Treatment of solar lentigines

Jean-Paul Ortonne, MD,a Amit G. Pandya, MD,b Harvey Lui, MD,c and Doris Hexsel, MDd
Nice, France; Dallas, Texas; Vancouver, British Columbia, Canada;
and Rio Grande do Sul, Brazil

Therapy for solar lentigines is diverse but can be divided into two broad categories: physical therapy and
topical therapy. Physical therapies are frequently used with excellent clinical success rates, but this has to
be balanced against associated side effects and recurrence rates with certain therapies. A range of topical
therapies have been used and, more recently, fixed combinations of topical agents have been investigated.
The Pigmentary Disorders Academy undertook to evaluate the clinical efficacy of the different treatments of
solar lentigines in order to generate a consensus statement on their management. Clinical papers published
during the past 20 years were identified through MEDLINE searches and methodology and outcome were
assessed according to guidelines adapted from the US Preventive Services Task Force (USPSTF) on health
care. The consensus of the group was that first-line therapy for solar lentigines was ablative therapy with
cryotherapy. Although no large-scale studies have been completed, there is also good evidence to suggest
that lasers are an effective treatment. An alternative to ablative therapy is topical therapy and there is good
evidence to support the use of a fixed double combination, as well as retinoids, such as adapalene and
tretinoin. Topical therapy can also be considered as maintenance therapy after the primary therapy has
been applied. Because of the diversity of scoring systems used in the assessment of treatment outcome, the
group recommends the development of treatment guidelines. ( J Am Acad Dermatol 2006;54:S262-71.)

S olar lentigines are macular hyperpigmented

lesions ranging in size from a few millimeters
to more than a centimeter in diameter. They
tend to be multiple with individual lesions gradually
Abbreviations used:
4HA:
HQ:
IPL:
4-hydroxyanisole
hydroquinone
intense pulsed light
increasing in size to larger macules or patches. PDA: Pigmentary Disorders Academy
Synonyms for this condition include actinic lentigi- RA: retinoic acid (tretinoin)
TCA: trichloroacetic acid
nes, liver spots, age spots, and sun spots. The VLP: Versapulse long-pulse [Nd:YAG 532-nm
potential negative social impact of this condition laser]
should not be disregarded in view of the fact that VQS: Versapulse Q-switched [Nd:YAG 532-nm
laser]
lesions appear on highly visible parts of the body,
such as the face, neck, hands, and forearms.1
Macules can also be regarded as the first signs of
the photoaging process, which can also have a persons older than 50 years of age.2 In the differential
significant impact on patients. The incidence in- diagnosis, solar lentigines should be distinguished
creases with age, affecting more than 90% of white from ephelides, lentigo simplex, pigmented actinic
keratosis, flat seborrheic keratosis, melanocytic ne-
From the Department of Dermatology, University of Nice-Sophia
vus, and malignant melanoma. These can be differ-
Antipolisa; Department of Dermatology, University of Texas entiated based on clinical appearance.
Southwestern Medical Center, Dallasb; Division of Dermatology, Therapy for solar lentigines can be divided into
University of British Columbia, Vancouverc; and School of two broad categories: physical therapy and topical
Medicine, University of Passo Fundo, Rio Grande do Sul.d therapy. Physical therapy of solar lentigines includes
Supported by Galderma International.
Disclosure: All authors are members of the Pigmentary Disorders cryotherapy, laser therapy, pulsed light, and chem-
Academy (PDA) and receive honoraria from Galderma for their ical peels. These are frequently used with excellent
work on behalf of the Academy. clinical success rates; however, this type of therapy
Reprint requests: Jean-Paul Ortonne, MD, Department of Dermatology, should be balanced against associated side effects
Archet-2 Hospital, 151 Rte St Antoine de Ginestière, BP 3079, 06202, and recurrence rates with certain therapies.3 A range
Nice Cedex 3, France.
0190-9622/$32.00
of topical therapies are currently in use, including
ª 2006 by the American Academy of Dermatology, Inc. hydroquinone (HQ), tretinoin, adapalene and, more
doi:10.1016/j.jaad.2005.12.043 recently, a stable fixed combination of mequinol

S262
J AM ACAD DERMATOL
VOLUME 54, NUMBER 5
and tretinoin. Although topical therapies usually take
longer than physical therapies to achieve a good
result, patients have control over their own treatment
and side-effects may be decreased. In addition to
active therapy and to maintain the treatment success,
patients are generally advised to use sunscreens as
a preventive treatment on the basis of their ability to
absorb ultraviolet radiation.
