BJD

R EV IE W AR TI C LE British Journal of Dermatology

Facial hyperpigmentation: causes and treatment

N.A. Vashi1 and R.V. Kundu2
1
Department of Dermatology, Boston University School of Medicine, Boston Medical Center, 609 Albany St J602, Boston, MA, 02118, U.S.A.
2
Department of Dermatology, Northwestern University Feinberg School of Medicine, 676 N. St Clair Street Suite 1600, Chicago, IL,60611, U.S.A.

Summary

Correspondence By midcentury, the U.S.A. will be more ethnically and racially diverse. Skin of
Neelam A. Vashi. colour will soon constitute nearly one-half of the U.S. population, and a full
E-mail: nvashi@bu.edu
understanding of skin conditions that affect this group is of great importance.
Accepted for publication Structural and functional differences in the skin, as well as the influence of cul-
11 June 2013 tural practices, produce variances in skin disease and presentation based on skin
type. In the skin of colour population, dyschromia is a growing concern, and a
Funding sources top chief complaint when patients present to the physician. A thorough under-
This supplement was kindly sponsored by LOreal standing of the aetiology and management strategies of facial hyperpigmentation
Research & Innovation and Beiersdorf.
is of importance in caring for those afflicted and also in the development of new
Conflicts of interest therapies.
None declared

DOI 10.1111/bjd.12536 Whats already known about this topic?

In the skin of colour population, facial hyperpigmentation is a common and grow-
ing concern when presenting to the physician.
Facial hyperpigmentation can cause significant cosmetic disfigurement with subse-
quent emotional impact. Therapy continues to be challenging as there is no univer-
sally effective treatment. Existing agents have varying degrees of efficacy and
potential risk of postinflammatory hyperpigmentation with different treatment pro-
tocols.

What does this study add?

Persons of colour will soon comprise a majority of the international and domestic
populations.
A comprehensive knowledge and approach to assessment and treatment is necessary
to care properly for skin of colour patients.
This review thoroughly discusses aetiologies of facial hyperpigmentation and cate-
gorizes appropriate treatment strategies.

Skin of colour, also known as ethnic skin, constitutes a
wide range of racial and ethnic groups traditionally
referring to persons of African, Asian, Native American,
Middle Eastern and Hispanic backgrounds. By 2050, nearly
one-half of the U.S. population will be nonwhite.1 These
skin types are generally categorized as Fitzpatrick types IV
VI, and are more richly pigmented. Structural and functional
differences in the skin, as well as the influence of cultural
practices, produce variances in skin disease, presentation and
treatment based on skin type. Darker skin phenotypes are
characterized by higher content of melanin, higher
eumelanin to pheomelanin ratio, and more effective distri-
bution of melanin for protection against ultraviolet (UV)
radiation.2
In skin of colour, the amount and epidermal distribution of
melanin is an important biological feature.35 Melanin is not a
single compound; rather, it is a mixture of biopolymers syn-
thesized by melanocytes located in the basal layer of the epi-
dermis.2 Based on their chemical composition, melanins are
broadly classified into two types: eumelanin and pheomela-
nin.2 Multiple studies have reported that individuals with
darker skin have higher total melanin content, and a higher
amount of eumelanin than lighter-skinned individuals.2
Furthermore, studies on cultured human melanocytes have

