Repeated Treatment Protocols for Melasma andAcquired Dermal Melanocytosis
KOTARO YOSHIMURA, MD, KATSUJIRO SATO, MD, EMIKO AIBA-KOJIMA, MD,
Daisuke Matsumoto, MD, Chiaki Machino, MD, Takashi Nagase, MD,
Koichi Gonda, MD, and Isao Koshima, MDBACKGROUND AND OBJECTIVE Melasma and acquired dermal melanocytosis (ADM; acquired bilateral nevus of Ota-like macules) are both seen most commonly symmetricallyon the face of women with darker skin and are also known as difficult conditions to treat.
METHODS Our topical bleaching protocol with 0.1 to 0.4% tretinoin gel and 5% hydroquinone was performed repeatedly (1–3 times) for melasma (n = 163), and a combination
treatment with topical bleaching and Q-switched ruby (QSR) laser was performed repeatedly (1–3 times) for ADM (n = 62).
RESULTS There is a significant correlation between clinical results (clearance of pigmentation) and the number of sessions in both melasma (p = .019) and ADM (po.0001).
CONCLUSION The repeated treatment protocol for melasma and ADM showed successful
clinical results compared with conventional ones, and they may be applied to other pigment conditions. It may be better that epidermal and dermal pigmentations are treatedseparately, especially in dark-skinned people who are more likely to suffer postinflammatory hyperpigmentation after inflammation-inducing therapies.
The authors have indicated no significant interest with commercial supporters.

Melasma is acquired andsymmetrical hypermelanosis, usually spread widelyon the malar prominence andcheek, and less frequently on theforehead and upper lip. Melasma
usually appears in patients in their
30s or 40s after pregnancy orcontraceptive use, suggesting thatthe triggering of melasma is hormonally related.1 Conventional
treatments for melasma include
sunscreen, hypopigmenting
agents, often in combination withother therapies, such as tretinoin,
topical corticosteroids, or superficial peeling agents.2–7 On theother hand, acquired dermal me-

lanocytosis (ADM) is a pigmented
lesion involving bilateral grayishbrown facial macules first reported as acquired bilateral nevus of
Ota-like macules (Hori’s nevus)
by Hori and colleagues8 ADM
usually onsets in patients in their
20s and represents bilateral involvements, with the malar regions almost always affected
while the lateral forehead andnasal alas are sometimes involved.
The distribution pattern, its grayish round-spot appearance with
unclear margins, and the difference in color are critical points
that distinguish it from melasma.
As both melasma and ADM arebilateral lesions and some patients
have both, inexperienced doctors
could misdiagnose them.
Melasma and ADM are frequently seen in Oriental females,
and indeed 225 of 1,184 patients(19.1%) who were treated for
pigmented skin problems in our
outpatient clinic had either orboth. The authors previously described an aggressive and optimaluse of tretinoin along with hydroquinone for various kinds ofskin hyperpigmentation9–11 and a
combination therapy with Qswitched ruby (QSR) laser for
ADM.12 The topical bleaching

All authors are affiliated with Department of Plastic Surgery, University of Tokyo, School of Medicine,Tokyo, Japan& 2006 by the American Society for Dermatologic Surgery, Inc.  Published by Blackwell Publishing 
ISSN: 1076-0512  Dermatol Surg 2006;32:365–371  DOI: 10.1111/j.1524-4725.2006.32074.x
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treatment with tretinoin andhydroquinone is a most effective
tool for removal of epidermal
pigmentation. In this study, theclinical results of repeated therapies for melasma and ADM wereanalyzed; we performed repeatedtretinoin–hydroquinone bleaching
therapy for melasma, and a repeated combination therapy of
topical bleaching and QSR laser
for ADM.

Patients and Methods

treatment with a high-resolution
digital camera (EOS-D30, Canon,
Tokyo, Japan). The percentage of
pigmentary clearance was evaluated via photographs by two experienced plastic surgeons who
did not perform this treatment.
The mean data of the pigmentary
clearance of each patient wereclassified into four categories:‘‘excellent’’ (80% or more clearance), ‘‘good’’ (50% to less than
80% clearance), ‘‘fair’’ (0% to lessthan 50% clearance), and ‘‘poor’’(no change or worse).

Sites affected by melasma or
ADM are summarized in Table 1.

