Actinic keratoses, also called solar or senile keratoses, were described by Dubreuilh in 1826.1,2 Later, the term “keratoma senilis” was proposed by Freudenthal, and in 1958 Pinkus renamed the lesions as actinic keratoses.3 Although classically categorized as pre-neoplastic lesions, some authors suggest considering them as in situ neoplasms, since they derive from clonal DNA modifications in keratinocytes.2,4–7 In this sense, actinic keratoses are considered as having characteristics of malignancy since their genesis, both from the standpoint of cytological alterations presented by epidermal keratinocytes, which are similar to those observed in spinocellular carcinomas (SCCs), including loss of polarity, nuclear pleomorphism, dysregulated maturation, and increased number of mitoses, as well as from the molecular standpoint, presenting identical mutations in the p53 protein.3 The difficulty in establishing unambiguous criteria for determining when an actinic keratosis undergoes SCC transformation reinforces this hypothesis. According to Ackerman, there is no clear threshold between actinic keratoses and thin SCCs, and actinic keratosis are considered a part of the evolutionary spectrum of SCC, described as an “embryonic” SCC.2 Therefore, proposed nomenclatures replacing the term actinic keratosis would include keratinocytic intraepidermal neoplasia and intraepidermal solar keratotic SCC.3

Actinic keratoses are formed by proliferation of keratinocytes with varying degrees of dysplasia in the epidermis, i.e., they represent intraepithelial keratinocytic dysplasias; besides, they have a potential for malignant transformation into non-melanoma skin cancer (NMSC), especially in the case of SCC, and they occur preferentially in sun exposed areas.1,8,9

Actinic keratoses represent the third reason for dermatological consultation, losing only to acne and dermatitis.10 With the overall aging of the population, a gradual increase in the frequency of actinic keratoses is expected.10 Regarding the prevalence of actinic keratoses, the World Health Organization estimates that the highest levels are observed in Caucasians living close to the Equator.11

In the international scenario, the prevalence of actinic keratoses is higher in Australia, where fair skin type individuals are predominant and high exposure to UV radiation occurs, followed by the United States and Europe.12 The prevalence of actinic keratoses ranges from 40% to 60% in Australia among Caucasians over 40 years of age, and 11.5% to 26% in the United States in individuals over 30 years of age.13–18 In England, a population-based study observed a prevalence of actinic keratoses of 15.4% in men and 5.9% in women over 40 years; this prevalence was elevated to 34.1% and 18.2% for men and women, respectively, when only patients older than 70 years were considered.19 In a Spanish study, the prevalence of actinic keratoses was 28.6% in patients above 45 years; this prevalence was higher in men than in women and the values increased according to age for both sexes.20 Another study, carried out in Austria, found a prevalence of actinic keratoses of 31% in patients over 30 years of age; the prevalence was higher in men than in women, and increased according to age for both sexes (39.2% in males vs. 42.3% in females).21 Finally, in the Asian population, studies have demonstrated a lower prevalence of actinic keratoses: in South Korea, values vary from 0.02% in patients aged 40 years, 0.09% in patients aged 60 years, and 0.21% in patients aged 70 years22; in China, a population-based study (1,590,817 patients evaluated) observed a prevalence of 0.52%, with a mean age of 69.8±11.8 years.23

In Brazil, actinic keratoses represent the fourth most common dermatological diagnosis.1 In addition, they represent the main reason for dermatological consultation in Brazil in individuals over 65 years (17.2%); in Southern Brazil, this corresponds to 7.4% of the diagnoses and in the North region, to 2.89% of visits.24 In a study conducted in Curitiba with 491 patients, with a mean patient age of 59.8 years, the prevalence of actinic keratosis was 60.79% in women and 30.9% in men.25 Another study, conducted in Bauru, evaluated the prevalence of actinic keratoses only in Japanese descendants living in Brazil; the study observed a prevalence of 13.4%, with a mean age of 68.9 years; this prevalence is higher than that observed in individuals of the same ethnic composition living in Japan.26

