Background: Although a variety of topical treatments have
been used for skin hyperpigmentation, the effectiveness
is variable after prolonged treatment.
Objective: One hundred and thirty six Oriental patients followed
up for more than 12 weeks were analyzed in this study.
Methods: The protocol was composed of two steps: a bleaching
step (2-6 weeks) and a healing step (2-6 weeks). 0.1-0.4%
all-trans retinoic acid aqueous gel was originally prepared
and applied concomitantly with hydroquinone, lactic acid
ointment for bleaching. After obtaining sufficient improvement
of the hyperpigmentation, corticosteroid was topically applied
with hydroquinone and ascorbic acid in the healing step.
Improvement was evaluated with a narrow-band reflectance
Results: The results were successful in more than 80% of
senile lentigines and postinflammatory hyperpigmentations,
especially on the face. Sixty percent of nevus spilus were
also successfully treated.
Conclusion: Although transient adverse effects may be more
severe, this strong bleaching protocol enables an improvement
of a variety of hyperpigmented lesions including nevus spilus
with a higher success rate and a shorter period of treatment
than conventional protocols.
All-trans retinoic acid (atRA; tretinoin) has been topically
used for the treatment of acne, photodamaged skin and hyperpigmentation as well
as before and after skin resurfacing such as carbon dioxide laser and chemical
peeling101,102. Kligman’s well-known regimen1 and several modifications2, 3 have
been widely used as a topical bleaching formula for two decades and a number
of products based on them are commercially available. However, the improvement
is variable and sometimes limited or unrecognizable, and it usually takes a prolonged
time of treatment.
The authors proposed a new bleaching protocol with a high concentration
of atRA aqueous gel and have treated over 300 Oriental patients with skin hyperpigmented
lesions such as senile lentigines, postinflammatory hyperpigmentation, melasma,
and nevus spilus. These skin lesions with hyperpigmentation have been treated
with a variety of therapies including laser and chemical peeling, and except
with senile lentigines, the results have not been very satisfactory4, 5, 6,100.
The management of postoperative hyperpigmentation is quite important for dermatologic
or plastic surgeons performing facial skin resurfacing. Furthermore, there have
been no reports indicating the effectiveness of topical treatments on nevus spilus
for which there is no standard therapy to date (6,100). Although our protocol
requires two steps (a bleaching step and a healing step), and transient adverse
skin reactions associated with this protocol may be more severe, it enables an
improvement of a variety of hyperpigmented lesions including nevus spilus with
a higher success rate and a shorter period of treatment than those of conventional
Preparation of Ointments: AtRA aqueous gels (atRA gel) with
3 different concentrations (0.1, 0.2, and 0.4 %) were originally
prepared at the Department of Pharmacy, University of Tokyo.
The precise regimen of 0.1-0.4% atRA aqueous gel for 1000g
was as follows: atRA (Sigma Chemical, St. Louis, MO) 1-4g,
Carbopol 940 (Goodrich Chemical, Hounlow, UK) 10g, polyoxyethylene
oleyl ether (Kao, Tokyo, Japan) 20g, methyl p-hydroxybenzoate
(Wako Pure Chemical Industries, Osaka, Japan) 0.26g, propyl
p-hydroxybenzoate (Wako Pure Chemical Industries, Osaka,
Japan) 0.14g, 10% sodium hydroxide aqueous solution 6ml,
purified water ad.1000g. An ointment including 5% hydroquinone
and 7% lactic acid (HQ-LA ointment) and one including 5%
hydroquinone and 10% l-ascorbic acid (HQ-AA ointment) were
also prepared at the Department of Pharmacy, University of
Tokyo. Plastibase? (petrolatum polyethylene ointment base,
Taisho Pharmacology, Osaka, Japan) and hydrophilic ointment
were used as the ointment bases of the HQ-LA ointment and
HQ-AA ointment, respectively. Because all ointments (atRA
gel, HQ-LA ointment, and HQ-AA ointment) are pharmacologically
unstable, fresh ointments were prepared at least once a month
and stored in a dark and cool (4?C) place.
Patients: Each ointment was topically applied under signed
informed consent in more than 300 patients with hyperpigmented
skin lesions. One hundred and thirty six patients, who had
hyperpigmented lesions of which the relative melanin value
(RMV; see below) were more than 30 and were followed up for
more than 12 weeks, were analyzed in this study. All of them
were Oriental: 128 Japanese, 3 Chinese, 3 Korean and 2 Indian.
