Introduction
Actinic keratosis (AK) is a common skin condition marked by hyperkeratotic lesions developing on photodamaged or aged skin, occurring most frequently in Caucasians [1, 2].
In the literature, AK is defined as a precancerous condition of the skin or as squamous cell carcinoma (SCC) in situ arising from the transformation of keratinocytes, which has the potential to progress to SCC [3].
AK lesions are typically numerous and rarely occur individually. Most commonly, several to dozen foci are seen in a single patient.
Molecular studies indicate that AK lesions represent the initial clinical stage that can trigger a sequence of pathological processes in skin damaged by ultraviolet radiation (UVR). These lesions may spontaneously regress, remain unchanged for many years, or progress to squamous cell carcinoma, which currently accounts for 15–20% of all skin cancer cases [4, 5]. Because skin cancers where UVR plays a significant pathogenetic role are an important medical concern, understanding the clinical characteristics of AK and the principles of diagnosis and therapy of the condition is paramount.
AK treatment is a prolonged process, and the choice of optimal therapy in most patients involves the physician in charge considering the patient’s preferences when making treatment decisions.
Epidemiology
Epidemiological data suggest that the incidence of AK varies significantly based on geographic location (distance from the equator) and the age of the patient [6–8]. In addition, it correlates with the presence of other signs of skin photodamage, such as solar elastosis, skin thickening, prominent wrinkles, and lentigines [9].
In Europe, the prevalence of actinic keratosis is estimated to be approximately 15% and 6% in men and women, respectively. In 70-year-old patients, AK is diagnosed in about 34% of men and about 18% of women. For comparison, in the United States, the prevalence varies from about 11% to 26%, while in Australia, which has the highest skin cancer rate globally, the prevalence of actinic keratosis among the adult population over the age of 40 ranges from approximately 40% to 60%.
Due to the high prevalence of the disease and the potential for individual AK lesions to transform into squamous cell carcinoma, all current national and international guidelines strongly recommend the treatment of AK [10–14].
Currently, skin cancers account for over 30–50% of all diagnosed malignancies. The lifetime risk of developing the disease is over 20% in Caucasians, and the incidence increases with age, with most cases observed in patients who are over 80 years old. In 2017, a total of 14,180 new cases were registered in Poland. At the same time, however, underestimations occur due to incomplete reporting to the National Cancer Registry [4].
Studies indicate low awareness of the nature of actinic keratosis among both primary care physicians (PCPs) and patients, leading to delayed diagnosis and late initiation of treatment [15–20].
This underscores the need for educational training targeted at PCPs, who have significantly more contact with patients than other specialists.
Pathogenesis
An important factor in the pathogenesis of actinic keratosis is UVR. Skin exposure to ultraviolet rays leads to DNA damage in keratinocytes and the formation of photoproducts. Subsequently, when DNA repair mechanisms fail, mutations occur in suppressor and regulatory proteins, including p16 (INK4a), p14 (ARF), p15 (INK4b), and p53. These mutations promote the formation of AK lesions followed by their progression to SCC [21–23].
Photoproducts are formed under the influence of both UVA and UVB radiation. UVB rays directly impact nucleic acids and lipid membranes, while UVA rays cause indirect damage through the generation of reactive oxygen species. These compounds interfere with normal cell proliferation and intracellular signaling [24–27]. UVB radiation also inactivates the p53 suppressor protein, an important factor in cutaneous photocarcinogenesis. Additionally, UVR induces immunosuppression, enhances the expression of prostaglandins and cyclooxygenase-2, increases the secretion of pro-inflammatory cytokines and anti-
inflammatory interleukin (IL)-10, and promotes the formation of regulatory T lymphocytes [25, 28].
Inflammation, oxidative stress, impaired apoptosis, local immunosuppression, and dysregulated cell cycle collectively create an environment that promotes tumor development [29]. Another significant factor implicated in the development of AK is infection with human papillomavirus (HPV). The underlying mechanism of this phenomenon is not fully understood. However, it is known that HPV-E6 protein can reduce the expression of Bak protein, which is one of the key regulators in the apoptosis process [30, 31].
Clinical presentation
Typical clinical features of AK include thick hyperkeratotic foci, yellow and brown in color, with a rough surface. The lesions vary in size from a few millimeters to 2–3 cm. Often, multiple foci occur in a small area.
The classification of actinic keratosis depending on severity is shown in the table 1.