Patients(1) Topical bleaching treatment:
The purpose of this treatment is toimprove epidermal pigmentationby accelerating discharge of epidermal melanin (with tretinoin)and suppressing new epidermalmelanogenesis (with hydroquinone). The two-stage (bleaching
and healing) treatment was performed as follows:

Preparation of Ointments
Tretinoin aqueous gels (tretinoingel) at three different concentrations (0.1%, 0.2%, and 0.4%), an
ointment including 5% hydroquinone and 7% lactic acid (HQ-LA
ointment), and one including 5%hydroquinone and 7% ascorbic
acid (HQ-AA ointment) wereoriginally prepared at the Department of Pharmacy, University ofTokyo Hospital. The precise regimens of these ointments have been
described before.10,12 These gelscan be prepared relatively easily
because the tretinoin powder (Sigma Chemical, St. Louis, MO,
USA) is commercially available.
Aqueous gel is most suitable forthe ointment base of tretinoin because of its good permeability.
Tretinoin gel is pharmacologicallyunstable, so fresh batches wereprepared at least once a month andstored in a dark, cool (41C) place.
Evaluations of Results
Photographs were taken for every
patient at baseline and after

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Of 1,184 Asian patients who underwent cosmetic treatments, 163
had melasma and 62 sufferedfrom ADM (six also had melasma). All patients with melasma
or ADM were women except for
two men with melasma. Patientage at the start of the treatment
for melasma and ADM ranged
from 27 to 62 years (42.3 7 7.1;
mean 7 SD) and from 22 to 53
years (36.4 7 8.1), respectively.

Treatment Methods
For melasma, our topical bleaching treatment was performed. If
patients wanted, the treatment
was repeated two or three times.
For ADM, a combination therapyof topical bleaching and QSR laser was performed. The number oftreatment sessions depended on
the patient’s decision. Typical timecourses of the treatment protocols
are shown in Figure 1A and B.

(a) Bleaching phase: 0.1% tretinoin gel and HQ-LA ointment
were initially applied to the

TABLE 1. Summary of Frequency of Melasma or Acquired Dermal
Melanocytosis (ADM) Affected Sites in Patients

ForeheadUpper eyelids
Lower eyelids
Nasojugal groove
Malar prominence
Cheek
Nasal dorsum
Nasal ala
Upper lip
Lower lip

MelasmaADM

10 (6.1%)
43 (26.4%)

22 (35.5%)
10 (16.1%)
15 (24.2%)
18 (29.0%)
53 (85.5%)

157 (96.3%)
90 (55.2%)
68 (41.7%)
38 (23.3%)
16 (9.8%)422 sites
163 cases

14 (22.6%)
9 (14.5%)

141 sites
62 casesYOSHIMURA ET AL

quested to visit our hospital at
1, 2, 4, 6, and 8 weeks after
starting this treatment, andevery 4 weeks thereafter.
When the appropriate skin reaction (mild erythema andscaling) was not observed at 1
week, the concentration oftretinoin was increased to
0.4%, because 0.2% tretinoin
gel was usually not strong
enough to get a sufficient reaction in these cases. The
concentration of tretinoin andfrequency of its application
were appropriately modified
according to the skin condition and degree of erythemaand scaling. It took 4 to 8
weeks to finish this phase. In
the second or third bleachingtreatment, tretinoin gel of the
final strength used in the mostrecent step was used from the
beginning.

Figure 1. (A) A representative time course of our topical bleaching treatment
with tretinoin and hydroquinone. Tretinoin is used for 6 weeks in each bleachingphase, and can be restarted with at least an 4-week interval of healing phase. (B)A representative time course of the combined treatment. Tretinoin is used for 4
weeks in the initial bleaching pretreatment, and for 2 weeks in the following
pretreatments. If Q-switched ruby (QSR) laser treatment is performed threetimes, the total treatment period is 32 weeks.

