of several studies with varying designs and disparate results. However, it must be remembered that over 80% of invasive SCCs on exposed areas develop on or adjacent to an AK lesion.28,32–34 In a prospective study that followed patients for 12 months, Marks et al.35 reported an incidence of progression to invasive SCC within the year of 0.24%. Most patients have more than a single lesion, however, so the risk of progression to invasive SCC over 10 years would be between 6.1% and 10.2%36; that figure rises to 40% in immunodeficient patients,37–40 as has been noted by the European guideline.8 It is important to remember that AKs are considered a sign of chronic actinic damage and identify a group of patients at high risk for nonmelanoma cancer41 (level of evidence 4, grade D√ recommendation).

Both primary and secondary measures are available to prevent AK. Information and education on sun-protection measures are fundamental for primary prevention. Such steps are especially important for transplant recipients, who are at very high risk for AK and invasive SCC and must start to take precautions as soon as they are placed on a wait list.8,42,43 Secondary measures include self-examination even before consulting a physician because early detection is of great importance for achieving a cure and preventing progression to invasive SCC. Products that combine sun screens with DNA reparative agents are currently being tested.44

In transplant patients, prevention must be stressed and careful inspection at frequent follow-up visits (every 3 or 4 months) will be essential. Several studies in the general population and in transplant recipients have demonstrated that sun-protection behaviors are effective not only for preventing new lesions but also for clearing existing ones.45–48

Recurrence is common in these patients and the appearance of new lesions in the cancerized field is a marker of chronic sun damage and thus a risk factor for the development of invasive disease; therefore, the patient with AKs should be followed at individualized intervals based on the number of lesions, patient characteristics, associated risk factors, and other relevant aspects, with insistence on early diagnosis and treatment and the importance of sun protection2749–52 (level of evidence 4, grade D recommendation).

The authors of the present paper seem to have reached agreement on recommending that all AKs be treated because they are considered carcinomas in situ that may progress to invasive SCC6,8,22 (level of evidence 4, grade D recommendation). The treatment algorithm developed by Stockfleth et al.27 states that after AK is diagnosed, sun protection and individually tailored treatment should be initiated. When lesions are few and isolated, treatment should target individual lesions. When lesions are many or field cancerization is suspected, treatment should target both the field and the specific lesion (Fig. 1).

Figure 1.

Treatment algorithm for actinic keratosis. CO2 indicates carbon dioxide; 5-FU, 5-fluorouracil; PDT, photodynamic therapy.

(0.22MB).

The presence of field cancerization has important implications for treatment. If a lesion is the sole target for treatment, or only clinically visible lesions are targeted, they will be eliminated but the field will continue to be a problem, giving rise to new AKs over time.49 If the field is treated, however, visible and subclinical AKs will also be covered, along with clones of cells that will become AKs. This approach thus prevents both new AKs and invasive SCC; periods of remission will be longer, and AK treatment sessions can be scheduled farther apart.27 Whenever possible, therefore, field cancerization should be targeted for treatment with the aim of preventing the progression of subclinical lesions to visible ones, which in turn might progress further to become invasive SCCs (level of evidence 4, grade D√ recommendation).

The physician must weigh the various factors relevant to each case and choose a tailored treatment approach. It is important to remember that combining destructive treatments (generally, those that target the lesion) and topical ones (useful for treating both an AK and field cancerization) may be advisable in some circumstances, such as when there is progression to invasive SCC (level of evidence 4, grade D√ recommendation). Treatment combinations may be required to first eliminate the lesion by destroying it and then treating the field. The choice of a destructive treatment combined with medical treatment will depend on patient profile, lesion characteristics, what options are locally available, and other constraints at the time of treatment. Topical treatment with PDT and imiquimod may also be a beneficial combination. The clinical and histologic response to these treatments in combination is better than the response to monotherapy with either alone; tolerance is also better.50 Little is currently known about the usefulness of topical treatment combinations, although the possibility of unknown interactions should be taken into consideration.

The decision to target the lesion or to treat field cancerization, as well as the choice of modality, will be affected by a number of factors (Table 4).

Single or isolated lesions should be destroyed before they progress to invasive SCC (level of evidence 4, grade D√ recommendation).