The diagnosis of actinic keratosis is based on the clinical presentation. A comprehensive comprehensive differential diagnosis conditions such as lentigines, seborrheic keratosis, discoid lupus erythematosus, viral warts, epidermal nevus, dyskeratoma, keratoacanthoma, and Bowen’s disease [32]. Dermoscopy is used in clinical diagnosis of AK, helping to make treatment decisions and monitoring their effects [33]. Furthermore, dermoscopic examination enables non-invasive assessment of the AK surface and surrounding skin before therapeutic intervention, monitoring the outcomes of topical therapies, and providing long-term follow up of the skin changes [34, 35]. The dermoscopic characteristics of AK widely reported in the literature include erythema forming a reddish-pink vascular pseudonetwork surrounding hair follicles, yellowish-white scale, linear wavy vessels around hair follicles, and follicular ostia filled with keratin plugs. These structures form the so-called ‘strawberry pattern’ and represent the characteristic dermoscopic features of facial AK. In contrast, dermoscopy of AK lesions beyond the face reveals erythema and superficial scale, occasionally accompanied by dot vessels. Erythematous pseudonetwork can also be seen, though the feature is also characteristic of facial AK [36]. The dermoscopic features of AK have been extensively studied, yet there remains limited evidence regarding their diagnostic accuracy. The latest research suggests that dermoscopic criteria are reliable indicators for distinguishing between non-pigmented actinic keratosis (NPAK) and pigmented actinic keratosis (PAK), among other conditions [37]. Facial PAK is identifiable by the strawberry pattern, which is characterized by background erythema consisting of unfocused, large vessels located between the hair follicles, surrounded by a white halo. In contrast, NPAK is marked by numerous, slate-grey to dark-brown dots and globules occurring around the follicular ostia, an annular pattern, and a brown to grey network [38].
While biopsy is typically not required to establish the diagnosis of AK, it is recommended for evaluating disease severity and differentiating between AK and SCC [39]. Histopathological evaluation is advised in cases involving large-sized lesions, acutely inflamed and bleeding, manifesting with pruritus and skin hyperesthesia [2].
Risk factors
Risk factors for the development of AK include older age, male gender, cumulative lifetime exposure to UVR, low skin phototypes (I and II), residence in geographic regions near the equator, and chronic use of immunosuppressive drugs [40].
The specific clinical features of AK lesions that increase the risk of progression to SCC have not been clearly identified [40].
Histopathological features
Histopathologically, AK is characterized by abnormal keratinocyte maturation and the presence of atypical cells in the basal layer of the epidermis. In more severe eruptions, these alterations extend through the suprabasal layers of the epidermis. Abnormal basal and suprabasal keratinocytes are noted, exhibiting variations in size and shape, along with nuclear atypia [41, 42].
Epidermal hyperkeratosis is present, with atypical nuclei that are enlarged, irregular, hyperchromatic, and lose their parallel arrangement (loss of polarity). Depending on the predominant pathomorphological type of lesions, several variants of AK are distinguished: atrophic, hyperkeratotic, bowenoid, acantholytic, lichenoid, and pigmented [41, 42].
Proposals have also been made to apply terminology similar to that used in cervical cancer for histopathological diagnosis. Specifically, a three-stage KIN (keratinocytic intraepidermal neoplasia) classification based on clinical and histopathological features has been suggested, where:
• KIN I is characterized by the presence of subclinical lesions, occasionally brownish-red patches with no surface roughness, while histopathological findings include discrete abnormalities manifested as hyperchromatic nuclei with an irregular outline, loss of nuclear polarity in a proportion of cells, increased alkalinity and acidity of the cytoplasm, with no features of hyper- and parakeratosis.
• KIN II manifests clinically as hyperkeratotic rough lesions. Histopathologically, it is characterized by focal proliferation of atypical keratinocytes occupying two-thirds of the epidermis. Furthermore, the morphological alterations in the basal and suprabasal layer cells are more pronounced compared to KIN I.
• In KIN III, the clinical presentation is characterized by reddish-brown scaly plaques within areas of sun-damaged skin. Histopathologically, typical keratinocytes are observed in almost all layers of the epidermis and skin appendages epithelia
[43, 44].
However, there is no established gold standard for classifying histopathological diagnoses specifically for AK lesions [45].
Natural disease course
In UVR-damaged skin, numerous mutated cells may undergo uncontrolled proliferation, clinically manifesting as AK-type lesions, basal cell carcinoma (BCC), and squamous cell carcinoma (SCC) [46].
AK lesions are generally absent during the early decades of life; however, genetic and environmental factors predispose to greater skin damage from UV radiation exposure. Lesions typically appear in individuals with low skin phototypes in the most sun-damaged skin areas, including the head, auricles, neck, dorsal arms and hands, and lower extremities, due to their extensive solar exposure. The scalp, especially with hair loss, is another common site affected by AK [47, 48].
AK-type lesions may spontaneously regress, remain unchanged for many years, or progress to SCC [49]. The spontaneous regression rate of AK-type lesions within 1 year is estimated to range between 15% and 25% [7, 50]. The risk of AK progression to SCC has not been definitively established. Some studies have estimated it to be 0.075–0.096% for a single lesion over a period of 1 year, or 1–10% over 10 years [51, 52]. In patients with multiple AK lesions, the progression rate is higher, ranging from 0.15% to 80% during 1 year [53]. For a typical patient with 7–8 AK lesions, the estimated risk of progression to the invasive form varies between 6.1% and 10.2% [54].
