Cosmetic
Experience with a Strong Bleaching
Treatment for Skin Hyperpigmentation in
Orientals
Kotaro Yoshimura, M.D., Kiyonori Harii, M.D., Takao Aoyama, Ph.D., and Tatsuji Iga, Ph.D.
Tokyo, Japan

Although a variety of topical treatments have been used
for skin hyperpigmentation, the effectiveness of each varies after prolonged treatment. In this study, 136 Oriental
patients who were followed up for more than 12 weeks
were analyzed. The treatment protocol was composed oftwo steps: bleaching (2 to 6 weeks) and healing (2 to 6
weeks); 0.1% to 0.4% all-trans retinoic acid aqueous gel
was originally prepared and applied concomitantly withhydroquinone-lactic acid ointment for bleaching. Afterobtaining sufficient improvement of the hyperpigmentation, a corticosteroid was applied topically with hydroquinone and ascorbic acid for healing. Improvement wasevaluated with a narrow-band reflectance spectrophotometer. The results were successful in more than 80 percent
of cases of senile lentigines and postinflammatory hyperpigmentations, especially on the face. Sixty percent ofcases of nevus spilus were also successfully treated. Although the transient adverse effects of this treatment may
be more severe than conventional treatment, this strong
bleaching protocol improves a variety of hyperpigmented
lesions, including nevus spilus, with a higher success rate
and a shorter treatment period than conventional protocols. (Plast. Reconstr. Surg. 105: 1097, 2000.)

ing an aqueous gel with a high concentrationof atRA, and we have treated more than 300
Oriental patients who have hyperpigmented
skin lesions, such as senile lentigines, postinflammatory hyperpigmentation, melasma, andnevus spilus, with it. These hyperpigmented
skin lesions were previously treated with a variety of therapies, including laser and chemical
peeling; except for senile lentigines, the results
were not very satisfactory.9 –12 The managementof postoperative hyperpigmentation is quite
important for dermatologic or plastic surgeons
performing facial skin resurfacing. Furthermore, no reports exist on the effectiveness of
topical treatments for nevus spilus, for which
no standard therapy exists to date.11,12 Although our protocol requires two steps (ableaching step and a healing step) and transient adverse skin reactions associated with thistreatment may be severe, it improves a variety
of hyperpigmented lesions, including nevus
spilus, with a higher success rate and a shorter
treatment period than conventional protocols.

All-trans retinoic acid (atRA; tretinoin) has
been used topically for the treatment of acne,
photodamaged skin, and hyperpigmentation
and before and after skin resurfacing procedures, such as carbon dioxide laser treatment
and chemical peeling.1–5 Kligman and Willis’6
well-known regimen and several modifications
to it7,8 have been widely used topical bleaching
formulas for two decades, and a number of
products based on them are commerciallyavailable. However, patient improvement withthese treatments is variable and sometimes limited or unrecognizable, and it usually takes aprolonged course of treatment.
We proposed a new bleaching protocol us-

PATIENTS AND METHODS
Preparation of Ointments

AtRA aqueous gels (atRA gel) with threedifferent concentrations (0.1%, 0.2%, and0.4%) were prepared at the Department ofPharmacy at the University of Tokyo. The precise formula for 1000 g of 0.1% to 0.4% atRA
aqueous gel was as follows: 1 to 4 g of atRA
(Sigma Chemical, St. Louis, Mo.), 10 g of Carbopol 940 (Goodrich Chemical, Hounlow,
U.K.), 20 g of polyoxyethylene oleyl ether

From the Departments of Plastic, Reconstructive, and Aesthetic Surgery and Pharmacy, University of Tokyo. Received for publication June30, 1999.