Clinical diagnoses of hyperpigmented lesions were classified
into four categories; senile lentigines (SL), melasma (ML),
postinflammatory hyperpigmentation (PIH), and nevus spilus
(NS) which included caf? au lait spots. Patients with PIH
of less than 6 months duration were excluded from this study.
The age of patients varied from 4 to 88 years old (age=44.6±15.3;
mean?S.D.), and 112 cases were female. The data of patients
are summarized in Table 1. Some patients had hyperpigmented
lesions and underwent the treatment on more than one part
of the body, so that the total number of patients in the
data is 146. The data were analyzed according to the clinical
diagnosis and the sites of the skin lesions, and included
90 patients with SL (on the face in 61 patients, on the trunk
in 3, on the upper extremities in 24, and on the lower extremities
in 2), 10 patients with ML (on the face in all patients),
28 patients with PIH (on the face in 11 patients, on the
trunk in 6, on the upper extremities in 7, and on the lower
extremities in 4), and 18 patients with NS (on the face in
9 patients, on the trunk in 5, on the upper extremities in
2, and on the lower extremities in 2).
Our bleaching protocol is composed of two steps,
a bleaching step and a healing step. In the bleaching
step, the pigmentation is aggressively treated,
and transient adverse skin effects such as erythema
and irritation are usually observed. Once satisfactory
improvement is obtained, the healing step is
started in order to reduce the erythema and inflammation.
In some cases, a pretreatment was conducted before
the bleaching step.
1) pretreatment: The application of HQ-LA ointment (HQ-AA
ointment in some cases) to the skin lesions twice daily for
several weeks was recommended to those who wanted to start
the bleaching treatment in several weeks for personal reasons. In
summer, every patient was advised to have only a pretreatment
with HQ-LA ointment until September to avoid strong UV irradiation
during the bleaching step. In the daytime, a broad-spectrum
sunscreen cream was always concomitantly applied with the
other ointments throughout the treatment period.
2) bleaching step: 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 skin lesions: 0.1% atRA gel for the face,
0.2% for the trunk or upper extremities, and 0.4% for the
lower extremities. Patients were requested to visit our hospital
at 1, 2, 4, 6, 8, 12, and 16 weeks after starting this treatment.
When the appropriate 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
If a satisfactory improvement (= 80% improvement of relative
melanin value; see below) was not obtained after 8 weeks’ continual treatment
of atRA gel and HQ-LA ointment, the treatment was discontinued. In those
cases, the second treatment was started after a 2 to 3 months interval of atRA
gel application. Throughout this interval, HQ-LA (or HQ-AA) ointment was recommended
as a pretreatment for the 2nd treatment, which is the same protocol as the first
3) healing step: After sufficient improvement of the hyperpigmentation
was obtained, the application of atRA gel and HQ-LA ointment
was discontinued, and topical application of corticosteroids
(0.12% betamethasone valerate or 0.3% prednisolone butylacetate
ointment) and HQ-AA ointment (HQ-LA ointment in some cases)
for as short a time as possible (usually 1 to 3 weeks) was
started to reduce the reactive erythema and inflammation.
After the erythema was reduced to some extent, the application
of corticosteroid was discontinued and only HQ-AA ointment
was continuously applied. In cases in which erythema was
not reduced after a few weeks’ application of corticosteroid
and HQ-AA ointment, HQ-AA ointment was also discontinued
for a few weeks. In some cases in which reactive erythema
was not so severe, this step was omitted.
4) Post-treatment maintenance: After the bleaching and healing
steps were finished, the continual application of HQ-LA or
HQ-AA ointment for several months was advised for post-treatment
maintenance in some cases including all cases with NS. In
cases with NS, when clinical signs of recurrence of pigmentation
were observed, atRA gel was also used as maintenance or the
2nd treatment was started.
Evaluations of results:
1) Spectrophotometry: As an objective measurement of the
color of the designated lesion and surrounding normal
skin, a narrow-band reflectance spectrophotometer (Mexameter
MX 16, COURAGE+KHAZAKA electric GmbH, K?ln, Germany)
was used at each clinical visit. The overall results
were objectively evaluated by the melanin and hemoglobin
values measured with Mexameter?. A measuring probe with
a measuring area of 5mm diameter emits light of 3 pre-defined
wavelengths (568 nm: green, 660 nm: red, and 880 nm:
infrared), and measures the light reflected by the skin.