The Pigmentary Disorders Academy (PDA) under-
took to evaluate the clinical efficacy of the different
treatments of solar lentigines to generate a consensus
statement on their management. A MEDLINE search
was conducted on therapeutic options for solar
lentigines. Clinical studies that have been published
over the past 20 years were reviewed and the data
classified according to specific criteria (see below).
Subsequent treatment recommendations were gen-
erated on the basis of this published clinical evidence
and expert experience.
PHYSICAL THERAPY
Cryotherapy
Cryotherapy is one of the most widely used
techniques to remove solar lentigines, particularly
in Western Europe and the United States. The tech-
nique can be used with a number of cryogens,
including carbon dioxide, nitrous oxide, and liquid
nitrogen. The most commonly used agent is liquid
nitrogen, either applied with a cotton swab or more
commonly with a small hand-held spray unit. The
principle of the treatment in solar lentigines is tissue
injury by cell freezing. Melanocytes are especially
vulnerable to cold injury and can be destroyed by
temperatures of ÿ48C to ÿ78C.4 A single freeze-thaw
cycle is usually sufficient to treat solar lentigines;
repeated freeze-thaw cycles can lead to nonspecific
and deep tissue necrosis. Temporary adverse effects
that commonly occur include local pain during
and/or shortly after treatment, bulla formation, and
local edema. More permanent side effects are le-
sional hypopigmentation and/or peripheral hyper-
pigmentation. Recurrence rates have not been
widely reported; however, one study reported a
recurrence rate of 55% at 6 months.3
Almond-Roesler and Zouboulis5 reported a
randomized study of 20 patients with small solar
lentigines treated with 5 or 10 seconds of contact
cryosurgery at e328C using the Kryomed device
(http://www.medium-tech.de/english/produkte/
kryomed/). This system generates freezing temper-
atures by a Peltier effect cooler, which is a closed
system for cryoprobe applications. The probe tip
temperature of e328C is produced by a thermoelec-
tric procedure and therefore does not involve the use
of a cryogen. Lesions were present on the hands and
Ortonne et al S263
Fig 1. Solar lentigines on hand before treatment. (Figure
courtesy of Dr A. Pandya, University of Texas Southwest-
ern Medical Center, Dallas, Tex.)
measured 3 mm in diameter or more. Visual inspec-
tion at 1 and 6 months after treatment as well as a
chromametric evaluation indicated substantial light-
ening in 80% of patients treated for 5 seconds and
100% of patients treated for 10 seconds. Minimal skin
atrophy was observed in 10% and 60% of patients
treated for 5 and 10 seconds, respectively.
Zouboulis et al6 have reported the use of nitrous
oxide contact surgery in 6 patients with solitary large
solar lentigo lesions (3-16 cm in diameter). The
treatment involved a single freeze-thaw cycle of 30
to 40 seconds with nitrous oxide used as refrigerant;
skin temperature was e868C. Two patients with large
lesions (14 and 16 cm) underwent two fragmented
treatment sessions with an interval of 3 to 4 months.
Full remission of all lesions was reported with
excellent cosmetic results; no significant color im-
pairment or scar formation was observed and no
recurrence was noted within a 10-month follow-up
period.
Laser therapy
Because of the broad absorption spectrum of
melanin, which ranges from 351 to 1064 nm, various
lasers have been used to treat cutaneous pigmented
lesions, including solar lentigines, many with excel-
lent results (Figs 1 and 2). Laser usage in published
reports include the pulsed dye (510 nm), copper
vapor (511 nm), krypton (520-530 nm), frequency-
doubled Nd:YAG (532 nm), Q-switched ruby (694 nm),
Q-switched alexandrite (755 nm), Q-switched
S264 Ortonne et al
Fig 2. Solar lentigines on hand 4 months after Nd:YAG
laser at 532 nm. (Figure courtesy of Dr A. Pandya, Univer-
sity of Texas Southwestern Medical Center, Dallas, Tex.)
Nd:YAG (1064 nm, CO2 (10,600 nm), and argon (488-
630 nm) diode lasers. Continuous and quasicontin-
uous lasers are associated with an increased risk
of hypopigmentation and hyperpigmentation and
textural changes compared with pulsed lasers, par-
ticularly in darker skin types.7 With short pulse
duration, greater temperatures can be used and con-
trol exerted over the extent of the damage induced.
The Q-switched ruby laser was developed to
emit light in very short pulses that is preferentially
absorbed by melanin, thereby reducing damage to
other skin structures. Q-switched lasers can induce
both photothermal and photomechanical reactions.
