Actinic keratoses (AKs) are rough, scaly epidermal lesions caused by cumulative, non-ionizing ultraviolet (UV) radiation. They represent the most common premalignant skin lesions in fair-skinned adults, affecting over 58 million Americans. While an individual AK lesion carries a low annual rate of malignant transformation—typically cited between 0.025% and 16% per lesion per year (averaging approximately 0.6% per lesion per year)—longitudinal epidemiological data demonstrates that patient-level risk accumulates significantly over time, reaching 3.13% at 3 years and 4.03% at 5 years (Balcere et al., 2022, PMC9571814). Crucially, recent genomic and histopathological analyses reveal that up to 82% of cutaneous squamous cell carcinomas (SCCs) arise within or directly adjacent to existing actinic keratoses (Li et al., 2025, PMID 39925808).

Because sun-damaged skin develops extensive subclinical genetic alterations—a phenomenon known as field cancerization—treating individual visible spots with localized destructive techniques like liquid nitrogen cryotherapy often fails to stop new lesions from emerging nearby. Dermatology has therefore shifted toward field-directed therapies, including topical antimetabolites (5-fluorouracil), topical immune response modifiers (imiquimod), and targeted photodynamic therapy (Levulan Kerastick plus BLU-U blue light).

This comprehensive guide evaluates field-directed AK modalities, details the clinical protocols, insurance coding (CPT 96567), and out-of-pocket costs for photodynamic therapy (PDT), addresses post-procedure risks such as post-inflammatory hyperpigmentation (PIH) in skin of color, and explains why the once-popular short-course topical gel Picato (ingenol mebutate) was removed from global markets following FDA and EMA safety actions.

Direct Answer: How Actinic Keratoses Are Treated

If your dermatologist diagnoses actinic keratosis, treatment falls into two main categories depending on whether you have isolated spots or widespread sun damage:

Lesion-Directed Therapy (Single Spots): Liquid nitrogen cryotherapy is first-line for isolated, discrete lesions. It freezes target keratinocytes at -196°C in a single brief in-office visit, though it leaves localized subclinical field cancerization untreated.
Field-Directed Therapy (Widespread Sun Damage): For areas with multiple lesions or broad photodamage (face, scalp, forearms), field therapy eradicates visible lesions while clearing microscopic subclinical precancers:
- Topical 5-Fluorouracil (5-FU 0.5%–5%; Efudex, Carac): Applied daily or twice daily for 2 to 4 weeks. Produces intense redness, crusting, and erosion before clearing.
- Topical Imiquimod (3.75%–5%; Aldara, Zyclara): Applied 2 to 3 times weekly for 4 to 16 weeks to stimulate local cell-mediated immunity against dysplastic keratinocytes.
- Photodynamic Therapy (PDT; Levulan Kerastick + BLU-U): A two-stage treatment in which the clinician applies 20% aminolevulinic acid (ALA) solution and the patient returns for 16 minutes 40 seconds of 417 nm blue light after an FDA-label incubation of 14 to 18 hours for face/scalp AK (or 3 hours with occlusion for upper-extremity AK). Typically requires 1 treatment course (costing $400 to $1,000+), with an FDA-approved option to repeat once at 8 weeks if lesions persist.
The Picato Withdrawal: Ingenol mebutate (Picato gel) was suspended in Europe in 2020 and saw its US FDA label updated with a Non-Melanoma Skin Cancer warning (Section 5.3) in March 2021 before being voluntarily discontinued by LEO Pharma due to clinical trial data showing increased skin cancer incidence in treated areas.

What Is Actinic Keratosis and How Fast Does It Turn into Skin Cancer?

Actinic keratosis is an intraepidermal proliferation of atypical, dysplastic keratinocytes restricted to the basal layer of the epidermis. Clinical presentation ranges from barely perceptible "sandpaper-like" rough patches to hyperkeratotic, cutaneous-horn-like plaques on sun-exposed anatomical sites: scalp, forehead, cheeks, lower lip (actinic cheilitis), ears, dorsal hands, and forearms.