The efficacy and safety of destructive therapies are difficult to assess because very few controlled clinical trials have been done, they have enrolled only a small number of patients, or none have been done for some treatments.8

None of the destructive therapies are useful for treating field cancerization. All but cryotherapy require local anesthesia and can leave scars or affect pigmentation.51 These procedures are generally easy to perform, rapid from the physician's point of view, and effective for treating isolated AKs. However, there is little standardization.

Topical treatments are preferable to destructive ones in patients with multiple AKs and in cases with evident field cancerization, because these options treat both the lesion and the field26 (level of evidence 4, grade D recommendation).

These treatments offer several advantages over destructive therapies. By treating both lesion and field, the topical medication eliminates new visible AKs and subclinical ones as well as clones of cells that will become AKs.57 If field cancerization is treated, therefore, the intervals between treatment sessions can be lengthened and progression to invasive SCC prevented.27

An important consideration is that topical treatments for field cancerization are compatible with concomitant or sequential use of any of the treatments directed at particular lesions.27 We will now describe the mechanisms of action of the topical treatments listed in Table 5.

New drugs and formulations of existing ones have recently appeared on the market, expanding the therapeutic arsenal (Table 6).

A new topical formulation of 5-FU 0.5% with 10% salicylic acid was recently approved and is already being sold in some European countries. This formulation boasts fewer side effects than 5-FU 5%. Salicylic acid is a keratolytic agent that has long been used to treat various skin diseases with a hyperkeratotic component. In combination with a low dose of 5-FU (0.5%) it can reduce the hyperkeratosis of AKs and enhance penetration of the principal ingredient.8

Oral systemic retinoids, dermabrasion, chemical peeling, and carbon dioxide laser therapy are considered second-line or coadjuvant treatments and they should be considered for possible use in special circumstances8,71,72 (level of evidence 4, grade D√ recommendation).

Preventive therapy with oral retinoids is recommendable in combination with the topical treatment of field cancerization, at least in patients with a history of invasive SCC who have multiple AK lesions73 (level of evidence 4, grade D recommendation).

Long-term immunosuppression in solid-organ transplant recipients to prevent graft rejection increases the risk of infections and the development of precancerous and cancerous lesions; among them are AKs, which often have an atypical clinical presentation in these patients. The relative risk of AK is 250-fold higher in transplanted patients than in immunocompetent individuals.74 Multiple AKs are common in these patients (cumulative 5-year incidence, 35% to 40%), and there is greater risk of progression to invasive SCC as well as faster progression.75–77

For AKs at high risk of progression to invasive SCC, the physician should consider treatments that will facilitate pathologic diagnosis, although topical treatments can also be applied to increase efficacy78–83 (level of evidence 4, grade D recommendation). Particularly risky are lesions on the lips, ears, or around the eyes, as invasive SCCs in these locations have greater ability to metastasize.82,84 The possibility of metastasis should also be considered when AKs appear in patients who have a history of invasive SCC, have lesions that are secondary to ionizing radiation, are positive for the human immunodeficiency virus, or are solid-organ transplant recipients.27 In the last group, good results have been reported for application of diclofenac 3% and imiquimod 5%, so a promising approach is to combine medical treatment with destructive procedures that facilitate a pathologic diagnosis.78,85–87

Measures to prevent AK (extreme sun protection measures) are recommended for solid-organ transplant recipients; moreover, in view of the higher prevalence of AK in this group and faster progression to invasive SCC in comparison with immunocompetent individuals, these patients should also be examined periodically so that lesions can be detected and treated early42,75–77 (level of evidence 4, grade D recommendation).

Surgery is recommended in patients with AK that resists treatment or that recurs so that material for pathologic diagnosis can be obtained and invasive SCC ruled out.

Based on the social, epidemiologic, cultural, and climate characteristics in Spain, we can expect the prevalence of diseases like AK to rise and the demand for care to increase. Although a sun-safety culture is becoming better established, we must also cope with population aging and the reduction in atmospheric protection because of ozone layer depletion, making us more vulnerable to the effects of UV radiation.