These lasers generate high-energy radiation that
leads to a rapid rise in temperature (10008C), result-
ing in evaporation of targeted pigments within the
skin and vacuolization (photothermal damage). The
collapse of the temperature gradient that is created
between the target tissue and the surrounding tissue
also causes fragmentation of the target (photome-
chanical damage). The use of the Q-switched ruby
laser has been reported in 8 women with 196 solar
lentigines on their forearms.8 Therapy was delivered
as a single brief pulse of 40 nanoseconds to a 4-mm2
area. A single course of treatment resulted in fading
of the lesions without scarring and no recurrence
within a 6- to 8-week follow-up period. Histopath-
ological examination of biopsy specimens showed
vacuolization of superficial pigmentation to a max-
imum depth of 0.6 mm immediately after treatment.
Immunohistochemical examination of specimens
stained with anti-melanocyte-specific antibodies
J AM ACAD DERMATOL
MAY 2006
did not indicate remaining melanocytic structures
in moderately pigmented lesions. Other staining of
samples (nitroblue tetrazolium chloride) suggested
the presence of melanin-containing cells and/or
melanosome debris around the vacuoles in the basal
cell area.
The alexandrite laser with a treatment duration
of 5 ms (range for this apparatus was 5-40 ms) to
a 7-mm spot area has been reported in 11 patients
with 32 solar lentigines, of which 11 were used
as untreated controls.9 Skin types varied from
Fitzpatrick types II to IV and all lesions were of
medium darkness. Of the 21 treated lesions, 5 did not
respond and required a second treatment at 4 weeks.
Independent assessment of patient images indicated
that of the 16 lesions that did respond initially at
4 weeks, two lesions were graded as ‘‘good’’ (51%-
75% improved), 14 as ‘‘excellent’’ (76%-90% im-
proved) and 5 as ‘‘clear’’ (91%-100% improved).
This improvement was statistically significant com-
pared with the untreated lesions, all of which showed
no improvement (P \ .001). Side effects were
observed in only two lesions and consisted of mild
hypopigmentation. No cases of erythema, hyperpig-
mentation, or scarring were reported. Two studies
have reported in the use of the Nd:YAG laser in Asian
skin. Chan et al10 compared the clinical efficacy and
the adverse event profile of 3 different lasers:
Versapulse Q-switched (VQS) Nd:YAG 532-nm,
Versapulse long-pulse (VLP) Nd:YAG 532-nm, and
a conventional Q-switched Nd:YAG 532-nm laser
system (Medlite, Continuum Biomedical, Livermore,
Calif). The VLP, unlike the VQS laser, causes tissue
destruction purely through photothermal effects.
Thirty-four Chinese patients with 68 solar lentigines
on the face were treated with one of the 3 lasers. For
the VLP laser, the spot diameter was 2 mm with a
pulse duration of 2 ms and fluence of 9 to 12 J/cm2.
For the VQS, the spot size was 3 to 4 mm with a
fluence of 1.0 to 1.5 J/cm2. The Medlite laser system
involved a spot size of 2 mm with a fluence of 0.9 to
1.0 J/cm2. The mean scores (maximum, 10) for the
degree of clearing achieved using both patients’ and
clinicians’ assessments were 4.751, 4.503, and 4.78
for the Medlite, VQS, and VPS lasers, respectively,
indicating no difference in efficacy.
Hyperpigmentation was the most common com-
plication, occurring in 9 of the 34 patients (13 sites),
and the risk was greatest with the VQS system. Three
patients withdrew from the study because of this
effect. Hypopigmentation and erythema occurred
with all 3 lasers, and the risk was again greatest
with the VQS system. A rationale for this was
proposed by the authors. The lowest fluence with
the VQS system when a 2-mm spot diameter is used
J AM ACAD DERMATOL Ortonne et al S265
VOLUME 54, NUMBER 5

is 3.2 J/cm2. Because this fluence is too high to treat Table I. Lightening of lentigines by treatment
lentigines, a lower fluence is selected by increasing at 6 and 12 weeks as determined by physician
the spot size. This can result in damage to surround- evaluation (n = 75)*
ing tissue and the complications of hypopigmenta- Observer grades
tion and hyperpigmentation.
Poor Fair Good Excellent Clear
The quasicontinuous, frequency-doubled Nd:YAG (0%- (26%- (51%- (76%- (91%-
(532 nm) laser has been studied in 6 Pakistani Treatment 25%) 50%) 75%) 90%) 100%)
patients with solar lentigines and Fitzpatrick skin 6 weeks
type IV.11 The pulse duration applied was 1.6 micro- Liquid nitrogen 8 7 20 44 21
seconds; exposure time was 0.01 second to continu- Q-switched 4 3 10 36 47
ous; and spot size 2 mm. Irradiation was delivered Nd:YAG laser
during 3 to 8 sessions at 4- to 12-week intervals. All Krypton laser 3 5 18 47 27
patients had a greater than 50% improvement and no Diode-pumped 3 8 22 43 24
vanadate laser
recurrence was reported at 24-month follow-up.
