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CONTINUING

MEDICAL EDUCATION

Melasma: A comprehensive update


Part I
Vaneeta M. Sheth, MD,a and Amit G. Pandya, MDb
Boston, Massachusetts, and Dallas, Texas

CME INSTRUCTIONS
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
CME INFORMATION AND DISCLOSURES
Statement of Need:
The American Academy of Dermatology bases its CME activities on the
Academys core curriculum, identied professional practice gaps, the
educational needs which underlie these gaps, and emerging clinical research
ndings. Learners should reect upon clinical and scientic information
presented in the article and determine the need for further study.
Target Audience:
Dermatologists and others involved in the delivery of dermatologic care.
Accreditation
The American Academy of Dermatology is accredited by the
Accreditation Council for Continuing Medical Education to provide
continuing medical education for physicians.
AMA PRA Credit Designation
The American Academy of Dermatology designates this journal-based
CME activity for a maximum of 1 AMA PRA Category 1 Credits.
Physicians should claim only the credit commensurate with the extent of
their participation in the activity.
AAD Recognized Credit
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 Dermatologys Continuing
Medical Education Award.
Disclaimer:
The American Academy of Dermatology is not responsible for statements made by the author(s).
Statements or opinions expressed in this activity reect the views of the author(s) and do not reect
the ofcial 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 specic patients medical condition.

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 nancial 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 nancial
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 nancial relationships. The editorial and education staff involved with this journal-based CME activity have reported no relevant
nancial 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 mechanisms, prior to the planning and implementation of this Journal-based
CME activity, to identify and mitigate conicts 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
2010 by the American Academy of Dermatology, Inc.
doi:10.1016/j.jaad.2010.12.046

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.

689

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690 Sheth and Pandya

OCTOBER 2011

d Melasma predominantly affects Fitzpatrick


Melasma is a common disorder of hyperpigmenskin phototypes III and IV and often lasts for
tation that affects more than 5 million people in the
many years after pregnancy
United States alone.1 Found most commonly in
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 ransignificant negative impact on patients quality of
domly sampled the general population (Table I). In
life.2-6 The avoidance of exa randomized study involvacerbating factors such as UV
ing self-reporting of melasma
CAPSULE SUMMARY
light and hormonal contrain a Hispanic female populaceptives and testing for unMelasma is a common disorder of
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 underphotoprotection and avoidance of
prevalence has been relying basis for melasma may
trigger factors a critical part of
ported to be as high as 40%
be more complex than origmanagement.
in females and 20% in
inally thought. These findmales10; however, these
Recently identified pathogenic factors
ings also provide new
were patients presenting to
include stem cell factor and c-kit along
avenues for research into
a dermatology clinic, indicatwith neural and vascular growth factors.
better understanding and
ing some ascertainment bias.
treating this challenging
An increased understanding of the
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 hyfifth most commonly reperpigmentation appearing
ported skin condition, mentioned by 14.5% of peoas 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 delikely to have a positive family history of melasma.12
7
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 menomelasma comes from the Greek melas, meaning
pause. Importantly, only 8% noted spontaneous
black.
remission. Only 25% of patients taking oral contraceptives had an onset of melasma after starting their
contraceptive. While melasma was thought to be a
EPIDEMIOLOGY
pregnancy- and contraceptive-related disorder in the
Key points
past, recent studies show that in many patients it is a
d The reported prevalence of melasma ranges
chronic disorder that may last for decades. Although
from 8.8% among Latino females in the
common, there is much to learn about the epidemiSouthern United States to as high as 40% in
ology of melasma worldwide.
Southeast Asian populations
d

From the Departments of Dermatology at Brigham and Womens


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

CLINICAL AND PATHOLOGIC FEATURES


Key points
d

The centrofacial pattern of melasma is the


most common
While a Wood lamp examination was previously thought to accurately predict epidermal versus dermal pigment deposition,
recent studies have shown that dermal melanin deposition is common and may be
underrecognized

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Table I. Worldwide prevalence of melasma


Author

Location

Sample population

Werlinger et al9

Dallas/Fort Worth, TX

Sanchez37

New York, NY

Failmezger38
Parthasaradhi
and Al Gufai39
Sivayathorn10

Cuzco, Peru
Hail, Saudi Arabia

Random sample of
Latino women in the
general population
Latinos private clinic
Latinos Hospital clinic
Incas dermatology clinic
Dermatology clinic

