Skin & Subcutaneous Tissue

Actinic keratosis: management and prevention

Clinical Overview and When to Suspect Actinic Keratosis

— Cumulative lifetime UV exposure is the dominant driver; prevalence rises sharply after age 50

— Fitzpatrick skin types I–II (fair, freckled, blue/green eyes, blonde/red hair) carry the highest risk

— Immunosuppression markedly accelerates AK and cSCC: solid organ transplant recipients (especially heart/lung on azathioprine or voriconazole), CLL, HIV, chronic systemic corticosteroids

— Occupational outdoor work (farmers, sailors, construction), tanning bed use, prior PUVA, ionizing radiation, arsenic exposure, xeroderma pigmentosum, albinism

— Older fair-skinned patient with rough, gritty, "sandpaper" papules on sun-exposed sites (face, scalp vertex in bald men, ears, dorsal hands/forearms, lower lip = actinic cheilitis)

— Lesions are often felt more easily than seen — palpation is part of the exam

— May be erythematous, skin-colored, or pigmented; size 2–6 mm typically

— Per-lesion annual progression to cSCC is low (~0.1–1%) but field cancerization means patients with multiple AKs have a meaningful cumulative risk

— Regression occurs but recurrence is common; the "field" matters more than any single lesion

Actinic keratosis (AK) is a UV-induced intraepidermal keratinocyte dysplasia considered a precursor to cutaneous squamous cell carcinoma (cSCC) — some experts now classify it as SCC in situ (KIN I–III) on a continuum.

Epidemiology and risk factors

When to suspect on the Step 3 exam

Natural history

Board pearl: On Step 3, an elderly fair-skinned patient presenting for a routine visit with multiple gritty pink papules on the bald scalp and forearms is AK until proven otherwise — examine the lower lip for actinic cheilitis, which has a higher malignant potential than cutaneous AK and warrants more aggressive treatment.

Primary care framing: AK is one of the most common reasons for outpatient dermatologic visits in adults > 60 and a cornerstone preventive-medicine topic in the USPSTF skin cancer counseling framework.

Presentation Patterns and Key History

— Age > 50, Fitzpatrick I–III, history of significant outdoor exposure or prior skin cancer

— Prior AK or non-melanoma skin cancer is the strongest single predictor of new AKs and future cSCC

— Duration: lesions typically persist for months to years; rapid growth over weeks suggests invasive cSCC

— Symptoms: usually asymptomatic but may itch, sting, bleed with minor trauma, or feel tender when rubbed ("painful when patient washes face")

— Tenderness, induration, ulceration, or rapid enlargement = red flags for transformation to invasive SCC → biopsy

— Childhood/adolescent blistering sunburns

— Occupation, recreational activities (golf, fishing, gardening), latitude of residence

— Tanning bed use — quantify sessions; counsel cessation

— Photosensitizing medications: hydrochlorothiazide, voriconazole, tetracyclines, amiodarone, NSAIDs, fluoroquinolones, BRAF inhibitors

— Prior skin cancers (BCC, SCC, melanoma) and treatments received

— Solid organ transplant — ask about year of transplant and immunosuppressive regimen; SOT patients have 65–100× increased cSCC risk

— Hematologic malignancy (CLL), HIV, autoimmune disease on biologics or chronic prednisone

— Family history of skin cancer or genodermatoses (xeroderma pigmentosum, Gorlin)

— Current sunscreen use, hat/protective clothing habits — anchor for counseling

— Smoking (synergistic with UV for lip SCC)

— Alcohol — relevant for lip cancer risk

Typical patient profile

Symptom history to elicit

Sun-exposure history (high yield for counseling questions)

Personal and family history

Social and review of systems

Step 3 management: When a transplant patient presents with new AKs, lower the threshold for biopsy and field therapy, document a full-body skin exam every 6–12 months, and coordinate with the transplant team about reducing immunosuppression intensity or switching to an mTOR inhibitor (sirolimus/everolimus), which reduces new cSCC formation.

Physical Exam Findings

— Total-body skin exam with good lighting; palpate sun-exposed areas because AKs are often better felt than seen

— Use a hand lens or dermatoscope; document number, size, location, and presence of induration

— Erythematous macule or thin papule with adherent, dry, yellow-white scale on a background of photodamaged skin (telangiectasias, solar lentigines, mottled pigmentation)

— Size 2–6 mm; multiple lesions in a "field"

— Sandpaper texture on palpation is pathognomonic in the right context

— Hypertrophic AK: thick scale, hyperkeratotic; hard to distinguish clinically from SCC

— Cutaneous horn: conical hyperkeratosis — ~15–20% have invasive SCC at the base → excisional biopsy

— Pigmented AK: tan-brown, mimics lentigo maligna

— Actinic cheilitis: diffuse scaling, atrophy, blurring of the vermilion border on the lower lip — higher SCC risk

— Lichenoid AK: inflamed, erythematous, may itch

— Induration, tenderness, diameter > 1 cm, rapid growth, bleeding, ulceration

— Recurrence after appropriate treatment

— Lesions in immunosuppressed patients that fail to respond to field therapy

— "IDRBEU" mnemonic: Induration, Diameter, Rapid growth, Bleeding, Erythema, Ulceration

— Face (forehead, temples, nose, cheeks), bald scalp, helix of ears (men), dorsal hands/forearms, lower lip

— Spare double-covered areas (under watch, hair-bearing scalp)

General approach

Classic morphology

Subtypes to recognize

Red-flag features mandating biopsy

Distribution mapping

Key distinction: A thick, tender, indurated lesion on the lip or ear in a sun-damaged patient is invasive SCC until biopsy proves otherwise — these sites have higher metastatic potential (lip cSCC metastasizes in 10–15%), so do not assume AK and treat empirically with topical therapy. Shave or punch biopsy first.