2013 The Authors British Journal of Dermatology (2013) 169 (Suppl. 3), pp4156 41
BJD 2013 British Association of Dermatologists
42 Facial hyperpigmentation, N.A. Vashi and R.V. Kundu
demonstrated that melanocytes derived from darker skin have
higher total melanin and eumelanin contents, and a higher
ratio of eumelanin to pheomelanin, than those derived from
lighter skin.2,6 Pheomelanin differs from eumelanin in its bio-
logical behaviour, importantly in the ability of pheomelanin
to activate oxygen resulting in the formation of the superoxide
radical anion.2,7,8 These properties may be responsible for the
high phototoxic potential of pheomelanin, which may con-
tribute to the occurrence of photoinduced malignancies in
lighter-skinned individuals.
Biosynthesis of melanin occurs within the melanosome, a
lysosome-like organelle and metabolic unit of the melanocyte,
where melanin granules are synthesized using the amino acid
tyrosine as the major substrate.35,9 Variations in the number,
size and aggregation of melanosomes within the melanocyte and
keratinocyte contribute to racial and ethnic differences.10 For
example, darker skin types have nonaggregated and larger mela-
nosomes.3,11 There are no racial differences in the overall num-
ber of melanocytes; however, melanocyte number may differ by
anatomical location.10,12,13 For example, the head and forearm
have the highest numbers of melanocytes.8 Total melanin con-
tent is also greater in individuals with darker skin types.3,14
Melanin is the major determinant of colour in the skin. The
concentration of epidermal melanin in melanosomes is double
in darker skin types compared with lightly pigmented skin
types.5 In addition, melanosome degradation within the kerat-
inocyte is slower in darkly pigmented skin when compared
with lighter skin types.15 The melanin content and melanoso-
mal dispersion pattern is thought to confer protection from
damage induced by UV radiation.3,16 Kaidbey et al.16 demon-
strated that black epidermis, on average, provides a sun-
protection factor (SPF) of 13
4. Although the increased
melanin provides protection from harmful effects of UV radia-
tion, including photodamage and skin cancers, it also makes
darkly pigmented skin more vulnerable to postinflammatory
dyspigmentation.
Given these functional and structural differences, common
conditions may require special considerations in ethnic skin.
Additionally, there are many skin conditions relatively unique
to persons with skin of colour. The aim of this review is to
summarize what is currently known about facial hyperpig-
mentation as it relates to those with skin of colour. Table 1
summarizes causes of facial hyperpigmentation.
Methods
We identified relevant articles by the systematic search of sci-
entific and medical electronic search engines (PubMed, 1962
2013). Key terms for searches included: dyschromia, postin-
flammatory hyperpigmentation, facial hyperpigmentation,
hyperpigmentation, melasma, naevus of ota, ephelides, lenti-
gines, ochronosis, melanosis, dark skin, melanin, acanthosis
nigricans, skin lightening, depigmentation, hydroquinone, ret-
inoid, kojic acid, azelaic acid, niacinamide, glycolic acid,
N-acetylglucosamine, lignin peroxidase, chemical peels,
peeling, dermabrasion and laser.
British Journal of Dermatology (2013) 169 (Suppl. 3), pp4156
Causes of facial hyperpigmentation
Postinflammatory hyperpigmentation
Postinflammatory hyperpigmentation (PIH) refers to the dark-
ening of skin that occurs after an inflammatory eruption or
cutaneous injury. The hyperpigmentation results from the
melanocytes response to the cutaneous insult, which causes
an increased production and/or redistribution of melanin.
Patients of darker skin are predisposed to this pigment alter-
ation.
Postinflammatory changes can occur both in the epidermis
and dermis. In the epidermal form of hyperpigmentation,
there is increased melanin production and/or transfer to kerat-
inocytes. In dermal PIH, a damaged basement membrane
allows melanin to enter the dermis, where it is phagocytosed
by dermal macrophages, referred to as melanophages. Macro-
phages may also migrate into the epidermis, phagocytose mel-
anosomes, and then return to the dermis.17,18 Melanin within
dermal melanophages may persist for years.
As the skin in darker patients recovers from an acute
inflammatory disease, it may become hyperpigmented (PIH)
or hypopigmented (known as postinflammatory hypopigmen-
tation). Lightening or darkening of the skin is associated with
many primary disorders including but not limited to discoid
lupus erythematosus, seborrhoeic dermatitis, tinea versicolor,
atopic dermatitis and sarcoidosis (Fig. 1). History may include
any type of prior inflammation or injury, e.g. acne, arthropod
assault, viral exanthems, eczema, psoriasis, trauma. Physical
examination findings include small to large hyperpigmented
macules and patches of varying size in any distribution.
Although usually a clinical diagnosis, difficult cases can be
aided with a biopsy for histopathological evaluation. Disorders
such as melasma, morphoea, atrophoderma and other rarer
aetiologies should be considered in patients without evidence
of preceding inflammation by history or examination. The
time required for the dyspigmentation to normalize is highly
variable and relates to many factors including the patients
baseline skin tone, the type and intensity of the injury or
inflammation, and the patients sun-exposure habits. The time
can take years and can be psychologically distressing. Treat-
ments with skin-lightening agents, chemical peeling agents
and lasers can be tried; however, they can also result in wors-
ening of the original dyspigmentation and should always be
used with caution.
Maturational dyschromia
Darkening of facial skin tone, even outside of extensive sun
exposure, can be seen in mature dark skin. Maturational dys-
chromia, or a general uneven tone, can be described as diffuse
hyperpigmentation that generally occurs on the lateral fore-
head and cheekbones (Fig. 2). One survey found that uneven
skin tone was a chief complaint in more than one-third of
black women.19 These changes in skin tone probably occur
from chronic sun exposure over many years. Maturational dys-
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 Facial hyperpigmentation, N.A. Vashi and R.V. Kundu 43
Table 1 Hyperpigmentary disorders of the face: distinguishing features and treatments
Disease Distinguishing features
Postinflammatory History or presence of inflammation with
hyperpigmentation erythema and/or scaling
Maturational dyschromia Darkening of malar cheeks and forehead in
mature richly pigmented skin
Periorbital hyperpigmentation Darkening around the eyes
Riehl melanosis Brown-grey colour
Typically preceded by mild erythema and
pruritus, followed by a diffuse-to-reticulated
hyperpigmentation
Favours sites of application of contactants,
especially cosmetics
Melasma Symmetric, centrofacial distribution of light to
dark brown patches with irregular borders
History of exacerbation with pregnancy,
hormonal therapy such as oral contraceptives,
and intense sun exposure
Exogenous ochronosis History of hydroquinone application
Banana-shaped, yellow-brown deposits in the
dermis
Acanthosis nigricans Symmetric, hyperpigmented, velvety plaques on
the neck and axillae
History of diabetes and/or obesity
Dermatosis papulosa nigra 1- to 5-mm pigmented papules that are
distributed bilaterally across the malar
eminences, forehead
Naevus of Ota Blue-grey confluence of individual macules
varying from pinhead-sized to several
millimetres in diameter
Distribution of the first two branches of the
trigeminal nerve
Onset in infancy or puberty
Hori naevi Asians, primarily Chinese and Japanese, women
aged 2070 years
Blue-grey to grey-brown macules primarily on
the zygomatic area and less often on the
forehead, temples, upper eyelids, and root
and alae of the nose
Ephelides 13-mm well-demarcated hyperpigmented
macules that are round, oval or irregular in
shape
Lentigines 3-mm to 2-cm well-circumscribed, round, oval
or irregularly shaped macules or patches that
vary in colour from tan to dark brown
Lichen planus pigmentosus Oval or irregularly shaped grey-brown to
brown macules and patches in sun-exposed
areas
Erythema dyschromicum Grey to blue-brown lesions
perstans Inflammatory phase with rim of erythema
Distribution also includes nonsun-exposed
areas
Actinic lichen planus Fine scale overlying violaceous lesions
Photodistributed
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Treatment
Skin-lightening agents, chemical peeling agents
and laser
Skin-lightening agents, antioxidants, sunscreen,
microdermabrasion or chemical peels
Skin-lightening agents, chemical peels, IPL,
Q-switched ruby laser, autologous fat
transplantation, combinations of fat grafting
and blepharoplasties, fillers
Complete avoidance of the suspected allergen
and allergen-free soaps and cosmetics
Sun-protective measures, skin-lightening
agents and chemical peels
Combination approach with strict sun
protection, cosmetic camouflage, skin-
lightening agents, chemical peels and laser
therapy
Dermabrasion, CO2 laser, glycolic acid peelings
and Q-switched laser
Keratolytics, skin-lightening agents, calcipotriol,
urea and salicylic acid
Snip excision, curettage, electrodesiccation, light
cryotherapy and laser destruction
Q-switched ruby, alexandrite and Nd:YAG lasers
Q-switched ruby, alexandrite and Nd:YAG
lasers, cryotherapy
Sun-protective measures, skin-lightening agents,
cryotherapy and laser surgery
Sun-protective measures, skin-lightening agents,
cryotherapy and laser surgery
Topical steroids, immunomodulators and
skin-lightening agents
Oral corticosteroids, antibiotics (e.g.
doxycycline), antimalarials, isoniazid,
griseofulvin and UV light therapy have
produced variable results
Successful treatment with dapsone and
clofazimine has been reported in small series
Topical and intralesional corticosteroids,
antimalarials (e.g. hydroxychloroquine),
acitretin and ciclosporin
44 Facial hyperpigmentation, N.A. Vashi and R.V. Kundu
Table 1 (continued)
Disease Distinguishing features
Erythromelanosis follicularis Well-demarcated erythema, hyperpigmentation
faciei et colli and follicular papules
Post-chikungunya pigmentation Small macules of brown-black pigmentation or
slate-like pigmentation of the centrofacial
area
History of fever, morbilliform skin eruption
and polyarthritis
IPL, intense pulsed light; UV, ultraviolet.
Fig 1. Postinflammatory hyperpigmentation secondary to
pseudofolliculitis barbae: multiple, small, brown, coalescing macules
on the beard area.
Fig 2. Maturational dyschromia: hyperpigmented, ill-defined patches
over the lateral zygoma in a middle-aged African-American woman.
chromia may be misdiagnosed as melasma, acanthosis nigri-
cans or PIH. This is a diagnosis of exclusion and any type of
allergic contact dermatitis or photoallergic dermatitis should
be ruled out. Treatment options include sunscreen, skin-
lightening agents, antioxidants, microdermabrasion and/or
chemical peels.
British Journal of Dermatology (2013) 169 (Suppl. 3), pp4156
Treatment
Topical and systemic retinoids, hydroquinone
Conservative and symptomatic treatment
Fig 3. Secondary periorbital hyperpigmentation: hyperpigmented
brown patches on the periorbital area.
Periorbital hyperpigmentation
Periorbital hyperpigmentation, also referred to as idiopathic
cutaneous hyperchromia of the orbital region (ICHOR), peri-
orbital melanosis, dark circles or infraorbital pigmentation, is
more frequently observed in the skin of colour population
and can be of primary or secondary aetiology.20 The cause of
secondary periorbital hyperpigmentation often has a multifac-
torial pathogenesis including genetic or constitutional pigmen-
tation, dermal melanocytosis, PIH secondary to atopic and/or
allergic contact dermatitis, periorbital oedema, excessive sub-
cutaneous vascularity and shadowing due to skin laxity and
tear trough associated with ageing (Fig. 3).20,21 Excessive sun
exposure, drugs, hormonal causes and extension of pigmen-
tary demarcation lines have also been considered to be con-
tributory.20,22 ICHOR is characterized by bilateral darkening
of the orbital skin and eyelid, which is not secondary to sys-
temic or local disease.20 In a study by Ranu et al.15 on 200
patients with periorbital hyperpigmentation, possible causes
were delineated according to history, physical examination
and assessment by dermatologists measuring with a Mexame-
ter (CourageKhazaka Electronics, Cologne, Germany). They
found the commonest forms to be the vascular type (41
8%)
characterized by the presence of erythema involving inner
aspects of lower eyelids with prominent capillaries/telangiec-
tasia or presence of bluish discoloration due to visible blue
veins; constitutional form (38
6%) characterized by the pres-
ence of brown-black hyperpigmentation of the lower eyelid
skin along the shape of orbital rim; PIH (12%); and shadow
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effects (11
4%) due to an overhanging tarsal muscle or deep
tear trough.15 Other causes included skin laxity, dry skin, hor-
monal disturbances, nutritional deficiencies and other chronic
illnesses.15 Verschoore et al.23 confirmed that not only melanin
deposits but also blood stasis may play a role in the pathogen-
esis of ICHOR.
Regarding the localization of the pigmentation, earlier stud-
ies by Watanabe et al. and Malakar et al. examined skin biop-
sies and found the presence of dermal melanocytosis and
melanin pigment in upper dermal macrophages, respectively,
partially explaining the recalcitrance of this condition to sev-
eral treatments.22,24 Skin-lightening creams, chemical peels,
intense pulsed light (IPL), Q-switched ruby laser, autologous
fat transplantation, combinations of fat grafting and blepharo-
plasties as well as fillers have all been tried, but none have
provided long-term satisfactory treatment.15
Riehl melanosis
Riehl melanosis, or pigmented contact dermatitis, is character-
ized by a brown-grey colour secondary to dermal melanin
deposits. It favours sites of application of contactants, espe-
cially cosmetics. Cases are typically preceded by mild erythema
and pruritus, followed by a diffuse-to-reticulated hyperpig-
mentation. Pigmentation varies, often dependent upon the
causal agent. It can be brown or brown-grey, and can also
have red and blue hues. Diagnosis is assisted with closed patch
testing to standard series, cosmetic series, fragrance series and
patients personal products. Photopatch testing can also be
considered. When results are equivocal or negative, the pro-
vocative use test or repeated open application test can be
administered.24 Treatment involves complete avoidance of the
suspected allergen. Sun-protective measures, skin-lightening
agents and chemical peels can hasten resolution of pigmenta-
tion changes.
A rarer aetiology of facial hyperpigmentation and probably
a variant of Riehl melanosis is termed erythrose peribuccale
pigmentaire de Brocq. It is most likely caused by photo-
dynamic substances in cosmetics. It is characterized by diffuse,
symmetric red-brown pigmentation around the mouth with
sparing of the vermillion border and may extend to the fore-
head, temples and angles of the jaw.25 Pigmentation will per-
sist unless the cause is eliminated. A similar
hyperpigmentation has been reported in patients with subsid-
ing perioral dermatitis secondary to topical steroids.25
Melasma
Melasma is an acquired form of hyperpigmentation that is
seen most commonly on the face. It is a common disorder of
hyperpigmentation affecting millions worldwide. It predomi-
nantly affects Fitzpatrick skin phototypes III and IV,26 and at
least 90% of those affected are women. The exact pathogenesis
is unknown; however, it is hypothesized that rather than an
increase in melanocytes, melasma may be caused by the pres-
ence of more biologically active melanocytes in the affected
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Facial hyperpigmentation, N.A. Vashi and R.V. Kundu 45
Fig 4. Melasma: light brown patch with irregular borders over the
malar eminence in a middle-aged Hispanic woman.
skin.26 Following exposure to UV irradiation, the melanocytes
produce increased amounts of melanin compared with unin-
volved skin. Exacerbating factors include pregnancy, hormonal
therapy, such as oral contraceptives, and intense sun exposure.
Sun exposure exacerbates melasma, probably because of the
UV-induced upregulation of melanocyte-stimulating cytokines.