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(Kao, Tokyo, Japan), 0.26 g of methyl phydroxybenzoate (Wako Pure Chemical Industries, Osaka, Japan), 0.14 g of propyl phydroxybenzoate (Wako Pure Chemical
Industries), 6 ml of 10% sodium hydroxideaqueous solution, and 1000 g of purified water.
An ointment including 5% hydroquinone and
7% lactic acid (HQ-LA) and one including 5%hydroquinone and 10% L-ascorbic acid (HQAA) were also prepared at the Department ofPharmacy at the University of Tokyo. Plastibase(petrolatum polyethylene ointment base,Taisho Pharmacology, Osaka, Japan) and hydrophilic ointment were used as the ointmentbases of the HQ-LA and HQ-AA ointments,
respectively. Because all ointments (atRA gel,
HQ-LA ointment, and HQ-AA ointment) were
pharmacologically unstable, fresh ointments
were prepared at least once a month andstored in a dark, cool (4°C) place.
Patients

After receiving written, informed consent,
each ointment was topically applied to morethan 300 patients with hyperpigmented skinlesions. A total of 136 patients who had hyperpigmented lesions in which the relative melanin value was more than 30 and who were
followed up for more than 12 weeks were analyzed in this study. All of them were Oriental:
128 were Japanese, three were Chinese, threewere Korean, and two were Indian. Clinicaldiagnoses of hyperpigmented lesions were classified into four categories: senile lentigines,
melasma, postinflammatory hyperpigmentation, and nevus spilus, which included café aulait spots. Patients with postinflammatory hyperpigmentation with a duration less than 6months were excluded from this study. The
ages of the patients ranged from 4 to 88 years(44.6 ⫾ 15.3 years), and 112 patients werefemale. Patient data are summarized in Table I.
Some patients had hyperpigmented lesions on
more than one part of the body, so the total
number of cases is 146. The data were analyzed
according to clinical diagnosis and site of skinlesion. We had 90 cases of senile lentigines(face, 61; trunk, 3; upper extremities, 24; andlower extremities, 2), 10 cases of melasma (allon the face), 28 cases of postinflammatory hyperpigmentation (face, 11; trunk, 6; upper extremities, 7; and lower extremities, 4), and 18
cases of nevus spilus (face, 9; trunk, 5; upper
extremities, 2; lower extremities, 2).

PLASTIC AND RECONSTRUCTIVE SURGERY, March 2000

TABLE I
Patient Data
No. of patientsAge (years)
Sex (male:female)Clinical diagnosis (site of lesions:face/trunk/UE/LE, no. of cases)
SL
ML
PIH
NS
Total no. of cases*

136
44.6 ⫾ 15.3
24:11290 (61/3/24/2)
10 (10/0/0/0)
28 (11/6/7/4)
18 (9/5/2/2)
146 (91/14/33/8)

UE, upper extremity; LE, lower extremity; SL, senile lentigines; ML, melasma; PIH, postinflammatory hyperpigmentation; NS, nevus spilus.
* Because some patients had skin lesions at more than one site, the total
number of cases exceeds the number of patients.

Treatment Protocol

Our treatment protocol is composed of two
steps, bleaching and healing. In the bleaching
step, pigmentation is aggressively treated, andtransient adverse skin effects, such as erythemaand irritation, are usually observed. Once satisfactory improvement is obtained, the healing
step is started to reduce the erythema andinflammation. In some cases, pretreatment was
conducted before bleaching.
Pretreatment. The application of HQ-LA ointment (HQ-AA ointment in some cases) to theskin lesions twice daily for several weeks wasrecommended to those who wanted to start thebleaching treatment in several weeks for personal reasons. In the summer, every patient wasadvised to have only a pretreatment with HQ-LA
ointment until September to avoid strong ultraviolet irradiation during the bleaching step.
In the daytime, a broad-spectrum sunscreen
cream was always concomitantly applied withthe ointments throughout the treatment period.
Bleaching. AtRA gel and HQ-LA ointment
were applied to the skin lesions twice a day.
Initially, the concentration of atRA was determined according to the location of the skinlesions: 0.1% atRA gel was used for the face,
0.2% for the trunk or upper extremities, and
0.4% for the lower extremities. Patients weretold to visit our hospital 1, 2, 4, 6, 8, 12, and 16
weeks after starting this treatment. When theappropriate skin reaction was not observed at 1
week, the concentration of atRA was changed(usually to a higher one). In most cases, it took
2 to 6 weeks to finish this step.
If satisfactory improvement (80 percent improvement of relative melanin value) was not
obtained after 8 weeks of continual treatment

