Artigo Melasma

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Received: 20 January 2022 | Revised: 26 June 2022 | Accepted: 29 June 2022
DOI: 10.1002/der2.144
I N V I T ED R EV I EW
Differential diagnosis of melasma and hyperpigmentation
Anthony Honigman1 | Michelle Rodrigues2,3
1Dermatology Department, The Royal
Melbourne Hospital, Melbourne, Australia
2Chroma Dermatology, Pigment and Skin of
Colour Centre, Victoria, Australia
3Department of Dermatology and Department
of Paediatrics, Royal Children's Hospital,
Melbourne University, Melbourne, Victoria,
Australia
Correspondence
Michelle Rodrigues, Ground Floor, suite
15/202 Jells Rd, Victoria 3150, Australia.
Email: dr.rodrigues@gmail.com
Abstract
Background: Melasma is a common disorder of acquired hyperpigmentation
affecting millions of people worldwide, predominantly women. Despite the
incidence, there are numerous hyperpigmentary conditions which may clinically
resemble melasma. The differential diagnosis of melasma is therefore wide and may
prove to be a diagnostic challenge for clinicians. This can delay the appropriate
treatment, adversely impacting sufferers. Our review aims to provide clinicians with
an understanding of and a comprehensive approach to assessing, diagnosing and
treating melasma and other disorders of hyperpigmentation.
K E YWORD S
hyperpigmentation, melanogenesis, melasma, pigmentary disorders
1 | INTRODUCTION
Melasma is an acquired hyperpigmentation disorder and is charac-
terized by light‐to‐dark brown‐colored irregular macules or patches
on sun‐exposed areas of skin, usually the face.1 It is the most
common cause of facial pigmentation and is a cutaneous disorder
affecting all races with particular prominence in darker‐skinned
individuals.2 Despite being a common condition with strong
therapeutic demand, diagnosis may prove challenging for physi-
cians as there are numerous conditions that can present similarly
to melasma. It is, thus, imperative for dermatologists to
appreciate and consider common differential diagnoses when
assessing patients with melasma.
2 | MELASMA
Melasma is an acquired hyperpigmentation disorder that is seen
most typically on the face. It is a common disorder of
hyperpigmentation affecting millions worldwide and predomi-
nantly affecting women (90% of cases) and those with Fitzpatrick
skin type III and IV.2
2.1 | Presentations and clinical classifications
Melasma presents clinically as brown macules or patches and is
generally a clinical diagnosis. It is classified by both location and
depth of involvement.
2.1.1 | Location
There are three types of melasma as classified clinically according to
their facial distribution, and these include centrofacial, malar, and
mandibular patterns (see Table 1).3,4 The most common clinical
pattern (in 50%–80% of cases) is the centrofacial pattern, where lesions
are predominant in the center of the face – affecting the forehead,
cheeks, nose, upper lip, or chin (Figure 1A). The malar pattern is restricted
to the malar cheeks on the face and can include the nose (Figure 1B),
while mandibular melasma is present on the ramus of the mandible
(jawline) and may include the chin.5,6 The mandibular pattern of melasma
tends to be noted in postmenopausal women.4,7
Variants of melasma have been reported on other sun‐exposed
areas of the body, and a newer classification termed “extra‐facial”
melasma has emerged. This classification pattern encompasses
Dermatological Reviews. 2022;1–8. wileyonlinelibrary.com/journal/der2 | 1
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http://orcid.org/0000-0002-4872-6340
http://orcid.org/0000-0002-9747-1882
mailto:dr.rodrigues@gmail.com
https://wileyonlinelibrary.com/journal/der2
nonfacial body parts, including the forearms.3 This new variant
manifests itself as hyperchromic, irregular, symmetrical skin dyspig-
mentation mainly occurring in older, menopaused women and is more
common in those who have hormone replacement therapy.4,8,9T
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F IGURE 1 (A) Hyperpigmented macules of melasma in a
centrofacial distribution (forehead, cheeks, upper lips, nose, and chin).
