CONTINUING MEDICAL EDUCATION
Melasma: A comprehensive update
Part I
Vaneeta M. Sheth, MD,a and Amit G. Pandya, MDb
Boston, Massachusetts, and Dallas, Texas
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The following is a journal-based CME activity presented by the American
Academy of Dermatology and is made up of four phases:
1. Reading of the CME Information (delineated below)
2. Reading of the Source Article
3. Achievement of a 70% or higher on the online Case-based Post Test
4. Completion of the Journal CME Evaluation
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Statement of Need:
The American Academy of Dermatology bases its CME activities on the
Academy’s core curriculum, identified professional practice gaps, the
educational needs which underlie these gaps, and emerging clinical research
findings. Learners should reflect upon clinical and scientific information
presented in the article and determine the need for further study.
Target Audience:
Dermatologists and others involved in the delivery of dermatologic care.
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The American Academy of Dermatology is accredited by the
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continuing medical education for physicians.
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The American Academy of Dermatology designates this journal-based
CME activity for a maximum of 1 AMA PRA Category 1 CreditsÔ.
Physicians should claim only the credit commensurate with the extent of
their participation in the activity.
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This journal-based CME activity is recognized by the American Academy
of Dermatology for 1 AAD Recognized Category 1 CME Credits and may
be used toward the American Academy of Dermatology’s Continuing
Medical Education Award.
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The American Academy of Dermatology is not responsible for statements made by the author(s).
Statements or opinions expressed in this activity reflect the views of the author(s) and do not reflect
the official policy of the American Academy of Dermatology. The information provided in this CME
activity is for continuing education purposes only and is not meant to substitute for the independent
medical judgment of a healthcare provider relative to the diagnostic, management and treatment
options of a specific patient’s medical condition.
Melasma is a common disorder of hyperpigmentation affecting millions of people worldwide. While it is
thought to be triggered or exacerbated by sun exposure and hormones, much remains to be understood
about its pathogenesis. A thorough understanding of the etiology of melasma and the research tools
available to study this condition are crucial to enhancing management and developing novel targeted
therapies of this often frustrating condition. ( J Am Acad Dermatol 2011;65:689-97.)
Key Words: chemical peels; chloasma; hydroquinone; laser therapy; melasma; pigmentation.
Disclosures
Editors
The editors involved with this CME activity and all content validation/
peer reviewers of this journal-based CME activity have reported no
relevant financial relationships with commercial interest(s).
Authors
Dr. Pandya has been an investigator and consultant for Galderma
Laboratories within the last 5 years and has received grants and
honoraria for these services. Dr. Sheth reported no relevant financial
relationships with commercial interest(s).
Planners
Matthew Zirwas, MD, served as a peer reviewer for this CME activity and
is a speaker and consultant for Coria Laboratories and has received
honoraria for these services. He is also a consultant for Onset
Therapeutics and has received honorarium for this service. The other
planners involved with this journal-based CME activity have reported no
relevant financial relationships. The editorial and education staff in-
volved with this journal-based CME activity have reported no relevant
financial relationships with commercial interest(s).
Resolution of Conflicts of Interest
In accordance with the ACCME Standards for Commercial Support of
CME, the American Academy of Dermatology has implemented mech-
anisms, prior to the planning and implementation of this Journal-based
CME activity, to identify and mitigate conflicts of interest for all
individuals in a position to control the content of this Journal-based CME
activity.
Learning Objectives
After completing this learning activity, participants should be able to
describe the epidemiology of melasma; delineate the pathogenesis of
melasma; and describe the appropriate diagnostic workup of a patient
with suspected melasma.
Date of release: October 2011
Expiration date: October 2012
Ó 2010 by the American Academy of Dermatology, Inc.
doi:10.1016/j.jaad.2010.12.046
689
690 Sheth and Pandya J AM ACAD DERMATOL
OCTOBER 2011