As mentioned above, the prevalence of actinic keratoses increases according to the age of the patients, ranging from <10% in Caucasians aged 20–29 years, to 80% in individuals aged 60–69 years.27 Exceptions occur in albinos and patients carrying other genodermatoses that present defects in DNA repair genes, such as xeroderma pigmentosum, Rothmund–Thompson syndrome, Cockayne's syndrome, and Bloom's syndrome, which may present lesions in the first decade of life, and lesions with greater aggressiveness and risk.1,28–30 Age is an independent risk factor for the development of actinic keratoses, with odds ratios (OR) ranging from 1.6 to 41.5 according to age; the OR is of 4.8 for individuals between 46 and 60 years and up to 41.5 years in individuals over 70.31–34

Men have a higher prevalence of actinic keratoses, with an OR of 1.7–3.9, due to the higher average UV exposure to which men receive during life.31,32,34–36

Populations whose ethnic composition predominantly present individuals with fair skin (types I and II), who are more susceptible to the carcinogenic effects of UV radiation, also present a higher risk of developing actinic keratoses, with an OR of 1.7–6.9.31,32,34–36 In addition, geographical location is also of great importance because it represents the rate of UV radiation that a given population is exposed to and may even modify the prevalence rates in populations that have migrated, as observed is the study carried out with Japanese descendants in Bauru.26

Few studies evaluating the incidence of actinic keratoses are available. The first was held in Maryborough/Australia (37° S), in 1986, with 1040 individuals over 40 years. In the study all patients were evaluated twice in a 12-month period. In the baseline evaluation, 59% of the subjects had actinic keratosis; in the follow-up, 60% presented new lesions. Among the patients without lesions in the baseline evaluation, 19% developed lesions observed at follow-up.37 A population study conducted in Wales with 1034 individuals over 60 years of age observed an incidence rate of actinic keratoses of 149 lesions per person-year and a prevalence of 23%.38 Another study, conducted in South Korea, evaluated 77,975 individuals with actinic keratoses above 40 years who had consulted with dermatologists between 2006 and 2015 at least twice over a one-year period.22 The incidence rate in the ranged from 17.95 per 100,000 person-years in 2006 to 53.99 per 100,000 person-years in 2015, these values were lower than the expected rates in the Western population. In addition, the authors observed an increase in the incidence rate as the patient's age increased, and this increase was higher in the 70-year age range.22

The etiology of actinic keratoses involves both individual and environmental factors.13

Excessive exposure to UV radiation is the major factor, acting as a complete carcinogen, both inducing and promoting tumor expansion.8,39,40 UV radiation activates molecular signaling cascades that result in modifications of regulatory cytokines levels, immunosuppressive effects, and defective cell differentiation and apoptosis.8 UV radiation is divided into UVA, UVB, and UVC; about 94–97% of the radiation that reaches Earth's surface is composed of UVA rays, UVB rays are partially absorbed by the ozone layer and represent only 3–6%, and UVC rays are filtered by the ozone layer in the atmosphere and only minimum levels reach the Earth's surface.8

UVA radiation (320–400nm) penetrates the skin more deeply and stimulates reactive oxygen species production, which damage cell membranes, their nuclei, and proteins41; in addition, UVA promotes guanine (G) to thymine (T) replacement mutations in DNA.42 As a result, signal transduction and cellular interaction pathways are affected and abnormal cell proliferation occurs.8

UVB radiation (290–320nm) is absorbed by cellular DNA, promoting errors in the repair of cyclobutane pyrimidine dimers and production of 6–4 photoproducts, as well as characteristic cytosine–thymine (C–T) DNA substitutions.41 These effects result in mutations in the p53 protein, which regulates the cell cycle and acts on DNA damage repair, mutations in the telomerase gene, and increase of proinflammatory cytokine production.42,43

Thus, mechanisms involved in the onset of actinic keratoses include inflammation, oxidative stress, immunosuppression, impaired apoptosis, cell cycle deregulation and cell proliferation, and tissue remodeling (Fig. 1).8

Figure 1.