Diagnostic Workup — Initial Approach

— Experienced clinicians diagnose typical AKs by inspection and palpation alone

— No routine labs, imaging, or serologies are required for uncomplicated AK

— Nonpigmented AK: "strawberry pattern" — pseudonetwork of erythema with white-yellow keratotic plugs in follicular openings on the face

— Pigmented AK: gray-brown dots/globules in pseudonetwork — helps differentiate from lentigo maligna, though overlap exists

— Hypertrophic AK: rosettes, scale, vessels — overlap with SCC makes biopsy prudent

— Diagnostic uncertainty vs cSCC, BCC, melanoma, or other lesion

— Any red-flag feature (see chunk 3): induration, > 1 cm, ulceration, bleeding, tenderness, rapid growth

— Failure to respond to two appropriate courses of therapy

— Recurrence at a previously treated site

— Immunosuppressed patients with atypical or refractory lesions

— Lesions on high-risk sites: lip, ear, periocular, nasal ala

— Shave biopsy to the mid-dermis is usually sufficient for AK vs SCC differentiation

— Punch biopsy preferred if pigmented (to evaluate melanoma) or if depth assessment matters

— Document anatomic site precisely (photograph if possible) for follow-up

— Atypical keratinocytes confined to the lower epidermis, parakeratosis, "flag sign" (alternating ortho- and parakeratosis), solar elastosis in dermis

— Full-thickness atypia = SCC in situ (Bowen disease); invasion through basement membrane = invasive SCC

Diagnosis is primarily clinical in the vast majority of cases

Dermoscopy as an adjunct

Indications for biopsy (shave or punch)

Biopsy technique

Histopathology (what the report will say)

Board pearl: Step 3 will reward you for biopsying before treating any lesion with red-flag features. Empirically treating a lip or ear "AK" with 5-FU and missing an invasive SCC is a recurring distractor — and a real malpractice scenario. When in doubt, biopsy.

Diagnostic Workup — Advanced and Confirmatory Considerations

— Non-invasive in vivo imaging used in some referral centers to differentiate AK from cSCC and monitor field therapy

— Not standard primary care tools; mention only if explicitly cued

— Routine imaging not indicated for AK

— For biopsy-proven invasive cSCC with high-risk features (perineural invasion, > 2 cm, > 6 mm depth, recurrent, immunosuppressed, poorly differentiated): CT or MRI of the affected region to assess local extension and nodal disease; PET-CT for advanced disease

— Palpate regional lymph nodes on every visit for known cSCC patients

— No routine labs for AK

— Before initiating systemic therapy in advanced cSCC (cemiplimab, cetuximab): baseline CBC, CMP, TSH (immune checkpoint inhibitors), HIV, hepatitis serologies

— In immunosuppressed patients, review calcineurin inhibitor levels, mTOR inhibitor levels, and overall immunosuppression intensity with the transplant team

— Consider in young patients (< 40) with multiple AKs/cSCCs: xeroderma pigmentosum, oculocutaneous albinism, epidermodysplasia verruciformis, Ferguson-Smith syndrome

— Refer to medical genetics if syndromic features present

— AKASI (Actinic Keratosis Area and Severity Index) quantifies field burden — used in research and increasingly in clinic to track response to field therapy

— Number of AKs, presence of hypertrophic lesions, and history of prior cSCC predict future cSCC risk

Reflectance confocal microscopy (RCM) and optical coherence tomography (OCT)

Mohs micrographic surgery — not indicated for AK (used for invasive cSCC/BCC in high-risk areas)

Imaging

Laboratory workup

Genetic and syndromic evaluation

Risk stratification tools

Step 3 management: For a patient with biopsy-proven AK but extensive field cancerization (≥ 5–10 lesions in a region), the workup endpoint is clinical mapping plus dermatology referral for field-directed therapy — not imaging, not labs. Anchor your answer choice to the clinical/topical management pathway unless invasive SCC is documented.