Melasma is a common disorder of hyperpigmen- d Melasma predominantly affects Fitzpatrick

tation that affects more than 5 million people in the skin phototypes III and IV and often lasts for
United States alone.1 Found most commonly in many years after pregnancy
women with Fitzpatrick skin phototypes III through
Several studies from around the world have
V living in areas of intense ultraviolet (UV) light
attempted to discern the prevalence of melasma in
exposure, melasma is often difficult to treat and has a
the general population; however, few have ran-
significant negative impact on patients’ quality of
domly sampled the general population (Table I). In
life.2-6 The avoidance of ex-
a randomized study involv-
acerbating factors such as UV
light and hormonal contra- CAPSULE SUMMARY ing self-reporting of melasma
in a Hispanic female popula-
ceptives and testing for un-
Melasma is a common disorder of
d
tion in Texas, Werlinger et al9
derlying thyroid disorders
hyperpigmentation found in all parts of noted the prevalence to be
can lead to improvement in
the world that significantly affects 8.8%, with an additional 4%
certain subsets of patients.
quality of life; it is exacerbated by sun reporting melasma in the
Recent studies, however,
exposure and hormonal factors, making past. In Southeast Asia, the
have shown that the under-
photoprotection and avoidance of prevalence has been re-
lying basis for melasma may
trigger factors a critical part of ported to be as high as 40%
be more complex than orig-
management. in females and 20% in
inally thought. These find-
Recently identified pathogenic factors males10; however, these
ings also provide new d

include stem cell factor and c-kit along were patients presenting to
avenues for research into
with neural and vascular growth factors. a dermatology clinic, indicat-
better understanding and
ing some ascertainment bias.
treating this challenging An increased understanding of the
d
A survey of Arab Americans
condition. etiology of melasma will aid in the living in the United States
Melasma is an acquired development of novel therapies. found that melasma was the
disorder of symmetrical hy-
fifth most commonly re-
perpigmentation appearing
ported skin condition, mentioned by 14.5% of peo-
as light brown to dark, muddy brown macules
ple surveyed.11 A recent multicenter survey of
and patches on the face, especially the forehead,
females from nine countries found that Fitzpatrick
malar areas, and chin. It is also sometimes referred
skin phototypes III and IV were most commonly
to as chloasma or the mask of pregnancy, a term
affected, and that African Americans were more
used in the dermatology literature for several de-
7 likely to have a positive family history of melasma.12
cades. The term chloasma comes from the Greek
It was also noted that 41% of women surveyed had
chloazein, meaning to be green,8 whereas the term
onset of disease after pregnancy but before meno-
melasma comes from the Greek melas, meaning
pause. Importantly, only 8% noted spontaneous
black.
remission. Only 25% of patients taking oral contra-
ceptives had an onset of melasma after starting their
EPIDEMIOLOGY contraceptive. While melasma was thought to be a
Key points pregnancy- and contraceptive-related disorder in the
d The reported prevalence of melasma ranges past, recent studies show that in many patients it is a
from 8.8% among Latino females in the chronic disorder that may last for decades. Although
Southern United States to as high as 40% in common, there is much to learn about the epidemi-
Southeast Asian populations ology of melasma worldwide.

CLINICAL AND PATHOLOGIC FEATURES

From the Departments of Dermatology at Brigham and Women’s
Hospital,a Harvard Medical School, and the University of Texas
Southwestern Medical Center,b Dallas.
Funding sources: None.
Reprints not available from the authors.
Correspondence to: Amit G. Pandya, MD, Department of
Dermatology, The University of Texas Southwestern Medical
Center, 5323 Harry Hines Blvd, Dallas, TX 75390-9190. E-mail:
amit.pandya@utsouthwestern.edu.
0190-9622/$36.00
Key points
d The centrofacial pattern of melasma is the
most common
d While a Wood lamp examination was previ-
ously thought to accurately predict epider-
mal versus dermal pigment deposition,
recent studies have shown that dermal mel-
anin deposition is common and may be
underrecognized
J AM ACAD DERMATOL Sheth and Pandya 691
VOLUME 65, NUMBER 4