Mechanisms involved in actinic keratoses pathogenesis. Adapted from: Berman B, Cockerell CJ. Pathobiology of actinic keratosis: ultraviolet-dependent keratinocyte proliferation. Berman B, et al. (2013).8

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The inflammatory process is mediated by the arachidonic acid pathway, by the production of proinflammatory cytokines, and by the activation of mast cells and inhibitory factor of macrophage migration; the results of the activation of these mediators include lipid peroxidation, increase in intralesional levels of T lymphocytes and Langerhans cells, increase of p53 and Bcl-2, and reduction in Fas (cd95) and Fas-ligand, which are important initial factors in the apoptosis process of UV-mutated cells.8 A link between inflammation and actinic keratoses development is observed in lesions that have progressed to SCC; in some cases actinic keratoses undergo an inflammatory phase before becoming invasive.44 This is corroborated by the fact that anti-inflammatory therapies are effective in the treatment of actinic keratoses.45

Oxidative stress is also involved in the photocarcinogenesis process, as a result of the excessive exposure to ultraviolet radiation, which leads to the production of reactive oxygen species and culminates with lipid peroxidation and cell destruction, with damage to genomic and mitochondrial DNA.8 Altered signal transduction pathways result from membrane tyrosine kinase phosphorylation, alterations in the epidermal growth factor, in the Ras and RAF, and in the dissociation of the nuclear factor κB from the inhibitory B complex.46–49 These events result in the production of cytokines, including interleukin (IL)-1, tumor necrosis factor, and IL-6, and in the activation of the arachidonic acid pathway. The final result is the shift of transcription factors to the cell nuclei, with gene expression modifications.50

Apoptosis disorders occur by suppression, elimination, or activation of apoptotic mediators, such as CD95 and tumor necrosis factor-associated apoptosis, and of pro-apoptotic tumor suppressor genes, as well as by regulation of p53 apoptotic activity.51,52 Moreover, mutation of the p53 tumor suppressor gene induced by UVB radiation occurs in an early stage in cutaneous tumorigenesis.8

The five most important independent risk factors for actinic keratoses development are age, sex, phototypes I and II, previous history of cutaneous neoplasms, and sun exposure due to occupational reasons.34 The history of previous skin neoplasms (OR=6.47) is important because it reflects the association of individual genetic factors, which may influence the sensitivity to UV radiation, and the degree of chronic UV radiation exposure to which the individual has been exposed during life.33,34 When assessing the impact of occupational sun exposure for actinic keratoses development, workers from outside areas present a risk two-to-three times higher of developing actinic keratoses and are at increased risk for all cutaneous neoplasms, with an OR of 3.45 for actinic keratoses, 3.67 for SCC, 3.32 for basal cell carcinoma (BCC), and 1.97 for melanoma (p<0.005).53,54 Other risk factors for actinic keratoses include episodes of painful sunburn before the age of 20 years (OR=1.21), not using sunscreen (OR=1.81), and a positive family history for cutaneous neoplasms (OR=1.85).34 Episodes of painful sunburn before 20 years of age could represent the initiating events of the carcinogenesis process, since both acute and chronic UV radiation exposure can lead to mutations in the p53 gene and subsequent clonal keratinocytic expansion.55