Risk Stratification and First-Line Management Logic

— Lesion-directed therapy for few (< 5), discrete, well-defined AKs → cryotherapy, curettage, excision

— Field-directed therapy for multiple AKs, field cancerization, or subclinical lesions → topical 5-FU, imiquimod, tirbanibulin, diclofenac, or photodynamic therapy (PDT)

— Combination lesion + field approaches are common and often most effective

— Low risk: immunocompetent, few AKs, no prior cSCC, low-risk anatomic sites → cryotherapy ± watchful waiting acceptable

— Intermediate risk: multiple AKs, prior AK history → field therapy preferred

— High risk: immunosuppressed (especially SOT), prior cSCC, hypertrophic AKs, high-risk sites (lip, ear) → aggressive field therapy + close surveillance + low biopsy threshold

— Adherence: field therapies require weeks of self-application and cause significant inflammation — set expectations

— Cosmetic concern: PDT and tirbanibulin have shorter courses and may be preferred for face

— Cost and insurance coverage: 5-FU generic is cheapest; imiquimod and PDT more costly; tirbanibulin is brand-only

— Occupation: downtime from field-therapy erythema/crusting may affect work

— Discuss that no treatment eliminates risk of future AKs or cSCC — surveillance is lifelong

— Discuss expected reaction: erythema, erosion, crusting are signs the medication is working

— Treatment of subclinical field disease reduces future AKs more than lesion-directed therapy alone

— Cryotherapy and topical prescriptions: primary care or dermatology

— PDT, curettage with biopsy, complex cases, transplant patients: dermatology referral

Treatment decision framework

Stratify by risk profile

Patient-centered factors

Shared decision-making points

Setting of care

CCS pearl: In a CCS-style outpatient case, the correct sequence is usually (1) full-body skin exam, (2) biopsy any suspicious lesion, (3) cryotherapy for isolated AKs or prescribe topical 5-FU/imiquimod for field disease, (4) counsel sun protection, (5) schedule follow-up at 4–8 weeks to assess response and every 6–12 months for surveillance.

Pharmacotherapy — First-Line Topical Regimens

— Mechanism: thymidylate synthase inhibition → selective destruction of dysplastic keratinocytes

— Dose: apply BID to affected field × 2–4 weeks (face); up to 4 weeks for trunk/extremities

— Expected reaction: erythema → vesiculation → erosion → crusting → re-epithelialization over 2–4 weeks post-treatment

— Clearance rate: 50–75% at 6–12 months; highest efficacy of topical agents

— Avoid in pregnancy (Category X); avoid in DPD deficiency

— Mechanism: TLR-7 agonist → local cytokine-mediated immune response

— Dose: 5% — 2–3×/week × 16 weeks; 3.75% — daily × 2 weeks, off 2 weeks, then daily × 2 weeks

— Useful for face/scalp; significant inflammation expected

— Avoid in autoimmune disease activation concerns

— Microtubule inhibitor; daily × 5 days only to a 25 cm² field on face/scalp

— Mild local reactions, short course → favored for adherence

— Clearance ~50% at day 57

— BID × 60–90 days; modest efficacy; better tolerated; useful for elderly with mild disease

— Topical aminolevulinic acid (ALA) or methyl aminolevulinate + blue or red light

— Office-based; 1–2 sessions; excellent for facial field; photosensitivity for 24–48 h

— High clearance, good cosmesis

— Apply with gloved finger or cotton swab; wash hands after

— Avoid eyes, lips (unless prescribed for cheilitis), mucosa

— Strict sun protection during and 2 weeks after treatment

— Expect "looks worse before better" — photo at baseline helps patient understand response

5-Fluorouracil (5-FU) 5% cream (also 0.5%, 4%, 1% formulations)

Imiquimod 5% cream (also 3.75%, 2.5%)

Tirbanibulin 1% ointment

Diclofenac 3% gel

Photodynamic therapy (PDT)

Counseling points common to all topicals

Board pearl: When the stem describes an elderly patient who stopped 5-FU early because "my face is red and crusting," the correct counseling is to continue therapy — this is the expected therapeutic response, not a drug reaction. Premature discontinuation is the leading cause of treatment failure.

Procedural Management — Lesion-Directed Therapies

— Mechanism: cell death from rapid freeze-thaw cycles

— Technique: spray or cotton-tipped applicator; freeze time 5–10 seconds with 1–2 mm halo; thicker AKs may need 2 freeze-thaw cycles

— Clearance: 39–76% per lesion; highly operator-dependent

— Side effects: pain, blistering, hypopigmentation (especially in darker skin types), rarely scarring or alopecia

— Best for few, discrete, thin AKs; not for field disease (misses subclinical lesions)

— Useful for hypertrophic AKs and cutaneous horns

— Allows tissue for histology — send specimen if any suspicion of SCC

— More scarring than cryotherapy

— Therapeutic and diagnostic for suspicious lesions

— Mandatory for cutaneous horn, indurated lesions, or any red-flag morphology

— Adjunct for field therapy in cosmetic dermatology; less standard

— For severe field disease or actinic cheilitis refractory to topical therapy

— Specialty procedure

— Vermilionectomy (lip shave) for severe/refractory cases

— CO₂ laser ablation or PDT

— Topical 5-FU or imiquimod (off-label but commonly used)

— 1–5 discrete AKs → cryotherapy

— Hypertrophic or horn → curettage/biopsy first

— Diffuse field (face/scalp) → 5-FU, imiquimod, or PDT

— Transplant or recurrent → field therapy + dermatology co-management

Cryotherapy with liquid nitrogen — most common in-office treatment

Curettage (with or without electrodesiccation)

Shave/excisional biopsy

Photodynamic therapy (PDT) — see chunk 7; bridges lesion- and field-directed therapy

Chemical peels (trichloroacetic acid, Jessner's)

Laser resurfacing (ablative CO₂ or Er:YAG)

Actinic cheilitis-specific options

Choosing the right modality (Step 3 logic)

Step 3 management: For a patient with 3 thin AKs on the dorsal hand and no red-flag features, the single best next step is cryotherapy in clinic, with counseling on sun protection and a return visit in 8–12 weeks to assess response and screen for additional lesions. Reserve topical field therapy for higher lesion counts or recurrent disease.