Clinically, there are light to dark brown patches with irregular
borders most commonly distributed symmetrically on the cen-
trofacial, malar and mandibular regions and can also be on
the forearms (Fig. 4). Depending on the location of melanin,
melasma can be differentiated into different types. In the epi-
dermal type, the pigment is brown and margins are geograph-
ical and more well-defined, whereas, in the dermal type,
pigment is of a more grey-brown quality and margins are
poorly defined. Mixed type occurs when there is melanin in
both the epidermis and dermis, and the term indeterminate
type may be used when it is difficult to classify even with the
assistance of Woods light.25 The differential diagnosis
includes PIH, solar lentigines, acanthosis nigricans, and other
more rare pigmentary disorders including exogenous ochrono-
sis, lichen planus pigmentosus (LPP) and erythema dyschromi-
cum perstans (EDP). Treatment includes a combination
approach with strict sun protection, cosmetic camouflage, top-
ical lightening agents, chemical peels and laser therapy. First-
line therapy often includes nondestructive modalities including
broad-spectrum photoprotection and topical compounds that
affect the pigment production pathway. Second-line therapy
consists of the addition of chemical peels, although these must
be used cautiously so as not to induce further postinflammato-
ry changes. Laser and light therapies are promising; however,
like chemical peeling agents, carry the risk of PIH. Lastly, for
women who note the onset of melasma after beginning oral
contraceptives, the medication should be stopped if possible.26
Exogenous ochronosis
Ochronosis appears grossly as blue-black pigment and refers
to deposition of polymerized homogentisic acid in collagen-
containing structures. Exogenous ochronosis occurs when for-
eign substances cause homogentisic acid to be deposited in
the dermis, causing macular and papular hyperpigmentation.
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46 Facial hyperpigmentation, N.A. Vashi and R.V. Kundu
Fig 5. Exogenous ochronosis: bluish-grey discoloration overlying a
pink hue on the zygomatic arch.
It is a rare disease, characterized by an asymptomatic hyper-
pigmentation of the face, sides and back of the neck, back and
extensor surfaces (Fig. 5).27 It is clinically and histologically
similar to endogenous ochronosis, also known as alkaptonuria;
however, it exhibits no systemic effects and is not an inherited
disorder. It has been associated with the use of products con-
taining hydroquinone, resorcinol, phenol, mercury and/or
picric acid. It is relatively uncommon within the U.S.A. and is
more prevalent in Africa. According to a 2007 literature
review,28 there were 789 cases of exogenous ochronosis
reported worldwide, only 22 of these were reported from the
U.S.A. The aetiology for this phenomenon remain elusive, but
could be a result of the use of skin-care products containing
resorcinol in combination with hydroquinone or use of
hydroquinone in a hydroalcoholic lotion. In both endogenous
and exogenous ochronosis, a microscopic deposition of ochre-
coloured pigment is found in the dermis. Exogenous ochrono-
sis often needs histological confirmation as it can easily be
confused with PIH, pigmented contact dermatitis and mel-
asma. Treatment is difficult. Although not uniform, satisfactory
results have been described with dermabrasion, CO2 laser,
glycolic acid peels and Q-switched laser.27,29,30
Acanthosis nigricans
Acanthosis nigricans is characterized by hyperpigmented, vel-
vety plaques often in a symmetric distribution. Although most
commonly appearing on the intertriginous areas of the axilla,
groin and posterior neck, acanthosis nigricans may occur in
almost any location including the face. Patients typically pres-
ent with a darkening and thickening of the skin. Acanthosis
nigricans is commonly associated with insulin resistance and
obesity, and it is more common in Hispanic and black people.
No treatment of choice exists for acanthosis nigricans. The
goal of therapy is to correct the underlying disease process.
Topical medications that have been effective in some cases of
acanthosis nigricans include keratolytics (e.g. topical tretinoin
0
05%, ammonium lactate 12% cream) and triple-combination
depigmenting cream (tretinoin 0
05%, hydroquinone 4%, flu-
ocinolone acetonide 0
01%) nightly with daily sunscreen.31
Calcipotriol, podophyllin, urea and salicylic acid have also
been reported with variable results.32
British Journal of Dermatology (2013) 169 (Suppl. 3), pp4156
Fig 6. Dermatosis papulosa nigra: 12-mm brown discrete papules
over the malar eminences in an older African-American woman.
Dermatosis papulosa nigra and seborrhoeic keratoses
Dermatosis papulosa nigra (DPN) is a common manifestation
diagnosed primarily in African-American, Afro-Caribbean and
sub-Saharan African black patients; however, it is also seen in
other races. The cause and pathogenesis is unknown. DPN
tends to have an earlier age of onset than that of seborrhoeic
keratoses, but otherwise is similar and considered a variant of
seborrhoeic keratosis. DPN presents as 1- to 5-mm pigmented
papules that are distributed bilaterally across the malar emi-
nences, forehead and, less often, on the neck, chest and back
(Fig. 6). They appear during adolescence and increase in size
and number over time, peaking in the sixth decade. Usually
the lesions are asymptomatic but can occasionally be pruritic
or irritated. The differential diagnosis includes seborrhoeic
keratoses, acrochordons, melanocytic naevi, lentigines, verru-
cae and other adnexal tumours. Treatment is generally per-
formed for cosmetic purposes and should be exercised with
great care given the risks of dyspigmentation. Modalities
include snip excision, curettage, electrodesiccation, light cryo-
therapy and laser destruction.
Naevus of Ota
Although naevus of Ota has been documented in all skin
types, it occurs predominantly in more darkly pigmented
individuals, especially in Asian and black people. The lesions
occur during infancy, with the majority presenting at birth,
and also around puberty. Onset between 1 and 11 years of
age and after 20 years of age is unusual. Naevus of Ota is
characterized by a blue-grey confluence of individual ma-
cules varying from pinhead-sized to several millimetres in
diameter. The overall appearance is that of an irregularly
demarcated, mottled patch. Size varies from a few centime-
tres to extensive unilateral and even occasional bilateral
involvement. It favours the distribution of the first two
branches of the trigeminal nerve, and the most common
sites of involvement are the periorbital area, temple, fore-
head, malar area, earlobe, pre- and retroauricular regions,
nose and conjunctivae. Seen in about two-thirds of patients,
a characteristic feature is the involvement of the ipsilateral
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sclera. Naevus of Ota persists for life and has been treated
successfully by Q-switched ruby, alexandrite and Nd:YAG
lasers.33,34
Hori naevi
Hori naevi, or acquired bilateral naevus of Ota-like macules,
are a common dermal melanocytic hyperpigmentation in
Asians, primarily Chinese and Japanese women from 20 to
70 years of age. They are characterized by blue-grey to grey-
brown macules primarily on the zygomatic area and less often
on the forehead, temples, upper eyelids, and root and alae of
the nose35 (Fig. 7). The eye and oral mucosa are not involved.
Hori naevi may be misdiagnosed as melasma, lentigines or
ephelides. Treatment modalities including cryotherapy, various
Q-switched lasers including a combination of a 532-nm
Q-switched Nd:YAG laser (QSNY) followed by a 1064-nm
QSNY, or combined use of a scanned CO2 laser or IPL with a
Q-switched ruby laser, have been introduced with various
clinical outcomes.36,37
Ephelides and lentigines
Ephelides and lentigines are a common manifestation of sun
exposure in white patients and less so in those with skin of
colour. Ephelides, or freckles, are the result of increased pho-
toinduced melanogenesis and transport of an increased num-
ber of fully melanized melanosomes from melanocytes to
keratinocytes. Ephelides occur on sun-exposed areas of the
body, particularly the face, dorsal hands and upper trunk.
They are 13-mm well-demarcated, hyperpigmented macules
that are round, oval or irregular in shape. They may increase
in number and distribution and show a tendency for conflu-
ence, but they can fade over time with ageing. Ephelides are
benign and show no propensity for malignant transforma-
tion.38 Some ephelides may represent a subtype of solar len-
tigo.39
Solar lentigines are found in 90% of the white population
aged > 60 years, and their incidence increases with advancing
Fig 7. Hori naevi: small discrete greyish-brown macules over the
malar eminence in an Asian woman.
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Facial hyperpigmentation, N.A. Vashi and R.V. Kundu 47
age.40 Lentigines are more common in white subjects, but also
occur in Asians. Inherited patterned lentiginosis favours more
lightly pigmented African-Americans, including those with
mixed American Indian heritage. Solar lentigines are 3 to
2-cm well-circumscribed, round, oval or irregularly shaped
macules or patches that vary in colour from tan to dark brown.
They occur on sun-exposed areas, predominantly the dorsal
aspects of hands and forearms, face, upper chest and back.
Treatment options for ephelides and lentigines include sun-
protective measures, skin-lightening agents, cryotherapy and
laser surgery.
Erythema dyschromicum perstans
EDP, or ashy dermatosis, is an asymptomatic, slowly progres-
sive eruption characterized by dermal pigmentation in circum-
scribed areas.41 The majority of patients afflicted with this
disorder are from Latin America. There is no gender predilec-
tion, and EDP usually presents during the second to third dec-
ade of life. The aetiology of EDP is unknown, although it has
been postulated that a cell-mediated immune reaction to an
ingestant, contact or microorganism underlies the areas of pig-
mentary incontinence.18,41 There have been reports of EDP
development in association with oral ingestion of medications
(e.g. benzodiazepines, penicillin), ammonium nitrate and
X-ray contrast media; exposure to pesticides or toxins; endo-
crinopathies; and whipworm and human immunodeficiency
virus infections.18 It has also been postulated that the HLA-DR4
allele may represent a risk factor for EDP in Mexican patients.
Clinically, EDP presents as slate-grey to blue-brown oval,
circular or irregularly shaped macules and patches that gradu-
ally develop in a symmetric distribution (Fig. 8). The long
axis of lesions may follow skin cleavage lines. In earlier stages,
lesions may have a thin, raised and erythematous border.
Lesions typically involve the trunk with spread to the neck,
upper extremities and, sometimes, the face. Although usually
asymptomatic, EDP may be mildly pruritic. EDP can be diffi-
cult to diagnosis and may be confused with other entities
including LPP, lichenoid drug eruption, infectious diseases
(e.g. leprosy and pinta), and other forms of dermal PIH. EDP
Fig 8. Erythema dyschromicum perstans: multiple, ill-defined,
circular, grey-brown patches on the neck.
British Journal of Dermatology (2013) 169 (Suppl. 3), pp4156
48 Facial hyperpigmentation, N.A. Vashi and R.V. Kundu
is very difficult to treat, and there is no consistently effective
treatment. Oral corticosteroids, antibiotics (e.g. doxycycline),
antimalarials, isoniazid, griseofulvin and UV radiation therapy
have produced variable results. Successful treatment with dap-
sone and clofazimine has been reported in small series. Topi-
cal therapies with corticosteroids and hydroquinone are
generally of no benefit. The disease progresses slowly and usu-
ally does not regress in adults.
Lichen planus pigmentosus
LPP is an uncommon variant of lichen planus that favours
skin phototypes IIIV. It generally affects young to middle-
aged adults, especially those from India, Latin America and
the Middle East. Clinically, it presents as oval or irregularly
shaped grey-brown to brown macules and patches in sun-
exposed areas, including the forehead, temples and neck, or
intertriginous areas (Fig. 9). Lesions are symmetric in the
majority; however, they can present in a unilateral, linear
fashion. It is typically asymptomatic, but some do describe
mild pruritus and/or burning. In one series of 124 patients
with LPP, 19 were also noted to have typical lesions of
lichen planus.42
The aetiology for LPP is unknown. Photodistribution sug-
gests that UV radiation may play a pathogenic role. Also, topi-
cal application of mustard oil which contains a potential
photosensitizer, allyl isothiocyanate, and also amla oil have
been proposed as possible inciting agents.42 The differential
diagnosis includes lichen planus, EDP, melasma, lichenoid
drug eruptions and PIH. Of note, in contrast to EDP, an
erythematous border of early lesions is not a feature of LPP.
LPP is a chronic disorder with exacerbations and remissions.
Treatment is similar to EDP and LP if lesions typical of LP are
found. Options include topical steroids, immunomodulators and
skin-lightening agents. In one uncontrolled study, lightening of
the pigmentation occurred in 54% (seven of 13) of patients trea-
ted with topical tacrolimus for 1216 weeks.43 In addition, in a
Fig 9. Lichen planus pigmentosus: ill-defined, reticulated, brown-grey
patches on the neck.
British Journal of Dermatology (2013) 169 (Suppl. 3), pp4156
recent case report, a combination of low-fluence 1064 nm QSNY
with topical tacrolimus was reported to be successful.44
Actinic lichen planus
Actinic lichen planus (ALP) represents a rare photodistributed
variant of lichen planus and has also been reported under
the names of lichen planus actinicus, lichen planus subtropi-
cus, lichen planus tropicus and lichenoid melanodermatitis. It
has been observed worldwide; however, the majority of
reported patients have been from Middle Eastern coun-
tries.45,46 It typically occurs in young adults and/or children
with no gender predilection. The lesions usually consist of
red-brown plaques with an annular configuration, but mel-
asma-like hyperpigmented patches have been observed.18
Lesions are typically photodistributed involving areas of the
forehead, face and dorsal surfaces of the upper extremities
and neck. Lesions typically appear and/or are exacerbated
during the summer months and may improve spontaneously
in the winter. The differential diagnosis of ALP includes pho-
tosensitive lichenoid drug eruptions, discoid lupus erythemat-
osus, actinic prurigo, fixed drug eruption and polymorphous
light eruption. Treatment includes sun-protective measures.
Various therapies have been tried in ALP with variable out-
comes, including topical and intralesional corticosteroids, an-
timalarials (e.g. hydroxychloroquine), acitretin and
ciclosporin.45,47
Other aetiologies of facial hyperpigmentation
Erythromelanosis folliculis faciei et colli
Erythromelanosis follicularis faciei et colli (EFFC) is a rare aeti-
ology of facial hyperpigmentation with fewer than 50
reported cases in the literature, mostly from Japan.25,48 It is
characterized by well-demarcated erythema, hyperpigmenta-
tion and follicular papules. It mainly affects young and mid-
dle-aged men with onset in adolescence but can also be seen
in female subjects. The cause is unknown. Clinically, EFFC
manifests as gradually progressive reddish-brown pigmenta-
tion and telangiectasias surmounted with small follicular pap-
ules from which vellus, but not terminal hairs, are lost.25 The
pigmentation involves the periauricular areas and sometimes
extends to the sides of the neck. Often patients have keratosis
pilaris lesions on the trunk, with no history of related disor-
ders or family history of atopy. Treatment has included isotre-
tinoin, topical retinoids and hydroquinone. Although clinical
regression is difficult to achieve and relapse is common,
lesions have been noted to respond to treatment.48
Post-chikungunya pigmentation
Post-chikungunya pigmentation is a rare aetiology of facial
pigmentation noted in India since 2005.25 Chikungunya fever
is a febrile, mosquito-borne (Aedes aegypti and Aedes albopictus),
viral illness, first reported in Tanzania and thereafter epidemics
2013 The Authors
BJD 2013 British Association of Dermatologists
 Facial hyperpigmentation, N.A. Vashi and R.V. Kundu 49

