Whether a decision is made to treat actinic keratoses or simply observe the lesions initially depends on various factors. The assessment of how high the risk of progression to cutaneous squamous cell carcinoma is plays a key role. When selecting the appropriate treatment option, lesion characteristics and patient-related features must be taken into account.
At the EADO Annual Meeting, Dr Nicole Kelleners-Smeets from the Department of Dermatology at Maastricht University Medical Centre (NL) explained the recommendations of the new interdisciplinary guideline on the diagnosis, treatment and prevention of actinic keratoses, epithelial UV-induced dysplasia and field carcinogenesis published in JEADV in 2024 [1,2]. Various European specialist associations were significantly involved in the creation of the guidelines, including EADO (European Association of Dermato-Oncology), EDF (European Dermatology Forum) andEADV (European Academy of Dermatology and Venereology) [2]. The speaker is one of the many co-authors, so this is first-hand knowledge, so to speak [1,2].
AK = actinic keratosis ALA = aminolevulinic acid 5-FU = 5-fluorouracil MAL = methylaminolevulinate PDT = photodynamic therapy SA = salicylic acid |
Determine therapy indication on a case-by-case basis
Actinic keratosis (AK) is by definition a precancerous lesion that can progress into an invasive cutaneous squamous cell carcinoma (cSCC). AKs typically present as scaly or hyperkeratotic macules or plaques that occur singly or confluently (“field carcinomatization”). A treatment indication should be case-based, taking into account patient-related factors and the characteristics of the lesion, explained the speaker [1]. Among other things, the localization and extent of the lesions, age, comorbidity, skin cancer history, immunosuppression and patient preferences should be taken into account. If there is an increased risk, for example due to the presence of numerous AKs, a history of cSCC and/or current immunosuppressive treatment, Dr. Kelleners-Smeets advised patients to be persuaded to have their AKs treated [1]. The risk of AK progressing to cSCC is reported to be 0.025-20% per year. In patients with a history of cSCC in the area of the AK field, the risk of developing another cSCC within 5 years is 40%. However, the risk of progression is also significantly increased in immunosuppressed patients. If a lesion is suspected to be AK, the diagnostic clarification is primarily based on the clinical presentation and dermoscopic features. If there are indications that it could be a cSCC or another differential diagnosis, a biopsy should be performed.
If it is AK according to the overall diagnostic assessment, it is classified as follows:
- individual AK lesions
- multiple AK lesions or field carcinogenization
- AK in immunosuppressed patients
- AK in special localizations (lip, ears, back of the hand, forearms, lower leg).
All AK patients should be educated about AK and receive advice on the use of emollients and sun protection measures. If hyperkeratotic lesions are involved, careful curettage is recommended before other treatments. If AK recurs at a later stage, it may be appropriate to choose a different treatment option for a further treatment sequence. In addition, chemoprevention with nicotinamide or retinoids can be considered as a preventive measure. If the same lesion recurs several times, a biopsy should be considered.
Single AK lesion – multiple treatment options possible: For single, widely scattered AK lesions, patients can be informed that progression to cSCC is possible but unlikely [1,2]. Patients can then be instructed to monitor the lesions and arrange a new dermatologic consultation if the lesion(s) grow or become hyperkeratotic. If the isolated AK lesions become hyperkeratotic, or if patients request treatment, one of the following treatment modalities is usually used: cryotherapy, curettage orCO2/Er:YAG laser. However, topical therapy (5-FU/SA, 4% or 5% 5-FU cream, 5% imiquimod cream or tirbanibulin cream) can also be used, according to Dr. Kelleners-Smeets [1,2].
Multiple AK lesions – field-directed therapy recommended. “If multiple AK lesions are present, field-directed therapy should be carried out,” recommended the speaker [1,2]. The relevant options are shown in Overview 1 . It is important to discuss the various treatment options with the patient. For example, 5-FU has been proven to be an effective therapy, but it must be administered by the patient at home for several weeks, which requires a high level of compliance. Tirbanibulin cream, on the other hand, only requires a treatment period of five days and PDT can be carried out in the dermatologist’s office, which is less problematic in terms of compliance. If patients still have visible and/or hyperkeratotic lesions after field-directed therapy, cryotherapy can provide relief. It is often the case that only a combined therapy approach is effective, the speaker reported.
