Development of a treatment algorithm for actinic keratoses: a European Consensus

ARTICLE

Auteur(s) : Eggert Stockfleth¹, Carlos Ferrandiz², Jean Jacques Grob³, Irene Leigh⁴, Hubert Pehamberger⁵, Helmut Kerl⁶

¹Department of Dermatology, Charité Universitätsmedizin Berlin, Skin Cancer Center Charité, Charitéplatz 1, 10117 Berlin, Germany
²Department of Dermatology. Hospital Universitario Germans Trias I Pujol. Universidad Autónoma de Barcelona, Spain
³Hôpital Sainte Marguerite, Marseille, France
⁴School of Medicine, Dentistry and Nursing, University of Dundee, Scotland
⁵Department of Dermatology, Medical University of Vienna, Austria
⁶Department of Dermatology, Medical University of Graz, Austria

accepté le 2 Juillet 2008

Actinic keratoses (AKs) are ultra-violet (UV)-induced keratotic macules, papules or plaques, usually found on sun exposed areas. Epidemiological data shows that the prevalence of actinic keratosis (AK) is increasing throughout the world and that it represents a major health risk to susceptible individuals [1]. The overall prevalence of AK is reported to be between 11-25% [2-4], and up to 60% in individuals over the age of 40 years old in the southern hemisphere [5, 6]. Important risk factors for AK are the combination of genetic propensity (fair skin phenotype) and cumulative sun exposure [6]. In susceptible individuals (Fitzpatrick’s skin type 1 and 2), sun exposure in normal everyday life can be enough to cause AK [7].

Historically, AK was classified as pre-malignant and sometimes seen only as a ‘cosmetic problem’. In recent years, investigations have shown that there are tumour initiating cells in both actinic keratosis (AK) and in squamous cell carcinomas (SCCs), which undergo progressive genetic changes to result in an invasive tumour. AKs are part of a continuum in a multi-step carcinogenesis process [8]. Consequently, it was declared that AK represents an early stage in a continuum that leads from carcinoma in situ to invasive SCC and therefore AK has been referred to as early squamous cell carcinoma in situ corresponding to the classification of cervical neoplasia [4, 9-14]. Following progression, clonal escape can occur following further UV radiation-induced DNA damage and a failure of local defence mechanisms (e.g. apoptosis); however most AKs do not develop into invasive SCCs. Nevertheless, approximately 10% (6-16%) of immunocompetent patients with AK [1, 15, 16] and approximately 40% of immunosuppressed patients [17, 18] develop invasive SCC. Green et al., demonstrated that the relative risk (RR) of SCC increases with the number of AK lesions: RR increases from 1% with 5 or fewer lesions to 20% for patients with > 20 AK lesions [19]. Further evidence of the link between AK and SCC is provided by data demonstrating that up to 82% of SCCs arise within, in close proximity to, or are contiguous with an AK and although parameters like induration, ulceration and rapid growth may indicate invasion, clinical differentiation may be difficult to obtain [19-22]. A growing consensus considers that AK should be interpreted as a bio-marker indicating that a patient is at risk of developing skin cancer [13].

In 2007 a clinical classification for grading AK (Grade 1, 2 and 3) was developed. Grade 1 describes slightly palpable AK (better felt than seen), Grade 2 shows moderately thick AK (easily felt and seen), and Grade 3 is very thick, hyperkeratotic and/or obvious [23]. The clinical diagnosis between grade 3 AK and early invasive SCC is subject to variable clinical interpretation. A similar scheme for the histological grading of AK has also been established [23].

Actinic keratosis rarely develops as solitary lesions; in fact multiple lesions are commonly present; a phenomenon known as “field change”. The concept of field change was first proposed in 1953 by Slaughter et al. [24] to explain the development of multiple primary tumours, in a field of genetically altered cells, which plays a central role in locally recurrent cancer. In 2003, Braakhuis BJ, et al. provided molecular evidence that has supported the carcinogenesis model, demonstrating that ‘patches’ of genetically altered stem cell clones develop into individual fields, and ultimately contiguous fields of (pre)neoplastic cells [25].

