IN THIS ISSUE

Energy-based Photoaging and Sunscreens How to Achieve

PHOTODAMAGE 1
Devices for the Best Cosmetic
Treatment of Non-surgical Therapies Outcome for
Photodamaged Skin for Skin Cancer Actinic Keratoses

OPINIONS AND PROGRESS IN

Cosmetic Dermatology

VOLUME 01 / ISSUE 03 / NOVEMBER 2021

Australasian Society of Cosmetic Dermatologists
 -A Im a Hybrid'"
- - - -=MASTER YOUR CRAFT
 OPINIONS AND PROGRESS IN

Cosmetic Dermatology

PHOTODAMAGE 1
VOLUME 01 / ISSUE 03 / NOVEMBER 2021
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Clinical Prof Saxon D Smith For full details of Editorial Advisory Group members, please go to
Dr Adrian Lim  https://www.ascd.org.au/journal

Dr Katherine Armour
Founding Editor
Assoc Prof Philip Bekhor
Prof Greg J Goodman
Dr Anina Fitzgibbon
Assoc Prof Michael Freeman
Guest Editor
Prof Greg J Goodman (Founding editor)
Assoc Prof Michael Freeman
Dr Adrian Lim (Co-editor-in-chief)
Dr John R Sullivan
Dr Davin Lim (Industry editor)
Dr Shobhan Manoharan
Dr Cara McDonald
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Australasian Society of Cosmetic Dermatologists / Opinions and Progress in Cosmetic Dermatology VOLUME 01 / ISSUE 03 / NOVEMBER 2021
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 OPINIONS AND PROGRESS IN

Cosmetic Dermatology

PHOTODAMAGE 1
VOLUME 01 / ISSUE 03 / NOVEMBER 2021
www.ascd.org.au/
medical_journal

Welcome to Contents
“Photodamage 1”
– the first of a two-part PAGE

series on sun damage,

1 / Photodamage 1 Guest Editorial
skin cancers and Michael Freeman, John R Sullivan
photoaging.
3 / Photodamage and Photoaging:
Epidemiology and Pathogenesis
Prudence Gramp, Michael Freeman
We are delighted to have Associate
Professor Michael Freeman and 10 / A Historical Perspective on the Evolution
Dr John Sullivan as guest editors for of Ageing
this issue. They have put together an Saxon D Smith
excellent content covering key aspects
12 / Photoaging and Sunscreens
of photodamage that will continue
Joseph Joseph, Kelvin Truong, Saxon D Smith
the OPCD aims of educating and
informing our readers. 19 / Non-Surgical Therapies for Skin Cancer
Joshua Farrell, Stephen Shumack
In this issue we are introducing the
OPCD podcasts, hosted by Dr Davin 26 / Oral Preventive Therapies in Photodamaged Skin
Lim, to further explore topics of Sarah Hanna, Patricia M Lowe, Andrew C Chen
interest through a series of interviews
35 / Photodynamic Therapy
with opinion leaders and experts.
for Superficial Sun Damage
The journal will now move to a John R Sullivan, Peter D Sharpe
triannual publication schedule: March,
42 / Energy-Based Devices
July and November issues. We are for Treatment of Photodamaged Skin
indeed fortunate to be able to call on Monique Mackenzie, Shobhan Manoharan
local and international Dermatology
colleagues for contributions. In 48 / Commentary: Are Deeper Laser Treatments
particular, we are very grateful to
Advantageous in Treating Solar Dysplasia?
Davin Lim
be able to work with Australian
Dermatologists and their Research 50 / How to Achieve the Best Cosmetic Outcome
Fellows to produce interesting and Treating Actinic Keratoses
relevant content for the journal. Joshua Farrell, Robert Rosen

As we launch this issue, Melbourne

58 / Podcasts
and Sydney have celebrated their
versions of “Freedom Day”, followed  Insights into photodynamic therapy

by a graduated re-opening of & laser assistance
international borders. We hope these John Sullivan
are forward steps towards safe,  Field treatments for solar dysplasia

celebratory and socially interactive Cara McDonald
COVID-normal times.
 Photobiology & photoprotection

Off the back of the success of the first Michelle Wong
two issues of OPCD, we appreciate  Photoaging, cultural viewpoints,

any feedback to help us to continue to and how to spend $1500 to get glowing skin
improve on future editions and meet Saxon Smith
your education needs.  Chemoprevention; oral and topical.

What's the evidence?
Co-Editors in Chief Trish Lowe
Dr Adrian Lim  Chemical peels; why peels trump lasers

Clinical Professor Saxon D Smith Philip Artemi

Australasian Society of Cosmetic Dermatologists / Opinions and Progress in Cosmetic Dermatology VOLUME 01 / ISSUE 03 / NOVEMBER 2021
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 PHOTODAMAGE 1
Photodamage 1
Guest Editorial
Guest Editors: Michael Freeman1,2 and John R Sullivan3,4,5
1. Gold Coast University Hospital, Queensland, Australia
2. The Skin Centre, The Gold Coast, Queensland, Australia
3. Kingsway Dermatology & Aesthetics, Miranda, NSW, Australia
4. The Sutherland Hospital, Caringbah, NSW, Australia
5. School of Medicine, University of NSW, Kensington, NSW, Australia
Correspondence: Michael Freeman  Michael@skincentre.com.au

Freeman M, Sullivan JR. Photodamage 1. Guest Editorial. Opin Prog Cosmet Dermatol 2021;1(3):1.

T
his edition of the journal is the first of two the risk of photodamage. Infrared remains a complex
parts on photodamage. It is well recognised topic as it can be both beneficial and deleterious
that chronic exposure to sunlight is the most depending on breadth of wavelength and dosage.
significant extrinsic risk factor for photoaging, poor
cosmesis and benign and malignant skin lesions. Sarah Hanna et al. clarifies the different oral preventive
Patients and clinicians alike spend a significant amount therapies available for skin cancer chemoprevention.
of time and resources in preventing and treating the These are particularly important for sufferers of
consequences of photodamage. In this issue, readers non-melanoma skin cancer (NMSC) in particular, where
will rediscover the biologic mechanisms of photo reductions in squamous cell carcinoma can be achieved
damage and photoaging together with prevention and with acitretin and nicotinamide by up to 30%. One
the treatment of its dysplastic consequences. would assume the finding of lower vitamin D levels
found in cohorts of NMSC is due to the more extreme
Saxon Smith discusses the historical perspective of photoprotection that has been recommended. Oral
ageing from the pock marked face of Queen Elizabeth antioxidants are covered and the protective evidence
I of England to the realities of self-criticism of facial for leafy green vegetables.
features with Zoom conferences. In Prudence Gramp’s
article, you will be reminded that 80% of ageing signs This issue introduces some of the therapeutic measures
can be increased by photodamage and as much as 50% that can tackle photodamage. Farrell and Shumack
of the total sun exposure prior to the age of 60 occur explore the non-surgical therapies for skin cancer
before the age of 20. including cryotherapy, 5-flurouracil and imiquimod,
which are providing alternative options to patients other
The different wavelengths of UVA and UVB are than the gold standard of surgical excision. John Sullivan
discussed and while both are damaging to the skin, expertly details the nuances of photodynamic therapy
they can have different effects and because of this, and the ability to increase absorption with fractionated
preventative measures need to be considered. CO2 laser and the various modalities to activate the
Prevention is paramount to reduce the effects of protoporphyrin with not just LED lamps but IPL.
photodamage with sun-protection the most important
measure. Sunscreens do not always provide equal We hope this edition provides insight into the
protection against different wavelengths of light mechanisms of photodamage and introduces you to the
which is discussed by Joseph and colleagues in their preventative and treatment options available, which
article, which outlines the different sunscreen options. will be explored further in part two. It is an exciting
When selecting a sunscreen, we have a responsibility time to be in clinical dermatology as we have a new
to consider that Hawaii has banned oxybenzone and understanding of the complexity of the science behind
octinoxate because of studies suggesting adverse photodamage and the different effects of radiation
effects on corals and other aquatic life. types on the skin. We look forward to watching future
research and ongoing evaluation of the multitude
Previously, the effects of visible light and infrared of treatments to broaden our understanding of
radiation were not given much consideration. While photodamage and we hope this aids you to provide
tanning beds are now out of fashion, consumers of better outcomes for your patients.
saunas, that emit infrared light, may need to reconsider

Australasian Society of Cosmetic Dermatologists / Opinions and Progress in Cosmetic Dermatology VOLUME 01 / ISSUE 03 / NOVEMBER 2021 1
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Adverse events should be reported to: Australia - AU-CoolSculpting@Allergan.com or New Zealand - NZ-CoolSculpting@Allergan.com
REFERENCES: 1. Allergan, CoolSculpting® System User Manual. BRZ-101-TUM-EN6-K 2. Levison ME, et al. Inventors; Zeltiq Aesthetic Inc, assignee. Monitoring the cooling of subcutaneous lipid-rich cells,
such as the cooling of adipose tissue. US Patent US8,285,390 B2. Oct 9 2012. 3. O’Neil MP, et al. Inventors; Zeltiq Aesthetics, Inc, assignee. Compositions, treatment systems and methods for improved
cooling of lipid-rich tissue. US Patent US9,861,421 B2. Jan 9 2018. 4. DeBenedictis LC, et al. Inventors. Zeltiq Aesthetics, Inc, assignee. Temperature-dependent adhesion between applicator and skin
during cooling of tissue. US Patent US10,524,956 B2. Jan 7 2020.
THIS PRODUCT MAY NOT BE RIGHT FOR YOU. READ THE WARNINGS BEFORE PURCHASE. WARNINGS CAN BE FOUND BY ASKING YOUR HEALTH PROFESSIONAL FOR THE INSTRUCTIONS
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Numbness can persist for up to several weeks. A sensation of fullness in the back of the throat may occur after submental treatment. Rare side effects such as paradoxical
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The CoolSculpting® procedure is not a treatment for obesity.1
CoolSculpting® and its design are registered trademarks of ZELTIQ Aesthetics, Inc., an Allergan affiliate. ™ Trademark(s) of Allergan, Inc. © 2021 Allergan. All rights
reserved. Allergan Australia Pty Ltd. 810 Pacific Highway, Gordon NSW 2072. ABN 85 000 612 831. Allergan New Zealand Limited, Auckland. NZBN 94 290 3212 0141.
DA2160CB. AN-CSC-2150065 V1. Date of preparation: July 2021
 PHOTODAMAGE 1
Photodamage and Photoaging:
Epidemiology and Pathogenesis
Prudence Gramp1, Michael Freeman1,2
1. Gold Coast University Hospital, Queensland, Australia
2. The Skin Centre, The Gold Coast, Queensland, Australia
Assoc Professor Michael Freeman
Correspondence: Prue Gramp  prudence.gramp@health.qld.gov.au
CLICK IMAGE TO LINK TO VIDEO DUR ATION_01:07
Disclosures: none

OUTLINE: Photoaging is a type of extrinsic ageing caused by chronic exposure of the skin to sunlight (photodamage).
Many of the signs of chronological ageing are shared with photoaging however it is now clear that 80% of ageing signs
can be increased by photodamage. Increased radiation exposure can result from outdoor lifestyle choices such as in
Australia where most of the population resides on the coastlines and the warm climate promotes outdoor living with a high
ultraviolet (UV) index for much of the year. The most significant cause of photoaging is chronic, repeated exposure to UV
radiation. UVB is recognised to be the major risk factor for the majority of skin cancers and UVA is the major risk factor for
photoaging. UV radiation has been shown to cause mitochondrial DNA alterations and epigenetic changes within skin. The
production of reactive oxygen species can cause collagen degradation and remodelling and an increase in proinflammatory
cytokines which leads to many of the visual effects of photoaging. The visual changes of photoaging manifest as fine and
coarse wrinkles, telangiectasias, pigment changes, as well as a loss of tone, translucency, and elasticity. Chronic exposure
to sunlight also increases the risk of benign and malignant skin lesions such as lentigines, senile purpura, actinic keratoses,
basal cell carcinoma, squamous cell carcinoma and melanomas. Infrared radiation has a variable impact on the skin with
small doses causing skin rejuvenation and a photoprotective effect, however large doses can increase photoaging by acting
on fibroblasts and degrading collagen and elasticity. This new understanding of the contributing factors of photoaging will
assist in prevention and treatment and will also prompt new areas for research.

KEYWORDS: photodamage, photoaging, skin ageing, epidemiology, pathogenesis, UV radiation

Gramp P, Freeman M. Photodamage and Photoaging: Epidemiology and Pathogenesis. Opin Prog Cosmet Dermatol 2021;1(3):3-8.

Introduction and remodelling and an increase in proinflammatory

cytokines which leads to many of the visual effects
Photoaging is a type of extrinsic ageing caused by of photoaging. Risk of photodamage and subsequent
chronic exposure of the skin to sunlight (photodamage). photoaging is increased with older age, male sex, fair
The visual changes of photoaging manifest as fine and skin (skin types I to III) and chronic and prolonged sun
coarse wrinkles, telangiectasias, pigment changes exposure over a lifetime.1,2 Increased sun exposure can
as well as a loss of tone, translucency, and elasticity. be a result of residing in cities with high radiation levels
Chronic exposure to sunlight also increases the risk of as well as occupational and recreational activities that
benign and malignant skin lesions such as lentigines, include outdoor exposure.1 The tendency to live on
senile purpura, actinic keratoses, basal cell carcinoma, the coastlines and adopt outdoor lifestyles contributes
squamous cell carcinoma and melanomas which are significantly to increased photoaging in the Australian
cosmetically undesirable and can be life threatening. population.

Ageing of the skin has been shown to be influenced by

many factors including genetics, pollution, smoking, Epidemiology
heavy alcohol use and chronic poor nutrition.1 However,
ultraviolet (UV) radiation and infrared radiation are Genetics and skin type are strong risk factors for
the most significant causes of photoaging and have photoaging, however cumulative sun exposure
been shown to cause mitochondrial DNA alterations remains the most damaging. Sun exposure can occur
and epigenetic changes within skin. The production of from outdoor recreational activities or occupational
reactive oxygen species can cause collagen degradation exposure, however the amount of sun exposure in

Australasian Society of Cosmetic Dermatologists / Opinions and Progress in Cosmetic Dermatology VOLUME 01 / ISSUE 03 / NOVEMBER 2021 3
Photodamage and Photoaging: Epidemiology and Pathogenesis | Gramp and Freeman

PHOTODAMAGE 1
childhood years (often with direct links to location of UV radiation varies depending on the time of day
residence) has been demonstrated to have a strong and latitude of location as the UV index is greater in
influence in photodamage risk later in life. the middle of the day and increases depending on
the proximity to the equator. Australia has one of
It is estimated that around 50% of the total sun the highest levels of UV radiation with Queensland,
exposure prior to the age of 60 occurs before the age Northern Territory and Western Australia having an
of 20 with young people spending more time in the average annual noon-clear sky UV index of between 8
sun than adults.3 Photoaging, melanocytic naevi and and 14 (very high to extreme).8 UV radiation is also at
melanoma rates are higher in Australian compared with its worst when there are reflective surfaces such as
British children, which is thought to be due to increased snow and sand.8 The UV index is typically at its highest
time spent outdoors.3 It is estimated that children of between 11am and 1pm (12pm and 2pm daylight savings
Australia, Europe, Japan, Mexico, UK and USA spent an time), and sun protection is recommended whenever the
average of between 1.5 to 5.1 hours outdoors per day intensity exceeds a rating of 3.8 In Australia the UV index
between 1990 and 2005.3 Studies among Queensland is highest in January with an average of 11 in the whole of
school children showed an average of 1.7 to 3.0 daily Australia and lowest in June and July where it can vary
hours in the sun, with 3.2 to 4.1 hours in some parts widely depending on location with an average of 2 in
of Queensland such as Nambour.3,4 Male sex has also Tasmania and 9 in far northern Australia.8 The regions
been recognised as a risk factor which is supported by in the world with the highest UV index are those that lie
a Queensland study showing boys spent 28% more time closest to the equator including many South American
in the sun than girls.3 countries such as Peru, Chile and Argentina.9

After adjusting for confounding factors such as skin

type and age, severity of photoaging has been linked Signs and assessment of photoaging
with high rates of sun exposure as well as multiple
episodes (>10) of sunburning.5 Damage to the skin in Diagnosis and assessment of severity of photoaging
childhood may not be seen for many years but after the can be evaluated with histological analysis that shows
age of 30 there is a rapid advance in photoaging signs dermal elastosis: a pathological degenerative change
with an estimated 14% risk of more severe photoaging which occurs from increased elastin accumulation and
signs for every year of age after 30.3 collagen breakdown.2,10 There can also be epidermal
atrophy and a thinning of the spinous layer.1
Ethnicity influences type and extent of photoaging
with multiple studies showing that while Asian women A less invasive and more common method to evaluate
develop wrinkles at a later age than European women extent of photoaging is through clinical examination
with the same sun exposure, they exhibit an earlier and photomapping of visual signs.11 A French study from
onset of pigmentation changes.6,7 2013 developed standardised photographic scales to
allow for objective evaluation of photoaging signs on the
face.12 The Glogau photo-damage/wrinkle classification
scale is a simplified scale to help clinicians quickly
identify levels of skin ageing (see figure 1).13

Figure 1. Glogau Photoaging and Wrinkle Classification Scale13

Type I Mild Expected age No wrinkles Early photoaging, minimal wrinkles, mild pigment changes,
28-35 years no keratoses

Type II Moderate Expected age Wrinkles in motion Early-moderate photoaging, wrinkles induced by movement,
35-50 years some pigmentation changes, mild skin texture changes, early
actinic keratoses

Type III Advanced Expected age Wrinkles at rest Advanced photoaging, wrinkles present at rest, prominent
50-65 years pigmentation changes, telangiectasias, actinic keratoses

Type IV Severe Expected age Only wrinkles Severe photoaging, widespread wrinkles, yellow/grey skin
65-70 years + discolouration, pigmentation changes, actinic keratoses
+/- cancerous lesions

Australasian Society of Cosmetic Dermatologists / Opinions and Progress in Cosmetic Dermatology VOLUME 01 / ISSUE 03 / NOVEMBER 2021 4
Photodamage and Photoaging: Epidemiology and Pathogenesis | Gramp and Freeman

PHOTODAMAGE 1
Skin type influences the extent and type of photoaging Dermatoporosis is a process that leads to chronic
signs. Fine lines (rhytides) are more commonly found cutaneous insufficiency and its causes are multifactorial
with Fitzpatrick skin types I and II while deep wrinkles with photoaging being a contributor. Patients with
are more common in skin types III and IV.2 In Caucasian dermatoporosis have very fragile skin and suffer from
people photoaging can also be classified as hypertrophic senile purpura, stellate pseudoscars and wound healing
(more likely in type III or IV) and atrophic (more likely in issues.14
type I and II) (see Figure 2).14
Figure 3. Photoaging signs12

Figure 2. Hypertrophic and atrophic photoaging skin types14

Pigmentation Hyperpigmentation
Photoaging  hole face pigmentation however
W
Hypertrophic Atrophic
signs most pronounced in the lower part of
the face, the outer lateral maxilla and
Pigmentation Dyschromia Focal
the malar area
hypopigmentation

Texture Leathery Smooth Melasma

 V exposure contributes to the
U
Wrinkles Coarse wrinkles Minimal or fine development of melasma with an
lines increase in melanin deposition
Vascular Minimal changes Telangiectasia
Dyschromia
Dysplastic Minimal changes Common: Solar  neven patches of skin colour of
U
keratoses, BCC, hyper or hypopigmentation including
SCC guttate hypomelanosis
Fitzpatrick Type III or IV Type I or II  ost pronounced in the lower third of
M
Skin Type the face

Wrinkles Fine and coarse wrinkles

While there are many signs of skin ageing it has
been estimated that 80% of visual skin ageing Upper lip – vertical lines
signs are attributable to or increased with UV Lower lip – from corner of lower lip,
exposure (see Figure 3).12 A study which evaluated directing towards the chin
298 Caucasian women with a standardised visual
Cheeks – course wrinkles with random
scale implemented by 12 dermatologists found that
direction, no connection with lines of
increased pigmentation was more prominent with
muscular structure
greater sun exposure, demonstrating a statistically
significant risk.12 Pigmentation changes can include Jawline – course wrinkles/folds
hyperpigmentation, hypopigmentation, dyschromia and extending from subauricular along the
lines of the neck
melasma. Photodamage has also been shown to cause
solar lentigos due to an increase in melanocytes and
Solar Elastosis Thickening, yellowing, coarsely wrinkled
production of melanin in sun exposed areas, especially
skin due to increased deposition of
on the dorsum of the hands or the face.15
elastin

It has been demonstrated that changes in skin texture Texture Deposition of elastin and breakdown of
and an increase in wrinkles are associated with both collagen can be perceived as coarseness
increased sun exposure and chronological ageing.12 or fine nodularity
The extracellular matrix of the dermis consists of elastic
Upper-lip – thickened, accentuated
fibres and collagens (mostly type I and III) which give
microrelief
it strength and provides structure. The loss of parts of
this extracellular matrix, most prominently collagen, Cheeks – dryness or leathery texture
leads to wrinkling of the skin. Photoaging causes an Chin – thickened or dimpled appearance,
increase in both fine and course wrinkles as well as accentuated microrelief
making the microrelief more pronounced, giving the
skin a leathery feel.2,12 Vascular Telangiectasias (broken capillaries)
– small linear red blood vessels
Vascular changes such as telangiectasia are a common
skin ageing sign but the cause is multifactorial including Dermatoporosis Chronic cutaneous insufficiency/atrophy
smoking and photodamage. Chronic photodamage has Fragile skin, senile purpura, stellate
been shown to disrupt normal vasculature of the skin pseudoscars, wound healing issues
and show an increase in telangiectasias.16,17

Australasian Society of Cosmetic Dermatologists / Opinions and Progress in Cosmetic Dermatology VOLUME 01 / ISSUE 03 / NOVEMBER 2021 5
Photodamage and Photoaging: Epidemiology and Pathogenesis | Gramp and Freeman

PHOTODAMAGE 1
Pathophysiology This is consistent with clinical findings which find that
pigmentation disorders have the highest correlation
Ultraviolet radiation with heavy sun exposure.12
UV radiation from sunlight is comprised of UVA (320-
400 nm), UVB (280-320 nm), and UVC (200-290 nm). Vascular changes have also been recognised as a sign
UVC, which is highly damaging to skin does not reach of photoaging. Acute exposures to UV radiation and
the earth’s surface as it is absorbed by ozone and infrared cause an increase in vascular endothelial
moisture.18 Of the UV radiation that does reach the skin, growth factor which promotes skin angiogenesis.27
95% is UVA while 5% is UVB.18 UVB, due to its short These newly formed blood vessels are immature
wavelength, is absorbed in the epidermis and can cause however and have increased permeability leading
sunburn, immunosuppression and is carcinogenic. UVA to increased inflammation. Over time this increased
has a longer wavelength and is able to penetrate to the inflammation is thought to be a contributor to the
dermis. UVA radiation can cause tanning abd sunburn decreased dermal vasculature in chronically photoaged
and has recently been recognised as a major cause of skin and chronically damaged skin is also associated
photodamage and photoaging.19 UVA is not blocked with the development of telangiectasias.17,27
by glass or clouds and has less variability throughout
daylight hours.17 UVB is considered to be the main cause Infrared radiation
of the majority of skin cancers and UVA is understood Until recently, most photoaging was considered
to have a significant role in both photoaging and the attributable to UV radiation. It has been suggested that
formation of some skin cancers.17 Sunbeds for artificial chronic low-dose exposure to longer wavelengths such
tanning exposes users to large amounts of UVA as well as infrared radiation may contribute to the age-related
as UVB and have not only been shown to increase risk volume changes in the face.28 Severe skin aging may
of skin cancer but are also implicated in pre-mature develop on those exposed to chronic infrared sources
photoaging.20 due to professions such as on bakers’ arms because
of exposure to hot ovens and on the faces of glass
Cumulative UV radiation causes photoaging by direct blowers.29
cellular damage and production of reactive oxygen
species.18 Chromophores absorb UV radiation in the Recent research is looking into the effects of infrared
skin and include melanins, DNA, urocanic acid and radiation (also known as thermal radiation) and visible
amino acids.21 When UV radiation is absorbed, reactive light in photoaging. Kim et al. showed that chronic
oxygen species including singlet oxygen are produced repetitive exposure to heat via infrared radiation also
which causes a cascade of events involving alteration of leads to skin wrinkling in mice.30 The fluence was
mitochondrial DNA in fibroblasts and keratinocytes, and far higher than natural irradiance; the dose was the
an increase in the action of matrix metalloproteinase equivalent to 31/2 hours of natural infrared radiation
(MMP).18,22,23 This unregulated increase in MMP causes exposure 5 days a week for 15 weeks.
destruction of collagen types I and III, a reduction in
skin elasticity and a resultant increase in wrinkling of Infrared radiation comes from both natural sources
the skin.22,23 such as sunlight (of the solar energy that reaches
the skin infrared A, B, and C make up about 40% of it
DNA also suffers from direct effects when it absorbs and about 40% of that represents IR-A) and fire, and
UVB photons. This causes nucleotide rearrangements artificial sources such as heaters, tanning beds, lamps
which activates the nucleotide excision repair and saunas.31 Visible light comprises 39% of solar energy
pathway.19 Some people have a deficiency in the 9 major that reaches the skin. Due to the longer wavelengths
proteins in this pathway and incomplete repair leads in infrared radiation (760 nm-1 mm) and visible light
to cellular dysfunction and increased photoaging.19 It (400-760 nm) there is deeper penetration into the skin
has recently also been demonstrated in mouse models layers, reaching to the deep dermis and subcutaneous
that UV radiation can shorten telomeres that cap and affecting cells involved in the extracellular
chromosomes in stem cells in the skin.24 Shortening matrix of the skin such as fibroblasts.22 The effects of
of telomeres leads to cell senescence (cell cycle arrest infrared radiation in the skin can be both beneficial
and dysfunction) and apoptosis (cell death) which and deleterious depending on breadth of wavelength
gives weight to the theory that UV radiation causes and dosage.
photoaging through stem cell depletion.19,24
Controlled exposure to low intensity infrared radiation
UV radiation has been linked with pigmentation (also known as photobiomodulation) has been used
disorders such as melasma through direct and indirect to improve wound healing and tissue regeneration, to
processes that cause an increase in melanin. Visible treat pain and stiffness of rheumatoid arthritis, and to
light upregulates opsin 3 which causes an increase in encourage neural stimulation.32 It is believed that this
melanin stimulating hormone receptor activity in the controlled level of near infrared bands promotes tissue
epidermis resulting in greater melanin deposition.25,26 changes due to the light exposure, without the thermal