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TABLE II
Treatment Results

Face
Trunk
Upper extremities
Lower extremities
Total
Success rate*

Senile Lentigines

MelasmaPostinflammatory
Hyperpigmentation

Nevus Spilus

Total

Success Rate*

61 (23/35/3/0)
3 (0/2/1/0)
24 (4/10/8/2)
2 (0/0/1/1)
90 (27/47/13/3)†
82.2%

10 (2/5/2/1)
0 (0/0/0/0)
0 (0/0/0/0)
0 (0/0/0/0)
10 (2/5/2/1)
70.0%

11 (5/6/0/0)
6 (2/3/1/0)
7 (1/4/1/1)
4 (2/1/1/0)
28 (10/14/3/1)
85.7%

9 (3/3/3/0)
5 (2/1/1/1)
2 (0/1/1/0)
2 (0/1/0/1)
18 (5/6/5/2)
61.1%

91 (33/49/8/1)
14 (4/6/3/1)
33 (5/15/10/3)
8 (2/2/2/2)
146 (44/72/23/7)†
79.5%

90.1%
71.4%
60.1%
50.0%

Results are described in number of cases as total (excellent/good/fair/poor).
* Success rates were calculated as follows: (number of “excellent” and “good” cases)/(number of total cases).
† Because some patients had skin lesions on more than one part of the body, the numbers shown exceed the actual number of patients.

with atRA gel and HQ-LA ointment, the treatment was discontinued. In these cases, a second treatment was started after a 2- to 3-monthinterval. Throughout this interval, we recommended pretreatment with HQ-LA (or HQAA) ointment before the second treatment,
which was the same protocol as the first treatment.
Healing. After sufficient improvement of thehyperpigmentation was obtained, the application of atRA gel and HQ-LA ointment was discontinued, and topical application of corticosteroids (ointment with 0.12% betamethasone
valerate or 0.3% prednisolone butylacetate)and HQ-AA ointment (HQ-LA ointment insome cases) for as short a time as possible (usually 1 to 2 weeks) was started to reduce thereactive erythema and inflammation. After theerythema was reduced to some extent, the application of the corticosteroid ointment was discontinued, and only HQ-AA ointment was continuously applied. In cases in which erythema
was not reduced after a few weeks of the application of corticosteroid and HQ-AA ointment,
HQ-AA ointment was also discontinued for a
few weeks. In cases in which the reactive erythema was not severe, this step was omitted.
Posttreatment maintenance. After the bleaching and healing steps were finished, continualapplication of HQ-LA or HQ-AA ointment forseveral months was advised for posttreatment
maintenance in some patients, including all patients with nevus spilus. When clinical signs ofpigmentation recurrence were observed in patients with nevus spilus, atRA gel was also usedas maintenance or a second treatment wasstarted.
Evaluation of Results

Spectrophotometry. As an objective measurement of the color of the designated lesion andthe surrounding normal skin, a narrow-bandreflectance spectrophotometer (Mexameter
MX 16, COURAGE⫹KHAZAKA electricGmbH, Köln, Germany) was used at each clinical visit. The overall results were objectively
evaluated by the melanin and hemoglobin values measured with the Mexameter.13 A measuring probe with a diameter of 5 mm emits lightat three predefined wavelengths (568 nm,
green; 660 nm, red; and 880 nm, infrared) andmeasures the light reflected by the skin. The
melanin value was measured by using two wavelengths (660 and 880 nm) to achieve different
absorption rates by the melanin granules. For
the hemoglobin measurement, two wavelengths (568 nm and 660 nm) were also used.
The melanin and hemoglobin values are calculated as follows:

