Acquired Hyperpigmentation Disorders

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Acquired hyperpigmentation disorders

AUTHORS: Neelam Vashi, MD, Roopal V Kundu, MD
SECTION EDITOR: Erik Stratman, MD
DEPUTY EDITOR: Rosamaria Corona, MD, DSc
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: May 2023.

This topic last updated: Apr 05, 2022.
INTRODUCTION
Disorders of cutaneous discoloration comprise a large group of skin conditions characterized

by an increase of chromophores of melanotic origin (hyperpigmentation) and/or an increase
of nonmelanotic chromophores (hyperchromias) [1,2]. Hyperpigmentation is the darkening
or increase in the natural color of the skin, usually due to an increased deposition of melanin
(hypermelanosis) in the epidermis and/or dermis. Less frequently, it may be caused by the
deposition in the dermis of endogenous or exogenous pigments, such as hemosiderin, iron,
or heavy metals.
Hyperpigmentation is a feature of a multitude of clinical conditions, ranging from normal

variations of skin color to acquired and inherited syndromes, and is one of the most common
reasons for dermatologic consultation, particularly in patients with darkly pigmented skin
[1,3-5]. Although hyperpigmentation is not harmful, it can cause significant cosmetic
disfigurement and become a persistent psychosocial burden for the patient [6] due to the
limited efficacy of available treatments.
This topic will review the approach to the patient with acquired hyperpigmentation disorders.
Melasma and postinflammatory hyperpigmentation are discussed separately. Congenital and
inherited hyperpigmentation disorders are also discussed separately.
● (See "Melasma: Epidemiology, pathogenesis, clinical presentation, and diagnosis".)

● (See "Melasma: Management".)
● (See "Postinflammatory hyperpigmentation".)
● (See "Congenital and inherited hyperpigmentation disorders".)
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PATHOPHYSIOLOGY OF HYPERPIGMENTATION
Determinants of skin color — The color of human skin is mainly determined by the two
types of melanin: black-brown eumelanin and yellow-red pheomelanin. Other significant
determinants are capillary blood flow, chromophores (eg, carotene or lycopene), and the
collagen content of the dermis.
Eumelanin and pheomelanin are present in individuals of all skin colors, but their ratio is
highly variable and determines the hue of the skin [7]. Differences in the number, size, and
aggregation of melanosomes within the melanocytes and keratinocytes, but not in the overall
number of melanocytes, contribute to ethnic differences in skin color [8,9]. Skin that is darkly
pigmented has a higher content of melanin, higher eumelanin-to-pheomelanin ratio,
nonaggregated and larger melanosomes, and slower melanosome degradation within the
keratinocytes [10].
Melanin — Melanin is produced by melanocytes, specialized cells of neural crest origin that

reside in the basal layer of the epidermis. The biosynthesis of melanin occurs in lysosome-like
organelles called melanosomes, which are transported to the cell periphery and transferred
from the dendritic tips of the melanocytes to the surrounding keratinocytes [11]. Each
melanocyte is associated with approximately 36 basal keratinocytes to form the so-called
epidermal melanin unit.
Melanin synthesis is triggered by the hydroxylation of L-phenylalanine to L-tyrosine or

directly from L-tyrosine. Tyrosinase hydroxylates L-tyrosine to 3,4-L-dihydroxyphenylalanine
(L-DOPA), which further undergoes oxidation to dopaquinone. Thereafter, two main pathways
diverge, leading to production of black-brown eumelanin and yellow-red pheomelanin.
Melanin synthesis is regulated by multiple complex signaling pathways, including
melanocyte-stimulating hormones (MSH)/cAMP and KIT [11].
Hypermelanosis — Skin hyperpigmentation is, in most cases, caused by increased

biosynthesis and deposition of melanin in the epidermis and/or dermis. Epidermal
hypermelanosis results from an excess of melanin in the basal and suprabasal layers of the
skin due to increased melanin production. These abnormalities may be due to both acquired
and genetic factors.
The normal dermis does not contain melanin. Dermal hypermelanosis may develop through
several mechanisms:
● Transfer of melanin from the epidermis to the dermis and accumulation within
melanophages ("pigmentary incontinence"). This process is commonly observed in
inflammatory skin diseases that involve a damage of the basal layer and/or the
dermoepidermal junction.

● Production of melanin by ectopic dermal melanocytes. Examples of dermal

melanocytosis are the nevus of Ota and nevus of Ito.
● Binding of melanin to exogenous pigments deposited in the dermis.
Other pigments — Cutaneous hyperpigmentation can be caused by the deposition in the

dermis of endogenous or exogenous pigments, such as hemosiderin, iron, or heavy metals.
Recurrent extravasation of red blood cells in the dermis leads to deposition of hemosiderin,
resulting in a red-brown discoloration of the skin. Dermal hyperpigmentation mimicking
dermal hypermelanosis can be caused by topical or systemic exposure to heavy metals (eg,
silver, gold, mercury). Some metals, such as iron, may also stimulate melanogenesis, as
observed in patients with hemochromatosis.
PATIENT EVALUATION AND DIAGNOSIS
The diagnosis of hyperpigmentation disorders may be challenging. An algorithmic approach

to the diagnosis based upon history and clinical parameters is shown in the figure
( algorithm 1). In most cases, the initial patient evaluation involves a detailed family and
personal medical history and a complete physical examination, which should include a careful
search for additional cutaneous and extracutaneous signs and symptoms.
Questions that may be useful for the evaluation of patients with hyperpigmentation
disorders include [3]:
● Is the disorder congenital or acquired?

● Is the pigmentation localized or diffuse?
● Is the pigmentation well circumscribed or ill defined?
● Does the pigmentation have a pattern (eg, linear, reticular)?
● Is the pigmentation associated with inflammation and/or prior cutaneous injury?
● Is the pigmentation stable, progressing, or regressing?
● Does the patient have concomitant systemic diseases?
● Does the patient have a history of exposure to a new medication?
History — A detailed medical history should be obtained from the patient to determine if the
hyperpigmentation is related to an underlying disease. The possibility of drug-induced
pigmentation must be kept in mind. Patients should also be questioned about occupational
and or hobby-related exposure to chemicals that may cause hyperpigmentation.
The course of the disorder is also a useful parameter in the clinical diagnosis of
hyperpigmentation disorders. Inherited disorders of hyperpigmentation are often stable,
whereas most acquired forms show progression or regression.

Skin examination — In all patients with hyperpigmentation disorders, a complete skin

examination should be performed under visible light and Wood's light. Important clinical
parameters include:
● Extent of the pigmentary abnormality (localized versus diffuse)

● Color hue (shades of brown/black, slate-gray/blue)
● Morphology of individual lesions
● Distribution (eg, sun-exposed areas, areas previously involved by inflammatory
processes)
● Pattern (eg, linear, reticular, nonfigurate)
A careful search for associated cutaneous and extracutaneous signs and symptoms may
provide important clues to the diagnosis, particularly in patients with hyperpigmentation
disorders associated with systemic diseases or genetic syndromes.
Wood's light examination — Wood's light, also known as "black light," is ultraviolet A (UVA)
light with a peak emission at 365 nm [12]. The patient is examined in a darkened room with
the light source held at 10 to 15 cm from the skin. Wood's light can be helpful in determining
whether the pigment deposition is predominantly epidermal, dermal, or mixed. However, its
effectiveness is limited in patients with darkly pigmented skin [13,14]:
● Epidermal hypermelanosis – Under natural light, epidermal hypermelanosis appears

light brown to dark brown in color. The pigmentation, as well as the contrast between
involved and uninvolved skin, is enhanced when viewed under a Wood's lamp.
● Dermal hypermelanosis – Under natural light, dermal hypermelanosis has a bluish or

ashen gray hue with margins less defined than epidermal hypermelanosis. The
pigmentation is not accentuated by the Wood's light.
● Mixed hypermelanosis – Mixed hypermelanosis appears light to dark brown under

natural light, whereas Wood's light examination will show enhancement in some areas
and none in others.
Dermoscopy — Dermoscopy (dermatoscopy) refers to skin examination using

surface microscopy. It requires a high-quality magnifying lens and a powerful lighting system,
which allows examination of skin structures and patterns. (See "Overview of dermoscopy".)
Dermoscopy is a noninvasive technique that has traditionally been utilized in the assessment
of melanocytic lesions. Observational studies have suggested a role for dermoscopy for both
the identification and differentiation of pigmentary disorders [15]. Under dermoscopy, certain
characteristics of skin lesions can be assessed, such as symmetry versus asymmetry,
homogeneity versus heterogeneity, pigment distribution, vascular morphology, and lesion