Although accurate evaluation of the probability of a single AK lesion progressing to a more invasive form remains challenging, research has shown that SCC can develop from lesions previously diagnosed as AK or within skin regions where AK has been identified. Various studies have reported the frequency of invasive transformation to range from 65% to even 97% [49, 55, 56]. However, no differences were found based on the patient’s sex, age, or the location of the lesion [46].
Some authors have hypothesized that AK-type lesions may also initiate BCC. One study found that the risk of developing BCC in patients with AK lesions is 10 times higher compared to patients without AK [57]. In addition, the presence of multiple AK lesions has been explicitly shown to be a significant risk factor for non-melanoma skin cancers (NMSC) [50, 58, 59].
In view of the fact that some AK lesions progress to SCC, which has the potential to metastasize, it is crucial to establish a set of uniform diagnostic and therapeutic procedures. The presence of AK lesions in a patient indicates a high cumulative dose of UVR, which is a well-recognized risk factor for the development of SCC. Therefore, these patients should undergo regular examinations for cancerous lesions by both dermatologists and PCPs. This is the position officially endorsed by the American Cancer Society [60] and should be advocated especially for patients with multiple risk factors for developing skin cancer, including individuals with low skin phototypes (Fitzpatrick I and II), age over 65 years, frequent exposure to ultraviolet radiation (UVR), and a positive history of cancer. Furthermore, special care should be provided to patients receiving chronic immunosuppressive treatment.
The risk factors for SCC development from existing AK lesions are listed in the table 2.
Field cancerization
The concept of field cancerization (FC) was proposed in the 1950s, based on histopathological observations revealing that in the margins of excised squamous cell carcinomas there was an area exhibiting varying degrees of epithelial dysplasia.
FC refers to a region of skin photocancerogenesis characterized by visible, subclinical, and morphologically unchanged fields in the epidermis that has suffered chronic damage by UVR. Furthermore, it has been claimed that keratinocytes within the FC undergo genetic alterations that potentially increase the risk of cancer development [53, 61–63]. Over the past few years, the concept of FC has been gaining importance, which underscores the need for appropriate diagnosis and treatment of AK in FC.
Importantly, the approach to actinic keratosis itself has also evolved recently, with a shift towards viewing AK as a dynamic process and a greater emphasis now placed on prevention rather than solely on treatment. The revision in approach is due to the link between clinically manifest AK and subclinical AK lesions and progression to invasive cancer, as well as the fact that subclinical AK can develop from morphologically normal keratinocytes within a short time frame [25].
Therefore, the concept of FC treatment involves removing both visible and palpable lesions and subclinical lesions within the area of UVR-damaged skin characterized by a high risk of developing AK and SCC [64–67].
Patients eligible for this therapy include those with newly diagnosed lesions as well as individuals with recurrent disease. Treating the entire FC not only clears visible lesions but also reduces the risk of emergence of new lesions and the development of SCC.
Treatment
There are three potential strategies for treating actinic keratosis:
• “wait and see” approach;
• treatment of individual clinically visible AK lesions identified by the physician as “increased risk” lesions;
• treatment of a broader area of skin affected by photodamage and AK, i.e. treatment of the fields of cancerization.
The most appropriate therapy for a given patient should be selected from the available options by taking into account the factors listed below:
• number of AK lesions, degree of skin photodamage, duration of lesions, location and clinical evolution of lesions;
• age of the patient, concomitant diseases (immunosuppression);
• history of skin cancer and chronic exposure to UV radiation;
• cost of the procedure;
• expertise of the physician in using a specific technique;
patient preferences.
When selecting a treatment approach, the physician should consider both the number of AK lesions and the concurrent presence of signs of skin photodamage. Opting for techniques that focus on removing a single lesion or monitoring the affected skin area is advisable in patients with only a few AK lesions (less than five within a specific treatment zone). Conversely, when AK lesions are numerous and accompanied by signs of skin photodamage, AK is classified in the high-risk group for the development of squamous cell carcinoma. In such cases, different therapeutic strategies are warranted. Furthermore, immunosuppressed patients should be included in the high-risk group irrespective of the number of AK lesions and the extent of skin photodamage.
Regardless of the therapy, appropriate photoprotection should always be recommended, as it is essential to reduce the risk of developing cancerous skin lesions, including AK. Before initiating therapy, it is important to determine the location and grade of AK lesions. This is necessary for monitoring and evaluating response to treatment, which in turn facilitates informed decisions about potential adjustments to the therapeutic regimen.
Treatment recommendations are shown in the figure 1 diagram.
General principles
To reduce the risk of cancerous skin lesion development, including actinic keratosis itself, education on appropriate photoprotection is essential. Experts underscore that photoprotection is the most important aspect of both prevention and treatment [68]. A comprehensive approach is recommended, involving minimized exposure to both natural and artificial sources of UV radiation, sun protective clothing, and application of UVB and UVA sunscreens. Results obtained at the 6-month mark in a study comparing the use of a sunscreen cream (SPF 17) and vehicle creams showed that sunscreen users had fewer new AK lesions and a greater chance of remission of AK lesions present at baseline. Similarly, it was observed that the ratio of AK-type lesions was lower among subjects in the daily sunscreen group than in those in the discretionary sunscreen group during the 2-year follow-up period. The study findings suggest a 24% reduction in AK count with the use of sunscreens [13, 64].