in several countries. All age groups have been affected. Clini- for research into pathogenesis and treatment. Overall, treat-
cally, an asymptomatic, brownish-black pigmentation in the ment includes removal of provoking factors, photoprotection,
form of freckle-like macules or, less commonly, slate pigmen- and forms of active pigment reduction with either topical for-
tation can be seen. The pigmentation generally involves the mulations or physical modalities (Table 2).
centrofacial area. Other patterns of pigmentation that have
been observed include melasma-like pigmentation over the
General instructions
face, periorbital melanosis, and a flagellate pattern of pigmen-
tation on the face and extremities.25,49 Lesions may persist for Those with skin types IVVI need special considerations in
36 months after the infection. Pigmentation changes were preventing and treating various aetiologies of facial hyper-
found to be the most common cutaneous finding (42%), fol- pigmentation. Peak hours of sunlight (between 11:00 and
lowed by a maculopapular eruption (33%) and intertriginous 16:00 h) should be avoided in addition to seeking shade and
aphthous-like ulcers (21
4%).49 The exact cause of cutaneous wearing protective clothing (e.g. broad-brimmed hats and
manifestations is not known. Biopsy from hyperpigmented long-sleeved shirts). Avoiding provoking triggers is necessary
lesions shows an intact basal layer with diffuse hypermelanosis for many types of facial hyperpigmentation including mel-
of the entire epidermis, suggesting an increased intraepidermal asma, pigmented contact dermatitis and PIH. If melasma has
melanin dispersion and retention from the virus.25,49 All been induced by the use of oral contraceptives, discontinua-
patients responded well to symptomatic, conservative treat- tion should be considered.
ment.49
Sunscreens
Treatment of facial hyperpigmentation
Several studies have shown that light from both the UV and
Facial hyperpigmentation can cause significant cosmetic disfig- visible spectrum can induce pigmentary changes in the
urement with subsequent emotional impact.25,50,51 Treatment skin.52,53 Redistribution and oxidation of pre-existing melanin
continues to be challenging as there is no universally effective cause immediate pigment darkening and occurs after low-dose
therapy, and existing agents have varying degrees of efficacy. UVA exposure and usually fades after 2 h.53,54 After high
Because the majority of reports regarding treatment consist of doses of UVA exposure, persistent pigment darkening may
small series of patients and anecdotes, it is difficult to evaluate develop, lasting up to 24 h. Both UVA and UVB exposure can
the efficacy of different forms of therapy. In addition, cause melanin synthesis resulting in delayed tanning. Given
although multiple options do currently exist, some therapies clinical experience and available data, broad-spectrum UVA
have come under increasing scrutiny, underscoring the need and UVB protective sunscreen with an SPF of at least 30 ide-
ally including a physical block (e.g. titanium dioxide or zinc
oxide) should be used for prevention of facial hyperpigmenta-
Table 2 Skin-lightening agents. Adapted from [52]. tion. Vitamin D is essential for bone health, and as cutaneous
synthesis is a well-known source, it is important to counsel
Mechanism of action Compound patients properly when advocating strict sun protection. Dar-
Tyrosinase inhibition Arbutin ker-skinned patients have an inherently lower vitamin D level
Azelaic acid and those that live in environments that do not have regular
DeoxyArbutin sun exposure and/or are adhering to strict sun-protective
Glycolic acid measures may require supplementation and monitoring. The
Hydroquinone National Academy of Sciences Institute of Medicine recom-
Liquorice extract
mended dietary allowance (RDA) for vitamin D is 400 inter-
Mequinol
N-Acetylglucosamine
national units (IU) for infants/children aged 01 years,
N-Acetyl-4-S-cysteaminylphenol 600 IU for those aged 170 years and 800 IU for those aged
Reduction in Niacinamide 71 years. Sources include fortified milk, cheese, yogurt and
melanosome transfer Retinoids cereal and also oily fish (i.e. salmon and tuna). Fortified foods
Soybean trypsin inhibitor are rich in both vitamin D and calcium and maintain phos-
Interaction with copper Ascorbic acid phate levels, which are also needed for bone health.
Kojic acid
Stimulation of Glycolic acid
keratinocyte turnover Retinoids Cosmetic camouflage
Inhibition of melanosome Arbutin
maturation DeoxyArbutin Physical blocking opaque sunscreens have the dual benefit of
Inhibition of protease-activated Soybean trypsin camouflaging facial hyperpigmentation and preventing photo-
receptor 2 inhibitor induced darkening. Many of these physical blockers now come
Oxidation and breakdown Lignin peroxidase in tinted blends to help with camouflaging. In addition, many
of melanin
patients find that the use of make-up helps even out skin tone.
Several available brands that provide heavy coverage include