border. Dermoscopy can provide information to identify pigmentary disorders and also help
assess disease severity and treatment response.
Reflectance confocal microscopy — In vivo reflectance confocal microscopy is a technique

that allows noninvasive imaging of the epidermis and papillary dermis at histologic resolution
[16]. The confocal microscope emits a near-infrared light from a diode laser source focused
on a microscopic skin target. As this light penetrates cellular structures with different
refraction indexes, it is naturally reflected and then captured and recomposed by computer
software into a two-dimensional grayscale image [17,18].
Reflectance confocal microscopy is not widely available and is mainly employed in research
settings. However, it is a promising technique to diagnose and/or monitor treatment of hypo-
and hyperpigmentation disorders without performing repeated biopsies [19,20].
Skin biopsy — A skin biopsy for histopathologic evaluation is not routinely performed for the
diagnosis of hyperpigmentation disorders. However, it may be necessary when the clinical
diagnosis is uncertain. Standard stains (eg, hematoxylin and eosin, Fontana-Masson silver
stain) and histochemical techniques (eg, Mart-1, Melan-A) are used to evaluate the number
and localization of melanocytes and melanin granules in the epidermis and dermis. The main
histopathologic findings in selected hyperpigmentation disorders are summarized in the
table ( table 1).
CIRCUMSCRIBED HYPERPIGMENTATION
Ephelides — Ephelides, or freckles, are small, well-demarcated, hyperpigmented macules

usually 2 to 4 mm in diameter that occur most frequently in individuals with red or blond hair
and lightly pigmented skin ( picture 1). They first appear during early childhood on sun-
exposed skin and are most numerous on the face, dorsal hands, and upper trunk. Ephelides
increase in number, size, and depth of pigmentation during the summer months and are
smaller, lighter, and fewer in number in the winter. Melanocortin-1 receptor gene variants
play a role in the development of ephelides [21,22].
Ephelides are benign lesions and have no propensity for malignant transformation [23].
Histologically, there is a normal epidermis and normal number of melanocytes with large
melanosomes, resembling those seen in patients with darkly pigmented skin.
Treatment involves the use of sun-protective measures. Additional treatment is for cosmetic
purposes only. Topical retinoids and depigmenting agents may lighten lesions to a minimal
extent. Pigment-specific lasers and light-based therapy are additional therapeutic modalities
[24]. (See "Laser and light therapy for cutaneous hyperpigmentation".)
Lentigines

Simple lentigines — Lentigines are benign pigmented macules that result from increased
activity of epidermal melanocytes. Simple lentigines are usually small (<5 mm), darker than
ephelides, and appear during childhood. They have a scattered distribution and do not show
a predilection for sun-exposed areas. Multiple lentigines are a feature of numerous genetic
disorders ( table 2). (See "Benign pigmented skin lesions other than melanocytic nevi
(moles)", section on 'Lentigo' and "Congenital and inherited hyperpigmentation disorders",
section on 'Genetic syndromes associated with lentiginosis'.)
Solar lentigines — Solar lentigines are tan to dark brown macules, 3 to 20 mm in size, that
occur on sun-exposed areas, such as the face ( picture 2A-B), dorsal aspect of hands
( picture 3) and forearms, upper chest ( picture 4), and upper back ( picture 5), in
response to excessive or chronic sun exposure. In younger individuals, they often appear
after an acute sunburn. The differential diagnosis and management of lentigines is discussed
elsewhere. (See "Benign pigmented skin lesions other than melanocytic nevi (moles)", section
on 'Lentigo'.)
Other than for cosmetic purposes, treatment of lentigines is unnecessary. Therapeutic

options include lightening agents, retinoic acid, trichloroacetic acid, cryotherapy, intense
pulsed light therapy, and laser therapy with quality-switched (Q-switched) lasers [25].
Psoralen plus ultraviolet A lentigines — Psoralen plus ultraviolet A (PUVA) lentigines are

large, irregularly shaped, darkly pigmented macules arising also in sun-protected areas in
patients treated with long-term PUVA phototherapy, particularly in those with light
phototypes. Histologically, these macules are characterized by a lentiginous proliferation of
large melanocytes with mild atypia [26]. Similar macules have been noted in patients with
mycosis fungoides treated with narrowband ultraviolet B (UVB) phototherapy [27].
Partial unilateral lentiginosis — Partial unilateral lentiginosis (PUL) is a rare disorder

characterized by the presence of multiple lentigines arising on normally pigmented skin in a
unilateral or segmental pattern [28]. PUL is in most cases an acquired disorder, with
lentigines first appearing during childhood or adolescence. The pigmented macules can
occur anywhere on one side of the body and may have a zosteriform distribution.
Histologically, there is increased pigmentation of the basal layer, with normal or slightly
increased number of melanocytes [29].
In a minority of cases, PUL may be a manifestation of segmental neurofibromatosis type 1

(NF1), a noninherited mosaic form of NF1, characterized by unilateral neurofibromas and/or
café-au-lait macules [30]. (See "Neurofibromatosis type 1 (NF1): Pathogenesis, clinical
features, and diagnosis", section on 'Segmental NF1'.)
Laugier-Hunziker syndrome — Laugier-Hunziker syndrome is an acquired, benign disorder

presenting in adults with lentigines on the lips and buccal mucosa ( picture 6).

Approximately one-half of the patients also have longitudinal melanonychia and macular
pigmentation of the genitals [31] (see "Longitudinal melanonychia"). Palms and soles are
frequently involved. There are no underlying systemic abnormalities and no malignant
predisposition.
The diagnosis of Laugier-Hunziker syndrome is one of exclusion and is usually made after
ruling out other causes of oral and labial hyperpigmentation, including physiologic
pigmentation seen in patients with darkly pigmented skin and inherited diseases associated
with lentiginosis (eg, Peutz-Jeghers syndrome, LEOPARD [lentigines, electrocardiogram
abnormalities, ocular hypertelorism, pulmonic stenosis, abnormal genitalia, retardation of
growth, and sensorineural deafness] syndrome). The absence of systemic symptoms such as
fatigue, weight loss, cardiovascular, or gastrointestinal disorders and negative findings in
upper gastrointestinal endoscopy and colonoscopy support the diagnosis of Laugier-
Hunziker syndrome. (See "Congenital and inherited hyperpigmentation disorders", section on
'Genetic syndromes associated with lentiginosis'.)
No treatment is necessary. However, some patients may require the removal of pigmented
lesions for cosmetic reasons. Cryosurgery, neodymium-doped yttrium aluminum garnet
(Nd:YAG) lasers, and the Q-switched alexandrite laser have been used in single case reports
[32-34]. (See "Laser and light therapy for cutaneous hyperpigmentation".)
Cronkhite-Canada syndrome — Cronkhite-Canada syndrome is a rare, noninherited

disorder characterized by polyposis of the digestive tract associated with variable anomalies
of ectodermal tissues, including diffuse, nonscarring alopecia, nail dystrophy ( picture 7),
and lentigines of the buccal mucosa, face, hands, and feet [35]. Approximately two-thirds of
the patients are of Japanese descent [36].
The disease typically manifests in the sixth decade of life. Presenting symptoms include
diarrhea, weight loss, nausea, vomiting, hypogeusia, and anorexia. A diffuse polyposis is
present throughout the gastrointestinal tract. Complications include protein-losing
enteropathy, gastrointestinal bleeding, intussusception, and prolapse.
Cronkhite-Canada syndrome is a progressive disease with variable course and poor

prognosis. Regardless of therapy, the mortality rate exceeds 50 percent. (See "Overview of
colon polyps", section on 'Cronkhite-Canada syndrome'.)
Oral melanotic macule — Oral melanotic macules are small, well-circumscribed, brown-to-

black macules commonly occurring on the vermilion border of the lower lip ( picture 8) or
on the oral mucosa, more often on the gingiva ( picture 9) and hard palate ( picture 10).
They range in size from a few millimeters to more than one centimeter, are often solitary but
can be multiple, and are frequently seen in individuals with darkly pigmented skin.

