UV-induced precancerous keratinocyte lesion on sun-damaged skin; low per-lesion risk of progression to invasive SCC, but the precursor of most cutaneous SCCs.
Also known as: actinic keratosis, AK, solar keratosis, actinic cheilitis
Overview
A common precancerous lesion of keratinocytes caused by chronic UV exposure, considered an early step in the actinic keratosis–squamous cell carcinoma continuum. AKs share genetic features with invasive SCC and are increasingly considered intraepithelial SCC in some classification systems.
Epidemiology
Most common in older fair-skinned adults; prevalence 11-26% in US adults >50, rising sharply with age and sun exposure. Most common reason for dermatologist visits. Per-lesion progression to SCC (invasive or in situ) is low (about 0.6% at 1 year and 2.6% at 4 years, and many AKs regress), but about 60-65% of cutaneous SCCs arise from a pre-existing AK, so patients with many AKs carry a substantial cumulative risk.
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Question 1DermatologyEasy
A 65-year-old male farmer presents with a lesion on the back of his left hand that he has noticed for several months. He has spent decades working outdoors and reports multiple similar rough patches on his scalp and forearms. On examination, there is a 0.8 cm erythematous patch with adherent, sandpaper-like scale that is more easily felt than seen. The lesion is flat, non-indurated, and non-tender, with no ulceration, bleeding, or surrounding induration. Which of the following is the most likely diagnosis?
ASeborrheic keratosis
BActinic keratosis
CDiscoid lupus erythematosus
DSquamous cell carcinoma in situ
EBasal cell carcinoma
Reveal answer & full explanation
Correct answer: B — Actinic keratosis
ASeborrheic keratosis
BActinic keratosis✓
CDiscoid lupus erythematosus
DSquamous cell carcinoma in situ
EBasal cell carcinoma
Why Actinic keratosis is correct
Actinic keratosis (AK) is an ultraviolet-induced epidermal dysplasia arising on chronically sun-exposed skin of older, fair-skinned, outdoor-working patients
AKs serve as precursors to invasive squamous cell carcinoma, although the risk that any single lesion transforms is low (under 0.1 percent per lesion per year in most cohorts, up to about 0.5 percent in patients with prior nonmelanoma skin cancer)
Classic finding: small, ill-defined erythematous macule or patch with a rough, adherent, sandpaper-like scale that is often better appreciated by palpation than inspection
Multiple similar lesions on other sun-exposed sites (field cancerization) further supports AK
Why the others are wrong
Seborrheic keratosis — a benign keratinocyte proliferation that appears as a sharply demarcated, waxy, greasy, stuck-on papule or plaque with a verrucous surface and horn cysts; not a flat erythematous scaly patch on sun-damaged skin
Squamous cell carcinoma in situ — the most important mimic (Bowen disease); characteristically presents as a larger, well-demarcated, persistent erythematous plaque with thicker scale; features that should raise concern for in situ or invasive SCC and prompt biopsy include induration, ulceration, bleeding, marked hyperkeratosis, rapid growth, tenderness, or size greater than 1 cm — none of which are present here
Discoid lupus erythematosus — produces erythematous plaques with adherent scale, follicular plugging, atrophy, and scarring, typically on the face and scalp in younger patients; not driven by occupational sun exposure in an older farmer
Basal cell carcinoma — the most common skin cancer overall and frequent on sun-damaged skin, but it classically forms a pearly, translucent papule with rolled borders and telangiectasias (the superficial subtype is a pink patch with a thin, thread-like pearly border), not a rough, sandpaper-like patch that is felt more easily than seen
Additional high-yield points
Management: cryotherapy for solitary AKs; topical field therapy (5-fluorouracil, imiquimod, or tirbanibulin) for multiple lesions; sun protection for all patients
Question 2DermatologyEasy
A 72-year-old man with numerous actinic keratoses on his scalp and face asks about field-directed therapy. In head-to-head comparative trials, which of the following topical regimens most reliably produces sustained 12-month lesion clearance?