Research indicates that sunscreen creams are most commonly used in children aged 6 months to 11 years. However, their usage significantly declines in teenagers and adults [69, 70]. Consequently, awareness campaigns are conducted in primary and secondary schools in many countries in order to highlight the importance of photoprotection for adolescents and adults as well [71, 72]. As demonstrated in studies, sunscreens with SPF > 15 can inhibit the formation of thymine dimers, which translates into improved protection against mutations causing skin cancer. Moreover, sunscreens with broad-spectrum UVA protection have been demonstrated to counteract DNA damage caused by reactive oxygen species and inactivation of the p53 protein, and prevent the development of local immunosuppression occurring in the skin due to UVR exposure [73–78]. Very interesting findings regarding the beneficial effects of protective sunscreen creams were obtained by researchers who evaluated the impact of regular sunscreen use on the development of AK, SCC, and BCC in patients after organ transplantation. The study demonstrated that among sunscreen users, significantly fewer AK lesions developed over a 2-year period, and no patient was diagnosed with SCC. In contrast, among those not using sunscreen, 8 (13%) patients were diagnosed with SCC. Additionally, BCC was diagnosed in 2 (3.3%) sunscreen users, compared to 9 (15%) patients not using this type of photoprotection. These findings strongly suggest that consistent use of photoprotective creams offers substantial protection against the development of AK lesions and SCC [79].
>Key recommendations
The use of UV sunscreens along with education about sun protection is the cornerstone of the prevention and treatment of AK.
It is important to ensure that at the outset of active spot therapies patients receive information on the application method and the expected adverse effects of treatment.
Spot treatment is suitable in both, primary and specialist care settings. Whenever possible, a treatment plan should be developed to provide care to patients on an outpatient basis.
Spot treatment is appropriate for managing individual lesions as well as entire therapeutic areas.
In FC treatment, it is essential to define the treatment area in collaboration with the patient. This approach helps determine the extent of potential adverse events and assess the patient’s tolerance to them.
When there is no response to topical therapy, further steps should include specialist consultation, change of treatment modality, or histological verification.
Cryosurgery, curettage, electrocoagulation, and laser therapy
When managing actinic keratosis, the traditional approach based on surgical excision is not recommended.
The most commonly used therapeutic option for AK with a low risk of developing SCC is cryodestruction (cryosurgery). It is a simple, inexpensive, fast, and effective method, with a success rate of 57.0% to 98.8% in treating individual lesions [80–82]. Cryodestruction is used to remove isolated AK lesions [51, 83]. Treatment may result in minor post-procedure discomfort and skin discoloration, which can be minimized by shorter freeze times. However, reducing the duration of freezing may also decrease the overall treatment response rate [84].
The most widely reported adverse effects include pain, hyper/hypopigmentation, and skin exfoliation. Cryodestruction can be performed using contact or spray techniques. However, in AK treatment, the spray method appears to be superior [85–88]. Early retrospective studies suggested that cryotherapy was effective in almost 99% of cases [53], but more recent research has significantly revised these claims. The success of therapy is determined not only by the clinical condition of the patient, but also the appropriate technique of performing the procedure, especially the freezing time. The cosmetic effects of treatment are not always satisfactory. Cryotherapy can also be combined with other treatment modalities, such as topically applied 5-fluorouracil or salicylic acid [89, 90].
Ablative lasers, particularly the CO₂ and Er:YAG lasers, can be used for the treatment of isolated AK lesions. However, the ultimate outcome relies significantly on the practitioner’s proficiency in performing this procedure. Another potential issue is the relatively high cost of this therapy. Other destructive methods used in the treatment of AK include curettage and electrocoagulation. While these methods are effective and inexpensive, it is currently claimed that they offer no therapeutic advantage over cryotherapy. The disadvantages of these methods include the need for local anesthesia, high rates of scarring and depigmentation [91, 92], higher costs compared to cryotherapy, and the requirement for more experience with the technique [71–73]. Although the adverse effects of cryosurgery and CO2 laser ablation have not been systematically studied, patient satisfaction surveys show a significant advantage for cryosurgery. Despite moderate-quality evidence, cryosurgery can be an alternative to CO₂ laser ablation [68].
For FC treatment, both spot therapy and cryosurgery of the affected skin area are viable therapeutic options. The method should be chosen based on factors including the number of AK lesions, their size, duration, and location. It is also essential to consider the patient’s individual clinical characteristics and preferences. In patients with multiple hyperkeratotic lesions, therapeutic benefits can be achieved through sequential application of topical treatment and therapy of the affected skin area.