Hiletework40
Tomb and Nassar41

Addis Ababa, Ethiopia


Beirut, Lebanon

Bangkok, Thailand

University dermatology
clinic
Dermatology clinic
Dermatology clinic

No. of patients
sampled

Percent of cases
with melasma

500

8.8%

1000
1000
1277
3298

8.2%
4.1%
10.1%
2.88%

679

33%

7760
6822 patients examined
over a 5-year period

1.8%
3.4%

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 forehead, 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 damage.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 characterized.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.
Few histopathologic studies have been performed
on melasma, but several recent publications have
provided new insight into its pathogenesis. A study by
Sanchez et al13 examined biopsy specimens of lesional skin. The authors found two basic patterns of
melasma: an epidermal form that featured melanin
deposition mainly in the basal and suprabasal layers

Fig 1. Melasma involving the cheek, showing inhomogeneous pigmentation.

and melanocytes that were highly dendritic and full of


pigment, and a dermal form with superficial and deep
perivascular melanophages in the dermis with noticeably less prominent epidermal pigmentation.
Electron microscopy revealed highly melanized stage

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692 Sheth and Pandya

OCTOBER 2011

Fig 2. Melasma of the cheek.

Fig 3. Melasma of the lateral 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 prominent epidermal hyperpigmentation on light microscopic examination. Expanding on this work, Grimes
et al17 studied patients with Fitzpatrick skin phototypes 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 melanocyte number, but the melanocytes themselves were
larger and had more prominent dendritic processes.
This last finding was confirmed with electron microscopy. 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

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 melanin 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; however, 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 apparent epidermal melasma.

ETIOPATHOGENESIS
Key points
d

The high incidence of melasma among family members suggests a genetic component

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Fig 4. Melasma of the cheek, temple, forehead, and upper


lip.
d

Sun exposure is a commonly reported exacerbating factor, likely because of the


UV-induced upregulation of melanocytestimulating cytokines
While melasma is known to occur with hormonal changes, clinical evidence to date
does not clearly associate serum hormone
levels to melasma
For women who note the onset of melasma
after beginning a course of an oral contraceptive, 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 exogenous hormones (ie, oral contraceptives and
hormone replacement therapy).1 A genetic predisposition 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 percent 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 keratinocytes, which in turn upregulate melanocyte
proliferation and melanogenesis. Examining the local expression of cytokines in lesional and perilesional 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 granulosum than in perilesional skin. There was, however,
no difference in the amount of melanocortin-1 receptor 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 worsening 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 immunohistochemical staining that lesional melasma skin
had increased estrogen receptor expression as compared to nearby normal skin. In addition, incubation
of melanocytes from normal skin with estradiol has
been found to increase the proliferation of melanocytes but downregulate tyrosinase activity and melanogenesis.23 A similar study found that melanocytes
from healthy skin increase in size and produce more
tyrosinase when incubated with MSH, ACTH, luteinizing hormone (LH), and follicle-stimulating hormone (FSH).25 Interestingly, estradiol, estriol, and
progesterone incubation led to increased cell proliferation, 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, phototoxicity, and antioxidants, may also be involved.
Perez et al26 examined the link between circulating 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 counterpart controls. The authors also found that there
was no difference in serum levels of beta MSH
(b-MSH), ACTH, FSH, progesterone, prolactin, thyroid 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, decreasing 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 cosmetics. While evaluating thyroid hormone levels in
female Argentinean patients with melasma, Lut
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 abnormalities 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 nonlesional 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 injected into human skin explants. A trial evaluating
breast cancer patients receiving subcutaneous injections of recombinant human stem cell factor found
that five out of 10 patients developed persistent
hyperpigmentation at the injection site.31 Light microscopy confirmed an increase in epidermal melanization 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

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keratinocytes expressing NGFR and more hypertrophic 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 component in its pathogenesis. Kim et al33 found that
biopsy specimens of lesional melasma skin had
greater vascular endothelial growth factor expression in keratinocytes compared to nearby nonlesional skin. Factor VIIIerelated antigen staining
showed that melasma skin had more numerous
and larger blood vessels compared to uninvolved
skin. Furthermore, using tristimulus colorimetry specifically measuring redegreen wavelengths, the authors found that involved skin had higher values for
this variable, implying that the clinical observation of
increased vascularity correlates with histopathologic
findings.
In summary, there appears to be a complex
interplay of hormonal and environmental factors
that predispose certain patients to developing melasma. The presence of local hormones in the skin
may play a greater role than originally thought.
While the exact link between hormones and melasma is not clear, it is recommended that patients
who develop melasma while taking an oral contraceptive 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 postinammatory hyperpigmentation, solar
lentigines, ephelides, drug-induced pigmentation
(Fig 6), actinic lichen planus, facial acanthosis
nigricans (Fig 7), frictional melanosis, acquired bilateral nevus of Otaelike macules (Horis nevus),
and nevus of Ota.34,35 These can sometimes coexist
in patients with melasma, making distinction important 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 inflammatory 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 evaluating the effectiveness of therapies. The Melasma
Area and Severity Index (MASI) was created by
Kimbrough-Green et al36 in an attempt to standardize the subjective evaluation of melasma. It is

Fig 6. Minocycline hyperpigmentation, a mimicker of


melasma.