A biopsy may be required to rule out mucosal melanoma. Histologically, melanotic macules
show an increased deposition of melanin without increase in the number of basal
melanocytes. Melanin pigment is also observed in melanophages in the upper portion of the
lamina propria.
Dermatosis papulosa nigra — Dermatosis papulosa nigra (DPN) is a common benign

condition, which is considered to represent a variant of seborrheic keratosis. Lesions present
as multiple 1 to 5 mm dark brown to black papules most commonly on the face, neck, and
upper back. DPN affects 35 to 77 percent of individuals of African descent and can also
present in other ethnic groups with darkly pigmented skin. DPN typically present at a
younger age compared with seborrheic keratoses and can uncommonly be found in children
[37,38].
The pathogenesis of DPN is unknown. Studies have found mutations in fibroblast growth
factor receptor 3 and phosphatidylinositol 3-kinase genes [39]. Since many patients report a
family history of DPN, a genetic predisposition is most likely. Histopathologic features include
acanthosis, papillomatosis, and increased pigmentation of the epidermis.
The diagnosis is typically made clinically. However, if the diagnosis is uncertain, a biopsy can
be performed to differentiate this entity from viral warts, melanocytic and epidermal nevi,
and melanoma.
DPN is a benign condition requiring no therapy. However, some patients may desire
treatment for cosmetic reasons. Treatment modalities include topical therapies (eg, 40%
hydrogen peroxide), electrodesiccation and curettage, cryotherapy, snip removal, long-pulsed
1064 nm Nd:YAG laser, 532 nm diode laser, pulsed dye laser, fractional photothermolysis
1550 nm laser, potassium titanyl phosphate (KTP) laser, and carbon dioxide (CO2) ablative
laser [40-46].
Smoker's melanosis — Smoker's melanosis is characterized by irregular macular

hyperpigmentation of the oral mucosa secondary to tobacco smoking [47-49]. It may be due
to the stimulating effect of nicotine on the melanocytes located in the basal layer of the oral
mucosa. (See "Oral lesions", section on 'Smoker's melanosis'.)
Lesions consist of brown patches most commonly located on the mandibular anterior gingiva
in cigarette smokers and buccal mucosa in pipe smokers [48]. In those who engage in reverse
smoking (smoking from the lit end), pigmentation changes are most common on the hard
palate.
The diagnosis is usually clinical. However, a biopsy for histopathologic examination may be
warranted if the diagnosis is unclear or the lesion is suspicious for malignancy. The
differential diagnosis includes physiologic pigmentation (mucosal melanosis) in patients with
darkly pigmented skin, amalgam tattoo, drug-induced hyperpigmentation, Addison's disease,
melanoacanthoma, and mucosal melanoma. (See "Oral lesions", section on 'Pigmented

lesions'.)
There are no treatments for smoker's melanosis. Lesions tend to resolve spontaneously over
a period of several years of smoking discontinuation [50].
Becker's melanosis — Becker's melanosis, also called Becker's nevus, is a benign cutaneous

hamartoma usually presenting in adolescents as a unilateral, hyperpigmented macule or
slightly elevated plaque located on the shoulder or upper trunk ( picture 11A-B). In one-half
of the cases, there is an associated hypertrichosis. Becker nevus is discussed in greater detail
elsewhere. (See "Benign pigmented skin lesions other than melanocytic nevi (moles)", section
on 'Becker nevus'.)
Maturational hyperpigmentation — Darkening of facial skin tone is frequently seen in

older individuals with darkly pigmented skin. Maturational hyperpigmentation or
maturational dyschromia are controversial and uncommonly used terms that refer to a
primary darkening of both mature and sun-exposed skin [51]. The onset is in adulthood and
is not associated with prior inflammation or skin injury. The hyperpigmentation generally
occurs on the lateral aspects of the face and also dorsal hands and feet as a result of chronic
sun exposure ( picture 12). (See "Photoaging".)
The etiopathogenesis of maturational hyperpigmentation remains unclear. Chronic sun

exposure is likely implicated; obesity and diabetes have been postulated as predisposing
factors [51]. The histologic evaluation of hyperpigmented skin reveals mild to moderate
proliferation of melanocytes, minimal to absent dermal inflammation, and some reports of
papillomatous epidermal proliferation.
Maturational hyperpigmentation is a diagnosis of exclusion. It is most commonly confused

with melasma, postinflammatory hyperpigmentation, or acanthosis nigricans. The differential
diagnosis also includes photoallergic dermatitis and exogenous ochronosis. (See 'Exogenous
ochronosis' below.)
Treatment includes sun-protective measures and topical skin-lightening agents. (See

"Melasma: Management", section on 'Topical skin-lightening agents'.)
Periorbital hyperpigmentation — Periorbital hyperpigmentation, also called idiopathic

cutaneous hyperchromia of the orbital region, periorbital melanosis, dark circles, or
infraorbital pigmentation, is a common finding in otherwise healthy individuals [52]. The
dyspigmentation around the orbital skin is typically bilateral and of a medium to dark brown
color, sometimes extending to the upper nose and glabella regions. It may be present on the
upper, lower, or both eyelids. It affects males and females equally and is more common in
individuals with darkly pigmented skin [53]. A familial form has also been recognized, with
variable clinical expression in different members of the family [54]. In familial cases, the
hyperpigmentation usually starts during childhood in the lower eyelids and progresses with
age to involve the entire periorbital area.
The cause of periorbital hyperpigmentation is multifactorial. Contributing factors include

genetic or constitutional pigmentation; dermal melanocytosis; postinflammatory
hyperpigmentation; periorbital edema; excessive subcutaneous vascularity; thin, translucent
lower eyelid skin overlying the orbicularis oculi muscle; or a shadow effect due to skin laxity
and prominent tear trough [10,52,53].
Excessive sun exposure, drugs, hormonal causes, and extension of pigmentary demarcation
lines may be additional contributing factors [55]. Histologically, there is an increase in dermal
melanin and hemoglobin [56,57].
There are no therapies of proven efficacy for periorbital hyperpigmentation. Treatment

should be directed to the most apparent etiologic factor (eg, topical lightening agents for
postinflammatory hyperpigmentation, soft tissue filler for prominent tear trough). However,
topical skin-lightening agents, chemical peels [58], lasers [59-61], autologous fat
transplantation, fat grafting with and without blepharoplasty [62,63], and dermal fillers [64]
have all been tried, but none have provided long-term satisfactory treatment. (See "Melasma:
Management", section on 'Topical skin-lightening agents' and "Injectable soft tissue fillers:
Overview of clinical use".)
Melasma — Melasma is an acquired hyperpigmentation of the skin that typically affects the

sun-exposed areas of the face, including the centrofacial, malar, and mandibular regions. It is
most common in female individuals with darkly pigmented skin who live in areas of intense
ultraviolet (UV) radiation exposure [65]. The clinical features, diagnosis, and management of
melasma are discussed in detail separately. (See "Melasma: Management".)
Poikiloderma of Civatte — Poikiloderma of Civatte (PC) is a common disorder characterized

by mottled pigmentation (hyper- and hypopigmentation), skin atrophy, and telangiectasias
involving the lateral aspect of the face, neck, and V of chest ( picture 13) caused by chronic
exposure to UV radiation [66]. The submental area is typically spared. PC is usually seen in
individuals older than 40 years with lightly pigmented skin and is more common in females.
Histologically, PC is characterized by thinning of the spinous layer, hydropic degeneration of

the basal cell layer, solar elastosis in the papillary dermis, presence of melanophages in the
papillary dermis, and dilatation of the papillary dermal capillaries [67].
PC has a chronic, progressive, and irreversible course that continues with exposure to UV
light. Photoprotection is an essential part of management. Therapies directed at reducing the
hyperpigmentation and the telangiectatic component include intense pulsed light [68-71] and
nonablative fractional laser. (See "Laser and light therapy for cutaneous vascular lesions" and
"Laser and light therapy for cutaneous hyperpigmentation".)
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Nevus of Hori — Acquired bilateral nevus of Ota-like macules (ABNOM), or nevus of Hori, is a

common, dermal, melanocytic hyperpigmentation seen in some Asian populations, primarily
in young and middle-aged Chinese and Japanese females [72-74]. It is characterized by blue-
gray to gray-brown macules, primarily on the zygoma and less often on the forehead,
temples, upper eyelids, and root and alae of the nose.
Although nevus of Hori shares histologic similarities with nevus of Ota, it can be clinically
distinguished from nevus of Ota by late onset in adulthood, bilateral presentation, speckled
or confluent distribution, and lack of ocular and mucosal involvement. The differential
diagnosis includes melasma, lentigines, and ephelides. (See "Melasma: Management" and
"Benign pigmented skin lesions other than melanocytic nevi (moles)".)
Laser therapy alone or in combination with chemical peels is the major treatment modality
for nevus of Hori [73]. Pigment-selective lasers and their combinations (eg, 532 nm Q-
switched Nd:YAG laser followed by a 1064 nm Q-switched Nd:YAG laser, or scanned CO2 laser
or intense pulsed light with a Q-switched ruby laser) have been successfully used in small
series [75-79]. Adverse effects of treatment include postinflammatory hypo- and
hyperpigmentation. (See "Laser and light therapy for cutaneous hyperpigmentation".)
Postinflammatory hyperpigmentation — Postinflammatory hyperpigmentation is a