In Poland, reimbursement for treating actinic keratosis primarily covers outpatient procedures including cryotherapy, curettage, electrocoagulation, laser therapy, and lesion excision [93].
Key recommendations
Before initiating therapy, the patient should always be informed about potential adverse events.
Cryosurgery is an effective therapeutic modality for treating isolated AK lesions.
Curettage may be warranted for advanced AK (grade 3), when lesions are refractory to topical therapy, and when there is clinical suspicion that they may be an early transicion SCC.
Photodynamic therapy, pharmacology and other treatment options for AK
Current treatment modalities for FC encompass 5-fluorouracil, topical immune response modifiers, photodynamic therapy (PDT) or diclofenac. High efficacy and safety of these therapeutic options have been demonstrated in a number of studies. However, it is important to note that treatment regimens can be lengthy, and some patients may experience local inflammatory reactions that they consider unacceptable.
Photodynamic therapy (PDT) is characterized by high therapeutic efficacy and very good clinical outcomes after just 1–2 treatments. However, the application of the method is constrained by its high cost and discomfort experienced by patients. PDT is based on the selective uptake by cancer cells of a photosensitizing substance (5-aminolevulinic acid – 5-ALA or its methyl ester – MAL) at a precisely defined wavelength. Photosensitizers (dyes) accumulate at significantly higher concentrations in pathological cells compared to normal keratinocytes. The dye then absorbs electromagnetic radiation, leading to the generation of oxygen free radicals, superoxide anion radicals, and hydroxyl radicals. These molecules induce permanent damage to proteins, DNA, and phospholipids. Furthermore, a cascade of immune reactions is initiated, leading to the destruction of partially or fully transformed cells in the epidermis. The literature indicates that PDT has a high efficacy, both immediate and long-term, with success rates ranging from 75% to 92% after a single treatment or two sessions [91, 94–96].
The most commonly used photosensitizer is 5-aminolevulinic acid (ALA). ALA can be administered topically, orally, or intravenously. The substance is non-photoreactive, and it is a natural metabolite in the porphyrin metabolism pathway, serving as a precursor to protoporphyrin IX (PpIX), an endogenous compound known for its potent photosensitizing effect. The topical route of 5-ALA administration bypasses the regulation of ALAS1 inhibition by heme in a negative feedback mechanism that usually leads to the production of PpIX in such quantities that can be efficiently converted to heme by ferrochelatase (FECH). As a result of these processes, overproduced PpIX is not converted to heme by FECH quickly enough, resulting in its accumulation in cells, where it can be excited by red light [97].
Undoubtedly, PDT is a valuable option for treating AK in an outpatient setting. Conducting the procedure in an outpatient treatment room has been found to improve patient compliance. There is a wealth of literature data demonstrating the efficacy of PDT with methyl aminolevulinate (MAL) as a photosensitizer in the treatment of AK [98–100].
For patients with AK, photodynamic therapy using 5-aminolevulinic acid (ALA) in conjunction with red light (ALA-red light PDT) is the recommended option. Results from four studies with 10% ALA gel as the photosensitizing agent [98–101] indicate that ALA-red light PDT is superior to PDT with placebo (PLC) and red light both in terms of reduction and complete resolution of AK lesions, and prevention of tumor growth. Furthermore, findings from long-term studies revealed that 12 months after one or two PDT sessions, skin cancer in the treatment area was diagnosed in only 3.6% of patients treated with ALA-PDT, compared to 5.0% of study participants treated with PLC-PDT. These findings align with the results of a network meta-analysis comparing the relative efficacy of 10 treatment modalities for AK, including topical therapies and PDT, where ALA-PDT was demonstrated to have superior efficacy compared to placebo. To improve the overall efficacy of photodynamic therapy with red light and minimize the risk of adverse events (local skin irritation), ALA incubation time of 1–4 hours can be employed [102]. Furthermore, clinical experts suggest that ALA-red light PDT can be considered as an alternative to cryotherapy alone [12].
Patients with AK can also be treated with ALA-daylight PDT. This approach has demonstrated comparable effectiveness to ALA-red light PDT, while being less painful. Daylight PDT protocols rely on harnessing natural sunlight as an energy source to activate a photosensitizing chemical substance. Studies comparing the therapeutic efficacy and occurrence of pain during ALA-red light PDT and ALA-daylight PDT repeated every 2 weeks for three sessions with 2-hour exposure showed comparable benefits of both treatments, with 96% and 97% reductions in skin lesions, respectively. For the daylight method to be effective, weather conditions must permit optimal light exposure of the treated lesions. Daylight can be used for PDT if the patient can comfortably remain outdoors for 2 hours (at > 10°C) [103].
Patients with AK can also be treated with ALA-blue light PDT. Studies show that ALA-blue light PDT offers significant advantages compared to placebo in terms of complete and partial resolution of lesions, lesion reduction, and cancer prevention. Furthermore, subsequent studies found that after 8 weeks, 82.2% of AK lesions were successfully treated with one cycle of ALA-blue light PDT, compared to just 28.8% of lesions effectively treated with placebo and blue light [104–106]. Patients with actinic keratosis should not be treated with hydroxy acids prior to ALA-blue light PDT [12].