Special Populations — Elderly and Renal/Hepatic Impairment

— AK prevalence in those > 70 in sun-belt regions exceeds 50%

— Frailty assessment matters: aggressive field therapy with 5-FU may be poorly tolerated in cognitively impaired or frail elderly due to weeks of inflammation, risk of secondary infection, and adherence challenges

— Cryotherapy or short-course tirbanibulin are often preferred for fragile elderly

— Polypharmacy: review for photosensitizing drugs (HCTZ, voriconazole, amiodarone, tetracyclines) — consider deprescribing when feasible

— Skin atrophy increases blistering risk with cryotherapy — adjust freeze times downward

— Consider life expectancy and goals of care: for a patient with limited life expectancy and asymptomatic thin AKs, watchful waiting with sun protection is reasonable; for symptomatic or rapidly changing lesions, treat

— Topical 5-FU, imiquimod, tirbanibulin, diclofenac: minimal systemic absorption, no dose adjustment for renal disease

— Caution with topical diclofenac in advanced CKD (theoretical, minimal systemic effect)

— PDT: no renal adjustment

— Same — minimal systemic absorption of topicals

— In rare DPD-deficient patients, even small systemic 5-FU absorption can cause severe toxicity

— Self-application of topical field therapy requires manual dexterity, vision, cognition — engage caregivers

— Provide written instructions with anatomic diagrams

— Schedule early follow-up (1–2 weeks) in elderly starting 5-FU to verify proper use and tolerance

— AK is less common but does occur; lesions may appear hyperpigmented

— Cryotherapy can cause persistent hypopigmentation — counsel before treatment

Elderly patients (the modal AK patient)

Renal impairment

Hepatic impairment

Cognitive and functional considerations

Skin of color considerations (often elderly with cumulative UV)

Key distinction: Elderly patients with multiple AKs and short life expectancy do not automatically need aggressive field therapy — Step 3 may test whether you recognize that treating asymptomatic preclinical disease in a frail patient with < 2-year life expectancy offers limited benefit, and the right answer may be sun protection counseling plus targeted treatment of symptomatic lesions only.

Special Populations — Pregnancy, Transplant, and Immunosuppressed Patients

— AK in pregnancy is rare (younger demographic) but if encountered:

— 5-FU: contraindicated (Category X) — embryotoxic

— Imiquimod: Category C — limited human data; generally avoided; consider deferral until postpartum

— Tirbanibulin, diclofenac topical: limited pregnancy data; defer if possible

— Cryotherapy is safe in pregnancy — preferred lesion-directed option

— PDT: limited data; defer if possible

— During lactation: cryotherapy safe; topical agents generally avoided on the breast and ideally deferred

— AK is exceedingly rare in children — if present, evaluate for xeroderma pigmentosum, albinism, or other genodermatosis

— Refer to dermatology and genetics

— 65–100× increased risk of cSCC compared to general population

— AKs appear earlier, more numerous, and progress faster

— Aggressive prevention and treatment paradigm:

— Baseline full-body skin exam pre-transplant

— Surveillance every 6–12 months, every 3–6 months if prior skin cancer

— Aggressive field therapy at lower lesion thresholds

— Switch immunosuppression to mTOR inhibitor (sirolimus, everolimus) in patients with multiple/recurrent cSCC — reduces new skin cancer incidence

— Nicotinamide 500 mg PO BID reduces new AKs and non-melanoma skin cancers by ~23% (ONTRAC trial); especially useful in high-risk patients

— Voriconazole is photocarcinogenic — switch to alternative antifungal if possible

— Similar accelerated risk; same surveillance and treatment intensification principles

Pregnancy and lactation

Pediatric patients

Solid organ transplant recipients (SOTRs) — the highest-yield special population

HIV, CLL, chronic immunosuppression

Board pearl: A renal transplant patient on tacrolimus, mycophenolate, and prednisone presenting with multiple new AKs and a prior cSCC should prompt three actions: (1) dermatology co-management with field therapy + biopsy of any suspicious lesion, (2) discuss switching to sirolimus with the transplant team, and (3) start nicotinamide 500 mg BID for chemoprevention.

Complications and Adverse Outcomes

— Annual per-lesion progression risk 0.025–16% depending on study; pragmatic estimate ~1% per lesion per year

— Patients with multiple AKs (≥ 10) carry a 6–10% cumulative 10-year risk of cSCC

— ~60–80% of cSCCs arise in or adjacent to AKs

— Higher progression risk: hypertrophic, immunosuppressed host, lip/ear location, history of prior cSCC

— Bleeding, pain, ulceration

— Cosmetic disfigurement, especially facial fields

— Psychological impact — body image, anxiety about cancer

— Topical therapies: severe local reaction (expected but distressing), secondary bacterial infection, contact dermatitis to vehicle

— 5-FU systemic toxicity in DPD deficiency — rare but can cause myelosuppression even from topical