12 weeks
Complications included hypopigmentation, mild
Liquid nitrogen 8 9 15 44 24
textural changes, and hyperpigmentation, although Q-switched 0 3 8 29 60
these were mild and resolved in 2 to 6 months. Nd:YAG laser
No cases of purpura were observed. Krypton laser 1 5 14 48 32
The efficacy of laser therapy has been compared Diode-pumped 0 9 20 44 28
with cryotherapy in two studies.12,13 The first of these vanadate laser
was a randomized study involving 13 patients and
99 lesions, which compared CO2 laser, argon laser *Each treatment received 75 observer grades (each of 25 patients
graded by 3 observers). Numbers shown indicate the number of
light, and cryotherapy within the same patient.12 grades achieved following treatment at a particular degree of
Fluences of 3 to 5 J/cm2 and 1 J/cm2 were adminis- lightening.
tered for the CO2 and argon laser techniques, Reprinted from Todd MM, Rallis TM, Gerwels JW, Hata TR. Arch
respectively. Significantly better results, assessed Dermatol 2000;136:841-6. Copyright ª 2001, American Medical
by independent reviewers of patients’ slides, were Association. All rights reserved.
produced by cryotherapy than either of the laser
therapies. Good results were reported in 61% (P\.05 Nd:YAG laser was found to provide superior light-
vs cryotherapy), 62% (P \ .01 vs cryotherapy), and ening compared with the other treatments (Table I).
75% of patients treated with the CO2 laser, argon The level of response at 12 weeks after treatment was
laser, and cryotherapy, respectively. Moderate atro- not reduced over that at 6 weeks. Again at 12 weeks,
phy was reported infrequently for all therapies. Todd the frequency Q-switched Nd:YAG laser was again
et al13 have reported a comparative study of the shown to achieve results significantly superior to
frequency-doubled Q-switched Nd:YAG laser (532 those of the other treatments (P \ .001). From the
nm), the HGM K1 krypton laser (521 nm) (HGM patients’ perspective, a survey showed that they
Medical Systems Inc, Salt Lake City, Utah), the DioLite considered this form of laser therapy to produce
532-nm diode-pumped vanadate laser (Index Corp, the best results (n = 18) followed by diode-pump
Mountain View, Calif), and cryotherapy. A total of vanadate laser (n = 6), cryotherapy (n = 2), and
27 patients with a minimum of 6 lesions on the backs krypton laser (n = 1). The fewest adverse events were
of their hands were enrolled in the study. Each hand reported from use of the Q-switched laser, whereas
was divided into 4 sectors and one treatment applied the krypton laser had the highest. Mild transient
per sector. Treatment with the frequency-doubled erythema was reported for all therapies; hypopig-
Q-switched Nd:YAG laser involved treatment for mentation and/or hyperpigmentation and scarring
30 nanoseconds to a 3-mm spot; comparative treat- occurred infrequently. Laser therapy has also been
ments with the HGM K1 krypton laser and the DioLite compared with facial peels and shown to be
532-nm diode-pumped vanadate laser were 0.2 sec- superior.14
ond on/0.2 second off to a 1-mm spot and 39 ms to
a 1-mm spot, respectively. Independent assessors Intense pulsed light therapy
categorized improvement according to a graded Intense pulsed light (IPL) involves the use of a
scale of the degree of lightening using patient pho- broadband visible light emitted from a noncoherent,
tographs. The 5-point grading scale was as follows: nonlaser, filtered flashlamp. Kawada et al15 have
poor, nonee25%; fair, 26%-50%; good, 51%-75%; reported a greater than 50% improvement in 18 of 45
excellent, 76%-90%; and clear, 91%-100%. At 6 weeks patients (40%) with solar lentigines using this tech-
after treatment, the frequency-doubled Q-switched nique as assessed by observation and photography
S266 Ortonne et al
in Asian patients. Each patient received 3 to 5
treatments (average number, 4) at 2- to 3-week
intervals. No hyperpigmentation or scarring was
reported. The same group of researchers has con-
ducted a histopathological study to examine the
changes that occur in the skin with IPL.16 They report
that microcrusts appear over the lesions 1 to 2 days
after irradiation. These crusts contain melanin and
drop off after 2 weeks to reveal a normally pig-
mented area. It was suggested that crust formation
may result from the photothermal effects of IPL.