Image Source: Dr. Michelle Rodrigues, Chroma Dermatology.
(B) Melasma is a malar pattern over the cheeks and upper lip region.
Image source: Dr. Michelle Rodrigues, Chroma Dermatology.
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2.1.2 | Depth
Melasma can be further characterized depending on the depth of
pigment deposition and divided into three histological types:
epidermal, dermal, and mixed. Epidermal melasma is the most
common form and is characterized by pigment deposition throughout
the layers of the epidermis, particularly in the basal and suprabasal
layers, and occasionally extending throughout the entire epidermis.
Melanocytes in the epidermis are generally enlarged, have prominent
dendrites, and increased melanosomes. Dermal melasma shows
pigment deposition throughout the epidermis and the upper and
middle layers of the dermis, occasionally involving the deep dermis.
Mixed‐type melasma has a combination of both dermal and
epidermal pigmentation.10,11
2.2 | Diagnosis and histology
2.2.1 | Wood's lamp examination
Wood's lamp examination can be used to assist with or confirm a
melasma diagnosis in lighter skin types. Epidermal melasma tends to
accentuate under Wood's lamp examination, which may help
distinguish epidermal and dermal subtypes. In epidermal melasma,
the light is absorbed by the excess melanin in the basal and
suprabasal regions. Melasma that does not accentuate in color under
Wood's light is likely to be dermal in location. Lesions that have both
enhancing and nonenhancing areas are said to have a mixed pattern.
One report found that despite a Wood's lamp examination
indicating epidermal melasma in some patients, all samples examined
had increased melanin deposition in the epidermis and dermis. This
study showed that patients with apparent epidermal melasma on
Wood light examination may have significant melanin in the dermis
suggesting most cases are thus mixed melasma.10,12
2.2.2 | Dermoscopy
On dermoscopic examination, it is possible to see pronounced
hyperpigmentation in the pseudoridges of the skin.13The color
intensity of melanin and the regularity of the pigment network reveal
the density and location of the melanin. It presents as a dark brown,
well‐defined network when located in the stratum corneum and as a
light brown, irregular network when located in the lower epidermal
layers. Melanin will appear a blue or bluish‐gray color when located in
the dermis.8
2.2.3 | Histopathology
Occasionally, a skin biopsy with histopathological examination is
needed to confirm the diagnosis. Melasma is characterized histologically
by epidermal hyperpigmentation. The number of melanocytes is not
increased, but rather hypertrophied – showing a greater number of
dendritic cells and cytoplasmic organelles, indicating higher metabolic
activity. There is an increased amount of melanin and mature
melanosomes in all layers of the epidermis. In the dermis, there is a
moderate mononuclear infiltrate with melanin‐laden macrophages, the
presence of mast cells, increased vascularity, and elastosis.8
2.2.4 | Reflectance confocal microscopy
Reflectance confocal microscopy (RCM) has also been used to
evaluate pigmentary changes in melasma on a cellular level, in vivo. It
enables real‐time visualization from the epidermis down to the
papillary dermis and can identify histological changes associated with
melasma in a direct and noninvasive way. RCM's resolution is almost
comparable to conventional histology and is analogous to a “virtual
biopsy.”12 At the level of the epidermis, there is an increase in
hyperrefractile cobblestoning cells corresponding to hyperpigmented
basal keratinocytes on histology. In some patients, epidermal
dendritic cells can also be found corresponding to activated
melanocytes. At the dermal level, RCM shows plump bright cells
corresponding to melanophages as well as solar elastosis and blood.14
3 | DIFFERENTIAL DIAGNOSIS
3.1 | Melanocytic lesions
3.1.1 | Ephelides and solar lentigines
Both ephelides and solar lentigines almost always occur as a result of
ultraviolet exposure.