Patients with chronic use of systemic immunosuppressive drugs are a specific risk group for developing cutaneous neoplasias and dysplasias as a result of UV radiation carcinogenic effects.56 In solid organ transplant patients, NMSC is the most prevalent neoplasm, occurring in 27% of them.56,57 Besides, immunosuppressed patients have a higher prevalence of actinic keratoses and a higher risk of progression of these lesions to SCC.58 In as study conducted in Queensland, Australia, with 495 renal and hepatic transplant patients, mean age of 54 years, and mean time of immunosuppression of 8.9 years, the authors observed the presence of actinic keratoses in 80% of the sample, and 30% of the patients had more than five lesions.59 The prevalence of NMSC in immunosuppressed patients is higher than in the general population and these patients have a higher risk of progression of their actinic keratoses to SCC (the incidence of SCC in immunosuppressed patients is 65 times higher than in the general population), and their SCCs are at higher risk of progression to stage IV (occurrence of metastases in 0.5–5% in the general population vs. 8% in immunosuppressed patients).58–61 Time of immunosuppression is the most important factor for the increased risk of developing NMSC in these patients, and lesions tend to occur on field cancerization areas, with an OR of 93 for SCC development vs. 20-fold in patients with isolated actinic keratoses.61,62

The development of actinic keratoses in immunosuppressed patients involves the factors previously described and aspects related to immunosuppressive medications that may even act as carcinogens, e.g., azathioprine. The medication causes direct damage to the DNA when the patient is exposed to UVA radiation, in addition to being photosensitizing. In the case of cyclosporin, carcinogenic effects occur through up-regulation of TGF-β. The scientific evidence available demonstrates an increased risk of developing SCC in patients using azathioprine, cyclosporine, tacrolimus, prednisolone, and mammalian target of rapamycin (m-TOR) inhibitors, such as sirolimus and everolimus. However, patients taking m-TOR inhibitors have a 51% lower risk of developing SCC when compared to patients taking cyclosporine or tacrolimus.63 In addition, chronic immunosuppressive status affects the correction pathways of pre-oncogenic mutations.57 The role of human papillomavirus in the skin carcinogenesis of immunosuppressed patients remains controversial and the proposed mechanism is not clear.63 The risk of developing NMSC in the first five years after transplantation has significantly reduced in patients undergoing solid organ transplantation from 1983–1987 to 2003–2007. In the Norwegian population, the incidence of SCC was 102-fold higher than that observed in the general population in the former period, reducing to 21.6 times in 2003–2007.64 The implementation of individualized and less aggressive immunosuppressive protocols, periodical clinical follow-up of these patients, as well as education about sun safety habits were responsible for this decrease.57,64

Additional features considered to be risk factors for actinic keratoses development include facial telangiectasias, ephelides, solar lentigos (OR=1.6),65 solar elastosis (OR=4.4), cutis rhomboidalis nuchae (OR=2.9), and ≥10 melanosis on the dorsa of the hands (OR=6).31,65

Actinic keratoses present as erythematous macules, papules, or plaques, usually with poorly defined borders, and they may be covered by adherent dry scales. Sometimes they are better identified by palpation than by visual inspection, and they can present varying degrees of hyperkeratosis.1,66 The lesions are either single or multiple (Fig. 2) and their color may vary from pink to erythematous or brownish, in the case of pigmented actinic keratoses.67,68 Infiltration degree can also be variable according to the intensity and to the extent of lesion dysplasia. They are asymptomatic in most of the cases, although some patients refer to the experience of discomfort, such as burning, pain, bleeding, and pruritus.1,66,69

Figure 2.

Non-pigmented facial actinic keratoses: multiple small papules and erythematous plaques with whitish scales on the surface and varying degrees of hyperkeratosis.