In Spain, the treatment of AK usually falls to the dermatologist, who uses ablative therapies that target lesions without regard for field cancerization. The therapeutic arsenal has expanded, mainly through the development of topical treatments for AK that are highly useful against field cancerization. We therefore believe experts need consensus-based recommendations (Table 7) that facilitate their choice of the best treatment options for individual patients. The choice will be based on the features of the treatment, the type of lesion, the presence or absence of field cancerization, and the patient's preferences. 5-FU can be applied on multiple lesions twice a day for 2 to 4 weeks; the rate of initial clearance of lesions is high with this cream, but the 12-month recurrence rate is also high.88 It can cause such adverse effects as serious rashes, phototoxicity, or contact dermatitis that can lead patients to stop treatment.89 The formulation combining 5-FU 0.5% with 10% salicylic acid, however, has a better safety profile.90 Treatment with imiquimod 5% is associated with a lower recurrence rate, and the clearance rate 12 months later is high. Maintenance of skin quality at the end of treatment with imiquimod 5% is also good. Some patients have to abandon imiquimod use, however, when they develop serious rashes, although this drug is generally reasonably well tolerated.88 The imiquimod 3.75% cream can be applied over larger areas of skin, such as the scalp or face, although it is indicated only for visible or palpable AKs that are neither hyperkeratotic nor hypertrophic, or it can be used when other topical treatments are contraindicated or inappropriate.65 Diclofenac 3% in 2.5% hyaluronic acid gel can also be applied over large areas, the treatment can be continued for 60 to 90 days,91 and tolerance is excellent. Ingenol mebutate, on the other hand, is only applied for 3 days and the results are not assessed until 8 weeks later.69 This formulation has only recently been approved in Spain, and there is little clinical experience with it as yet. Finally, PDT is an excellent choice but has the drawbacks of high cost and scarce availability; moreover, patients must travel to clinics where it can be administered, with consequent loss of work time.

Given the unceasing rise in the incidence and prevalence of skin cancers, including AK, and considering that the primary care doctor is the first to see the patient, there is no doubt that this physician will play an important role in the diagnosis and treatment of AK. A primary care doctor's duty goes beyond recognizing AKs when the patient asks about them; it is also necessary to look for them actively because patients who visit with other complaints may be unaware of the nature of visible lesions that are asymptomatic. The primary care doctor's ability to find cases, treat incipient lesions, and refer patients to the dermatologist (when lesions are doubtful, require ablation, or there is field cancerization) will be crucial in the effort to lower the incidence of AK and invasive SCC.

Implementing recommendations based on systematic review of the available evidence will not only help reduce variability in clinical practice between specialists but will also facilitate more effective use of health care resources, bringing the patient to the point of diagnosis and appropriate treatment as quickly as possible. The periodic updating of reviews of the literature on the diagnosis and treatment of AK provides information for improving patient care, encourages greater consistency in decision making, and promotes awareness among all involved health care providers.

Laboratorios Almirall S.A. has sponsored the collaboration necessary to produce this paper, without interfering in the decisions of the expert group.

Carlos Ferrándiz, in relation to AK, has received fees for speaking at conferences, collaborating with clinical trials, and consulting or otherwise assisting with research from Almirall, Leo-PharmayIsdin. Eduardo Fonseca Capdevila has participated in continuing professional development activities and clinical trials funded by Abbott, Almirall, Celgene, FaesFarma, Janssen, MSD, and Pfizer. Amaro García Diez has served as a consultant, given talks, assisted with research, and received grants from Almirall, Isdin, Serono, Abbott, Abbie, Leo Pharma, Pfizer, and MSD. Carlos Guillén Barona has received consulting or speaking fees and funds for collaboration with clinical trials, consulting, or conducting research from Almirall, Leo-Pharma, 3M, Meda, and Galderma; all such funding was related to nonmelanoma skin cancer. Isabel Belinchón Romero has collaborated with research, conferences, and training courses sponsored by Abbott, MSD, Pfizer, Janssen, Leo Pharma, and Almirall. Pedro Redondo Bellón has received fees from Almirall, MSD, Galderma, and Allergan. José Carlos Moreno Giménez has received grants from the following laboratories or collaborated with research, conferences, and publications they sponsored: MSD, Pfeizer, Leo-Pharma, GSK, Galderma, Amirall, Abbot, and Janssen. Rosa Senan has received consultancy fees from Almirall and conference funding from GSK.