common reactive hypermelanosis that develops as a sequela of a variety of insults to the
skin, including inflammatory diseases, chemical or physical injuries, or trauma [80-82]. It
presents with hyperpigmented macules and patches in the same area involved by the
preceding inflammation ( picture 14A-B) or trauma ( picture 15). The color varies from
light brown to slate-gray or black, depending upon the skin color and location of melanin
deposition (epidermal or dermal). Patients with darkly pigmented skin are particularly
predisposed to postinflammatory hyperpigmentation.
The clinical presentation, diagnosis, and treatment of postinflammatory hyperpigmentation

are discussed in detail separately. (See "Postinflammatory hyperpigmentation".)
Riehl's melanosis — Riehl's melanosis or pigmented contact dermatitis is a dermal

melanosis involving the face and neck caused by repeated contact with cosmetic ingredients
[83]. A mild erythema and pruritus typically precede the development of a diffuse or
reticulated hyperpigmentation ( picture 16). The involved skin appears brown, brown-gray,
or blue-gray, depending upon the causal agent, depth of pigment deposition, and
background skin color.
Histologically, there is vacuolar degeneration of the basal layer of the epidermis resulting in
pigment incontinence in the dermis [84]. The papillary dermis contains an infiltrate of
lymphocytes and macrophages containing large amounts of melanin.

The diagnosis is based upon the clinical appearance and history of cosmetic use. Patch
testing to standard series, cosmetic series, fragrance series, and additional ingredients found
in patients' personal products may be helpful in identifying the offending agent. Photopatch
testing may be useful in some patients. When results are equivocal or negative, provocative
use test or repeated open application test (ROAT) can be administered [56]. (See "Patch
testing".)
The differential diagnosis includes melasma, nevus of Hori, photosensitivity reactions, and
berloque dermatitis (phytophotodermatitis). (See "Melasma: Management" and "Clinical
features and diagnosis of allergic contact dermatitis".)
Treatment involves complete avoidance of the suspected allergen. Sun-protective measures,

skin-lightening agents, and chemical peels can accelerate the resolution of pigmentation
changes.
Erythrose péribuccale pigmentaire de Brocq — A rare form of facial hyperpigmentation

and probably a variant of Riehl's melanosis is the so-called "erythrose péribuccale
pigmentaire de Brocq" or "erythrosis pigmentosa mediofacialis." It is characterized by diffuse,
symmetric, red-brown pigmentation around the mouth with sparing of the vermillion border
[85]. It may extend to the forehead, temples, and angles of the jaw.
Histologic examination shows orthokeratotic hyperkeratosis, no specific inflammatory

epidermal reaction pattern, and pigment incontinence with melanophages in the upper
dermis. Enlarged follicular openings containing keratin plugs and often Demodex folliculorum
have also been noted [86,87].
The pigmentation tends to be persistent. Treatment is difficult and involves sun avoidance
and the use of skin-lightening agents [88].
Erythromelanosis follicularis faciei et colli — Erythromelanosis follicularis faciei et colli is a

rare clinical variant of keratosis pilaris primarily seen in adolescents and young adults [89]. It
presents with a gradually progressive, reddish-brown pigmentation surmounted by small
follicular papules ( picture 17) [85]. The pigmentation involves the preauricular areas and
extends to the cheeks and sides of the neck. Classic keratosis pilaris lesions are often present
on the trunk. (See "Keratosis pilaris".)
There is no effective treatment for erythromelanosis follicularis faciei et colli. Topical

retinoids, topical tacalcitol, hydroquinone, and laser therapy have been used in a few patients
with temporary improvement [89-91]. Complete regression is difficult to achieve, and relapse
is common.
Erythema dyschromicum perstans — Erythema dyschromicum perstans (EDP), also called

ashy dermatosis or dermatosis cenicienta, is an uncommon, slowly progressive dermatosis

characterized by hyperpigmented macules of variable size and shape of an ashen-gray color

[92]. The majority of patients with this disorder are from Latin America. EDP is usually seen in
young adults, but it may also occur in children [93].
The etiology of EDP is unknown. There are isolated reports of EDP associated with exposure
to medications (most commonly, benzodiazepines and penicillin), radiographic contrast
media, pesticides, endocrinopathies, Trichuris trichiura (whipworm) infestation, and human
immunodeficiency virus (HIV) infection [80,94,95]. However, in most cases, a cause or trigger
cannot be identified. HLA-DR4 allele may be a risk factor for EDP in Mexican patients [96].
Histologic examination of the active border of the lesions shows vacuolar alterations of the
basal layer with occasional necrotic keratinocytes and colloid bodies resembling lichen planus
[97]. In the papillary dermis, there is a mild to moderate perivascular infiltrate of lymphocytes
and histiocytes with melanophages. Based upon these findings, it has been hypothesized
that EDP may represent a cell-mediated immune reaction to an ingestant, contact allergen, or
microorganism [92,98]. Regardless, a diagnosis of EDP cannot be made based on histologic
findings alone.
EDP presents with slate-gray to blue-brown, oval, circular, or irregularly shaped macules and
patches that develop gradually in a symmetric distribution ( picture 18A-B). The long axis of
the lesions may follow the skin cleavage lines. Early lesions may have a thin, raised, and
erythematous border. Lesions typically involve the trunk, but they may spread to the neck,
upper extremities, and face. EDP is usually asymptomatic, but mild pruritus may occur.
EDP is difficult to diagnose. It may share clinical and histologic features with other entities,
including lichen planus pigmentosus, lichenoid drug eruption ( picture 19), infectious
diseases (eg, leprosy, pinta), and postinflammatory hyperpigmentation. (See "Lichen planus"
and "Lichenoid drug eruption (drug-induced lichen planus)".)
There are no effective therapies for EDP. Topical agents, such as corticosteroids and
hydroquinone, are usually of limited benefit. Oral corticosteroids, antibiotics (eg, doxycycline),
antimalarials, isoniazid, griseofulvin, and UV light therapy have been tried with variable
results. Successful treatment with topical tacrolimus [99], dapsone [100], clofazimine
[101,102], and isotretinoin [103] has been reported in a small number of patients. Sustained
resolution with narrowband UVB has been reported in one patient [104].
The disease is slowly progressive and persistent. Spontaneous resolution over months to
years has been reported in children [105].
Atrophoderma of Pasini and Pierini — Atrophoderma of Pasini and Pierini is a rare disorder

of unknown etiology presenting with single or multiple oval-shaped, well-demarcated areas
of skin that appear depressed and hyperpigmented ( picture 20A-B). The diagnosis,

differential diagnosis, and treatment of atrophoderma of Pasini and Pierini are discussed
separately. (See "Atrophoderma of Pasini and Pierini".)
Acquired brachial cutaneous dyschromatosis — Acquired brachial cutaneous

dyschromatosis (ABCD) has been reported as a pigmentary disorder occurring on the dorsal
aspect of the forearm of older individuals, particularly in females [106]. It presents with large,
geographic, gray-brown patches localized to the forearms, usually in a bilateral distribution.
The differential diagnosis includes extrafacial melasma. The presence of hypopigmented
macules and the absence of characteristic facial melasma lesions and any relation to
estrogens, pregnancy, or hormone replacement therapy can help distinguish ABCD from
melasma. On histology, the hyperpigmented patches are characterized by poikilodermatous
changes, including epidermal atrophy, increased basal layer pigmentation, solar elastosis,
and telangiectasias. Based upon the histologic similarity with poikiloderma of Civatte, ABCD
is thought to be a manifestation of chronic sun damage [107].
Fixed drug eruption — Fixed drug eruption (FDE) is a distinctive type of cutaneous drug
reaction that characteristically recurs in the same locations upon re-exposure to the
offending drug. When fixed drug eruptions are encountered in practice following the acute
phase, lesions often appear as hyperpigmented, round patches. Acute FDE usually presents
with a single or a small number of dusky red or violaceous plaques that resolve leaving
postinflammatory hyperpigmentation ( picture 21A-C). The clinical features, diagnosis, and
management of fixed drug eruption are discussed separately. (See "Fixed drug eruption".)
Exogenous ochronosis — Exogenous ochronosis is a rare condition resulting from the

deposition of homogentisic acid in the dermis following a prolonged exposure to a variety of
topical products used in skin-lightening agents, such as hydroquinone, resorcinol, phenol,
mercury, and picric acid [108,109]. The highest incidence is reported in African countries, due
to the widespread use of these agents [110,111].
Exogenous ochronosis presents as an asymptomatic, localized, symmetric, blue-gray

discoloration of the skin with characteristic hyperchromic, pinpoint, caviar-like papules in
photo-exposed regions (eg, face, sides and back of the neck, back, and extensor surfaces of
limbs ( picture 22)). There is often an erythematous, pinkish hue of the skin underlying and
surrounding the hyperchromic papules.
The diagnosis is made by careful history-taking but often requires a skin biopsy, since
exogenous ochronosis can be easily confused with postinflammatory hyperpigmentation,
melasma, and pigmented contact dermatitis (Riehl's melanosis). Histology shows a
microscopic deposition of ochre-colored pigment in the papillary dermis, resembling the
endogenous ochronosis associated with alkaptonuria [112]. (See "Topical skin-lightening
agents: Complications of use in the nonmedical setting", section on 'Exogenous ochronosis'.)