          ┌─────────────────────────────────────────────────────────────┐
          │             CUMULATIVE ULTRAVIOLET RADIATION                │
          └──────────────────────────────┬──────────────────────────────┘
                                         │
                                         ▼
          ┌─────────────────────────────────────────────────────────────┐
          │            UV-INDUCED TP53 DNA MUTATIONS IN BASAL LAYER     │
          └──────────────────────────────┬──────────────────────────────┘
                                         │
                                         ▼
          ┌─────────────────────────────────────────────────────────────┐
          │           FIELD CANCERIZATION (SUBCLINICAL DYSPLASIA)        │
          └──────────────────────────────┬──────────────────────────────┘
                                         │
                    ┌────────────────────┴────────────────────┐
                    ▼                                         ▼
    ┌───────────────────────────────┐         ┌───────────────────────────────┐
    │   SOLITARY VISIBLE LESION     │         │   MULTIPLE CONFLUENT LESIONS  │
    │   (Cryotherapy Candidate)     │         │   (Field-Therapy Candidate)   │
    └───────────────┬───────────────┘         └───────────────┬───────────────┘
                    │                                         │
                    ▼                                         ▼
    ┌───────────────────────────────┐         ┌───────────────────────────────┐
    │   Lesion-Directed Clearance   │         │   5-FU / Imiquimod / Levulan PDT  │
    └───────────────┬───────────────┘         └───────────────┬───────────────┘
                    │                                         │
                    └────────────────────┬────────────────────┘
                                         │
                                         ▼
    ┌─────────────────────────────────────────────────────────────────────────┐
    │    Malignant Transformation Risk: ~0.6%/yr per lesion (~4.03% at 5 yrs) │
    │    Invasive Cutaneous Squamous Cell Carcinoma (cSCC)                    │
    └─────────────────────────────────────────────────────────────────────────┘

A frequent point of clinical confusion for patients is distinguishing actinic from seborrheic keratosis. While seborrheic keratoses are completely benign, "stuck-on" epidermal growths that can be scraped or frozen without field considerations, actinic keratoses are premalignant precursors requiring careful dermatological surveillance.

Histopathology and Genomic Driver Mutations

Histologically, actinic keratosis demonstrates nuclear atypia, pleomorphism, hyperchromatism, and a total loss of normal orderly keratinocyte maturation throughout the lower layers of the epidermis. Solar elastosis—the breakdown of normal dermal collagen and elastin fibers into amorphous basophilic material—is universally present in the underlying dermis, reflecting decades of chronic solar UV exposure.

At the molecular level, chronic UV radiation (specifically UVB light causing pyrimidine dimer formation) induces characteristic driver mutations in key tumor suppressor and oncogenic pathways:

TP53 Gene Mutations: Mutated TP53 allows dysplastic cells to evade UV-induced apoptosis. TP53 mutations are present in up to 90% of human cutaneous SCCs and are found extensively in subclinical sun-damaged skin surrounding visible AKs.
NOTCH1 and NOTCH2 Inactivation: Loss-of-function mutations in NOTCH receptors occur early in field cancerization, impairing normal epidermal differentiation.
CDKN2A Alterations: Inactivation of the CDKN2A locus (encoding p16INK4a) marks the transition from early intraepidermal dysplasia to invasive squamous cell carcinoma.

Progression Dynamics and Epidemiological Evidence

The transformation from AK to invasive cutaneous squamous cell carcinoma (cSCC) involves mutations in tumor suppressor genes, most notably TP53. Key statistical parameters established across major epidemiological studies include:

Per-Lesion Annual Rate: Historical studies report annual progression rates of 0.025% to 16%, with consensus dermatological guidelines utilizing ~0.6% per lesion per year.
Cumulative Patient-Level Risk: Patients presenting with multiple AKs face a 3-year cSCC transformation risk of 3.13% and a 5-year risk of 4.03% (Balcere et al., 2022, PMC9571814).
Precursor Proportion: Genomic lineage tracing by Li et al. (2025, PMID 39925808) verified that approximately 82% of primary cutaneous SCCs arise within a background of pre-existing actinic keratosis.
Spontaneous Regression: Up to 15% to 63% of individual AK lesions may undergo spontaneous regression over 12 months, but subclinical driver mutations persist in the surrounding field, leading to high local recurrence rates (up to 57% within one year).