Numerous studies indicate that photodynamic therapy using a topical photosensitizer is effective and relatively safe. The only adverse event observed during the procedure at the irradiation site is pain. Apart from that, the treatment is well tolerated, and adverse events reported in the literature, such as heightened sensitivity to light, nausea, vomiting, muscle tremors, and elevated blood pressure, are extremely rare. Limitations in the application of photodynamic therapy stem primarily from the insufficient number of studies and treatment guidelines for specific indications [107].
According to data in the Register of Medicinal Products, two of the aforementioned medicinal products are authorized for marketing in Poland, containing aminolevulinic acid in the form of gel and medicated patch; though the patch form is no longer available. However, there are currently no registered medicinal products in Poland containing methyl 5-aminolevulinate (MAL).
The medicinal product in the form of patch (4 cm²) has restricted utility because it is suitable only for the treatment of mild actinic keratosis lesions on the face or scalp (non-hairy regions). The gel formulation of the medicinal product, containing 5-aminolevulinic acid hydrochloride at a concentration of 78 mg/g, without any special restrictions regarding the application area.
The therapeutic efficacy of this medicinal product has been substantiated through a systematic review comparing various therapies against PLC. ALA PDT 78 mg/g proved to be the most effective therapy (RR = 8.06; 95% CI: 2.07–31.37), followed by other modalities characterized by lower success rates including imiquimod 5%, PDT with MAL, and cryosurgery (RR = 4.67; 95% CI: 1.36–16.66). Furthermore, in the meta-analysis, ALA-PDT demonstrated the highest relative risk (RR) for complete clearance of lesions (RR = 5.08; 95% CI: 2.49–10.33) [108].
It is recommended to evaluate the treated lesions 3 months post-therapy. After determining the response of each skin lesion, the physician may decide to repeat treatment.
European guidelines recommend ALA PDT as an effective therapy for actinic keratosis (quality of evidence 1+, strength of recommendation A) [68].
5-fluorouracil (5-FU) is a topical chemotherapeutic agent that inhibits DNA synthesis and alters RNA function. 5-FU is typically used at a 5% concentration, but lower concentrations, including 0.5% combined with 10% salicylic acid, are also available. According to a 2007 publication, the drug should be used for AK therapy twice a day for 6 weeks, which leads to a high cure rate of 60–70%. Some authors report that the therapeutic efficacy is lower (approximately 55%). The main disadvantages of 5-FU treatment include its prolonged duration and the associated symptoms, including pruritus, erythema, pain, ulceration, erosions, secondary infections, and depigmentation. Exposure to ultraviolet radiation (UVR) intensifies these reactions, which makes it essential to concurrently use photoprotection [109]. In order to improve the benefit-risk balance, researchers conducted trials using a lower concentration of FU, i.e. 0.5% combined with 10% salicylic acid. However, further research is needed to confirm the effectiveness of this therapeutic approach. Experts recommend 5-fluorouracil either for treating individual lesions or as part of the therapy for FC. Some studies also suggest combining 5-FU with tretinoin to improve the therapeutic benefit of AK treatment [110, 111].
Imiquimod is an organic chemical compound that modulates the immune response by stimulating monocytes and macrophages. The cells are activated through the TLR-7 receptor. Activated TLR receptors have been shown to play a role in anticancer and antiviral effects. The anticancer mechanism of action of imiquimod is based on enhancing cell response in antigen presentation to T cells and stimulating the secretion of pro-inflammatory cytokines, including IL-1, IL-6, IL-8, IL-12, TNF-a, and IFN-g. Recent experimental studies indicate that the anticancer activity of imiquimod persists for a long period after treatment. Imiquimod is most commonly used in the form of a 5% cream. Randomized studies have shown imiquimod to be effective (45–84%) when used two or three times per week for a total of 12–16 weeks. There have been only sparse studies on imiquimod 3.75%. Lower concentrations are used to enable larger areas of skin to be treated within a shorter period of time. Imiquimod can also be prescribed in combination therapy after cryosurgery. Imiquimod (5%) is applied when the number of lesions makes cryotherapy impractical and other treatments are either contraindicated or less appropriate. The most frequent adverse effects include excessive skin inflammatory reactions [94, 112]. Adverse events associated with imiquimod include erythema (30.6%), scabbing (29.9%), and erosions or ulcers (10.2%).
Another potentially promising therapy is resiquimod, a local immunomodulator that acts as an agonist for multiple TLRs. This results in a more robust response of dendritic cells and increased secretion of IL-12 and INF-a. The product is applied three times a week for 4 weeks to a skin area of 25 cm². However, comprehensive data regarding its therapeutic efficacy and safety are still lacking. Resiquimod is available at concentrations of 0.01%, 0.03%, 0.06%, or 0.1%, and it shows the highest effectiveness when applied three times a week for 4 weeks. In one of the studies it was found that resiquimod 0.1% used twice daily for 90 days resulted in complete regression of AK lesions in 48% of cases. However, other studies showed a high rate of adverse events associated with resiquimod 0.1%, resulting in treatment discontinuation [113]. Resiquimod therapy is currently unavailable in Poland.