The melanin value is measured by using 2 wavelengths
(660nm and 880 nm) to achieve different absorption rates
by the melanin granules. For the hemoglobin measurement
as well, 2 wavelengths (568 nm and 660 nm) are used.
The melanin and hemoglobin values are calculated as follows:
Melanin value = 500/ log 5 x (log infrared-reflection/ red-reflection
+ log 5)
Hemoglobin value = 500/ log 5 x (log red-reflection/ green-reflection
+ log 5)
Each spot was measured 3 times and the average of 3 measured
values was calculated. The difference in the absolute melanin
and hemoglobin value between a skin lesion and the surrounding
normal skin is referred to in this paper as the relative
melanin value (RMV) and the relative hemoglobin value (RHV)
of the skin lesion, respectively. RMV and RHV indicate the
intensity of pigmentation and erythema relative to the surrounding
normal skin, respectively. A negative RMV means that
the measured spot is lighter than the control. RMV was compared
between before and after the 1st treatment, and the results
were classified into the 4 following grades: “excellent”,
final RMV was 5 or less; “good”, final RMV was reduced to
less than 20% of the RMV before treatment; “fair”, final
RMV was reduced to less than 60% of the RMV before treatment;
“poor”, final RMV was more than 60% of the RMV before treatment.
The absolute melanin value of normal skin in Japanese and
the RMV of hyperpigmented lesions are usually 460-500 and
20-120, respectively. Five or less of RMV is difficult to
2) Statistics: The results were analyzed according to the
diagnosis and locations of the skin lesions. Significant
differences were sought using Kruskal-Wallis test. Differences
were considered significant when H values > x2(0.95).
In general, erythema was seen in a few days, followed by
continuous scaling during the first week25. Erythema
and scaling was usually continuously seen throughout
the bleaching step. Formation of a thin crust was also
seen in some cases during the second week. After the
thin crusts came off, the elimination of pigmentation
was usually obtained. An improvement of hyperpigmentation
was obtained after a bleaching step of 2-4 weeks in most
cases with SL or PIH, while a somewhat longer period
was usually required for NS. The second treatment was
performed for further improvement in 19 cases (21.1%)
with SL, 6 cases (60.0%) with ML, 1 cases (3.6%) with
PIH, and 16 cases (88.9%) with NS.
The results of the treatment were evaluated with spectrophotometry
and summarized in Table 2. Cases evaluated as “excellent”
or “good” were referred to as successful in this paper and
success rates were calculated as following: [number of “excellent”
and “good” cases]/ [number of total cases].
In the cases with SL, 27 cases (23 cases on the face and
4 on the upper extremities) were evaluated as “excellent”,
47 cases (35 cases on the face, 2 on the trunk, and 10 on
the upper extremities) as “good”, 13 cases (3 cases on the
face, 1 on the trunk, 8 on the upper extremities, and 1 on
the lower extremities) as “fair”, and 3 cases (2 cases on
the upper extremities and 1 on the lower extremities) as
“poor”. In the cases with ML, 2 cases were evaluated as “excellent”,
5 cases as “good”, 2 cases as “fair”, and 1 case as “poor”.
In the cases with PIH, 10 cases (5 cases on the face, 2 on
the trunk, 1 on the upper extremities, and 2 on the lower
extremities) were evaluated as “excellent”, 14 cases (6 cases
on the face, 3 on the trunk, 4 on the upper extremities,
and 1 on the lower extremities) as “good”, 3 cases (1 case
on the trunk, 1 on the upper extremities, and 1 on the lower
extremities) as “fair”, and 1 case (on the upper extremities)
as “poor”. In the cases with NS, 5 cases (3 cases on the
face and 2 on the trunk) were evaluated as “excellent”, 6
cases (3 cases on the face, 1 on the trunk, 1 on the upper
extremities and 1 on the upper extremities) as “good”, 5
cases (3 cases on the face, 1 on the trunk, and 1 on the
upper extremities) as “fair”, and 2 cases (1 case on the
trunk and 1 on the lower extremities) as “poor”.