Cryotherapy vs 5-FU vs Imiquimod vs Levulan PDT: Comparison Matrix

When evaluating treatment options, dermatologists balance efficacy, treatment duration, cosmetic downtime, and patient compliance. The matrix below compares the four principal evidence-backed field and lesion therapies.

Therapy	Mechanism of Action	Standard Protocol	Expected Clearance Rate	Downtime & Local Reaction	Typical Cost & Coverage
Liquid Nitrogen Cryotherapy	Thermal destruction (-196°C) of target keratinocytes	1 session (5–15 sec spray per lesion)	75%–90% for single discrete lesions	1–2 weeks; blistering, scabbing, risk of hypopigmentation	Covered by insurance (CPT 17000 for first lesion, CPT 17003 for 2–14)
Topical 5-Fluorouracil (5-FU 5%)	Antimetabolite inhibiting thymidylate synthase (DNA synthesis)	Twice daily for 2–4 weeks (face/scalp)	74%–86% complete field clearance	3–4 weeks; intense erythema, erosion, ulceration, crusting	$40–$150 copay/cash with coupon; covered under pharmacy benefit
Topical Imiquimod (5%)	TLR7 agonist inducing local interferon-alpha & cytokine cascade	2–3 times/week for 4–16 weeks	45%–55% complete field clearance	4–6 weeks; moderate erythema, flaking, systemic flu-like symptoms	$50–$200 copay/cash; covered under pharmacy benefit
Levulan Kerastick + BLU-U PDT	Protoporphyrin IX photoactivation generating singlet oxygen	Drug application + illumination 14–18 hr later (face/scalp) or 3 hr later w/ occlusion (arms); 16m 40s light	70%–80% complete field clearance	1–2 weeks; sunburn-like peeling, stinging, phototoxic erythema	$400–$1,000+ per session; covered by Medicare/commercial (CPT 96567 + J0350)

A seminal 12-month randomized controlled trial by Jansen et al. (2019, published in the New England Journal of Medicine) comparing 5-FU, imiquimod, MAL-PDT, and ingenol mebutate in 624 patients demonstrated that 5-fluorouracil maintained the highest cumulative probability of remaining free from lesion failure at 12 months (74.7%), compared to 53.9% for imiquimod, 37.7% for MAL-PDT, and 28.9% for ingenol mebutate. However, PDT offers superior cosmetic compliance because the active inflammatory downtime is compressed into 7–10 days rather than 4 continuous weeks of facial erosion.

How Levulan Kerastick plus BLU-U Photodynamic Therapy Works

Photodynamic therapy combines a topical photosensitizing agent with a specific wavelength of non-thermal visible light to selectively destroy dysplastic cells while sparing underlying dermal structures.

Step-by-Step Clinical In-Office Workflow

Understanding the exact sequence of an in-office Levulan PDT appointment helps patients prepare effectively:

Pre-Treatment Degreasing: The clinical assistant scrubs the target treatment area (face, scalp, or arms) thoroughly with isopropyl alcohol or acetone wipes. Degreasing removes surface sebum, stratum corneum lipids, and dead keratin scales, ensuring uniform absorption of the Levulan solution.
Lesion Preparation: Hyperkeratotic, thick AK crusts are gently curetted or debrided with a scalpel blade without causing bleeding. Removing hyperkeratotic scale allows the photosensitizing drug to penetrate directly to the basal layer of dysplastic keratinocytes.
Ampule Activation & Application: The practitioner activates the Levulan Kerastick ampules by breaking the internal glass vials and mixing the 20% aminolevulinic acid HCl solution. The solution is dabbed evenly across target AK lesions and surrounding field skin.
Incubation Period: Per the FDA Levulan Kerastick label (NDA 20-965), the drug incubates for 14 to 18 hours for face/scalp AK (an overnight protocol — the patient is sent home and returns the next day for illumination) or 3 hours with occlusion for upper-extremity AK. During this window, cellular enzymes convert ALA into Protoporphyrin IX (PpIX), and the patient must avoid sunlight and bright indoor light. (Shorter 1–3 hour, non-occluded incubations are an off-label and research variation, not the FDA-label face/scalp protocol.)
BLU-U Blue Light Illumination: Protective dark goggles are placed over the patient's eyes. The patient is positioned beneath the BLU-U blue light illuminator, emitting 417 nm blue light at 10 J/cm² for exactly 16 minutes and 40 seconds.
Post-Illumination Cooling & Cleanse: Immediately after light exposure, the skin is sprayed with cool thermal spring water or cooled with forced cold air. The remaining Levulan solution is washed off thoroughly with a mild cleanser.