Australasian Society of Cosmetic Dermatologists / Opinions and Progress in Cosmetic Dermatology VOLUME 01 / ISSUE 03 / NOVEMBER 2021 6
Photodamage and Photoaging: Epidemiology and Pathogenesis | Gramp and Freeman

PHOTODAMAGE 1
effects.32 It has been demonstrated in acute controlled Conclusion
exposure that infrared radiation stimulates collagen
production and improves elasticity in the skin.33 A Recent research has led to a greater understanding
sub-division of infrared radiation (far infrared radiation, of the risks and causes associated with photoaging.
FIR, 3-25 μm), has also been observed to stimulate Multiple contributing factors have been identified
cells and tissue in both in vitro and in vivo studies.34 within the literature. Chronic repeated exposure to UV
Moreover, FIR therapy is considered a promising light and infrared A radiation causes photodamage over
treatment modality for insomnia and arthritis.35 a lifetime that leads to photoaging. Photoaging results
in distinct changes in the skin including wrinkling,
Environmental infrared radiation which has a wider pigmentation, vascular and texture changes, and loss of
spectrum is now being heavily researched as it is tone and elasticity. Many of the signs of chronological
implicated as a contributor to skin ageing. Infrared ageing are shared with photoaging however it is now
radiation causes production of reactive oxygen species clear that 80% of ageing signs can be increased by
which, in small amounts, has a rejuvenating effect and photodamage. UV radiation leads to direct DNA damage
some protective effects against UV radiation damage.32 and the loss of extracellular matrix, most prominently
However larger amounts and chronic exposure to collagen types I and III, which leads to wrinkling of
reactive oxygen species can be degenerative to the skin. Photodamage causes significant pigment
the skin.32 Similar to UV radiation, chronic infrared changes in the skin due to an increased deposition of
radiation increases MMP which results in a reduction melanin. Epigenetic changes have been demonstrated
in collagen types I and III and further reduction in skin with increased UV radiation exposure, however the
elasticity.22,23 The direct contribution of heat energy implication of this is difficult to ascertain. Infrared A
from infrared further increases MMP but also promotes radiation has a variable impact on the skin with small
angiogenesis resulting in chronic vascular changes.23 doses causing skin rejuvenation and a photoprotective
Long term exposure to environmental infrared effect, however large doses can increase photoaging
radiation is now being considered a likely contributor by acting on fibroblasts and degrading collagen and
to photoaging. It appears that lower irradiance elasticity. UVB is recognised to be the major risk
(< 50 mW/cm2 - approximately half of the sun’s mid-day factor for the majority of skin cancers and UVA is the
fluence) is less likely to induce skin hyperthermia major risk factor for photoaging, although they both
which would otherwise lead to potential deleterious contribute to either effect. This new understanding
effects.36 Thus avoidance of prolonged middle of the of the contributing factors of photoaging will assist in
day exposures would seem prudent. prevention and treatment and will also prompt new
areas for research.
Epigenetic changes
Recent studies have been exploring the possibility that
UV radiation can cause epigenetic changes in epithelial References
cells which are permanent, heritable alterations to the
genetic material. With the differentiation of cells, DNA 1. Chien A and Kang A. Photoaging. UpToDate. [Online] July 2021
at: https://www.uptodate.com/contents/photoaging
methylation is a requirement for the many different
functions of cells in the skin. Methylation of DNA causes 2. Green A, Hughes M, McBride P, Fourtanier A. Factors associated
with premature skin aging (photoaging) before the age of 55: a
an alteration of gene expression and can change the
population-based study. Dermatology. 2011;222(1):74-80.
function of the cell, often by suppression. A recent
3. Green A, Wallingford S, McBride P. Childhood exposure to
systematic review by de Oliveira and colleagues found
ultraviolet radiation and harmful skin effects: epidemiological
that UV radiation can cause hypermethylation of some of evidence. Prog Biophys Mol Biol. 2011;107(3):349-55.
the tumour suppressor genes (such as p16 and RASSF1)
4. Gies P, Roy C, Toomey S, MacLennan R, Watson M. Solar UVR
and hypomethylation of oncogenes (such as WNT1).37 exposures of primary school children at three locations in
This resulted in a decrease in tumour suppression gene Queensland. Photochem Photobiol. 1998;68:78–83.
activity and an increase in oncogene expression, which 5. Lucas R, Ponsonby A, Dear K, Taylor B, Dwyer T, McMichael A,
overall increases the risk of malignancy.37 Some of the et al. Associations between silicone skin cast score, cumulative
studies in this review demonstrated that individuals who sun exposure, and other factors in the Ausimmune study:
had a disruption of the DNA methylation homeostasis a multicenter Australian study. Cancer Epidemiol. Biomark
Prevent. 2009;18:2887–94.
in the epidermis and dermis also had a concurrent
increase in photoaging signs. Others, however, did not 6. Nouveau-Richard S, Yang Z, Mac-Mary S, Li L, Bastien P, Tardy I,
et al. Skin ageing: a comparison between Chinese and European
demonstrate evidence that global methylation was
populations. A pilot study. J Dermatol Sci. 2005; 40(3):187-93.
disrupted with UV radiation.37 Because light is used as
7. Vierkötter A, Krutmann J. Environmental influences on skin
a therapy in dermatology and is needed for vitamin
aging and ethnic-specific manifestations. Dermatoendocrinol.
D production, further research in epigenetic changes 2012;4(3):227-31.
would be of benefit.

Australasian Society of Cosmetic Dermatologists / Opinions and Progress in Cosmetic Dermatology VOLUME 01 / ISSUE 03 / NOVEMBER 2021 7
Photodamage and Photoaging: Epidemiology and Pathogenesis | Gramp and Freeman

PHOTODAMAGE 1
8. Bureau of Meteorology. Average solar ultraviolet (UV) Index. 29. Cho S, Shin M, Kim Y, Seo JE, Lee Y, Park C, et al. Effects of
2016. [Online] August 2021 at: http://www.bom.gov.au/jsp/ infrared radiation and heat on human skin aging in vivo. J
ncc/climate_averages/uv-index/index.jsp Investig Dermatol Symp Proc. 2009:14(1):15-9.
9. Liley B, McKenzie R. Where on Earth has the highest UV. 30. Kim H, Lee M, Lee S, Kim K, Cho K, Eun H, et al. Augmentation
National Institute of Water and Atmospheric Research (NIWA). of UV-induced skin wrinkling by infrared irradiation in hairless
2006. [Online] August 2021 at: https://www.researchgate.net/ mice. Mech Ageing Dev. 2005;126(11):1170-7.
publication/306157374_Where_on_Earth_has_the_highest_UV
31. Holzer A, Athar M, Elmets C. The Other End of the Rainbow:
10. Wright B. Elastosis. Dermnet. 2012. [Online] August 2021 at: Infrared and Skin. J Invest Dermatol. 2010:130(6):1496-9.
https://dermnetnz.org/topics/elastosis/
32. Tsai S, Hamblin M. Biological effects and medical applications of
11. Marks R, Edwards C: The measurement of photodamage. infrared radiation. J Photochem Photobiol B. 2017:170:197-207.
Br J Dermatol 1992;127:7–13.
33. Tanaka Y, Matsuo K, Yuzuriha S. Long-term evaluation of
12. Flament F, Bazin R, Laquieze S, Rubert V, Simonpietri E, Piot B. collagen and elastin following infrared (1100 to 1800 nm)
Effect of the sun on visible clinical signs of aging in Caucasian irradiation. J Drugs Dermatol. 2009;8(8):708-12.
skin. Clin Cosmet Investig Dermatol. 2013;6:221-32.
34. Vatansever F, Hamblin M. Far infrared radiation (FIR): its
13. Glogau R. Glogau Wrinkle Scale. Glogau Dermatology. [Online] biological effects and medical applications. Photonics Lasers
Aug 2021 at: https://sfderm.com/glogau-wrinkle-scale/ Med. 2012:4:255-66.
14. Ayer J. Skin Ageing. Dermnet. 2018. [Online] Aug 2021 at: 35. Inoue S, Kabaya M. Biological activities caused by far-infrared
https://dermnetnz.org/topics/ageing-skin/ radiation. Int J Biometeorol. 1989:33(3):145-50.
15. Bolognia J, Jorizzo J, Schaffer J. Chapter 112, Benign Melanocytic 36. Barolet D, Christiaens F, Hamblin M. Infrared and skin: Friend or
Neoplasms. Dermatology. 3rd edition. 2012. Harold S Rabinovitz foe. J Photochem Photobiol B. 2016:155:78-85.
and Raymond L Barnhill. Pages 1854-55.
37. de Oliveira NFP, de Souza BF, de Castro Coêlho M. UV Radiation
16. Chung JH, Yano K, Lee MK, Youn CS, Seo JY, Kim and Its Relation to DNA Methylation in Epidermal Cells: A
KH, et al. Differential Effects of Photoaging vs Intrinsic Review. Epigenomes. 2020;4(4):23.
Aging on the Vascularization of Human Skin. Arch
Dermatol. 2002;138(11):1437–42.

17. Dermnet. Ageing Skin CME. Dermnet. 2008. [Online] Aug 2021
at: https://dermnetnz.org/cme/lesions/ageing-skin/

18. McDaniel D, Farris P, Valacchi G. Atmospheric skin

aging-Contributors and inhibitors. J Cosmetic Dermatol.
2018;17(2):124-37.

19. Panich U, Sittithumcharee G, Rathviboon N, Siwanon J.

Ultraviolet Radiation-Induced Skin Aging: The Role of DNA
Damage and Oxidative Stress in Epidermal Stem Cell Damage
Mediated Skin Aging. Stem Cells International. 2016:7370642.

20. Cancer Council. Solariums. Cancer Council Australia. Skin

Cancer Statistics and Issues. 2021. [Online] Aug 2021 at:
https://wiki.cancer.org.au/skincancerstats/Solariums

21. Young A. Chromophores in human skin. Phys Med Biol.

1997;42(5):789-802.
22. Calles C, Schneider M, Macaluso F, Benesova T, Krutmann J,
Schroeder P. Infrared A Radiation Influences the Skin Fibroblast
Transcriptome: Mechanisms and Consequences. J Invest
Dermatol. 2010:130(6):1524-36.

23. Schroeder P, Lademann J, Darvin M, Stege H, Marks C, Bruhnke

S, et al. Infrared Radiation-Induced Matrix Metalloproteinase
in Human Skin: Implications for Protection. J Invest Dermatol.
2008:128(10):2491-7.

24. Stout G, Blasco M. Telomere length and telomerase activity

impact the UV sensitivity syndrome xeroderma pig-mentosum
C. Cancer Res. 2013:73(6):1844–54.

25. Bolognia J, Murray M, Pawelek J. UVB-Induced Melanogenesis

May Be Mediated Through the MSH-Receptor System. J Invest
Dermatol. 1989:92:651-6.

26. Tran A, Nguyen D, Vaidya S. Melasma Pathogenesis. Opinions

and Progress in Cosmetic Dermatology. 2020:1(1):12-14.

27. Chung J, Eun H. Angiogenesis in skin aging and photoaging. J

Dermatol. 2007;34:593–600.

28. Goodman G, Armour K, Kolodziejczyk J, Santangelo S, Gallagher

C. Comparison of self-reported signs of facial ageing among
Caucasian women in Australia versus those in the USA, the UK
and Canada. Australas J Dermatol. 2018;59(2):108-17.

Australasian Society of Cosmetic Dermatologists / Opinions and Progress in Cosmetic Dermatology VOLUME 01 / ISSUE 03 / NOVEMBER 2021 8
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 PHOTODAMAGE 1
A Historical Perspective on
the Evolution of Ageing
Saxon D Smith1,2
1. Discipline of Dermatology, Sydney Medical School, The University of Sydney, New South Wales, Australia
2. The Dermatology and Skin Cancer Centre, St Leonards, New South Wales, Australia
Correspondence: Saxon D Smith  dr.saxon.smith@gmail.com
Disclosures: none

KEYWORDS: ageing, historical perspective, tanning, cosmetic, selfie

Smith SD. A Historical Perspective on the Evolution of Ageing. Opin Prog Cosmet Dermatol 2021;1(3):10-11.

P
hotoageing and antiageing is big business in 2021. With the advent of the industrial age, the classes and
There are topical therapies, oral therapies, and distribution of wealth shifted, with the middle classes
device-based therapies to attempt to prevent or thriving. This resulted in larger populations having
repair the damage that ultraviolet rays (UVR) have on access to disposable incomes as well as technology
our skin throughout our lifetime. However, the focus bringing down the price of cosmetics; affording people
on the role of UVR in ageing of the skin is a relatively to holiday, often by the seaside. This saw a dramatic
new concept in recent decades and associated with an shift away from the ‘peaches and cream’ complexion as
accelerated consciousness in the age of ‘The Selfie’. the sign of social stature, towards a ‘healthy tanned’ skin
indicating the ability and financial means to holiday and
For centuries, there was a classist distinction by the pursue idle outdoor activities.
complexion of one’s face. The aristocracy and the
wealthy class strived for a porcelain appearance to their In the 1960s, especially in countries like Australia and
skin and differentiation from the sun beaten, outdoor- New Zealand, idle play and outdoor activities were
working lower classes. The skin of the upper classes was commonplace. The clothing worn to pursue these
not necessarily naturally a smooth milky complexion activities covered less and less skin, exemplified by
but rather more often achieved through the thick the advent of bikinis and Speedo briefs. Tanning had
application of lead-based foundation. In fact, Queen become largely a national occupation with a plethora
Elizabeth I of England had very pockmarked skin and of commercial brands and homemade concoctions to
was famous for her religious application of “Venetian promote the tanning process.
ceruse”, a mixture of vinegar and lead. However, this
pursuit of long-term beauty was the cosmetic’s use of However, the relationship between UVR exposure and
white lead as its base pigment, potentially leading to skin cancer risk gradually became part of the social
poisoning, damaging the skin, causing hair loss, and if vernacular with the introduction of public health
used over an extended period could cause death.1 campaigns advocating the need to ‘slip, slop, slap’
in the 1980s. As an adjunct to this, individuals were
By the 1800s in Europe and the UK, there had been becoming more concerned with the appearance of
a move away from makeup and a ‘naturally’ clear their skin as they aged and sought more therapeutic
complexion became the ideal. Young upper-class options to remedy the impact of photoageing on their
women were directed to stay out of the sun as a way skin. Although the use of sunscreens when outdoors
by which to encourage a porcelain skin.2 They might remained ado and family dependent.
bathe a few times a month to encourage a natural light
rouge tinge to their cheeks. On the other hand, makeup By the late 2000s it had been well established that UV
was still an expensive option for the lower classes who exposure is likely to contribute up to 80% of visible signs
would make do with red tissue paper, extracting the red of ageing in the skin including wrinkling.3 Antiageing
dye to lightly apply to their cheeks.2 products and treatments had become more affordable
and accessible with the role of retinoids and retinols
becoming popular to help repair photodamaged skin.4

Australasian Society of Cosmetic Dermatologists / Opinions and Progress in Cosmetic Dermatology VOLUME 01 / ISSUE 03 / NOVEMBER 2021 10
A Historical Perspective on the Evolution of Ageing | Smith

PHOTODAMAGE 1
Currently, we live in the age of digital cameras in References
everyone’s pocket; accompanied by the belief that
an event never happened unless a selfie was taken 1. St Clair K. The secret lives of colour. London: John Murray;
2016. 45–46 p.
and uploaded to one’s various social media platforms.
However, the raw selfie itself is rarely enough unless it 2. Montez L. The arts of beauty or, secrets of a lady’s toilet, with
hints to gentlemen on the art of fascinating. New York: Dick
has had numerous filters to ‘perfect’ the image. Now, this
Fitzgerald; 1858. 48-49 p.
has been further exacerbated by COVID-19 leading to
3. Grant WB. The effect of solar UVB doses and vitamin D
Zoom meetings being the norm. This has made us even
production, skin cancer action spectra, and smoking in
more aware of perceived imperfections as we regularly explaining links between skin cancers and solid tumours. Eur J
see ourselves in the ‘gallery’ of Zoom attendees. Cancer 2008;44:12–15.

4. Varani J, Warner RL, Gharaee-Kermani M, Phan SH, Kang

S, Chung JH, et al. Vitamin A antagonizes decreased cell growth
and elevated collagen degrading matrix metalloproteinases and
stimulates collagen accumulation in naturally aged human skin.
J Invest Dermatol 2000;114:480-486.

Australasian Society of Cosmetic Dermatologists / Opinions and Progress in Cosmetic Dermatology VOLUME 01 / ISSUE 03 / NOVEMBER 2021 11
 PHOTODAMAGE 1
Photoaging and Sunscreens
Joseph Joseph1, Kelvin Truong2, Saxon D Smith3, 4
1. Australian General Practice Training Program, Lower Eastern New South Wales, Sydney, Australia
2. Westmead Hospital Dermatology Department, Sydney, New South Wales, Australia
3. Discipline of Dermatology, Sydney Medical School, University of Sydney, New South Wales, Australia
4. The Dermatology and Skin Cancer Centre, St Leonards, New South Wales, Australia
Correspondence: Saxon D Smith  dr.saxon.smith@gmail.com
Disclosures: none

KEYWORDS: photoaging, sunscreens, infrared radiation, ultraviolet radiation, visible light

OUTLINE: Aging is an inevitable part of life and the skin is not spared in this process; however, premature skin aging is an
undesirable, preventable, and treatable condition. Sun exposure leads to the most significant premature aging of the skin,
known as photoaging, and will be the focus of this review. Although traditionally ultraviolet (UV) light has been implicated in
most of the deleterious effects of sunlight, including photoaging, visible light and infrared light also have a role to play.

UV radiation, visible light and infrared radiation have been shown to cause photoaging through mechanisms involving
the generation of reactive oxygen species (ROS), inflammatory pathway activation and matrix metalloproteinase (MMP)
activation which lead to collagen degradation and abnormal elastin deposition. Sunscreens provide adequate protection
against UVB light with broad-spectrum sunscreens providing UVA protection. There are limited options for the protection
against visible light and infrared radiation and studies have focused on additives such as iron oxide and antioxidants for
each condition, respectively.

Photoaging exacerbates the natural aging process and leads to unattractive skin changes such as deep wrinkles, thickened
skin, roughness and pigmentation abnormalities. Employing a sun smart routine is essential to prevent this. This involves
seeking shade when outdoors, wearing protective clothing, hats, sunglasses and most importantly, the application of
a broad-spectrum high sun protection factor (SPF) sunscreen. Visible light and infrared radiation also have a role and
strategies to protect against their effects are in infancy. Further research is important to provide a reliable answer regarding
their efficacy and methods to demonstrate this.

Joseph J, Truong K, Smith SD. Photoaging and Sunscreens. Opin Prog Cosmet Dermatol 2021;1(3):12-17.

Introduction is anchored on the use of sunscreens and sun avoidance

by either remaining under cover, indoors or using hats
Aging is an inevitable part of life and the skin is not and garments that cover most of the skin. This type of
spared in this process; however, premature skin aging advice is often poorly received, especially in a country
is an undesirable, preventable, and treatable condition. like Australia, where there is a culture of deliberate
The causes of skin aging are broadly split into intrinsic tanning and sun exposure despite well-known risks
and extrinsic aetiologies. Intrinsic causes are difficult to of skin cancer and photoaging.3 This review aims to
prevent; they are genetically determined and represent summarise current knowledge of photoageing, the use
the degradation process of the entire body.1 Extrinsic of sunscreens and future trends in this field.
causes are where prevention and treatment have a
critical role and include smoking, diet, stress, sleep,
environmental pollution and most importantly, sun Photoageing
exposure. Sun exposure leads to the most significant
premature aging of the skin, known as photoaging, Photoageing refers to the phenotypic changes in
and will be the focus of this review. Almost all parts of skin that occur in addition to the effects of intrinsic
the electromagnetic spectrum have been implicated in chronological ageing. Intrinsic aged skin leads to
photoaging including ultraviolet (UV)B, UVA, visible light atrophy, fine wrinkling and dryness; this is compared
and infrared radiation (Table 1).2 Preventing photoaging to the photoaged skin which has deeper wrinkling,

Australasian Society of Cosmetic Dermatologists / Opinions and Progress in Cosmetic Dermatology VOLUME 01 / ISSUE 03 / NOVEMBER 2021 12
Photoaging and Sunscreens | Joseph, Truong, and Smith