AK in immunocompromised patients and in specific localizations: For the subgroup of AK patients, there is the most evidence for the treatment options listed in overview 2 . There is a higher risk of progression to cSCC in AKs in the lip, ear, back of the hand, forearm or lower leg. Therefore, a more aggressive treatment approach should be chosen. In the case of AK on the back of the hand, it is advisable to perform a curettage before any other treatment if hyperkeratotic lesions are present. If larger areas are affected by AK, 5-FU cream is the treatment of choice for topical treatment options.
Wide range of topical active ingredients
While lesion-directed therapy options (e.g. surgical excision, curettage, cryotherapy) are used for the physical destruction or elimination of atypical keratinocytes, primary field-directed therapies for AK are aimed at the destruction, elimination or remission of atypical keratinocytes, whereby not only the reduction of manifest AK areas is intended: Latent, subclinical or atypical keratinocytes in a chronically sunlight-damaged field are also targeted. The field-directed therapies include topical agents or procedures supported by topical agents (Table 1) [3–5].
5-FU 4% and 5%: This is a cytostatic drug that acts as an antimetabolite. Due to its structural similarity to thymine (5-methyluracil), which is found in nucleic acids, FU prevents its formation and utilization and therefore inhibits both DNA and RNA synthesis. This results in an inhibition of growth, particularly in cells that are in a stage of accelerated growth – such as in AK – and therefore take up an increased amount of FU.
Salicylic acid (SA): Topical salicylic acid has a keratolytic effect and reduces the hyperkeratosis associated with AK. Its mode of action as a keratolytic and corneolytic is associated with the interference on corneocyte adhesion, the solubilizing effect on the intercellular cement substance as well as with the loosening and detachment of the corneocytes.
Imiquimod: this active ingredient modulates the immune response by activating a toll-like receptor (TLR) on immune cells. In animal models, imiquimod proves to be effective against viral infections and develops its anti-tumor properties primarily through the induction of interferon-alpha and other cytokines.
Diclofenac 3%: Diclofenac is a non-steroidal anti-inflammatory drug. The mechanism of action in AK is not fully understood, one hypothesis is that the therapeutic effects are related to inhibition of the cyclooxygenase pathway followed by reduced synthesis of prostaglandin E2 (PGE2).
Tirbanibulin: Tirbanibulin damages the microtubules by direct binding to tubulin, which induces an interruption of the cell cycle and the apoptotic death of proliferating cells and is associated with an interruption of the Src (cellular sarcoma) tyrosine kinase signaling pathway. Src is present in the cytosol of the cell and is the gene product of the protooncogene of the same name, Src. It is known that Src is increasingly expressed in AKs.
Aminolevulinic acid (ALA) and methylaminolevulinate (MAL): These active ingredients are used as part of PDT. After topical application of ALA, the substance accumulates in AK lesions and is metabolized to protoporphyrin IX, a light sensitizer that massively increases the toxic effect of UV light and accumulates intracellularly in the treated AK lesions. Protoporphyrin IX is activated by illumination with red light of a suitable wavelength and energy. In the presence of oxygen, reactive oxygen compounds are formed. They damage cell components and ultimately destroy the target cells.
Congress: EADO Annual Meeting (Paris)
Literature:
- “Tailored treatment for AK patients”, Dr. Nicole Kelleners-Smeets, Symposium 7, EADO Annual Meeting, 04.-06.04.2024.
- Kandolf L, et al; EADV, EDF, EADV and Union of Medical Specialists (Union Européenne des Médecins Spécialistes): European consensus-based interdisciplinary guideline for diagnosis, treatment and prevention of actinic keratoses, epithelial UV-induced dysplasia and field cancerization on behalf of European Association of Dermato-Oncology, European Dermatology Forum, European Academy of Dermatology and Venereology and Union of Medical Specialists (Union Européenne des Médecins Spécialistes). JEADV 2024; 38(6): 1024-1047.
- Flexikon, www.doccheck.com,(last accessed 29.07.2024).
- PharmaWiki, www.pharmawiki.ch,(last accessed 29.07.2024).
- Topical agents: “Actinic keratosis”, Kassenärztliche Bundesvereinigung, www.akdae.de,(last accessed 29.07.2024).
- Swiss Drug Compendium, https://compendium.ch,(last accessed 29.07.2024).
DERMATOLOGIE PRAXIS 2024; 34(4): 36-37 (published on 30.8.24, ahead of print)
Cover picture: Actinic keratoses on the back of the hand, so-called field carcinomatization. © Dr. Thomas Brinkmeier, wikimedia