Ephelides, commonly known as freckles, are 1–3mm well‐
demarcated, hyperpigmented macules that are round, oval, or
irregular in shape (Table 2). They are a result of increased
photoinduced melanogenesis and transportation of melanosomes
from melanocytes to keratinocytes.2 These benign lesions show no
propensity for malignant transformation despite occurring on sun‐
exposed areas of skin including the face, dorsal hands, and upper
trunk.15 Large numbers of these lesions may confluence but can also
fade with time with aging.
Solar lentigines are characterized by well‐demarcated hyperpig-
mented round or oval macules also presenting in sun‐exposed areas.
They can occur at any age and are often found in those with
Fitzpatrick skin types I–III. These lesions are found in approximately
90% of the Caucasian population over 60 years of age and this
incidence increases with advancing age.16,17
3.1.2 | Café‐au‐lait macules
Café‐au‐lait macules (CALMs) are common pigmented lesions found
in 10%–30% of the general population and may appear at birth or
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early in life (Table 2). They are asymptomatic and present as light‐to‐
dark brown well‐circumscribed, pigmented macules or patches
usually greater than 20mm in size and often located on the trunk.
They are epidermal in origin, representing an increase in melanin in
melanocytes and basal keratinocytes. Multiple CALMs are often
associated with genetic syndromes, with more than six CALMs (5mm
or larger, prepubertal; 15 mm or larger postpubertal) raising suspicion
for disorders such as neurofibromatosis (most commonly NF1),
tuberous sclerosis, Albright syndrome, Legius syndrome, or Fanconi
anemia.18 CALMs are diagnosed clinically and a skin biopsy is usually
not required to confirm the diagnosis.
3.2 | Postinflammatory hyperpigmentation
Postinflammatory hyperpigmentation (PIH) is skin darkening occur-
ring after cutaneous injury or inflammation that arises in all skin
types (Table 2), but more frequently affects the skin of color
patients (Fitzpatrick skin type IV–VI). Often, as the skin in darker
patients recovers from an acute inflammatory cutaneous disease
or injury, it may become hyperpigmented or hypopigmented
(postinflammatory hypopigmentation). PIH can occur in both the
epidermis and dermis and is a result of melanocytes responding to
a cutaneous insult which causes increased production and irregular
redistribution of melanin.2,19
The location of excess pigment within the layers of the skin will
determine its color. Epidermal hypermelanosis will appear tan, brown, or
dark brown and may take months to years to resolve without
treatment.1 Hyperpigmentation within the dermis has a blue–gray
appearance and may either be permanent or resolve over a protracted
period of time if left untreated.19,20 PIH should be considered when
patients provide a history of any type of inflammation or injury before
its onset, for example, acne, eczema, psoriasis, or trauma. Patients will
often present with hyperpigmented macules and patches of varying size
in the same distribution as the initial inflammatory process. Although
usually a clinical diagnosis, more difficult cases can be aided with a
biopsy for histopathological evaluation.