ATopical 5-fluorouracil cream
BTopical ingenol mebutate gel
CTopical imiquimod cream
DTopical diclofenac sodium gel
EMethyl aminolevulinate photodynamic therapy
Reveal answer & full explanation
Correct answer: A — Topical 5-fluorouracil cream
ATopical 5-fluorouracil cream✓
BTopical ingenol mebutate gel
CTopical imiquimod cream
DTopical diclofenac sodium gel
EMethyl aminolevulinate photodynamic therapy
Why Topical 5-fluorouracil cream is correct
Field-directed therapy treats the entire sun-damaged field, including subclinical actinic keratoses, not just visible lesions
In the head-to-head randomized comparative trial (Jansen et al., NEJM 2019), 5% 5-fluorouracil produced the highest probability of sustained success at 12 months among the four common field treatments
5-FU induces apoptosis of dysplastic keratinocytes; a typical course is twice-daily application for 2-4 weeks, with brisk inflammation expected as a sign of response
For greatest durable (12-month) field clearance, 5-FU is the guideline-supported first choice
Why the others are wrong
Topical imiquimod cream — effective immunomodulator, but in the comparative trial its sustained 12-month clearance was inferior to 5-FU (confused-with initial clearance)
Topical diclofenac sodium gel — the weakest field agent, with the lowest sustained clearance of the options (premature closure on tolerability)
Methyl aminolevulinate photodynamic therapy — high initial clearance and good cosmesis, but its durable 12-month success did not exceed 5-FU in the head-to-head trial (anchoring on early response)
Topical ingenol mebutate gel — appealing because a 3-day course is far shorter than a 5-FU or imiquimod regimen, and it was directly compared with 5-FU in the head-to-head trial; but its 12-month sustained success there was well below that of 5-FU, and it was later withdrawn in Europe over a possible skin cancer risk (anchoring on short course)
Additional high-yield points
Tirbanibulin is a newer 5-day field option; cryotherapy treats only visible lesions and is not field-directed
Nicotinamide 500 mg twice daily provides chemoprevention, reducing new AKs and non-melanoma skin cancer in high-risk patients
A combined approach (cryotherapy of visible lesions plus field therapy for subclinical disease) is common in practice
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Cumulative UVB-induced DNA damage produces TP53 mutations in keratinocytes. Clonal expansion of mutated keratinocytes forms 'field cancerization' — broad areas of subclinical genetic damage that produce visible AKs and predispose to multiple SCCs. Confined to epidermis until basement membrane breach defines invasive SCC.
Clinical presentation
Symptoms
Usually asymptomatic; some lesions tender or pruritic with friction
Sandpaper texture often felt before lesion is seen — diagnostic clue
Squamous cell carcinoma in situ (Bowen disease) — Larger, more demarcated erythematous scaly plaque; biopsy if uncertain
Invasive squamous cell carcinoma — Hyperkeratotic, indurated nodule with ulceration; biopsy any lesion with these features
Discoid lupus — Annular plaques with follicular plugging, scarring, sun-exposed areas; ANA may be positive
Lichenoid keratosis — Single irregular lesion mimicking AK on biopsy shows lichenoid inflammation; benign
Verruca — Verrucous surface with pinpoint black dots, disrupts skin lines
Solar lentigo — Flat tan-brown macule without keratosis
Diagnostic workup
Diagnostic criteria
Clinical: characteristic rough scaly papule on sun-damaged skin of older adult; biopsy if suspicion of SCC.
Labs
Clinical diagnosis sufficient for typical lesions
Skin biopsy if atypical features (induration, ulceration, bleeding, rapid growth, >1 cm, tenderness, refractory to therapy) — to exclude invasive SCC
Dermoscopy: strawberry pattern (red pseudonetwork with white halos around hair follicles) helpful for non-pigmented facial AKs; pigmented AKs show gray dots and granules and can mimic lentigo maligna
Imaging
Not indicated
Diagnostic algorithm
Scenario
Preferred Treatment
Few isolated AKs
Cryotherapy lesion-directed
Multiple AKs / field cancerization
Topical 5-FU, imiquimod, tirbanibulin, or PDT
Hypertrophic AK / cutaneous horn
Biopsy at base; curettage or excision
Actinic cheilitis
5-FU or PDT to lip; severe → vermilionectomy / laser
Immunocompromised / transplant
Aggressive treatment + acitretin chemoprevention; surveillance q3-6 mo
Actinic keratosis management by clinical scenario.