Analysis of chromosome aberrations and gene mutations reveal that normal skin, AKs and SCC have an altered p53 gene [26, 27], bearing signature UV mutations in stem cell related clones. Further changes in the anti-apoptotic gene bcl-2 are found in AKs and SCCs, and altered p16 and growth hormone receptor proteins are found in SCCs [28, 29]. Analysis of differentially expressed genes in cutaneous SCC by microarray expression profiling has revealed variable results with few consistent patterns between studies, which tend to have small sample numbers.

There is a wide range of therapies for the treatment of AK and a number of published guidelines for the treatment of AK are available, including recent guidelines by the European Dermatological Forum (EDF) [11, 12]. Although a valuable review of the literature, the published summaries do not provide advice on applying treatment recommendations for AK in clinical practice. This is an important issue, since there are considerable variations in the care of patients with AK across Europe, with major economic issues [30].

Due to the limited evidence base, a methodology of consultation and discussion of best practice was adopted as a means of formulating a consensus of opinion across Europe. The Skin Academy comprises a group of key opinion leaders from across Europe, who gather to discuss pertinent topics on the diagnosis and treatment of AK, sponsored by an unrestricted educational grant from Almirall Hermal. As a result of their recent discussions, an algorithm was designed for the treatment of AK (figure 1).

Scope of the algorithm

In order to standardise and improve the care of AK among patients across Europe, the recommendations aim to provide a simple algorithm to assist physicians with treatment decisions commonly experienced in clinical practice (figure 1).

The algorithm was designed to be simple, and is aimed at the most common AK lesions, i.e. those found on the most sun-exposed areas, such as the face, scalp and back of the hand. Recommendations for the treatment of difficult to reach areas are given in the text (see below), but for reasons of clarity are not included in the diagrammatic representation of the algorithm.

The algorithm covers 5 decision-making steps involved in the management of AK, including initial diagnosis, the decision to treat, the treatment approach, treatment selection factors and treatment choice.

The treatment algorithm for AK

Diagnosis of AK

AKs present clinically in a variety of ways: rough and dry textured skin lesions (single or multiple); flesh-coloured, gray, pink, or red (erythematous) macules, papules or plaques occurring in areas of chronic sun-exposed skin; either limited to a discrete area (known as “localised”) or diffuse. They may be initially flat and scaly on the surface, becoming slightly raised, hard and wart-like, or rough and “sandpapery”. They may also develop a horn-like texture from overgrowth of the skin keratin layer (hyperkeratosis).

Many AKs are asymptomatic, but some cause pruritus, burning, or a splinter-like sensation in the skin [32]. There are no distinct clinical boundaries between AK and invasive SCC.

Histologically, AK is a proliferation of atypical cells confined to the lower levels of the epidermis. In later stages, all levels of the epidermis may be involved. Actinic keratoses are characterised by dysplasia of varying degrees (from mild changes through to typical carcinoma in situ), predominantly in keratinocytes of the interadnexal epidermis. Parakeratosis is usually present. The dermis underlying and adjacent to AKs typically shows the presence of ectatic vessels and solar elastosis [12]. If microscopic examination reveals involvement of the dermis, the lesion is termed invasive SCC [33]. The concordance between histopathologists is very high about the squamous cell carcinogenesis process, but rather low about the distinction between AKs and early SCC [34].

Biopsies may be used to verify the clinical diagnosis or exclude the possibility that the lesion is an invasive SCC. According to the European guidelines, histological confirmation is necessary in several situations. Firstly, when clinical doubts exist because of thickening, induration, infiltration, inflammation, ulceration and bleeding, or rapid accretion. Secondly, recurrence or persistence following standard treatment (in which case the lesions should be examined to preclude progression to invasive SCC). Finally, when special forms of treatment are considered, which could be damaging if the diagnosis is incorrect. A biopsy that includes the dermis (or an immediate resection if the lesion is small) is required if invasive SCC is to be excluded [11].

AKs almost always occur in association with solar elastosis in the dermis [3]. If solar elastosis is not present, the diagnosis should be reconsidered. Where multiple lesions are present there is likely to be an underlying and surrounding area of actinic damage (a concept known as field cancerisation or field change); the extent of this area may not be evident visually or by physical examination.

Treatment of AK

Among this population are individuals who will develop invasive SCC, whether from pre-existing AK or from within the surrounding sun-damaged skin. It is not possible to predict which AK may progress to invasive SCC, but it is accepted that the presence of AK is a bio-marker of risk for patients. Since AKs are not only risk markers but also an early phase of a process which may turn into an invasive SCC, it is usually recommended that all AKs are treated [11].

