Definitions and term inology
Actinic keratoses (AK) are precancerous cutaneous lesions that rarely occur as a single lesion, but most often occur as multiple lesions. This chronic condition is also considered to be a risk marker for cutaneous malignancies.
Cutaneous SCC include primitive cutaneous malignant epithelial tumours that show squamous transformation and that differ from basal-cell carcinomas. SCC can develop de novo or after progression of precursor lesions such as AK. Only SCC arising from AK are considered in this expert opinion report. Indeed, de novo SCC or SCC caused by burns, chronic ulcers or chronic skin infections differ epidemiologically and biologically from SCC arising from AK.
In the literature, the advocates of a unicist theory consider that AK are already in situ SCC. The expert opinion is that AK are an in situ form of carcinoma that does not require the same management as invasive SCC. Indeed, although histological images and data based on the molecular biology of AK show that they are intra-epidermal carcinomas, evolutionary clinical data show that the risk of transformation to invasive SCC of any given AK is low and the outcome is variable.
Actinic keratoses can evolve following three major directions: the apparent spontaneous disappearance, persistence without progression to invasive SCC, or progression to invasive SCC. The spontaneous regression rate of AK, determined over a 1-year period, has been estimated as being 15–25% in the literature.[8, 20, 21] Some authors therefore highlight the potential importance of the spontaneous disappearance and emergence of new AK lesions. The occurrence rate of invasive SCC in patients with AK is evaluated in the literature as being 5–20% over follow-up periods of 10–25 years.[22, 23] The transformation rate from AK to SCC is much lower, ranging between 0.1% and 0.24% in 1 year.[20, 24] Remarkably, 82.4–100% of patients with invasive SCC on sun-exposed areas have a history of AK.[21, 25, 26]
Overall, experts agree that the progression rate from AK to SCC is low, spontaneous regression can occur but is difficult to assess, and a clinicopathological continuum of transformation from AK to invasive carcinoma exists but there is an element of uncertainty. No clinical, histological or biological criterion can, to date, be used to predict, with certainty, the type of AK progression. However, some AK are clinically more suspicious than others. These suspicious clinical signs are defined below (see ‘Initial evaluation: when to biopsy?’).
The ‘field of cancerization’ is defined as an area of subclinical changes in the periphery of visible AK lesions that can be highlighted histologically or using molecular biology or by imaging (reflectance confocal microscopy).[27, 28] Clinically, this risk field of cancerization is defined as a chronically photo-exposed anatomical area in which multiple and/or recurrent AK appear. Other histological and clinical photo-ageing signs (solar elastosis, wrinkles, sunspots, lentigines, telangiectases) can often appear in this risk area as well. Most affected skin areas include the forehead, temples, nose, scalp, ears, neckline, back of hands and forearms. Experts agreed with these definitions.
Diagnosis of actinic keratoses
The diagnosis of AK is essentially clinical. Most often, they occur in individuals with a fair skin phototype, on sun-exposed areas (face, dorsum of hands, and scalp in patients with alopecia). Signs of heliodermia are often associated (wrinkles, freckles, sunspots). On visual examination, the AK lesions are keratotic, of variable thickness, poorly delimited, with a diameter of 1 cm or less, a variable degree of erythema, and sometimes pigmented (Fig 1). They can also have a cutaneous horn shape. Lesions are keratotic and rough on palpation.
When analysing the literature, some semantic difficulties have appeared, such as whether to use the term ‘hyperkeratotic AK’ or ‘hypertrophic AK’, and whether to use the term ‘AK recurrence’ or to use ‘new lesion’ when a lesion re-occurs on a treated area. Expert opinion on these issues is summarized in Table 1.
Table 1. Semantic issues
|Hyperkeratotic or hypertrophic actinic keratoses?|
|Hypertrophic actinic keratoses show infiltration unlike hyperkeratotic actinic keratoses. The experts have retained the term ‘hyperkeratotic actinic keratoses’ for the treatment algorithm.|
|Recurrence or new lesion on treated areas?|
|In a given area, the interpretation of the term ‘recurrence’ should be modulated as it is not always possible to determine whether it is a recurrence or a new lesion.|
Clinically, differential diagnosis of AK mainly includes seborrheic keratoses, actinic lentigines (sunspots), flat warts, melanocytic lentigines, but also sometimes SCC, Bowen's disease, basal-cell carcinoma, melanocytic nevus or melanoma. The examination of patients with AK must be carried out primarily by a dermatologist searching for other AK or even skin carcinomas that may already be associated. In the screening setting, it is essential to educate other health professionals who are likely to examine patients with AK (e.g. transplanters, rheumatologists, general practitioners, geriatricians, occupational physicians) about AK risk and advise them to refer the patient to a dermatologist for regular follow-up.
Initial evaluation: when to biopsy?