Diclofenac is a non-steroidal anti-inflammatory drug. It exerts its effects by inhibiting cyclooxygenase 2, which is often overexpressed in various cancerous tumors. In addition to its anti-inflammatory properties, diclofenac can inhibit the proliferation of cancer cells by inducing apoptosis through the activation of bcl-2 and caspase 8. Topical use of diclofenac causes contact dermatitis-type reactions and skin erosions. Diclofenac is used as a 3% gel suspended in 2.5% hyaluronic acid. It is applied twice a day for a total of 60–90 days [91, 114–116]. Diclofenac gel 3% can be used to treat individual lesions or the entire field. Importantly, it produces less intense skin reactions compared to 5-FU or imiquimod. In clinical trials, it demonstrated an approximately 30% advantage over placebo. Extending the treatment duration to 180 days was found to improve the outcome by an additional 5%. Diclofenac gel is well-tolerated but should be reserved for use in the treatment of mild AK. Similar to other topical and systemic NSAIDs, diclofenac is known to induce adverse effects involving the cardiovascular and gastrointestinal systems. Diclofenac can also be used in combination with cryosurgery, as detailed in the section on combined treatment.
Tretinoin is commonly applied topically to address changes associated with the process of skin photoaging. However, the use of tretinoin in FC remains a topic of controversy. Limited studies have indicated a moderate benefit of using retinoids in AK treatment. Experts recommend tretinoin primarily for the treatment of photodamage rather than specifically for AK therapy. Limited trials have demonstrated an efficacy range of 35% to 55% after multiple months of treatment. Tretinoin can be used in combination with other therapies, and it seems that it may improve their outcomes [117].
As of 1 January 2024, none of the aforementioned technologies – 5-ALA, 5-fluorouracil, imiquimod, resiquimod, diclofenac (3% gel), and tretinoin – are included in the list of reimbursed medicines, foods for special medical purposes and medical devices, according to the Notice of the Minister of Health of 11 December 2023. It is also important to note that photodynamic therapy is not billed as a standalone medical service. The treatment is provided during some hospitalizations in DRGs.
Ingenol mebutate, a plant-derived drug, was adopted for the treatment of AK in clinical studies. Ingenol mebutate is a medicinal product approved for use in adults with non-keratotic and non-hypertrophic grade 1–2 AK lesions. Adverse effects of therapy include red skin, scabbing, pain, and pustular lesions. In 2015, the FDA highlighted the risk of serious adverse effects associated with ingenol mebutate, including local and systemic allergic reactions, as well as shingles. Studies also revealed that over a 3-year follow-up period, the risk of cancer in areas treated with ingenol mebutate was three times greater compared to those treated with imiquimod [118]. In February 2020, the medicinal product containing ingenol mebutate had its marketing authorization revoked in the EU.
Tirbanibulin as a topical ointment (1%) was approved by the FDA in December 2020 for treating AK lesions on the skin of the face and scalp. The findings from two phase III clinical trials, which included a total of 702 patients, demonstrated that tirbanibulin outperformed a standard drug ointment in the treatment of AK lesions on the face and scalp. The lesion resolution rates were 44% compared to 5% in one study, and 54% compared to 13% in the other study, respectively. Among study participants who achieved a complete response to tirbanibulin, the estimated percentage of patients with recurrent lesions at 1-year follow-up was 47%. Adverse events comprised primarily mild to moderate local reactions, but no participants were withdrawn from the study because of their occurrence [119]. In Poland, neither ingenol mebutate nor tirbanibulin are currently available for therapy.
Medium-deep peels and dermabrasion are commonly used in dermatological practice; however, they carry a range of risks such as bleeding, bacterial and viral infections, and a higher relapse rate compared to other treatment methods [68].
For patients with AK, ALA-red light PDT is recommended as the preferred treatment over trichloroacetic acid peels. Studies comparing the efficacy and safety of ALA-red light PDT and 35% trichloroacetic acid chemical peel for treating AK lesions on the scalp showed PDT to have a greater efficacy, resulting in a 58% reduction in lesions compared to 32% in the peel group. Additionally, PDT led to complete resolution of lesions in 74% of cases (versus 49% in the peel group) within 12 months of therapy [120]. Clinical experience suggests that PDT is the preferred treatment option, especially for patients with severe lesions, because of its higher therapeutic efficacy, while chemical peels are recommended as adjunctive treatment or in the early stages of the disease.
Key recommendations
Photodynamic therapy is a beneficial method for treating confluent AK lesions, particularly those located on the scalp that are challenging to manage or unresponsive to therapy in the absence of invasive disease.