Dermabrasion
Dermabrasion is a mechanical abrasive process
that removes epidermis and superficial dermis. A fine
and superficial abrasion is produced by using a low-
rotation motor with brushes or diamond fraises
mounted on a handpiece. The depth of the derma-
brasion is controlled by the pressure applied to the
skin and can be varied according to needs. However,
there are certain risks; fine hemorrhagic spots after
treatment can occur indicating a depth of abrasion
greater than the papillary dermis. In terms of side
effects, hyperpigmentation and hypopigmentation
are generally temporary, but can sometimes per-
sist.17 Recurrence rates of 55% have been described
at 6 months.3
Cotellessa et al18 have reported that microabra-
sion or microabrasion plus 15% trichloroacetic acid
(TCA) is equally effective in treating women with
multiple hyperpigmented macules of the face.
Group 1 was treated at 2-week intervals with micro-
abrasion and group 2 received microabrasion plus
TCA every 3 weeks. All patients underwent up to
8 treatments. In group 1 complete remission was
visually observed in 8 women (40%), partial remis-
sion in 10 women (50%), and no remission in 2
women (10%). Equivalent numbers for group 2 were
as follows: complete remission in 10 women (50%),
partial remission in 8 women (40%), and no remis-
sion in 2 women (10%). The only side effects
reported were mild erythema in all patients, which
disappeared after a few hours; mild desquamation
lasted for 3 to 4 days in all patients.
Chemical peels
Chemical peels to improve irregular pigmentation
have been performed on the nonfacial area using
glycolic acid,19 TCA,20 Jessner’s solution,21 salicylic
acid ointment,22 and salicylic acid liquid.23 Cook and
Cook24 have used a solution of 40% TCA in combi-
nation with 70% glycolic acid to successfully treat
irregular pigmentation of nonfacial skin, including
solar lentigines. The principles underlying this treat-
ment are that glycolic acid decreases the incidence
J AM ACAD DERMATOL
MAY 2006
of postinflammatory pigment changes, whereas TCA
is able to penetrate deeply but uniformly into the
skin.24
The efficacy of chemical peels has been compared
with that of cryotherapy25 and laser therapy.14
The first comparative study involved treating each
hand of 25 patients with multiple solar lentigines
at random with either 30% TCA or liquid nitrogen
spray as a single treatment.25 Patients were evaluated
at 8 weeks using photography. At this time, 9 patients
(47%) in the TCA group achieved more than 50%
improvement compared with 15 patients (71%) in
the cryotherapy group; the difference was signifi-
cant (P \.05). Overall, patients with Fitzpatrick skin
type II achieved moderate or marked improvements
that were approximately twice those of patients with
skin type IV. Postinflammatory hyperpigmentation,
atrophy, or residual hypopigmentation were infre-
quently noted for either therapy. A patient survey
indicated that 62% of patients (13/21) believed that
cryotherapy achieved the best results; 76% (16/21)
believed that treatment with TCA was the quickest to
heal, and 86% (18/21) thought that cryotherapy was
the most painful treatment.
The comparative study between TCA and laser
therapy involved 20 patients (Fitzpatrick skin types
III-IV) with 37 facial lentigines and indicated greater
improvement with laser therapy.14 Each lentigo was
divided into medial and lateral halves and frequency-
doubled Q-switched Nd:YAG laser (10 nanoseconds;
2-mm spot size; 532 nm) and 35% TCA applied to the
medial and lateral halves of each lentigo, respec-
tively. Independent assessment of photographs in-
dicated that 24 patients (65%) showed better results
in their medial halves (laser therapy) than in their
lateral halves (TCA), 5 (14%) got better results in their
lateral halves, and 8 patients (21%) showed similar
improvement with both treatments. No textural
changes, hypopigmentation, or hyperpigmentation
were noted after either therapy.
TOPICAL THERAPY
A range of topical therapies are currently available
for the treatment of solar lentigines. The principal
mode of action is the disruption of melanin forma-
tion. Hydroquinone (HQ) and tretinoin (retinoic acid
[RA] or vitamin A acid) are the most widely used
agents for the treatment of hyperpigmentation; other
topical agents that have been used as monotherapy
or in combination include mequinol (4-hydroxyani-
sole [4HA]), adapalene (synthetic retinoid), and
azelaic acid. HQ inhibits the conversion of dopa
to melanin by inhibiting the tyrosinase enzyme.
Other proposed mechanisms of action for HQ are
inhibition of DNA and RNA synthesis, degradation of
J AM ACAD DERMATOL
VOLUME 54, NUMBER 5
melanosomes, and destruction of melanocytes.26 RA
causes gross depigmentation through the induction
of desquamation. RA is also thought to have an
inhibitory effect on tyrosinase and potentially on
dopachrome conversion factor, thus interrupting
melanin synthesis.27 4HA is a phenolic derivative of
the HQ family.
