Received: 20 January 2022 | Revised: 26 June 2022 | Accepted: 29 June 2022

DOI: 10.1002/der2.144

INVITED REVIEW

Differential diagnosis of melasma and hyperpigmentation

Anthony Honigman1 | Michelle Rodrigues2,3

1
Dermatology Department, The Royal
Melbourne Hospital, Melbourne, Australia Abstract
2
Chroma Dermatology, Pigment and Skin of Background: Melasma is a common disorder of acquired hyperpigmentation
Colour Centre, Victoria, Australia
affecting millions of people worldwide, predominantly women. Despite the
3
Department of Dermatology and Department
of Paediatrics, Royal Children's Hospital, incidence, there are numerous hyperpigmentary conditions which may clinically
Melbourne University, Melbourne, Victoria, resemble melasma. The differential diagnosis of melasma is therefore wide and may
Australia
prove to be a diagnostic challenge for clinicians. This can delay the appropriate
Correspondence treatment, adversely impacting sufferers. Our review aims to provide clinicians with
Michelle Rodrigues, Ground Floor, suite
an understanding of and a comprehensive approach to assessing, diagnosing and
15/202 Jells Rd, Victoria 3150, Australia.
Email: dr.rodrigues@gmail.com treating melasma and other disorders of hyperpigmentation.

KEYWORDS
hyperpigmentation, melanogenesis, melasma, pigmentary disorders

1 | INTRODUCTION 2.1 | Presentations and clinical classifications

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 | M E L A SM A
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
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

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HONIGMAN AND RODRIGUES | 33

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) Sun exposed sites Any age
round/oval macules

Ephelides Well‐demarcated, sharply defined macules Sun exposed sites Typically childhood
a
Café‐au‐lait macules Tan to brown patches Commonly on trunk Birth or early
childhood

Post‐inflammatory Hyperpigmentation ± erythema and/or scaling Any site Any age

hyperpigmentation

Drug‐induced Greyish hyperpigmentation Face ± involvement of other special sites Any age
hyperpigmentation

Exogenous ochronosis Blue–black confluent hyperpigmentation Sites of hydroquinone application Any age

Acquired dermal macular Gray–brown to brown macules and patches Mainly the face but may occur on the trunk Middle age (typically
hyperpigmentation over 30 years
(ADMH) of age)

Acanthosis nigricansa Symmetric, hyperpigmented, velvety plaques Intertriginous areas – neck, groin, and axillae Usually less than
40 years of age

Dermatosis papulosis Pigmented papules Bilateral malar eminences and forehead During adolescence
nigra (DPN)

Nevus of Otaa Blue–gray confluence of individual macules Distribution of the first two branches of the Infancy or puberty
trigeminal nerve

Hori's nevus Blue–gray to gray–brown macules Bilateral zygomatic areas 20–70 years
a
Entities with possible systemic involvement.

early in life (Table 2). They are asymptomatic and present as light‐to‐
dark brown well‐circumscribed, pigmented macules or patches
usually greater than 20 mm 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 (5 mm
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.
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.

3.2 | 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
2,19
redistribution of melanin.
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,

34 | HONIGMAN
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
23
ocher‐colored, banana‐shaped fibers within the dermis.
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
26377489, 2023, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/der2.144 by Nat Prov Indonesia, Wiley Online Library on [31/07/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
AND RODRIGUES
F I G U R E 2 Acanthosis nigricans on the malar region of a male of
Sri Lankan background. Image source: Dr. Michelle Rodrigues,
Chroma Dermatology.
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 5 mm 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

36 | HONIGMAN
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.
A C KN O W L E D G M E N T
Open access publishing facilitated by The University of Melbourne, as
part of the Wiley ‐ The University of Melbourne agreement via the
Council of Australian University Librarians.
CO NFL I CT OF INTERES T
The authors declare no conflict of interest.
D A TA A V A I L A B I L I T Y S T A T E M E N T
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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