The initial evaluation is clinical; no paraclinical examination is justified. It must include at least the examination of photo-exposed areas to search for other AK lesions and possibly associated SCC. The physician must also assess the phototype of the patient and markers of chronic sun exposure (wrinkles, sunspots). In clinical practice, a biopsy for histological analysis is not necessary in typical cases in order to confirm the diagnosis of AK. However, a biopsy may be performed in the following cases to exclude or confirm invasive SCC, the management of which would be different: in cases where the skin is thickened, size >1 cm, induration, inflammation, ulceration, bleeding, rapid expansion or pain on palpation; in cases of rapid recurrence (2–3 months) (see Table 1) or persistence of the treated lesion after standard treatment; and in cases located on a risk zone (lip, back of hand, ear).
Treatment: when and who to treat?
The need for systematically treating all AK to reduce the risk of skin cancer has not been demonstrated. However, treatment can be justified depending on the clinical characteristics of AK, but also cutaneous history (previous skin carcinomas). And subjective signs as patient request, impact of lesions on quality of life, and when requested, regular monitoring of the patient should be undertaken to detect a SCC as early as possible.
A treatment algorithm has been determined by the experts, who took into account both the literature and their own clinical experience. In this algorithm, criteria for choosing a treatment are based on daily practice and selection of the literature: the number of lesions, their non-hyperkeratotic nature (see Table 1) and their non-suspicious clinical appearance (Fig 2). Physical destruction methods (cryotherapy or curettage and electrocoagulation) are indicated as first-line treatments for isolated or small numbers of AK, surgery or laser being then proposed as second-line treatment in cases of recurrence (see Table 1) or treatment resistance. Any suspicious AK must be biopsied or excised.
Figure 2. Treatment algorithm proposed by the experts for actinic keratosis management, depending on lesion number and appearance.
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First-line topical treatments for multiple AK include 5% 5-FU, 3% diclofenac, 5% imiquimod, and 150 μg/g (face and scalp) or 500 μg/g (trunk and extremities) ingenol mebutate. The treatment choice will depend on factors such as patient adherence to treatment, quality of life, other illnesses and treatments associated and adverse events that may occur. Physical treatments can then be considered, especially for elderly and lonely patients for whom topical application can be difficult.
The management of patients with AK is often long as AK is a chronic disease and may require the use of sequential treatments or combined approaches. However, to date, the literature does not support a particular order for sequential therapy, nor the interest of maintenance therapy and did not conclude the most effective combined approaches.
Local inflammatory reactions: What should be done at the practical level?
An inflammatory skin reaction may be induced by some topical drugs and could cause an early cessation of treatments. Patients with inflammatory reactions are recommended to use a gentle cleanser gel that is compatible with skin pH. Depending on the severity of the painful, inflammatory and/or oedematous lesions induced, analgesic intake associated with thermal water sprays should be recommended. When lesions are erosive or crusted, a healing dermo-cosmetic may be applied twice-daily. An emollient can be combined when skin dryness occurs. When the inflammatory reaction is strong, a break from treatment can be considered. Corticosteroid prescription should be avoided because the anti-inflammatory action could inhibit the local inflammatory reactions necessary for agent effectiveness.
Photoprotection is needed on treated areas, especially during the spring or summer, to avoid photosensitivity damages and the risk of post-inflammatory pigmentation. It is sometimes better to wait until the autumn or winter to medically treat AK.
Particular situation: organ transplant patients
Organ transplant patients are a population at elevated risk of skin cancer. In these patients, AK incidence is extremely high and SCC incidence is nearly 100 times higher than that of the general population having the same age and phototype. The risk is variable, and is related to the degree of immunosuppression, its duration, and the type of transplanted organ (higher risk for cardiac transplant than for kidney transplant patients). Existing data suggest that AK progress more rapidly to SCC in these patients. However, the greater SCC aggressiveness in transplant patients described in the literature is currently questioned. Usual treatments for AK are often less effective than in non-transplant patients and result in resistance or frequent recurrence. A close monitoring and more rigorous treatment approach are necessary in these patients. AK treatment should be considered before organ transplantation. A regular clinical follow-up is carried out by the dermatologist for early detection and treatment of these lesions. In addition, patient education on skin self-examination is fundamental and allows delaying the development of potential cancerous lesions in transplant patients.
Monitoring and secondary prevention
Patients with AK should be monitored regularly because of the chronic nature of lesions and an invasive SCC should be detected as early as possible.
In patients at risk, the monitoring rate proposed is at least a yearly consultation. During these consultations, the patient should be educated on the need for reconsulting earlier if any lesion changes rapidly or in case of recurrence after treatment. Organ transplant patients must be managed in a particular way, especially in terms of personalized monitoring.
Sun protective clothing and behaviour, and the use of sunscreen products (chemical or mineral filters), should be recommended to patients to minimize the worsening of photo-induced skin damage and to prevent skin cancer. It has been demonstrated that sunscreen is an effective AK prevention method. Applying sunscreen (greater than SPF-15 applied every 2–3 h) reduces the risk of AK lesions by up to 24% over time, even compared with beta-carotene and topical tretinoin cream 0.05%. The AAD (Amercian Association of Dermatology) states that selecting a sunscreen with broad-spectrum cover (UVB/UVA) is vital and that daily use of an SPF-30 product is recommended on all exposed skin before daylight exposure.[65-68]