— Imiquimod: flu-like systemic symptoms (fatigue, myalgia, headache, low-grade fever); flare of psoriasis or autoimmune disease

— Cryotherapy: hypopigmentation (often permanent, especially in skin of color), blistering, scarring, alopecia at scalp sites, nerve injury near digital and facial nerves

— PDT: severe pain during illumination, photosensitivity 24–48 h, post-inflammatory hyperpigmentation

— All modalities have substantial recurrence; 5-FU and PDT generally outperform cryotherapy and imiquimod at 12 months for sustained clearance of fields

— Treating an undiagnosed invasive SCC, BCC, amelanotic melanoma, or Merkel cell carcinoma as AK

— Lentigo maligna masquerading as pigmented AK

— Always biopsy red-flag lesions

— Patients with AK have higher all-cause skin cancer risk including melanoma — comprehensive skin surveillance is warranted

Progression to invasive cSCC

Local complications of untreated AK

Treatment-related complications

Recurrence

Missed diagnoses (medicolegal high-yield)

Long-term outcomes

Step 3 management: Any AK that fails to clear after two appropriate treatment courses, recurs at the same site, or develops new induration must be biopsied promptly — this is the single most common preventable error in AK management and a recurring Step 3 patient-safety stem.

When to Escalate — Referral, Consultation, and Inpatient Considerations

— Diagnostic uncertainty or biopsy needed in challenging anatomic sites (periocular, nasal ala, lip, ear)

— Extensive field cancerization or > 10 AKs

— Failure of two appropriate primary care–initiated therapies

— Recurrence at previously treated sites

— All immunosuppressed patients (transplant, CLL, HIV, biologics) with AKs

— Suspected invasive SCC or other skin cancer

— Actinic cheilitis, especially with induration or non-healing erosions

— Cutaneous horn, hypertrophic AK

— Pigmented AK with features overlapping lentigo maligna

— For biopsy-proven cSCC or BCC in high-risk sites (face, lip, ear, genitals, hands), recurrent tumors, immunosuppressed patients, or tumors with aggressive histology

— Biopsy-proven cSCC with metastatic disease, perineural invasion, or locally advanced disease unresectable for surgery → consider cemiplimab (anti–PD-1) in metastatic/locally advanced cSCC

— Multidisciplinary tumor board for complex head and neck cSCC

— Adjuvant radiation for high-risk cSCC after Mohs (perineural invasion, positive margins, large tumors)

— Primary RT for non-surgical candidates

— Discuss immunosuppression reduction or switch to mTOR inhibitor for multiple/recurrent cSCC

— Coordinate antifungal switch off voriconazole when feasible

— Young patients with multiple AKs/cSCCs (xeroderma pigmentosum, etc.)

— AK itself is not an inpatient diagnosis

— Admission is rare and only for advanced cSCC complications (large infected tumors, hemorrhage, perioperative care for major resection/flap reconstruction, severe immune-related adverse events from cemiplimab)

Dermatology referral indications (outpatient)

Mohs surgery referral

Oncology referral

Radiation oncology

Transplant team coordination

Genetic counseling

Inpatient considerations

CCS pearl: In a CCS case with a transplant patient and a 2 cm tender ulcerated nodule on the temple within a field of AKs, the right sequence is: punch biopsy → if cSCC, refer to Mohs surgery + dermatology, obtain regional nodal exam ± imaging if high-risk features, and notify the transplant team to discuss switching to sirolimus — not just topical 5-FU.

Key Differentials — Other Keratinocyte and Skin Cancer Lesions

— Well-demarcated, scaly, erythematous plaque often > 1 cm; usually solitary

— Full-thickness epidermal atypia on biopsy (AK = partial thickness)

— Treatment: 5-FU, imiquimod, PDT, cryotherapy, or excision; lower limb lesions are slower to heal

— Indurated, often tender, may ulcerate or have keratotic core

— Biopsy any suspicious AK — invasion through basement membrane is the diagnostic distinction

— Higher metastatic risk on lip, ear, in immunosuppressed

— Pearly papule with telangiectasias, rolled borders, central ulceration ("rodent ulcer")

— Superficial BCC: scaly pink patch — mimics AK; biopsy distinguishes

— Treatment: ED&C, excision, Mohs, topical imiquimod/5-FU for superficial type

— Rapidly growing dome-shaped nodule with central keratin plug; considered a well-differentiated cSCC variant

— Treat as cSCC — excision preferred

— "Stuck-on," waxy, warty, sharply demarcated; benign

— Common in same demographic as AK; horn pearls on dermoscopy

— No treatment needed unless symptomatic

— Descriptive term, not a diagnosis — base may be AK, SCC, KA, or wart

— Excisional biopsy of the base

— Slowly enlarging brown-black macule on sun-damaged skin; irregular borders, color variation

— Critical to distinguish from pigmented AK — dermoscopy and biopsy when uncertain

— Annular lesions with raised hyperkeratotic rim ("cornoid lamella" on histology); sun-exposed; precancerous potential

Squamous cell carcinoma in situ (Bowen disease)

Invasive cutaneous squamous cell carcinoma

Basal cell carcinoma (BCC)

Keratoacanthoma

Seborrheic keratosis

Cutaneous horn

Lentigo maligna / melanoma in situ

Porokeratosis (disseminated superficial actinic — DSAP)

Key distinction: A non-healing, indurated, scaly lesion on the lower lip of a smoker with sun exposure is SCC or actinic cheilitis with focal SCC — not a "stubborn cold sore" or simple AK. Step 3 will reward biopsy and dermatology referral over empirical antiviral or topical therapy.