Following diagnosis, most immuno-competent patients can be treated with one of the currently recommended treatment options (see Treatment Choice section). Patients who are immuno-compromised, e.g. patients with HIV or those who have undergone organ transplantation, may require special consideration (see Special Situations section). When deciding on the preferred method of treatment, there are a number of factors that should be considered. These factors are reviewed in more detail later.

Treatment selection factors

Currently, comparative studies involving different topical treatments for AK are underway. Informative data are expected within the next few years and it is hoped that this will permit a more individual approach to the choice of treatment for each patient and also will establish whether treating AKs or field change prevents the formation of invasive tumours.

Lesion vs field-directed treatment

Treating the entire field rather than solely those lesions that are immediately visible aims not only to eliminate the clinically visible lesions, but also sub-clinical lesions within the cancerous field. Many (ten or more AK lesions) may indicate a preference for a field-directed treatment approach. We note from the literature that this figure is chosen in most clinical trials of AK as the main exclusion or inclusion criterion for field versus solitary lesion treatment [36]. Field change has been shown to play an important part in the development of non-melanoma skin cancers [37]. An important clinical implication of this process is that fields often remain after removal of the primary tumour, which may lead to new neoplasms [25].

Treatment of epithelial cancers should, therefore, not only focus on the tumour itself, but also on the field from which it developed [25]. Depending on the lesion and patient characteristics, a field-directed approach to treatment of AK is preferable where feasible.

Field-directed therapy involves the application of topical treatment to the area of photodamaged skin, containing both visible and sub-clinical lesions. The aims of field-directed therapy are to:

• – Eradicate clinically evident AKs, sub-clinical AKs and smaller foci of transformed clones.
• – Prevent the development of invasive SCC.
• – Provide longer remission (i.e. prolong the time to new AK development in the treated field).
• – Increase the interval between treatment sessions.

To date, however, no clinical trials have investigated the preventative effect on the field of these field-directed treatment changes i.e. their ability to reduce the rate of new AKs and invasive SCC. Field-directed therapy may be repeated or combined with lesion-directed therapy, either concomitantly or sequentially, to clear any lesions that do not initially resolve. Conversely, it is also possible to treat single lesions with field-directed therapy; this strategy would also treat any field change that may be present in the treatment area.
Table 1 Summary of treatment options for actinic keratosis (adapted from Stockfleth, et al. 2006) [68]

Treatment choice

Total treatment costs are also important and have an influence on therapeutic management. However these costs may vary in different countries around Europe and have therefore not been specifically calculated.

Lesion-directed therapies

Laser therapy is more difficult to perform than cryotherapy, and so experience with the technique, and specialist equipment are needed. It is also costly but can be used for single lesions, as well as for large area resurfacing, and results in good cosmesis. However, there is also pain associated with this technique, which may be less acceptable to patients [39].

Ablative techniques may be useful for removal of limited AK lesions. These include curettage and dermabrasion. Curettage may be considered when histological analysis of lesions is necessary and it offers the detection of potential invasion. However, these treatments require local anaesthesia and may result in epidermal changes and scarring [40].

Field-directed treatments

These topical therapies are not invasive, and can usually be delivered by the patient themselves. These therapies also reduce the risk of pain, infection, and scarring, and allow treatment of lesions in cosmetically sensitive or difficult-to-treat locations (e.g. face, back of the hands, lower legs). Most field-directed therapies target rapidly-dividing cells. This includes cells that have undergone neoplastic changes, as well as other rapidly dividing cells – including epidermal cells.

A non-steroidal anti-inflammatory drug (NSAID), Diclofenac 3% gel (Solaraze^® 3% gel) used to destroy target dysplastic cells, is an approved topical NSAID drug for the treatment of AK. The precise mechanism of action of diclofenac 3% gel on AK is not completely understood, but it is thought that it clears AK lesions via cell signalling mechanisms. This may allow cells to be “checked” and either repaired for damage or identified for discrete apoptosis. This, along with a reduction in angiogenesis as well as an induction of apoptosis (either directly or through a cytotoxic independent pathway), are possible mechanisms of action for diclofenac 3% gel [41].