Photodynamic treatment is associated with the lowest risk of scarring compared to other surgical modalities, and it is recommended for the management of AK lesions.
Initial topical treatment improves the success rates of subsequent surgical therapies.
If an individual lesion fails to respond to therapy, it indicates the need for further evaluation and potentially surgical removal.
When managing patients with multifocal high-grade (i.e. grade 3) disease, a history of squamous cell carcinoma, and undergoing immunosuppression, the multidisciplinary team should collaboratively consider different therapeutic options.
Combination therapy
There are various approaches to combination therapy, which can be considered from two perspectives. One strategy is based on a sequential treatment plan, where subsequent therapy is recommended based on the outcomes of a previous therapeutic modality. The other approach entails incorporating more than one therapy into the initial treatment plan, with the goal of maximizing or consolidating the response to one treatment modality. For example, cryosurgery or PDT may be used either before or after treatment with diclofenac. The other strategy involves using a product combining two active ingredients. For example, 10% salicylic acid can break down surface keratin, enhancing penetration and thereby improving the therapeutic benefit of 0.5% 5-FU. In patients with AK, combination treatment with 5-fluorouracil and cryotherapy is preferred over cryotherapy alone [121, 122]. According to the American guidelines [12], combination therapy with imiquimod and cryotherapy is recommended over cryotherapy alone for treating AK [123, 124]. Also, topical retinoids combined with cryotherapy are not considered suitable for patients with AK as an alternative to cryotherapy alone. Imiquimod treatment is not recommended after ALA-blue light PDT [125]. Additionally, published guidelines highlight the importance of further research to assess the efficacy and safety of combining 5-fluorouracil and calcipotriol for the topical treatment of AK [12].
Essentially, combination therapy should be considered for patients who have multiple and/or hyperkeratotic lesions, require treatment over a large area, or exhibit signs of resistance to monotherapy.
There are multiple interventions for treating AK which are often used in combination, either concurrently or sequentially. The rationale for combination treatment lies in utilizing different mechanisms of action from various interventions to achieve a synergistic therapeutic effect. FC therapy can be complemented with spot treatment, such as cryosurgery, particularly when managing hyperkeratotic lesions or those refractory to standard treatment. In clinical practice, there are also instances where initial topical treatment reveals subclinical alterations that require the initiation of FC therapy.
Selection of treatment depending on the location of lesions
According to recent reports, the selection of treatment modality should be based on the location of the lesions. The eye area is especially susceptible to adverse events, and it is important to consider this factor when selecting an appropriate therapy for AK. Research shows that the treatment of this specific body area can be effectively carried out with close supervision, and the therapeutic intervention should be combined with eye care [126].
AK lesions and SCC commonly involve the auricles. Furthermore, it has been observed that the risk of metastasis is higher for SCC located in the ear. Consequently, the approach to treating lesions in this location may need to be adjusted accordingly. In patients with deeper AK lesions, it is advisable to perform a biopsy or surgical excision followed by histological examination to rule out invasive SCC. These interventions can serve as a treatment for AK or as a preliminary step to SCC therapy.
AK lesions on the dorsal surface of the hands are often numerous and hyperkeratotic. Consequently, early topical treatment or PDT may decrease the necessity for subsequent surgical interventions. Within this specific area, the skin exhibits greater tolerance to adverse effects associated with inflammation treatment. This allows for a longer duration of PDT in this group of patients. Additionally, combination therapy with salicylic acid and 5-FU or curettage may be a useful component of the treatment of grade 3 AK lesions on the forearms and dorsum of the hands [68].
Conclusions
Actinic keratosis is becoming an increasing problem in routine dermatological practice. The shift towards viewing AK primarily as potential early-stage skin cancer lesions should encourage dermatologists to take a holistic approach to the condition, prescribe appropriate treatments with due consideration given to FC, and place a strong emphasis on prevention strategies.
In treating FC, cryosurgery and phototherapy with a photosensitizer play an essential role. These therapeutic options are highly effective and, importantly, enable the treatment of skin lesions at their site of occurrence, frequently eliminating the need for pharmacological treatment and adjunctive therapies for managing AK. These methods also allow outpatient treatment for the majority of patients.
The following table 3 summarizes essential information about the principles of therapy using various available methods.
Actinic keratosis represents a multifocal manifestation of sun-induced damage, encompassing a diverse range of clinical symptoms and pathological changes. They follow a relapsing and remitting course, which contributes to the chronic nature of the disease. In many cases, treatment may also require minimal medical intervention beyond providing guidance on sun protection and self-monitoring. Importantly, the choice of therapy should be based on the patient’s individual circumstances. In view of the chronic nature of the condition and the associated risk of cancer development, long-term follow-up to monitor the elevated risk of NMSC is essential.
Funding
The writing of this manuscript was supported by an unrestricted grant provided by Medac GmbH.
Ethical approval
Not applicable.
Conflict of interest
The authors declare no conflict of interest.
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