Melanin value ⫽ 500/log 5⫻ 关共 log infrared-reflection/red-reflection兲
⫹ log 5]
Hemoglobin value ⫽ 500/log 5⫻ 关共 log red-reflection/green-reflection兲
⫹ log 5]
Each spot was measured three times, and theaverage of three measured values was calculated. The differences in the absolute melaninand hemoglobin values between a skin lesion
and the surrounding normal skin are referred
to in this article as the relative melanin value
and the relative hemoglobin value of the skinlesion, respectively. These values indicate theintensity of pigmentation and erythema, respectively, relative to the surrounding normal
skin. A negative melanin value means that the

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measured spot is lighter than the control. Relative melanin values were compared before
and after the first treatment, and the results
were classified into the following four grades:
excellent (final value ⱕ 5), good (final value ⬍20 percent of value before treatment), fair (final value ⬍ 60 percent of that before treatment), and poor (final value ⱖ 60 percent ofthat before treatment). The absolute melaninvalue of normal skin in Japanese persons andthe relative melanin values of hyperpigmented
lesions are usually 460 to 500 and 20 to 120,
respectively. A relative melanin value of lessthan 5 is difficult to recognize clinically.
Statistics. The results were analyzed according to the diagnoses and locations of the skinlesions. Significant differences were sought using the Kruskal-Wallis test. Differences wereconsidered significant when H values ⬎ x2
(0.95).
RESULTSIn general, erythema was seen in a few days;
this was followed by continuous scaling during
the first week.14 Erythema and scaling wereusually seen continuously throughout thebleaching step. Formation of a thin crust wasalso seen in some patients during the second
week. After the thin crusts came off, the elimination of pigmentation was usually obtained.
An improvement of hyperpigmentation was obtained after bleaching for 2 to 4 weeks in mostcases of senile lentigines or postinflammatory
hyperpigmentation, but a somewhat longer period was usually required for patients with nevus spilus. A second treatment was performed
for further improvement in 19 cases (21.1 percent) with senile lentigines, six cases (60.0 percent) of melasma, one case (3.6 percent) of
postinflammatory hyperpigmentation, and 16
cases (88.9 percent) of nevus spilus.
The results of the treatment were evaluatedwith spectrophotometry; they are summarizedin Table II. Cases evaluated as excellent or
good are referred to as successful in this article,
and the success rates were calculated as follows:(number of excellent and good cases)/(number of total cases).
Of the senile lentigines cases, 27 (23 on theface and four on the upper extremities) were
evaluated as excellent, 47 (35 on the face, two1101

on the trunk, and 10 on the upper extremities)
as good, 13 (three on the face, one on thetrunk, eight on the upper extremities, and one
on the lower extremities) as fair, and three(two on the upper extremities and one on thelower extremities) as poor. Of the melasmacases, two were evaluated as excellent, five as
good, two as fair, and one as poor. In the casesof postinflammatory hyperpigmentation, 10(five on the face, two on the trunk, one on theupper extremities, and two on the lower extremities) were evaluated as excellent, 14 (sixon the face, three on the trunk, four on theupper extremities, and one on the lower extremities) as good, three (one on the trunk,
one on the upper extremities, and one on thelower extremities) as fair, and one (on theupper extremities) as poor. In the cases ofnevus spilus, five (three on the face and two on
the trunk) were evaluated as excellent, six(three on the face, one on the trunk, one on
the upper extremities, and one on the lower
extremities) as good, five (three on the face,
one on the trunk, and one on the upper extremities) as fair, and two (one on the trunk
and one on the lower extremities) as poor.
The success rate for cases of senile lentigines
was 82.2 percent (95.1 percent, face, and 58.3
percent, upper extremities). The success rates
for cases of melasma, postinflammatory hyperpigmentation, and nevus spilus were 70.0, 85.7,
and 61.1 percent, respectively. Significant differences were not seen among the four diagnoses (H value ⫽ 2.67; x2(0.95) ⫽ 7.81). However, when the legions were classified
according to location, a significant difference
did exist (H value ⫽ 12.44; x2(0.95) ⫽ 7.81).
The success rates for the face, trunk, upper
extremities, and lower extremities were 90.1,
71.4, 60.1, and 50.0 percent, respectively. The
total success rate for the 146 cases was approximately 80 percent.
CASE REPORTS
Case 1
A 54-year-old woman with a senile lentigo on her left cheekunderwent combined topical applications of 0.1% atRA gel
and HQ-LA ointment without pretreatment (Fig. 1, above,left). The initial reaction (erythema and scaling) was appropriate (Fig. 1, above, right) and, at 2 weeks, the hyperpigmentation had disappeared completely, despite the severe ery-

