ARTICLE IN PRESS+ MODEL
Journal of Plastic, Reconstructive & Aesthetic Surgery (2008) xx, 1e9

A therapeutic strategy based on histologicalassessment of hyperpigmented skinlesions in Asians*
Masakazu Kurita, Harunosuke Kato, Kotaro Yoshimura*
Department of Plastic Surgery, University of Tokyo School of Medicine, Tokyo, Japan
Received 17 May 2007; accepted 28 October 2007

KEYWORDS
tretinoin;hydroquinone;
laser;
inflammation;melasma;melanin incontinence

Summary Hyperpigmentation is the most common cosmetic skin complaint in Asians, butthere is no standard treatment strategy. The aim of this study was to establish a simple therapeutic strategy based on the histological features of hyperpigmented skin lesions in Asians.
Fifty-nine biopsies were analysed from 49 Japanese patients with 17 types of hyperpigmented
skin lesions. In 10 patients, skin samples were also taken during a topical bleaching treatmentthat used tretinoin and hydroquinone. These samples were evaluated after staining withhaematoxylineeosin and FontanaeMasson stains. Our experience of treating a variety ofpigmented lesions with aggressive topical bleaching and lasers was reviewed.
Hyperpigmented lesions were classified into seven categories based on pathologicalfeatures, especially on the degree of hyperkeratosis and epidermal melanin deposits, andon the existence of melanin incontinence and the location of dermal melanocytes. Tretinoin
and hydroquinone therapy was histologically effective for treating epidermal melanin
deposits, but not dermal melanosis or dermal melanocytes. Based on pathological featuresand our extensive clinical experience with hyperpigmented skin, we propose a therapeuticstrategy for treating hyperpigmented skin lesions, which may be particularly useful in Asian
populations.
ª 2008 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Publishedby Elsevier Ltd. All rights reserved.

*
Conflict of Interest Disclosure: None declared.No funding sources for this work.
* Corresponding author. Department of Plastic Surgery, Universityof Tokyo School of Medicine, 7-3-1, Hongo, Bunkyo-Ku, Tokyo 1138655, Japan. Tel.: þ81 3 5800 8948; fax: þ81 3 5800 8947.
E-mail address: yoshimura-pla@h.u-tokyo.ac.jp (K. Yoshimura).

In Caucasians, the most common complaints about photoaged skin are fine wrinkles and telangiectasia, but thesecomplaints are less common in populations with darker
skin. In Asians, hyperpigmentation is the most common
cosmetic complaint, but a standard strategy for treating
hyperpigmented skin lesions has not been established. We
have found that aggressive use of topical tretinoin(0.1e0.4%) along with hydroquinone can successfully treat
various skin hyperpigmentation conditions in Asians.1e8

1748-6815/$ - see front matter ª 2008 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.bjps.2007.10.079

Please cite this article in press as: Kurita M et al., A therapeutic strategy based on histological assessment of hyperpigmented skin lesionsin Asians, J Plast Reconstr Aesthet Surg (2008), doi:10.1016/j.bjps.2007.10.079

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M. Kurita et al.

Although the bleaching protocol we routinely use requires
two steps (a bleaching step and a healing step), and severe
but transient adverse skin reactions are possible, this protocol is quite effective in removing epidermal pigmentationand especially useful for treating pigmented lesions thatare not effectively treated by lasers, such as melasma,post-inflammatory hyperpigmentation (PIH) and pigmented
nipples/areolas. Unfortunately, this bleaching protocol has
less or no effect on dermal pigmentation and hyperkeratotic pigmented lesions.
In order to establish a simple therapeutic strategy that
addresses a wide range of hyperpigmented conditions, weused a topical bleaching treatment, Q-switched (QS) rubylaser, CO2 lasers or combination treatment in our clinic, andanalysed histological specimens from patients. This analysis
and our clinical experience led us to propose a therapeuticstrategy for treating pigmented skin conditions based on
histological features.

event (PIH-S) (n Z 1); seborrheic keratosis (n Z 1); melasma(n Z 1); pigmented external genitalia (n Z 1); and erythromelanosis follicularis faciei et colli (EFFC) (n Z 1). In addition, 10 samples were taken from 10 patients at baselineand during our topical bleaching therapy with tretinoin(all-trans retinoic acid; RA) and hydroquinone (HQ) (RA-HQ
therapy; see below for details). These were diagnosed as
ADM (n Z 1), solar lentigines (n Z 1), lichen pilaris (n Z 2),
RHAD (n Z 1), nevus spilus (n Z 1), pigmented contact
dermatitis (n Z 2), PNAC (n Z 1) and PPA (n Z 1).
Biopsied tissue was fixed in 4% buffered neutral formaldehyde solution and embedded in paraffin for sectioning.
The sections were stained with haematoxylineeosin and
FontanaeMasson stains. The pathological examination
focused on the existence of hyperkeratosis and the location(layers) of melanin deposits or melanocytes, since these two
factors determined our therapeutic strategy. Comparing
samples obtained before and during treatment, morphological alterations due to the RA-HQ treatment were observed.