PHOTODAMAGE 1
a thickened epidermis, laxity, dullness, roughness and to increased absorption in melanin pigment of cells.12
pigment abnormalities.4 Sunlight is the primary extrinsic Visible light does not directly damage the DNA and has
factor that can expedite the molecular changes that not been shown to increase the levels of inflammatory
lead to skin ageing and each part of the electromagnetic cytokines that UV does;13 moreover, the levels of ROS
spectrum has a role to play in this process.2 that form are far lower when compared to UV radiation,
especially in lighter-skinned individuals (Fitzpatrick
UV radiation type II or less).14 Although its effect is not as potent as
UV radiation comprises of UVC (100-290nm) which has UV, it is still worth considering the role of visible light in
the highest energy but is absorbed by the atmosphere; photoageing, especially in darker-skinned patients.
UVB (290-320nm) and UVA (320-400nm), which is
further split into UVA2 (320-340nm) and UVA1 (340- Infrared light
400nm). UV radiation poses a significant health burden Infrared radiation (IR) occurs at the electromagnetic
as it is a primary cause of DNA damage that leads to wavelengths between 700nm to 1mm and is further
cell death, photoageing and oncogenesis.2 UVB forms divided into IR-A (700-1400nm), IR-B (1400-3000nm)
the minority of UV light that reaches the skin (5%) and and IR-C (3000nm-1mm). It accounts for half of
penetrates into the upper dermis contributing mostly the radiation that reaches the earth and shorter
to oncogenesis whereas UVA is the majority (95%), wavelengths can penetrate deep into the skin; IR-A
penetrates deeper into the dermis and exerts a more can infiltrate as deep as the subcutaneous tissue and
potent photoageing effect.5 Mechanisms of UV induced 65% reaches the dermis15 whereas IR-C is absorbed in
photoageing include increased expression of matrix the epidermis and increases its temperature.16 IR-A is a
metalloproteinases (MMPs) including collagenase (MMP- potent regulator of gene expression in skin cells and has
1), gelatinase (MMP-9) and stromelysin (MMP-3). These been shown to be involved in photoageing by eliciting
are zinc-dependent endopeptidases that degrade skin a molecular response similar to UV radiation.16 The
collagen and lead to impaired structural integrity and mechanism, however, is different with the formation
accumulation of abnormal elastic fibres in the dermal of mitochondrial ROS in skin fibroblasts that lead to
connective tissue.6 Moreover, UV light is absorbed by increased membrane permeability, apoptotic pathway
chromophores in the skin cells which generate reactive activation and MMP-1 activation, which as a whole lead
oxygen species (ROS) that have multiple effects. ROS to dermal collagen breakdown and abnormal elastin
are volatile and unstable molecules that need to oxidise deposition.15 IR-A radiation has also been shown to
nearby molecules to become stable. In the absence of cause cutaneous neoangiogenesis which is a prominent
endogenous antioxidants, ROS may directly damage feature of photoaged human skin.17 Finally, despite its
lipids, amino acids, and DNA. The proposed mechanism potential harmful effects, IR-A has been successfully
in the context of UV-induced photoageing is the release used therapeutically to treat sclerotic skin lesions or
of proinflammatory cytokines and activation protein-1 stimulate wound healing and further research into
(AP-1) and nuclear factor-κB (NF-κB) which up-regulate its therapeutic properties is important, much like the
key MMPs.7 Furthermore, UV-induced ROS have been therapeutic properties of UV radiation in inflammatory
shown to decrease transforming growth factor–β dermatoses.18
expression, which decreases collagen production
and enhances elastin production, contributing to
photoageing.8 ROS may also activate enzymatic and Sunscreens
non-enzymatic cellular responses, and interfere with
gene expression.9 Since complete avoidance of the sun is not a practical
approach, sunscreens are a critical measure in the
Visible light prevention of photoageing and have the additional
Visible light exists between the electromagnetic benefits of preventing sunburns, reducing mutagenesis
wavelengths of 400-700nm. It comprises 40% of and preventing skin cancer. The main protection
solar radiation that reaches the earth and can lead conferred by sunscreens is towards UVA and UVB and
to dermatological issues such as solar urticaria, there are limited mainstream options for the damage
photoallergic skin reactions, porphyrias and caused by visible light and IR-A radiation.
pigmentation issues.10 Visible light, especially at the
higher energy blue spectrum, has been shown to induce UV protection
oxidative damage in vitro11 leading to the production of Good UV protection requires uniform protection across
ROS and MMP-1 activation.2 These damage the collagen the UVA and UVB range, an SPF and cosmetic elegance
and lead to the deposition of disorganised elastin which will enhance compliance.19 It is important to
that causes the clinical phenotype of photoaged skin. have uniform protection across the UV range because
Melanin pigment protects darker-skinned individuals even though UVB rays are higher energy, cause more
(Fitzpatrick IV or more) against the effect of UV erythema and may induce more DNA damage, the
radiation, however, it has been shown that visible light absolute amount of UVA that reaches the skin is much
may have more of an effect in these individuals due higher and therefore substantially contributes to

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Photoaging and Sunscreens | Joseph, Truong, and Smith

PHOTODAMAGE 1
the deleterious effects of UV radiation overall.19 UV claims of effectiveness could be misleading.18 Since
protection in sunscreens is conferred by UV filters IR-A penetrates deep into the dermis, systemic delivery
which must be efficacious (absorb UV light within the of antioxidants via dermal vasculature through oral
range of 290-400nm), safe and registered. These filters supplementation is also an option to consider. There
include inorganic particulate materials such as titanium are no major studies known to the authors that validate
dioxide and zinc oxide which absorb UV energy through this strategy in IR-A radiation. Moreover, ROS are
their semiconducting properties.19 They also include important in the homeostasis of human physiological
organic particulate UV filters which absorb energy systems, especially in the maintenance of cellular
through electrons in their aromatic rings, a process function and integrity. There exists a balance between
which is described in detail by Herzog.20 The UV filters adequate and excessive antioxidants and the effects
used in Australian sunscreens are summarised in on normal physiological function.23 It is for this reason
Table 2. The SPF is a measure of sunscreen protection that the use of antioxidants at supraphysiological
against the effects of UVB – it measures the time concentrations may adversely affect physiological
taken until the minimal erythemal dose (MED) of antioxidative balance.23 Therefore, oral antioxidants
sunlight is reached on the skin and allows comparison may better be used in situations in which there is an
between different products. Assuming the MED of skin inability to neutralize, both by the ROS excess and
phototype I is 10 minutes; it would take 20 minutes for by the decline of endogenous systems, such as in UV
erythema to occur if an SPF 2 sunscreen was used and related photoageing. Moreover, exogenous antioxidants
over 8 hours if an SPF 50 sunscreen was used. This is available on the market have varying scientific evidence
assuming ideal conditions including application of on efficacy, prompting close scrutiny on which product
2mg/cm2 and disregards the effects of water, sweat and to use.23 Finally, inorganic UV filters have IR-A reflecting
the varying intensity of UV light throughout the day. properties but face significant compliance issues due to
Finally, compliance is a requirement for any treatment their visibility after application.
to be effective and sunscreens are no exception;
formulating sunscreens with good cosmetic profiles and
pleasing properties enhances patient compliance and Future trends
as a result, prevents UV damage including photoageing.
Internationally, acceptable and pleasing properties of UV protection is established, effective, safe and
sunscreens may differ. Lotions and creams are popular comparable. Protection against visible light and
worldwide and there is particular popularity of sprays IR-A requires further research for certain products
in the European and American markets.19 to be routinely recommended. Antioxidants have
been the focus of research when aiming to prevent
Visible light protection damage related to IR-A and this is based on the
Current sunscreens have minimal protection against pathophysiological mechanisms of increased ROS.
visible light induced ROS and photoageing; for this Broad-spectrum sunscreens containing topical
reason, research should focus on finding suitable antioxidants could provide the best protection against
alternatives.18 There are limited studies on products to UV and IR-A radiation and could be recommended.
protect against visible light. One such study by Schalka There is a paucity of data for oral antioxidant
et al. evaluated pigmented sunscreens to determine supplementation and this should be the focus of future
their solar visible light protection factor (PF-VIS) and research.
pigment protection factor (PPF).21 They found that
products containing iron oxide in their formulation had DNA repair enzymes, such as photolyase, have also
greater photoprotective efficacy against visible light. been proposed as an additive to sunscreens to prevent
Given there is an effect of visible light on photoageing, oncogenesis and photoageing. These work by repairing
additional research would be beneficial in preventing cyclobutane dimers which form as a result of DNA
this, especially in darker-skinned individuals. irradiation and supplement the endogenous DNA
repair mechanisms. As a result of this, studies have
Infrared protection demonstrated reduced the number of actinic keratoses,
Photoprotection against infrared light can be provided non-melanoma skin cancers and photoageing and this
by inorganic UV filters and antioxidants.18 A small has been reviewed by Leccia et al.24
proof of principle study showed that a topical mixture
containing vitamin C, vitamin E, ubiquinone and a There is also evidence that different skin types may
grape-seed extract prevented IR-A induced MMP-1 have unique photoprotective properties as well as
mRNA expression in vivo in human skin.22 This has led vulnerabilities. Therefore, there may be a role for
to an increase in sunscreen and daily skincare products individualised protective methods and sunscreen
which include antioxidant properties that may improve ingredients. For example, darker-skinned patients who
IR-A induced photoageing effects. The difficulty with should benefit much more from visible light protection
regulating such products is the lack of an endpoint, can be offered sunscreens with ingredients that protect
such as erythema with UV protection, and therefore against this.

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PHOTODAMAGE 1
Conclusion it is UV radiation that classically has been attributed
to the photoageing effect of sunlight, the role of the
Photoageing exacerbates the natural ageing process rest of the electromagnetic spectrum that reaches our
and leads to unattractive skin changes such as deep skin has only recently been elucidated. Visible light
wrinkles, thickened skin, roughness and pigmentation and infrared radiation reach our skin in much higher
abnormalities. These changes have negative effects proportions compared to UV light and strategies to
on the appearance, image and self-esteem of patients protect against their effects are in infancy and include
and methods of prevention are important to discuss. additives to sunscreens such as antioxidants and iron
Completely avoiding sunlight is the ideal way to stop oxide. It remains to be seen whether these methods
photoageing; however, it is not realistic and employing are truly effective and methods of studying their
a sun smart routine is essential. This involves seeking efficacy is difficult. Further research into topical and
shade when outdoors, wearing protective clothing, oral antioxidants is important to provide a reliable
hats, sunglasses and most importantly, the application answer regarding their efficacy and methods to
of a broad-spectrum high SPF sunscreen. Although demonstrate this.

Table 1. Radiation from sunlight, mechanism of photoageing and methods of protection

Proposed mechanisms
Radiation Wavelength Penetration Protection
of photoageing

UVC 200-290nm No skin penetration Absorbed in the atmosphere

UVB 290-320nm Epidermal skin Damages DNA, generates ROS Sunscreens with
penetration which activate inflammatory UVB filters
pathways, activates MMPs which
UVA2 320-340nm Dermal skin degrade collagen Sunscreens
penetration with UVA filters
(broad-spectrum)
UVA1 340-400nm Dermal skin
penetration

Visible light 400-700nm Subdermal skin Generates ROS which active Sun avoidance,
penetration inflammatory pathways and activate clothing, hats, iron
MMP-1 production (much lesser oxide pigment
extent than UV) sunscreen

IR-A 700-1400nm Shorter wavelengths Generate ROS in fibroblast Sun avoidance,

penetrate into mitochondria leading to increased clothing, hats,
subcutaneous skin membrane permeability, apoptosis antioxidant additive
and MMP-1 activation. Also causes to sunscreen, oral
IR-B 1400-3000nm No skin penetration cutaneous neoangiogenesis antioxidant
IR-C 3000nm-1mm No skin penetration

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PHOTODAMAGE 1
Table 2. UV filters used in Australia (adapted from Osterwalder et al19)

INCI
Spectrum of protection International nomenclature of cosmetic ingredients (INCI)
abbreviation

Broad-spectrum including Bis-ethylhexyloxyphenol methoxyphenyl triazine BEMT

340-400nm
Butyl methoxydibenzoylmethane BMBM
— UVA1
Diethylamino hydroxybenzoyl hexyl benzoate DHHB

Disodium phenyl dibenzimidazole tetrasulfonate DPDT

Drometrizole trisiloxane DTS

Menthyl anthranilate MA

Methylene bis–benzotriazolyl tetramethylbutylphenol MBBT

Terephthalylidene dicamphor sulfonic acid TDSA

Zinc oxide ZnO

Protection against 290-320 nm 4-Methylbenzylidene camphor MBC

— UVB Benzophenone-3 BP3

— UVA2 Benzophenone-4 BP4

Polysilicone-15 PS15

Diethylhexyl butamido triazone DBT

Ethylhexyl dimethyl PABA EHDP

Ethylhexyl methoxycinnamate EHMC

Ethylhexyl salicylate EHS

Ethylhexyl triazone EHT

Homomenthyl salicylate HMS

Isoamyl p-methoxycinnamate IMC

Octocrylene OCR

Phenylbenzimidazole sulfonic acid PBSA

Titanium dioxide TiO2

Tris biphenyl triazine TBPT

6. Fisher GJ, Wang ZQ, Datta SC, Varani J, Kang S, Voorhees JJ.
References Pathophysiology of premature skin aging induced by ultraviolet
light. N Eng J Med. 1997;13;337(20):1419-28.
1. Zouboulis CC, Hoenig LJ. Skin aging revisited. Clin Dermatol.
7. Chen L, Hu JY, Wang SQ. The role of antioxidants in
2019;37(4):293-5.
photoprotection: A critical review. J Am Acad Dermatol.
2. McDaniel D, Farris P, Valacchi G. Atmospheric skin aging - 2012;67(5):1013-24.
Contributors and inhibitors. J Cosmet Dermatol. 2018;17(2):124-
8. Uitto J. The role of elastin and collagen in cutaneous aging:
37.
intrinsic aging versus photoexposure. J Drugs Dermatol.
3. Day AK, Wilson CJ, Hutchinson AD, Roberts RM. Sun-related 2008;7:s12-6.
behaviours among young Australians with Asian ethnic
9. Forman HJ, Fukuto JM, Miller T, Zhang H, Rinna A, Levy S. The
background: differences according to sociocultural norms and
chemistry of cell signaling by reactive oxygen and nitrogen
skin tone perceptions. Eur J Cancer Care. 2015;24(4):514-21.
species and 4-hydroxynonenal. Arch Biochem Biophys. 2008;
4. Zouboulis CC, Ganceviciene R, Liakou AI, Theodoridis A, Elewa 477(2):183-95.
R, Makrantonaki E. Aesthetic aspects of skin aging, prevention,
10. Fisher GJ, Kang S, Varani J, Bata-Csorgo Z, Wan Y, Datta S, et al.
and local treatment. Clin Dermatol. 2019;37(4):365-72.
Mechanisms of photoaging and chronological skin aging. Arch
5. Huang AH, Chien AL. Photoaging: a Review of Current Dermatol. 2002;138:1462-70.
Literature. Curr Dermatol Rep. 2020;9(1):22-9.

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Photoaging and Sunscreens | Joseph, Truong, and Smith

PHOTODAMAGE 1
11. Hoffmann-Dörr S, Greinert R, Volkmer B, Epe B. Visible light
(>395 nm) causes micronuclei formation in mammalian cells
without generation of cyclobutane pyrimidine dimers. Mutat
Res. 2005;572:142-9.

12. Mahmoud BH, Ruvolo E, Hexsel CL, Liu Y, Owen MR, Kollias
N, et al. Impact of long-wavelength UVA and visible light on
melanocompetent skin. J Invest Dermatol. 2010;130(8):2092-7.

13. Liebmann J, Born M, Kolb-Bachofen V. Blue-light irradiation

regulates proliferation and differentiation in human skin cells. J
Invest Dermatol. 2010;130(1):259-69.

14. Lohan SB, Müller R, Albrecht S, Mink K, Tscherch K, Ismaeel

F, et al. Free radicals induced by sunlight in different
spectral regions - in vivo versus ex vivo study. Exp Dermatol.
2016;25(5):380-5.

15. Schroeder P, Haendeler J, Krutmann J. The role of near

infrared radiation in photoaging of the skin. Exp Gerontol.
2008;43(7):629-32.

16. Schieke SM, Schroeder P, Krutmann J. Cutaneous effects of

infrared radiation: from clinical observations to molecular
response mechanisms. Photodermatol, Photoimmunol &
Photomed. 2003;19(5):228-34.

17. Kim MS, Kim YK, Cho KH, Chung JH. Infrared exposure induces
an angiogenic switch in human skin that is partially mediated by
heat. Br J Dermatol. 2006;155(6):1131-8.

18. Grether-Beck S, Marini A, Jaenicke T, Krutmann J.

Photoprotection of human skin beyond ultraviolet radiation.
Photodermatol, Photoimmunol & Photomed. 2014;30(2-3):167-
74.

19. Osterwalder U, Sohn M, Herzog B. Global state of sunscreens.

Photodermatol, Photoimmunol & Photomed. 2014;30(2-3):62-80.

20. Herzog B. Photoprotection of human skin. Photoprotection;

2012;245-73.

21. Schalka S, de Paula Corrêa M, Sawada LY, Canale CC, de

Andrade TN. A novel method for evaluating sun visible light
protection factor and pigmentation protection factor of
sunscreens. Clin Cosmet Investig Dermatol. 2019;12:605-16.

22. Schroeder P, Lademann J, Darvin ME, Stege H, Marks

C, Bruhnke S, et al. Infrared radiation-induced matrix
metalloproteinase in human skin: implications for protection. J
Invest Dermatol. 2008;128(10):2491-7.

23. Addor FAS. Antioxidants in dermatology. An Bras Dermatol.

2017;92(3):356-62.

24. Leccia M-T, Lebbe C, Claudel J-P, Narda M, Basset-Seguin N.

New Vision in Photoprotection and Photorepair. Dermatol Ther.
2019;9(1):103-15.

Australasian Society of Cosmetic Dermatologists / Opinions and Progress in Cosmetic Dermatology VOLUME 01 / ISSUE 03 / NOVEMBER 2021 17
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 PHOTODAMAGE 1
Non-Surgical Therapies
for Skin Cancer
Joshua Farrell1, Stephen Shumack 2,3,4
1. Southern Suburbs Dermatology, Sydney, NSW, Australia
2. Sydney Medical School (Northern) at The University of Sydney, NSW, Australia
3. Royal North Shore Hospital, St Leonards, NSW, Australia Assoc Professor Stephen Shumack
4. St George Dermatology & Skin Cancer Centre, Kogarah, NSW, Australia CLICK IMAGE TO LINK TO VIDEO DUR ATION_01:10

Correspondence: Joshua Farrell  Joshua.farrell1@uqconnect.edu.au

Disclosures: none

KEYWORDS: cryotherapy, radiotherapy, imiquimod, 5-fluorouracil, photochemotherapy

OUTLINE: Skin cancers are exceedingly common, with keratinocyte (non-melanoma) skin cancers (KC) estimated to
outnumber all other cancers combined. Surgical excision remains the “gold standard” as the only therapeutic option
that not only provides histopathological diagnosis but also proof of margin control. However, due to patient preference,
comorbidities, and tumour size and location, not all skin cancers are appropriate for surgical management. Fortunately,
a number of topical therapies have been developed to assist with KC management. Cryotherapy with liquid nitrogen,
5-fluorouracil cream, imiquimod cream, photodynamic therapy, and radiotherapy are all widely used options with good
efficacy rates. There are also newer oral therapies as a topic of emerging research.

Farrell J, Shumack S. Non-Surgical Therapies for Skin Cancer. Opin Prog Cosmet Dermatol 2021;1(3):19-24.

Introduction SCCs constitute 20% of keratinocyte cancers.2 Up to 5%

of patients will develop metastasis, with survival rates
Skin cancers constitute the largest number of cancers of 70% to 90% at 3-5 year follow up.4 Pre-cancerous
diagnosed in Australia each year.1 Furthermore, actinic keratoses arise from sun-damaged skin. Actinic
Australia has the highest incidence of skin cancer in keratoses in turn may uncommonly develop into SCC
the world with 300 diagnoses per 100,000 population in situ or Bowen’s Disease, and then invasive SCC.
in 2018.2 There has been an increasing incidence of Exposure to ultraviolet light is the strongest risk factor
both melanoma and keratinocyte (non-melanoma) for SCC development.2
skin cancers (KC), with KC estimated to outnumber all
other cancers combined.1 While surgical management Melanomas comprise less than 2% of skin cancers.2
remains the “gold standard” there is a great demand for Queensland, Australia has the highest rate of melanoma
alternative treatment options. globally, with 71 cases per 100,000 people between
2009-2013.2 Melanomas range from lentigo maligna,
The commonest skin cancers are basal cell carcinomas or melanoma in situ, in the epidermis to more invasive
(BCCs), squamous cell carcinomas (SCCs), and disease. The gold standard of treatment is primary
melanomas. BCCs are the commonest skin cancer and surgical excision with wide margins of 0.5-2 cm.5 Due to
arise from follicular stem cells in the epidermis. They the risk of metastatic disease, non-surgical treatment
arise from skin exposed to UV radiation, and thus have options are used far less frequently. However, for in situ
a high mutational burden.3 BCCs cause significant disease there is a role for topical therapy where surgery
morbidity through local tissue invasion and destruction. is not desirable.
They have the very rare potential to metastasise
although they rarely cause death. There are three Surgical excision remains the gold standard for most
main subtypes: superficial, nodular, and sclerosing. skin cancers as it is the only treatment option that
Superficial BCCs have a low risk of recurrence, however provides histopathological confirmation of diagnosis
nodular, and in particular sclerosing, BCCs may recur and clearance. However, the decision to operate
more commonly. These subtypes are thus less suitable is affected by considerations including patient
for topical therapy which does not have the same high comorbidities, tumour size, and location. Additionally,
efficacy rates as surgical excision.4 in cases where there are many clinical and subclinical

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PHOTODAMAGE 1
lesions over a large anatomical area, there is an obvious Cryotherapy can be used to treat Bowen’s disease.
benefit from field therapy. However, less well-differentiated lesions, recurrent
lesions, or lesions on the head and neck are better
We discuss below the non-surgical therapies for treated via an alternative method.4 Cure rates of greater
skin cancers including cryotherapy, 5% fluorouracil, than 95% are quoted in the literature, even with a
5% imiquimod, photodynamic therapy (PDT), and single freeze cycle of 30 seconds and a minimum of
radiotherapy. We will finish by touching on the 3 mm margins.4 As with cryotherapy for BCCs, there
emerging systemic agents. is slow healing for lesions larger than 20 mm diameter
and lesions on the lower legs. Unlike with BCCs, larger
lesions do not have a reduced response to treatment
Topical therapies and they have the option of being treated with
overlapping treatment fields.4
Cryotherapy
Cryotherapy with liquid nitrogen is the most common Cryotherapy is not currently recommended to treat
treatment for actinic keratoses in Australia.6 It lentigo maligna.5 The main drawback to topical therapy
causes the formation of ice within the extracellular for lentigo maligna is the lack of histopathological
compartment, which then mechanically damages the confirmation of adequate treatment. This appears to be
cell membrane. Further, it induces vasoconstriction, an issue especially in cryotherapy, with recurrence rates
endothelial damage and thus ischaemic necrosis of of up to 40%.10 Melanocytes are sensitive, however, to
the tissue.7 The intent is to affect a similar amount of temperatures between -4 to -7°C. A depth of at least
tissue as would be removed with surgical excision. 3 mm must be achieved with cryotherapy in order to
Cryotherapy has advantages in that it is simple and destroy atypical melanocytes that extend into hair
inexpensive.4 Further, it is useful when treating patients follicles.10 Two cycles of one minute freeze followed
with large numbers of lesions where other therapies by 2 minutes thaw, with margins of 10 mm, has been
may be impractical. shown to achieve disease-free outcome for a mean of
75.5 months in 18 patients.10 Cryotherapy has also been
Cryotherapy can be used for well-demarcated studied as an adjunctive treatment in combination
superficial or nodular BCCs. It is contraindicated for with imiquimod to increase local inflammation with
ill-defined or sclerosing BCCs. The recommendation variable results.10
is to freeze the tumour and 5-10 mm of surrounding
skin for 30 seconds. This is allowed to thaw for 5-Fluorouracil
up to 5 minutes before being refrozen for another 5-Fluorouracil (5-FU) is approved only for actinic
30 seconds.7 There is a cure rate of at least 95% with keratoses and Bowen’s disease in Australia,4 but
this method.7,8 In general, cryotherapy is operator elsewhere is commonly used to treat superficial BCCs.2
dependent, although the greater the size of the tumour, 5-FU is a pyrimidine analogue that binds to thymidylate
the lower the cure rate.4 Typically, there tends to be synthase through the co-factor 5,10-methylene
slow healing over 1-2 months and a hypopigmented tetrahydrofolate. This then inhibits thymidine synthesis
scar. It is thus a less suitable treatment option for and causes defects in DNA replication and hence
cosmetically sensitive areas on the face or ears, or for apoptosis.4 Local reactions are to be expected, and
lesions in pigmented skin.4 Tumour location below the include localised pain, burning, crusting, erosions and
knee is a relative contraindication due to prolonged hyperpigmentation. The lesions can develop secondary
wound healing6,8 and potential ulcer formation. infections, including herpes simplex.4

Although cryotherapy is commonly used to treat 5-FU was the first topical therapy registered by the US
actinic keratoses, it does not have comparatively high Food and Drug Administration (FDA) for the treatment
success rates. A randomised study with one year follow of superficial BCC.11 Although there are different
up compared cryosurgery (20-40 seconds per lesion), formulations, the 5% formulation is the most widely
5-fluorouracil twice daily for four weeks, and imiquimod used and approved internationally.2 A large randomised
three times per week for four weeks.9 Cryosurgery controlled trial with 601 histopathologically confirmed
achieved 68% clinical clearance, 5-fluorouracil superficial BCCs compared the use of 5-FU to PDT
achieved 96% clinical clearance and imiquimod 85%. with methyl aminolevulinic acid (MAL), and topical
In comparison, sustained clinical clearance after imiquimod.12 The PDT arm consisted of two sessions
12 months was most optimal in the imiquimod group one week apart, the 5-FU arm of twice daily application
(73%) compared to 5-fluorouracil (54%) and cryotherapy for 4 weeks, and the imiquimod arm consisted of daily
(28%).9 In general, response rates usually correlate with application for five days per week for 6 weeks. Patients
the duration of freeze time. However, cryotherapy does clinically tumour free at 3 and 12 months follow up were
have the advantage of treating the patient in the clinic, 80.1% for 5-FU, 83.4% for imiquimod, and 72.8% for PDT.12
rather than a 3- to 4-week treatment course.4 5-FU was found to be non-inferior to and imiquimod was