The Biochemical Mechanism: PpIX Accumulation

Inside cellular mitochondria, ALA enters the heme biosynthetic pathway and is converted into Protoporphyrin IX (PpIX), a potent endogenous photosensitizer. Absorption of blue light energy by PpIX transfers energy to molecular oxygen, producing short-lived singlet oxygen ($^1O_2$) and reactive oxygen species (ROS). ROS destroy mitochondrial membranes, triggering selective apoptosis and necrosis of dysplastic cells.

       [ Topically Applied Levulan (20% ALA Solution) ]
                              │
                              ▼
    [ Preferential Cellular Uptake by Dysplastic Keratinocytes ]
                              │
                              ▼
      [ Biosynthetic Conversion into Protoporphyrin IX (PpIX) ]
                              │
                              ▼
     [ Exposure to BLU-U Blue Light (417 nm, 10 J/cm², 16m 40s) ]
                              │
                              ▼
        [ Generation of Singlet Oxygen ($^1O_2$) & ROS ]
                              │
                              ▼
     [ Selective Apoptosis & Necrosis of Dysplastic AK Cells ]

Protocol, Retreatment Rules, and Pain Management

Retreatment Schedule: Per FDA prescribing guidelines (NDA 20-965 s015), if target AK lesions are not completely cleared at the 8-week follow-up evaluation, a second Levulan PDT treatment session may be administered using the identical protocol.
Intra-Procedure Pain: Photodynamic illumination causes a distinct burning, stinging sensation as PpIX photoactivates. Clinical management includes handheld forced-cold-air cooling devices (e.g., Zimmer cooler), thermal water sprays, or brief illumination pauses.
Daylight PDT Alternative: In European and specialized US centers, daylight PDT utilizes natural outdoor daylight (2 hours of continuous daylight exposure after a 30-minute incubation) to activate PpIX continuously as it forms. Randomized studies (Mei et al., 2019) show daylight PDT achieves equivalent clearance rates to blue-light lamps while dramatically reducing intra-procedure pain scores.

Photosensitivity and Sunscreen Boundaries

The FDA Levulan label emphasizes a critical post-procedure safety directive: patients experience severe photosensitivity for approximately 40 hours following solution application.

During this window, patients must completely avoid direct sunlight and bright indoor lighting. Standard broad-spectrum mineral or chemical sunscreens do not protect against PpIX photoactivation, because sunscreens block UV radiation (290–400 nm), whereas PpIX photoactivation occurs in the visible spectrum at 417 nm (the Soret band) and 635 nm. Physical light avoidance (wide-brimmed hats, dark clothing, staying indoors) is mandatory. Patients seeking post-procedure guidance should review our analysis on why standard sunscreen will not protect during the Levulan photosensitivity window.

Clinical Trial Pipeline Analysis

Analysis of clinical trial registries provides valuable insight into emerging PDT protocols and incubation optimizations. Dedicated clinical trials evaluating actinic keratosis and photodynamic therapy protocols highlight several ongoing clinical developments:

Trial Status Distribution: Multiple active, recruiting, and completed clinical studies focus on short-incubation photodynamic protocols.
Key Active Protocols:
- NCT03906253 & NCT06507644: Investigating ultra-short incubation times (30–60 minutes) combined with pre-treatment fractional laser micro-channeling to enhance Levulan penetration.
- NCT07335003 & NCT06428721: Evaluating blue-light versus red-light (633 nm) PDT for field clearance efficiency and pain reduction.
- NCT05080764 & NCT06577311: Clinical trials examining daylight-mediated ALA-PDT in immunocompromised transplant patients with high field-cancerization burden.
Pipeline Summary: Clinical trial development remains overwhelmingly focused on optimizing aminolevulinic acid (ALA/Levulan) incubation times, blue-to-red light conversion, and painless daylight protocols rather than introducing novel synthetic photosensitizers.