Methods
RA-HQ therapy
Fifty-nine biopsies were taken from 49 Japanese female
patients (four males and 45 females; age range 16e60 years,
mean 36.16) with hyperpigmented skin lesions after informed consent using an IRB-approved protocol. The lesions
were clinically diagnosed as follows: acquired dermal melanocytosis (ADM) (n Z 12); solar (senile) lentigines (n Z 8);lichen pilaris (n Z 4); ripple/reticulate hyperpigmentation
in atopic dermatitis (RHAD) (n Z 7); nevus spilus (caféau-lait macules) (n Z 4); pigmented contact dermatitis(n Z 4); pigmented nipple areolar complex (PNAC) (n Z 3);
pigmentatio petaloides actinica (PPA) (n Z 4); ephelides(n Z 2); friction melanosis (n Z 2); periorbital hyperpigmentation (n Z 2); nevus of Ota (n Z 2); post-inflammatory
hyperpigmentation resulting from a single inflammatory
Table 1The purpose of this treatment is to improve epidermal
pigmentation by accelerating discharge of epidermal melanin (with aggressive use of tretinoin) and suppressing new
epidermal melanogenesis (with hydroquinone). Details of
the RA-HQ protocol were described previously4e6 and a brief
outline is presented here.
Preparation of ointment
Tretinoin aqueous gels (tretinoin gel) at three different
concentrations (0.1%, 0.2% and 0.4%), an ointment including
5% hydroquinone and 7% lactic acid (HQ-LA ointment), andone including 5% hydroquinone and 7% ascorbic acid (HQ-AA
ointment) were originally prepared at the Department of

Summary of histological characteristics of samples stained with FontanaeMasson

Clinical diagnosis

PIH-S
PNAC
Ephelides
Nevus spilus
Lichen pilaris
Seborraic keratosis
Solar lentigines
Melasma
Pigmented external genitalia
Pigmented contact dermatitis
Friction melanosis
RHAD
PPA
EFFC
ADM
Periorbital hyperpigmentation
Nevus of Ota

Epidermis

DermisHyperkeratosis

Melanindeposits

Melanophages(pigmentary
incontinence)

Dermalmelanocytes


/þ

/þ
þ
þþþ
/þ/þþ

/þ

/þ
/þ
þ
þþ




þ
þ/þþ
þ/þþ
þ/þþ
þ/þþ
þþ
þ/þþ
þ/þþ
þþ
þþ
þ/þþ
þ/þþ
þþ/þþþ
þþ
þ/þþ
þ/þþ






/þ

/þ/þþ
/þ/þþ
þ
þþ/þþþ
þþ/þþþ
þþ/þþþ
þþ
þþ


















þ (upper dermis)þ (upper dermis)
þþ (throughout the dermis)

: negative, þ: slightly positive, þþ: positive, þþþ: highly positive; e.g.: ‘/þ’ means ‘negative or slightly positive’.

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ARTICLE IN PRESS+ MODEL
Hyperpigmented skin lesions in Asians
Table 2

3

Proposed seven-category classification for hyperpigmented lesions

Category

Pathological features

Morbidities

Comments

I

Melanosis with hyperkeratosis

Soborrheic keratosis
Lichen pilaris*

II

Reactive epidermal melanosis

PIH
Sunburn

III

Epidermal melanosis

IV

Reactive epidermalmelanosis & dermal melanosis

Solar lentigines*
PNAC
Ephelides
Nevus spilus
Lichen pilaris*
Lentigino simplex
Melasma*
Pigmented external genitalia
Friction melanosis
RHAD
Pigmented contact dermatitis

Hyperkeratosis is marked
and the lesion
is clinically protruded
Epidermal melanocytes
are activated, mainly
by external factors
Genetic alterationsin epidermal melanocytes
lead to enhanced
melanin production. Histologicalfindings similar to thoseof Category II lesions