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PHOTODAMAGE 1
found to be superior to MAL PDT, with more severe side of control patients.18 Current guidelines suggest 3
effects in the PDT group. A five year follow up on this non-consecutive days per week in 4-week cycles.
study found that 70% of 5-FU, 80.5% of imiquimod, and This is continued until clearance is achieved for up
62.7% of PDT patients were tumour free.13 to 16 weeks, although it usually requires two cycles.4
Local reactions are very common, and include
Surgical removal is the mainstay of treatment for other significant erythema, scabbing and crusting, itching and
BCC subtypes. It is also the mainstay of treatment burning.4 This reaction may vary between patients and
for SCCs. However, the precursor lesions of actinic even between lesions on the same patient. Secondary
keratosis and Bowen’s disease are not infrequently infections may occur. This may require a rest period to
treated with 5-FU. A randomised controlled trial of allow the inflammation to settle before recommencing
932 patients found that 5-FU applied twice daily for treatment.4 Alternatively, formulations of 2.5% and
4 weeks lead to complete clearance of actinic keratoses 3.75% imiquimod have fewer adverse reactions but may
in 38% of patients compared to 17% of patients in the have greater recurrence of lesions.19 5% imiquimod has
control group.14 5-FU tends to only be used twice daily superior clinical and cosmetic outcomes compared
for 2 weeks on more sensitive areas such as the face.4 to 5-FU: one randomised controlled trial reported
This causes inflammation that takes 1-2 weeks to settle. complete field clearance of actinic keratosis of 73% with
For Bowen’s disease, current recommendations are imiquimod at 12 months, compared to 54% complete
for twice daily treatment for 4-8 weeks.4 This appears clearance in the 5-FU group.9
to provide roughly 90% cure, with a 70% 12-month
complete response rate with good cosmesis.4 There are Bowen’s disease can be treated with daily application
further studies comparing surgical excision compared for a total of 16 weeks.20 This may provide 73% clearance
to 5-FU currently underway. for greater than 9 months.20 In practice, more common
treatment regimens involve 3-5 applications per
5-FU does not currently appear to have a role in week for 4-6 weeks. Breaks between applications may
lentigo maligna, although combination treatment with be required to allow inflammation to settle in some
imiquimod has been explored with mixed results.15 patients.4

Imiquimod Melanoma in situ can be a difficult condition to treat

Imiquimod is a nucleoside analogue of the because there is frequently subclinical extension of
imidazoquinoline family based on an adenine derivative.2 disease beyond what is clinically evident. This leads to
It acts as an agonist of toll-like receptors 7 and 8 incomplete clearance by surgical excision with 5 mm
on the surface of antigen presenting cells, leading margins in 50% of cases.21 There are ongoing clinical
to upregulation of immune antitumour responses.4 trials currently exploring the use of imiquimod for
Although originally approved for genital warts, it has lentigo maligna but current evidence is suggestive of
since been approved for treatment of actinic keratosis 75% clearance as monotherapy and 95% clearance
on the face and scalp, and superficial BCCs where as adjunctive therapy post primary surgical excision
surgery is considered inappropriate.2,4 without clear margins.2,22 This is inferior to the results
achieved with radiotherapy, however there is potentially
The recommended treatment regimen for primary a role for imiquimod as a preferred topical therapy in
superficial BCCs is application to the tumour with a more challenging lentigo maligna lesions in elderly
5 mm margin, 5 times per week for 6 weeks.4,16 The patients who may be unable to attend radiotherapy
patient should be followed up 3 months post therapy. sessions regularly. Oversight by experienced clinicians
A study comparing imiquimod for both superficial BCCs is required.
and nodular BCCs demonstrated 85.1% clearance at
3 years and 83.8% clearance at 5 years for superficial
BCCs, in comparison to 81.8% clearance at 3 years and Photodynamic therapy
81.1% clearance at 5 years for nodular BCCs.17 However,
since it is only currently approved for superficial BCCs, PDT involves topical administration of a
histological confirmation of diagnosis is required for photosensitising agent (such as 5-aminolevulinic acid
Pharmaceutical Benefits Scheme (PBS) reimbursement. [ALA]), followed by an incubation period, and then
Imiquimod has very good cosmetic outcomes.12 the administration of light to trigger the release of
Unfortunately, it is not as effective as surgical excision reactive oxygen species. These reactive oxygen species
with clear margins of 4 mm, which has 98% clearance damage cell membranes and thus trigger cell death.2
at 3 years and 97.7% clearance at 5 years.6 An alternative photosensitising agent is a methyl ester
of ALA, MAL, which appears to have greater tissue
Imiquimod is effective in the treatment of actinic penetration and thus can target deeper lesions.2 PDT is
keratoses. 5% imiquimod used three times per week currently approved to treat actinic keratoses, Bowen’s
for 16 weeks leads to complete clearance of actinic disease, and superficial and thin nodular BCCs.2,4
keratoses in 57.1% of patients compared to 2.2%

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Non-Surgical Therapies for Skin Cancer | Farrell and Shumack

PHOTODAMAGE 1
A treatment session involves gentle debridement the exception of daylight PDT. It is therefore restricted
of the lesion, or debulking of a nodular BCC, before to centres specialising in skin cancer management.
application of the photosensitising cream to a thickness
of 1 mm with a 5 mm margin. This is covered with
an occlusive dressing and left in place for 3 hours. Radiotherapy
The area is then cleaned and exposed to illumination
for up to 9 minutes.4 A variation of this, daylight PDT, Radiotherapy is an effective treatment that can be
has recently been approved for actinic keratoses.4 used to achieve cure, as well as in an adjunctive role
The recommendation is for application of MAL before post-operatively. It has a place in treating recurrent
daylight exposure for 2 hours. and metastatic disease, as well as in palliative therapy.
Radiotherapy achieves this by affecting DNA. Normal
PDT for BCC is usually well-tolerated with some pain tissue cells can repair much of the radiotherapy damage
during the illumination phase followed by formation to their DNA within 6 hours after a single treatment.
of erosions and then healing over several weeks.16 However malignant cells have poor repair capacity
Occasionally, the pain can be sufficient to require and do not survive.4,25 Thus when used properly,
temporary suspension of illumination or injection of radiotherapy has the ability to eradicate cancer cells
local anaesthetic.4 It offers a good cosmetic outcome.12,16 whilst sparing normal tissue.
Superficial BCCs appear to be more responsive to
PDT compared to other subtypes.16 Cure rates range There are different types of radiotherapy. Brachytherapy
from 72% to 100%.2,12 There is evidence however that is a method in which isotopes are applied to the surface
there is less recurrence with a second session of PDT, of the tumour or inserted into it. The isotopes can
with 91% clearance compared to 68% at follow up of be covered by a casing, which determines the dose
6 years.16 ALA and MAL PDT seem to have comparable rate.4 This method allows for a high dose between the
effectiveness for BCCs.16 Thin, nodular BCCs can be isotope and the tumour with a rapid fall off to deeper,
treated via PDT so long as lesions deeper than 2 mm non-malignant tissue. Brachytherapy also conveniently
are first debulked via curette or shave excision.4 This allows for irregular and curved targets to be treated.16 An
is to allow the treatment to reach the full depth of alternative method is superficial x-ray therapy, which is
the lesion. Thin nodular BCCs may achieve a 5-year appropriate for depths up to 5 mm.4 For lesions deeper
clearance rate of 76% with a good cosmetic outcome.23 than 5 mm, options include orthovoltage radiotherapy,
It is worth noting that previous PDT does not affect megavoltage electrons, or photons produced by a linear
future surgical outcomes. accelerator.4 As with other treatments, the radiation
field includes the lesion as well as a surrounding margin
Actinic keratoses and Bowen’s disease can also be depending on the tumour type.
treated with PDT. Actinic keratoses can be treated
effectively by PDT as large surface areas can be Radiotherapy has the advantage of conserving tissue.25
treated concurrently. For actinic keratoses, the It can thus achieve superior functional and cosmetic
recommendation is for a single session of PDT with outcomes compared to surgery, especially for cancers
effects assessed at 3 months.4 Residual lesions should of the lips, eyelid commissures and nasal ala.4 The main
be treated again at this stage. ALA/PDT and MAL/ disadvantage is the requirement for multiple treatments
PDT have a similar response rate of 90% when two (fractionation). Small doses, or fractions, are given to
sessions are used.4 Unfortunately, lesion recurrence avoid exceeding the repair capacity of normal tissue and
is a significant issue with perhaps 20% recurrence thus only remove malignant cells.4 Smaller doses require
of actinic keratoses. Similar results can be achieved a greater number of treatments and so the patient must
with daylight PDT with a reduced side effect of pain visit the radiotherapy facility more often. However,
due to the reduced intensity of light exposure.4 smaller doses correlate with improved function and
Bowen’s disease can be treated with PDT, with a cosmesis.4
recommendation for two sessions of treatment 1-4
weeks apart.4 There appears to be clearance at 6 A commonly quoted disadvantage of radiotherapy is
months of 89% for ALA/PDT and 78% for MAL/PDT.24 in-field radiation-induced cancer. This risk is likely
Recurrence may be as low as 17% after 64 months.4 overstated and is in the order of a rate of 1 in 1000 every
PDT is well-suited to the treatment of slower ten years.25 The association of radiotherapy with poor
healing sites such as the lower limb, with less risk cosmetic outcomes (hypopigmentation, cicatrisation,
of development of a non-healing ulcer or infection telangiectasia, in-field fibrosis) is likely due to
compared to more destructive or surgical therapies.4 historical observations that do not take into account
recent advances in the field.4,25 Due to these concerns,
ALA/PDT has not been shown to be useful for the radiotherapy was traditionally considered only in
treatment of melanoma due to inefficient penetration patients over the age of 70. It has been argued that it
of ALA into the skin.2 The main disadvantage for PDT is should be considered in patients as young as 40.25
the specialised equipment and training required, with

Australasian Society of Cosmetic Dermatologists / Opinions and Progress in Cosmetic Dermatology VOLUME 01 / ISSUE 03 / NOVEMBER 2021 22
Non-Surgical Therapies for Skin Cancer | Farrell and Shumack

PHOTODAMAGE 1
One consideration in radiotherapy-treated skin is the Immunotherapy for melanoma, in particular metastatic
poor surgical healing often encountered should the disease, has a growing evidence base. Currently, there
patient require an excision. Dehiscence leading to radio- are recommendations for an anti-PD-1 immunotherapy
necrotic ulcers and fistulae can occur.25 Radiotherapy as first-line for patients with unresectable stage III/
can be considered to re-treat any recurrence at the IV melanoma.5 Melanoma with a positive mutation for
margin of the initial lesion, but due to the risk of radio- V600 BRAF should have first-line treatment with a
necrotic ulcers and fistulae, is usually avoided to re-treat BRAF inhibitor combined with a MEK inhibitor.5 There
the centre of previous radiotherapy fields.25 are currently no head-to-head trials comparing these
two treatments. However, there is agreement that
There are few clinical trials examining radiotherapy and all patients with unresectable stage III/IV melanoma
skin cancer. There is thus limited high-level evidence should have testing for the V600 BRAF mutation, and
regarding optimal treatment duration and therapy.4,16 should be considered for clinical trials.5

For BCCs, radiotherapy is not limited to certain

histological subtypes.4 Several studies have reported Conclusion
efficacy of up to 90% after 5 years of follow up.4
Recurrence is likely slightly higher than compared to Non-surgical therapies for skin cancers have a role in
surgical excision alone. Radiotherapy usually achieves patients in whom the benefits of non-surgical therapy
good cosmesis, although brachytherapy has the least outweigh the reduced efficacy rates compared to
impressive results among the different radiotherapy surgical therapy. Tumour type and subtype also have
subtypes.4 Follow up post radiotherapy should occur great importance in determining appropriate treatment
4 months afterwards, as the acute radiation reaction choice. Topical therapy is an attractive option as it may
resolves 4-6 weeks after finishing radiotherapy and achieve improved cosmesis and can be used to treat a
occasionally complete resolution clinically of a BCC wider field. This has the benefit of treating a greater
can take 4 months.4 number of lesions, and may also improve diagnostic
accuracy in clearing less significant lesions to reveal
Radiotherapy for actinic keratoses has typically been hidden tumours. However, no topical therapy has the
considered as a last-line treatment for a minority of same efficacy as surgical excision, with most recurrence
patients who fail other therapies.4 Recent advances in occurring within the first three years.4 Thus, close
external beam radiotherapy compared to the traditional follow up is warranted in these patients for at least
brachytherapy moulds seem to provide better 3 years following treatment.
treatment for convex areas of field cancerisation such
as the scalp.4 Radiotherapy has also been reported to
be useful in periungual Bowen’s disease.4 References

As noted above, lentigo maligna is a difficult condition 1. Australian Institute of Health and Welfare 2016. Skin cancer in
Australia. Cat. no. CAN 96. Canberra: AIHW.
to treat.21 Radiotherapy appears to be the best of the
topical therapies, as it can provide 95% clearance 2. Cullen JK, Simmons JL, Parsons PG, Boyle GM. Topical
treatments for skin cancer. Adv. Drug Deliv Rev 2020;153:54-64.
of lentigo maligna after 3 years.21 This is superior to
imiquimod. Superficial radiotherapy is thus currently 3. Bonilla X, Parmentier L, King B, Bezrukov F, Kaya G, Zoete
V, et al. Genomic analysis identifies new drivers and
recommended as a suitable alternative to surgical
progression pathways in skin basal cell carcinoma. Nat Genet.
excision of lentigo maligna, or as adjuvant therapy post- 2016;48(4):398–406.
surgery for larger lesions with inadequate margins.5
4. Cancer Council Australia Keratinocyte Cancers Guideline
Working Party. Clinical practice guidelines for keratinocyte
cancer. Sydney: Cancer Council Australia. 2019.
Systemic therapies 5. Cancer Council Australia Melanoma Guidelines Working Party.
Clinical practice guidelines for the diagnosis and management
Metastatic KC is rare, with metastatic BCC less than of melanoma. Sydney: Melanoma Institute Australia.
0.1% of all cases and metastatic SCC less than 5%.4 6. Shumack S. Non-surgical treatments for skin cancer. Aust
Metastatic BCC may be treated via targeted therapy Prescr 2011;34:6-7.
against the hedgehog signalling pathway, such as with 7. Mallon E, Dawber R. Cryosurgery in the treatment of basal
vismodegib and sonidegib.4 The high mutation burden cell carcinoma: assessment of one and two freeze‐thaw cycle
of BCC lends itself to checkpoint immunotherapy. In schedules. Dermatol Surg 1996;22(10):854-8.
SCC, conventional chemotherapy is typically used 8. Paoli J, Gyllencreutz J, Fougelberg J, Backman E, Modin M,
despite limited evidence. Similar to BCCs, there is Polesie S, et al. Nonsurgical options for the treatment of basal
cell carcinoma. Dermatol Pract Concept 2019;9(2):75-81.
increasing evidence of the efficacy of checkpoint
inhibitor immunotherapy in SCCs.4

Australasian Society of Cosmetic Dermatologists / Opinions and Progress in Cosmetic Dermatology VOLUME 01 / ISSUE 03 / NOVEMBER 2021 23
Non-Surgical Therapies for Skin Cancer | Farrell and Shumack

PHOTODAMAGE 1
9. Krawtchenko N, Roewert-Huber J, Ulrich M, Mann I, Sterry W, 17. Williams H, Bath-Hextall F, Ozolins M, Armstrong S, Colver
Stockfleth E. A randomised study of topical 5% imiquimod vs. G, Perkins W, et al. Surgery versus 5% imiquimod for nodular
topical 5-fluorouracil vs. cryosurgery in immunocompetent and superficial basal cell carcinoma: 5-year results of the SINS
patients with actinic keratoses: a comparison of clinical and randomized controlled trial. J Invest Dermatol 2017;137(3):614–9.
histological outcomes including 1-year follow-up. Br J Dermatol
18. Szeimies R, Gerritsen M, Gupta G, Ortonne J, Serresi S, Bichel
2007;157 Suppl. 2:34–40.
J, et al. Imiquimod 5% cream for the treatment of actinic
10. Iznardo H, Garcia-Melendo C, Yélamos O. Lentigo maligna: keratosis: results from a phase III, randomized, double-blind,
clinical presentation and appropriate management. Clin Cosmet vehicle-controlled, clinical trial with histology. J Am Acad
Investig Dermatol 2020;13:837-55. Dermatol 2004;51(4):547–55.
11. Gross K, Kircik L, Kricorian G. 5% 5-fluorouracil cream for the 19. Swanson N, Smith C, Kaur M, Goldenberg G. Imiquimod 2.5%
treatment of small superficial basal cell carcinoma: efficacy, and 3.75% for the treatment of actinic keratoses: two phase 3,
tolerability, cosmetic outcome, and patient satisfaction. multicenter, randomized, double- blind, placebo-controlled
Dermatol Surg 2007;33(4):433–9. studies. J Drugs Dermatol 2014;13(2):166–9.
12. Arits A, Mosterd K, Essers B, Spoorenberg E, Sommer A, De 20. Patel G, Goodwin R, Chawla M, Laidler P, Price P, Finlay A, et al.
Rooij M, et al. Photodynamic therapy versus topical imiquimod Imiquimod 5% cream monotherapy for cutaneous squamous
versus topical fluorouracil for treatment of superficial basal- cell carcinoma in situ (Bowen’s disease): a randomized,
cell carcinoma: a single blind, non-inferiority, randomised double-blind, placebo-controlled trial. J Am Acad Dermatol
controlled trial, Lancet Oncol 2013;14(7):647–54. 2006;54(6):1025-32.
13. Jansen M, Mosterd K, Arits A, Roozeboom M, Sommer A, 21. Fogarty G, Hong A, Economides A, Guitera P. Experience
Essers B, et al. Five-year results of a randomized controlled treating lentigo maligna with definitive radiotherapy. Dermatol
trial comparing effectiveness of photodynamic therapy, Res Pract 2018;2018:7439807.
topical imiquimod, and topical 5-fluorouracil in patients
22. Swetter S, Chen F, Kim D, Egbert B. Imiquimod 5% cream
with superficial basal cell carcinoma. J Invest Dermatol
as primary or adjuvant therapy for melanoma in situ,
2018;138(3):527–33.
lentigo maligna type. J Am Acad Dermatol 2015;72:1047-53.
14. Pomerantz H, Hogan D, Eilers D, Swetter S, Chen S, Jacob S,
23. Rhodes L, de Rie M, Leifsdottir R, Yu R, Bachmann I, Goulden
et al. Long-term efficacy of topical fluorouracil cream, 5%,
V, et al. Five-year follow-up of a randomized, prospective
for treating actinic keratosis: a randomized clinical trial. JAMA
trial of topical methyl aminolevulinate photodynamic therapy
Dermatol 2015;151(9):952–60.
vs surgery for nodular basal cell carcinoma. Arch Dermatol
15. Florin V, Desmedt E, Vercambre-Darras S, Mortier L. Topical 2007;143(9):1131-6.
treatment of cutaneous metastases of malignant melanoma
24. Tarstedt M, Gillstedt M, Wennberg Larkö A, Paoli J.
using combined imiquimod and 5-fluorouracil. Invest New
Aminolevulinic acid and methyl aminolevulinate equally
Drugs 2012;30(4):1641–5.
effective in topical photodynamic therapy for non-melanoma
16. Paoli J, Gyllencreutz J, Fougelberg J, Backman E, Modin M, skin cancers. J Eur Acad Dermatol Venereol 2016;30(3):420-3.
Polesie S, et al. Nonsurgical options for the treatment of basal
25. Fogarty G, Shumack S. Common dermatology questions and
cell carcinoma. Dermatol Pract Concept 2019;9(2):75-81.
answers about the radiation treatment of skin cancer in the
modern era. Int J Radiol Radiat Ther 2018;5(2):108–14.

Australasian Society of Cosmetic Dermatologists / Opinions and Progress in Cosmetic Dermatology VOLUME 01 / ISSUE 03 / NOVEMBER 2021 24
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References. 1. Ellipse Nordlys CE Mark 2. Bjerring P, Christiansen K, Troilius A, Dierickx C. Facial photo rejuvenation using two different intense pulsed light (SWT) wavelength bands. Lasers Surg
of Prof. Agneta Troilius Rubin, M.D. - Sweden
Med. Prof. Agneta Troilius Rubin, M.D. - Sweden
2004;34(2):120-126. 3. Negishi K, Kushikata N, Takeuchi K, Tezuka Y, Wakamatsu S. Photorejuvenation by intense pulsed light with objective3measurement
3 treatments
treatments of VL
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555555in Japanese patients. Dermatol Surg.
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4141

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 PHOTODAMAGE 1
Oral Preventive Therapies
in Photodamaged Skin
Sarah Hanna1, Patricia M Lowe1,2, Andrew C Chen1,2
1. Department of Dermatology, Royal Prince Alfred Hospital, Camperdown, NSW, Australia
2. University of Sydney, Faculty of Medicine and Health, Sydney, NSW, Australia
Dr Andrew C Chen
Correspondence: Sarah Hanna  sarah_hanna@y7mail.com
CLICK IMAGE TO LINK TO VIDEO DUR ATION_00:34
Disclosures: none

KEYWORDS: photodamage, prevention, non-melanoma skin cancer, photoprotection, chemoprevention

OUTLINE: Skin cancer risk increases with the level of ultraviolet radiation (UVR) exposure or photodamage. UVR is
estimated to cause 65% of melanomas and 90% of non-melanoma skin cancers (NMSC). NMSC are the most common
form of cancer diagnosis with significant morbidity for the patient and economic burden. In light of these factors, the
prevention of NMSC is essential. Oral therapies for skin cancer chemoprevention include retinoids which are recommended
for use in patients at high risk for developing multiple, invasive, or metastatic squamous cell carcinoma (SCC); nicotinamide
which is well tolerated and has been shown to reduce actinic keratoses and SCCs; and non-steroidal anti-inflammatory
drugs which may reduce SCC and basal cell carcinoma (BCC) but have well established side effects with prolonged use.
Difluoromethylornithine has been shown to reduce BCCs but is limited by its side effect profile, including ototoxicity. There
is evidence for using vitamin D, selenium, and plant-derived and animal-derived dietary products in the prevention of NMSC,
but further studies are required to support their use and the required therapeutic regimen. Multiple novel agents are currently
being investigated for NMSC prevention, including capecitabine, epidermal growth factor inhibitors, and synthetic alpha-
melanocyte-stimulating hormones.

ABBREVIATIONS
5-FU: Fluorouracil NAD: Nicotinamide adenine dinucleotide
AKs: Actinic keratosis NF-κB: Nuclear factor-kappa B
ATP: Adenosine triphosphate NMSC: Non-melanoma skin cancer
BCC: Basal cell carcinoma NO: Nitric oxide
COX: Cyclooxygenase PARP-1: Poly [ADP-ribose] polymerase 1
CPDs: Cyclobutene pyrimidine dimers PGE2: Prostaglandin E2
DFMO: Difluoromethylornithine PL: Polypodium leucotomos
DNA: Deoxyribonucleic acid ROS: Reactive oxygen species
EGFR: Epidermal growth factor receptor RR: Relative risk
ES: Effect size SCC: Squamous cell carcinoma
HR: Hazard ratio UVR: Ultraviolet radiation

Hanna S, Lowe PM, Chen AC. Oral Preventive Therapies in Photodamaged Skin. Opin Prog Cosmet Dermatol 2021;1(3):26-33.