2013 The Authors British Journal of Dermatology (2013) 169 (Suppl. 3), pp4156
BJD 2013 British Association of Dermatologists
50 Facial hyperpigmentation, N.A. Vashi and R.V. Kundu
Dermablend (Vichy Laboratories, Paris, France), Cover FX
(Cover FX Skin Care, Toronto, Ontario, Canada), Covermark/
CM Beauty (CM Beauty, Northvale, NJ, U.S.A.).52
Topical treatments
Topical treatments for disorders of facial hyperpigmentation
are aimed at disrupting the enzymatic processes of pigment
production within the melanocytes. In the process of melanin
production, tyrosinase is the rate-limiting enzyme converting
L-tyrosinase to L-3,4-dihydroxyphenlalanine (L-DOPA). L-
DOPA is a required cofactor, and copper is also an important
molecule that interacts at tyrosinases active site. Many com-
pounds target these molecules leading to a decrease in
melanization.
Hydroquinone
Hydroquinone (1,4-dihydroxybenzene) is the gold standard for
the treatment of facial hyperpigmentation and has been used for
more than 50 years. It is thought to act by inhibition of tyrosinase
thus reducing the formation and melanization of melanosomes.
This also leads to the destruction of melanosomes and possibly
even the inhibition of DNA and RNA synthesis.55,56 Being an oxi-
dizing agent, hydroquinone changes from white to brown at
which time it needs to be discarded as it is ineffective.57
The efficacy of hydroquinone depends on several factors
including location of pigment with epidermal pigmentation
responding better than dermal, concentration of hydroquinone
and vehicle of administration, hydroalcoholic solution being
the most effective.25 Used in concentrations of 25%, the
response in melasma becomes evident after 57 weeks and
therapy may be continued for 312 months.25,50 Ennes et al.
found that 38% of patients with melasma treated with 4%
hydroquinone had a complete response vs. only 8% treated
with placebo.58 In a nonrandomized trial, 4% hydroquinone
and broad-spectrum sunscreen was shown to be efficacious in
the treatment of melasma, with 89
5% of subjects showing
good to excellent responses.59
Adverse reactions to hydroquinone are dose and duration
dependent. Reactions include asymptomatic transient
erythema, irritation, confetti-like depigmentation with higher
concentrations and exogenous ochronosis. Uncontrolled access
to high concentrations of hydroquinone and/or overuse can
increase the risk of adverse events. Over the past few years,
concern has been growing over the use of topical hydroqui-
none. One concern is the potential risks from benzene deriva-
tives after hepatic metabolism, which are proposed to cause
bone marrow toxicity and exert antiapoptotic effects.60 Topical
hydroquinone, however, bypasses the liver initially, and the
major route of metabolism is via water soluble, renally
excreted molecules.52,60 In a review of hydroquinone safety
issues, Nordlund et al. maintained that there does not appear
to be more than a theoretical risk of malignancy and very low
risk of other side-effects, including exogenous ochronosis,
when using prescription topical preparations of hydroquinone
British Journal of Dermatology (2013) 169 (Suppl. 3), pp4156
under physician supervision.61 In addition, there have been
no reports to date of skin or internal organ malignancies
occurring in humans as a result of topical hydroquinone appli-
cation.61
Azelaic acid
Azelaic acid is a 9-carbon dicarboxylic acid derived from Pity-
rosporum ovale, which is antiproliferative and cytotoxic to mela-
nocytes. It acts as a weak, reversible, competitive inhibitor of
tyrosinase. Another possible mechanism of action includes
decreased free radical formation. It has been used in the treat-
ment of both melasma and PIH. In patients with melasma,
20% azelaic acid was found to be as effective as 4% and supe-
rior to 2% hydroquinone, but without side-effects.62 Overall,
azelaic acid is well tolerated with the most commonly
reported side-effects including pruritus, mild erythema, scal-
ing and burning.
Retinoids
Retinoids reduce hyperpigmentation through multiple
mechanisms including promoting loss of melanin through the
stimulation of keratinocyte turnover, reducing melanosome
transfer and allowing for greater penetration of other active
ingredients.63 Retinoids are thought to inhibit tyrosinase tran-
scription, interrupt melanin synthesis and inhibit tyrosinase-
related proteins 1 and 2.63 Available retinoids (retinoic acid,
tretinoin, adapalene, tazarotene) have been used to treat mel-
asma and PIH, either as monotherapy or combined with other
agents including hydroquinone and topical steroids. As mono-
therapy, higher percentages of retinoic acid (0
1%) have been
found to be more effective for melasma than lower percent-
ages (0
05%, 0
025%), however, also more irritating.64 In a
randomized controlled trial, 0
1% tretinoin was found to be
more effective than the vehicle for treating patients with mel-
asma.65 Importantly, it took longer, 24 weeks, in these studies
to see significant improvement. Adapalene (0
1%) has been
found to be as efficacious as tretinoin (0
05%) with signifi-
cantly less irritation in the treatment of melasma.66 Once-daily
application of 0
1% tazarotene cream was shown to be effec-
tive against PIH, achieving significantly greater reductions
compared with vehicle in overall disease severity and in the
intensity and area of hyperpigmentation within 18 weeks.67
In a study comparing 0
1% tazarotene cream and 0
3% adapa-
lene gel, both were found to be effective and well tolerated in
the treatment of PIH; however, tazarotene was more effec-
tive.68 Topical 0
05% isotretinoin gel applied daily with SPF
28 sunscreen has been evaluated in the treatment of melasma
in Thai patients; however, this application did not show
increased efficacy vs. vehicle and sunscreen alone.69
Retinoids have been found to be effective when combined
with other agents including but not limited to hydroquinone,
lactic acid and ascorbic acid. Irritation is the most common
side-effect and may even cause hyperpigmentation so should
be used cautiously.
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BJD 2013 British Association of Dermatologists