V

Epidermal melanosis &dermal melanosis

Solar lentigines*
Melasma* (dermal melasma)
EFFC
PPA

VI

Epidermal melanosis & dermalmelanocytosis

ADM
Periorbital hyperpigmentation

VII

Dermal melanocytosis

Nevus of Ota
Nevus of Ito
Mongolian spots

Exposure to external
factors, such
as UV irradiationand inflammation, activates
epidermal melanocytes and leads
to enhanced melanin
production. Melanin
deposits are observedin the epidermis
and upper dermis(pigmentary incontinence)
Genetic alterationsin epidermal melanocytes
lead to enhanced
melanin production, and melanin
deposits are observedin the epidermis
and upper dermis(pigmentary incontinence). Histologicalfindings similar to thoseof Category IV lesions
Enhanced melanin
production by epidermalmelanocytes. Dermalmelanocytosis can be observedin the upper dermis
Dermal melanocytes
are scattered throughout
the dermis* Morbidities classified into two categories.

Pharmacy, University of Tokyo Hospital. The precise regimensof those ointments were previously described.2 These gelscan be easily prepared, as the tretinoin powder (Sigma
Chemical Co., St. Louis, MO, USA) is commercially available.
Aqueous gel is most suitable for the ointment base of tretinoin
because of its good permeability. Tretinoin gel is pharmacologically unstable, so fresh batches were prepared at least
once a month and stored in a dark, cool (4  C) place.
Bleaching treatment protocol with tretinoin
gel and hydroquinone ointment (RA-HQ)
The two-stage (bleaching and healing) treatment was
performed as follows.

(a) Bleaching phase: 0.1% tretinoin gel and HQ-LA ointment
were initially applied to the skin lesions twice a day. A
small amount of tretinoin gel was carefully applied only
on pigmented spots using a small cotton-tip applicator(excess gel was wiped off), while the HQ-LA ointment
was widely applied with fingers (e.g. all over theface) a few minutes later, after allowing the tretinoin
aqueous gel to dry. The method of ointment applicationis critical in this aggressive treatment in order to obtainmaximal bleaching effects with minimal irritant dermatitis. In cases in which severe irritant dermatitis was
induced by the HQ-LA ointment, HQ-AA ointment wasused instead. Patients were requested to visit our

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Figure 1 Hyperpigmented lesions in Asians: clinical manifestations. (A) PIH-S. (B) PNAC. (C) Ephelides. (D) Nevus spilus. (E)Lichen pilaris. (F) Seborrheic keratoses. (G) Solar lentigines. (H) Melasma. (I) Pigmented external genitalia. (J) Pigmented contact
dermatitis. (K) Friction melanosis. (L) RHAD. (M) PPA. (N) EFFC. (O) ADM. (P) Periorbital hyperpigmentation. (Q) Nevus of Ota.

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Hyperpigmented skin lesions in Asians
hospital at 1, 2, 4, 6 and 8 weeks after starting treatment, and every 4 weeks thereafter. If the appropriate
skin reaction (mild erythema and scaling) was notobserved at 1 week, the concentration of tretinoin
was increased to 0.4%, as 0.2% tretinoin gel was usually
not strong enough to get a sufficient reaction in thesecases. The concentration of tretinoin and frequency
of its application were appropriately modified according to the skin condition and degree of erythema andscaling. It took 2e8 weeks to complete this phase.
(b) Healing phase: After the bleaching phase, the application of tretinoin gel and HQ-LA ointment was discontinued, and application of HQ-AA ointment was initiated inorder to prevent PIH until redness was sufficiently
reduced. It usually took 4 weeks to complete thisphase. Topical corticosteroids, which reduce melanindischarge accelerated by tretinoin, were not employedin either the bleaching or healing phase.

Results
Biopsies of pigmented lesions
The histological characteristics and diagnoses of the biopsied samples are summarized in Table 1 and pigmented
morbidities tentatively categorized in Table 2. Clinicalappearance and histology of representative cases for eachmorbidity are shown in Figs. 1 and 2, respectively.
Horny layers
In general, dermatoses located on the trunk and extremities rather than on the face have a physiological tendency
toward hyperkeratosis. Solar lentigines and relatively flat
seborrheic keratoses resembled each other histologicallyand were characterized by distinctive hyperkeratosis. Notethat in solar lentigines mild hyperkeratosis was observed
even in lesions that appeared flat. Lichen pilaris and EFFC
also showed mild hyperkeratosis, but this feature was more
distinctive in lichen pilaris. No other dermatoses investigated in this study showed hyperkeratosis.
Epidermal pigmentation
Epidermal pigmentation was enhanced in all the morbidities in this study except for the nevus of Ota case. The
degree of epidermal melanin pigmentation varied among
the morbidities, and substantial differences were foundbetween cases.
Dermal pigmentation
Dermal melanosis (melanin incontinence) was observed insome of the morbidities. Lesions resulting from chronic or
repeated inflammation, such as pigmented contact dermatitis, friction melanosis, RHAD and PPA, showed breakdownof the dermo-epidermal junction and severe dermal melanosis (deposits of melanophages) in the upper dermis. Somemelanophage deposits in the upper dermis were also seen
in cases of melasma and solar lentigines, although degenerative changes of the dermo-epidermal junction were
not detected. ADM and periorbital hyperpigmentation (asubtype of ADM) had dermal melanocytes with a highly