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 performed. A numerical value for area of involvement,
ranging from 1 (\10% of the area involved) to 6 (90100% of the area involved) is assigned. The total
score is calculated as follows:
MASI 0:3A D1H 1 0:3A D1H 1 0:3A D1H
forehead

1 0:1A D1H

R malar

L malar

chin

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 populations have shown that even a small amount
of melasma can cause significant emotional
and psychological distress
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 translated into Spanish and Portuguese and thus far has
been shown to be readily adaptable to other cultures.3-6 In the Spanish version, patients with little to
no education were found to have higher scores,
indicating greater emotional and psychological burdens 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 environmental, hormonal, and cellular factors, and new
research has increased our understanding of this
diseasebut much work still needs to be done.
Additional studies to understand the genetic pathways that trigger melasma and to identify the roles of
cellular growth factors in the pathogenesis of melasma 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.
REFERENCES
1. Grimes PE. Melasma: etiologic and therapeutic considerations.
Arch Dermatol 1995;131:1453-7.
2. Balkrishnan R, McMichael AJ, Camacho FT, Saltzberg F, Housman TS, Grummer S, et al. Development and validation of a
health-related quality of life instrument for women with
melasma. Br J Dermatol 2003;149:572-7.
3. Cestari TF, Balkrishnan R, Weber MB, Prati C, Baratz
Menegon D, Gollo Mazzotti N, et al. Translation and cultural
adaptation to Portuguese of a quality of life questionnaire
for patients with melasma. Med Cutan Ibero Lat Am 2006;
34:270-4.
4. Cestari TF, Hexsel D, Viegas ML, Azulay L, Hassum K, Almeida
ART, et al. Validation of a melasma quality of life questionnaire
for Brazilian Portuguese language: the MelasQoL-BP study and
improvement of QoL of melasma patients after triple combination therapy. Br J Dermatol 2007;156(suppl 1):13-20.
5. Freitag FM, Cestari TF, Leopoldo LR, Paludo P, Boza JC. Effect
of melasma on quality of life in a sample of women living in
southern Brazil. J Eur Acad Dermatol Venereol 2008;22:
655-62.
6. Dominguez AR, Balkrishnan R, Ellzey AR, Pandya AG. Melasma
in Latina patients: cross-cultural adaptation and validation of a
quality-of-life questionnaire on Spanish language. J Am Acad
Dermatol 2006;55:59-66.
7. Baker H. Adverse cutaneous reaction to oral contraceptives. Br
J Dermatol 1969;81:946-9.
8. Patient UK web site. Chloasma. Available from http://www.
patient.co.uk/showdoc/40002152/. Accessed November 8,
2009.
9. Werlinger KD, Guevara IL, Gonzalez CM, Rincon ET, Caetano R,
Haley RW, et al. Prevalence of self-diagnosed melasma among
pre-menopausal Latino women in Dallas and Forth Worth, Tex.
Arch Dermatol 2007;143:424-5.
10. Sivayathorn A. Melasma in Orientals. Clin Drug Invest 1995;
10(suppl 2):34-40.
11. El-Assawi D, Musial JL, Hammad A, Lim HW. A survey of skin
disease and skin-related issues in Arab-Americans. J Am Acad
Dermatol 2007;56:933-8.
12. Ortonne JP, Arellano I, Berneburg M, Cestari T, Chan H, Grimes
P, et al. A global survey of the role of ultraviolet radiation and
hormonal influences in the development of melasma. J Eur
Acad Dermatol Venereol 2009;23:1254-62.
13. Sanchez NP, Pathak MA, Sato S. Melasma: a clinical, light
microscopic, ultrastructural, and immunofluorescence study.
J Am Acad Dermatol 1981;4:698-709.
14. Mandry-Pagan RM, Sanchez JL. Mandibular melasma. P R
Health Sci J 2000;19:231-4.
15. OBrien TJ, Dyall-Smith D, Hall AP. Melasma of the forearms.
Australas J Dermatol 1997;38:35-7.
16. Gilchrest BA, Fitzpatrick TB, Anderson RR, Parrish JA. Localization of melanin pigmentation in the skin with Woods lamp. Br
J Dermatol 1977;96:245-8.
17. Grimes PE, Yamada N, Bhawan J. Light microscopic, immunohistochemical, and ultrastructural alterations in patients with
melasma. Am J Dermatopathol 2005;27:96-101.