FIG. 1. Case 1. A 54-year-old woman with a senile lentigo on the left cheek. (Above, left) Before treatment, (above, right) after 1
week, (center, left) after 2 weeks, (center, right) after 4 weeks, and (below) after 8 weeks of treatment.

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PLASTIC AND RECONSTRUCTIVE SURGERY, March 2000

FIG. 2. Case 2. A 60-year-old man with senile lentigines on the face. Lateral views before
treatment (left) and after 20 weeks of treatment (right).
thema and formation of a thin crust on the treated region(Fig. 1, center, left). AtRA gel and HQ-LA ointment were discontinued, and topical application of corticosteroid and
HQ-AA was started. Corticosteroid ointment was applied for
2 weeks (Fig. 1, center, right). Four weeks after the discontinuation of the corticosteroid, the erythema disappeared completely (Fig. 1, below). HQ-AA ointment was applied throughout healing for 6 weeks and the final relative melanin value
after 8 weeks of treatment was 4.3. The result was evaluatedas excellent. Although the extent of erythema seen at 2 weeks
was nearly the most severe among the cases we treated, thetime course of the clinical changes in this patient was typicalfor the treatment. The relative melanin and hemoglobinvalues before treatment were 166.7 and 46.0, respectively.
The relative hemoglobin value is generally positive in hyperpigmented lesions. During the bleaching step, the relativemelanin value was considerably reduced, but the relative
hemoglobin value increased as inflammation progressed.
During healing, the relative hemoglobin value gradually decreased, but the improvement in the relative melanin value
was maintained. The relative hemoglobin value was thenreduced to below the level before treatment. The final relative melanin and hemoglobin values after 8 weeks of treatment were 4.3 and 18.8, respectively.

Case 2
A 60-year-old man with multiple senile lentigines on bothcheeks underwent combined topical applications of 0.1%
atRA gel and HQ-LA ointment without pretreatment (Fig. 2,left). Appropriate reactions were seen during the first andsecond week, and the healing step was started at 2 weeks. The
hyperpigmentation and erythema had almost disappeared by
the eighth week. Occasional application of atRA and HQ-LA
ointment was done after treatment for maintenance (Fig. 2,

right). The relative melanin value of a pigmented spot before
treatment was 52.3, and the final value after 8 weeks of treatment was ⫺4.0. The result was evaluated as excellent.

Case 3A 23-year-old woman who had suffered superficial abrasive
wounds on her face in a traffic accident 1 year before her firstclinical visit showed postinflammatory hyperpigmentation at
the sites of the wounds (Fig. 3, left). Topical applications of
0.1% atRA gel and HQ-LA ointment were started without
pretreatment. On day 5, scaling was seen; thereafter, hyperpigmentation was reduced significantly. At 3 weeks, the healing step was started, and the erythema was almost eliminatedat 8 weeks (Fig. 3, right). Relative melanin values before andafter treatment were 41.4 and 6.1, respectively. The evaluation of this case was good.

