Actinic Keratosis (AK)

Keratinocytic intraepidermal neoplasia (KIN), solar keratosis, senile keratosis, keratoma senile, precancerous keratosis, in situ squamous cell carcinoma (SCC in situ).

UV-induced intraepidermal keratinocytic dysplasia. Increasingly recognized by dermatopathological societies (e.g., WHO, EADV) as early SCC in situ, especially high-grade (KIN II–III) lesions.

• Most common premalignant lesion in sun-exposed skin.
• Prevalence in Europe: ~15 % in men, ~6 % in women; >70 years: ~34 % in men, ~18 % in women.
• Particularly frequent in outdoor workers and immunosuppressed persons.
• Often occurs as part of field cancerization.
   

Histologic grading (Röwert Huber):

• KIN I: basal layer atypia
• KIN II: atypia in lower 2/3 of epidermis
• KIN III: full-thickness atypia = SCC in situ
• International guideline bodies now often reclassify AKs, especially KIN II–III, as SCC in situ. 
• Olsen grading is considered clinically less relevant.

Clinical Variants

• Classical erythematous AK
• Hypertrophic/hyperkeratotic AK
• Atrophic or bowenoid AK
• Pigmented, lichenoid variants and actinic cheilitis
   

• Cumulative UVB exposure → TP53, NOTCH1, and other mutations, causing keratinocyte dysplasia.
• Risk factors: fair skin, immunosuppression (100–250 fold risk in transplant recipients), xeroderma pigmentosum, possible cofactor role of HPV.
• Inflammatory microenvironment and field cancerization contribute to lesion progression and cluster formation.

• Sharply marginated, scaly erythematous macule/papule/plaque
• Texture: rough (“sandpaper”)
• Usually asymptomatic; sometimes mild pruritus or burning
• Common sites: forehead, scalp (esp. bald areas), ears, nose, lips, dorsal hands, forearms
• Cutaneous horn (cornu cutaneum) in hypertrophic variants, with elevated malignant risk

• Clinical inspection and palpation are essential
• Dermoscopy: “strawberry pattern” (red pseudo-network with white scale)
• Biopsy if lesions are hypertrophic, tender, or persist: to exclude invasive SCC
• Histology: parakeratosis, keratinocyte atypia, solar elastosis, loss of normal epidermal architecture

Sun-exposed regions: face, bald scalp, ears, neckline, lips, dorsal hands, forearms.

Chronic sun exposure, outdoor work, history of sunburns, fair skin. Transplant patients typically have multiple and treatment-resistant AKs.

• Dysplastic keratinocytes (notably in basal and lower epidermal layers), parakeratosis, solar elastosis
• Full-thickness atypia in KIN III (SCC in situ)
• Invasion beyond BM indicates cSCC

• ~10 % of AKs progress to invasive SCC (range 0.1–20 %)
• ~60 % of cutaneous SCCs arise from prior AKs
• Spontaneous regression in up to 30 %; ~50 % recurrence within 12 months
• Risk increased in hypertrophic AKs, immunosuppression, and in field cancerization

• Avoid sun exposure, especially 11 am–3 pm
• Use UV-protective clothing and broad-spectrum sunscreen (SPF ≥ 50)
• Regular skin checks in high-risk individuals
• Retinoids can be considered for chemoprevention in immunosuppressed patients

Favorable with early diagnosis and treatment. Field cancerization mandates ongoing surveillance. Untreated AKs may progress to SCC.

Lesion-targeted management

• Cryotherapy: standard for solitary AKs (5–20 s freeze; cure rate correlates with duration; side effects: pigment change, scarring)
• Curettage: useful for hypertrophic lesions

Field-directed topical therapies

• 5 Fluorouracil 5 % cream: gold standard; 1–2×/day for 3–6 weeks; liposomal 0.5 % formulation reduces irritation
• Imiquimod 5 % or 3.75 %:
  • 5 %: 3×/week for 16 weeks
  • 3.75 %: daily for two 2-week cycles (with breaks)

Tirbanibulin 1 % ointment (Klisyri®, Onakta):

• FDA and EMA approval for face or scalp AK up to 25 cm², expanded to 100 cm² in June 2024
• Mechanism: microtubule inhibitor and Src kinase blocker → G2/M arrest and apoptosis
• Pivotal phase III trials: once-daily application for 5 days; clearance rates ~44 54 % vs vehicle ~5–13 % at day 57
• Real-world data (Italy): 51 % complete clearance, 73 % partial clearance (≥75 %) with excellent adherence; no discontinuation due to adverse events
• RE expanded sNDA study treating up to 100 cm²: similar efficacy and tolerability; erythema in ~96%, flaking ~85%, resolved by day 29; lesion count reduced from mean 7.7 to 1.8 by day 57; 78 % mean reduction
• Expert consensus guidelines (EADV, EDF, EADO, UEMS): recommend tirbanibulin as first-line option for most AK patients due to short regimen, favorable tolerability, and high compliance

Photodynamic Therapy (PDT)

• Conventional red-light PDT and daylight PDT are recommended in field cancerization
• Daylight PDT: equally effective and more tolerable
• Pulsed daylight PDT (PUL PDT): emerging technology under study 2023–2024

Laser / Peeling procedures

• CO₂ or Er:YAG laser: 90–91 % clearance; 10–15 % recurrence
• 35–50 % TCA peeling or Jessner’s mix: lesion reduction up to 84 %, but higher recurrence rates in long term

Radiotherapy

• Option for elderly or therapy-resistant patients
• Fractionated low-dose kV therapy tailored to lesion size

Surgical excision

• Reserved for lesions suspicious for invasive SCC or refractory to other treatment

Recent Innovations (2023–2024)

• Resiquimod (topical TLR7/8 agonist): in phase II trials, showing greater efficacy than imiquimod (off-label)
• Pulsed daylight PDT: less painful, similar effectiveness; clinical trials in progress
• AI assisted dermoscopy and automated risk assessment tools are in development for clinical grading and progression prediction
   

1. Stockfleth et al. Field cancerization in AK. JEADV. 2023;37(2):210–221.
2. Dirschka et al. AK treatment options. J Clin Aesthet Dermatol. 2022;15(1):S11–24.
3. Piaserico et al. Reclassifying AK as SCC in situ. Br J Dermatol. 2022;187(4):509–516.
4. Blauvelt et al. Phase III tirbanibulin trials. N Engl J Med. 2021;384(6):512–520.
5. Bhatia et al. Safety/tolerability over 100 cm². JAAD Int. 2024;17:6–14.
6. Dao et al. Tirbanibulin 1 % ointment review. Ann Pharmacother. 2022;56(4):494–500.
7. Real-world Italian study: 51 % total clearance. Int J Dermatol. 2024.
8. Schmitz et al. AI risk prediction in AK. Skin Res Technol. 2023;29(5):e13321.