Introduction to deoxyribonucleic acid (DNA) and exerts an

immunosuppressive effect that impedes the skin’s
The risk of skin cancer increases with the level of ability to respond to developing NMSC.3 Direct DNA
ultraviolet radiation (UVR) exposure or photodamage, damage occurs as photons of UVR are absorbed by
especially with repeated UVR exposure with incidents chromophores in the skin, including DNA, melanin,
of severe sunburn.1 UVR causes an estimated 65% of amino acids, carotene and trans-urocanic acid.4 DNA
melanomas and 90% of non-melanoma skin cancers predominantly absorbs UVB radiation which causes
(NMSC), including basal cell carcinoma (BCC) and photochemical reactions. UVR is also able to cause
squamous cell carcinoma (SCC).2 indirect damage to the DNA through the production
of reactive oxygen species (ROS) and reactive nitrogen
The pathophysiological mechanisms by which intermediates, which cause oxidative damage. The
UVR is implicated in the development of NMSC is immunosuppressive effect of UVR is linked to the
complex. UVR can cause direct and indirect damage production of photolesions such as cyclobutene

Australasian Society of Cosmetic Dermatologists / Opinions and Progress in Cosmetic Dermatology VOLUME 01 / ISSUE 03 / NOVEMBER 2021 26
Oral Preventive TherapiesiIn Photodamaged Skin | Hanna, Lowe, and Chen

PHOTODAMAGE 1
pyrimidine dimers (CPDs)5 and induction of other Oral therapies for skin cancer
molecules with immunosuppressive properties such as chemoprevention in photodamaged skin
interleukin-10, prostaglandins, platelet-activating factor
and ROS.6 UVR also results in changes to the skin’s Retinoids
adaptive immune system by migration of Langerhans Retinoids, which are natural and synthetic derivatives
cells to draining lymph nodes7, depletion of NAD and of vitamin A, have anti-tumoral abilities as they
adenosine triphosphate (ATP) in the skin8, inhibition of regulate epithelial maturation, cellular differentiation,
mast cells9, cytotoxic T cells10, and memory T cells.11 growth arrest, and apoptosis by activating nuclear
retinoid receptors. The use of oral retinoids for
In 2002, NMSC was estimated to be the most common chemoprevention of SCC has been extensively
form of cancer diagnosed, with more NMSC diagnosed investigated in the transplant population, and current
each year than all other cancers combined. From guidelines advocate for their use in patients at high risk
2001 to 2016, the age-specific incidence rate of NMSC for developing multiple, invasive, or metastatic SCC.15,16
increased for people aged 50-59, 70-79, and 80 and
over.12 Although mortality due to NMSC is relatively There have been several clinical trials evaluating the
low, with the age-standardised mortality rate for use of oral retinoids as chemoprevention for NMSC.
NMSC in 2016 estimated at 1.9 deaths per 100 00012, The largest double-blind, randomised controlled trial
the morbidity, such as disfigurement, is high. Further, to date included 2297 patients and demonstrated that
NMSC is a significant economic burden with the cost of oral retinol 25,000IU daily reduced numbers of new
diagnosing and treating skin cancer in Australia in 2010 SCCs (hazard ratio [HR] 0.74, p=0.04) but did not affect
exceeding $536 million.13 numbers of new BCCs (HR 1.06, p=0.36).17 Furthermore,
a nested cohort study conducted by Nijsten and Stern
In light of the significant morbidity and economic in 135 psoriasis patients demonstrated that oral retinoid
burden of NMSC, prevention is essential and a focus of use was associated with a reduction in new SCCs when
current research. As the cause of most NMSC is known, compared to that patient’s own tumour experience
it is largely preventable if suitable strategies can be while not using retinoids with an incidence rate ratio
developed. Primary prevention strategies are lacking, of 0.79 (95% CI 0.65-0.95) but showed no significant
and given that the incidence of NMSC remains high, association between retinoid use and BCC.18 George and
numerous systemic preventive methods have been colleagues published a prospective open randomised
explored over the past decades. Ultimately, the aim is crossover trial on 23 renal transplant recipients with a
to develop an oral photoprotective or chemopreventive history of NMSC. Patients were crossed over at the end
agent that can be used in addition to primary of one year, and 47.8% completed the two-year trial.
prevention strategies. The number of SCCs observed in patients treated with
acitretin 25 mg daily or second daily was significantly
Potential targets for chemoprevention have been lower than that in the drug-free period (p=0.002)
elucidated by previous studies and are outlined in and non-significantly reduced BCCs.19 Bavinck and
Figure 1. colleagues performed a double-blind, randomised

Figure 1: Proposed candidates for chemoprevention14

Excessive UVR Immunosuppressed History of NMSC Genetic syndromes Exposures

exposure
 rgan transplant
O  5-10 NMSC per
>  eroderma
X  PUVA

 evere
S recipients year pigmentosum
 hronic radiation
C
photodamage
 hronic
C  I
ncreased turnover  Albinism
 dermatitis
 Multiple AKs
 immunosuppressive of NMSC
 ecessive
R  Trauma

therapies
 ultiple NMSC in
M dystrophic
 Extensive burns

 aematological
H high risk locations epidermolysis
malignancies bullosa
 Metastatic NMSC

 uman
H  evoid BCC
N
 ruptive
E
Immunodeficiency syndrome
keratoacanthomas
Virus
 pidermodysplasia
E
verruciformis

 Bazex syndrome


 Rombo syndrome


Australasian Society of Cosmetic Dermatologists / Opinions and Progress in Cosmetic Dermatology VOLUME 01 / ISSUE 03 / NOVEMBER 2021 27
Oral Preventive TherapiesiIn Photodamaged Skin | Hanna, Lowe, and Chen

PHOTODAMAGE 1
placebo-controlled trial on 44 renal transplant A phase 3 double-blind, randomised control trial
recipients with more than ten keratotic skin lesions conducted by Chen and colleagues was published in
assessing the efficacy of 6-months’ treatment with 2015, assessing 386 participants who had at least two
acitretin 30 mg daily. Of the 48 assessable patients, NMSC in the preceding five years. Participants were
the authors demonstrated that oral acitretin was allocated to receive nicotinamide 500 mg twice daily
significantly more effective than placebo at preventing or placebo for 12 months assigned in a 1:1 ratio. The
NMSC (p=0.01) and reducing keratotic lesions without primary endpoint was the number of new NMSC. The
adversely impacting renal function.20 Similarly, a study showed that at 12 months, the rate of new NMSC
study by McKenna and Murphy in the Royal Infirmary, was lower by 23% in the nicotinamide group compared
Edinburgh, with 16 renal transplant patients who with placebo (95% CI 4-38, p=0.02). There was a 20%
received oral acitretin 0.3 mg/kg daily for five years reduction in BCCs in the nicotinamide group compared
showed that new NMSCs were reduced during the with placebo (95% CI -6-49); however, the result
treatment period compared to the pre-treatment was non-significant (p=0.12), and a 30% reduction in
period.21 new SCCs (95% CI 0-51, p=0.05). The number of AKs
was 13% lower in the nicotinamide group compared
These studies suggest that oral retinoids are likely with placebo at 12 months (p=0.001). There was nil
to be effective in preventing SCCs and conceivably significant difference between the number or type of
effective in preventing BCCs and reducing AKs. The adverse events during the 12-month intervention period
use of oral retinoids is limited by their relatively and no evidence of benefit after nicotinamide was
poor tolerability and side effects which are dose discontinued.27
dependent such as mucocutaneous dryness, hair
loss, hypercholesterolaemia, hypertriglyceridemia, Therefore, nicotinamide seems to be well tolerated, and
liver toxicity, skeletal demineralisation/hyperostosis, at the cost of $5-10 per month, appears to be a cost-
increased intracranial pressure and teratogenicity.22 effective method to protect against the development of
Therefore, oral retinoid use for the prevention of NMSC NMSC and AKs in photodamaged skin.
is generally limited to high-risk patients.
Non-steroidal anti-inflammatory drugs (NSAIDs)
Nicotinamide Prostaglandin E2 (PGE2) has been implicated as a
Nicotinamide is a water-soluble form of vitamin B3. The mediator of UVR induced skin damage28 and enhances
chemoprophylactic effect of nicotinamide is postulated proliferation of keratinocytes by activation of growth-
to occur as it replenishes cellular energy8, reduces inducing pathways, including epidermal growth factor
inflammation23, enhances DNA repair24, and reduces receptor (EGFR) and cyclic adenosine monophosphate
UV-immunosuppression.25 production.29 Further, UVR-induced PGE2 contributes
to UVR-induced immunosuppression.30 Inflammation
In a phase 2 double-blinded randomised control trial and increased expression of cyclooxygenase (COX)-2
published in 2012, 76 immunocompetent volunteers enzyme have been shown to be associated with NMSC.31
with ≥4 AKs were allocated to receive 500 mg of COX-2 produces prostaglandins, including PGE2.
nicotinamide once (n=41) or twice daily (n=37) for four
months, or placebo. The primary endpoint of the study A 2020 meta-analysis that combined 26 original
was AK count. After two months, there was a 35% studies (223,619 cases and 1,398,507 controls) showed
reduction in AK count in the group on nicotinamide that NSAIDS and non-selective COX inhibitors were
500 mg twice daily (p<0.0001) and a 15% reduction in significantly associated with a reduced risk of skin
AK count in those on nicotinamide 500 mg once daily cancer in the general population. Skin cancer was
(p=0.046) compared with placebo. At four months, defined as NMSC, BCC, SCC or melanoma. The effect
there was a 35% reduction in AK count in those taking size (ES) for NSAIDs was 0.944 (95% CI 0.897-0.944,
nicotinamide 500 mg twice daily (p=0.0006) and a 29% p=0.027) compared with ES=0.928 for non-selective
reduction in AK count in those taking 500 mg once COX inhibitors (95% CI 0.872-0.987, p=0.017). In
daily (p=0.005) compared with placebo. The study also contrast, there was no evidence that selective COX-2
found that nicotinamide reduced AK count regardless inhibitors had such an effect (p=0.285). Eleven studies
of whether a patient had many AKs at baseline or only a were combined to assess the effect of NSAIDs on
few. While not a primary endpoint, the authors pooled BCC risk (ES=0.926, 95% CI 0.870-0.985, p=0.015)
the data from the two studies (nicotinamide 500 mg and the effect of non-selective COX inhibitors on the
once daily and nicotinamide 500 mg twice daily) and risk of BCC (ES=0.943, 95% CI 0.892-0.997, p=0.037).
noted that in the nicotinamide group, there was only Similarly, there was no association between selective
four new NMSC (2 BCCs and 2 SCCs), compared with 20 COX-2 inhibitors and BCC in the same population
new NMSC in the placebo group (12 BCCs and 8 SCCs), (p=0.683). Ten studies were combined to assess the
representing a relative rate of 0.24 (p=0.010).26 effect of NSAIDs on SCC (ES=0.875, 95% CI 0.792-0.966,

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p=0.008), and nonselective COX inhibitors (ES=0.903, Selenium
95% CI 0.831-0.983, p=0.018). Again, selective COX-2 Selenium is an essential dietary trace element. Selenium
inhibitors did not appear to prevent the development has been shown to prevent UVR-induced carcinogenesis
of SCC (p=0.292). However, this study was limited by in mice.43 Case-control studies have shown that low
significant heterogeneity and limitations of mechanistic plasma selenium was associated with NMSC44 and
classification due to available data provided from melanomas.45 A prospective cohort study found that
original articles.32 baseline serum selenium was inversely associated with
both BCCs and SCCs.46 However, a multicentre, double-
Therefore, there is evidence that oral NSAIDS, including blind, randomised controlled trial with 1,312 participants
non-selective COX inhibitors, may reduce the rates of found that oral selenium at the dose of 200 mcg daily
skin cancer, including SCC and BCC. These drugs are did not significantly reduce BCCs or SCCs.47
likely photoprotective due to their ability to protect
the immune system from UVR and limit UVR-induced Plant-derived products
keratinocyte growth. However, NSAIDs are known Polypodium leucotomos (PL) is a tropical fern from
to be associated with significant side effects such the Phlebodium genus found in Central and South
as gastrointestinal toxicity, renal toxicity, and major America. PL contains polyphenolic compounds, mainly
cardiovascular events33, which limit their potential benzoate and cinnamate, and 4-hydroxycinnamic acid
widespread use as a chemopreventive agent for NMSC. (caffeic acid), which inhibits UV-induced peroxidation
and production of NO, while its derivative, ferulic acid,
Difluoromethylornithine is a UV photon acceptor. PL extracts have multiple
Difluoromethylornithine (DFMO) is a medication used to beneficial properties by protecting tissue damage and
treat hirsutism. DFMO inhibits ornithine decarboxylase, limiting inflammation. PL supplementation has been
which is a rate-limiting enzyme in the synthesis of shown to reduce UV-induced inflammation, facilitate
polyamines.34 Ornithine decarboxylase is induced the removal of photoproducts (CPDs), decrease
by UVB radiation and is upregulated in skin tumours UV-mediated oxidate DNA mutations, and has some
as compared to normal skin.35 Polyamines regulate protective effects against photoaging and PUVA
cell survival, and increased levels of polyamines are induced phototoxicity. Therefore, PL extracts could
associated with NMSC carcinogenesis.35 have significant implications in skin cancer prevention.
Furthermore, pharmacological surveillance of oral PL
An animal study in mice demonstrated that oral DFMO treatments conducted in Spain and South and Central
prevented UVR-induced immunosuppression as well as America shows that PL is well absorbed and has no
skin cancers.36 A double-blind, randomised controlled recognisable toxic effects. However, the necessary
trial with 291 patients who received oral DFMO 500 dosage of PL extracts are yet to be investigated, and
mg/m2/day for 4-5 years found a non-significant trend large scale randomised controlled trials are lacking.48
toward reduced new NMSC (260 versus 363 NMSC,
p=0.069), though it did demonstrate a significant An Australian study has suggested the protective
reduction in new BCCs (163 versus 243 BCCs, p=0.03). role of plant-based dietary products by showing
There was little difference in regard to the development that humans with a history of skin cancer showed a
of new SCCs.37 decreased risk of SCC tumours for high intakes of leafy
green vegetables (RR=0.45, 95% CI 0.22-0.91, p=0.02).49
The use of oral DFMO as a chemopreventive agent is Another Australian study published in 2009 by Hughes
limited by clinically significant side effects, including and colleagues performed a community-based study of
ototoxicity.38 1119 participants showed that AK acquisition decreased
by 27% (RR=0.73, 95% CI 0.54-0.99) in those with the
Vitamin D highest consumption of wine (average of half a glass per
Vitamin D is a fat-soluble vitamin that is essential day).50
for bone development. It has been shown to be anti-
proliferative, activates apoptotic pathways, and inhibits Garlic has been reported to have anti-tumoral
angiogenesis.39 There have been observational studies40 properties, including the inhibition of skin cancer.
and a randomised, controlled trial41 that suggest Aged garlic extract has increased stability and is
vitamin D reduces overall cancer incidence in humans. more consistent in composition compared to raw
A nested case-control study found that patients with garlic juice whilst still retaining biological activity.
the highest quintile of vitamin D had 47% lower odds When aged garlic was used to supplement the diets of
of having a history of NMSC when compared to those mice, it was found to reduce UVR-induced systemic
with the lowest quintile of vitamin D (p=0.026).42 suppression of hypersensitivity from 48% to 19% and
Further randomised controlled trials are necessary had a moderate protective effect against oedema.51
to determine if vitamin D effectively reduces NMSC Since garlic protected from cis-urocanic acid induced
incidence in humans. immunosuppression it has been suggested to work

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by antagonising the effect of this UVR induced observational studies.63 However, this finding was not
immunosuppressive mediator. replicated in two case-control studies.64,65

Tomatoes contain high concentrations of lycopene. Animal-derived products

Lycopene is a carotenoid that works as an effective Carnosine (b-alanylhistidine) is a histidine-containing
quencher of singlet oxygen. When given orally to dipeptide. Carnosine is found in high concentrations
humans, lycopene provides some protection against (1-20 mM) of mammalian muscle and brain and,
UVR induced erythema.52 A randomised control study therefore, is supplied by dietary intake of meat
on 20 healthy women who ingested 55 g tomato paste or poultry. When used as a dietary supplement,
(16 g lycopene) showed reduced UVR induced erythema, carnosine has been shown to reduce UVR-induced
UVR-induced matrix metalloproteinase-1 production, systemic immunosuppression in mice from 65% to 17%
and mitochondrial DNA damage.53 suppression.66 While studies have not elucidated how
carnosine mediates its photoprotective effect, it has
Goji berries (Lycium barbarum) are used in traditional antioxidant properties. In contrast, diets high in meat
Chinese medicine and are rich in antioxidants. A study and fats are associated with a higher risk of SCC.67
by Reeve and colleagues54 found that Skh:hr-1 mice Therefore, while carnosine could be photoprotective,
fed 5% goji berry juice in their water had reduced other animal meat or fat components may promote
UVR-induced oedema and immunosuppression. UVR-induced skin cancers.
Although the active ingredient that provided the
photoprotective effect was not ascertained, the authors Similarly, dietary butter fed to Skh:hr-1 mice has been
found that goji berry juice decreased UVA-induced lipid shown to protect against UVR induced suppression of
peroxidation. contact hypersensitivity, seemingly due to the fatty acid
composition of the butter.68
Pomegranate fruit has also been shown to be
photoprotective when fed to Skh:hr-1 mice. Diets rich in omega-3 fatty acids have been shown
Pomegranate has antioxidant and anti-inflammatory to be protective against UVB radiation-induced skin
properties, inhibiting UVB-induced oxidation of lipids carcinogenesis in mice as mice fed high-fat fish oil
and proteins, epidermal hyperplasia, and inflammation in their diet had increased latency before developing
of the skin. Pomegranate is able to prevent UVR-induced UVB-induced skin cancer and a reduced incidence of
activation of multiple signal transduction pathways, the tumours, partially due to a reduced inflammatory
including COX-2 and inducible NO synthase.55 response.69 A community-based study in Queensland
found that people with the highest consumption of oily
Monoterpenes include both perillyl alcohol and fish (average one serving every five days) compared
limonene. Perillyl alcohol is found in the oils of plants with those with minimal intake had a 28% reduction in
such as cherries, lavender, spearmint, and peppermint, AK acquisition (RR=0.72, 95% CI 0.55-0.95).50 Rhodes
while limonene is found in the peels of citrus fruits. and colleagues published a non-randomised study
Monoterpenes have been found to enhance the repair of in 1995 which showed that humans who received
photoproducts (CPDs) in cells.56 A case-control study on supplementation of fish oil rich in omega-3 fatty
470 participants found that consumption of citrus peel acids reduced both UVA and UVB radiation induced
reduced SCC risk (OR=0.66, p=0.03).57 inflammation, possibly by lowering PGE2 levels.70
Pilkington and colleagues published a randomised
Polyphenols are found in various plants, including most controlled trial of oral omega-3 supplementation in
legumes, many grains, some fruits, vegetables, honey, 79 volunteers and showed a photo immunosuppressive
red wine, chocolate, coffee and green tea. Polyphenols effect, postulating that this may translate into a
have an antioxidant, anti-inflammatory and immune chemopreventive role.71
protective properties. Many studies demonstrate the
power of polyphenols as a photoprotective agent.58,59 These studies provide evidence that while animal-
derived products do not protect from UVR, fats found
The stimulant compound caffeine, which is structurally in oily fish and other animal-derived products such as
similar to adenosine and acts as an antagonist of carnosine are likely to be photoprotective.
adenosine receptors60, has been shown to inhibit
UVB radiation-induced carcinogenesis in mice.61
Observational studies in humans have shown that Future direction
those with the highest quintile of caffeine compared to
those with the lowest quintile of caffeine intake had a Several novel agents have been proposed for
reduced BCC risk (RR=0.82 for women and 0.87 for men, chemoprevention; however, further studies are required
p<0.0001) although there was no association with SCC to support their use.
or melanoma.62 This finding has been mirrored in other

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Capecitabine is a prodrug of fluorouracil (5-FU) that and plant and animal-derived products are required.
has shown efficacy in the treatment of SCC. As a Multiple new agents are currently being investigated
monotherapy, administered orally at a dose of 1 g/m2 as chemopreventive agents for NMSC, including
divided into two daily doses on days 1-14 of a 21-day capecitabine, afamelanotide, and EGFR inhibitors.
treatment cycle in 14 organ transplant recipients with
recurrent NMSC, the difference in incidence rates of
SCC, BCC, and AK before and after treatment were References
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stimulant: mechanism of action. Cell Mol Life Sci 2004;61(7-
8):857-72.

61. Huang MT, Xie JG, Wang ZY, Ho CT, Lou YR, Wang CX, et al.
Effects of tea, decaffeinated tea, and caffeine on UVB light-
induced complete carcinogenesis in SKH-1 mice: demonstration
of caffeine as a biologically important constituent of tea. Cancer
Res 1997;57(13):2623-9.
62. Song F, Qureshi AA, Han J. Increased caffeine intake is
associated with reduced risk of basal cell carcinoma of the skin.
Cancer Res 2012;72(13):3282-9.

63. Miura K, Hughes MC, Green AC, van der Pols JC. Caffeine intake
and risk of basal cell and squamous cell carcinomas of the skin
in an 11-year prospective study. Eur J Nutr. 2014;53(2):511-20.

64. Corona R, Dogliotti E, D’Errico M, Sera F, Iavarone I, Baliva G, et

al. Risk factors for basal cell carcinoma in a Mediterranean
population: role of recreational sun exposure early in life. Arch
Dermatol 2001;137(9):1162-8.

65. Milan T, Verkasalo PK, Kaprio J, Koskenvuo M. Lifestyle

differences in twin pairs discordant for basal cell carcinoma of
the skin. Br J Dermatol 2003;149(1):115-23.

66. Reeve VE, Bosnic M, Rozinova E. Carnosine (beta-

Alanylhistidine) Protects from the Suppression of Contact
Hypersensitivity by Ultraviolet-B (280-320 nm) Radiation or by
cis Urocanic Acid. Immunology 1993;78(1):99-104.

67. Ibiebele TI, van der Pols JC, Hughes MC, Marks GC, Williams
GM, Green AC. Dietary pattern in association with squamous
cell carcinoma of the skin: a prospective study. Am J Clin Nutr
2007;85(5):1401-08.

68. Cope RB, Bosnic M, Boehm-wilcox C, Mohr D, Reeve VE.

Dietary Butter Protects Against Ultraviolet Radiation-Induced
Suppression Of Contact Hypersensitivity In Skh-Hr-1 Hairless
Mice. J Nutr 1996;126(3):681-92.

Australasian Society of Cosmetic Dermatologists / Opinions and Progress in Cosmetic Dermatology VOLUME 01 / ISSUE 03 / NOVEMBER 2021 33
 PHOTODAMAGE 1
Photodynamic Therapy for Superficial
Sun Damage
John R Sullivan1,2,3, Peter D Sharpe1
1. Kingsway Dermatology & Aesthetics, Miranda, NSW, Australia
2. The Sutherland Hospital, Caringbah, NSW, Australia
3. School of Medicine, University of NSW, Kensington, NSW, Australia
Correspondence: John Sullivan  John.Sullivan1@health.nsw.gov.au
Disclosures: John Sullivan Speaker for Candela APAC

OUTLINE: In sun-damaged skin photodynamic therapy (PDT) can have both therapeutic medical and cosmetic actions. PDT
is effective for the treatment of actinic keratosis, superficial (+/- thin nodular) basal cell carcinoma and Bowen’s disease
where it is a good option particularly in patients presenting with actinic field cancerisation skin changes. PDT has also been
used off-label for a range of skin diseases along with cosmetic dermatology particularly for photorejuvenation.

Sun damage, from UV radiation exposure, is responsible for a range of skin changes characterised as photoaging along
with the formation of precancerous and cancerous skin lesions. Aesthetic PDT indications include dyspigmentation, solar
lentigines, fine lines and wrinkles, mottled hyperpigmentation, telangiectasia, erythema, skin roughness and skin texture
changes including sallowness and actinic elastosis.

Laser-assisted PDT involves the skin’s laser pretreatment to enhance drug delivery of the photophore. This can be utilised to
enhance both actinic keratosis response, and photorejuvenation aesthetic outcomes.

Key steps in PDT involve skin preparation (fractional ablative laser in laser-assisted PDT), application of photophore
(5-aminolevulinic acid or methyl aminolevulinate), occlusion, an incubation period then illumination. Illumination can utilise
light-emitting diodes, laser, intense pulsed light, sunlight, or a combination of light sources.

The beneficial effects from PDT include upregulation of collagen production and decrease of elastotic material in the dermis.
Although traditional PDT is not as effective as more invasive techniques for the treatment of deep wrinkles and severe skin
laxity, repeated treatments and in particular laser-assisted PDT can be utilised to enhance aesthetic benefits.

KEYWORDS: photodynamic therapy, photoaging, photorejuvenation, laser-assisted drug delivery, intense pulsed light

Sullivan JR, Sharpe PD. Photodynamic Therapy for Superficial Sun Damage. Opin Prog Cosmet Dermatol 2021;1(3):35-40.