skin lesions twice a day. A
small amount of tretinoin gel
was carefully applied only on
pigmented spots using a small
cotton-tip applicator (an excessive volume of tretinoin gel
can be wiped off), while the
HQ-LA ointment was widely
applied with fingers (eg, allover the face) a few minutes
later, after allowing the ap-

plied tretinoin aqueous gel todry. The method of ointment
application is critical in thisaggressive treatment in orderto obtain maximal bleachingeffects with minimal irritantdermatitis. In cases in which
severe irritant dermatitis was
induced by the HQ-LA ointment, HQ-AA ointment wasused instead. Patients were re-(b) Healing phase: After a 4- to 8week bleaching phase, the application of tretinoin gel and
HQ-LA ointment was discontinued, and application of HQAA ointment was started inorder to prevent postinflammatory hyperpigmentation(PIH) until the redness was
sufficiently reduced. It usually
took 4 weeks to complete thisphase. Topical corticosteroids
were not used in either the
bleaching or healing phase.
(2) QSR laser treatment: In patients with ADM, topical anesthesia (lidocaine patch; Penless,
Wyeth Lederle Japan Inc., Tokyo,
Japan) was applied 60 to 120

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TABLE 2. Clinical Results of Cases with Melasma

One treatmentTwo treatments
Three treatments
Total

Excellent

Good

Fair

Poor

Total

Excellent orGood Cases (%)

ExcellentCases (%)

25
21
7
53

40
20
3
63

27
15
1
43

4
0
0
4

96
56
11
163

67.7
73.2
90.9
71.2

26.0
37.5
63.6
32.5

The treatment means a topical bleaching treatment (See Figure 1A).

minutes before the laser treatment. For QSR 694.5 nm laser(Model IB101, Niic Co. Ltd., Tokyo, Japan) treatment, 5 mm spot
size, 1 Hz repeat rate, 20 ns pulse
duration, and 4.0 to 5.0 J/m2
fluences were used. After laser
treatment, topical gentamicin sulfate ointment (Gentacins,
Schering-Plough, NJ, USA) wasapplied twice a day until a scale orthin crust disappeared (usually 5–
7 days). At 2 weeks after laser
treatment, application of HQ-AA
ointment was started.
At 4 weeks after each laser treatment, topical bleaching treatment
with tretinoin gel of appropriate
concentration (usually the same as
the final concentration in thebleaching phase) and HQ-AA
ointment were started as a pretreatment for the next laser irradiation, and also as a treatment
for postlaser PIH in some cases. In

most cases, a bleaching phase for
2 weeks was sufficient, and we
can usually estimate the clinicalresults at 8 weeks after each laser
treatment. When some hyperpigmentation remains, we can carryout another session.
Statistics
Spearman’s correlation coefficientby rank test was used to analyze
statistical significance between theextent of clinical improvement
and the number of treatments.
Results
In 163 patients with melasma, 96
underwent only one topicalbleaching treatment (see Figure1A) with excellent results in 25
and good in 40; 56 underwent
two treatments with excellent results in 21 and good in 20; 11
underwent three treatments withexcellent results in 7 and good in

3 (Table 2). In 62 patients with
ADM, 16 underwent only one
treatment (a combination of topical bleaching and QSR laser; see
Figure 1B) with excellent resultsin 1 and good in 6; 26 underwent
two treatments with excellent results in 14 and good in 8; and 20
underwent three treatments withexcellent results in 17 and good in
3 (Table 3). Representative caseswith melasma are shown in Figures 2 and 3, and those with
ADM in Figures 4 and 5.
As for side effects, mild erythemaand scaling are indications of appropriate administration of tretinoin and were seen in almost allcases during the bleaching phase.
Patients were well informed about
the local adverse effects in advance and were requested to apply
the tretinoin gel on only highly
pigmented areas to keep the dermatitis as limited as possible. PIH

TABLE 3. Clinical Results of Cases with Acquired Dermal Melanocytosis (ADM)

One treatmentTwo treatments
Three treatments
Total

Excellent

Good

Fair

Poor

Total

Excellent orGood Cases (%)

ExcellentCases (%)

1
14
17
32

6
8
3
17

9
4
0
13

0
0
0
0

16
26
20
62

43.8
84.6
100.0
79.0

6.3
53.8
85.0
51.6

The treatment means a combination of topical bleaching treatment and Q-switched ruby laser (See Figure 1B).

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YOSHIMURA ET AL

Figure 3. Case 2. (top, left, and right) A baseline view of a 27-year-old woman withmelasma. (bottom, left, and right) At 5 months, after two sessions of Q-switchedruby laser and topical treatments. The clinical result was evaluated as ‘‘excellent.’’