3.3 | Drug‐induced hyperpigmentation
A number of different medications have been associated with skin
pigmentation, including neurological medications (chlorpromazine,
amitriptyline), cytotoxic agents (bleomycin, anthracycline), analgesics,
anticoagulants, antimicrobials (chloroquine, minocycline), antiretro-
virals, metals, and antiarrhythmics (amiodarone).21
Drug‐induced hyperpigmentation can occur at any age and often
presents as a slate‐gray coloration affecting the face and other areas
of the body.1 Melasma typically lacks this deep, slate‐gray appear-
ance and does not commonly involve other body sites (upper limbs,
TABLE 2 Summary of common pigmentation disorders
Disorder Clinical appearance Location of the lesion(s) Age of onset
Melasma Symmetric, light to dark brown patches Centrofacial 20–40 years
Solar lentigines Well‐demarcated tan to dark brown)
round/oval macules
Sun exposed sites Any age
Ephelides Well‐demarcated, sharply defined macules Sun exposed sites Typically childhood
Café‐au‐lait maculesa Tan to brown patches Commonly on trunk Birth or early
childhood
Post‐inflammatory
hyperpigmentation
Hyperpigmentation ± erythema and/or scaling Any site Any age
Drug‐induced
hyperpigmentation
Greyish hyperpigmentation Face ± involvement of other special sites Any age
Exogenous ochronosis Blue–black confluent hyperpigmentation Sites of hydroquinone application Any age
Acquired dermal macular
hyperpigmentation
(ADMH)
Gray–brown to brown macules and patches Mainly the face but may occur on the trunk Middle age (typically
over 30 years
of age)
Acanthosis nigricansa Symmetric, hyperpigmented, velvety plaques Intertriginous areas – neck, groin, and axillae Usually less than
40 years of age
Dermatosis papulosis
nigra (DPN)
Pigmented papules Bilateral malar eminences and forehead During adolescence
Nevus of Otaa Blue–gray confluence of individual macules Distribution of the first two branches of the
trigeminal nerve
Infancy or puberty
Hori's nevus Blue–gray to gray–brown macules Bilateral zygomatic areas 20–70 years
aEntities with possible systemic involvement.
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shins, scar sites) assisting clinicians in their diagnosis (Table 2).
Pathophysiology of medication‐induced pigmentation occurs through
several different mechanisms depending on the drug itself. Some
medications trigger an accumulation of melanin (antimalarials) which
is often found to be worse in sun‐exposed areas, while other
medications accumulate within dermal macrophages and cause
pigmentation itself. Some medications cause the synthesis of new
pigment (lipofuscin) or the accumulation of iron and lysis of red blood
cells (minocycline).21,22 Diagnosing drug‐induced hyperpigmentation
can prove difficult and clinicians should be vigilant in examining a
patient's complete medical history to determine the specific culprit
and rule out other conditions that may be leading to skin findings.
3.4 | Exogenous ochronosis
Exogenous ochronosis (EO) is a rare, blue–black pigmentation of the
face, lateral and posterior neck, and extensor surfaces and is caused by
the deposition of microscopic ocher‐colored pigment in the dermis
(Table 2). The term ochronosis is derived from the word “ocher” in Greek
language, which refers to yellow discoloration.23 The etiology of EO is not
fully understood; however, it has been linked with the use of skin‐care
products containing hydroquinone, resorcinol, phenol, mercury, and picric
acid as well as unprotected prolonged sun exposure.2,23,24
It is thought that hyperpigmentation associated with EO is due to
local competitive inhibition of the enzyme homogentisic oxidase by
hydroquinone, which leads to local accumulation of homogentisic
acid and its metabolic products that polymerizes to form the typical
“ochronotic” pigment in the papillary dermis.23,25 EO is clinically and
histologically similar to its endogenous counterpart – endogenous
ochronosis, also known as alkaptonuria, although it does not exhibit
systemic effects and is not an inherited disorder.
Clinically, it manifests as hyperpigmentation in photoexposed
regions, often affecting the zygomatic regions in a symmetrical
pattern. The lesions are typically blue–black macules usually
with pinpoint and caviar‐like papules23,26 and are often confused
with melasma, PIH, and Riehl's melanosis. Diagnosis is confirmed on
histology, which remains the gold standard of EO diagnosis.
