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. Kligmanfs 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
Materials and Methods
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).
Treatment protocol: 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
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 weeksf 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 weeksf 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: gexcellenth,
final RMV was 5 or less; ggoodh, final RMV was reduced to
less than 20% of the RMV before treatment; gfairh, final
RMV was reduced to less than 60% of the RMV before treatment;
gpoorh, 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 gexcellenth
or ggoodh were referred to as successful in this paper and
success rates were calculated as following: [number of gexcellenth
and ggoodh 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 gexcellenth,
47 cases (35 cases on the face, 2 on the trunk, and 10 on
the upper extremities) as ggoodh, 13 cases (3 cases on the
face, 1 on the trunk, 8 on the upper extremities, and 1 on
the lower extremities) as gfairh, and 3 cases (2 cases on
the upper extremities and 1 on the lower extremities) as
gpoorh. In the cases with ML, 2 cases were evaluated as gexcellenth,
5 cases as ggoodh, 2 cases as gfairh, and 1 case as gpoorh.
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 gexcellenth, 14 cases (6 cases
on the face, 3 on the trunk, 4 on the upper extremities,
and 1 on the lower extremities) as ggoodh, 3 cases (1 case
on the trunk, 1 on the upper extremities, and 1 on the lower
extremities) as gfairh, and 1 case (on the upper extremities)
as gpoorh. In the cases with NS, 5 cases (3 cases on the
face and 2 on the trunk) were evaluated as gexcellenth, 6
cases (3 cases on the face, 1 on the trunk, 1 on the upper
extremities and 1 on the upper extremities) as ggoodh, 5
cases (3 cases on the face, 1 on the trunk, and 1 on the
upper extremities) as gfairh, and 2 cases (1 case on the
trunk and 1 on the lower extremities) as gpoorh.
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 weeksf treatment was 4.3. The result
was evaluated as gexcellenth. 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 weekf treatment were 4.3 and
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 weeksf treatment were ?1.2
(left) and -4.0 (right), respectively. The result
was evaluated as gexcellenth.
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 gexcellenth.
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 gexcellenth.
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 gexcellenth.
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 gaqueous gel
gand 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 Kligmanfs 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 weeksf 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
gexcellenth. 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.
Correspondence to: Kotaro
Yoshimura, M. D.
Department of Plastic, Reconstructive, and Aesthetic Surgery,
University of Tokyo,
7-3-1, Hongo, Bunkyo-Ku, Tokyo 113-8655, Japan.
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102) Leyden, J. J. Treatment of photodamaged skin with topical
tretinoin: an update. Plast. Reconstr. Surg. 102: 1667, 1998.
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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 15 months.