Figure 2. Case 1. (top) Baseline photoof a 47-year-old woman with melasma. (bottom) At 5 months, the pigmentation was cleared up after three
sessions of topical bleaching treatments.

was seen after the first session of
the repeated treatments in 14% ofmelasma patients, and a few
weeks after the first QSR irradiation in 21% of ADM patients.
The PIH was easily treated withthe following topical bleachingtreatment in both melasma and
ADM patients.
Statistical analysis showed there isa significant correlation between
clinical results (clearance of pigmentation) and the number ofsessions in both melasma(p = .019) and ADM (po.0001).
Discussion
The authors previously reported
on a topical bleaching therapy

Figure 4. Case 3. (top) A baseline view of a 41-year-old woman
with acquired dermal melanocytosis. (bottom) Two months after
the third Q-switched ruby laser treatment (8 months from thebaseline). The result of the clearance was evaluated as ‘‘excellent.’’

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relatively good clearance of melasma,2–7 complete clearance of
pigmentation is rare. On the basisof our experiences, the differential
use of tretinoin and hydroquinone
is quite important for melasma,
because if we use tretinoin on alarger area such as the whole face,
the surrounding nonpigmented
area is also bleached, and consequently the macules would remain
clinically recognizable. Althoughmelasma is well known as adifficult condition to treat, repetition of the topical bleaching on
only the pigmented area improved
it completely in some cases.
Figure 5. Case 4. (left) A baseline view of a 49-year-old woman with acquireddermal melanocytosis. She had spotty pigmentations on the cheeks, lateral
forehead, and nasal alars. (right) After three sessions of Q-switched ruby laser
and topical treatments (32 weeks from the baseline). The pigmentations were
almost completely cleared and also the yellowish color of surrounding skinchanged to pinkish.

with aggressive use of retinoids inaqueous gel only on the pigmented spots and use of hydroquinone all over the face.12,13 This
treatment can only clear epidermal
pigmentation, but with excellent
efficiency compared with otherconventional treatments, such as
AHA peeling or single applications of tretinoin or hydroquinone. Corticosteroids are not usedin the bleaching protocol, and,furthermore, tretinoin is not continually used over 2 months. It is
well known that long-term continual use of tretinoin, either topicalor oral, reduces its clinical effects.14,15 It has been suggested that
this phenomenon may be due tointracellular production of cellularretinoic acid binding proteins(CRABPs) induced by the retinoid
signal. This is why we use repeated

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bleaching protocols with intervals
instead of continual tretinoin use.
The present results demonstratethat the results for ADM (excellent cases; excellent and goodcases = 6.3%; 43.8%) are not as
good as for melasma (26.0%;
67.7%) in one-session cases, but
in three-session cases ADM was
improved at a higher rate (85.0%;100%) than melasma (63.6%;
90.9%). Actually, we often detected apparent improvement
during the second session in caseswith ADM.
Melasma usually has most of its
pigmentation in the epidermis.
Although previous reports withtretinoin, hydroquinone, AHA or
others, or combinations of multiple agents showed moderate to

ADM has significant epidermal
pigmentation, unlike nevus of
Ota, and this fact suggests thatclearance of epidermal pigmentation before QSR treatment is important in order to promote theefficiency of the QSR laser fordermal melanocytosis and to reduce PIH induced by inflammation around the basal layer.12
Topical bleaching treatment clears
postinflammatory hyperpigmentation induced by the QSR laser
and also plays an important role
as a pretreatment for the next
QSR irradiation.
Melasma and ADM are sometimes difficult to distinguish fromeach other because they are both
symmetrical, and they coexist insome cases. Indeed, we have a few
cases in our series which were firstdiagnosed as melasma, but dermal
pigmentation was found after the
first topical bleaching and the diagnosis was corrected to ADM

YOSHIMURA ET AL

later. In our repeated protocols
the topical bleaching treatment
can be started for either condition, so the treatment plan can becorrected without any loss oftreatment periods.
We here propose repeated treatment protocols for melasma and
ADM with better effectivenessthan conventional ones, and they
may be applied to other pigmented conditions. It may bebetter that epidermal and dermal
pigmentations are treated separately, especially in dark-skinned
people who are more likely tosuffer PIH after inflammation-inducing therapies.

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Address correspondence and reprint
requests to: Kotaro Yoshimura, MD,
Department of Plastic Surgery, University of Tokyo School of Medicine,
7-3-1, Hongo, Bunkyo-Ku, Tokyo
113-8655, Japan, or e-mail:yoshimura@cosmetic-medicine.jp.

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