Why Picato (Ingenol Mebutate) Disappeared from the Market

One of the most frequent questions from patients treated for AK prior to 2020 is what happened to Picato (ingenol mebutate gel 0.015% / 0.05%). Picato was hailed at its 2012 FDA launch because it required only a 2-day or 3-day once-daily application course, compared to weeks of 5-FU.

┌─────────────────────────────────────────────────────────────────────────┐
│                       PICATO REGULATORY TIMELINE                        │
├───────────────┬─────────────────────────────────────────────────────────┤
│ Jan 23, 2012  │ FDA approves Picato (ingenol mebutate, NDA 202-833).    │
├───────────────┼─────────────────────────────────────────────────────────┤
│ Jan 17, 2020  │ EMA suspends EU marketing authorisation as a            │
│               │ precautionary measure while it reviews a skin-cancer    │
│               │ safety signal from a 484-patient trial.                 │
├───────────────┼─────────────────────────────────────────────────────────┤
│ Feb 11, 2020  │ European Commission withdraws the EU marketing          │
│               │ authorisation at LEO Pharma's request.                   │
├───────────────┼─────────────────────────────────────────────────────────┤
│ Apr 30, 2020  │ EMA completes its review, concluding Picato's risks     │
│               │ outweigh its benefits (higher skin-cancer incidence).    │
├───────────────┼─────────────────────────────────────────────────────────┤
│ Mar 2021      │ FDA updates US Picato prescribing label Section 5.3    │
│               │ (Reference ID 4765051) highlighting Non-Melanoma Skin   │
│               │ Cancer risk; LEO Pharma has ceased US sales.            │
└───────────────┴─────────────────────────────────────────────────────────┘

The Regulatory Chronology

Initial Approval (January 23, 2012): The FDA approved Picato (NDA 202-833, LEO Pharma) derived from the sap of Euphorbia peplus. Its mechanism combined rapid cell membrane disruption (necrosis) with protein kinase C (PKC) activation.
The European Safety Signal (2019–2020): Pooled data from a 3-year safety trial (LP0041-1013) comparing ingenol mebutate to imiquimod in 484 patients revealed a statistically significant excess of non-melanoma skin cancers—specifically squamous cell carcinoma (SCC)—in the Picato treatment field.
EMA Suspension (January–April 2020): The European Medicines Agency's Pharmacovigilance Risk Assessment Committee (PRAC) suspended Picato's EU marketing authorization on January 17, 2020, as a precautionary measure while its review continued. The European Commission then withdrew the marketing authorization on February 11, 2020 at LEO Pharma's request, and the EMA completed its review on April 30, 2020, concluding that Picato's risks outweighed its benefits.
FDA Action and US Discontinuation (March 2021): The FDA strengthened Section 5.3 (Warnings and Precautions: Non-Melanoma Skin Cancer) of the US Prescribing Information (Reference ID 4765051). LEO Pharma subsequently discontinued manufacturing and distribution of Picato in the United States. Today, Picato is no longer marketed globally.

What About Metvixia (Methyl Aminolevulinate)?

Another discontinued PDT drug is Metvixia (methyl aminolevulinate / MAL, NDA 021415), approved by the FDA in July 2004 for use with red light (Aktilite). Unlike Picato, which was withdrawn due to oncological safety signals, Metvixia was discontinued from the US market in 2015 for commercial and business reasons (Federal Register Notice, October 13, 2015). MAL-PDT remains widely available throughout Europe and Asia, but US practices rely almost exclusively on Levulan Kerastick (ALA) or Ameluz (ALA 10% gel).

Is Photodynamic Therapy Safe for Darker Skin (Fitzpatrick IV–VI)?

A critical clinical boundary often overlooked in patient literature is the safety profile of field-directed AK therapies in patients with darker skin tones (Fitzpatrick skin types IV, V, and VI).

While actinic keratoses occur predominantly in Fitzpatrick I–III individuals due to lower epidermal melanin protection, individuals with darker skin who have extensive sun exposure or occupational UV exposure do develop AKs.