There is no effective treatment for exogenous ochronosis. Foremost, the offending

medication should be stopped. Topical agents, dermabrasion, CO2 laser, chemical peels, Q-
switched Nd:YAG laser, Q-switched alexandrite laser, and fractional CO2 laser have been used
in a small number of patients with inconsistent results [108,113-118].
DIFFUSE HYPERPIGMENTATION
Linear pattern
Phytophotodermatitis — Phytophotodermatitis is a phototoxic reaction to contact with

plants containing furocoumarins ( table 3). Patients with phytophotodermatitis typically
present with erythema, edema, and bullae in linear, streaked, or splashed configurations on
sun-exposed skin that reflect the manner in which they have come in contact with the causal
furocoumarin. Some patients do not experience the acute inflammatory phase and only
present with bizarre, unexplained pigmentation patterns in areas of exposed skin. The acute
lesions typically heal leaving linear hyperpigmented lesions ( picture 23A-B). (See
"Photosensitivity disorders (photodermatoses): Clinical manifestations, diagnosis, and
treatment", section on 'Phytophotodermatitis'.)
Drug-induced linear hyperpigmentation
Serpentine hyperpigmentation — Serpentine persistent supravenous

hyperpigmentation describes a pigmentary pattern that follows the course of an underlying
vein proximal to an infusion site. This phenomenon can be caused by a variety of
chemotherapy agents, such as vinorelbine, carboplatin, daunorubicin, and topical
fluorouracil, but is most commonly associated with topical fluorouracil infusions ( table 4)
[119,120].
Flagellate hyperpigmentation — Flagellate hyperpigmentation, also called flagellate

erythema, is a characteristic cutaneous reaction to treatment with bleomycin [121,122].
Patients present with multiple linear, erythematous or hyperpigmented streaks arising at
sites of scratching or other minor traumas to the skin ( picture 24). Generalized pruritus is
common and may precede the eruption. Histology shows hyperkeratosis, epidermal
spongiosis, lymphocyte exocytosis, increased melanin in the basal layer, dermal edema, and
perivascular lymphocytic infiltrate.
Reticulate pattern
Drug-induced reticulate hyperpigmentation — A reticulate hyperpigmentation is an

uncommon side effect of several drugs, most often chemotherapy agents such as paclitaxel,
cytarabine, topical fluorouracil, and idarubicin [123,124]. Diltiazem and topical benzoyl
peroxide have also been reported as a cause. Patients present with a diffuse reticulate

hyperpigmentation predominantly located on the trunk and lower extremities. Pruritus is

often an accompanying symptom. Histologically, lesions show increased melanin in the basal
layer of the epidermis and presence of melanophages in the dermis. The pigmentation tends
to slowly resolve after discontinuation of the offending drug.
Erythema ab igne — Erythema ab igne is a reticular, erythematous, pigmented dermatosis

resulting from repeated exposures to moderate heat or infrared radiation. Once common
among people who sat near open fires or stoves, it is infrequently seen after the introduction
of central heating. However, it is still seen in relation to occupational exposure to heat
sources (foundry workers, bakers), use of hot water bottles, heating pads or blankets
( picture 25A-C), heated car seats, and among laptop users who hold computers on their
thighs [125-127].
Erythema ab igne can occur at any site, more often in an asymmetrical distribution, and is
usually asymptomatic. The early skin changes usually clear spontaneously in several weeks to
months, after the removal of the heat source from the skin. However, longstanding lesions
may be associated with permanent hyperpigmentation ( picture 25A-C).
Confluent and reticulated papillomatosis — Confluent and reticulated papillomatosis

(CARP) of Gougerot and Carteaud is an uncommon dermatosis characterized by
hyperpigmented, scaly macules or papillomatous papules coalescing into confluent patches
or plaques centrally and exhibiting a reticular pattern peripherally ( picture 26A-B). It
occurs in young adults and is usually persistent if left untreated. The pathogenesis, clinical
presentation, diagnosis, and treatment of CARP are discussed separately. (See "Confluent and
reticulated papillomatosis".)
Nonpatterned
Drug-induced — A wide variety of drugs and chemicals can lead to diffuse cutaneous
hyperpigmentation [128-130]. An increased production of melanin and/or the deposition of
drug complexes or metals in the dermis are responsible for the skin discoloration.
The drugs most often causing hyperpigmentation and associated clinical features are
summarized in the table ( table 4). The hyperpigmentation usually resolves with
discontinuation of the offending agent, but the course may be prolonged over months to
years.
Idiopathic eruptive macular pigmentation — Idiopathic eruptive macular pigmentation is

an exceedingly rare condition of unknown etiology that presents in both children and adults
with the eruption of asymptomatic, brown macules on the face, neck, proximal extremities,
and trunk [131-133]. Histologically, there is a basal layer hyperpigmentation with occasional
dermal melanophages; some specimens may show papillomatosis [131,134].

The diagnosis is based upon history and clinical and histopathologic findings. Reflectance
confocal microscopy has been used in idiopathic eruptive macular pigmentation [135].
Proposed diagnostic criteria include eruption of brown, nonconfluent, asymptomatic macules
involving the trunk, neck, and proximal extremities in children or adolescents; no preceding
inflammatory lesions; no recent drug exposure; and histopathologic findings of basal cell
layer hyperpigmentation, prominent dermal melanophages without visible basal layer
damage or lichenoid inflammatory infiltrate, and normal mast cell count [131,132].
Most patients will undergo spontaneous clearance in months to years [131].
Associated with endocrine, metabolic, and autoimmune diseases
Addison's disease — Addison's disease or primary adrenal insufficiency is a clinical

syndrome caused by glucocorticoid, mineralocorticoid, and in women, androgen deficiency
[136]. Signs and symptoms of chronic adrenal insufficiency include malaise, fatigue,
hypotension, anorexia, weight loss, and hyperpigmentation. (See "Clinical manifestations of
adrenal insufficiency in adults".)
The diffuse hyperpigmentation of Addison's disease is caused by the melanocyte stimulating

hormone (MSH)-like effect of elevated plasma levels of adrenocorticotropic hormone (ACTH).
The pigmentation is typically diffuse, with accentuation in sun-exposed areas, flexures,
palmar and plantar creases, and areas of pressure or friction ( picture 27).
Normally hyperpigmented skin areas, such as the nipples and genitals, become darker. The
buccal, conjunctival, and genital mucosa may also be involved ( picture 28). The nails and
hair may also darken ( picture 29). (See "Clinical manifestations of adrenal insufficiency in
adults", section on 'Hyperpigmentation'.)
The evaluation of the patient with suspected Addison's disease involves the measurement of
basal serum cortisol and plasma ACTH. The finding of low basal cortisol and elevated plasma
ACTH is diagnostic of primary adrenocortical insufficiency. (See "Diagnosis of adrenal
insufficiency in adults".)
The hyperpigmentation usually fades after a few months of adequate glucocorticoid therapy,
due to cornification and desquamation of hyperpigmented basal keratinocytes. Fading of hair
and nails takes longer because the pigmented part of the hair shaft and nail grows out
slowly.
Diabetic dermopathy — Diabetic dermopathy, also called shin spots or pigmented

pretibial patches, occurs in approximately one-half of diabetic patients, most often in patients
with microangiopathic complications [137,138].
It presents with multiple asymptomatic, round, dull red to pink papules or plaques
predominantly located on the pretibial skin. Lesions evolve in one to two weeks to well-
circumscribed, atrophic, brown macules and patches, often with fine scale ( picture 30).
The diagnosis of diabetic dermopathy is clinical. A skin biopsy is not routinely done. If
performed, it shows nonspecific findings, including edema of the epidermis and papillary
dermis, red blood cell extravasation, and a mild perivascular lymphohistiocytic infiltrate [137].
Older lesions show epidermal atrophy and scattered hemosiderin deposits.
There is no treatment for diabetic dermopathy. The lesions may resolve spontaneously over
time or persist indefinitely.
Acanthosis nigricans — Acanthosis nigricans is a common disorder characterized by