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Actinic keratoses predominantly occur in chronic photoexposed skin areas, such as the face, scalp in the bald area, neck, cervical region, shoulders, forearms, and back of the hands.13 In both sexes, the lesions tend to occur most commonly in the upper limbs, and the face and scalp regions.13 These regions, especially the head, neck, and forearms, are responsible for 75% of the reported lesions.15

Actinic keratoses can manifest in different forms and present clinical variants, such as hyperkeratotic actinic keratosis, atrophic, pigmented lichenoid actinic keratosis, cutaneous horn, and actinic cheilitis. Different variants present specific clinical and morphological characteristics and, consequently, their recognition is necessary for correct management, since certain subtypes of actinic keratoses respond better to some therapeutic modalities, as shown below (Table 1).68

Actinic keratoses may be multiple and poorly delimited in patients with severe photodamage; sometimes in such cases the lesions cannot be counted. In these situations so-called field cancerization is observed, characterized by pre-neoplastic alterations of the epithelium after long exposure to carcinogenic agents, in particular UV radiation; the field cancerization consists of lesions in different phases, from subclinical actinic keratoses to SCC.72,73 Field cancerization was described by Slaughter in 1957, by analysis of the perilesional stratified squamous epithelium of SCC in the oral mucosa; Slaughter reported histological changes in specimens of skin adjacent to SCC, such as cellular atypia and even SCC in situ, although clinically the skin was unchanged.73 This concept of multiple contiguous foci of altered clonal keratinocytes in the field cancerization represents the set of alterations found in chronic photodamaged skin with multiple NMSC, including multiple actinic keratoses; in this case the perilesional skin without apparent clinical alterations may present cytogenetic modifications associated with carcinogenesis.1,74 The concept of field cancerization corroborates the chronic course of actinic keratoses, with frequent recurrences. It also reinforces the need to treat the whole field cancerization area to achieve long-term remission. Contrastingly, if only visible lesions are treated, adjacent mutated areas may further develop new lesions.74

Although the diagnosis of actinic keratoses is based on clinical examination, in some cases a skin biopsy is necessary; these are the major criteria for biopsies: large lesions (>1cm in diameter), bleeding, ulceration or induration, rapid lesional growth and erythema. The minor criteria are intense lesional pruritus, pain, pigmentation, hyperkeratosis, and palpable lesion; in addition, absence of response to usual treatments and presence of some unusual characteristics may also be associated with the progression of actinic keratoses to SCC and indicate the need for histopathological examination.3,5,68,75,76

It should be noted that SCCs that in mucosal areas present a higher risk of progression; for this reason, early clarification of the etiology of labial lesions is essential. In this context, performing a biopsy and sending the material for histopathological analysis is mandatory. Performing a cutaneous biopsy is imperative in cases of suspected SCC: when there is ulceration, increased semimucosa thickness, lip texture changes, or loss of definition between the transition from labial commissure to adjacent skin.71

Different proposals for the classification of actinic keratoses have been described. They take into account clinical, dermatoscopic, and histopathological aspects, whether isolated or associated (Table 2). Initially, Olsen et al. classified the lesions in three grades according to clinical aspects. They recommended assessing the severity of the lesions in clinical practice.76,77 Another classification –proposed by the 2015 European Guideline for the treatment of actinic keratoses and created by Röwert-Huber et al. – orders the lesions according to histological examination from grade I to grade III.6,76 It is important to emphasize that the degree of agreement between the clinical and histological graduation is low, which reinforces that every actinic keratoses should be treated, independently of their grade.78 In addition to the grading systems mentioned above, others are available, including Cockerell's, which associates clinical examination and degree of keratinocyte atypia and Goldberg's, which classifies them as proliferative or non-proliferative based on clinical behavior and histological characteristics.3,79,80 Moreover, Zalaudek et al. used dermoscopy to classify facial actinic keratosis. Based on histopathological examination, it is also possible to categorize actinic keratoses into seven subtypes: hypertrophic, atrophic, bowenoid, acantholytic, epidermolytic, lichenoid, and pigmented.1,7,81 In this grading system an overlap of histological subtypes may occur in a single lesion.43 Finally, there is a lack of consensus in the validation of these classifications. Their use remains controversial and it is still not possible to define a gold-standard grading system for actinic keratoses in clinical practice.82

Actinic keratoses are diagnosed clinically in the majority of the cases. Lesions presenting compatible history data and physical examinations may be recognized and do not need complementary analyses. Dermoscopy has been shown to be extremely important in increasing the level of confidence and accuracy in equivocal lesions. Other noninvasive imaging methods, such as confocal microscopy (CM), may also be useful in specific situations when available. Finally, doubtful cases will require histopathological study to confirm the diagnosis.