Mequinol
Mequinol (4-hydroxyanisole) is a derivative of hydroquinone
and acts as a competitive inhibitor of tyrosinase, reducing the
formation of melanin precursors. For the treatment of solar
lentigines, a topical combination of 2% mequinol and 0
01%
tretinoin solution was well tolerated and superior to either
active component and vehicle,70 and in another study, it was
found to be superior to hydroquinone 3% for solar lentigines
on the forearm and similar efficacy for facial lesions.71 This
combination has also resulted in complete clearance in four
of five men with melasma at 12 weeks with all patients
maintaining improvement at 16 weeks.72 Treatment-related
adverse events for combination productions include erythema,
burning/stinging/tingling, desquamation, pruritus, hypopig-
mentation and halo hypopigmentation. Symptomatic side-
effects were found to decrease when used with sunscreen of
SPF 25 or greater.73 Although efficacious in combination
products, controlled clinical trials are still needed to establish
the place of mequinol in the management of facial
hyperpigmentation.
Kojic acid
Kojic acid is produced by Aspergillus oryzae and Penicillium spp.74
It inhibits the production of free tyrosinase by inhibiting
tyrosinase through chelation of copper at the enzymes active
site. The agent is usually available over the counter in a 2%
concentration. When used alone, 14% formulations are only
modestly efficacious; however, it can also be used in combi-
nation formulations. Studies have found mixed results. For
melasma, in one split-face trial, a gel containing glycolic
acid, hydroquinone and kojic acid showed more improve-
ment (60%) in patients than a gel that contained only gly-
colic acid and hydroquinone (47
5%).75 In another split-face
trial comparing a combination glycolic acid and kojic acid
preparation with a glycolic acid and hydroquinone prepara-
tion, authors found no statistically significant difference in
clinical efficacy.76 Important to note is that kojic acid is a
known sensitizer and may cause contact dermatitis and ery-
thema.77
Ascorbic acid
Ascorbic acid, also known as vitamin C, has antioxidant prop-
erties and reduces melanogenesis by interacting with copper at
the active site of tyrosinase and by reducing dopaquinone by
blocking dihydrochinindol-2-carboxyl acid oxidation.52,77 In a
randomized trial, patients with melasma found greater subjec-
tive improvement to one side of the face treated with 4%
hydroquinone cream (93%) than the other side of the face
treated with 5% ascorbic acid cream (62
5%).78 However,
ascorbic acid had a better safety profile causing significantly
less irritation than hydroquinone; therefore, it may be a useful
adjunctive treatment in those unable to tolerate hydroquinone.
In another study, a 25% L-ascorbic acid formulated with a
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BJD 2013 British Association of Dermatologists
Facial hyperpigmentation, N.A. Vashi and R.V. Kundu 51
penetration enhancer was found to improve melasma signifi-
cantly.79
Because of its instability in aqueous solution, esters like
magnesium ascorbyl-2-phosphate (MAP) with similar proper-
ties have been used.80 MAP was found to reduce pigmentation
significantly in 19 of 34 patients with melasma and senile
freckles but only in three of 25 patients with normal skin.81
Ascorbic acid can be used alone or in combination therapy.
Overall, this molecule is rapidly oxidized, highly unstable and
does not work well alone; it is, therefore, usually combined
with other agents such as liquorice extracts and soy to increase
efficacy.
Liquorice derivatives
Liquorice is the root of the perennial herb, Glycyrrhiza glabra.
Liquorice extract has anti-inflammatory properties and con-
tains glabridin, which inhibits tyrosinase in vitro.82 Other active
ingredients are liquiritin and isoliquiritin, which, respectively,
disperse melanin and contain flavonoids. In a split-face trial, a
20% liquiritin cream was found to be effective at 4 weeks in
the treatment of epidermal melasma.83 The use of 1 g per day
for 4 weeks is often used before any benefit is seen.77
Soy
Soybean trypsin inhibitor reversibly inhibits the protease-acti-
vated receptor-2 pathway that is needed for melanosome
transfer.84 Inhibition of this pathway caused a dose-dependent
loss of pigmentation by as early as 4 weeks at the highest
tested dose.85 Additional work on this pathway has shown
that soymilk and the soybean-derived serine protease inhibi-
tors can inhibit both baseline and UVB-induced pigmentation
in vitro.86 In a multiagent comparative trial, soy extract was
shown to have a modest effect in lightening solar lentigines.87
Arbutin/deoxyArbutin
Arbutin is the naturally occurring b-D-glucopyranoside deriva-
tive of hydroquinone that is derived from the bearberry plant,
and deoxyArbutin is a dehydroxylated derivative of arbutin.
Arbutin is hydrolyzed in the skin to hydroquinone and pro-
duces skin lightening by direct, dose-dependent inhibition of
tyrosinase.88 The synthetic deoxyArbutin is a more potent
tyrosinase inhibitor, and in guinea pig and human tests has
been shown to be more rapidly effective.89 Although good
controlled clinical trials are lacking, initial in vitro and in vivo
experiments have demonstrated its safety and efficacy in hy-
permelanotic disorders.90 It has been used in Japan at concen-
trations of 3%; of note, at higher concentrations it may cause
paradoxical hyperpigmentation.77
Niacinamide
Niacinamide reduces pigmentation by reversibly preventing
the transfer of melanosomes from melanocytes to the keratino-
British Journal of Dermatology (2013) 169 (Suppl. 3), pp4156
52 Facial hyperpigmentation, N.A. Vashi and R.V. Kundu
cytes.91 It is an important component of many over-the-coun-
ter lightening creams. Hakozaki et al. showed that niacinamide
decreases hyperpigmentation compared with vehicle alone
after 4 weeks of use.92 By enhancing percutaneous absorption,
its efficacy was doubled by low-frequency sonophoresis.93
N-Acetylglucosamine
N-Acetylglucosamine (NAG) is a carbohydrate and represents
the monomeric unit of chitin, the main component of the cell
walls of fungi and the exoskeletons of arthropods such as
crustaceans and insects. It is proposed to work by inhibiting
the conversion of protyrosinase to tyrosinase. NAG has been
shown to decrease melanin synthesis and downregulate the
expression of various pigmentation-related genes.94 Clinical
studies have used either NAG alone or in combination with
niacinamide. In an 8-week, double-blind, placebo-controlled,
split-face clinical trial, 2% NAG reduced the appearance of
facial hyperpigmentation. In a 10-week, double-blind, vehicle-
controlled, parallel-group study, the combination 2% NAG
and 4% niacinamide was significantly better than vehicle in
reducing the detectable area of facial spots and the appearance
of hyperpigmentation.95 Overall, NAG has high tolerance, ease
of formulation and stability in solution making it a suitable
depigmenting agent.
Glycolic acid
Glycolic acid directly inhibits tyrosinase and also reduces hy-
perpigmentation due to its effects on epidermal remodelling
and accelerated desquamation.96 A combination of 10% gly-
colic acid and 4% hydroquinone was shown to be effective in
treating melasma. Side-effects include irritation and erythema,
which resolves upon withdrawal and moisturization.97
Lignin peroxidase
Lignin peroxidase is a novel method of skin lightening and
acts by targeting, enzymatically oxidizing and breaking down
melanin in the skin. In a randomized, double-blind, placebo-
controlled, split-face, single-centre study of 51 patients,
patients were randomized to receive day and night lignin
peroxidase cream on one side of the face and either 2%
hydroquinone or placebo on the other.98 The application of
lignin peroxidase cream provided a significantly more rapid
and observable skin-lightening effect than 2% hydroquinone
or placebo. Overall, lignin peroxidase is well tolerated with
minimal to no side-effects.
Miscellaneous agents
There are multiple other agents either under investigation or
combined with other products to enhance skin-lightening
effects. N-Acetyl-4-S-cysteaminylphenol (NCAP) acts as an
alternative substrate for tyrosinase, inhibiting its activity. In a
retrospective analysis of 12 patients with melasma who used
British Journal of Dermatology (2013) 169 (Suppl. 3), pp4156
4% NCAP, 66% showed marked improvement as early as after
24 weeks.25,99 Other agents known to affect melanin pig-
mentation are thiotic acid (a-lipoic acid), gentisic acid and
mulberry extract. In addition, a-tocopheryl ferulate absorbs
UV radiation and significantly slows melanogenesis, possibly
by inhibiting tyrosine hydroxylase. Flavonoids including
catechin, ellagic acid and aloesin are naturally occurring
polyphenols with antioxidant properties.25
Combination products
Topical agents when combined have the ability to give better
therapeutic results as they act on different stages of melano-
genesis. Combining agents can also reduce side-effects. For
example, topical steroids reduce hydroquinone- and retinoid-
induced irritation, while retinoids can counter steroid-induced
atrophy. Other agents can be used as stabilizers, and sunsc-
reens are also often added to combination agents.
As the gold standard in the treatment of hyperpigmentation
disorders, hydroquinone is often combined with different
agents including retinoids, corticosteroids, glycolic acid, kojic
acid and ascorbic acid. The most extensively studied and
widely used is the combination therapy of hydroquinone, reti-
noic acid and corticosteroid. First proposed by Kligman and
Willis, the original combination contained 5% hydroquinone,
0
1% tretinoin and 0
1% dexamethasone.100 This combination
treatment was found to be effective in melasma, ephelides and
PIH, and time to see benefit with twice-daily usage was
approximately 3 weeks.100 Researchers also found that fluori-
nated steroids were more effective than nonfluorinated ste-
roids. The theory behind the effectiveness of this combination
is that tretinoin prevents the oxidation of hydroquinone and
improves epidermal penetration while the topical steroid
reduces irritation from the other two ingredients and
also decreases cellular metabolism, which inhibits melanin
synthesis.101
Since this discovery, multiple dual and triple combination
therapies have been studied. Due to the irritation, the combi-
nation has been modified to reduce hydroquinone to 24%
and tretinoin to 0
0250
05%, and the concomitant use of
regular photoprotection of at least SPF 15 has been shown to
increase efficacy of topical therapy significantly.101 One of the
most successful combination formulations has been 4% hydro-
quinone, 0
05% tretinoin and 0
01% fluocinolone acetonide.
In a multicentre, investigator-blinded, randomized, prospec-
tive trial in patients with melasma, this triple combination
cream was found to be more efficacious than dual-combina-
tion creams containing either hydroquinone plus tretinoin,
hydroquinone plus fluocinolone or tretinoin plus fluocinolone
with nightly use.52,61,102 Seventy-seven per cent of patients on
the triple-combination treatment achieved complete or near-
complete clearance compared with a maximum of 46
8% of
patients on the dual-combination treatment.102 A more recent
trial comparing the triple-combination regimen with 4%
hydroquinone alone in patients with melasma also confirmed
the superiority of the combination regimen, 35% achieving
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BJD 2013 British Association of Dermatologists