Hydroquinone
Petit and Piérard28 have conducted a study using
2% HQ-cyclodextrin in 20 Asian adults (22 women,
8 men) with solar lentigines. The cyclodextrin was
part of a technology to improve delivery of HQ to
the skin. Therapy was applied once daily to lesions
on the forearm for 2 months; the untreated arm acted
as a control. Monthly assessment was conducted by
means of spectrophotometry and fluorescence video
recording combined with image analysis. After these
assessments, corneomelametry was performed on
cyanoacrylate skin surface strippings. Spectropho-
tometry indicated a small but significant reduction in
melanin on treated areas compared with controls;
the differential M index (calculated as the difference
between the median values of melanin of lesional
and nonlesional skin on each forearm) was reduced
by 3.5% and 8.7% after 1 and 2 months, respectively
(P \.05). There was a 3.8% decrease in relative area
of pigmentation after 1 month using video image
analysis, but this decreased by a small but signifi-
cant 17% at 2 months (P \ .01). Corneomelametry
revealed a progressive decrease in the melanin con-
tent of the stratum corneum in treated sites com-
pared with baseline; a reduction of 4.9% (P \ .01)
and 18.6% (P \ .001) occurred at 1 and 2 months,
respectively. The treatment was well tolerated with
no change in the erythema index in treated sites.
Tretinoin
The efficacy of topical RA 0.05% and 0.01% has
been examined in 251 patients with mild to moderate
photodamaged facial skin in a randomized, double-
blind, vehicle-controlled, multicenter study.29 A total
of 100 patients received 0.01% RA, 100 received the
0.05% dose, and 99 received vehicle. Overall im-
provement in photodamaged skin, including solar
lentigines, was reported in 79% of patients at the
0.05% dose compared with improvement in 57% at
the 0.01% dose and 48% of controls (vehicle-treated).
In addition, histological changes of increased epi-
dermal thickness, decreased melanin content, and
stratum corneum compaction provide independent
evidence supporting this clinical improvement. Side
effects of erythema, peeling, and stinging were
usually mild and well tolerated.
Ortonne et al S267
RA at a concentration of 0.1% has been studied in
58 patients with lentigines over a 10-month period in
a randomized, double-blind study.30 Fifteen patients
who responded well were then randomly assigned to
continue RA therapy or use vehicle alone for a further
6 months. Results indicated that after 1 month, RA use
produced a significant lightening of hyperpigmented
lesions compared with controls (P \ .002). After 10
months, 20 of the 24 patients (83%) with facial lesions
who were treated with RA had lightening of these
lesions, according to investigator rating scores, com-
pared with 8 (29%) of the 28 patients with facial
lesions in the control group. During the 6-month
follow-up study, specifically identified lesions that
had disappeared during the first 10 months of RA
treatment did not return in any patient, and 6 of the
7 patients who continued to use RA had showed
further improvement.
Tazarotene
A 24-week multicenter, double-blind, randomized
study was conducted on 0.1% tazarotene used in
563 patients with facial photodamage, primarily
fine wrinkling and mottled hyperpigmentation, but
also solar lentigines.31 Global response to treatment
was assessed using a 7-point scale (0 = complete
response through to 6 = worsening). Once-daily
application of tazarotene resulted in significantly
more patients achieving clinical improvement (at
least a 1-grade improvement) in lentigines than with
placebo (55% vs 15%; P # .001).
Adapalene
A prospective two-center, randomized, controlled
trial was conducted on the use of adapalene gel
(0.1% or 0.3%) to treat 90 patients with actinic
keratoses and solar lentigines (at least 75% of pa-
tients had at least 1 solar letingo).32 Patients were
randomized to receive treatment with one of the two
doses of adapalene or drug vehicle, and treatment
was then applied daily for 4 weeks followed by
twice-daily applications for up to 9 months if no
intolerance was observed. Assessment included
color changes, total number of lesions before and
after treatment, and investigators’ global assessment
of overall improvement. Results indicated that after
1 month of treatment there was significant lightening
of solar lentigines compared with controls. At 9
months, 57% and 59% of patients had lighter lesions
in the 0.1% and 0.3% adapalene gel groups, respec-
tively, compared with 36% in the control group
(P \.05). Side effects of erythema, peeling, dryness,
burning, and pruritus were reported in both active
treatment groups and were mild.
S268 Ortonne et al
Fig 3. Treatment of solar lentigines with 2% 4HA and
0.01% RA. Before treatment (A) and after 16 weeks (B) and
24 weeks (C) of treatment shown. (Images courtesy of
Galderma International.)