Key Differentials — Inflammatory and Infectious Mimics

— Erythematous scaly plaques with follicular plugging, scarring, and atrophy on sun-exposed sites

— Often associated with photosensitivity; ANA may be positive

— Biopsy: interface dermatitis, basement membrane thickening, perifollicular inflammation

— Treatment: sun protection, topical/intralesional steroids, hydroxychloroquine

— Well-demarcated erythematous plaques with silvery scale; symmetric; extensor surfaces, scalp, nails

— Not typically confined to sun-exposed sites

— Greasy yellow scale on scalp, eyebrows, nasolabial folds; pruritic; responds to antifungals and topical steroids

— Pruritic, ill-defined, often with vesicles, weeping, lichenification; history of exposure

— HPV-induced; verrucous papule with black dots (thrombosed capillaries); on hands, fingers

— Cryotherapy, salicylic acid — treatment overlaps with AK but pathology differs

— Annular plaque with raised scaly border, central clearing; KOH positive

— Genital, HPV-related, multifocal SCC-in-situ in young patients

— Rare but consider in atypical, rapidly enlarging lesions in cancer patients

— Photo-distributed but pruritic eruption, not keratotic

— KOH prep for tinea

— Biopsy for diagnostic uncertainty — the cost of a biopsy is far less than the cost of missing a malignancy

— Skin scraping/dermoscopy adjuncts

— Hydrochlorothiazide, voriconazole, BRAF inhibitors, doxycycline — eruption resolves with discontinuation

Discoid lupus erythematosus (DLE)

Psoriasis

Seborrheic dermatitis

Eczema/contact dermatitis

Verruca vulgaris (common wart)

Tinea (faciei, corporis)

Bowenoid papulosis

Cutaneous metastasis or lymphoma cutis

Polymorphous light eruption / chronic actinic dermatitis

Approach when uncertain

Drug-induced photo-reactions

Board pearl: A patient with scaly erythematous plaques on the face that scar and cause alopecia is more likely DLE than AK — order ANA, dsDNA, complement, and consider a biopsy showing interface dermatitis with basement membrane thickening. Sun protection is shared management, but DLE adds hydroxychloroquine and screening for systemic lupus.

Secondary Prevention and Long-Term Plan

— Broad-spectrum sunscreen SPF ≥ 30, water-resistant, reapply every 2 hours and after swimming/sweating

— Daily use reduces incidence of AKs and cSCC in randomized trials (Nambour study)

— Mineral (zinc oxide, titanium dioxide) preferred in sensitive/inflamed skin and pediatrics

— Protective clothing: wide-brimmed hat, UPF-rated long sleeves, sunglasses

— Avoid peak UV (10 am–4 pm); seek shade

— No tanning beds — strongly counsel cessation

— Nicotinamide (vitamin B₃) 500 mg PO BID — reduces new AKs (~13%) and non-melanoma skin cancers (~23%) in high-risk patients (ONTRAC trial)

— Distinguish from niacin — nicotinamide does not cause flushing

— Particularly useful in transplant patients and those with prior skin cancer

— Oral retinoids (acitretin) — chemoprevention in transplant recipients with recurrent cSCCs (specialist-initiated); teratogenic, hepatotoxicity, hyperlipidemia

— Topical 5-FU short-course "field rejuvenation" every 1–2 years reduces future cSCC (VA Keratinocyte Carcinoma Chemoprevention trial showed 75% reduction in SCC on the face/ears at 1 year)

— Immunocompetent with AK history: full-body skin exam every 6–12 months

— Prior cSCC: every 3–6 months for 2 years, then every 6–12 months

— Transplant patients: every 3–12 months depending on prior skin cancer history

— Smoking cessation (synergy with UV for lip SCC)

— Alcohol moderation (lip SCC)

— Review/replace photosensitizing medications when feasible

— Monthly with mirror; teach "new, changing, non-healing" red flags

— Provide ABCDE for melanoma alongside AK counseling

Sun protection — the cornerstone (and the highest-yield USPSTF behavioral intervention)

Chemoprevention

Surveillance schedule

Modifiable risk reduction

Patient self-skin exam

Step 3 management: For a patient with a history of multiple AKs and one prior cSCC, the secondary prevention bundle is daily SPF ≥ 30, protective clothing, nicotinamide 500 mg BID, dermatology surveillance every 6 months, and periodic field-directed therapy — this combination is the highest-yield long-term plan and a recurring Step 3 answer.