The success rate for SL was 82.2% (95.1% for SL on the
face and 58.3% for SL on the upper extremities). The success rates for ML, PIH,
and NS were 70.0%, 85.7%, and 61.1%, respectively. Significant differences were
not seen among the four diagnosis (H value= 2.67, x2(0.95)=7.81). On the other
hand, classified according to the locations of the skin lesions, there was a
significant difference between four locations (H value= 12.44, x2(0.95)=7.81).
The success rates for face, trunk, upper extremities, and lower extremities were
90.1%, 71.4%, 60.1%, and 50.0%, respectively. The total success rate for
146 cases was approximately 80%.
Case 1: A 54-year-old
woman with a senile lentigine on her left cheek
underwent combined topical applications of 0.1%
atRA gel and HQ-LA ointment without a pretreatment
(Fig.2A: before treatment). The initial reaction
such as erythema and scaling was appropriate
(Fig 2B: at 1 week), and at 2 weeks the hyperpigmentation
had disappeared completely, despite the severe
erythema and formation of a thin crust on the
treated region (Fig. 2C: after a bleaching step
of 2 weeks). AtRA-gel and HQ-LA ointment were
discontinued and topical application of corticosteroid
and HQ-AA was started. Corticosteroid was applied
for 2 weeks (Fig. 2D: at 4 weeks). Four weeks
after the discontinuation of corticosteroid,
the erythema disappeared completely. (Fig. 2E:
after treatment for 8 weeks). HQ-AA ointment
was applied throughout the healing step for 6
weeks., and the final RMV after 8 weeks’ treatment
was 4.3. The result was evaluated as “excellent”.
The sequential data of spectrophotometry are
shown in Fig. 2F. Although the extent of erythema
seen at 2 weeks was nearly most severe among
the cases we experienced, the time course of
clinical changes of this case was typical in
this treatment. The RMV and RHV before treatment
were 166.7 and 46.0, respectively. RHV is generally
positive in hyperpigmented lesions. During the
bleaching step, RMV was considerably reduced,
while RHV was increased as the inflammation progressed.
During the healing step, RHV gradually decreased,
while the improvement of RMV was maintained.
RHV was reduced to even below the level before
treatment. The final RMV and RHV after 8 week’
treatment were 4.3 and 18.8, respectively.
Case 2: A 60-year-old
man with multiple senile lentigines on his bilateral
cheeks underwent combined topical applications
of 0.1% atRA gel and HQ-LA ointment without a
pretreatment (Fig. 3A, 3B: before treatment).
Appropriate reactions were seen during the 1st
and 2nd week, and the healing step was started
at 2 weeks. The hyperpigmentation and erythema
had almost disappeared by the 8th week. Occasional
application of atRA and HQ-LA ointment was done
after treatment for maintenance (Fig. 3C, 3D:
at 20 weeks). The RMVs of pigmented spots before
treatment were 65.3 (left) and 52.3 (right),
and the final RMVs after 8 weeks’ treatment were
?1.2 (left) and -4.0 (right), respectively. The
result was evaluated as “excellent”.
Case 3: A 28-year-old
man underwent a split-thickness skin graft from
the medial aspect of the right upper arm to the
face 3 years before his first clinical visit,
and postinflammatory hyperpigmentation remained
on the donor site of the graft (Fig. 5A: before
treatment). Topical applications of 0.2% atRA
gel and HQ-LA ointment were started without a
pretreatment. On day 5 scaling was seen, and
thereafter hyperpigmentation was reduced significantly.
At 3 weeks the healing step was started, and
the erythema was almost eliminated at 8 weeks.
No recurrence was seen at 20 weeks. (Fig. 5B:
at 20 weeks). RMV before and after treatment
was 41.4 and 2.1, respectively. The evaluation
of this case was “excellent”.
Case 4: A 16-year-old
woman with congenital nevus spilus on the left
cheek underwent combined topical applications
of 0.1% atRA gel and HQ-LA ointment without a
pretreatment (Fig. 6A: before treatment). The
initial reaction such as erythema and scaling
was appropriate, and thin crusts came off during
the 2nd to 3rd weeks (Fig. 6B: at 3 weeks).
The bleaching step was continued for 4 weeks,
followed by a healing step of 4 weeks. The RMV
before treatment was 41.7, and the RMV at 8 weeks
was ?3.5 (Fig. 6C: at 8 weeks). Although HQ-LA
ointment was continually applied after the treatment
for maintenance, signs of recurrence were detected
6 weeks later. Therefore, atRA as well as HQ-LA
ointment was applied once daily, and this maintenance
was working well even 10 months later (Fig. 6D:
at 12 months). The result was evaluated as “excellent”.