hyperchromic, velvety plaques located in intertriginous areas such as the axillae, groin, and
posterior neck ( picture 31). Histologically, it is characterized by hyperkeratosis, epidermal
papillomatosis, and slight, variable acanthosis, with normal melanocyte density [137]. There
is no melanin deposition, and the darkening is mainly due to hyperkeratosis.
Acanthosis nigricans occurs in approximately 40 percent of patients with diabetes mellitus

type 2. However, it may also occur in other endocrine and metabolic disorders, most of which
are associated with insulin resistance. Rarely, acanthosis nigricans may be a paraneoplastic
syndrome.
The etiology, clinical manifestations, diagnosis, and treatment of acanthosis nigricans are
discussed in detail separately. (See "Acanthosis nigricans".)
Hyperthyroidism — Cutaneous changes associated with thyrotoxicosis include a

localized or generalized hyperpigmentation with a distribution similar to that seen in
Addison's disease (eg, creases of palms and soles, buccal mucosa). The hyperpigmentation is
thought to be caused by increased release of pituitary ACTH in response to increased cortisol
degradation [139]. (See "Overview of the clinical manifestations of hyperthyroidism in adults",
section on 'Metabolic/Endocrine'.)
Hereditary hemochromatosis — Hereditary hemochromatosis is an autosomal

recessive disorder in which mutations in the HFE gene cause increased intestinal iron
absorption and abnormal accumulation of iron in the liver, pancreas, and other organs [140-
142]. Clinical manifestations include liver disease, skin pigmentation, diabetes mellitus,
arthropathy, and cardiac enlargement. (See "Clinical manifestations and diagnosis of
hereditary hemochromatosis".)
A generalized darkening of the skin is seen in approximately 70 percent of patients. The

hyperpigmentation is due to a combination of hemosiderin deposition, which causes a
diffuse, slate-gray discoloration of the skin and increased melanin production.
In patients with suspected hemochromatosis, screening tests include the measurement of

serum transferrin saturation and ferritin. Genetic testing for HFE mutations (C282Y, H63D)
should be performed in patients with elevated transferrin saturation and/or elevated ferritin
to confirm the diagnosis. (See "Approach to the patient with suspected iron overload".)
Diffuse melanosis cutis — Diffuse melanosis cutis (DMC) is a rare presentation of

metastatic melanoma characterized by a diffuse, blue-gray discoloration of the skin and
mucosae ( picture 32) [143,144]. Darkening of the urine (melanuria) is often associated with
DMC.
Histologic examination reveals intracellular and extracellular melanin deposition in the

dermis, with a pronounced perivascular distribution. It is thought that melanin and
melanosome released in the circulation by cytolysis of metastatic melanoma cells are
phagocytosed by dermal histiocytes, resulting in skin and mucosal discoloration.
DMC and melanuria portend a very poor prognosis. They have also been reported in patients
with advanced metastatic melanoma treated with molecularly targeted therapies and
checkpoint inhibitor immunotherapy [144,145].
Post-chikungunya fever pigmentation — Chikungunya fever is a mosquito-borne viral

illness endemic to West Africa, Southeast Asia, and the Indian subcontinent that causes acute
febrile polyarthralgia and arthritis [85,146]. Other mucocutaneous manifestations are
common, including a patchy or diffuse maculopapular rash that may involve the face,
intertrigo-like lesions, vesicobullous lesions, and aphthous ulcerations and gingivitis
[147,148]. (See "Chikungunya fever: Epidemiology, clinical manifestations, and diagnosis".)
Histologic examination of hyperpigmented lesions shows increased basal pigmentation,

pigmentary incontinence, and melanophages ( picture 33) [85,146,148]. These findings
support the hypothesis that the hypermelanosis associated with chikungunya fever is a form
of postinflammatory hyperpigmentation. (See 'Postinflammatory hyperpigmentation' above.)
Post-chikungunya fever facial pigmentation occurs in all age groups and presents as
asymptomatic, brownish-black, freckle-like macules involving the centrofacial area or diffuse
pigmentation of the face ( picture 34A-B) [149]. Other patterns of pigmentation include a
melasma-like pigmentation of the face, exacerbation of a pre-existent melasma, periorbital
melanosis, a flagellate pattern on the trunk and extremities, and generalized
hyperpigmentation [150].
Lesions may persist for three to six months after the infection [146]. Treatment involves sun
avoidance and the use of topical corticosteroids [146].
Lichen planus pigmentosus — Lichen planus pigmentosus (LPP) is a rare variant of lichen

planus that occurs predominantly in individuals with darkly pigmented skin (III to V) [151]. It
generally affects young to middle-aged adults, especially those from India, Latin America,
and the Middle East. (See "Lichen planus".)

The etiology is unknown. Photodistribution suggests that ultraviolet (UV) light may play a role
in the pathogenesis of LPP. A variety of oils, such as mustard oil (which contains allyl
isothiocyanate, a potential photosensitizer), amla oil, and olive oil, have been suggested as
possible inciting agents [152,153]. There are multiple reports of the coexistence of LPP and
frontal fibrosing alopecia, illustrating that LPP may be the herald sign of this scarring type of
hair loss and that both entities may have a pathogenic link [154,155]. (See "Lichen
planopilaris", section on 'Frontal fibrosing alopecia'.)
LPP typically presents with oval or irregularly shaped, brown to gray-brown macules and
patches in sun-exposed areas, including the forehead, temples, and neck ( picture 35). It
may also occur on the trunk and in intertriginous areas (lichen planus pigmentosus inversus).
Lesions are usually symmetric but can present in a unilateral, linear fashion. In contrast with
erythema dyschromicum perstans, early LPP lesions lack an erythematous border (see
'Erythema dyschromicum perstans' above). Many patients may also exhibit classic findings of
lichen planus [156].
In some patients, typical lesions of lichen planus may also be present [152]. LPP is usually
asymptomatic, but some patients report mild pruritus or burning.
The diagnosis of LPP is based upon clinical and histologic findings. Histology shows
hyperkeratosis, vacuolar cell degeneration in the basal layer with apoptotic keratinocytes, a
band-like dermal lymphocytic infiltrate with pigment incontinence, and melanophages. The
differential diagnosis includes lichen planus, erythema dyschromicum perstans, melasma,
lichenoid drug eruptions, and postinflammatory hyperpigmentation.
LPP is a chronic, relapsing disorder with exacerbations and remissions. First-line treatment
involves the use of sun-protective measures to prevent further darkening. Other treatment
options include topical corticosteroids, topical calcineurin inhibitors, skin-lightening agents,
oral retinoids, UV light therapy, antimalarials, and laser therapy [157-161]. (See "Lichen
planus", section on 'Treatment'.)
Actinic lichen planus — Actinic lichen planus (ALP), also known as lichen planus tropicus, is
a rare photodistributed variant of lichen planus [162]. (See "Lichen planus".)
ALP is most commonly seen in children and young adults from the Middle East, East Africa, or
India [163,164]. Its pathogenesis is unknown, but exposure to UV radiation appears to have a
precipitating effect.
ALP usually presents as red-brown plaques with an annular configuration, but melasma-like,
hyperpigmented patches have also been observed [98]. Lesions are typically
photodistributed, involving the forehead, face, neck, and dorsal aspect of upper extremities.
Lesions typically appear and are exacerbated during the summer months and may improve
spontaneously in winter.
The diagnosis of ALP is based upon clinical and histologic features. On histology, lesions show
the typical findings of lichen planus (eg, vacuolar degeneration of the basal cell layer,
dyskeratotic cells, band-like lymphocytic dermal infiltrate) with marked pigmentary
incontinence.
The differential diagnosis of ALP includes discoid lupus erythematosus, polymorphous light
eruption, melasma, and granuloma annulare. (See "Overview of cutaneous lupus
erythematosus", section on 'Discoid lupus erythematosus' and "Photosensitivity disorders
(photodermatoses): Clinical manifestations, diagnosis, and treatment", section on
'Polymorphous light eruption' and "Melasma: Management" and "Granuloma annulare:
Epidemiology, clinical manifestations, and diagnosis".)
Multiple therapies in combination with sunscreens have been tried in individual patients with
ALP with varying outcomes. Therapies include photoprotection, topical and intralesional
corticosteroids, antimalarials, acitretin, and cyclosporin [163,165-167]. There is a single case
report of successful treatment of ALP with intense pulsed light [168].
Primary cutaneous amyloidosis — Amyloidosis encompasses a spectrum of disorders