To know the clinical characteristics of the main differential diagnoses of actinic keratoses and how to use the auxiliary methods for diagnosis is crucial in this process.

Dermoscopy

Dermoscopy is a fast-performing, noninvasive method that helps in the diagnosis of actinic keratoses and allows them to be differentiated from their differential diagnoses; moreover, actinic keratoses have well established dermatoscopic criteria. Dermoscopy has high sensitivity and specificity for the diagnosis of actinic keratoses, with values of 98.7% and 95%, respectively.83,84

In facial actinic keratoses four dermoscopic findings are described as essential: (1) erythema forming a pink-reddish vascular pseudonetwork surrounding hair follicles, (2) yellowish-white scales, (3) thin and wavy vessels surrounding the follicles, and (4) follicular openings filled with keratotic plugs.83 These structures define the so-called “strawberry” pattern described for most of the facial actinic keratoses (Fig. 3).83 Anther finding is the “rosette” sign, seen only with polarized light dermoscopy, a figure resembling a four-leaf clover, formed by four whitish points surrounding the follicular opening.85–87

Figure 3.

Dermoscopic image (FotoFinder®, x20) of the “strawberry” pattern observed in facial actinic keratosis.

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Dermoscopic peculiarities are observed in some subtypes of actinic keratoses: Bowenoid actinic keratosis presents glomerular vessels regularly distributed along the lesion, differentiating it from Bowen's disease, whose vessels are irregularly distributed and grouped; hyperkeratotic actinic keratoses present a non-specific pattern due to hyperkeratosis, which prevents visualization of the underlying structures.66,88

Dermoscopy of non-facial actinic keratoses includes erythema and superficial scales, sometimes accompanied by dotted vessels.88,89 Furthermore, the erythematous pseudonetwork may eventually be found, although it is characteristic of facial lesions.89,90

When the patient has multiple actinic keratoses, some authors describe that the lesions tend to follow the same dermoscopic pattern.91 This tendency occurs in relation to pigmentation: patients with higher phototypes tend to present multiple pigmented lesions, while those with lighter phototypes tend to have non-pigmented lesions.91

Dermoscopy may be useful for evaluating the progression of actinic keratoses to invasive SCC, as described by Zalaudek et al. (Table 3).92

Table 3.

Progression model of actinic keratoses to invasive squamous cell carcinoma (SCC) based on dermoscopic analysis.

Clinical diagnosis	Dermatoscopic findings
Actinic keratosis	Red pseudonetwork
Actinic keratosis evolving to in situ SCC	Starburst pattern
In situ SCC	Yellowish opaque structures and dotted vessels
In situ SCC progressing to invasive SCC	White areas without structures, dotted and hairpin vessels
Minimally invasive SCC	Central keratin mass and vessels hairpin
Invasive SCC	Central keratin mass, ulceration, and irregular linear vessels

In relation to dermoscopy of pigmented actinic keratoses, the main types of pigmentation are: brownish pseudonetwork, homogeneous, annular–granular, brownish or grayish pigmentation in spots and globules, and inner gray halo.93 In the face, pigmented pseudonetwork and granular–annular pigmentation predominate (Fig. 4).

Figure 4.

Dermoscopy of facial pigmented actinic keratosis (FotoFinder®, x20): a brownish pseudonetwork that spares follicular ostia is observed, in addition to surface scales and underlying vascular pseudonetwork.

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Regarding non-facial pigmented actinic keratoses, they may present a reticular pattern with a delicate pigmented network, homogeneous pigmentation, or multiple irregular dots and globules of brownish to blue-gray color (Fig. 5).66

Figure 5.