Case 5: A 61-year-old
woman with nevus spilus on the left cheek, who
had undergone cryotherapy with dry ice 4 times
and dermabrasion 2 times resulting in no improvement,
underwent combined topical applications of 0.1%
atRA gel and HQ-LA ointment without a pretreatment
(Fig. 7A: before treatment). The initial reactions
such as erythema and scaling were appropriate,
and the pigmentation was reduced significantly.
As the erythema gradually reduced during the
bleaching step in this case, the bleaching step
was continued for 8 weeks, and no healing step
was required (Fig. 7B: at 8 weeks). The RMVs
before and after treatment were 72.3 and ?3.6,
respectively. Although the HQ-LA ointment was
continually applied after the treatment for maintenance,
signs of recurrence of the pigmentation were
observed one month after the cessation of atRA.
AtRA as well as HQ-LA ointment was continually
used for maintenance, and the pigmentation was
controlled very well even 15 months later (Fig.
7C: at 15 months). The result was evaluated as
Characteristics of the present protocol
For bleaching, atRA and hydroquinone play essential roles
in this protocol, while lactic acid and ascorbic acid were
utilized supplementally. Although ascorbic acid is also known
to have a depigmenting effect and fewer adverse effects than
hydroquinone, its depigmenting ability is far less than that
of hydroquinone8. It is clear that the same results can not
be obtained from the single use of either atRA9 or hydroquinone10.
Although hydroquinone was used also in the healing step,
but the authors did not expect it to further improve pigmentation
but to prevent postinflammatory hyperpigmentation and recurrence
of pigmentation, thus maintain the level of improvement obtained
in the bleaching step.
Based on our preliminary trials with several concentrations
of atRA in several vehicles and the concomitant use of corticosteroid
with atRA, we believe the critical points of this protocol
are: 1) to use a high concentration of atRA “aqueous gel
“and 2) to not use corticosteroid concomitantly with atRA.
Various kinds of atRA gels with higher concentrations than
those commercially available were originally prepared. 0.01
to 0.1% cream-base atRA (0.01-0.1% Retin-A?) has been widely
used and the concentration of atRA in aqueous gel-base products
is usually lower because of the higher permeability of the
vehicle. The authors prepared 0.1-0.4% atRA using aqueous
gel as a vehicle because of its higher permeability and economical
benefits. We assume that 0.1% atRA aqueous gel corresponds
to 0.3-0.4% atRA cream or hydrophilic ointment in terms of
the efficiency of drug delivery. As atRA is pharmacologically
unstable, its concentration in our vehicle is spontaneously
reduced to 90% in 1 month (data not shown) even when stored
in a refrigerator. Thus, it is necessary for new atRA gels
to be prepared at least once a month.
Effectiveness on skin
The present results demonstrated that the effectiveness of
the treatment varies according to the diagnosis and location
of the lesions. Although statistical significance in the
improvement scores was not detected, the success rates for
SL and PIH were very high, especially for those on the face.
On the other hand, the success rate for NS was approximately
60%. However, neither laser therapies nor any other therapies
even combined with hydroquinone can treat NS very well, and
the recurrence of pigmentation is also very common, suggesting
that our bleaching protocol has potential as a therapy for
The location of the skin lesions is also quite important
in this therapy. The success rate for the face was over 90%, while those for
the trunk and upper extremities were 71.4% and 60.1%, respectively. Although
the number of cases was small, the success rate for the lower extremities was
only 50%. Statistical significance in the improvement scores was found between
the face and upper extremities. 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
with the penetration and resorption of the reagent and wound healing, are suspected
to be the main reasons for the differences in the skin reactions. Therefore,
higher concentrations of atRA were utilized in this protocol for the trunk and
extremities; 0.2% atRA gel for the trunk and upper extremities, and 0.4% for
the lower extremities, leading to much better clinical results than those with
0.1% atRA gel.