Follow-Up, Monitoring, and Counseling

— Cryotherapy follow-up at 8–12 weeks to assess clearance and identify new lesions

— Topical 5-FU/imiquimod follow-up at 4–8 weeks post-completion (allow inflammation to resolve before assessment)

— PDT follow-up at 8–12 weeks

— Persistent or recurrent lesion at follow-up → biopsy

— Full-body skin exam every 6–12 months for AK patients

— Document number, location, size, and morphology at each visit; photographs valuable

— Re-treat new AKs at each visit; consider repeat field therapy every 1–2 years in high-burden patients

— Pre-treatment: set expectations, photograph baseline

— Mid-treatment phone or telehealth check at 1–2 weeks for tolerance

— Post-treatment review at 4–8 weeks

— Sun protection reinforcement (highest impact intervention)

— Self-skin exam technique

— Recognition of red flags: non-healing, bleeding, rapidly growing, painful, or changing lesions

— When to call: any new lesion that has not healed in 4–6 weeks

— Adherence to nicotinamide and topical therapies

— Primary care: longitudinal AK management, cryotherapy, topical prescriptions, counseling, nicotinamide

— Dermatology: biopsies, complex cases, PDT, transplant patients, suspicious lesions

— Transplant team: immunosuppression optimization

— Oncology/Mohs surgeon: invasive cSCC

— USPSTF behavioral counseling for skin cancer prevention (Grade B) in fair-skinned patients aged 6 months–24 years; selective counseling in adults > 24 based on risk

— Smoking cessation, sunscreen access counseling

— Patients with extensive AKs and prior skin cancers may have appearance-related distress; provide reassurance and resources

Visit cadence after initial treatment

Long-term surveillance

Monitoring during topical therapy

Counseling content (every visit)

Coordination of care

Quality and value metrics

Psychosocial support

CCS pearl: In a CCS outpatient case, after initiating topical 5-FU for facial field cancerization, the next correct scheduled action is return visit in 4–8 weeks after completion, not weekly visits during treatment. Order: counsel sun protection, prescribe topical agent, schedule follow-up, document.

Ethical, Legal, and Patient Safety Considerations

— Cryotherapy — discuss risks of hypopigmentation (particularly important in skin of color — failure to disclose is a recurring complaint), blistering, scarring, and that the lesion may not be biopsied if cryotherapy is performed, so the diagnosis is presumptive

— Topical therapies — discuss the expected severe inflammatory reaction in writing; patients who are not warned may discontinue prematurely or seek emergency care

— Document discussion of alternative modalities and the option of biopsy

— The highest-risk error in AK care is treating an undiagnosed invasive cSCC, BCC, or melanoma empirically as AK

— Mitigation: biopsy any red-flag lesion; re-examine all treated sites at follow-up; biopsy non-responders or recurrences

— Photograph and document lesions to track over time

— When a patient moves from primary care to dermatology, ensure referral includes lesion map, treatments tried, and biopsy results

— Patients lost to follow-up after biopsy showing AK with focal SCC are a recurring safety event — establish closed-loop systems for biopsy result communication

— AK and skin cancer are often under-recognized in patients with darker skin types, leading to delayed diagnosis of cSCC, especially on lip and acral sites

— Indoor tanning regulation: counsel adolescents (banned for minors in most US states) — physicians should screen and counsel

— Most cancers including cSCC are reportable to state cancer registries — typically institutional process; physicians document

— Many AK regimens (acitretin chemoprevention, imiquimod for cheilitis) are off-label; document indication and rationale

— Cosmetic vs medically necessary distinctions can affect coverage of PDT, tirbanibulin; advocate for patients with high-risk profiles

— Step 3 may test the obligation to counsel adolescents and young adults against tanning bed use (USPSTF Grade B for ages 6 months–24 years)

Informed consent for procedures

Patient safety — missed cancer

Transitions of care

Health equity considerations

Mandatory reporting and public health

Off-label prescribing

Insurance and access

Tanning bed counseling

Step 3 management: When a patient declines biopsy of a suspicious red-flag "AK" and requests cryotherapy only, document the shared decision-making conversation, the recommendation for biopsy, the risks of missed malignancy, and the patient's informed refusal — then schedule close-interval follow-up (4–6 weeks) and re-offer biopsy at each visit.

High-Yield Associations and Rapid-Fire Facts

— Nicotinamide ≠ niacin (no flushing)

AK = SCC continuum: many dermatopathologists consider AK as "SCC in situ, partial thickness" (KIN I–III)

60–80% of cSCCs arise in or adjacent to AK — field cancerization concept

Sandpaper feel is more sensitive than visual inspection alone

Lip and ear lesions carry higher metastatic potential (10–15% for lip cSCC)

Cutaneous horn: 15–20% have invasive SCC at the base → excisional biopsy mandatory

Solid organ transplant patients have 65–100× cSCC risk; consider switching to sirolimus

Voriconazole is photocarcinogenic; switch when feasible

Nicotinamide 500 mg BID reduces non-melanoma skin cancer by ~23% in high-risk patients (ONTRAC trial)

5-FU avoid in DPD deficiency and pregnancy (Category X)

Tirbanibulin: only 5 days of treatment — adherence advantage

PDT: photosensitive 24–48 h after; counsel sun avoidance

Imiquimod: flu-like systemic symptoms; TLR-7 agonist

Cryotherapy: hypopigmentation risk especially in skin of color

Daily sunscreen reduces AK incidence and cSCC (Nambour trial)

USPSTF: behavioral counseling for skin cancer prevention — Grade B for fair-skinned 6 mo–24 yr; selective counseling > 24 yr