Dermoscopy of extra-facial pigmented actinic keratosis located on the forearm: homogenous brownish pigment with whitish scales on the lesion surface can be observed (FotoFinder®, x20).

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The differential diagnoses of actinic keratoses include seborrheic keratosis, Bowen's disease, SCC, solar lentigo, stucco keratosis, basal cell carcinoma (BCC), porokeratosis, clear cell acanthoma, psoriasis, lupus erythematosus, lichen planus, and viral warts.1,90 In pigmented facial actinic keratoses, the main differential diagnosis is lentigo maligna, although other benign lesions enter the differential diagnosis, such as solar lentigo, seborrheic keratosis, and lichenoid keratosis (Table 4).93,104–106 The correct recognition of each of these differential diagnoses is essential, as they vary in relation to prognosis and necessary treatments.106 In this context, dermoscopy is fundamental, as it helps to differentiate them.

Despite the difficult differential diagnosis between pigmented actinic keratoses and lentigo maligna on the face, dermoscopy may be useful. The presence of homogeneous areas (obliteration of follicles) is highly suggestive of lentigo maligna, whereas spared follicular structures and inner gray halo plus follicular plugs favor the hypothesis of pigmented actinic keratosis.66,108

Actinic keratoses may follow three different paths, the most relevant being the transformation into SCC. However, a significant portion of lesions remain stable throughout their evolution and may also involute spontaneously, although recurrences are frequent.8,109,110

The carcinogenic process in actinic keratoses follows the multi-stage carcinogenesis model: an initial mutation in a tumor suppressor gene leads to a precursor lesion, and later mutations in oncogenes lead to invasive properties.111 This progression can occur by the classical pathway, in which there is progression of keratinocytic dysplasia from more superficial epidermal layers toward the basal layer and the dermis,3 or by the differentiated pathway, a more aggressive and common pathway in which keratinocyte dysplasia located only in the basal epidermal layers evolves into invasive SCC by adnexal invasion.112

Data about the risk of malignant transformation of a single actinic keratosis ranges from 0.1% to 16%.37,109,113–115 In 10 years, the risk of malignant transformation of a single lesion is of about 10% for immunocompetent patients and 20% for immunocompromised patients.67,115,116 Thus, when assessing the risk of malignant transformation of actinic keratoses in patients with multiple lesions, the risk will be higher than that described for patients presenting a single lesions.117 Indeed, their risk of developing basal cell carcinoma (BCC) and SCC is higher than in the general population.118 In a population-based study in the United States (mean age of the analyzed population of 79 years), the risk of developing skin cancer in a patient with actinic keratoses was six-fold higher than the population without actinic keratoses (p<0.001), both for NMSC and for melanoma.119 The study also showed that this risk was increased in the Caucasian population (p<0.01), with the risk raising as patient age increased.119

According to some authors, 60–80% of SCCs develop in areas of actinic keratoses.109,114,120,121 Some studies even suggest that time is a cofactor for the transformation of actinic keratoses into invasive lesions, with an average time to transformation for invasive lesions of 24.6 months (95% CI: 21.04–28.16 months).39,122

A significant proportion of actinic keratoses remain stable throughout their course (63.1%); this is the most frequent evolution in the natural course of actinic keratoses.37 They often grow in size, quantity, or become more hyperkeratotic if not treated.37

Finally, a minority of lesions (from 20% to 23% in patients with a single lesion and from 0% to 7.2% in patients with field cancerization) may disappear spontaneously; however, lesional recurrence occurs in a significant portion of patients, affecting 57% of the cases.110 The proposed mechanism to explain spontaneous remission of actinic keratoses involves a sufficient immune response leading to lesion destruction; in addition, the reduction of UV radiation exposure could be involved.37 Moreover, spontaneous lesion regression rates are even lower in immunosuppressed patients.123