Mechanisms of action
of atRA and hydroquinone
The mechanisms by which atRA and hydroquinone act in the
combined protocols(1,2) such as in Kligman’s regimen and
ours is still to be elucidated. Although a number of studies
have been performed concerning the effects of atRA on skin
in vivo or with keratinocytes and other cells in the skin
in vitro, there are some contradictory results the reasons
for which remain unknown11, 12, 16. Although it is reported
that even the topical application of atRA alone has a clinically
depigmenting effect 9, 13, 14, the suppressive effects of
atRA on melanocyte growth and melanogenesis have not been
established in vitro15 (Yoshimura, in preparation). AtRA
promotes the proliferation of keratinocytes in vivo, and
hyperplasia of the epidermis is a characteristic change after
the topical application of atRA16. However, the promotion
of keratinocyte growth is variable in vitro12. It was reported
that atRA can promote collagenesis and wound healing17, 18,103.
On the other hand, it is known that skin becomes atrophic
after the application of corticosteroid19, 20 and that corticosteroid
suppresses collagenesis and wound healing21. Thus, corticosteroid
appears to be antagonistic to retinoids in some aspects18,
19, 20, 22.
Corticosteroids are known to have a depigmenting effect
with single use23, and this is one of the reasons why Kligman employed corticosteroid
in his regimen1. However, based on our preliminary clinical trials and the differences
in the results of the present report and those of other conventional reports
in which atRA and corticosteroids were concomitantly used, we believe that corticosteroids
suppress the beneficial effects of atRA in the depigmenting treatment and should
not be used concomitantly with atRA. Also, in our experience, peeling such as
that by carbon dioxide laser followed by topical hydroquinone treatment could
not lead the same results, suggesting that the scaling or peeling effect is not
the primary cause of the effectiveness of atRA in this treatment. Taken together,
it is speculated that the strong promotion of keratinocyte proliferation and
wound healing is most likely to be the roles 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 treatment24.
Adverse effects on the skin such as irritation and erythema
may be seen at a higher rate in this protocol than in conventional ones because
of the high concentrations of atRA25. Indeed, 10-15% of the patients did not
complete the treatment, although accurate assessment of the number of dropouts
was difficult because there were some patients who did not revisit the hospital
for unknown reasons. Although it has been considered that high concentrations
of atRA accentuate irritation without a corresponding gain in effectiveness1,
18, our protocol with higher concentrations of atRA aqueous gel lead to much
better objective and clinical results and subjective satisfaction than the lower
concentrations. These differences may be partly derived from racial differences
in the subjects.
It is known that continuous application of atRA leads
to tolerance in the treated skin27. After a few weeks’ treatment, the side effects
such as erythema and irritation decrease with time even during the bleaching
step. Indeed, it was not necessary to conduct the healing step in some patients
such as case #6. Also, we have some patients who are using 0.4% atRA gel on the
face for maintenance without any adverse skin effects. Although the mechanism
by which tolerance is obtained and whether the beneficial effects of atRA are
also lost have not been established, the increased tolerance is the reason why
we usually use the higher concentration of atRA gel in the 2nd treatment.
Another possible side effect is PIH induced by the skin
inflammation of the bleaching step. During the healing step, erythema is gradually
reduced, but PIH occurred in some cases. In most of those cases, PIH gradually
disappeared in a couple of months. Otherwise, it can be treated by the present
treatment. The skin color of Oriental patients may be one of the factors of PIH.
In cases with SL or ML, which were followed up for more
than 6 months, recurrence of the lesion was occasionally observed, but the number
of such cases was small. Recurrence was seen several months after cessation of
the treatment. On the other hand, recurrence was rarely seen in cases with PIH.
Among cases with NS, nearly 80% exhibited some signs of recurrence a couple of
months after they stopped the treatment. However, recurring pigmentation was
usually reduced or eliminated by the 2nd treatment in cases in which the 1st
treatment was effective. Therefore, continual treatment with atRA or hydroquinone
would be recommended in NS cases even when the result of the 1st treatment is
“excellent”. Only for pregnant patients with NS, it could be a problem to continue
treatment with atRA which is known to be a possible teratogen28.
Indication of the
treatment and application to combination therapies
The present protocol can be applied to almost any kind of skin
lesions with hyperpigmentation, preferably when the intensity of pigmentation
is high, for example, when the RMV is over 30. Taking into consideration the
fact that the reactive inflammation accompanying the bleaching step possibly
induces PIH during the healing step, any other mild treatment could be recommended
for lesions the pigmentation of which is very weak, for example when the RMV
is less than 15. 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 prior to the bleaching step.