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18. Kang WH, Yoon KH, Lee ES, Kim J, Lee KB, Yim H, et al.
Melasma: histopathological characteristics in 56 Korean patients. Br J Dermatol 2002;146:228-37.
19. Moin A, Jabery Z, Fallah N. Prevalence and awareness of
melasma during pregnancy. Int J Dermatol 2006;45:285-8.
20. Goh CL, Dlova CN. A retrospective study on the clinical
presentation and treatment outcome of melasma in a tertiary
dermatological referral centre in Singapore. Singapore Med J
1999;40:455-8.
21. Vasquez M, Maldonado H, Benmaman C. Melasma in men. Int J
Dermatol 1988;27:25-7.
22. Im S, Kim J, On WY, Kang WH. Increased expression of
a-melanocyte-stimulating hormone in the lesional skin of
melasma. Br J Dermatol 2007;146:165-7.
23. Jee S-H, Lee S-Y, Chiu H-C, Chang C-C, Chen TJ. Effects of
estrogen and estrogen receptors in normal human melanocytes. Biochem Biophys Res 1994;199:1407-12.
24. Lieberman R, Moy L. Estrogen receptor expression in melasma:
results from facial skin of affected patients. J Drugs Dermatol
2008;7:463-5.
25. Maeda K, Naganuma M, Fukuda M, Matsunaga J, Tomita Y.
Effect of pituitary and ovarian hormones on human melanocytes in vitro. Pigment Cell Res 1996;9:204-12.
26. Perez M, Sanchez JL, Aguilo F. Endocrinologic profile of patients
with idiopathic melasma. J Invest Dermatol 1983;81:543-5.
27. Resnik S. Melasma induced by oral contraceptive drugs. JAMA
1967;199:601-5.
28. Lutfi RJ, Fridmanis M, Misiunas AL, Pafume O, Gonzalez EA,
Villemur JA, et al. Association of melasma with thyroid autoimmunity and other thyroidal abnormalities and their relationship
to the origin of melasma. J Clin Endocrinol Metab 1985;61:28-31.
29. Kang HY, Hwang JS, Lee JY, Ahn JH, Kim J-Y, Lee E-S, et al. The
dermal stem cell factor and c-kit are overexpressed in
melasma. Br J Dermatol 2006;154:1094-9.

30. Grichnik JM, Burch JA, Burchette J, Shea CR. The SCF/KIT
pathway plays a critical role in the control of normal human
melanocyte homeostasis. J Invest Dermatol 1998;111:233-8.
31. Costa JJ, Demetri GD, Harrist TJ, Dvorak AM, Hayes DF, Merica
EA, et al. Recombinant human stem cell factor (kit ligand)
promotes human mast cell and melanocyte hyperplasia and
functional activation in vivo. J Exp Med 1996;183:2681-6.
32. Bak H, Lee HJ, Chang S-E, Choi J-H, Kim MN, Kim BJ. Increased
expression of nerve growth factor receptor and neural endopeptidase in the lesional skin of melasma. Dermatol Surg 2009;
35:1244-50.
33. Kim EH, Kim YC, Lee E-S, Kang HY. The vascular characteristics
of melasma. J Derm Sci 2007;46:111-6.
34. Trout CR, Levine N, Chang MW. Disorders of hyperpigmentation. In: Bolognia JL, Jorizzo JL, Rapini RP, editors. Dermatology. New York: Mosby Elsevier Limited; 2003. pp. 975-6.
35. Pandya A, Berneburg M, Ortonne J-P, Picardo M. Guidelines for
clinical trials on melasma. Br J Dermatol 2007;156(suppl 1):
21-8.
36. Kimbrough-Green CK, Griffiths CEM, Finkel LJ, Hamilton TA,
Bulengo-Ransby SM, Ellis CN, et al. Topical retinoic acid
(tretinoin) for melasma in black patients. Arch Dermatol
1994;130:727-33.
37. Sanchez MR. Cutaneous disease in Latinos. Dermatol Clin
2003;21:689-97.
38. Failmezger C. Incidence of skin disease in Cuzco, Peru. Int J
Dermatol 1992;31:560-1.
39. Parthasaradhi A, Al Gufai AF. The pattern of skin disease in Hail
region, Saudi Arabia. Ann Saudi Med 1998;18:558-61.
40. Hiletework M. Skin diseases seen in Kazanchis health center.
Ethiop Med J 1998;36:245-54.
41. Tomb RR, Nassar JS. Profile of skin diseases observed in a
department of dermatology (1995-2000). J Med Liban 2000;48:
302-9.

Answers to CME examination


Identication No. JA1011
October 2011 issue of the Journal of the American Academy of Dermatology.

Questions 1 and 2, Sheth VM, Pandya AG. J Am Acad Dermatol 2011;65:689-97.

1. c
2. d