Post-Inflammatory Hyperpigmentation (PIH) Risks

Levulan PDT in Darker Skin: The intense reactive oxygen species cascade generated during BLU-U illumination triggers acute inflammation at the dermal-epidermal junction. In melanocompetent skin, this inflammation frequently stimulates melanocyte hyperactivity, leading to prolonged post-inflammatory hyperpigmentation (PIH) that can persist for 3 to 12 months.
5-FU and Imiquimod Risks: Extended inflammation from 5-FU or imiquimod can also cause persistent PIH or post-inflammatory hypopigmentation (loss of pigment due to melanocyte damage).
Clinical Safety Measures:
1. Pre-Treatment Priming: Dermatologists may prime Fitzpatrick IV–VI patients with topical tyrosinase inhibitors (azelaic acid 15% or hydroquinone 4%) for 2 to 4 weeks prior to field therapy.
2. Incubation Adjustment: Shortening Levulan incubation to 45–60 minutes reduces peak phototoxic inflammation.
3. Strict Post-Procedure Care: Immediate application of topical anti-inflammatory agents and strict visible-light avoidance minimize melanocyte activation.

Patients concerned about post-procedure discoloration should refer to our detailed analysis of PIH risk after PDT and 5-FU in skin of color.

Insurance Coverage, CPT Coding, and Out-of-Pocket Costs

Understanding medical insurance reimbursement versus cosmetic self-pay dynamics is essential for patients planning AK therapy.

CPT Coding and Coverage Rules

Because actinic keratosis is a recognized premalignant condition, treatment is classified as medically necessary by Medicare and commercial health plans when performed for medical indications:

CPT Code 96567: Photodynamic therapy by external light source for destruction of premalignant lesions, per session.
HCPCS Code J0350: Injection/topical, aminolevulinic acid HCl, 15%, topical, 5 mg (used to bill the Levulan Kerastick drug unit).
Medicare Local Coverage Determinations (LCDs): Medicare covers Levulan PDT for face and scalp AKs under National Coverage Determination (NCD CAG-00049N). However, Medicare and commercial insurers strictly deny coverage when PDT is billed for off-label cosmetic indications, such as photoaging, off-label acne vulgaris, or general skin rejuvenation.

Financial Breakdown

┌─────────────────────────────────────────────────────────────────────────┐
│                     ACTINIC KERATOSIS COST LANDSCAPE                    │
├──────────────────────────┬──────────────────────┬───────────────────────┤
│ Modality                 │ Insurance Copay/Deduct│ Cash-Pay Out-of-Pocket│
├──────────────────────────┼──────────────────────┼───────────────────────┤
│ Liquid Nitrogen (1–14)   │ $20 – $75 copay      │ $150 – $350           │
├──────────────────────────┼──────────────────────┼───────────────────────┤
│ Topical 5-FU 5% Cream    │ $15 – $100 copay     │ $40 – $180 (with card)│
├──────────────────────────┼──────────────────────┼───────────────────────┤
│ Topical Imiquimod 5%     │ $20 – $150 copay     │ $60 – $250            │
├──────────────────────────┼──────────────────────┼───────────────────────┤
│ Levulan PDT (1 session)  │ $50 – $250 copay     │ $400 – $1,000+        │
└──────────────────────────┴──────────────────────┴───────────────────────┘

What to Do If You Have High Field Cancerization Burden

For patients presenting with dozens of confluent actinic keratoses across the face, scalp, or forearms (a high field cancerization burden), dermatologists frequently employ combination sequential therapy protocols rather than relying on a single modality.

Sequential Combination Protocols

5-FU Followed by Levulan PDT: Applying topical 5-FU for 7 days to partially disrupt dysplastic hyperkeratotic scale enhances the uptake of aminolevulinic acid (Levulan) during subsequent PDT. Clinical studies show this combination reduces total PDT incubation time while achieving higher complete field clearance.
Fractional Laser-Assisted PDT: Utilizing a mild fractional non-ablative or thulium laser (such as 1927 nm Moxi) immediately before Levulan application creates microscopic treatment zones that accelerate drug absorption into deeper epidermal layers.
Calcipotriol plus 5-FU Combination: Combining 5-FU with calcipotriol (a synthetic vitamin D analog) for a 4-day application window stimulates a T-cell-mediated immune response against AKs with significantly less downtime than a standard 4-week 5-FU monotherapy course.