Introduction Photodynamic therapy for

skin rejuvenation
Aging is a multifactorial process influenced by
environmental, hormonal and genetic factors. This Photodynamic therapy (PDT) is an established treatment
results in functional and aesthetic changes in the skin. for actinic keratosis (AK), superficial basal cell carcinoma
The term photoaging highlights the importance sunlight and Bowen’s disease and utilised for both focal and field
and particularly ultraviolet radiation play in skin aging1 cancerisation treatments. The significant improvement
with its visible changes most evident in chronically sun in the signs of skin aging observed has resulted in
exposed areas including the face, neck, décolletage, clinical studies into PDT’s aesthetic benefits utilising
dorsum of hands and forearms. both 5-aminolevulinic acid (ALA)-PDT2,3 and methyl
aminolevulinate (MAL)-PDT.4 PDT has become an option
Sun damage is characterised by fine lines and wrinkles, to consider for skin photorejuvenation of sun-damaged
roughness, dryness, laxity, sallowness, dyspigmentation, skin because of its medical and aesthetic effects.
erythema and telangiectasias and can be associated
with premalignant and malignant skin lesions. These Aesthetic PDT indications include dyspigmentation,
highly visible areas are frequently the therapeutic target solar lentigines, fine lines and wrinkles, mottled
for aesthetic improvements. hyperpigmentation, telangiectasia, erythema, skin

Australasian Society of Cosmetic Dermatologists / Opinions and Progress in Cosmetic Dermatology VOLUME 01 / ISSUE 03 / NOVEMBER 2021 35
Photodynamic Therapy for Superficial Sun Damage | Sullivan and Sharpe

PHOTODAMAGE 1
roughness and skin texture changes including PDT has an oxygen-dependent direct phototoxic effect
sallowness and actinic elastosis.5,8 on target cells and as for skin cancer indications, when
used aesthetically, a reduction in epidermal atypical
The published studies utilise a range of regimens that cells is observed. PDT has been shown to modify
can differ from licensed protocols for the treatment of cytokine expression, induce immune-specific responses
AK and non-melanoma skin cancer. PDT is not licensed and cause vascular damage. There is a significant
for cosmetic indications and there are no standardised increase in skin thickness after MAL-PDT with an
guidelines for PDT in skin rejuvenation. Illumination increase in collagen and procollagen type I and III,
devices have on their own been shown to improve the along with a reduction in elastotic material and dermal
clinical signs of photoaging and include vascular laser inflammation.10 An increase in transforming growth
(pulsed dye laser [PDL]) and intense pulsed light (IPL) factor-beta and a decline in matrix metalloproteinases
which can have a synergistic effect on clinical outcome9 (MMP-1,-3 and MMP-12) has been observed, consistent
as demonstrated by split face studies utilising IPL and with increased collagen synthesis and reduced collagen
PDL.5,8 In laser-assisted PDT, the utilisation of fractional and elastin degradation.9 Markers of collagen synthesis
carbon dioxoide (CO2) laser and/or Erbium:YAG peak around 30 days after PDT and decline to day 60.9
(Er:YAG) laser prior to performing PDT increases Cosmetic benefits after utilising 0.5% liposome-
photophore delivery to enhance therapeutic PDT AK encapsulated ALA suggest a clinical inflammatory or
benefits and have their own direct and potentially phototoxic response is not required for all cosmetic
synergistic cosmetic skin benefits. benefits.13

Mechanism of action Pharmacology of ALA and MAL

PDT involves a photochemical reaction mediated Both ALA and MAL are prodrugs and require cell uptake
through the interaction of photosensitising agents, and transformation into their active form - PpIX -
light and oxygen. After application of the ALA or MAL within mitochondria. PpIX is the photosensitiser which
prodrug, there are significant differences in subsequent in the presence of oxygen is activated by light leading to
porphyrin accumulation seen between various tissues its phototoxic effects targeted on cells and tissues that
and cell types. Epidermal, sebaceous and in particular have absorbed, activated and accumulated the prodrug.
dysplastic and neoplastic cells accumulate both ALA
and MAL. This accumulation also occurs in blood vessel ALA is hydrophilic while MAL is lipophilic. The stratum
walls and in association with melanin. These are all corneum, the outermost layer of the skin, presents
important photorejuvenation and actinically damaged the main barrier to topical absorption particularly for
skin targets. hydrophilic compounds. Skin preparation prior to their
application is required to enhance penetration including
Most cells can transform ALA or MAL into porphyrins. topical keratolytic agents, curettage, abrasion, acetone
When an overwhelming quantity of the upstream and more recently fractional CO2 or Erbium laser in
porphyrin substrates (ALA) is supplied as in PDT, the laser-assisted PDT.
lipid-soluble protoporphyrin IX (PpIX) is predominately
accumulated in the target cells. This occurs because 20% ALA has been most utilised in aesthetic published
PpIX is the substrate for mitochondrial ferrochelatase, studies and in the same concentration used to treat
a rate-limiting enzyme in the porphyrin pathway. AK in the US (Levulan Kerastick Dusa Pharmaceuticals,
PpIX is largely responsible for the oxygen dependent Wilmington, MA).
phototoxicity reaction utilised therapeutically in PDT.10

After incubation, light is utilised to activate the Laser-assisted drug delivery

photosensitiser (PpIX) in the presence of oxygen. The
Soret band (approximately 405-420 nm blue light) Laser-assisted drug delivery (LADD) is a promising drug
represents the light excitation peak of PpIX, followed by delivery technique to enhance the efficacy of local skin
four much smaller peaks (known as Q bands). Q bands treatments. This involves (1) laser pretreatment followed
include green, yellow, orange and red (~635 nm) peaks. by (2) topical drug application aiming to (3) increase and
Blue light is about 50 times more effective for activating target the amount of drug that reaches the appropriate
PpIX than red light but has less depth of penetration skin component to improve treatment efficacy. The
(1-2 mm for blue vs ~4 mm for red).11 This makes blue best evidence for LADD is currently for PDT and AK
light highly effective for epidermal and upper papillary (ALA/MAL, Figure 1 and 2).14 The stratum corneum
dermal targets, and red light potentially better for deep is a tough barrier and its lipophilic nature makes it a
dermal penetration and targeting.11 formidable barrier particularly for hydrophilic (ALA)
or large substances. Ablative fractional lasers (AFL) are
an effective method used to overcome the epidermal

Australasian Society of Cosmetic Dermatologists / Opinions and Progress in Cosmetic Dermatology VOLUME 01 / ISSUE 03 / NOVEMBER 2021 36
Photodynamic Therapy for Superficial Sun Damage | Sullivan and Sharpe

PHOTODAMAGE 1
barrier. Absorption benefits plateau between 5-10% Patient skin preparation
density, with densities above 5% exerting only a
minimal additional effect.15 Greater density beyond 5%  Sun-protection before and after treatment assists
however can have aesthetic benefits but is associated treatment efficacy and reduces post-inflammatory
with greater severity skin reactions and downtime. For pigmentation risk.
hydrophilic molecules like ALA, greater laser channel
depth further enhances accelerated and increased  To facilitate more even and effective skin absorption
depth of drug deposition in skin layers (100 µm-750 of ALA and MAL, skin care during the 2 or more
µm-1500µm: corresponding to the dermoepidermal weeks prior to treatment, where appropriate, should
junction-superficial dermis-mid dermis) with the include either a topical α–hydroxy acid, salicylic
coagulation zone seen with the CO2 laser providing acid, retinoid and/or urea cream. The authors
a sponge to soak and draw in hydrophilic molecules commonly use a 4% lactic acid day and 10% lactic
and also provide a drug reservoir from which diffusion acid night cream for the face, neck or chest and a
occurs. For lipophilic drugs such as MAL, deeper laser combination lactic acid (10%) and urea (10%) cream
skin channels beyond 300 µm are not associated with twice a day for the dorsum of hands and forearms,
any further enhanced absorption. ALA/MAL should ceased the day before PDT treatment.
be applied within 30 minutes before significant pore
reduction starts to occur.  A series of superficial chemical peels has also been
utilised.
The disadvantages of laser-assisted PDT include greater
severity skin reactions, discomfort, exudate, and more  Topical 5% 5-fluorouracil cream daily for 6 days
frequent pustular skin reactions, but also a greater has been shown to increase PpIX levels in AK and
degree of tissue remodeling and cosmetic outcomes improves AK clearance response.16
including texture, dyspigmentation along with
enhanced field cancerisation improvement (Figure 3 and
4). When utilised away from the pilosebaceous gland Immediately before application
rich face, such as the neck, decolletage and hands, AFL of sensitizer
density greater than 5% and the use of deeper channels
should be utilised with care and caution. Topical anaesthetic cream should be considered prior
to ablative fractional laser treatment for laser-assisted
Non-ablative fractional laser (including erbium glass PDT.
and thulium) along with skin needling have also been
utilised however further study and quantification is Skin degreasing by wiping with gauze moistened with
required regarding LADD and PDT with these devices. acetone (or alcohol) can be performed particularly if
using hydrophilic ALA rather than hydrophobic MAL to
enhance its penetration. This is followed by:
Clinical assessment and patient selection
 Mechanical peeling such as sandpaper (or
As with all cosmetic treatments appropriate microdermabrasion) and/or
patient selection is key including managing patient
expectations and the strict need for sun avoidance in  Light curettage
the 48 hours following treatment.
 For laser assisted PDT this is followed by ablative
PDT is best utilised in fairer skin types. A reduced fractional laser (AFL) (Er:YAG or CO2)
PDT effect is seen in highly pigmented versus lighter
skin clinically and in animal models. There is also The authors usually combine curettage and AFL
a theoretically greater risk of post inflammatory based on AK study data. Consider anti-viral herpes
hyperpigmentation in darker skin types. This reduces prophylaxis where indicated.
the benefits and increases the risks of aesthetic PDT
when performed in darker skin types. Consideration
also needs to be given to the light source utilised based Laser-assisted PDT (AFL)
on patient skin type and skin changes being targeted.
Contraindications to PDT include porphyria, systemic  Density 5%.
lupus erythematosus and other photosensitivity
dermatoses along with allergy to MAL or excipients.  Depth 100 µm-300 µm (deeper channels of added
benefit for ALA but not MAL).

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Photodynamic Therapy for Superficial Sun Damage | Sullivan and Sharpe

PHOTODAMAGE 1
 Higher densities and deeper channels can be utilised improvement in crow’s feet, tactile roughness, mottled
for greater cosmetic benefits but are associated hyperpigmentation, facial erythema, and telangiectasia.
with greater severity skin reactions. IPL systems emit light in the wavelength range of
400-1200 nm. Depending on the IPL system and
 CO2 lasers produce a greater coagulation zone and handpiece this can variably span PpIX Soret band
may have drug delivery benefits over Er:YAG for peak and its four smaller Q bands. The variety of IPL
hydrophilic molecules such as ALA. handpieces (with differing wavelength ranges) along
with ability to vary pulse duration (single and double
pulses), pulse interval, energy density, and number
Application of prodrug of passes, all enhance the ability to target different
aesthetic skin changes but make comparing studies and
Formulations include 16.8% MAL cream, and 20% ALA devices used difficult.
spray or ointment. This is followed by occlusion and
incubation. Multiple IPL passes have been utilised and have
been associated with better AK response.18 PpIX skin
fluorescence monitoring can be used to assist enhance
Incubation period PDT treatment.19

MAL-Non-daylight For photorejuvenation indications, the authors

 3 hours (AK and NMSC) usually perform an initial IPL treatment pass with
settings based on patient skin type, tanning and skin
 2 hours (laser-assisted PDT)15 problem being targeted (e.g. telangiectasia, rosacea,
 Occlusion photorejuvenation) using the appropriate IPL handpiece
that incorporates 2-3 Q bands of PpIX. In patients with
MAL-Daylight AK, multiple passes are performed including utilising
 30 min (including laser-assisted PDT) a handpiece that includes the Soret band peak and
all four Q bands. The number of passes performed
ALA is guided by monitoring PpIX skin fluorescence
 120 min response (FluoDerm™ Denmark emitting wavelength:
400-420 nm; measuring excitation wavelength:
 90 min (laser-assisted PDT)15 610-720 nm).19 See Figures 1-4 for treatment examples.
 30-60 min purely aesthetic PDT
(including laser assisted PDT) Multiple treatment sessions of PDT with IPL may
be performed. Based on PDT studies, treatment
This should be performed in a warm room with intervals of 2 or more months9 can be considered for
protection of treated areas from visible light. Occlusion increased benefits and/or maintenance treatments.
should be routinely utilised during incubation to enhance The treatment parameters for PDT with IPL should be
photophore absorption (e.g., plastic cling film wrap). ideally based on published studies and PDT settings
validated for the device.

Illumination (aesthetic PDT)

PDT with red (and blue) light LED
Multiple light sources have been used successfully
including traditional PDT LED illumination and natural PDT with red LED light has been associated with
sunlight. For aesthetic PDT IPL is most commonly used improvement in mottled pigmentation, fine lines,
in reported studies. PDL has also been reported. Some roughness and sallowness (but not coarse wrinkles,
advocate use of multiple light sources during the same telangiectases, and facial erythema).9 Similar results
treatment such as IPL and/or PDL followed by LED. have been reported with blue light in regard to skin
photoaging.9 Differences in red and blue light in regard
Pulse durations in the millisecond range (IPL and to depth of skin penetration and photophore activation
PDL) compared to minutes with LED light have been and whether these affect cosmetic outcomes have not
associated with less pain.17 been specifically addressed by a controlled study.

PDT with intense pulsed light PDT with pulsed dye laser

IPL is used in PDT photorejuvenation and has in Activation with 595 nm PDL, which corresponds to the
split face studies been shown to be superior to IPL third (orange) Q band of PpIX, has shown greater global
alone.5,8 IPL PDT photorejuvenation benefits include photodamage improvement than blue light including

Australasian Society of Cosmetic Dermatologists / Opinions and Progress in Cosmetic Dermatology VOLUME 01 / ISSUE 03 / NOVEMBER 2021 38
Photodynamic Therapy for Superficial Sun Damage | Sullivan and Sharpe

PHOTODAMAGE 1
telangiectasia and erythema.20 This is similar to the Summary
synergy observed with PDT-enhanced IPL.
PDT is a promising treatment for sun-damaged skin
combining both medical and aesthetic benefits.
Pain management Licensed PDT protocols for AK field treatment are
associated with cosmetic skin benefits. PDT should
Premedication and topical anaesthetic prior to AFL for also be considered for the treatment of skin aging and
laser-assisted PDT should be considered. photoaging. Pre-treatment with fractional ablative
laser (best validated for CO2) represents an advanced
The application of ALA (and less so MAL) after AFL option that improves photosensitiser absorption and
leads to brief but intense stinging; the authors offer therapeutic outcomes, including AK clearance and
nitrous oxide analgesia to address this when treating photorejuvenation. For solar lentigo, dyschromia,
larger areas. Pain with conventional LED (greater with telangiectasia, erythema, and fine lines, IPL illumination
red versus blue light) illumination generally develops has been best studied. Further studies are required
quickly after the start of irradiation, cumulates - including those that compare light sources, PDT
during irradiation, and decreases over several hours therapy protocols for photorejuvenation - to better
following irradiation. Pain is generally less severe for quantify laser-assisted PDT for aesthetic photoaging
aesthetic millisecond IPL activation compared with treatment outcomes.
LED illumination.15 Cryo cooled air during and after
irradiation can be utilised and nerve blocks considered.
Post treatment cooling with saline compresses, cold
cream and/or ice packs can also be considered.

Figure 1 Figure 2
Baseline actinically Week 5 post laser-assisted
damaged scalp and PDT treatment. 5% CO2
forehead of a 77-year-old. fractionated laser with
Field cancerisation including 300 µm depth channels to
actinic keratoses, in situ field, targeting of clinical
squamous cell carcinoma. lesions with 700 µm
Laser-assisted PDT depth channels, 16.8%
performed as part of his MAL, 120 min incubation,
skin cancer management. illumination IPL, 4-5 passes
400-720 nm range, single
pulse 30 ms 3.4 J/cm2
indicated for PDT.
Fluorometer® Denmark pre
and post skin fluorescence
measurements utilised
to guide and assess
photophore activation.
Good field benefits have
been maintained 2 years
post single treatment.

Figure 3 Figure 4
Baseline face and neck of Post single laser-assisted
a 62-year-old female with PDT treatment. 5% CO2
skin changes of photoaging. fractionated laser with
300 µm depth channels,
20% ALA, 90 min incubation,
IPL, first pass 555-950 nm
range, double pulses of
2.5 ms, 10 ms pause,
9.6 J/cm2 indicated for
rosacea, telangiectasia and
photorejuvenation then 2nd
and 3rd passes 400-720 nm
range, single pulse 30 ms
3.4 J/cm2 indicated for PDT.

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PHOTODAMAGE 1
References 17. Babilas P, Knobler R, Hummel S, Gottschaller C, Maisch T,
Koller M, et al. Variable pulsed light is less painful than light-
emitting diodes for topical photodynamic therapy of actinic
1. Farage MA, Miller KW, Elsner P, Maibach HI. Intrinsic and
keratosis: a prospective randomized controlled trial. Br J
extrinsic factors in skin ageing: a review. Int J Cosmet Sci.
Dermatol. 2007;157:111–7.
2008;30(2):87-95.
18. Haddad A, Santos ID, Gragnani A, Ferreira LM. The effects of
2. Ruiz-Rodriguez R, Sanz-Sanchez T, Cordoba S. Photodynamic
increasing fluence on the treatment of actinic keratosis and
photorejuvenation. Dermatol Surg. 2002;28:742–4.
photodamage by photodynamic therapy with 5-aminolevulinic
3. Touma D, Yaar M, Whitehead S, Konnikov N, Gilchrest BA. A acid and intense pulsed light. Photomed Las Surg. 2011;29:427–
trial of short incubation, broad-area photodynamic therapy 32.
for facial actinic keratoses and diffuse photodamage. Arch
19. Bjerring P, Christiansen MS, Troillus A. Skin fluorescence
Dermatol. 2004;140:33–40.
controlled photodynamic photorejuventation (wrinkle
4. Palm MD, Goldman MP. Safety and efficacy comparison of reduction). Laser Surg Med. 2009;41:327-36.
blue versus red light sources for photodynamic therapy
20. Key DJ. Aminolevulinic acid-pulsed dye laser photodynamic
using methyl aminolevulinate in photodamaged skin. J Drugs
therapy for the treatment of photoaging. Cosmet Dermatol.
Dermatol. 2011;10:53–60.
2005;18:31-6.
5. Alster TS, Tanzi EL, Welsh CW. Photorejuvenation of facial skin
with 20% 5-aminolevulinic acid and intense pulsed light. J Drug
Dermatol. 2005;4:35-38.

6. Szeimies RM, Torezan L, Niwa A, Valente N, Unger P,

Kohl E, Schreml S, et al. Clinical, histopathological and
immunohistochemical assessment of human skin field
cancerization before and after photodynamic therapy. Br J
Dermatol. 2012;167:150-9.
7. Kohl E, Torezan LAR, Landthaler M, Szeimies RM. Aesthetic
effects of topical photodynamic therapy. J Eur Acad Dermatol
Venereol. 2010;24:1261–9.

8. Gold M, Bradshaw VL, Boring MM, Bridges TM, Biron JA.

Split-face comparison of photodynamic therapy with
5-aminolevulinic acid and intense pulsed light versus
intense pulsed light alone for photodamage. Deramtol Surg.
2006;32:795-801.

9. Karrer S, Kohl E, Feise K, Hiepe-Wegener D, Lischner S, Philipp-

Dormston W, et al. Photodynamic therapy for skin rejuvenation:
review and summary of the literature – results of a consensus
conference of an expert group for aesthetic photodynamic
therapy. J Dtsch Dermatol Ges. 2013.11(2):137-48.

10. Fritsch C, Lehmann P, Stahl W, Schulte KW, Blohm E, Lang

K, et al. Optimum porphyrin accumulation in epithelial skin
tumours and psoriatic lesions after topical application of delta-
aminolaevulinic acid. Br J Cancer.1999:79(9/10);1603-08.
11. Clement M, Daniel G, Trelles M. Optimising the design of a
broad band light source for the treatment of skin. J Cosmetic
Laser Ther. 2005;7:177–89.

12. Zane C, Capezzera R, Sala R, Venturini M, Calzavara-Pinton P.

Clinical and echographic analysis of photodynamic therapy
using methylaminolevulinate as sensitizer in the treatment of
photodamaged facial skin. Lasers Surg Med. 2007;39:203–9.

13. Christiansen K, Bjerring P, Troilius A. 5-ALA for photodynamic

photorejuvenation-optimization of treatment regime based on
normal-skin. Lasers Surg Med. 39;302-10.

14. Steeb T, Schlager JG, Kohl C, Ruzicka T, Heppt MV, Berking C.

Laser-assisted photodynamic therapy for actinic keratosis.
A systematic review and meta-analysis. J Am Acad Dermatol.
2019;80(4):947-56.

15. Haak CS, Christiansen K, Erlendsson AM, Taudorf EH, Thaysen-

Petersen D, Wulf HC, et al. Ablative fractional laser enhances
MAL-induced PpIX accumulation: Impact of laser channel
density, incubation time and drug concentration. J Photochem.
2016;159:42-8.

16. Maytin EV, Anand S, Riha M, Lohser S, Tellez A, Ishak R, et

al. 5-Fluorouracil enhances protoporphyrin IX accumulation
and lesion clearance during photodynamic therapy of actinic
keratoses: a mechanism-based clinical trial. Clin Cancer Res.
2018;24(13),3026-35.

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 PHOTODAMAGE 1
Energy-Based Devices
for Treatment of
Photodamaged Skin
Monique Mackenzie1, Shobhan Manoharan1
Dr. Shobhan Manoharan
1. Brisbane Skin, Queensland, Australia
CLICK IMAGE TO LINK TO VIDEO DUR ATION_00:39
Correspondence: Monique Mackenzie  mackenzie.monique@gmail.com
Disclosures: none

OUTLINE: The skin absorbs ultraviolet (UV) radiation as the body’s first line of defence against the sun and its harmful
effects on cellular DNA. Over time, absorption of UV light results in permanent and visible changes on the skin, including
dyschromia, increased vascularity, laxity, and rhytides. This article outlines the principles of using modern energy-
based devices such as intense pulsed light (IPL), laser devices, and radiofrequency needling to treat common signs of
photodamaged skin.

KEYWORDS: photodamaged skin, intense pulsed light, laser, fractional lasers, radiofrequency needling

Mackenzie M, Manoharan S. Energy-Based Devices for Treatment of Photodamaged Skin. Opin Prog Cosmet Dermatol 2021;1(3):42-47.