Table I. Worldwide prevalence of melasma

No. of patients Percent of cases
Author Location Sample population sampled with melasma
Werlinger et al9 Dallas/Fort Worth, TX Random sample of 500 8.8%
Latino women in the
general population
Sanchez37 New York, NY Latinos private clinic 1000 8.2%
Latinos Hospital clinic 1000 4.1%
Failmezger38 Cuzco, Peru Incas dermatology clinic 1277 10.1%
Parthasaradhi Hail, Saudi Arabia Dermatology clinic 3298 2.88%
and Al Gufai39
Sivayathorn10 Bangkok, Thailand University dermatology 679 33%
clinic
Hiletework40 Addis Ababa, Ethiopia Dermatology clinic 7760 1.8%
Tomb and Nassar41 Beirut, Lebanon Dermatology clinic 6822 patients examined 3.4%
over a 5-year period

d Melasma may be caused by the presence of

more biologically active melanocytes in the
affected skin, rather than an increase in
melanocytes
Several clinical patterns of melasma have been
described, but many patients have a mixture of these
patterns (Figs 1-5).13 The centrofacial pattern is the
most common and consists of lesions on the fore-
head, cheeks, nose, upper lip, or chin. The malar
pattern describes lesions located primarily on the
cheeks and nose. The mandibular pattern consists of
lesions on the ramus of the mandible. This latter
pattern may actually be a form of poikiloderma of
Civatte, because patients are often postmenopausal
and biopsy specimens reveal significant actinic dam-
age.14 Although melasma of the forearms has been
described, this entity is not always present in patients
with facial melasma and has not been well charac-
terized.15 Melasma can be further classified based on
a Wood lamp examination to help identify the
location of the pigment.16 Lesions that are enhanced
when viewed under a Wood lamp imply increased
epidermal melanin content, whereas those that are
not enhanced with a Wood lamp examination imply
an increase in dermal melanin content. Lesions that
have both enhancing and nonenhancing areas are
said to have a mixed pattern. Recent histologic
studies indicate that this construct may not be
accurate. Fig 1. Melasma involving the cheek, showing inhomoge-
Few histopathologic studies have been performed neous pigmentation.
on melasma, but several recent publications have
provided new insight into its pathogenesis. A study by and melanocytes that were highly dendritic and full of
Sanchez et al13 examined biopsy specimens of le- pigment, and a dermal form with superficial and deep
sional skin. The authors found two basic patterns of perivascular melanophages in the dermis with no-
melasma: an epidermal form that featured melanin ticeably less prominent epidermal pigmentation.
deposition mainly in the basal and suprabasal layers Electron microscopy revealed highly melanized stage
692 Sheth and Pandya
Fig 2. Melasma of the cheek.
IV melanocytes in lesional skin. Importantly, a Wood
lamp examination of lesional skin correlated with the
results of the biopsy; that is, patients who were judged
to have epidermal melasma clinically also had prom-
inent epidermal hyperpigmentation on light micro-
scopic examination. Expanding on this work, Grimes
et al17 studied patients with Fitzpatrick skin photo-
types IV through VI with epidermal and mixed
melasma by Wood lamp examination and examined
biopsy specimens both from lesional skin and nearby
normal-appearing skin.17 Unlike previous studies,
they found that despite a Wood lamp evaluation
indicating epidermal melasma in some patients, all
samples examined had increased melanin deposition
in the epidermis and dermis. They further used Mel-5
staining to show that there was no increase in mela-
nocyte number, but the melanocytes themselves were
larger and had more prominent dendritic processes.
This last finding was confirmed with electron micros-
copy. Therefore, patients with apparent epidermal
melasma after a Wood lamp examination may have
significant melanin in the dermis.
A similar study by Kang et al18 evaluated the
histopathologic characteristics of melasma skin
J AM ACAD DERMATOL
OCTOBER 2011
Fig 3. Melasma of the lateral cheek.
compared to nearby normal-appearing skin in
Asian patients, showing that melasma skin had
more severe solar elastosis, a greater number of
epidermal melanocytes, more dermal free melanin
and melanophages, and significantly increased mel-
anin in all layers of the epidermis. Interestingly, there
was no difference in the number of Langerhans cells,
appearance of the basement membrane, or collagen
between the involved and uninvolved areas; how-
ever, there was increased elastic fiber fragmentation
in the melasma skin. Furthermore, melanocytes in
melasma skin had more dendrites, mitochondria,
Golgi, and rough endoplasmic reticulum, suggesting
that they were more biologically active than their
counterparts in normal skin. The presence of dermal
melanin and melanophages in these studies may
explain the difficulty in treating patients with appar-
ent epidermal melasma.
ETIOPATHOGENESIS
Key points
d The high incidence of melasma among fam-
ily members suggests a genetic component
J AM ACAD DERMATOL
VOLUME 65, NUMBER 4
Fig 4. Melasma of the cheek, temple, forehead, and upper
lip.
d Sun exposure is a commonly reported exac-
erbating factor, likely because of the
UV-induced upregulation of melanocyte-
stimulating cytokines
d While melasma is known to occur with hor-
monal changes, clinical evidence to date
does not clearly associate serum hormone
levels to melasma
d For women who note the onset of melasma
after beginning a course of an oral contra-
ceptive, the medication should be stopped if
possible
While the exact underlying etiology for melasma
remains a mystery, several well known risk factors
exist. Melasma is more common in darker skin types,
particularly Fitzpatrick skin types III and IV. Other
reported risk factors include genetic predisposition,
exposure to ultraviolet light, pregnancy, and exog-
enous hormones (ie, oral contraceptives and
hormone replacement therapy).1 A genetic predis-
position is suggested by a high reported incidence in
family members in several studies. An Iranian survey
of pregnant women with melasma reported a 54.7%
Sheth and Pandya 693
Fig 5. Melasma predominantly involving the forehead
and mandible.
incidence of melasma in a family member.19 A similar
study from Singapore20 revealed a positive family
history of melasma in 10.2% of study subjects, and in
Latino men, Vasquez et al21 found a positive family
history in 70.4% of study subjects. Forty-eight per-