Case 4A 16-year-old woman with congenital nevus spilus on theleft cheek underwent combined topical applications of 0.1%
atRA gel and HQ-LA ointment without pretreatment (Fig. 4,
above, left). The initial reaction (erythema and scaling) wasappropriate, and the thin crusts came off during the second
to third weeks (Fig. 4, above, right). The bleaching step lasted
for 4 weeks; it was followed by a healing step of 4 weeks. The
relative melanin value before treatment was 41.7; at 8 weeks,
it was ⫺3.5 (Fig. 4, below, left). Although HQ-LA ointment wascontinually applied after the treatment for maintenance,
signs of recurrence were detected 6 weeks later. Therefore,
atRA and HQ-LA ointment were applied once daily; thismaintenance continued to work well, 10 months later (Fig. 4,
below, right). The result was evaluated as excellent.

Vol. 105, No. 3 / BLEACHING TREATMENT FOR HYPERPIGMENTATION
Case 5
A 61-year-old woman with nevus spilus on the left cheekwho had undergone cryotherapy with dry ice four times anddermabrasion two times with no improvement underwent
combined topical applications of 0.1% atRA gel and HQ-LA
ointment without pretreatment (Fig. 5, left). The initial reactions (erythema and scaling) were appropriate, and thepigmentation was reduced significantly. Because the erythema gradually reduced during bleaching, the bleaching
step was continued for 8 weeks, and no healing step was
required. The relative melanin values before and after treatment were 72.3 and ⫺3.6, respectively. The result was evaluated as excellent. Although the HQ-LA ointment was continually applied after treatment for maintenance, signs ofrecurrence were observed 1 month after the cessation of
atRA. AtRA and HQ-LA ointment were used continually for
maintenance, and the pigmentation was controlled well 18
months later (Fig. 5, right).

DISCUSSION
Characteristics of the Present Protocol

AtRA and hydroquinone play essential roles
in our treatment for bleaching, and lactic acidand ascorbic acid are used supplementally. Although ascorbic acid also has a depigmenting
effect and fewer adverse effects than hydroquinone, its depigmenting ability is far less thanthat of hydroquinone.15 It is clear that the same
results cannot be obtained from the single use

1103

of either atRA5 or hydroquinone.16 Althoughhydroquinone was used also in the healing
step, we did not expect it to further improve
pigmentation but to prevent postinflammatory
hyperpigmentation and the recurrence of pigmentation, thus maintaining the level of improvement obtained in the bleaching step.
On the basis of our preliminary trials withseveral concentrations of atRA in several vehicles and the concomitant use of corticosteroid
ointment with atRA, we think that the criticalpoints of this protocol are (1) to use a highconcentration of atRA aqueous gel and (2) not
to use corticosteroids concomitantly with atRA.
Various kinds of atRA gels with higher concentrations than those commercially available
were originally prepared. A cream-based,
0.01% to 0.1% concentration of atRA (0.01%
to 0.1% Retin-A) has been widely used, and theconcentration of atRA in aqueous gel-based
products is usually lower because of the higher
permeability of the vehicle. We prepared a
0.1% to 0.4% concentration of atRA using
aqueous gel as a vehicle because of its higher
permeability and economic benefits. We assume that 0.1% atRA aqueous gel corresponds
to 0.3% to 0.4% atRA cream or hydrophilic

FIG. 3. Case 3. A 23-year-old woman with postinflammatory hyperpigmentation on thecheek. Before treatment (left) and after 8 weeks of treatment (right).

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PLASTIC AND RECONSTRUCTIVE SURGERY, March 2000

ointment in terms of the efficiency of drugdelivery. Because atRA is pharmacologicallyunstable, its concentration in our vehicle isspontaneously reduced to 90 percent in 1
month (data not shown), even when stored ina refrigerator. Thus, it is necessary for new
atRA gel to be prepared at least once a month.

Effectiveness on Skin Hyperpigmentation

The present results demonstrated that theeffectiveness of the treatment varies according
to the diagnosis and location of the lesions.
Although statistical significance was not detected, the success rates for senile lentigines

FIG. 4. Case 4. A 16-year-old girl with congenital nevus spilus on the left cheek. (Above, left)
Before treatment, (above, right) after 3 weeks, (below, left) after 8 weeks, and (below, right) after
12 months of treatment.