characterized by the deposition of amyloid fibrils (insoluble aggregates of misfolded proteins,
some of which are constituents of plasma) within the skin and other tissues. Primary
cutaneous amyloidosis is a form of localized, organ-specific amyloidosis in which the amyloid
deposition is limited to the skin. It may be a feature of multiple endocrine neoplasia type 2A
and pachyonychia congenita [169,170]. (See "Cutaneous manifestations of amyloidosis".)
The pathogenesis of primary cutaneous amyloidosis is not fully understood. Prolonged

friction, genetic predisposition, Epstein-Barr virus infection, and sun exposure have been
proposed as possible etiologic factors, but their role remains inconclusive [171-173]. The
origin of the precursor protein in primary cutaneous amyloidosis is also unclear. One
hypothesis is that focal epidermal damage and filamentous degeneration of keratinocytes is
followed by apoptosis and conversion of filamentous masses into amyloid in the papillary
dermis [174].
The most common types of primary cutaneous amyloidosis are macular amyloidosis, lichen
amyloidosis, and biphasic amyloidosis [175]:
● Macular amyloidosis – Macular amyloidosis presents with hyperpigmented, pruritic

patches, exhibiting either a confluent configuration or a characteristic ripple pattern
with parallel bands or ridges of hyperpigmentation ( picture 36A-B). The rippled
pattern can be best appreciated by stretching the skin. The most common site of
involvement is the upper back, especially over the scapular area, followed by the
extensor surfaces of the extremities.

● Lichen amyloidosis – Lichen amyloidosis usually presents with persistent, pruritic

papules and plaques on the shins or other extensor surfaces of the extremities
( picture 37A-D). The initial lesions are discrete, firm, scaly, skin-colored, or
hyperpigmented papules, which later coalesce into plaques, often with a rippled
pattern. Lesions are usually unilateral at onset but can develop into a bilateral,
symmetrical distribution.
● Biphasic amyloidosis – In some patients, both macular and lichen amyloidosis can be
present, suggesting that the two forms may represent ends of a clinical spectrum.
● Amyloidosis cutis dyschromica – Amyloidosis cutis dyschromica is an exceedingly rare

type of primary cutaneous amyloidosis [176]. It is characterized by reticular
hyperpigmentation with hypopigmented macules distributed over nearly all of the body
( picture 38).
The diagnosis of cutaneous amyloidosis is based upon the clinical presentation and
histopathologic examination of a skin biopsy. Histology shows hyperkeratosis, necrotic
keratinocytes in the basal layer, and melanophages as well as amorphous eosinophilic
material (amyloid) deposits in the upper dermis.
There is no effective treatment for cutaneous amyloidosis. Several topical and systemic
therapies have been tried with inconsistent results, including topical and intralesional
corticosteroids, topical calcineurin inhibitors [177], systemic retinoids [178], thalidomide
[179], cyclosporine [180], low-dose cyclophosphamide, and narrowband ultraviolet B (UVB) or
psoralen plus ultraviolet A (PUVA) phototherapy [181]. Combination treatment (eg, ultraviolet
A1 [UVA1] phototherapy and high-potency topical corticosteroids) may provide optimum
results [182].
Terra firma-forme dermatosis — Terra firma-forme dermatosis is an acquired, idiopathic

condition characterized by retention hyperkeratosis, which results in the formation of dirt-like
plaques despite normal hygiene. It is relatively common and most often occurs in children
[183,184].
Lesions typically involve the neck, ankle (posterior to the medial or lateral malleolus), and
face but may also occur on other body areas ( picture 39A-B). Diagnosis and treatment can
be achieved by removing lesions with gentle isopropyl alcohol swabbing, with once-a-week
application as prophylaxis.
GENERAL PRINCIPLES OF TREATMENT
Treatment of cutaneous hyperpigmentation is challenging because of its chronic, persistent,

and relapsing nature. The approach to treatment involves the removal of provoking factors,

photoprotection, cosmetic camouflage, and a variety of pigment-reduction modalities,

including topical skin-lightening agents and laser therapy [185]. However, the various
treatment modalities for hyperpigmentation disorders have not been evaluated in high-
quality studies. In most cases, evidence for efficacy of topical or physical therapies is based
upon small series of patients or single-case reports and clinical experience.
Disorders associated with deposition of melanin in the epidermis (eg, melasma,

postinflammatory hyperpigmentation) usually respond to topical skin-lightening agents. In
contrast, disorders associated with deposition of melanin in the dermis do not respond to
topical therapies and may be successfully treated with lasers. (See 'Topical therapies' below
and "Laser and light therapy for cutaneous hyperpigmentation".)
Because sunlight is a major trigger of melanin synthesis, patients with hyperpigmentation

should adopt strict photoprotection measures. Cosmetic camouflage may be an option for
the management of facial hyperpigmentation.
Sun protection — All patients with hyperpigmentation disorders associated with increased

melanin production and deposition will benefit from sun avoidance and photoprotection,
which involves avoiding the peak hours of sunlight (between 11:00 AM and 4:00 PM), seeking
shade, wearing protective clothing (eg, broad-brimmed hats and long-sleeved shirts), and
using a broad-spectrum sunscreen with sun protection factor (SPF) of at least 30. The use of
tinted sunscreens that provide photoprotection against visible light, which has cutaneous
biologic effects (eg, pigment darkening and erythema), is increasingly recommended for
hyperpigmentation disorders [186]. (See "Selection of sunscreen and sun-protective
measures".)
Cosmetic camouflage — Physical-blocking opaque sunscreens and, in particular, those

containing iron oxide have the dual benefit of camouflaging hyperpigmentation and
preventing photo-induced darkening. Many of these physical blockers now come in tinted
blends to assist with camouflaging. In addition, many find that the use of make-up helps to
even out skin tone. (See "Melasma: Management", section on 'Cosmetic camouflage'.)
Topical therapies — Disorders associated with deposition of melanin in the epidermis (eg,

melasma, postinflammatory hyperpigmentation) can be often successfully treated with
topical skin-lightening agents. These include hydroquinone, azelaic acid, mequinol, kojic acid,
tretinoin, cysteamine, and several combinations of topical agents. Topical skin-lightening
agents are discussed in detail elsewhere. (See "Melasma: Management", section on 'Topical
skin-lightening agents'.)
Chemical peels — Chemical peels are an increasingly popular method for removal of

hyperpigmentation. Common peeling agents include alpha-hydroxy acids (eg, glycolic acid),
beta-hydroxy acids (eg, salicylic acid), trichloroacetic acid, Jessner's solution, and retinoids. In

skin of color, superficial to medium-depth peels are most typically used to reduce the risk of
scarring and dyspigmentation. (See "Chemical peels: Principles, peeling agents, and
pretreatment assessment" and "Chemical peels: Procedures and complications".)
Laser therapy — Hyperpigmentation disorders associated with melanin deposition in the

dermis (eg, nevus of Ota, nevus of Hori) do not respond to topical therapies but can be often
successfully treated with laser therapy [24]. In particular, quality-switched (Q-switched) lasers
(eg, 1064 nm Q-switched neodymium-doped yttrium aluminum garnet [Nd:YAG]) and
picosecond lasers are widely used for patients with darkly pigmented skin because of longer
wavelengths and short pulse durations, which allow for safe treatment.
The use of lasers for the treatment of specific hyperpigmentation disorders is discussed
separately. (See "Laser and light therapy for cutaneous hyperpigmentation".)
SOCIETY GUIDELINE LINKS
Links to society and government-sponsored guidelines from selected countries and regions
around the world are provided separately. (See "Society guideline links: Melasma and
hyperpigmentation disorders".)
SUMMARY AND RECOMMENDATIONS
● Pathophysiology – Skin hyperpigmentation is, in most cases, caused by increased

biosynthesis and deposition of melanin (hypermelanosis) in the epidermis and/or
dermis. Epidermal hypermelanosis results from an excess of melanin in the basal and
suprabasal layers of the skin due to increased melanin production. These abnormalities
may be due to both acquired and genetic factors. (See 'Pathophysiology of
hyperpigmentation' above.)
● Patient evaluation and diagnosis – The diagnosis of most hyperpigmentation

disorders is made on clinical grounds. The initial patient evaluation involves a detailed
medical history and a complete skin examination. Investigation of family history may be
helpful to determine whether the disorder is acquired or inherited. Skin examination
should be performed under visible light and Wood's light. Important clinical parameters
include:
• Extent of the pigmentary abnormality

• Color hue and morphology of individual lesions
• Distribution (circumscribed or diffuse)
• Pattern (linear, reticulate, nonpatterned)
• Stable or progressing
• Association with inflammation/cutaneous injury
An algorithmic approach to the diagnosis, based upon history and clinical parameters, is
shown in the figure ( algorithm 1). (See 'Patient evaluation and diagnosis' above and
'Circumscribed hyperpigmentation' above and 'Diffuse hyperpigmentation' above.)
● Treatment – Treatment of cutaneous hyperpigmentation is challenging because of its

chronic, persistent, and relapsing nature. The approach to management involves the
removal of provoking factors, photoprotection, cosmetic camouflage, and a variety of
pigment-reduction modalities, including topical skin-lightening agents and laser
therapy. (See 'General principles of treatment' above.)
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Season. JAMA Dermatol 2020; 156:99.
151. Rieder E, Kaplan J, Kamino H, et al. Lichen planus pigmentosus. Dermatol Online J 2013;
19:20713.
152. Kanwar AJ, Dogra S, Handa S, et al. A study of 124 Indian patients with lichen planus
pigmentosus. Clin Exp Dermatol 2003; 28:481.