cent of 324 women in a global survey reported a
family history of melasma.12
UV light is a commonly reported initiating or
exacerbating factor for melasma, likely because of its
effects on melanocytes and on cytokine production.
Melasma occurs in sun-exposed areas, and many
patients report an increased severity of melasma with
sun exposure. One reason for this appears to be that
UV radiation induces melanocyte proliferation,
migration, and melanogenesis. In addition, UV
radiation can lead to the production of multiple
cytokines, including interleukin-1, endothelin-1,
alphaemelanocyte-stimulating hormone (a-MSH),
and adrenocorticotropic hormone (ACTH) from ke-
ratinocytes, which in turn upregulate melanocyte
proliferation and melanogenesis. Examining the lo-
cal expression of cytokines in lesional and perile-
sional skin from 10 Korean women, Im et al22 used
694 Sheth and Pandya
immunohistochemistry to show that a-MSH was
expressed to a greater degree in lesional melasma
skin in the stratum spinosum and stratum granulo-
sum than in perilesional skin. There was, however,
no difference in the amount of melanocortin-1 re-
ceptor or ACTH expression. These findings suggest
that sustained overexpression of MSH in lesional skin
after UV exposure may be a significant factor for the
development of melasma.
The hormonal link to melasma is not clearly
elucidated. Many patients note the onset or worsen-
ing of disease with pregnancy or oral contraceptive
use, and several studies have sought to clarify the
roles of particular hormones in the pathogenesis of
melasma. Melanocytes from healthy skin have been
shown to express both nuclear and cytosol estrogen
receptors.23 Lieberman et al24 revealed by immuno-
histochemical staining that lesional melasma skin
had increased estrogen receptor expression as com-
pared to nearby normal skin. In addition, incubation
of melanocytes from normal skin with estradiol has
been found to increase the proliferation of melano-
cytes but downregulate tyrosinase activity and mel-
anogenesis.23 A similar study found that melanocytes
from healthy skin increase in size and produce more
tyrosinase when incubated with MSH, ACTH, lutei-
nizing hormone (LH), and follicle-stimulating hor-
mone (FSH).25 Interestingly, estradiol, estriol, and
progesterone incubation led to increased cell prolif-
eration, but to a lesser degree, and did not increase
tyrosinase activity. It is still unclear why certain areas
of the face are predisposed to developing melasma
while others are not involved. Hormone receptors
and blood vessels may play a role, but other factors,
such as sebaceous gland density and activity, pho-
totoxicity, and antioxidants, may also be involved.
Perez et al26 examined the link between circulat-
ing levels of hormones and their relationship to
melasma. The authors found that nulligravid women
with melasma had significantly higher serum levels
of LH and lower levels of estradiol than their coun-
terpart controls. The authors also found that there
was no difference in serum levels of beta MSH
(b-MSH), ACTH, FSH, progesterone, prolactin, thy-
roid hormone, or cortisol between the two groups. In
summary, there is some evidence of a hormonal
component in the pathogenesis of melasma, but the
available data are conflicting, possibly because of the
varied genetic backgrounds of the different study
populations. Further research into the effects of
hormones on melasma is needed.
While the exact link between hormones and
melasma remains unclear, several studies have noted
the onset of melasma with oral contraceptive use. In
1967, Resnick27 studied the records of 212 female
J AM ACAD DERMATOL
OCTOBER 2011
patients in an obstetrics and gynecology clinic and
noted that 29% of patient being followed developed
melasma as a direct result of oral contraceptive use.27
Of these patients, 87% also developed melasma
during pregnancy. In this cohort of women, decreas-
ing the estrogen component of the oral contraceptive
pill did not affect incidence of melasma. In more
recent work by Ortonne et al,12 of 324 women being
treated for melasma in dermatology clinics in several
countries, 25% reported the initial onset of melasma
with oral contraceptive use. The rates were higher in
patients without a positive family history of melasma.
Therefore, while the exact link between hormones
and melasma has yet to be clearly defined, it is
recommended that patients who develop melasma
while taking an oral contraceptive pill should stop
the medication and avoid the future use of such
drugs when possible.
Other less commonly reported risk factors include
thyroid disorders, phototoxic medications, and cos-
metics. While evaluating thyroid hormone levels in
female Argentinean patients with melasma, Lutfi
et al28 found that women who developed melasma
during pregnancy or while taking oral contraceptives
had a 70% incidence of mild thyroid abnormalities
compared to 39% of those with idiopathic melasma.
In addition, patients with melasma from any etiology
were four times more likely to have thyroid abnor-
malities than age- and sex-matched controls. These
findings suggest that thyroid disorders are related to
melasma, particularly in those with pregnancy- or
oral contraceptiveeassociated melasma, but this
needs to be confirmed in larger studies.
Several new papers have shed some light on the
role of stem cell factor in the pathogenesis of
melasma. Examining samples of lesional and nonle-
sional skin, Kang et al29 found that lesional melasma
skin had a greater expression of stem cell factor
around dermal fibroblasts and a greater expression
of c-kit in the basal layer of the epidermis. Grichnik
et al30 revealed that stem cell factor can increase
melanocyte number, size, and dendricity when in-
jected into human skin explants. A trial evaluating
breast cancer patients receiving subcutaneous injec-
tions of recombinant human stem cell factor found
that five out of 10 patients developed persistent
hyperpigmentation at the injection site.31 Light mi-
croscopy confirmed an increase in epidermal mela-
nization and numbers of melanocytes.
Recent studies have also examined the possibility
of a neural component to melasma. Bak et al32
obtained biopsy specimens of both lesional and
adjacent nonlesional skin in six Asian females with
melasma. Staining for nerve growth factor receptor
(NGFR) revealed increased numbers of
J AM ACAD DERMATOL Sheth and Pandya 695
VOLUME 65, NUMBER 4