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1105

FIG. 5. Case 5. A 61-year-old woman with nevus spilus on the left cheek. Before treatment(left) and after 8 months of treatment (right).

and postinflammatory hyperpigmentation
were very high, especially for lesions on theface. The success rate for nevus spilus was approximately 60 percent. However, neither laser
therapies nor any other therapies combinedwith hydroquinone can treat nevus spilus very
well, and the recurrence of pigmentation withthese other treatments is also very common,suggesting that our bleaching protocol has potential as a therapy for nevus spilus.
The location of the skin lesions is also quite
important in this therapy. The success rate forthe face was more than 90 percent, and that for
the trunk and upper extremities was 71.4 and60.1 percent, respectively. Although the number of cases was small, the success rate for the
lower extremities was only 50 percent. Statistical significance existed according to the locations of the lesions. The skin reactions to atRA
are milder and slower on the trunk and extremities, especially on the lower extremities,
than on the face. Differences in the permeability and vascularity of the skin, associated withthe penetration and resorption of the agent
and wound healing, are suspected to be themain reasons for the differences in the skinreactions. Therefore, higher concentrations of
atRA were used in this protocol for the trunkand extremities: 0.2 percent atRA gel for thetrunk and upper extremities and 0.4 percent
for the lower extremities. This led to muchbetter clinical results than using 0.1 percent
atRA gel.
Mechanisms of Action of atRA and Hydroquinone

The mechanisms by which atRA and hydroquinone act in the combined protocols,6,7 muststill be elucidated. Although a number of studies have been performed to determine the effects of atRA on skin in vivo or on keratinocytes
and other cells in the skin in vitro, contradictory results exist. The reasons for this remain
unknown.3,17,18 Although reportedly even the
topical application of atRA alone has a clinically depigmenting effect,5,19,20 the suppressive
effects of atRA on melanocyte growth and melanogenesis have not been established in vitro.21
AtRA promotes the proliferation of keratinocytes in vivo, and hyperplasia of the epidermis
is a characteristic change after the topical application of atRA.3 However, the promotion of
keratinocyte growth is variable in vitro.18 It wasreported that atRA can promote collagenesis
and wound healing.2,22,23 On the other hand,skin becomes atrophic after the application ofcorticosteroids,24,25 and corticosteroids suppress collagenesis and wound healing.26 Thus,

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PLASTIC AND RECONSTRUCTIVE SURGERY, March 2000

corticosteroids seem to be antagonistic to retinoids in some respects.2,24,25,27
Corticosteroids have a depigmenting effectwith single use,28 and this is one of the reasons
why Kligman and Willis6 used it in their regimen.6 However, on the basis of our preliminary
clinical results and the differences between the
results of the present report and those of otherconventional reports in which atRA and corticosteroids were concomitantly used, we thinkthat corticosteroids suppress the beneficial effects of atRA in the depigmenting treatment
and should be minimally used in bleaching
therapies with atRA. Also, in our experience,peeling procedures, such as the use of the
carbon dioxide laser followed by topical hydroquinone treatment, do not create the same
results, suggesting that the scaling or peeling
effect is not the primary role of atRA in thistreatment. Taken together, we speculate thatthe strong promotion of keratinocyte proliferation and wound healing is, most likely, therole of atRA in this depigmenting protocol.
The promotion of permeability induced by repeated scaling and mucinous accumulation in
the extracellular spaces may be a supplemental
benefit of atRA in this treatment.29

tenance, without any adverse skin effects. Although the mechanism by which tolerance isobtained and whether the beneficial effects ofatRA are lost have not been established, theincreased tolerance is the reason why we usually need to use the higher concentration of
atRA gel in the second treatment.
Another possible side effect is postinflammatory hyperpigmentation induced by the skininflammation of the bleaching step. During
the healing step, erythema is gradually reduced, but postinflammatory hyperpigmentation occurred in some patients. In most ofthese patients, the hyperpigmentation gradually disappeared in a couple of months. Otherwise, it can be treated by our treatment protocol. The skin color of Oriental patients may be
one of the factors causing postinflammatory
hyperpigmentation.