Possible side effects during the bleaching step should be explained well and
the firm intention of the patients to undergo aggressive treatment should be
confirmed before starting the bleaching step as with any other surgery or chemical
peeling. Finally, it is emphasized that repeated treatments with this protocol
can remarkably improve photoaged skin not only in terms of skin color but also
in skin texture and elasticity, eliminating surface roughness and fine wrinkles.
The authors proposed a strong bleaching protocol in which
atRA aqueous gels were used at high concentrations and
corticosteroids were minimally used. Although reactive
adverse effects may be more severe, the present protocol
enables improvement of hyperpigmentation with a higher
success rate and a shorter period of treatment than conventional
protocols, and is the first one indicating the effectiveness
on NS. The success rates varied according to diagnosis
and location of skin lesions. High success rates were
obtained for SL and PIH and on the face. The present
protocol can be applied to almost any kind of skin lesions
with hyperpigmentation, preferably when the intensity
of pigmentation is very high.
The authors express sincere appreciation to Yuka Kuwahara and
Takako Kato for their assistance in spectrophotometric measurements.
Kotaro Yoshimura, M. D.
Department of Plastic, Reconstructive, and Aesthetic Surgery,
University of Tokyo,
7-3-1, Hongo, Bunkyo-Ku, Tokyo 113-8655, Japan.
101) Apfelberg, D. B. Ultrapulse carbon dioxide laser with
CPG scanner for full-face resurfacing for rhytids, photoaging,
and acne scars. Plast. Reconstr. Surg. 99: 1817, 1997.
102) Leyden, J. J. Treatment of photodamaged skin with topical
tretinoin: an update. Plast. Reconstr. Surg. 102: 1667, 1998.
1) Kligman, A. M., and Willis, I. A new formula for depigmenting
human skin. Arch. Dermatol. 111: 40, 1975.
2) Gano, S. E., and Garcia, R. L. Topical tretinoin, hydroquinone,
and betamethasone valerate in the therapy of melasma. Cutis
3) Pathak, M. A, Fitzpatrick, T. B., and Kraus, E. W. Usefulness
of retinoic acid in the treatment of melasma. J. Am. Acad.
Dermatol. 15: 894, 1986.
4) Nordlund, J. J. Postinflammatory hyperpigmentation. Dermatol.
Clin. 6: 185, 1988.
5) Grimes, P. E. Melasma. Etiologic and therapeutic considerations.
Arch. Dermatol. 131, 1453, 1995.
6) Alster, T. S. Laser treatment of pigmented lesions. In:
Manual of Cutaneous Laser Techniques. Philadelphia(PA): Lippincott-Raven
Publishers; 1997. p. 45-62.
100) Taylor, C. R., and Anderson, R. R. Treatment of benign
pigmented epidermal lesions by Q-switch ruby laser. Int.
J. Dermatol. 32: 908, 1993.
7) Yoshimura, K., Harii, K., Masuda, Y., et al. Usefullness
of a narrow-band reflectance spectrophotometer in evaluating
effects of depigmenting treatment. Aesthetic Plast. Surg.,
8) Maeda, K., and Fukuda, M. In vitro effectiveness of several
whitening cosmetic components in human melanocytes. J. Soc.
Cosmet. Chem. 42: 361, 1991.
9) Rafal, E. S., Griffiths, C. E. M., Ditre, C. M., et al.
Topical tretinoin (retinoic acid) treatment for liver spots
associated with photodamage. N. Engl. J. Med. 326: 368, 1992.
10) Kenneth, A. A., and Fitzpatrick, T. B. Topical use of
hydroquinone as a depigmenting agent. JAMA 194: 117, 1965.
11) Eichner, R. Epidermal effects of retinoids: in vitro
studies. J. Am. Acad. Dermatol. 15: 789, 1986.
12) Fisher, G. J., and Voorhees, J. J. Molecular mechanism
of retinoid actions in skin. FASEB J. 10: 1002, 1996.
13) Griffiths, C. E. M., Finkel, L. T., Ditre, C. M., et
al. Topical tretinoin (retinoic acid) improves melasma: a
vehicle-controlled, clinical trial. Br. J. Dermatol. 129:
14) Griffiths, C. E. M., Goldfarb, M. T., Finkel, L. J.,
et al. Topical tretinoin (retinoic acid) treatment of hyperpigmented
lesions associated with photoaging in Chinese and Japanese
patients: a vehicle-controlled trial. J. Am. Acad. Dermatol.