keratinocytes expressing NGFR and more hypertro-

phic nerve fibers in the superficial dermis of lesional
compared to nonlesional skin. While intriguing, the
small sample size limits the generalizability of these
results.
Finally, melasma may also have a vascular com-
ponent in its pathogenesis. Kim et al33 found that
biopsy specimens of lesional melasma skin had
greater vascular endothelial growth factor expres-
sion in keratinocytes compared to nearby nonle-
sional skin. Factor VIIIerelated antigen staining
showed that melasma skin had more numerous
and larger blood vessels compared to uninvolved
skin. Furthermore, using tristimulus colorimetry spe-
cifically measuring redegreen wavelengths, the au-
thors found that involved skin had higher values for
this variable, implying that the clinical observation of Fig 6. Minocycline hyperpigmentation, a mimicker of
increased vascularity correlates with histopathologic melasma.
findings.
In summary, there appears to be a complex
interplay of hormonal and environmental factors
that predispose certain patients to developing me-
lasma. The presence of local hormones in the skin
may play a greater role than originally thought.
While the exact link between hormones and me-
lasma is not clear, it is recommended that patients
who develop melasma while taking an oral contra-
ceptive should stop the medication when possible.
Additional work in this area is needed to help
elucidate the underlying pathogenesis of this
condition.