Introduction While Finsen’s discovery opened a whole new field

of radiation medicine, it was not until the 1960s that
Photodamage of the skin is caused by extrinsic the first working 694 nm Ruby laser came into use.
exposure to ultraviolet A (UVA) (320–400 nm) and During an investigation on the safety of low-level laser
UVB (290–320 nm) light spectrums. Over time, UV irradiation and the potential risk of skin dysplasia
radiation causes damage to the skin via free radical (which was later discredited), it was discovered to
DNA damage, altered inflammatory pathways and accelerate wound healing.8,9 With the potential for
abnormal elastotic protein formation.1,2,3 As a result, enhanced skin repair and remodelling, subsequent
collagen and elastin fibres become disorganised murine and human studies identified several
and reduce in number, whilst melanocyte and fundamental mechanisms responsible for enhanced
melanosome activity can be locally increased. These skin repair. Mechanisms included enhanced cell
changes eventually result in the characteristic signs respiration and mitochondrial ATP synthesis, reduced
of photoaging including dyschromia, increased oxidative stress, and altered gene expression favouring
vascularity, skin laxity, fine lines and deeper rhytids. cellular repair.10
Whilst traditional therapies such as topical retinols,
hydroquinone, chemical peeling, microdermabrasion By using light energy, either non-coherent (e.g. IPL) or
and cosmetic injectables can effectively treat some monochromatic coherent (e.g. laser) light at specific
aspects of photodamage, energy-based devices are wavelengths, clinicians can target skin cell types
now commonplace as either stand-alone treatments and tissue chromophores based on their absorption
or in conjunction with other therapies. Their excellent characteristics and principles of selective photo
safety profile and shorter recovery times have also thermolysis.11 Melanin, for example, has a relatively
made them popular with patients who report increased linear absorption spectrum ranging from 335 nm and
overall satisfaction with energy-based treatments.4,5 decreasing exponentially to near-infrared wavelengths
at 1100 nm. Thus, Q-switched and picosecond 532 nm,
The benefits of light therapy to treat skin disorders can 670 nm and 1064 nm lasers can be effective in targeting
be dated back to ancient Egypt; however, it was not melanin at several points along this line. Haemoglobin,
until 1903 when Niels Finsen received a Nobel Prize however, has several peaks along the coefficient
for his work using concentrated light radiation to treat absorption curve, 418 nm, 542 nm, 577 nm and 1064 nm,
cutaneous tuberculosis that the therapeutic benefits which can be specifically targeted to cause optimal
of light or light energy was beginning to be realised.6,7 vascular ablation (Table 1).11,12 Modern energy-based

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PHOTODAMAGE 1
devices can optimally cause cell lysis and protein very quickly using an electric switch, be turned
denaturation with minimal surrounding tissue damage opaque to allow that light to escape momentarily.13
whilst associated biomodulatory responses enhance Q-Switched (QS) nanosecond lasers, including the QS
cell repair. Ruby, QS Alexandrite and QS Nd:YAG, have produced
excellent results in treating epidermal and dermal
Hence, with an improved understanding of the pigmentation.14,15,16
deleterious effects of UV radiation on skin and
the biophysics of energy-based devices, signs Newer picosecond lasers in 532 nm, 755 nm and
of photodamage can be effectively treated with 1064 nm wavelengths can deliver pulse durations of
sophisticated technologies such as IPL, non-ablative 300–900 picoseconds. Their mechanism of action is via
and ablative lasers. photoacoustic damage rather than photothermolysis.17
Due to their increased selectivity, treatments are safer,
particularly for individuals with darker skin types (III-VI)
Dyschromia who have previously been excluded from energy-based
light therapies due to the risk of post-inflammatory
Q-switched nanosecond lasers, picosecond lasers hyperpigmentation and poor-quality response to
and intense pulsed light treatments.
Chronic sun exposure is the primary determinant of the
development of solar lentigines, a common presentation For most epidermal pigmented lesions such as solar
resulting in uneven skin colour and possibly texture. lentigines, Q-switched nanosecond and picosecond
More common in Fitzpatrick skin type I-II,5 solar lasers between the range of 500–755 nm are utilised.5
lentigines should be carefully differentiated from other However, IPL is versatile with the ability to target
similar appearing lesions such as ephelides, lentigo pigmentation and increased vascularity at the same
simplex, familial lentiginoses, melanocytic naevi and time. Furthermore, due to larger spot sizes, areas of
melanoma. the body, notably legs, decolletage, dorsal hands and
arms, can be treated more efficiently.
Initially, treatment for solar lentigines had been
limited to topical and physical therapies such IPL differs from laser systems by emitting broadband
as retinol, hydroquinone, chemical peeling, (500–1200 nm), non-coherent light, then using filters to
electrodesiccation or cryotherapy. However, energy- select the light wavelengths which are emitted to the
based devices now provide superior accuracy in treating skin. However, a significant limitation is a requirement
excess pigmentation with minimal surrounding tissue for high contrast levels between the target areas of
damage. Lasers used to treat photopigmentation can concern and the background skin. This requirement,
be generally divided into three broad categories: (1) IPL therefore, limits treatments for dyschromia with IPL
and Q-switched nanosecond and picosecond lasers; (2) mainly to Fitzpatrick skin-types I-II.
ablative lasers, and (3) fractional non-ablative lasers
(e.g. Thulium 1927 nm laser). Occasionally ablative resurfacing lasers may be used
for discrete lentigines, especially those which are
Melanosome apoptosis occurs via selective photo palpable. The CO2 and Erbium:YAG lasers may both
thermolysis,10 whereby a wavelength is selected to be employed in this setting. The risk of hyper and
achieve maximum absorption of light and, therefore, hypopigmentation increases with ablative devices in
heat energy by the target chromophore, in this case, this setting and must be used with care.
melanin. Melanin’s relatively broad light absorption
spectrum (250–1200 nm) crosses both the vascular
(haemoglobin) and water spectrums, offering unique Increased vascularity
advantages and disadvantages in its treatment.
However, it is generally accepted that wavelengths of Pulse dye laser, KTP laser and intense pulsed light
532 nm (potassium titanyl phosphate; KTP), 690 nm Lighter skin types will often present with considerable
(Ruby), 755 nm (Alexandrite) and 1064 nm neodymium vascular changes as a result of photodamage.
yttrium aluminium garnet (Nd:YAG) lasers are most Therefore, careful assessment is required to ensure
useful for the treatment of epidermal and dermal alternate diagnoses are not missed, including rosacea,
pigmentation. seborrhoeic or photo contact dermatitis, systemic
lupus erythematosus, and dermatomyositis, all of
Due to melanin’s small particle size (sub-micrometre), which may require further medical evaluation and
ultra-short pulses of light are now considered optimal systemic treatments. Typical vascular changes
when targeting pigment. Q-switching, invented in associated with photodamage include erythema,
1962, allows a higher number of excited photos to telangiectasia and poikiloderma.
build up using Pockel cells with in the laser. These
contain crystals, which can propagate light and then,

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Pulsed dye laser (PDL) with a wavelength of 585 nm or Rhytides and laxity
595 nm, is considered the gold standard treatment for
increased vascularity associated with photodamage. Fully ablative laser resurfacing
The mechanism of action involves selecting for the Ablative laser resurfacing, primarily with the CO2
haemoglobin chromophore with enough fluence to or Erbium:YAG lasers, is often considered the gold
cause coagulation of the blood vessel and formation standard for treating moderate to severe photodamaged
of fibrosis permanently ablating the vessel. In skin and features such as rhytides, wrinkles and
telangiectasia, haemoglobin is the target chromophore dyschromia.19,20
found at various oxygenation states. Oxygenated
haemoglobin (oxyhemoglobin) has several absorption Ablative lasers vaporise tissue, exfoliate, cause tissue
peaks along the absorption coefficient curve, including contraction and result in collagen synthesis. They
418 nm, 524 nm, 577 nm and 1064 nm.5,12 Given that the produce significant improvements (Figure 1) with
first and second peaks overlap with important melanin tone, texture, and pigmentation. They often require
absorption spectrums, the optimal target wavelengths less treatment sessions but are also associated
have been established between 580 nm and 590 nm. with prolonged recovery time and increased risk of
complications and side effects.
Once the appropriate wavelength has been selected
a pulse duration based on the calibre of the vessel Complications from ablative laser resurfacing include
and subsequent thermal relaxation time will result in infection, prolonged erythema, hyperpigmentation,
maximum thermal damage to the vessel with minimal delayed hypopigmentation and scarring.
surrounding tissue damage. When treating small but
visible telangiectasia of less than 0.5 mm on the face, Patients need to be counselled regarding the length
pulse duration may range between 0.45 to 3 ms. of healing after ablative resurfacing and potential
complications, and if not suited, be directed towards
The endpoint for telangiectasia is either the fractional ablative or non-ablative resurfacing.
disappearance of vessels or purpura. Patients must be
counselled on possible vessel rupture causing purpura Fractional ablative resurfacing
lasting up to 7 days. However, this risk can be minimised Fractional ablative resurfacing involves delivering
with tissue cooling pre- and post-treatment and careful the CO2 or Erbium:YAG laser energy in microscopic
device settings. columns, or ‘micro-thermal zones’, to ablate segments
of the skin while sparing intervening tissue. As the bulk
Potassium titanyl phosphate (KTP) 532 nm lasers, of the skin surface is left unaffected, recovery time is
Alexandrite 755 nm, Nd:YAG 1064 nm and IPL with significantly reduced.5 It also allows for treating areas
vascular filters are also valuable devices for treating other than the face, darker skin types and compromised
facial erythema and telangiectasia. KTP and newer tissue (e.g. keloid and burn scars).
lithium triborate (LBO) containing 532 nm lasers target
oxyhaemoglobin closest to the 524 nm absorption Improvements with fractional ablative resurfacing may
peak, making them highly effective in targeting be more modest than traditional ablative resurfacing.
facial vascularities.18 Greater absorption overlap A study of fractional resurfacing versus fully ablative
with melanin, however, can result in more diffuse resurfacing with the Erbium:YAG laser for facial
inflammation compared with other vascular lasers. rejuvenation showed that mean epidermal thickness
Larger facial vessels usually require Nd:YAG 1064 nm improved with just one ablative session, compared with
laser, targeting deeper vessels of diameters greater four fractional sessions.21
than 0.5 mm. Longer pulse durations are selected
to match tissue relaxation times of vessels ranging Thus, treatment protocols generally require
between 15–50 ms. Additional care is required to avoid 2-6 treatments for significant improvements with
coagulation of deeper arteries, such as the alar artery photodamage, dyschromia and deep rhytides.
around the nose. The reduced risk of post inflammatory
hyperpigmentation in patients with skin of colour is of Fractional non-ablative resurfacing
added advantage. Non-ablative fractional resurfacing (NAFR) relatively
spares the epidermis while sending micro-thermal
IPL (500–1200 nm), similar to its use in treating zones into the dermis. Depending on the wavelength,
dyschromia, has the advantage of larger spot sizes fluence and density, NAFR lasers may improve
suitable for treating larger body areas and can be photodamage induced pigment, texture and fine lines
particularly useful in treating poikiloderma of Civatte by promoting collagen remodelling following controlled
of the neck. dermal injury (Figure 2).22

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PHOTODAMAGE 1
Commonly utilised wavelengths include the 1540 nm too has less downtime and complications than ablative
and 1550 nm Erbium:Glass and the 1927 nm Thulium.23 procedures.
More novel wavelengths include 1440 nm, which has
shown efficacy for photodamage.24 MFR utilises radiofrequency energy through insulated
or non-insulated microneedles, precisely delivering
The advantages of NAFR, and the reasons for its energy at the required depths and stimulating and
popularity, include the low downtime (typically inducing collagen modelling and regeneration.
1-7 days), option to treat all skin types with less risk
of dyschromia, and high safety profile with less risk MFR is particularly useful for darker skin types
of side effects and complications (Figure 2). as it is less likely to provoke post-inflammatory
hyperpigmentation than fractional lasers. A split-
Results are more modest than fully ablative and face study of Chinese women showed significant
fractional ablative lasers, and generally, a series improvement in deeper rhytides, fine lines, pore size
of treatments spaced at least a month apart is and skin texture, both related to photoaging and
recommended.25 intrinsic aging.26

Novel hybrid lasers

Lasers emerging in prominence in the market include Summary
hybrid devices, such as those incorporating ablative
Erbium:YAG laser to vaporise 100 microns into the As a result of chronic UV radiation, signs of skin ageing
epidermis and non-ablative (1470 nm) settings to become more visible with time, including dyschromia,
coagulate 100 to 700 microns to the epidermis and increased vascularity, laxity and rhytides. Tissue
dermis.23 chromophores such as melanin, haemoglobin and water
can be selectively targeted by choosing the appropriate
These allow for treatment of both epidermal energy-based device and corresponding wavelength.
photodamage and dermal remodelling, with less In addition to selective photothermolysis, low-level
downtime than purely ablative lasers. irradiation also promotes cellular repair pathways
and dermal collagen remodelling. Parameter settings
must be selected with care and a good understanding
Radiofrequency microneedling of the effect on the target tissue for optimum safety
and efficacy. In combination or alone, energy-based
Microneedle fractional radiofrequency (MFR) has also devices including IPL, laser and radiofrequency needling
become an option for skin rejuvenation in photoaging, have become powerful and effective tools for treating
particularly for wrinkles, fine lines and texture, as it photodamaged skin.

Table 1. Skin tissue chromophores and corresponding energy-based devices

Tissue chromophore Energy-based device

Melanin IPL 500 – 1200 nm

335 nm – 1100 nm
Q-switched and Picosecond lasers 532 nm, 670 nm, 755 nm and 1064 nm

Haemoglobin PDL 585 nm and 595 nm

418 nm, 542 nm, 577 nm and 1064 nm
KTP 532 nm laser
Alexandrite 755 nm
Nd:YAG 1064 nm laser
IPL 500 – 1200 nm laser

Water Erb:YAG 2940 nm laser

1064 nm – 10,600 nm
CO2 10,600 nm laser
Erbium:Glass 1540 nm and 1550 nm laser
Thulium 1927 nm laser

Erb:YAG, Erbium-doped yttrium-aluminium-garnet; IPL, Intense Pulsed Light; KTP, potassium titanyl phosphate; Nd:YAG, neodymium:yttrium-aluminium-
garnet; PDL, Pulsed Dye Laser; Q-switched, quality switched

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PHOTODAMAGE 1
Figure 1. 55-year-old female patient treated with combination IPL and Erbium:Glass 1550 nm for dyschromia, vascularity and texture

Photograph courtesy of Dr S Manoharan

Figure 2. 65-year-old female patient treated with one session of fully ablative CO2 resurfacing for lentigines, rhytids, tone and texture

Photograph courtesy of Dr S Manoharan

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PHOTODAMAGE 1
References 21. El-Domyati M, Abd-El-Raheem T, Abdel-Wahab H. Fractional
versus ablative erbium: yttrium-aluminium-garnet laser
resurfacing for facial rejuvenation; an objective evaluation. J Am
1. Rabe JH, Mamelak AJ, McElgunn PJ, Morison WL, Sauder DN.
Acad Dermatol. 2013;68(1); 103-12.
Photoaging: mechanisms and repair. J Am Acad Dermatol.
2006;55(1):1-19. 22. Ruiz-Esparza J. Painless, non-ablative, immediate skin
contraction induced by low-fluence irradiation with new
2. Marrot L, Meunier JR. Skin DNA photodamage and its biological
infrared device: a report of 25 patients. Dermatol Surg. 2006;
consequences. J Am Acad Dermatol. 2008;58(5 Suppl 2): S139-48.
32:601-10.
3. Gromkowska-Kępka KJ, Puścion-Jakubik A, Markiewicz-
23. Brauer JA, Alabdulrazzaq H, Bae YS, Geronemus RG. Evaluation
Żukowska R, Socha K. The impact of ultraviolet radiation on
of a Low Energy, Low Density, Non-Ablative Fractional 1927 nm
skin photoaging - review of in vitro studies. J Cosmet Dermatol.
Wavelength Laser for Facial Skin Resurfacing. J Drugs Dermatol.
2021 Mar 2. doi: 10.1111/jocd.14033.
2015;14(11):1262-7.
4. Han A, Chien AL, Kang S. Photoaging. Dermatol Clin.
24. Wang B, Deng YX, Yan S, Xie HF, Li J, Jian D. Efficacy of
2014;32(3):291-9.
non-ablative fractional 1440-nm laser therapy of treatment
5. Alexiades M, Zubek A. Cosmetic Dermatologic Surgery. Wolters of facial acne scars in patients with rosacea: a prospective,
Kluwer; 2019. 84 – 212p. interventional study. Lasers Med Sci. 2021;36(3):649-55.
6. Honigsmann H. History of phototherapy in dermatology.
25. Hunzeker CM, Weiss ET, Geronemus RG. Fractionated CO2 laser
Photochem Photobiol Sci. 2013; 12:16-21.
resurfacing: our experience with more than 2000 treatments.
7. Møller KI, Kongshoj B, Philipsen PA, Thomsen VO, Wulf HC. Aesthet Surg J. 2009;29(4):317-22.
How Finsen’s light cured lupus vulgaris. Photodermatol
26. Liu T, Sun Y, Tang Z, Li Y. Microneedle fractional radiofrequency
Photoimmunol Photomed. 2005;21(3):118-24.
treatment of facial photoaging as assessed in a split-face model.
8. Mester E, Spiry T, Szende B. Tota J. Effect of laser rays on Clin Exp Dermatol. 2019;44(4):e96-e102.
wound healing. Am J Surg 1971;122(4):532-5.

9. Mester E, Mester A, Mester A. The biomedical effects of laser

application. Lasers Surg Med. 1985;5(1):31-9.

10. Glass GE. Photobiomodulation: A review of the molecular

evidence for low level light therapy. J Plast Reconstr Aesthet
Surg. 2021;74(5):1050-60.

11. Anderson RR, Parrish JA. The Optics of Human Skin. Journal of
Investigative Dermatology 1981;77(1):13-19.

12. Burns T, Breathnach S, Cox NH, Griffiths C. Rook’s textbook of

dermatology. John Wiley & Sons Inc, Wiley-Blackwell publishing
2016. 595 - 611p.

13. Patil UA, Dhami LD. Overview of lasers. Indian J Plast Surg.
2008;41(Suppl): S101-S113.

14. Tse Y, Levine VJ, McClain SA, Ashinoff R. The removal of

cutaneous pigmented lesions with the Q-switched ruby
laser and the Q-switched neodymium: yttrium-aluminium-
garnet laser. A comparative study. J Dermatol Surg Oncol.
1994;20(12):795-800.

15. Kilmer SL, Wheeland RG, Goldberg DJ, Anderson RR. Treatment
of epidermal pigmented lesions with the frequency-doubled
Q-switched Nd:YAG laser. A controlled, single-impact, dose-
response, multicenter trial. Arch Dermatol. 1994;130(12):1515-9

16. Shimbashi T, Kamide R, Hashimoto T. Long-term follow-up

in treatment of solar lentigo and café-au-lait macules with
Q-switched ruby laser. Aesthetic Plast Surg. 1997;21(6):445-8.

17. Wu DC, Goldman MP, Wat H, Chan HHL. A Systematic

Review of Picosecond Laser in Dermatology: Evidence and
Recommendations. Lasers Surg Med. 2021;53(1):9-49.

18. Uebelhoer NS, Bogle MA, Stewart B, Arndt KA, Dover JS. A split-
face comparison study of pulsed 532-nm KTP laser and 595-nm
pulsed dye laser in the treatment of facial telangiectasias
and diffuse telangiectatic facial erythema. Dermatol Surg.
2007;33(4):441-8.

19. Preissig J, Hamilton K, Markus R. Current laser resurfacing

technologies: a review that Delves Beneath the surface. Semin
Plast Surg. 2012:26(3):109-16.

20. Mani N, Pajk F, Vizintin Z. Full-face skin resurfacing using a

combination of fractional and full spot ablative 2940 nm erbium
laser. J Cosmet Dermatol. 2021;20(1):110-15.

Australasian Society of Cosmetic Dermatologists / Opinions and Progress in Cosmetic Dermatology VOLUME 01 / ISSUE 03 / NOVEMBER 2021 47
 PHOTODAMAGE 1
Commentary: Are Deeper Laser Treatments
Advantageous in Treating Solar Dysplasia?
Davin Lim1
1. Cutis Clinic, Queensland, Australia
Correspondence: Davin Lim  info@drdavinlim.com
Disclosures: none

OUTLINE: When it comes to solar dysplasia and epidermal ablation, is more necessarily better?

KEYWORDS: solar dysplasia, solar keratosis, fractional laser, 1927 nm thulium

Lim D. Commentary: Are Deeper Laser Treatments Advantageous in Treating Solar Dysplasia? Opin Prog Cosmet Dermatol 2021;1(3):48-49.

H
ere’s a thought. An energy device that provides The first report of non-ablative fractional lasers for
deep ablation should give the highest clearance the treatment of solar keratosis was in 2013. Weiss et
for solar dysplasia. Logically, absolute ablation al. showed promising results in 24 participants with
of the entire epidermis should give the best clearance facial solar keratoses. At 1-, 3-, and 6-month follow-up,
and remission, as histologically solar keratoses are participants exhibited 91.3%, 87.3%, and 86.6%
confined to the epidermis. The question is do we really reduction in lesion counts, respectively, with on-label
need to abate the entire epidermis to give good results? laser densities of up to 70% with four treatments.7

Initial reports of fully ablative laser resurfacing gave Our group has demonstrated that super dense 1927 nm
us exciting news. Clearances between 92-100% were thulium with high densities of 92-94% adds a mere 36
obtained with CO2 and erbium resurfacing.1,2,3 More to 48 hours downtime compared to a maximum on-label
recent studies have shown that remission rates density of 70%. Solar keratosis clearance rates of up
following both fully ablative and deep fractional ablative to 85% have been sustained for 6 months using this
lasers are on par with 5-fluorouracil and in most cases protocol. Additionally, using high power settings and
inferior to photodynamic therapy and in the order of super densities, the stratum corneum is still preserved
44-80%.4,5,6 The question arises: are ablative lasers (Figure 1). With these parameters, 1927 nm thulium
still relevant? Yes, for the treatment of other aspects still remains non-ablative with laser induced changes
of solar damage, namely in the management of solar confined to the epidermis and upper papillary dermis.
elastosis and deep rhytides, fully ablative lasers do Preservation of the stratum corneum maintains skin
offer excellent aesthetic outcomes, however superficial barrier function. This reduces potential side effects
non-ablative wavelengths have been shown to have such as infection, poor healing and subsequent scarring.
similar clearances for solar keratosis. It also markedly accelerates healing.

The 1927 nm thulium wavelength is non-ablative, All field cancerization treatments are associated with
meaning it preserves the stratum corneum. Common recurrence of solar keratosis as ultraviolet (UV)-induced
on-label densities range from 3-70%. The chromophore mutations occur within the epidermis and in the
for this wavelength is water, however it has 10 times epithelium of follicular units. Hence the rate limiting
lower affinity for this target compared to ablative lasers. factor that determines sustained efficacy may not be
Compared to ablative lasers the depth of penetration the complete destruction of the epidermal layer, but
is over twenty times less - typically 150 to 250 microns the burden of dysplasia in deeper adnexal units. These
for 1927 nm thulium, compared to 4,000 microns for structures are located much deeper compared to the
short pulse CO2 lasers. Hence the histological level of safe depth profile of even the powerful ablative lasers.
laser induced apoptotic changes from 1927 nm thulium
are confined to the epidermis and the upper papillary Over the past decade we have realised that deeper
dermis (Figure 1). ablation does not always mean better clearance of

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Commentary: Are Deeper Laser Treatments Advantageous in Treating Solar Dysplasia? | Lim

PHOTODAMAGE 1
Degenerate keratinocytes

Haemorrhage

Minimal haemorrhage

Fibrinoid material

Thin epidermis

Figure 1. Histology of 1927 nm thulium 20 mJ, density coverage of 92%.

solar keratosis. We still do not fully understand why References

superficial non-ablative wavelengths, in particular 1927
nm thulium, consistently deliver superior outcomes 1. Trimas SJ, Ellis DA, Metz RD. The carbon dioxide laser: An
alternative for the treatment of actinically damaged skin.
out of proportion to the somewhat banal nature of
Dermatol Surg. 1997;23:885–9.
histology. A possible theory is that this wavelength
2. Jiang SB, Levine VJ, Nehal KS, Baldassano M, Kamino H,
induces a cytokine response of adjacent keratinocytes
Ashinoff RA. Er:YAG laser for the treatment of actinic keratoses.
that are undergoing involution, in turn causing an as Dermatol Surg. 2000;26:437–40.
yet undefined apoptotic cascade (the bystander effect).
3. Sherry SD, Miles BA, Finn RA. Long-term efficacy of carbon
This cytokine flow on effect may also affect adnexal dioxide laser resurfacing for facial actinic keratosis. J Oral
structures located deep within the reticular dermis, Maxillofac Surg. 2007;65(6):1135-9.
indirectly causing apoptosis of deeper dysplasia. 4. Iyer S, Friedli A, Bowes L, Kricorian G, Fitzpatrick RE. Full face
laser resurfacing: therapy and prophylaxis for actinic keratoses
Though the chromophore of water has been studied and non-melanoma skin cancer. Lasers Surg Med. 2004;34:114–
extensively, this wavelength may have additional 9.

unknown targets, akin to ‘carpet bombing’ or 5. Scola N, Terras S, Georgas D, Othlinghaus N, Matip R,
non-selective photothermolysis. Clinicians have Pantelaki I, et al. A randomized, half-side comparative study of
aminolevulinate photodynamic therapy vs. CO(2) laser ablation
recognised that this wavelength improves skin quality
in immunocompetent patients with multiple actinic keratoses.
beyond the targeted chromophore. An example is Br J Dermatol. 2012;167:1366-73.
erythema and dermal remodeling. Are ectatic vessels
6. Ostertag J, Quaedvlieg P, Neumann M, Krekels G. Recurrence
in the papillary dermis commonly encountered in sun rates and long-term follow-up after laser resurfacing as a
damaged secondary chromophores for this wavelength? treatment for widespread actinic keratoses on the face and
How do we explain profound dermal remodeling when scalp. Dermatol Surg. 2006;32(2):261-7.
histology is so superficial? 7. Weiss ET, Brauer JA, Anolik R, Reddy KK, Karen JK, Hale EK, et
al. 1927-nm fractional resurfacing of facial actinic keratoses:
As companies move to develop newer non-ablative a promising new therapeutic option. J Am Acad Dermatol.
2013;68:98-102.
wavelengths in addition to hybrid lasers (combining two
or more wavelengths in the one device) we can look
forward to novel treatments for solar keratoses in the
next decade.

Australasian Society of Cosmetic Dermatologists / Opinions and Progress in Cosmetic Dermatology VOLUME 01 / ISSUE 03 / NOVEMBER 2021 49
 PHOTODAMAGE 1
How to Achieve the Best Cosmetic Outcome
Treating Actinic Keratoses
Joshua Farrell1, Robert Rosen1,2
1. Southern Suburbs Dermatology, Kogarah, NSW, Australia
2. University of New South Wales, Kensington, NSW, Australia
Correspondence: Joshua Farrell  joshua.farrell1@uqconnect.edu.au
Disclosures: none

OUTLINE: Actinic keratoses (AK) represent epidermal hyperplasia with cellular atypia that result in areas of chronic
ultraviolet exposure. They are often considered premalignant and thus warrant treatment. The lesions often occur in multiple
individual lesions and larger plaques, which need to be treated via field therapy. They can be classified into three grades
of differing thickness which then influences treatment choice. Thicker lesions warrant destructive treatment. The most
common destructive option is cryosurgery. Thinner lesions can be treated via non-destructive methods applied to a field
of sun-damaged skin. These treatment options include 5-fluorouracil, imiquimod, photodynamic therapy, chemical peels,
diclofenac, keratolytics and emollients. These treatment options vary in their efficacy, treatment duration and side effect
profile. There is also a role for maintenance therapy in the form of emollients in between reviews in the dermatology office
to help reduce the number and thickness of AK. Ultimately, AK reflect a chronic process that require repeated treatment.
Therefore, we require options for treating large areas of damaged skin that also provide an acceptable cosmetic result.