clearance vs. 5
1%.103 Another combination using 6% hydro-
quinone, 0
05% tretinoin, 0
05% triamcinolone acetonide and
0
1% ascorbic acid nightly with daily photoprotection was
found to be efficacious, with five of six patients with epider-
mal or mixed melasma showing moderate to significant
improvement over an 8-week period.104
Side-effects of combination treatment include erythema,
irritation, pruritus and desquamation. In treating disorders of
hyperpigmentation, especially melasma, triple-combination
regimens appear to be the most clinically effective treatment.
While efficacious, the cost can be prohibitive. However,
although associated with increased upfront costs, a cost/bene-
fit analysis of combination therapy vs. hydroquinone alone for
melasma found that the combination regimen led to a 30%
greater rate of clearance with lower overall cost.105
Summary of topical treatments
Skin-lightening preparations are used by people all over the
world. Hydroquinone is the gold standard; however, there is
a constant search for novel treatment alternatives. Understand-
ing the molecular mechanisms involved in pigmentation has
resulted in multiple proprietary formulas that combine skin-
lightening agents that act via different mechanisms in the mel-
anin pathway. In the future, combination topical agents,
designed to affect multiple points in the pathway of melano-
genesis and melanin distribution, may provide additional
treatment options with clinical efficacy and lower rates of
cutaneous side-effects.
Physical therapies
Chemical peels
Chemical peels can be used to treat facial hyperpigmentation
either combined with other modalities or as stand-alone treat-
ment. Although chemical peeling may improve disorders of
hyperpigmentation, they can also cause irritation which can
lead to further dyspigmentation. Overall, epidermal melanin
responds best, and patients who combine treatment and con-
tinue topical therapy after peels are administered, maintain
improvement better than those who do not.105 Medium-depth
peels should be performed with great caution and deep peels
are overall not recommended because of high risk of pro-
longed and/or permanent pigmentary changes.
Dermabrasion
Another adjunctive treatment to facial hyperpigmentation is
dermabrasion. Patients with resistant melasma, especially with
a prominent dermal component that is often very hard to treat
have been successfully treated with local or full-face derm-
abrasion up to the upper or mid-dermis. Successful methods
have included use of a 16-mm diameter coarse grit diamond
fraise. Ninety-seven per cent of patients were found to have
improvement for a mean of 5 years, and < 1% of patients
2013 The Authors
BJD 2013 British Association of Dermatologists
Facial hyperpigmentation, N.A. Vashi and R.V. Kundu 53
developed hypertrophic scars or permanent hypopigmenta-
tion.106
Laser therapy
The treatment of hyperpigmentation with laser and light
sources is based on multiple observations of the biology of
pigmentation properties in the epidermis and dermis. First,
melanin has a broad absorption spectrum. Second, melano-
somes have a short thermal relaxation time, in the range of
50500 ns. Lastly, longer wavelengths penetrate deeper and
can target dermal pigment, but melanin absorption is better
with shorter wavelengths.52 Given these attributes, many light
and laser sources have been tried. This particular therapeutic
modality, however, is quite challenging because of the high
risk of damage to surrounding tissue that can lead to long-
lasting and delayed PIH.
For most aetiologies of facial hyperpigmentation, lasers
should be second- and third-line therapeutic modalities. How-
ever, for patients with naevus of Ota and/or Hori naevi, treat-
ment with lasers with Q-switched modalities are quite
efficacious. In particular, the 1064-nm QSNY is the most
widely used laser in darker skin types because of the longer
wavelengths that allow for a deeper penetration.
Overall, lasers and light sources should only be used in the
hands of the experienced physician, and in some disorders
should only be attempted after other modalities have been pro-
ven to be unsuccessful. Treatment with lasers for facial hyper-
pigmentation has been associated with an unpredictable
response, frequent relapses and high risk of both post-inflam-
matory hyper- and hypopigmentation. Proper patient counsel-
ling in regards to side-effects and expectations along with test
patch should always be employed prior to any laser procedure.
Conclusions
Persons of colour will soon comprise a majority of the inter-
national and domestic U.S. populations. A comprehensive
knowledge and approach to assessment and treatment is neces-
sary to care properly for our skin of colour patients. Inconsis-
tent pigmentation in the facial skin of ethnic patients is a
continued concern and successful treatment of disorders of
facial hyperpigmentation often proves challenging. Several
methods of treatment are available depending on the condi-
tion, and a thorough understanding of the underlying aetiolo-
gies of facial hyperpigmentation is essential for selecting the
best treatment options.
References
1 U.S. Census Bureau. An Older and More Diverse Nation by Midcentury,
2008. Available at: http://www.census.gov/newsroom/releases/
archives/population/cb08-123.html (last accessed 25 June
2013).
2 Sharma VK, Sahni K, Wadhwani AR. Photodermatoses in pig-
mented skin. Photochem Photobiol Sci 2013; 12:6577.
British Journal of Dermatology (2013) 169 (Suppl. 3), pp4156
54 Facial hyperpigmentation, N.A. Vashi and R.V. Kundu
3 Taylor SC. Skin of color: biology, structure, function, and impli-
cations for dermatologic disease. J Am Acad Dermatol 2002; 46(2
Suppl.):S4162.
4 Seiji M, Fitzpatrick TB, Simpson RT, Birbeck MS. Chemical com-
position and terminology of specialized organelles (melanosomes
and melanin granules) in mammalian melanocytes. Nature 1963;
197:10824.
5 Iozumi K, Hoganson GE, Pennella R et al. Role of tyrosinase as
the determinant of pigmentation in cultured human melanocytes.
J Invest Dermatol 1993; 100:80611.
6 Wakamatsu K, Kavanagh R, Kadekaro AL et al. Diversity of pig-
mentation in cultured human melanocytes is due to differences
in the type as well as quantity of melanin. Pigment Cell Res 2006;
19:15462.
7 Chedekel MR, Smith SK, Post PW et al. Photodestruction of
pheomelanin: role of oxygen. Proc Natl Acad Sci USA 1978;
75:53959.
8 Sarna T, Menon IA, Sealy RC. Photoinduced oxygen consumption
in melanin systems II. Action spectra and quantum yields for
pheomelanins. Photochem Photobiol 1984; 39:8059.
9 Parra EJ. Human pigmentation variation: evolution, genetic basis,
and implications for public health. Am J Phys Anthropol 2007; 134
(Suppl. 45):85105.
10 Society for Experimental Biology. Mitochondria and Other Cytoplasmic
Inclusions. New York: Academic Press, 1959.
11 Szabo G, Gerald AB, Pathak MA, Fitzpatrick TB. Racial differences
in the fate of melanosomes in human epidermis. Nature 1969;
222:10812.
12 Staricco RJ, Pinkus H. Quantitative and qualitative data on the
pigment cells of adult human epidermis. J Invest Dermatol 1957;
28:3345.
13 Toda K, Pathak MA, Parrish JA et al. Alteration of racial differ-
ences in melanosome distribution in human epidermis after
exposure to ultraviolet light. Nat New Biol 1972; 236:1435.
14 Montagna W, Carlisle K. The architecture of black and white
facial skin. J Am Acad Dermatol 1991; 24:92937.
15 Ranu H, Thng S, Goh BK et al. Periorbital hyperpigmentation in
Asians: an epidemiologic study and a proposed classification. Der-
matol Surg 2011; 37:1297303.
16 Kaidbey KH, Agin PP, Sayre RM, Kligman AM. Photoprotection
by melanin a comparison of black and Caucasian skin. J Am Acad
Dermatol 1979; 1:24960.
17 Masu S, Seiji M. Pigmentary incontinence in fixed drug eruptions.
Histologic and electron microscopic findings. J Am Acad Dermatol
1983; 8:52532.
18 Bolognia JL, Jorizzo JL, Schaffer JV et al., eds. Dermatology, 3rd edn.
St Louis: Mosby, 2012.
19 Baumann L, Rodriguez D, Taylor SC, Wu J. Natural consider-
ations for skin of color. Cutis 2006; 78(6 Suppl.):219.
20 Sarkar R. Idiopathic cutaneous hyperchromia at the orbital region
or periorbital hyperpigmentation. J Cutan Aesthet Surg 2012; 5:183
4.
21 Roh MR, Chung KY. Infraorbital dark circles: definition, causes,
and treatment options. Dermatol Surg 2009; 35:116371.
22 Malakar S, Lahiri K, Banerjee U et al. Periorbital melanosis is an
extension of pigmentary demarcation line-F on face. Indian J Der-
matol Venereol Leprol 2007; 73:3235.
23 Verschoore M, Gupta S, Sharma VK, Ortonne JP. Determination
of melanin and haemoglobin in the skin of idiopathic cutaneous
hyperchromia of the orbital region (ICHOR): a study of Indian
patients. J Cutan Aesthet Surg 2012; 5:17682.
24 Watanabe S, Nakai K, Ohnishi T. Condition known as dark rings
under the eyes in the Japanese population is a kind of dermal
British Journal of Dermatology (2013) 169 (Suppl. 3), pp4156
melanocytosis which can be successfully treated by Q-switched
ruby laser. Dermatol Surg 2006; 32:7859; discussion 789.
25 Khanna N, Rasool S. Facial melanoses: Indian perspective. Indian J
Dermatol Venereol Leprol 2011; 77:55263; quiz 564.
26 Sheth VM, Pandya AG. Melasma: a comprehensive update: part I.
J Am Acad Dermatol 2011; 65:68997; quiz 698.
27 Levin CY, Maibach H. Exogenous ochronosis. An update on clini-
cal features, causative agents and treatment options. Am J Clin Der-
matol 2001; 2:21317.
28 Levitt J. The safety of hydroquinone: a dermatologists response
to the 2006 Federal Register. J Am Acad Dermatol 2007; 57:854
72.
29 Zawar VP, Mhaskar ST. Exogenous ochronosis following hydro-
quinone for melasma. J Cosmet Dermatol 2004; 3:2346.
30 Charlin R, Barcaui CB, Kac BK et al. Hydroquinone-induced exog-
enous ochronosis: a report of four cases and usefulness of der-
moscopy. Int J Dermatol 2008; 47:1923.
31 Adigun CG, Pandya AG. Improvement of idiopathic acanthosis
nigricans with a triple combination depigmenting cream. J Eur
Acad Dermatol Venereol 2009; 23:4867.
32 Sinha S, Schwartz RA. Juvenile acanthosis nigricans. J Am Acad Der-
matol 2007; 57:5028.
33 Chan HH, Leung RS, Ying SY et al. A retrospective analysis of
complications in the treatment of nevus of Ota with the
Q-switched alexandrite and Q-switched Nd:YAG lasers. Dermatol
Surg 2000; 26:10006.
34 Chan HH, Ying SY, Ho WS et al. An in vivo trial comparing the
clinical efficacy and complications of Q-switched 755 nm alexan-
drite and Q-switched 1064 nm Nd:YAG lasers in the treatment
of nevus of Ota. Dermatol Surg 2000; 26:91922.
35 Hori Y, Kawashima M, Oohara K, Kukita A. Acquired, bilateral
nevus of Ota-like macules. J Am Acad Dermatol 1984; 10:9614.
36 Ee HL, Goh CL, Khoo LS et al. Treatment of acquired bilateral
nevus of ota-like macules (Horis nevus) with a combination of
the 532 nm Q-Switched Nd:YAG laser followed by the
1,064 nm Q-switched Nd:YAG is more effective: prospective
study. Dermatol Surg 2006; 32:3440.
37 Cho SB, Park SJ, Kim MJ, Bu TS. Treatment of acquired bilateral
nevus of Ota-like macules (Horis nevus) using 1064-nm Q-
switched Nd:YAG laser with low fluence. Int J Dermatol 2009;
48:130812.
38 Bliss JM, Ford D, Swerdlow AJ et al. Risk of cutaneous melanoma
associated with pigmentation characteristics and freckling: sys-
tematic overview of 10 casecontrol studies. The International
Melanoma Analysis Group (IMAGE). Int J Cancer 1995; 62:367
76.
39 Rhodes AR, Albert LS, Barnhill RL, Weinstock MA. Sun-induced
freckles in children and young adults. A correlation of clinical
and histopathologic features. Cancer 1991; 67:19902001.
40 Rhodes AR, Harrist TJ, Momtaz TK. The PUVA-induced pig-
mented macule: a lentiginous proliferation of large, sometimes
cytologically atypical, melanocytes. J Am Acad Dermatol 1983; 9:47
58.
41 Schwartz RA. Erythema dyschromicum perstans: the continuing
enigma of Cinderella or ashy dermatosis. Int J Dermatol 2004;
43:2302.
42 Kanwar AJ, Dogra S, Handa S et al. A study of 124 Indian patients
with lichen planus pigmentosus. Clin Exp Dermatol 2003; 28:481
5.
43 Al-Mutairi N, El-Khalawany M. Clinicopathological characteristics
of lichen planus pigmentosus and its response to tacrolimus oint-
ment: an open label, non-randomized, prospective study. J Eur
Acad Dermatol Venereol 2010; 24:53540.
2013 The Authors
BJD 2013 British Association of Dermatologists