Side Effects

Adverse effects on the skin, such as irritationand erythema, occurred at a higher rate in thisprotocol than in conventional ones because of
the high concentrations of atRA used.14 Indeed, 10 to 15 percent of the patients did notcomplete the treatment, although accurate assessment of the number of dropouts was difficult because some patients did not revisit thehospital for unknown reasons. Although it wasreported that high concentrations of atRA accentuate irritation without a corresponding
gain in effectiveness,2,30 our protocol withhigher concentrations of atRA aqueous gel led
to much better objective and clinical results
and subjective satisfaction than the lower concentrations. These differences may be partly
derived from the racial differences in the subjects.
Continuous application of atRA leads to tolerance in the treated skin.31 After a few weeks
of treatment, the side effects (such as erythemaand irritation) decrease, even during thebleaching step. Indeed, it was not necessary to
conduct the healing step in some patients,
such as case 5. Also, we have some patients who
use 0.4 percent atRA gel on the face for main-

Recurrence

In patients with senile lentigines or melasma
who were followed-up for more than 6 months,
recurrence of the lesion was occasionally observed, but the number of such cases was small.
It rarely occurred in patients with postinflammatory hyperpigmentation, but a total of 80 to
90 percent of the cases of nevus spilus exhibited some signs of recurrence a couple ofmonths after treatment ceased. However, recurring pigmentation was usually reduced oreliminated by the second treatment in cases inwhich the first treatment was effective. Therefore, continual treatment with atRA or hydroquinone is recommended in patients with nevus spilus, even when the result of the firsttreatment is excellent. Only in pregnant patients with nevus spilus could it be a problem tocontinue treatment with atRA, which is a possible teratogen.32
Indication of the Treatment and Application to
Combination Therapies

The present protocol can be applied to almost any kind of skin lesion with hyperpigmentation, preferably when the intensity of pigmentation is high, for example, when therelative melanin value is more than 30. Taking
into consideration the fact that the reactive
inflammation accompanying the bleaching
step may induce postinflammatory hyperpigmentation during the healing step, any othermild treatment could be recommended for lesions with weak pigmentation, for example,
when the relative melanin value is less than 15.

Vol. 105, No. 3 / BLEACHING TREATMENT FOR HYPERPIGMENTATION

It should be noted that our bleaching protocol
is not very effective for lesions with hyperkeratosis. In such cases, other treatments, such as
liquid nitrogen and carbon dioxide laser,should be applied before the bleaching step.
Possible side effects during the bleaching stepshould be explained well, and the firm intention of the patients to undergo aggressive treatment should be confirmed before starting thebleaching step, as with any other surgery or
chemical peel. Finally, it is emphasized that
repeated treatments with this protocol can remarkably improve photoaged skin, not only interms of skin color, but also in skin texture andelasticity; it eliminates surface roughness andfine wrinkles.
CONCLUSIONS

The authors propose a strong bleaching protocol in which atRA aqueous gels were used athigh concentrations and corticosteroids wereused minimally. Although reactive adverse effects may be more severe, the present protocol
improves hyperpigmentation, with a higher
success rate and a shorter treatment period
than conventional protocols. It is also the firstone with effectiveness in treating nevus spilus.
The success rates varied according to diagnosis
and location of skin lesions. High success rates
were obtained for cases of senile lentigines andpostinflammatory hyperpigmentation and lesions on the face. The present protocol can beapplied to almost any kind of skin lesion withhyperpigmentation, preferably when the intensity of pigmentation is very high.
Kotaro Yoshimura, M.D.
Department of Plastic, Reconstructive, andAesthetic Surgery
University of Tokyo
7-3-1, Hongo, Bunkyo-Ku
Tokyo 113-8655, Japan
yoshimura-pla@h.u-tokyo.ac.jp
ACKNOWLEDGMENTS
The authors thank Yuka Kuwahara and Takako Kato for
their assistance in spectrophotometric measurements.

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