The evolution of actinic keratoses varies according to patient's clinical characteristics. Immunosuppressed individuals or patients with previous NMSC present a higher risk of malignant transformation of their actinic keratoses. In addition, in the same individual, actinic keratoses have dynamic characteristics: some lesions regress spontaneously while others evolve into invasive lesions; Identifying which lesions will develop into SCC is a challenge.110 Another important consideration is that patients diagnosed with actinic keratoses present a risk of developing new lesions in one year of 60%, demonstrating the chronicity of this pathology.13,37

Patients with actinic keratoses usually have a good prognosis, as it is not directly associated with mortality; however, different degrees of morbidity associated with lesions treatment and with symptoms of the disease are frequent. In addition, the prognosis may vary in patients with more aggressive lesions and association with SCC. Moreover, the overall mortality for this neoplasm is around 3–4% of the cases.124 Furthermore, chronically photoexposed patients presenting actinic keratoses are at a higher risk of developing NMSC and melanoma; because of that, a higher level of surveillance for skin cancers is important in these individuals.125–127

Considering that actinic keratoses are potentially associated to malignant transformation and that it is not possible to predict which lesions it will occur, all lesions should be treated.1,9,116,128

Some practices are essential in the management of patients with actinic keratoses: (1) regular total body skin examination, (2) assessment of the presence and treatment of field cancerization, (3) focused ablative methods for hyperkeratotic lesions or similar, (4) patient education regarding the chronic course of actinic keratoses, the need for photoprotection, and frequent treatments, and (5) regular skin self-examination by the patient.129

Therapeutic alternatives for actinic keratoses include several modalities. Basically, they can be divided into ablative or surgical methods and topical therapy (Table 5).130 The use of these methods in association or in sequence is common in the management of these patients.131 Treatment selection varies according to the clinical presentation, its location, and the number and extent of lesions; therefore, treatment should be individualized according to the needs of each patient.132 Notably, 25–75% of the patients treated will need retreatment within 12 months due to the appearance of new lesions, demonstrating the chronicity of this condition, even if field cancerization treatment has been performed.127 The worst recurrence rates are observed in patients submitted only to cryotherapy and the lowest rates are observed in those who have undergone field cancerization treatment.133

A large systematic review for the treatment of actinic keratoses concluded that 5-fluorouracil (5-FU), diclofenac, imiquimod, and ingenol mebutate (IM) may present similar efficacy.134 Gupta et al. evaluated the efficacy of topical therapies for actinic keratoses, and observed that the following options presented, respectively, decreasing rates: 5-FU 5%, 5-FU 0.5%, photodynamic therapy (photodynamic therapy (PDT)) with aminolevulinic acid (ALA), imiquimod, IM, methylaminolevulinic (MAL) PDT, cryotherapy, and diclofenac gel.135 Another meta-analysis observed that PDT with ALA was the most effective in achieving complete response; however, this meta-analysis might not reflect updated results, as it excluded more recent studies.136,137

Classically, patients can be classified in four subgroups according to disease extension to define the best therapeutic modality to be used: patients with single lesions (<5 lesions per body area), with multiple lesions (six or more lesions per body area), those with areas of field cancerization, and immunosuppressed patients.76

Actinic keratoses represent a cutaneous condition with an impact on quality of life, and they are an important precursor of cutaneous neoplasias.92 For this reason, the recognition and prompt treatment of such lesions are of extreme importance, since progression of the disease can be prevented. Thus, clinical and non-invasive imaging techniques, especially dermoscopy, can help with this task. Therapeutic options available are extensive and the choice of the best alternative should be individualized within the context of each patient and, whenever possible, based on scientific evidence.

None declared.

Clarissa Prieto Herman Reinehr: Approval of the final version of the manuscript; conception and planning of the study; composition of the manuscript; critical review of the literature.

Renato Marchiori Bakos: Approval of the final version of the manuscript; conception and planning of the study; participation in the study design; critical review of the manuscript.

None declared.