The pathognomic histopathological feature is the presence of
ocher‐colored, banana‐shaped fibers within the dermis.23
3.5 | Acanthosis nigricans
Acanthosis nigricans is characterized by velvety hyperpigmented
macules and patches that progress to symmetrical palpable plaques
(Figure 2). Although most commonly appearing in intertriginous areas of
the body, including the axilla, groin, and neck, acanthosis nigricans can
occur in almost any anatomical location including the face (Table 2).27
Acanthosis nigricans typically occurs in individuals younger than 40
years of age and is associated with obesity, hypothyroidism, acromegaly,
polycystic ovary disease, insulin‐resistant diabetes, Cushing's disease, and
Addison disease. Familial acanthosis nigricans arises as a result of an
autosomal dominant trait due to mutations in fibroblast growth factor
receptor 3.28 Malignant acanthosis nigricans is associated with gastro-
intestinal adenocarcinomas and genitourinary cancer such as prostate,
breast, and ovarian. This subtype of acanthosis nigricans is typically rapid
in onset and may precede, accompany or follow the onset of internal
malignancy.29 Multiple medications have also been linked to acanthosis
nigricans, these include nicotinic acid, systemic glucocorticoids, diethyl-
stilboestrol, combined oral contraceptive pill, estrogen, growth hormone
therapy, protease inhibitors, niacin, and injected insulin.7,30,31 The
pathogenesis of acanthosis nigricans is thought to be related to growth
factor levels and insulin‐mediated activation of insulin‐like growth factors
on keratinocytes and increased growth factor levels. This activation
triggers the proliferation of fibroblasts and the enhanced stimulation of
epidermal keratinocytes.32 In patients with malignant acanthosis nigricans,
the most probable stimulating factors are secreted by cancer cells – likely
transforming growth factor or epidermal growth factor, as both levels are
high in those with gastric adenocarcinoma. Histology reveals papilloma-
tosis, hyperkeratosis with minimal hyperpigmentation. There is thinning of
the epidermis and an upward projection of the dermal papillae.27
3.6 | Dermatosis papulosis nigra
Dermatosis papulose nigra (DPN) is a benign epidermal growth that
presents as hyperpigmented or skin‐colored papules that develop on
the face and neck.
The lesions initially resemble freckles but may gradually become
papular and increase in both size and number with age. The lesions
range in size from 1 to 5mm and commonly appear symmetrically on
the malar cheeks, temples, and forehead (Table 2).
Although it is seen in other races, it is a common manifestation
diagnosed primarily in African–American, Afro‐Caribbean, sub‐Saharan
African, and Asian patients. The reported incidences in these populations
F IGURE 2 Acanthosis nigricans on the malar region of a male of
Sri Lankan background. Image source: Dr. Michelle Rodrigues,
Chroma Dermatology.
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and others of individuals with darker pigmentation range from 10% to
75%.33 DPN affects women twice as much as men and studies have
shown that patients with the condition reported positive family histories
in 77%–93% of cases.34
The cause of DPN is unknown but is considered a variant of
seborrheic keratoses, despite it being considered a clinically and
histologically distinct entity.35 On histology, DPN is characterized by
acanthosis, papillomatosis, and hyperkeratosis of the epidermis.
There are elongated and interconnected rete ridges with deposits
of pigment in the basal layer. Prominent fibrous stroma is seen within
papillomatous acanthotic structures.
3.7 | Nevus of Ota and Hori nevus
Nevus of Ota, also known as ocular dermal melanosis, is usually
benign melanosis that occurs predominantly in people of color,
especially in Asian and black populations (Table 2). It is primarily a
clinical diagnosis; however, there is an increased risk of glaucoma and
uveal melanoma with the disease (10% and 1 in 400, respectively).36
Nevus of Ota is characterized by blueish hyperpigmentation along
the ophthalmic and maxillary divisions (V1 and V2) of the trigeminal
nerve. Typical morphology consists of a confluence of individual
macules of varying sizes. Approximately two‐thirds of patients
present with the characteristic feature of ipsilateral scleral involve-
ment. A complete ophthalmic examination should be performed to
rule out choroidal melanoma or glaucoma.
The exact etiology is unknown but genetic factors such as BRAF
and NRAS mutations, or migration of melanoblasts during embry-
ogenesis have been postulated.36 Histopathology shows numerous
pigmented melanocytes in the dermis which are either dendritic in
shape or spindle‐shaped.