30: 76, 1994.
15) Ortonne, J. P. Retinoic acid and pigment cells: a review
of in-vitro and in-vivo studies. Br. J. Dermatol. 127: 43,
16) Kligman, A. M., Grove, G. L., Hirose, R., and Leyden,
J. J. Topical tretinoin for photoaged skin. J. Am. Acad.
Dermatol. 15: 836, 1986.
17) Schwartz, E.. Cruickchank, F. A., Mezick, J. A., and
Kligman, L. H. Topical all-trans retinoic acid stimulates
collagen synthesis in vivo. J. Invest. Dermatol. 96: 975,
18) Kligman, L. H., Duo, C. H., and Kligman, A. M. Topical
retinoic acid enhances the repair of ultraviolet damaged
dermal connective tisuue. Connect. Tissue Res. 12: 139, 1984.
103) Kang, S., Fisher, G. J., and Voorhees, J. J. Photoaging
and topical tretinoin: Therapy, pathogenesis, and prevention.
Arch. Dermatol. 133: 1280, 1997.
19) Mcmichael, A. J., Griffiths, C. E. M., Talwar, H. S.,
et al. Concurrent application of tretinoin (retinoic acid)
partially protects against corticosteroid-induced epidermal
atrophy. Br. J. Dermatol. 135: 60, 1996.
20) Lesnik, R. H., Mezick, J. A., Capetola, R. J., and Kligman,
L. H. Topical all-trans retinoic acid prevents corticosteroid-induced
skin atrophy without abrogating the anti-inflammatory effect.
J. Am. Acad. Dermatol. 21: 186, 1989.
21) Leyden, J. L., Thaw, M., and Kligman, A. M. Steroid rosacea.
Arch. Dermatol. 110: 619, 1974.
22) Ulland, A. E., Shearer, J. D., Coulter, C., and Caldwell,
M. D. Altered wound healing arginine metabolism by corticosterone
and retinoic acid. J. Surg. Res. 70: 84, 1997.
23) Arnold, J., Anthonioz, P., and Marchandd, J. P. Depigmenting
action of corticosteroids. Experimental study on guinea pigs.
Dermatologica 151: 274, 1975.
24) Bhawan, J. Short- and long-term histologic effects of
topical tretinoin on photodamaged skin. Int. J. Dermatol.
37: 286, 1998.
25) Yoshimura, K., Harii, K., Shibuya, F., et al. A new bleaching
protocol for hyperpigmented skin lesions with a high concentration
of all-trans retinoic acid aqueous gel. Aesthetic Plast.
Surg., in press.
26) Griffiths, C. E. M., Kang, S., Ellis, C. N., et al. Two
concentrations of topical tretinoin (retinoic acid) cause
similar improvement of photoaging but different degrees of
irritation. Arch. Dermatol. 131: 1037, 1995.
27) Helander, S. D. Treatment of photoaged skin. Efficacy,
tolerability and costs of available agents. Drugs Aging 8:
28) Nau, H. Embryotoxicity and teratogenesity of topical
retinoic acid. Skin Pharmacol. 6(suppl 1): 35, 1993.
Fig. 1. Case 1: 54-year-old woman with a senile lentigine
on the left cheek. (A) before treatment, (B) at 1 week, (C)
at 2 weeks, (D) at 4 weeks, and (E) at 8 weeks. (F): Sequential
changes in RMV, RHV. RMV: relative melanin value, RHV: relative
Fig. 2. Case 2. 60-year-old
man with senile lentigines on the bilateral forearms.
(A), (B): before treatment, (C), (D): at 2 weeks,
and (E), (F) at 20 weeks.
Fig. 3. Case 3. 28-year-old
man with postinflammatory hyperpigmentation of
donor site of split-thickness skin graft on the
medial aspect of the right upper arm. (A) before
treatment, and (B) at 20 weeks.
Fig. 4. Case 4. 16-year-old
woman with congenital nevus spilus on the left
cheek. (A) before treatment, (B) at 3 weeks,
(C) at 8 weeks, and (D) at 12 months.
Fig. 5. Case 5. 61-year-old
woman with nevus spilus on the left cheek. (A)
before treatment, (B) at 8 weeks, and (C) at