Treatment
First-line
Lesion-directed therapy for isolated AKs:
• Cryotherapy with liquid nitrogen — 5-10 seconds per lesion; most common; cure ~67-83%; possible hypopigmentation
• Curettage ± electrodessication for hypertrophic or persistent AKs
Field therapy for multiple AKs or field cancerization (preferred when ≥6-10 AKs in an area):
• 5-fluorouracil 5% cream BID × 2-4 weeks (significant inflammation during therapy) — most effective field therapy, with the highest sustained 12-month clearance in a head-to-head trial (5-FU ~75% vs imiquimod ~54% vs MAL-PDT ~38%; Jansen NEJM 2019); AAD strong recommendation
• Imiquimod 5% cream twice weekly × 16 weeks (or 3.75% daily in two 2-week cycles separated by a 2-week break); AAD strong recommendation
• Tirbanibulin 1% ointment daily × 5 days (newer agent, shorter course, less inflammation)
• Diclofenac 3% gel BID × 60-90 days (gentler but slower and the least effective field agent; AAD conditional recommendation)
• Photodynamic therapy with topical 5-aminolevulinic acid (ALA) or methyl aminolevulinate (MAL) + blue or red light — good cosmesis, but less durable clearance than 5-FU (AAD conditional recommendation)
• Combination therapy: cryotherapy of individual AKs + topical field therapy
Sun protection: broad-spectrum SPF 30+ daily, sun-protective clothing, hat, sunglasses, shade
Surveillance: total body skin examination every 6-12 months in patients with AKs
Hypertrophic / cutaneous horn
Biopsy at base (cutaneous horn is a clinical description — underlying lesion can be SCC, AK, or seborrheic keratosis)
Excision or curettage with margin pathology
Actinic cheilitis
Field therapy: 5-FU, imiquimod, or photodynamic therapy on lip vermilion
Vermilionectomy or CO2 laser ablation for severe diffuse involvement
Lip protection: SPF 30+ lip balm with reapplication; hat with brim
Organ transplant recipient
Aggressive treatment of all AKs
Acitretin 10-25 mg/day as chemoprevention (significantly reduces AK and SCC incidence)
Nicotinamide did not reduce keratinocyte cancers or AKs in organ transplant recipients (ONTRANS, NEJM 2023); its benefit is shown only in immunocompetent patients (ONTRAC), so acitretin is the evidence-based systemic chemoprevention here
Consider switching to mTOR inhibitor (sirolimus) from calcineurin inhibitor (in coordination with transplant team)
Second-line / adjunct
Nicotinamide 500 mg BID — proven to reduce new AK and non-melanoma skin cancer in immunocompetent high-risk patients (ONTRAC trial)
Resurfacing procedures (chemical peel, dermabrasion, fractional laser) for diffuse field disease
Counsel: AKs may recur after any therapy — surveillance and field maintenance are key
Complications
Progression to invasive SCC — low risk per lesion (under 1% per year), but ~60-65% of cutaneous SCCs arise from pre-existing AKs, so patients with many AKs carry substantial cumulative risk
Cosmetic disfigurement
Treatment-related inflammation, dyspigmentation, scarring (especially with cryotherapy in skin of color — use cautiously)
Recurrence after any therapy
Field cancerization with multifocal SCCs in immunosuppressed
PANCE pearls
AKs are felt more easily than seen — run a gloved hand over sun-exposed skin to detect rough sandpaper texture.
An AK that is indurated, ulcerated, bleeding, painful, or refractory to therapy should be biopsied — these features suggest invasive SCC.
Field therapy (5-FU, imiquimod, PDT) treats subclinical 'field cancerization' and reduces future cancer risk more than spot treatment alone.
Nicotinamide 500 mg BID is a cheap, well-tolerated, evidence-based chemoprevention for immunocompetent high-risk patients (ONTRAC trial showed ~23% reduction in new keratinocyte cancers).
Organ transplant recipients should be seen every 3-6 months — they develop multiple aggressive AKs and SCCs.
References
AAD 2021 — Guidelines of Care for the Management of Actinic Keratosis (Eisen et al., J Am Acad Dermatol 2021)
ONTRAC Trial — A Phase 3 Randomized Trial of Nicotinamide for Skin-Cancer Chemoprevention (Chen et al., NEJM 2015)
NCCN 2024 — NCCN Clinical Practice Guidelines — Squamous Cell Skin Cancer (Actinic Keratosis section)
Jansen 2019 — Randomized Trial of Four Treatment Approaches for Actinic Keratosis (Jansen et al., N Engl J Med 2019;380:935-946)
ONTRANS Trial — Nicotinamide for Skin-Cancer Chemoprevention in Transplant Recipients (Allen et al., N Engl J Med 2023;388:804-812)
Criscione 2009 — Actinic Keratoses: Natural History and Risk of Malignant Transformation in the Veterans Affairs Topical Tretinoin Chemoprevention Trial (Criscione et al., Cancer 2009;115:2523-2530)
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