44 Kim JE, Won CH, Chang S et al. Linear lichen planus pigmentosus
of the forehead treated by neodymium:yttrium-aluminum-garnet
laser and topical tacrolimus. J Dermatol 2012; 39:18991.
45 Dammak A, Masmoudi A, Boudaya S et al. Childhood actinic
lichen planus (6 cases). Arch Pediatr 2008; 15:11114 (in French).
46 Meads SB, Kunishige J, Ramos-Caro FA, Hassanein AM. Lichen
planus actinicus. Cutis 2003; 72:37781.
47 Ramirez P, Feito M, Sendagorta E et al. Childhood actinic lichen
planus: successful treatment with antimalarials. Australas J Dermatol
2012; 53:e1013.
48 Sardana K, Relhan V, Garg V, Khurana N. An observational analy-
sis of erythromelanosis follicularis faciei et colli. Clin Exp Dermatol
2008; 33:3336.
49 Inamadar AC, Palit A, Sampagavi VV et al. Cutaneous manifesta-
tions of chikungunya fever: observations made during a recent
outbreak in south India. Int J Dermatol 2008; 47:1549.
50 Perez-Bernal A, Munoz-Perez MA, Camacho F. Management of
facial hyperpigmentation. Am J Clin Dermatol 2000; 1:2618.
51 Rigopoulos D, Gregoriou S, Katsambas A. Hyperpigmentation and
melasma. J Cosmet Dermatol 2007; 6:195202.
52 Sheth VM, Pandya AG. Melasma: a comprehensive update: part II.
J Am Acad Dermatol 2011; 65:699714; quiz 715.
53 Pathak MA, Riley FC, Fitzpatrick TB. Melanogenesis in human
skin following exposure to long-wave ultraviolet and visible light.
J Invest Dermatol 1962; 39:43543.
54 Mahmoud BH, Hexsel CL, Hamzavi IH, Lim HW. Effects of visi-
ble light on the skin. Photochem Photobiol 2008; 84:45062.
55 Jimbow K, Obata H, Pathak MA, Fitzpatrick TB. Mechanism of
depigmentation by hydroquinone. J Invest Dermatol 1974; 62:436
49.
56 Briganti S, Camera E, Picardo M. Chemical and instrumental
approaches to treat hyperpigmentation. Pigment Cell Res 2003;
16:10110.
57 Draelos ZD. Cosmetic therapy. In: Comprehensive Dermatologic Drug
Therapy (Wolverton SE, ed), 2nd edn. Philadelphia: Saunders,
2007; 76174.
58 Ennes SBP, Paschoalick RC, Mota De Avelar Alchorne M. A dou-
ble-blind, comparative, placebo-controlled study of the efficacy
and tolerability of 4% hydroquinone as a depigmenting agent in
melasma. J Dermatolog Treat 2000; 11:1739.
59 Amer M, Metwalli M. Topical hydroquinone in the treatment of
some hyperpigmentary disorders. Int J Dermatol 1998; 37:44950.
60 Westerhof W, Kooyers TJ. Hydroquinone and its analogues in
dermatology a potential health risk. J Cosmet Dermatol 2005;
4:559.
61 Nordlund JJ, Grimes PE, Ortonne JP. The safety of hydroquinone.
J Eur Acad Dermatol Venereol 2006; 20:7817.
62 Balina LM, Graupe K. The treatment of melasma. 20% azelaic acid
versus 4% hydroquinone cream. Int J Dermatol 1991; 30:8935.
63 Ortonne JP. Retinoid therapy of pigmentary disorders. Dermatol
Ther 2006; 19:2808.
64 Kimbrough-Green CK, Griffiths CE, Finkel LJ et al. Topical retinoic
acid (tretinoin) for melasma in black patients. A vehicle-con-
trolled clinical trial. Arch Dermatol 1994; 130:72733.
65 Griffiths CE, Finkel LJ, Ditre CM et al. Topical tretinoin (retinoic
acid) improves melasma. A vehicle-controlled, clinical trial. Br J
Dermatol 1993; 129:41521.
66 Dogra S, Kanwar AJ, Parsad D. Adapalene in the treatment of
melasma: a preliminary report. J Dermatol 2002; 29:53940.
67 Grimes P, Callender V. Tazarotene cream for postinflammatory
hyperpigmentation and acne vulgaris in darker skin: a double-
blind, randomized, vehicle-controlled study. Cutis 2006; 77:45
50.
2013 The Authors
BJD 2013 British Association of Dermatologists
Facial hyperpigmentation, N.A. Vashi and R.V. Kundu 55
68 Tanghetti E, Dhawan S, Green L et al. Randomized comparison of
the safety and efficacy of tazarotene 0.1% cream and adapalene
0.3% gel in the treatment of patients with at least moderate facial
acne vulgaris. J Drugs Dermatol 2010; 9:54958.
69 Leenutaphong V, Nettakul A, Rattanasuwon P. Topical isotretinoin
for melasma in Thai patients: a vehicle-controlled clinical trial. J
Med Assoc Thai (Chotmaihet Thangphaet) 1999; 82:86875.
70 Fleischer AB, Schwartzel EH, Colby SI, Altman DJ. The combina-
tion of 2% 4-hydroxyanisole (mequinol) and 0.01% tretinoin is
effective in improving the appearance of solar lentigines and
related hyperpigmented lesions in two double-blind multicenter
clinical studies. J Am Acad Dermatol 2000; 42:45967.
71 Jarratt M. Mequinol 2%/tretinoin 0.01% solution: an effective
and safe alternative to hydroquinone 3% in the treatment of solar
lentigines. Cutis 2004; 74:31922.
72 Keeling J, Cardona L, Benitez A et al. Mequinol 2%/tretinoin
0.01% topical solution for the treatment of melasma in men:
a case series and review of the literature. Cutis 2008; 81:179
83.
73 Colby SI, Schwartzel EH, Huber FJ et al. A promising new treat-
ment for solar lentigines. J Drugs Dermatol 2003; 2:14752.
74 Kim YJ, Uyama H. Tyrosinase inhibitors from natural and syn-
thetic sources: structure, inhibition mechanism and perspective
for the future. Cell Mol Life Sci 2005; 62:170723.
75 Lim JT. Treatment of melasma using kojic acid in a gel contain-
ing hydroquinone and glycolic acid. Dermatol Surg 1999; 25:282
4.
76 Garcia A, Fulton JE Jr. The combination of glycolic acid and
hydroquinone or kojic acid for the treatment of melasma and
related conditions. Dermatol Surg 1996; 22:4437.
77 Draelos ZD. Skin lightening preparations and the hydroquinone
controversy. Dermatol Ther 2007; 20:30813.
78 Espinal-Perez LE, Moncada B, Castanedo-Cazares JP. A double-
blind randomized trial of 5% ascorbic acid vs. 4% hydroquinone
in melasma. Int J Dermatol 2004; 43:6047.
79 Hwang SW, Oh DJ, Lee D et al. Clinical efficacy of 25% L-ascorbic
acid (Censil) in the treatment of melasma. J Cutan Med Surg 2009;
13:7481.
80 Kobayashi S, Takehana M, Itoh S, Ogata E. Protective effect of
magnesium-L-ascorbyl-2 phosphate against skin damage induced
by UVB irradiation. Photochem Photobiol 1996; 64:2248.
81 Kameyama K, Sakai C, Kondoh S et al. Inhibitory effect of magne-
sium L-ascorbyl-2-phosphate (VC-PMG) on melanogenesis in vitro
and in vivo. J Am Acad Dermatol 1996; 34:2933.
82 Yokota T, Nishio H, Kubota Y, Mizoguchi M. The inhibitory
effect of glabridin from licorice extracts on melanogenesis and
inflammation. Pigment Cell Res 1998; 11:35561.
83 Amer M, Metwalli M. Topical liquiritin improves melasma. Int J
Dermatol 2000; 39:299301.
84 Rendon M, Berneburg M, Arellano I, Picardo M. Treatment of
melasma. J Am Acad Dermatol 2006; 54(5 Suppl. 2):S27281.
85 Seiberg M, Paine C, Sharlow E et al. The protease-activated recep-
tor 2 regulates pigmentation via keratinocytemelanocyte interac-
tions. Exp Cell Res 2000; 254:2532.
86 Paine C, Sharlow E, Liebel F et al. An alternative approach to
depigmentation by soybean extracts via inhibition of the PAR-2
pathway. J Invest Dermatol 2001; 116:58795.
87 Hermanns JF, Petit L, Pierard-Franchimont C et al. Assessment of
topical hypopigmenting agents on solar lentigines of Asian
women. Dermatology 2002; 204:2816.
88 Chawla S, deLong MA, Visscher MO et al. Mechanism of tyrosi-
nase inhibition by deoxyArbutin and its second-generation deriv-
atives. Br J Dermatol 2008; 159:126774.
British Journal of Dermatology (2013) 169 (Suppl. 3), pp4156
56 Facial hyperpigmentation, N.A. Vashi and R.V. Kundu
89 Boissy RE, Visscher M, DeLong MA. DeoxyArbutin: a novel
reversible tyrosinase inhibitor with effective in vivo skin lightening
potency. Exp Dermatol 2005; 14:6018.
90 Hamed SH, Sriwiriyanont P, deLong MA et al. Comparative effi-
cacy and safety of deoxyarbutin, a new tyrosinase-inhibiting
agent. J Cosmet Sci 2006; 57:291308.
91 Greatens A, Hakozaki T, Koshoffer A et al. Effective inhibition of
melanosome transfer to keratinocytes by lectins and niacinamide
is reversible. Exp Dermatol 2005; 14:498508.
92 Hakozaki T, Minwalla L, Zhuang J et al. The effect of niacinamide
on reducing cutaneous pigmentation and suppression of melano-
some transfer. Br J Dermatol 2002; 147:2031.
93 Hakozaki T, Takiwaki H, Miyamoto K et al. Ultrasound enhanced
skin-lightening effect of vitamin C and niacinamide. Skin Res Tech-
nol 2006; 12:10513.
94 Bissett DL, Farmer T, McPhail S et al. Genomic expression changes
induced by topical N-acetyl glucosamine in skin equivalent cul-
tures in vitro. J Cosmet Dermatol 2007; 6:2328.
95 Kimball AB, Kaczvinsky JR, Li J et al. Reduction in the appearance
of facial hyperpigmentation after use of moisturizers with a com-
bination of topical niacinamide and N-acetyl glucosamine: results
of a randomized, double-blind, vehicle-controlled trial. Br J Der-
matol 2010; 162:43541.
96 Usuki A, Ohashi A, Sato H et al. The inhibitory effect of glycolic
acid and lactic acid on melanin synthesis in melanoma cells. Exp
Dermatol 2003; 12(Suppl. 2):4350.
97 Guevara IL, Pandya AG. Safety and efficacy of 4% hydroqui-
none combined with 10% glycolic acid, antioxidants, and sun-
screen in the treatment of melasma. Int J Dermatol 2003;
42:96672.
British Journal of Dermatology (2013) 169 (Suppl. 3), pp4156
98 Mauricio T, Karmon Y, Khaiat A. A randomized and placebo-con-
trolled study to compare the skin-lightening efficacy and safety of
lignin peroxidase cream vs. 2% hydroquinone cream. J Cosmet Der-
matol 2011; 10:2539.
99 Jimbow K. N-acetyl-4-S-cysteaminylphenol as a new type of de-
pigmenting agent for the melanoderma of patients with melasma.
Arch Dermatol 1991; 127:152834.
100 Kligman AM, Willis I. A new formula for depigmenting human
skin. Arch Dermatol 1975; 111:408.
101 Lynde CB, Kraft JN, Lynde CW. Topical treatments for melasma
and postinflammatory hyperpigmentation. Skin Therapy Lett 2006;
11:16.
102 Torok HM, Jones T, Rich P et al. Hydroquinone 4%, tretinoin
0.05%, fluocinolone acetonide 0.01%: a safe and efficacious 12-
month treatment for melasma. Cutis 2005; 75:5762.
103 Ferreira Cestari T, Hassun K, Sittart A, de Lourdes Viegas M. A
comparison of triple combination cream and hydroquinone 4%
cream for the treatment of moderate to severe facial melasma. J
Cosmet Dermatol 2007; 6:369.
104 Guevara IL, Pandya AG. Melasma treated with hydroquinone,
tretinoin, and a fluorinated steroid. Int J Dermatol 2001; 40:212
15.
105 Cestari T, Adjadj L, Hux M et al. Cost-effectiveness of a fixed
combination of hydroquinone/tretinoin/fluocinolone cream
compared with hydroquinone alone in the treatment of melasma.
J Drugs Dermatol 2007; 6:15360.
106 Kunachak S, Leelaudomlipi P, Wongwaisayawan S. Dermabrasion:
a curative treatment for melasma. Aesthetic Plast Surg 2001;
25:11417.
2013 The Authors
BJD 2013 British Association of Dermatologists