Studies with diclofenac 3% gel show response rates to be around 80% and complete clinical clearance in approximately 50% of treated patients [38, 42-44]. Present data indicate that AK must be treated for 90 days with diclofenac 3% gel in order to achieve complete clinical clearance in approximately 50% of treated patients [38, 42-44]. Most adverse events with diclofenac are mild to moderate in intensity, but more severe inflammation has been observed in a few cases [45].

A very commonly used field-directed therapy is 5-FU. This drug acts by interfering with the DNA and RNA synthesis of all rapidly-dividing cells. The use of topical 5-FU can lead to severe inflammation, with pruritus, pain, erosions and possible ulceration, and infections which may scar in rare cases [46, 47]¹. Exposure to sunlight may also increase the intensity of the reaction. Due to these effects, 5-FU is often used only as a palliative therapy in such cases where no other form of treatment is possible (Efudix SmPC July 2007). Intermittent “pulse” 5-FU therapy can reduce severe side effects and may be of value in patients unwilling to accept the erosions and discomfort that accompany the traditional course of daily 5-FU applications [46]. The clearance rates reported are around 50% but there are very high recurrence rates (up to 55%) [47-49] noting that 5 FU is often used for severe and extensive cases with multiple lesions. In the USA, a new formulation with 0.5% of 5-FU is now available² [16, 49-51].

Photodynamic therapy is the light-activated destruction of atypical keratinocytes. The technique uses laser, or other light sources, combined with a photosensitising drug to destroy rapidly-dividing neoplastic cells, which accumulate more of the photosensitising drug than normal cells. Photodynamic therapy offers high efficacy rates on AKs (70-90%), although these rates may be enhanced by the concomitant curettage that is often used as part of the treatment [52-55], with good cosmetic clearance and a brief healing time. One of the major limitations of PDT is the potential for poor selectivity of the photosensitising drug, resulting in reduced treatment efficacy and hypersensitivity to daylight [11]. Another limitation of topical photosensitising drugs is their limited depth of penetration and the local pain that occurs during and after treatment [56, 57]. Exact penetration depths have not yet been established, but lesions with potentially deeper involvement may not be cleared effectively with PDT [58]. PDT is also costly in terms of clinic time and requires special hardware in the form of lamps.

Clinical data for the immune response modifier imiquimod have led to its approval as a treatment for AK in the USA and Europe (third line treatment). Imiquimod is applied once-daily, three times per week for four weeks, and the course of treatment can be repeated if lesions remain. The most commonly reported side-effects with imiquimod are pain, erythema, itching and pruritus (Aldara SmPC July 2007), however, the extent of these side effects varies widely. Response rates show complete remission in 84% of patients, with a recurrence rate of 10% within 1-year and 20% within 2-years [17, 59]. A randomised, double-blind, placebo-controlled study in 436 patients with AKs showed a complete resolution of all lesions in 45.1% of patients (vs. 3.2% placebo) and a partial reduction of AK in 59.1% of patients (vs. 11.8% placebo) after a treatment period of 16 weeks (twice per week) [60]. In general, clearance of AK is more common in patients exhibiting severe local reactions. This suggests that inflammation at the treatment site is involved in the mode of action of imiquimod on AK.

Chemical peeling with caustic agents is a little-used and more dramatic technique that can be a useful alternative for the treatment of extensive facial AK. However, associated pain, inflammation, risk of scarring and pigmentary alterations make this technique best reserved for patients with extensive facial AK who are resistant to other therapies [61, 62]. The efficacy of chemical peeling depends on the agent used and is quoted as approximately 75%, with recurrence rates ranging between 25-35% within one year after therapy [48, 63, 64]. It is likely that such high recurrence rates occur because this treatment does not address sub-clinical changes in the field surrounding the lesions.

In the past, retinoids (systemic and topical) were frequently used to treat AK. Besides counteracting the UV-induced vitamin A deficiency of the epidermis, topical retinaldehyde may have an antioxidant effect and decrease the number of photo damaged cells [65]. However, the evidence for the efficacy of retinoids is conflicting, with some studies showing that these drugs have no clinical or prophylactic effects on AK [66-68].

Follow-up and long-term efficacy

Special situations

Previous resistance to treatment

Lesions at high-risk of progression

Lesions in difficult-to-treat locations

Lesions on the ear are usually treated with surgery, 5FU, diclofenac, Imiquimod, cryotherapy, or laser surgery.

Amendments to the algorithm

Conclusion

Acknowledgements

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