KEYWORDS: actinic keratosis, cryosurgery, 5-fluorouracil, imiquimod, photodynamic therapy

Farrell J, Rosen R. How to Achieve the Best Cosmetic Outcome Treating Actinic Keratoses. Opin Prog Cosmet Dermatol 2021;1(3):50-57.

Introduction

Actinic keratoses (AK) represent epidermal hyperplasia

with cellular atypia that develops in areas with chronic
ultraviolet exposure.1,2 Many of the features of atypia are
present within squamous cell carcinomas (SCC), which
supports the classification of AK as a premalignant
process. Notably, the atypia is less than full thickness,
at which point it is reclassified as an SCC in situ.1,2 AK
classically develop as rough, scaly lesions. They may
be associated with discomfort, although tenderness
associated with the lesion is suggestive of a full-
thickness lesion.1 Diagnosis is made clinically, although
any suspicion of an invasive SCC should prompt a Figure 1. Cutaneous horn with SCC in situ that requires destructive therapy
biopsy for histopathological confirmation.

Histological variants of AK have been described, AK often present after several decades of sun exposure,
including hypertrophic, Bowenoid, lichenoid, and thus commonly occur on the head, ears, neck and
acantholytic and pigmented.2 They can be clinically arms in lighter skin phototypes.1,2 In Australia, 45% of
graded on a three-point scale: grade I lesions have the population over the age of 40 has on average eight
brawny scale, grade II lesions are spiky, while grade III AK, with men more commonly affected than women.3
lesions are hypertrophic, hyperkeratotic lesions.2 This is Other risk factors include chronic immunosuppression
a consideration when choosing treatment modality. such as with organ transplantation, long-term
treatment for inflammatory bowel and rheumatological
disease, exposure to arsenic and sunbed use.2

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AK can be persistent or spontaneously involute,
however untreated lesions have a risk of progressing
into keratinocyte cancers (Figure 1).1,2 The risk of
progression has been estimated to range from less than
0.1% to as high as 20%, although the greater the density
of the lesions the higher the risk.1,3 Although potentially
low, this risk is the rationale behind treatment, which
has been shown to be associated with a lower incidence
of skin cancer.2,4 AK can spontaneously regress, with
the rate likely 33% with quoted rates in the literature
between 15% and 70% per year, although these have a
high recurrence rate of as much as 50% within the first
year after spontaneous regression.1,2,3 Overall, patients
with more than 10 AK have a 14% risk of developing an Figure 2. Cutaneous horn on scalp that requires destructive therapy
SCC within 5 years.3

AK sometimes occur as diffuse plaques within an

anatomic site that has had prolonged ultraviolet light
exposure. Although individual treatment is most
common, there is a desire for field treatment to
cover all lesions quickly and simply. Other treatment
considerations include anatomic site, efficacy,
tolerability, and cosmetic appearance post treatment.
Removal of keratoses may reveal invasive tumours.2

Treatment options include destructive therapy

(cryosurgery, curettage and cautery, and excision),
field therapies (photodynamic therapy [PDT],
5-fluorouracil [5-FU], imiquimod, diclofenac, chemical
peels, keratolytics and retinoids), systemic therapies,
radiotherapy, and emerging therapies. Treatment
comparisons, advantages and disadvantages of
treatment options and treatment recommendations are
shown in Tables 1-3.

Destructive therapy Figure 3. Grade II and III lesions that require destructive therapy

Destructive therapies include cryosurgery, curettage

and cautery, and excision. These are best suited for
hypertrophic grade III lesions or lesions that are Cryosurgery
resistant to treatment (Figures 2 and 3). They are
lesion-specific treatments, with the benefit that they Cryosurgery is commonly considered the standard
are completed at consultation time and patients need of care. It is a long-standing and effective treatment,
only comply with post-procedural care. The benefit of which can be applied during the consultation with the
curettage and excision is histopathological confirmation dermatologist. Usually, liquid nitrogen spray is used
of diagnosis. These modalities have the disadvantages of (cotton buds do not work). The temperature of liquid
being unable to treat large numbers of AK concurrently, nitrogen is -196°C, and it lowers the skin temperature to
increased clinician time, and potential adverse events -60°C. Common side effects include blistering, oedema,
(infection, haemorrhage, scarring, pain).2 crusting, depigmentation and pain.2 These side effects
may lead patients to prefer alternative treatments.2

It is a taught technique, and there are large variations

in cosmetic results with scarring and permanent
depigmentation (Figure 4), which reflect freeze
time. A 10 second freeze can clear 85% of AK but has
significant rates of hypopigmentation (54.8%).5 Shorter
freeze times allow for good cosmesis in as many as
94% of patients,6 although there is evidence for an

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improved cosmetic result with alternative therapy.7 Slow However, the patient-administered options can
healing can be a problem especially below the knee in trigger more widespread local skin reactions that can
elderly patients.2 Overall, a dose of less than 10 seconds is affect compliance.8 They may also be less-suited to
usually sufficient to treat AK, however there remains risk treating hypertrophic lesions or lesions with follicular
of undesirable side effects.2 Depigmentation is a concern, involvement.8 It is therefore best for medical personnel
especially on the upper lip and decolletage in women. to treat thicker grade II-III lesions.

Figure 5. Widespread AKs requiring field therapy

5-Fluorouracil

5-FU is the work-horse of treatment options. It has

been available in Australia since 1991. It is a topical
cream that inhibits thymidylate synthetase and
therefore DNA synthesis.2,8 Although highly effective,
Figure 4. Depigmentation post cryosurgery it has significant side effects of pain, erythema, longer
treatment time, crusting and erosions (Figure 6).8 These
can be managed through emollients, a weak steroid,
a reduction in the frequency of application or a short
Surgery, curettage and cautery break in therapy.2,8 It is important to manage patient
expectations to improve compliance with treatment, as
There are no trials of surgery for AK.2 Logically, surgical the primary reason for discontinuation of treatment is
excision should provide focal effective treatment of a local irritation.1
lesion. It may also provide advantage in lesions with
follicular involvement.8 It supplies histopathological
confirmation of diagnosis where there is diagnostic
uncertainty, however a biopsy is preferable if the
diagnosis is unclear.

Curettage and cautery is good for persistent grade

III lesions. However, it has the issues of scarring,
depigmentation and post-operative wound care.
Furthermore, 28% of patients develop recurrence
after treatment.3

Field therapy Figure 6. Erythema and crusting due to 5-FU treatment of actinic cheilitis

Field therapies have been developed in the last

few decades. They have the benefit of treating The on-label treatment course is twice daily application
keratinocyte change in a contiguous area (Figure 5) for 4 weeks,2 which can provide a benefit for longer than
and reduce the risk of developing new AK, as well two years.9 Side effects require one month to settle.
as limiting recurrence.1,2,8 They also have benefit in However, less frequent initial use may allow titration of
treating lesions with ill-defined clinical borders.1,8 frequency of application to reaction. This use is off-label

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however and may not have the same efficacy. Care Imiquimod is applied nightly, and washed off in the
should be taken when treating areas with poor healing, morning 8 hours later. The recommended application
such as the lower leg.2 regimen of imiquimod is 2-3 times per week for 4
weeks, which can be extended for a total of 8 weeks if
5-FU most commonly comes in a 5% formulation; needed.2 Complete clearance with this regimen after
however, it is also available in more dilute formulations. 4 weeks is 26.8%, and after 8 weeks is 53.7%.13 There
These have the benefit of reduced irritation that quickly are improved clearance rates with a greater number of
resolves post treatment,10 although they may have applications: 30% clearance of AK with 9-24 doses of
reduced efficacy.11 5-FU can also be prescribed as a imiquimod, and greater than 40% clearance with 32-56
formulation with 10% salicylic acid. This preparation doses.1,2
may have higher efficacy, especially when treating
hyperkeratotic lesions.2 Unfortunately, as many as one third of patients will
discontinue treatment due to side effects on longer
Overall, a recent Dutch study published in the regimens.1 Standard concentration of imiquimod
New England Journal of Medicine found that 5-FU is a is 5%, and lower concentrations of imiquimod of
superior treatment option for AK at 12 months’ follow 3.75% and 2.5% are better tolerated whilst still
up post treatment compared to imiquimod, 5-methyl maintaining effectiveness.1,2 However, there is likely
aminolevulinate (MAL)-PDT, and the now discontinued a greater recurrence rate of AK with these lower
ingenol mebutate.11 Importantly, the comparative concentrations.1,2 Recurrence rate after 12 months
efficacy is found without regard for the grade of AK.11 with a standard 5% strength may be as low as 24%,2
Despite this, the authors of this study identified that compared to 40% with weaker formulations.2
only 90.3% of patients had good-to-excellent cosmetic
outcome, compared to 96.6% of MAL-PDT patients and Imiquimod generally provides a good cosmetic outcome;
89.7% of imiquimod patients.11 5-FU also has variable notably, a minority of patients may develop dyschromia,
efficacy in treating Bowen’s disease when this is a scarring and skin atrophy especially when used on the
possible alternative diagnosis.12 Overall, although low chest and face.13 These severe side effects need to be
cost, 5-FU has considerably more side effects. weighed against the benign nature of the problem.

Imiquimod Photodynamic therapy

Imiquimod, available in Australia since 1998, works by PDT, available in Australia since 2003, is an elegant
upregulating toll-like receptor 7 to trigger localised and finessed treatment whereby a photosensitising
inflammation.8 It thus has side effects of localised skin compound is applied to the target area several hours
irritation in up to 98% of patients, but may also cause prior to application of a light source. There are two
influenza-like symptoms in up to 10% of patients.1,2 Skin widely used sensitising agents: 5-aminolevulinic acid
irritation includes severe erythema (30%), scabbing (ALA) and its methyl ester, MAL.14 Metvix is the standard
(30%), and erosions (10%)2 (Figure 7). It can also cause MAL preparation. It is taken up selectively by malignant
erosions and scar formation, especially on the chest. cells, resulting in higher intracellular protoporphyrin
Influenza-like symptoms are more likely when treating IX. Activation by light generates reactive oxygen species
superficial basal cell carcinoma (BCC) or with more and thus cell death.15 Red spectrum light sources likely
frequent applications.2 Clinical response is often in provide higher response rates with shorter illumination
proportion to side effects, and thus patients who times, although other spectrum light sources are used.2
terminate their treatment early due to severe side
effects may still achieve a good clinical result.2 Around The treatment area is gently curetted prior to
2% of patients may also develop infections.1 application of the photosensitising compound to
increase absorption and then occluded. Longer
incubation times correlate with higher complete
clearance: 0.5 hours incubation equates to 51% of lesion
complete clearance whereas 4-hour incubation equates
to 86% complete clearance.16 A standard incubation
period is 3 hours.1 Often AK only require one treatment
session, but more hypertrophic lesions can require a
second treatment 1-2 weeks later. This provides 90%
clearance at 3 and 6 months.17

Figure 7. Imiquimod reaction. This figure illustrates that inflammatory

response is unpredictable and greater than the size of the treatment area

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PDT is a good treatment option, with improved Chemical peels
compliance compared to out-of-office treatment.1 A
network meta-analysis looking at treatment options for Chemical peels have long been used to treat AK
AK available in Europe found that the best treatment although less often more recently.15 They provide
option is ALA-PDT, which had complete clearance rates chemical ablation of skin, followed by regeneration
of 77% at 12 weeks post treatment.18 As noted above, of the epidermis and superficial dermis.15 The depth
there are higher rates of 90% complete clearance with of ablation can be controlled via chemical choice and
two treatment sessions 1-2 weeks apart.17 PDT appears concentration.2 Superficial peels induce epidermal
to work best for the face and scalp,2 although it is a safe injury whilst medium-depth peels penetrate into or
option in areas with poor healing such as the lower leg through the papillary dermis.19 AK can be treated by
in older patients.2 either, but are likely to be more completely treated with
medium-depth peels.
The side effects of PDT include skin irritation, variable
pain and erythema,1,2 although these are milder than Glycolic acid is a superficial agent used in chemical
in other treatments. The side effects correlate with peels. One study compared weekly application of 70%
incubation time and may represent increased efficacy glycolic acid for 2 minutes compared to 5-FU over
of treatment.16 An alternative method is daylight 8 weeks.20 This cleared only 20% of AK at 6 months.20
PDT, where the energy source is sunlight rather than Thus, glycolic acid and other superficial peels including
artificial. MAL is applied to the skin without occlusion salicylic acid are perhaps best used for the indications
for 30 minutes, before 2 hours of exposure to daylight.2 of mild acne, and epidermal and mixed melasma.19
This may have similar efficacy but reduced pain at time
of treatment.1 Daylight PDT is best suited for grade I and Trichloroacetic acid (TCA) is a common agent used for
II AK rather than hypertrophic lesions. medium-depth peels, and likely has the most evidence
of the chemical peels regarding efficacy.14,15 Despite
PDT has a good cosmetic result (Figure 8), and also has this, it is possibly less efficacious than other treatment
the benefit of clearing pigmentation and improving options, with one study finding mean clearance rates
photoageing. It can also be used to treat Bowen’s for 35% TCA of 79% after 3 months and 49% after 12
disease and BCC if this is a differential diagnosis. months, compared to PDT (89% and 74%, respectively).15
This result could be improved with the concomitant
application of 0.05% or 0.025% tretinoin before and
after treatment, or with the concurrent application of
Jessner’s solution (resorcinol, lactic acid, salicylic acid
in ethanol), which facilitates deeper penetration.14,15,21
Concurrent application with Jessner’s solution may
also provide sustained clearance.21 Similarly, higher
concentrations of 50% TCA have comparable clearance
rates to 35% TCA, but may have better sustained
clearance.14

Chemical peels are often well tolerated.21 They typically

cause transient erythema and discomfort for up to
one week after application.21 They have a high risk of
scarring, especially when used off the face and scalp.21
They may also cause hypopigmentation due to their
non-selective ablation which can be reversible.2,8,14
They can treat larger areas than other field treatments,
however, they are often used sparingly as they have
unpredictable cosmetic results.15 However, they have
a low cost and are easily used in 1-2 applications
in-office.15,21

Diclofenac

Diclofenac is a non-steroidal anti-inflammatory

Figure 8. PDT to the ankle for Bowen’s disease. Before treatment (top) and medication. Its mechanism of action for AK is
after treatment (bottom) unclear, however it may be related to inhibition of
the cyclooxygenase pathway which is responsible for
inhibiting apoptosis and promoting angiogenesis.2,8

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It is very well tolerated with far fewer intense local skin Radiotherapy
reactions than other treatments.2 It is licensed for twice
daily application for 60-90 days.2 Radiotherapy is a treatment modality in which the
target tissue is exposed to ionising radiation, which
The fewer side effects of diclofenac translate to reduced damages DNA. Malignant cells have poor DNA repair
efficacy, however twice daily application for 60 days capacity. Therefore, radiotherapy can destroy malignant
may clear 33% of AK whilst twice daily application for tissue and preserve normal tissue.17 Radiotherapy
90 days may clear 42%.22 Recurrence is around 19% has advantages of very good functional and cosmetic
after 12 months.2 Discontinuation from local side effects outcomes, especially where it is important to conserve
occurs in 15% of patients,1 with the commonest side tissue. However, it needs to be administered repeatedly
effects being pruritis (41% of patients) and a rash (40% (fractionation) and should the fractionation be too high,
of patients).2 Other side effects include paraesthesia, it exceeds the repair capacity of normal tissue causing
oedema, and contact dermatitis.8 However, diclofenac cell death and fibrosis. This causes tissue retraction and
carries warnings for increased thrombotic risk and thus poor cosmesis and function.17
gastrointestinal bleeding.1
Radiotherapy is usually considered to treat AK only in
There is a role for topical therapy in between patient the form of salvage treatment after repeated failures of
visits to the dermatologist to reduce AK disease burden, other therapies, especially for high grade lesions on the
and diclofenac is part of the therapeutic options. Other scalp.17 It does not have a role as a first-line treatment
options include keratolytics, emollients, and sunscreen. option given the risks of poor outcomes. It also has
the risks of radio-necrotic ulcers and fistulae should
re-treatment be required in the future.
Keratolytics and emollients

Keratolytics such as urea or salicylic acid may provide Tirbanibulin

some benefit.2 There is a role for keratolytics in between
treatment sessions in the dermatologist’s rooms to Topical tirbanibulin 1% has been recently approved by
treat grade I-II AK, and to reduce the thickness of the US FDA for treatment of AK on the face and scalp
hypertrophic lesions to improve subsequent treatment based on phase III trials.1 It is an ointment that is applied
efficacy. Commonly used keratolytics are urea 20% daily for 5 consecutive days.23 It completely clears AK
and salicylic acid 4% formulations. Treatment of milder in 44-54% of patients with a recurrence rate of 47%
AK may also reduce the frequency of attendance at after 12 months.23 Side effects are classed as mild-to-
dermatologists’ rooms. moderate, with 91% of patients experiencing erythema
and 82% experiencing scaling.23 No patients withdrew
Emollients have little evidence aside from acting as the from treatment in the phase II trials due erythema
placebo arm in clinical trials. It has been reported that and scaling.23 It thus represents an emerging option
up to 14.1% of AK are cleared with emollients applied for treatment although is not currently available in
3 times per week for 8 weeks.13 Australia.

Sunscreen is important in the prevention of skin cancer

and has a combined emollient and photoprotective Conclusion
effect.2 It has been associated with a resolution in
25% of AK over 12 months,3,17 as well as a subsequent Treatment of AK needs to take into account the
reduction in the number of SCC.2,17 Daily application of dynamic aspect of AK as a sign of a chronic evolution
sunscreen appears to have a greater protective effect of DNA damage which requires repeated treatment. A
than discretionary application.2 It thus has an important treatment option that is well-tolerated but also provides
position in AK maintenance therapy. acceptable clearance and cosmetic results is therefore
important. It also needs to be able to treat fields of
damaged skin. When treating AK, clinicians should note
Topical retinoids potential for progression to SCC. There are no data
on the benefit of follow up,2 although the presence of
There is not a lot of evidence for topical retinoids in the greater than 10 AKs is an indicator of higher risk for
treatment of AK. However, they do provide improvement keratinocyte cancers2 with a 14% risk of an SCC within
in wrinkles and lentigines.2 Their use tends to be 5 years.3 Patients should therefore be followed up within
sustained, rather than limited to one treatment course. five years, especially in cases where treatment is likely
Formulations include adapalene 0.3%, tretinoin 0.1%, to require evaluation and adjustment. Maintenance
tretinoin 0.05%, and isotretinoin 0.1%. There is some treatment in the form of emollients with keratolytics
evidence for adapalene 0.3% providing greater benefit such as urea or sunscreen is useful and should be
than adapalene 0.1% after 9 months of application.2 encouraged.

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Table 1. Comparison of treatment options

Treatment Doctor Patient Time Pain Scars Recurrence Cosmesis

Cryosurgery Y 10s Y Y 15% Depigmentation

C+C Y One session Y 28% Depigmentation

Surgery Y One session Y 0% Depigmentation

5-FU Y 2x daily Y Y 25% Significant erythema

for 4 weeks

Imiquimod Y 2-3x/week Y Y 24% Dyschromia,

for 4 weeks (on chest) depigmentation

PDT Y 2 sessions, Y 10% Excellent

2 weeks apart

5-FU, 5-fluorouracil; C+C, curettage and cautery; PDT, photodynamic therapy

Table 2. Advantages and disadvantages of treatment options

Treatment Advantages Disadvantages

Cryosurgery Low cost, quick, occurs in rooms Pain, cosmesis, treatment of single
lesions

5-FU Low cost, field therapy Significant side effects, poor cosmesis
for several months

5% Imiquimod Low cost Variable inflammatory reaction

PDT Occurs in rooms in 1-2 treatments Requires specialised equipment, high

cost

Diclofenac Low cost Relatively low efficacy, long treatment

course

Chemical peels 1-2 treatments in rooms, improves Unpredictable cosmetic results, low
photoageing efficacy

5-FU, 5-fluorouracil; PDT, photodynamic therapy

Table 3. Treatment recommendations

Treatment Treatment indication Cosmesis

Cryosurgery Lesions of all grades Hypopigmentation and depigmentation

especially on the face and decolletage,
blistering, pain and infection

5-FU Multiple grade I-II lesions Erythema, down-time for recovery

5% Imiquimod Multiple grade I-II lesions, can also treat Dyschromia, scarring, atrophy, infection,
Bowen’s disease uncontrolled inflammatory reaction,
down-time for recovery

PDT Multiple grade I-II lesions as well as Excellent cosmesis

Bowen’s disease, with 2 sessions of
PDT for persistent lesions

Diclofenac, 90 days Diffuse grade I lesions Not significant

Chemical peels, TCA Multiple grade I-III lesions Scarring, dyschromia

5-FU, 5-fluorouracil; PDT, photodynamic therapy; TCA, trichloroacetic acid

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References 18. Vegter S, Tolley K. A network meta-analysis of the relative
efficacy of treatments for actinic keratosis of the face or scalp
in Europe. PLoS One. 2014;9(6):e96829.
1. Eisen D, Asgari M, Bennett D, Connolly SM, Dellavalle RP,
Freeman EE, et al. Guidelines of care for the management of 19. Lee K, Wambier C, Soon S, Sterling JB, Landau M, Rullan P, et al.
actinic keratosis. J Am Acad Dermatol. 2021; 85(4):e209-e233. Basic chemical peeling: superficial and medium-depth peels. J
Am Acad Dermatol. 2019;81(2):313-24.
2. de Berker D, McGregor J, Mustapa M, Exton LS, Hughes BR.
British association of dermatologists’ guidelines for the care of 20. Marrero G, Katz B. The new fluor-hydroxy pulse peel. A
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3. Rosen R, Studniberg H. Solar keratoses: analysis in a 21. Brody HJ, Monheit GD, Lee KC. Chemical Peels as Field Therapy
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4. Stockfleth E. The paradigm shift in treating actinic keratosis: a 22. Jarvis B, Figgitt D. Topical 3% diclofenac in 2.5% hyaluronic
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outcomes. J Drugs Dermatol. 2011;10:1432–8. Keratosis. N Engl J Med. 2021;384(6):512-20.
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L, et al. A prospective study of the use of cryosurgery for the
treatment of actinic keratoses. Int J Dermatol. 2004;43:687–92.

7. Morton C, Campbell S, Gupta G, Keohane S, Lear J, Zaki I, et

al. Intraindividual, right–left comparison of topical methyl
aminolaevulinate-photodynamic therapy and cryotherapy in
subjects with actinic keratoses: a multicentre, randomized
controlled study. Br J Dermatol. 2006;155(5):1029–36.

8. Uhlenhake E. Optimal treatment of actinic keratoses. Clin

Interv Aging. 2013;8:29-35.

9. Pomerantz H, Hogan D, Eilers D, Swetter SM, Chen SC, Jacob

SE, et al. Long-term efficacy of topical fluorouracil cream, 5%,
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10. Jorizzo J, Stewart D, Bucko A, Davis SA, Espy P, Hino P, et

al. Randomized trial evaluating a new 0.5% fluorouracil
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11. Jansen MHE, Kessels JPHM, Nelemans PJ, Kouloubis N, Arits

AHMM, van Pelt HPA, et al. Randomized trial of four treatment
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12. Neubert T, Lehmann P. Bowen’s disease – a review of newer

treatment options. Ther Clin Risk Manag. 2008;4(5):1085-95.

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14. Di Nuzzo S, Cortelazzi C, Boccaletti V, Zucchi A, Conti ML,

Montanari P, et al. Comparative study of trichloroacetic acid vs.
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15. Holzer G, Pinkowicz A, Radakovic S, Schmidt JB, Tanew A.

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2017;176(5):1155-61.

16. Hauschild A, Popp G, Stockfleth E, Meyer KG, Imberger D, Mohr

P, et al. Effective photodynamic therapy of actinic keratoses on
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acid patch. Exp Dermatol. 2009;18(2):116-21.

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Working Party. Clinical practice guidelines for keratinocyte
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