Tanning bed use before age 35 increases melanoma risk 75%

Actinic cheilitis = lower lip, "blurring of vermilion border," higher SCC potential

Mohs surgery for high-risk cSCC (face, ear, lip, recurrent, immunosuppressed)

Cemiplimab (anti–PD-1) for advanced/metastatic cSCC

Hydrochlorothiazide use is associated with increased cSCC/lip cancer risk — counsel and consider alternative

Field therapy outperforms lesion-directed therapy for sustained 12-month clearance

Acitretin chemoprevention in transplant patients with recurrent cSCC — teratogenic, hepatotoxic

Dermoscopic "strawberry pattern" = nonpigmented facial AK

Board pearl: If a Step 3 stem mentions an older fair-skinned patient with multiple rough scaly papules on the face/scalp/dorsal hands, the highest-yield single intervention with the most evidence is daily broad-spectrum sunscreen SPF ≥ 30 plus dermatology surveillance, with nicotinamide 500 mg BID added if high-risk for new skin cancers.

Board Question Stem Patterns

— 68-year-old fair-skinned farmer with several rough, scaly, pink papules on bald scalp and dorsal hands. Best next step? → Cryotherapy for discrete lesions and/or topical 5-FU for field, plus sun protection counseling

— Patient with known AKs develops a 1.2 cm indurated, tender, ulcerated plaque on the lip that has grown over 6 weeks. Best next step? → Biopsy (shave or punch) — not cryotherapy, not topical 5-FU

— 55-year-old renal transplant on tacrolimus, mycophenolate, prednisone, with multiple new AKs and 2 prior cSCCs. Best next step? → Dermatology referral, field-directed therapy, nicotinamide 500 mg BID, discuss switching to sirolimus with transplant team

— Patient on topical 5-FU returns at week 2 with severe erythema, crusting, and discomfort. Best next step? → Continue therapy and reassure — this is the expected therapeutic response

— 72-year-old with a conical hyperkeratotic projection on the dorsal hand. Best next step? → Excisional biopsy of the base (cannot determine diagnosis clinically)

— Brown-tan macule with irregular border on sun-damaged cheek. Best next step? → Biopsy to distinguish pigmented AK from lentigo maligna

— High-risk patient with multiple AKs/prior cSCCs asks about preventing more skin cancers. Best answer? → Nicotinamide 500 mg PO BID (plus sunscreen)

— Pregnant patient with a few AKs requests treatment. Best option? → Cryotherapy; defer 5-FU/imiquimod

— Lung transplant on long-term voriconazole develops multiple AKs and cSCCs. Best next step? → Switch antifungal to alternative (posaconazole/isavuconazole) and intensify skin surveillance

— AK on cheek persists after 2 rounds of cryotherapy. Best next step? → Biopsy to exclude cSCC

— 17-year-old with regular tanning bed use. Best preventive intervention? → Behavioral counseling against tanning bed use (USPSTF Grade B)

Stem 1 — The classic AK presentation

Stem 2 — The red-flag lesion

Stem 3 — The transplant patient

Stem 4 — Treatment intolerance

Stem 5 — Cutaneous horn

Stem 6 — Pigmented lesion ambiguity

Stem 7 — Chemoprevention

Stem 8 — Pregnancy

Stem 9 — Voriconazole

Stem 10 — Failed therapy

Stem 11 — Adolescent tanning

CCS pearl: Step 3 CCS frequently rewards biopsy → cryotherapy or topical 5-FU → sun protection counseling → nicotinamide if high risk → 6-month follow-up. Penalizes empirical treatment of red-flag lesions and skipping skin cancer surveillance in transplant patients.

One-Line Recap

Actinic keratosis is a UV-driven precursor to cutaneous squamous cell carcinoma in fair-skinned, sun-damaged, often older or immunosuppressed patients, best managed by lesion-directed cryotherapy for few discrete lesions, field-directed therapy (topical 5-FU, imiquimod, tirbanibulin, or PDT) for multiple lesions and subclinical disease, lifelong sun protection plus nicotinamide chemoprevention in high-risk patients, and a low threshold for biopsy of any indurated, tender, ulcerated, rapidly growing, or refractory lesion.

Diagnose clinically, biopsy red flags: rough sandpaper papules on sun-exposed sites in fair-skinned older adults; biopsy if indurated, tender, >1 cm, bleeding, ulcerated, recurrent, or non-responsive

Treat the field, not just the lesion: cryotherapy for discrete AKs (1–5); topical 5-FU, imiquimod, tirbanibulin, or PDT for field cancerization; combination approaches outperform single-modality

Prevent aggressively: broad-spectrum SPF ≥ 30 daily, protective clothing, no tanning beds; nicotinamide 500 mg PO BID in high-risk patients reduces non-melanoma skin cancers by ~23%

Special populations matter: solid organ transplant recipients need 3–12 month skin surveillance, aggressive field therapy, consideration of switching to sirolimus, and avoidance of voriconazole; pregnancy → cryotherapy only; elderly → match treatment aggressiveness to life expectancy and goals

Board pearl: If you remember only three things — biopsy red-flag lesions, treat the field with topicals or PDT when multiple, and counsel sun protection plus consider nicotinamide for prevention — you will get almost every Step 3 AK question right.