Differential diagnosis
Disorders that can be confused for melasma
include postinflammatory hyperpigmentation, solar
lentigines, ephelides, drug-induced pigmentation
(Fig 6), actinic lichen planus, facial acanthosis
nigricans (Fig 7), frictional melanosis, acquired bi-
lateral nevus of Otaelike macules (Hori’s nevus),
and nevus of Ota.34,35 These can sometimes coexist
in patients with melasma, making distinction impor-
tant when devising treatment plans or enrolling
patients for clinical trials. A careful medial history,
an examination of the skin including a Wood lamp
examination, the recognition of concomitant inflam-
matory disorders, and a skin biopsy specimen are all
helpful in making the correct diagnosis.
Studying melasma: The Melasma Area and
Severity Index
Good outcome measures are important in evalu-
ating the effectiveness of therapies. The Melasma
Area and Severity Index (MASI) was created by
Kimbrough-Green et al36 in an attempt to standard-
ize the subjective evaluation of melasma. It is
Fig 7. Acanthosis nigricans mimicking melasma.
calculated by dividing the face into four areas: the
forehead, right malar area, left malar area, and
chin.36 Each area is weighted such that the forehead,
right malar area, and left malar area are 30% each,
and the chin is 10%. Scoring for darkness of pigment
when compared with normal skin and homogeneity
of the pigment in the specified area is then per-
formed. A numerical value for area of involvement,
ranging from 1 (\10% of the area involved) to 6 (90-
100% of the area involved) is assigned. The total
score is calculated as follows:
MASI ¼ 0:3A ðD1HÞ 1 0:3A ðD1HÞ 1 0:3A ðD1HÞ
½forehead ½R malar ½L malar
1 0:1A ðD1HÞ
½chin
The range of scores is 0 to 48. The MASI score is
the most commonly used measurement technique
696 Sheth and Pandya
for the study of melasma; however, validation and
reliability testing of this index has not yet been
reported.
QUALITY OF LIFE STUDIES: MEASURING
THE IMPACT OF MELASMA
Key points
d Validated questionnaires in several popula-
tions have shown that even a small amount
of melasma can cause significant emotional
and psychological distress
d Patients with lower levels of education or
underlying psychiatric disorders may be at
greater risk of emotional impairment
Melasma is often psychologically distressing in
affected patients. The most commonly used tool for
assessment of quality of life in patients with melasma
is the MelasQoL.2 This questionnaire was developed
by modifying items from the SKINDEX-16 and skin
discoloration questionnaire. By surveying 102
women with melasma, the authors found that the
areas most impacted by the disease were social life,
recreation/leisure, and emotional well being. These
results correlated well with results from the
SKINDEX-16 and the Dermatology Life Quality
Index (DLQI) questionnaires, validating the
MelasQoL. Interestingly, the effect of melasma on
quality of life was not correlated with the severity of
melasma, suggesting that even a small amount of
pigmentation can take a significant emotional toll.
The benefit of the MelasQoL is that it does not weigh
physical and psychological distress equally, which is
important for disorders of pigmentation, which lack
scaling, pruritus, pain, and other types of physical
impairment. This questionnaire has since been trans-
lated into Spanish and Portuguese and thus far has
been shown to be readily adaptable to other cul-
tures.3-6 In the Spanish version, patients with little to
no education were found to have higher scores,
indicating greater emotional and psychological bur-
dens of disease in this subset of patients, while the
Portuguese study found higher scores in patients
with underlying psychiatric disorders. It is clear that
melasma significantly affects quality of life, and its
effect on a particular patient may be profound.
Melasma involves a complex interaction of envi-
ronmental, hormonal, and cellular factors, and new
research has increased our understanding of this
disease—but much work still needs to be done.
Additional studies to understand the genetic path-
ways that trigger melasma and to identify the roles of
cellular growth factors in the pathogenesis of me-
lasma are needed, because these may serve as new
targets for therapy. In addition, the role of hormones
J AM ACAD DERMATOL
OCTOBER 2011
in initiating or exacerbating melasma still needs to be
better clarified. Given the impact that this condition
has on patients’ quality of life and the lack of highly
effective treatment options, additional research into
understanding the biologic basis of this disease will
be crucial to developing more effective treatment
options.
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