5
pigmented, elongated dendritic appearance in the upper
dermis, while dermal melanocytes were scattered throughout the dermis in nevus of Ota. In several morbidities suchas PIH-S, ephelides and nevus spilus, dermal pigmentation,either melanosis or melanocytosis, was not detectedirrespective of the degree of epidermal pigmentation.

Samples taken during RA-HQ treatment
The histological and clinical manifestations of representative cases of hyperpigmentation are shown in Figs. 3 and 4.
In sections obtained during RA-HQ therapy, substantial epidermal hyperplasia, dramatic reduction of melanin deposits
around the basal layer and temporal enhancement of parakeratosis were consistently observed (Fig. 3B and D). Thesechanges were most likely a result of enhanced basal keratinocyte mitosis and accelerated turnover of the epidermis.
Epidermal pigmentation was significantly reduced, whiledermal melanophages or melanocytes, if any, appeared
unchanged (Fig. 4B and D). The clinical observations agreed
with the histological findings. In lesions without dermal
pigmentation involvement, the pigmented colour was clinically improved (Fig. 3E), while in lesions with dermal pigmentation, the colour change was usually moderate(Fig. 4C) until laser therapy was also used (Fig. 4E).

Discussion
The total amount of epidermal melanin, the main determinant of skin colour, is the result of the balance
between production and discharge of melanin. Productionof epidermal melanin can be enhanced by external factors
such as UV irradiation9 and inflammation, and suppressedby agents such as hydroquinone that are toxic to melanocytes or inhibit melanogenesis. The discharge of epidermalmelanin is determined mainly by epidermal turnover, which
can be increased by topical retinoids. External factors suchas topical corticosteroids and aging can also attenuate melanin discharge. The regulatory mechanism of epidermal
pigmentation (skin colour) is a key concept for establishing
our bleaching strategy to epidermal hyperpigmentation;that is, a combined use of tretinoin (a discharge enhancer)
and hydroquinone (a production suppressor).
Based on the categorization of pigmented skin lesions(Table 2) and our extensive clinical experience, we propose
a simple therapeutic strategy that involves CO2 laser therapy, QS ruby laser irradiation and topical bleaching treatment (RA-HQ therapy). This is schematically summarized
in Fig. 5. For QS ruby laser (694.5 nm, Model IB101, Niic
Co. Ltd, Tokyo, Japan) treatment, a spot size of 5 mm,
pulse duration of 20 ns, 1-Hz repeat rate, and fluences
ranging from 3.5 to 5.0 J/m2 were routinely used. Fluence
was adjusted on each occasion to the minimal value that induced immediate whitening of the irradiated area. After laser treatment, topical antibiotic ointment was applied
twice a day until a scale or crust disappeared (usually for
5e7 days).
RA-HQ treatment accelerates the removal of accumulated melanosomes in the epidermis and replaces themwith much less pigmented cells. QS ruby laser irradiation
not only reduces dermal melanosis and melanocytosis, but

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Figure 2 Hyperpigmented lesions in Asians: histological findings. Specimens were obtained from lesions AeQ shown in Fig. 1.
Original magnification 100; alongside O, P and Q are corresponding images at 200 magnification.

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Figure 3 A 26-year-old woman with PNAC. (A) At baseline,
the NAC showed dark-brown hyperpigmentation. (B) Histological examination revealed epidermal pigmentation. (C) Two
weeks after starting bleaching treatment with 0.2% tretinoin
and 5% hydroquinone, the hyperpigmentation had improved.
Some tretinoin-associated erythema was observed. (D) Histological examination revealed hyperplasia of the epidermis.
Epidermal pigmentation was highly reduced. (E) Eight weeks
after starting treatment (final result). For 4 weeks, 0.2% tretinoin was used together with 5% hydroquinone, followed bytreatment with 5% hydroquinone alone for 4 weeks. Pigmentation improved and no post-inflammatory hyperpigmentation
was observed.

also removes the pigmented and hyperkeratotic epidermis
associated with solar lentigines. The former can also be
accomplished using a QS Alexandrite laser, and the lattercan be accomplished with other lasers, such as a QS Nd:YAG
laser. A CO2 laser was used to treat lesions with excessive
hyperkeratosis (Category I lesions) which could not be effectively treated with a QS ruby laser. Hyperkeratotic
lesions need to be treated with lasers; because the thickened horny layer prevents percutaneous absorption of
topical ointment, RA-HQ therapy does not work.