Frequently Asked Questions

How many PDT sessions will I need for actinic keratoses?

Most patients achieve substantial clearance (70% to 80% reduction in visible AKs) after 1 single Levulan PDT session. However, under FDA prescribing guidelines, if hyperkeratotic lesions persist at your 8-week follow-up appointment, a second PDT session using the same protocol can be administered.

Does insurance cover photodynamic therapy for actinic keratosis?

Yes. Medicare and virtually all commercial insurance policies cover PDT when prescribed for the treatment of documented actinic keratoses on the face, scalp, or arms (billed under CPT 96567 and HCPCS J0350). However, if PDT is performed for cosmetic photodamage, broad rejuvenation, or acne, it is classified as self-pay and costs between $400 and $1,000 per session.

Can actinic keratoses come back after treatment?

Yes. While field therapies destroy currently visible AKs and subclinical precancerous cells, they cannot alter your underlying genomic sun damage history. New AK lesions can develop in sun-exposed skin months or years later. Annual full-body skin examinations by a board-certified dermatologist, strict daily broad-spectrum sun protection, and periodic repeat field therapy are essential for long-term skin health.

What is the difference between Levulan and Ameluz for PDT?

Levulan Kerastick is a 20% aminolevulinic acid (ALA) solution approved for face, scalp, and upper extremity AKs with blue light. Ameluz is a 10% aminolevulinic acid nanoemulsion gel approved for face and scalp AKs with red light (BF-RhodoLED) or blue light. Both convert to Protoporphyrin IX inside cells; Ameluz's nanoemulsion formulation enhances skin penetration.

How painful is the post-PDT recovery period?

Post-PDT recovery feels like a moderate to severe sunburn for the first 48 to 72 hours. Tightness, stinging, swelling, and redness peak around day 2 or 3, followed by active peeling and flaking from days 4 to 7. Applying fragrance-free plain petrolatum or gentle barrier creams and avoiding all sunlight keeps discomfort manageable.

Sources

Levulan Kerastick FDA Prescribing Information (NDA 020965, s015, March 2018): https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/020965s015lbl.pdf
Picato (Ingenol Mebutate) FDA Label & Safety Warning (NDA 202-833, s013, March 2021): https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/202833s013lbl.pdf
StatPearls — Actinic Keratosis (Marques, Crowley, Shapiro): https://www.ncbi.nlm.nih.gov/books/NBK557401/
American Academy of Dermatology — Actinic Keratosis Overview & Treatment: https://www.aad.org/public/diseases/skin-cancer/actinic-keratosis-treatment
Jansen et al., N Engl J Med 2019 — Randomized Trial of Four Treatment Approaches for Actinic Keratosis (5-FU, Imiquimod, MAL-PDT, Ingenol Mebutate; 624 patients; NCT02281682): https://pubmed.ncbi.nlm.nih.gov/30855743/
Del Regno et al., PMC 2022 — Field-Directed Therapies in Actinic Keratosis Review: https://pmc.ncbi.nlm.nih.gov/articles/PMC9142445/
Li et al., 2025 — Precursor Proportion of Actinic Keratosis in Cutaneous Squamous Cell Carcinoma (PMID 39925808): https://pubmed.ncbi.nlm.nih.gov/39925808/
Balcere et al., 2022 — Actinic Keratosis Progression and cSCC Risk (PMC9571814): https://pmc.ncbi.nlm.nih.gov/articles/PMC9571814/
European Medicines Agency (EMA) — Picato Referral & Suspension Notice: https://www.ema.europa.eu/en/medicines/human/referrals/picato
Federal Register — Metvixia Discontinuation Notice (October 13, 2015): https://www.federalregister.gov/documents/2015/10/13/2015-25929/galderma-laboratories-la-withdrawal-of-approval-of-new-drug-application-for-metvixia

Actinic Keratosis Treatment: 5-FU, Imiquimod, PDT, and Why Picato Disappeared