Hori's naevi, also known as acquired bilateral nevus of Ota‐like
macules are a common dermal melanocytic hyperpigmentation, primarily
found on the cheeks of Chinese and Japanese women from 20 to 70
years of age. Clinically it is characterized by a benign blue–gray to
gray–brown patch and spotty pigmentation in the zygomatic region
bilaterally. It can also affect the forehead, temples,upper eyelids, and
nasal alar.2 Unlike the nevus of Ota, Hori naevi have no associated ocular
involvement. Similar to the nevus of Ota, Hori naevi fits under the
spectrum of conditions caused by dermal melanocytosis with the exact
etiology not fully understood, although it is thought both hormonal and
genetic factors play a role.12 The diagnosis is made clinically with
histopathology revealing melanocytes in the mid and upper dermis, with
no fibrosis or alteration of normal dermal structure. These melanocytes
are surrounded by an extracellular sheath whose thickness increases over
time, leading to lesion stability.12
3.8 | Acquired dermal macular hyperpigmentation
Acquired dermal macular hyperpigmentation (ADMH) is a relatively
new umbrella term that encompasses four previously described
conditions, with overlapping clinical and histological features – Riehl's
melanosis, pigmented contact dermatitis, lichen planus pigmentosus
(Figure 3), and erythema dyschromicum perstans (ashy dermatosis).37
ADMH can present at any age, but typically occurs over the third
decade of life and is of female preponderance. Asian, Middle‐Eastern,
and Latin American women are most frequently affected (Table 2).37
Pathogenesis may vary depending on the underlying condition.
Contact senitization from cosmetic products and optical whiteners,
such as fragrances, certain pigments and bactericides (carbanilides,
ricnoleic acid),38 amla and mustard oil, sunlight,2,39,40 and medications
(ethambutol, penicillins, benzodiazepines) have all been implicated in
this group of acquired hyperpigmentary conditions.41,42
The diagnosis of ADMH and its subtypes are based on cutaneous
features and detailed history. Unlike melasma, it may be seen on the
eyelids and earlobes.
Dermoscopically, the predominant features of ADMH include
pigment dots, globules and blotches, which can be distinguished from
the pseudo‐reticular network seen melasma. Other dermoscopic
features include owl‐eye‐like structures consisting of a central brown
dot surrounded by a hyperpigmented halo.43 The single unifying
histological feature of ADMH is current or resolved interface
dermatitis with pigment incontinence, without any clinically evident
prior inflammatory lesions.37,44
4 | CONCLUSION
Melasma and other causes of facial hyperpigmentation affect millions
of people worldwide. Often these conditions may prove difficult to
differentiate and diagnose, which can delay correct and timely
management. This may lead to disease progression, incorrect
treatment, and worsening of the condition. Furthermore, these
F IGURE 3 Lichen planus pigmentosus (LPP) of the face of a lady
of Indian background. LPP is now encompassed by the term acquired
dermal macular hyperpigmentation. Image source: Dr. Michelle
Rodrigues, Chroma Dermatology.
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conditions often negatively impact physical and emotional wellbeing.
Therefore, clinicians must have comprehensive knowledge and a
systematic approach to melasma and its common differential
diagnoses.
ACKNOWLEDGMENT
Open access publishing facilitated byThe University of Melbourne, as
part of the Wiley ‐ The University of Melbourne agreement via the
Council of Australian University Librarians.
CONFLICT OF INTEREST
The authors declare no conflict of interest.
DATA AVAILABILITY STATEMENT
There will be no data availability statement for the article.
ORCID
Anthony Honigman http://orcid.org/0000-0002-4872-6340
Michelle Rodrigues http://orcid.org/0000-0002-9747-1882
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How to cite this article: Honigman A, Rodrigues M.
Differential diagnosis of melasma and hyperpigmentation.
Dermatol Rev. 2022;1‐8. doi:10.1002/der2.144
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