7

Figure 4 A 56-year-old woman with pigmented contact(cosmetic) dermatitis. (A) At baseline, the patient showeddark-brown or dark-grey macules distributed symmetricallyon a wide area of the face. (B) Histology at baseline. The
dermo-epidermal junction was severely damaged and a numberof melanosomes were found in the upper dermis (pigmentary
incontinence). (C) At 8 weeks, just after topical bleachingtreatment with 0.1% and 0.4% tretinoin and 5% hydroquinone,
pigmentation was reduced with slight erythema, but themacules still had a greyish color. (D) Histology at 8 weeks.
Epidermal pigmentation was significantly improved, while thedermal melanocytosis appeared not to have changed at all.
(E) Clinical appearance at 20 weeks. QS ruby irradiation was
performed to reduce dermal melanosis at 8 weeks. Four weeks
later, RA-HQ therapy was performed again: 4 weeks of bleaching phase and 4 weeks of healing phase.

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M. Kurita et al.

Figure 5 Schematic summary of our therapeutic strategy for pigmented lesions. A treatment protocol is suggested for lesions ineach Category (IeVII) except for Category II, which was divided into three subclasses: solar lentigines (SL), melasma and others. SL
frequently has a thicker horny layer, so is initially treated with a QS ruby laser (QSR) followed by RA-HQ therapy for post-laser hyperpigmentation. Melasma sometimes requires two or three sessions of RA-HA. Category IVeVI lesions require combination protocols using QSR and RA-HQ therapy, while Category VII can be treated with QSR alone.

Lesions in Categories II and III are treated only with
topical RA-HQ therapy, except for solar lentigines withhyperkeratosis. The treatment usually needs to be performed repeatedly for melasma.4 PIH-S does not recur after
treatment, but ephelides, lentigo simplex and nevus spilus(café-au-lait macules) tend to reappear within a few
months unless topical hydroquinone is used for posttreatment maintenance. Although RA-HQ cannot be used
to treat dermal pigmentation and hyperkeratotic lesions,
it can be used as a pre-treatment for QS ruby laser irradiation of Categories IVeVI lesions. RA-HQ can also be used after QS ruby laser treatment, because it is quite effective
for treating the PIH frequently seen after QS ruby laser
treatment of darker coloured skin.
A critical difference between lesions in Category IVeVI
and those in Category VII is the extent of epidermal
pigmentation, which determines the beneficial and adverse effects of QS ruby laser on dermal pigmentation. If
the lesion has only dermal melanocytosis (Category VII),
it can be effectively treated with repeated sessions of QS
ruby laser irradiation alone.10,11 The sole use of QS rubylaser irradiation failed in the treatment of morbidities
with both epidermal and dermal pigmentation (Categories
IVeVI), resulting in a high frequency of PIH and/or depigmentation.12e14 We believe that, in these morbidities,
epidermal melanin deposits obstruct laser irradiations todermal pigmentation as competing chromophores. Laser
irradiation thus induces considerable inflammation in
the epidermis and, consequently, severe PIH results, especially in patients with darker coloured skin.6 To overcome these problems, we propose that topicalbleaching be performed prior to QS ruby laser therapy.
The pretreatment can be applied not only to ADM, butalso to other skin conditions with both epidermal anddermal pigmentation, such as friction melanosis, pigmented contact (cosmetic) dermatitis and RHAD (lesions
in Categories IVeVI; Fig. 4). For Category VI lesions (dermal melanocytosis), the combination of RA-HQ treatment
and QS ruby laser may need to be performed two or

three times, while only one QS ruby session is usuallyneeded for treating lesions in Categories IV and V (dermalmelanosis).
We refined a strategy for treating hyperpigmentation by
studying lesion histology and by reviewing our extensive
clinical experience in treating Asian skin. The histologybased treatment principles may be helpful for establishinga standardized treatment algorithm for hyperpigmented
skin lesions, especially in Asians.

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