Hydroquinone/tretinoin
A combination study of 0.1% to 0.4% RA plus 5%
HQ has been conducted in 136 Asian patients with
hyperpigmentary disorders, including 90 with senile
lentigines.33 HQ was applied to skin lesions twice
daily for several weeks before combination treat-
ment with RA plus HQ twice daily. The concentration
of RA used depended on location of the lesion; 0.1%
RA was used on the face, 0.2% on the trunk, and 0.4%
on the lower extremities. The concentration of RA
was increased if no response was observed at
1 week. An objective measure of the color of the
treated lesion and the surrounding normal skin was
recorded using a narrowband reflectance spectro-
photometer (Mexameter MX 16, Courage&Khazaka
electronic, Cologne, Germany), which actually mea-
sures melanin and hemoglobin values. At 8 weeks,
excellent or good benefits were produced in 58 of 61
patients with facial lesions, 2 of 3 patients with trunk
J AM ACAD DERMATOL
MAY 2006
lesions, and 14 of 28 patients with lesions on their
upper extremities. Successful lightening of lesions
was achieved in 82.2% of patients overall. Adverse
events such as irritation and erythema occurred at
higher rates with this protocol because of the high
concentration of RA used. Continued treatment with
RA led to the development of tolerance after a few
weeks and the incidence of erythema decreased.
Postinflammatory hyperpigmentation was observed
in some patients, although this mostly disappeared
after a few months.
Mequinol (4HA)/tretinoin
A fixed combination of 2% 4HA and 4HA/0.01%
RA has been studied in a number of comparative
studies. The first of these compared 4HA/RA with 3%
HQ as well as the components of the combination,
that is, RA and 4HA, in a parallel double-blind trial of
216 patients (Fitzpatrick skin types I-IV) with solar
lentigines on the face and arms.34 The solutions were
applied twice daily for 16 weeks and follow-up was
an additional 24 weeks (Fig 3). At week 16, results
indicated that a significantly higher proportion of
patients achieved clinical success with 4HA/RA
than with HQ on the forearm as measured by the
Physician’s Global Assessment (60% vs 38%; P # .05)
and Lesional Pigmentation (70% vs 50%; P # 0.05).
There was also a trend, albeit not significant, for
greater improvements with 4HA/RA compared with
HQ with in facial lesions on the face as measured by
Physician’s Global Assessment (72% vs 58%) and
Lesional Pigmentation (70% vs 65%). The 4HA/RA
combination was also more effective than 4HA or RA
alone on either the face or arms. For all treatment
groups, skin-related adverse events were mild or
moderate and transient.
Two double-blind randomized controlled trials
involving 1175 patients have compared 4HA/RA with
4HA, RA, or vehicle.35 Patients were required to have
at least 5 solar lentigines on the forearm or back
of the hand and 5 lesions on the face. One lesion on
the face and arm had to be 5 mm or larger. Treat-
ments were applied twice daily for up to 24 weeks.
Trial 1 had a 24-week no-treatment regression phase
and trial 2 had a 4-week no-treatment regression
phase. 4HA/RA was statistically superior to each of
its active components or vehicle in both trials 1 and 2
in terms of the Physician’s Global Assessment (P #
.002). Combined results from trials 1 and 2 indicate
that moderate improvement or better was reported
with 4HA/RA in 52% and 56% of patients on the
forearms and face, respectively, compared with 35%
and 43% in the RA group, 24% and 33% in the 4HA
group, and 17% and 19% in the vehicle groups,
respectively. In trial 1 during the 24-week follow-up
J AM ACAD DERMATOL Ortonne et al S269
VOLUME 54, NUMBER 5

Table II. Level of evidence Table IV. Level and quality of evidence for solar
lentigines therapies
A There is good evidence to support the use of this
procedure Quality of Level of Reference
B There is fair evidence to support the use of this Therapy evidence evidence no(s).
procedure Cryotherapy I A 5, 6, 12
C There is poor evidence to support the use of the Laser
procedure Q-switched ruby II-i A 8
D There is fair evidence to support the rejection of the Alexandrite II-i B 9
use of the procedure 532-nm Nd:YAG I A 10, 11, 13
E There is good evidence to support the rejection of the CO2 I-ii B 12
use of this procedure Argon I-ii B 12
HGM K1 krypton I-ii B 13
From Williams HC. Dermatology. In: Stevens A, Raferty J, editors. DioLite 522-nm II-i B 13
Health care needs assessment. Oxford (UK): Radcliffe Medical Press; vanadate
1997. p. 340. Reproduced with permission. IPL III B 15
Dermabrasion III D 18
Chemical peels
Table III. Quality of evidence 30% TCA II-ii C 14, 25
Topical
I Evidence obtained from at least one properly 3% HQ IV C 34, 35
designed, randomized controlled trial 0.01% RA I C 28, 35
II-i Evidence obtained from well designed controlled 0.05% RA I A 28
trials without randomization 0.1% RA I B 30, 35
II-ii Evidence obtained from well designed cohort or case 2% 4HA (mequinol) I B 35
control analytic studies, preferably from more than 2% mequinol 1 0.01% I A 34, 35
one center or research group RA
II-iii Evidence obtained from multiple time series with or 0.1%-0.4% RA 1 II-iii B 33
without the intervention. Dramatic results in 5% HQ
uncontrolled experiments (such as the results of the 2% HQ/cyclodextrin II-i C 28
introduction of penicillin in the 1940s) could also be 0.1%-0.3% Adapalene I B 32
regarded as this type of evidence 0.1% Tazarotene I B 31
III Opinions of respected authorities based on clinical
experience, descriptive studies, or reports of expert 4HA, 4-Hydroxyanisole; HQ, hydroquinone; IPL, intense pulsed
committees light; RA, tretinoin; TCA, trichloroacetic acid.
IV Evidence inadequate owing to problems of metho-
dology (e.g. sample size, or length or comprehen-
An open-label, noncontrolled study has assessed
siveness of follow-up or conflicts in evidence)
the combination of 4HA/RA with sunscreen in 406
From Williams HC. Dermatology. In: Stevens A, Raferty J, editors. patients (Fitzpatrick skin types I-IV) with solar len-
Health care needs assessment. Oxford (UK): Radcliffe Medical tigines on the forearms and face. Treatments were
Press; 1997. p. 340. Reproduced with permission. applied twice daily for 24 weeks, with a 4-week
follow-up phase.36 Of the target lesions treated,
80% and 88% were reported to be clear or almost
phase, 4HA/RA continued to show statistically supe- clear on the arms and face, respectively. Most
rior improvements over the other treatment or vehi- adverse events were mild or moderate and disap-
cle (P # .003). Similar results were reported for trial peared after treatment cessation. The most frequent
2 during the 4-week follow-up phase (P # .002). adverse events were erythema (127 events); bur-
Patients’ assessment of treatment indicated superior- ning/stinging (45 events); skin irritation (45 events);
ity for 4HA/RA over the individual components or desquamation (35 events); and pruritus (30 events).
vehicle in both studies. With regard to maintenance Twenty-two patients discontinued treatment be-
of response, 56% and 70% of patients treated with cause of an adverse event.
4HA/RA maintained the benefit on their forearms and
faces, respectively, at 24 weeks. Most skin-related RECOMMENDATIONS
adverse events were mild or moderate and were The PDA has reviewed the literature on treat-
similar for 4HA/RA and RA groups. The most com- ment of solar lentigines and categorized the clinical
mon adverse event was erythema (56% in 4HA/RA findings for each treatment according to guidelines
or RA groups) and burning/stinging/tingling (34% adapted from the US Preventive Services Task Force
4HA/RA; 36% RA). (USPSTF) on health care (Tables II and III).37
S270 Ortonne et al
As a result of reviewing the clinical evidence, as
shown in Tables II and III, the PDA has categorized
each therapeutic option for solar lentigines as shown
in Table IV.
Consensus statement
The clinical evidence reviewed by the PDA indi-
cates that cryotherapy is an effective ablative therapy
for the treatment of solar lentigines. Its use can result
in substantial lightening in the majority of patients
by 6 months. Although no large-scale studies have
been completed, there is also good evidence to sug-
gest that lasers are an effective treatment. Because of
the side effects associated with physical treatments,
patients may require or prefer a topical therapy.
Physical therapies are much faster than topical ther-
apy, with many patients clearing after just one or two
treatment sessions. However, topical therapies are
usually less costly than physical modalities. The
treatment of choice recommended by the panel in
these circumstances is topical therapy. The strongest
clinical evidence exists for a fixed double combina-
tion therapy of hydroxyanisole mequinol and RA.
However, there is also good evidence for the use
of monotherapy with RA, Adapalene, or tazarotene,
which could also be considered in those situations
in which choice will depend on patient preference,
sensitivity to ingredients, and availability. The com-
bination of ablative and topical therapies may also
be beneficial to patients. After cryotherapy, the use
of double combination topical therapy may be used
as a maintenance therapy to diminish the risk of
relapse.
Scoring systems for assessing treatment vary
considerably between different centers, making it
difficult to accurately compare outcomes. The group
recommends the development of treatment guide-
lines for solar lentigines in order to establish a
uniform scoring system, which will allow the critical
appraisal of specific treatments.
We acknowledge the assistance of Dr Christine
McKillop in the preparation of this document.
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