153. Haber R, Dib N, Gemayel ME. Lichen Planus Pigmentosus Associated with Topical Olive
Oil Application. Skinmed 2021; 19:142.
154. Dlova NC. Frontal fibrosing alopecia and lichen planus pigmentosus: is there a link? Br J
Dermatol 2013; 168:439.
155. Pirmez R, Duque-Estrada B, Donati A, et al. Clinical and dermoscopic features of lichen
planus pigmentosus in 37 patients with frontal fibrosing alopecia. Br J Dermatol 2016;
175:1387.
156. Marques LC, Santos LR, da Silva NC, et al. Oral Lichen Planus Associated With Lichen
Planus Pigmentosus and Lichen Sclerosus in Monozygotic Twins. Am J Dermatopathol
2021; 43:368.
157. Al-Mutairi N, El-Khalawany M. Clinicopathological characteristics of lichen planus
pigmentosus and its response to tacrolimus ointment: an open label, non-randomized,
prospective study. J Eur Acad Dermatol Venereol 2010; 24:535.
158. Kim JE, Won CH, Chang S, et al. Linear lichen planus pigmentosus of the forehead treated
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39:189.
159. Han XD, Goh CL. A case of lichen planus pigmentosus that was recalcitrant to topical
treatment responding to pigment laser treatment. Dermatol Ther 2014; 27:264.
160. Wu CY, Lin FL. A successful combination therapy of tacrolimus, hydroxychloroquine and
picosecond laser for lichen planus pigmentosus. Australas J Dermatol 2019; 60:e336.
161. Shah P, Ugonabo N, Liebman TN. A case of recalcitrant lichen planus pigmentosus
treated by oral isotretinoin. JAAD Case Rep 2020; 6:812.
162. Kim GH, Mikkilineni R. Lichen planus actinicus. Dermatol Online J 2007; 13:13.
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166. Jansen T, Gambichler T, von Kobyletzki L, Altmeyer P. Lichen planus actinicus treated with
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167. Gallo L, Ayala F, Ayala F. Relapsing lichen actinicus successfully treated with cyclosporin. J
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168. Santos-Juanes J, Mas-Vidal A, Coto-Segura P, et al. Pigmented actinic lichen planus
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169. Tidman MJ, Wells RS, MacDonald DM. Pachyonychia congenita with cutaneous
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amyloidosis from north India. Indian J Dermatol 2012; 57:269.
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sequential change of epidermal keratinocytes to amyloid via filamentous degeneration. J
Invest Dermatol 1979; 73:150.
175. Hurabe K, Nakayama J, Hori Y. Cutaneous amyloidosis. In: The Pigmentary System: Physi
ology and Pathophysiology, 2nd ed, Nordlund J, Boissy RE, Hearing VJ, et al (Eds), Blackw
ell Publishing Ltd, 2006. p.924.
176. Qiao J, Fang H, Yao H. Amyloidosis cutis dyschromica. Orphanet J Rare Dis 2012; 7:95.
177. Castanedo-Cazares JP, Lepe V, Moncada B. Lichen amyloidosis improved by 0.1% topical
tacrolimus. Dermatology 2002; 205:420.
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clinical resolution with cyclosporine. Arch Dermatol 2001; 137:553.
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32:39.
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Retrospective Study of an Uncommon Skin Disease in the Largest Tertiary Care Center in
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Duncan's dirty dermatosis and literature review. Dermatol Pract Concept 2015; 5:29.
185. Halder RM, Nordlund JJ. Topical treatment of pigmentary disorders. In: The Pigmentary S
ystem: Physiology and Pathophysiology, 2nd ed, Nordlund JJ, Boissy RE, Hearing VJ, et al
(Eds), Blackwell Publishing Ltd, 2006.
186. Lyons AB, Trullas C, Kohli I, et al. Photoprotection beyond ultraviolet radiation: A review
of tinted sunscreens. J Am Acad Dermatol 2021; 84:1393.
Topic 89268 Version 24.0

GRAPHICS
Algorithm for the diagnosis of hyperpigmentation disorders
Reproduced with permission from: Lapeere H, Boone B, Schepper SD, et al. Hypomelanosis and hypermelanoses. In: Fitzpatrick's D
Gilchrest B, et al (Eds), McGraw-Hill, New York 2012. Copyright © 2012 McGraw-Hill Education.
Graphic 93949 Version 3.0

Key histopathologic findings in selected hyperpigmentation disorders
Selected disorders Key histopathologic findings
Acanthosis nigricans Hyperkeratosis and papillomatosis of the epidermis

Basal layer hyperpigmentation
Minimal acanthosis (misnomer)
Actinic lichen planus Variable with typical findings of lichen planus including
hyperkeratosis without parakeratosis, hypergranulosis,
irregular acanthosis with "saw-toothed" rete ridges,
liquefaction degeneration of the basal layer, and band-
like lymphocytic infiltrate at the dermal-epidermal
junction
Addison's disease [1] Increased basal layer melanin, sometimes melanin

incontinence
Becker's melanosis [2] Variable papillomatosis, acanthosis, and

hyperkeratosis
Regular elongation of the rete ridges with or without
pilosebaceous unit hyperplasia
May have increased hair follicles or smooth muscle
Café-au-lait macules [1] Increased melanin in the basal layer

Normal number of hyperactive melanocytes
Dermal melanocytosis [1] Spindle-shaped dendritic melanocytes in the deep

dermis with abundant fine granules of melanin
Diabetes mellitus - diabetic Dermal hemosiderin, increased papillary dermal blood

dermopathy [1] vessels, sparse perivascular lymphocytes
Diabetes mellitus - necrobiosis Diffuse palisaded and interstitial granulomatous

lipoidica dermatitis with tiers of granulomatous inflammation
(includes multinucleated histiocytes) aligned parallel to
the surface
Dowling-Degos Delicate, elongated, hyperpigmented rete ridges

Sometimes resembles a reticulated seborrheic
keratosis
Drug-induced hyperpigmentation [1] Variable depending on drug or chemical:

Minocycline: brown dermal pigment that is positive
with iron and melanin stains
Gold: chrysiasis pigment appears as black particles
Bleomycin: basal layer with increased melanin
Clofazimine: brown lipofuscin that stains with PAS
Amiodarone: brown pigment that stains with PAS

Ephelides [1] Increased melanin in basal layer

Normal or decreased number of hyperactive
melanocytes
Erythema dyschromicum perstans [1] Liquefaction degeneration of the basal layer

Melanin incontinence
Interface changes with perivascular or interface
lymphocytes
Erythromelanosis follicularis faciei et Hyperkeratosis

colli [3] Dilatation of superficial dermal blood vessels
Follicular plugging
Variable melanin in basal layer
Exogenous ochronosis [1] Yellow-brown "banana-shaped" deposits on

homogenized collagen bundles
Small yellow-brown granules in endothelial cells and
sweat glands
Hemochromatosis [1] Increased melanin in the basal layer

Hemosiderin deposits scattered in the dermis, usually
around blood vessels and sweat glands, best seen with
Perl's stain
Lentigines [1] Hyperpigmented, often elongated rete ridges, usually

with increased melanocytes
Lichen planus pigmentosus Similar to erythema dyschromicum perstans with

marked pigment incontinence and epidermal atrophy
Melasma [4] Increased melanin deposition in all layers of the

epidermis
Solar elastosis
More abundant mast cells
Nevus of Ota, Nevus of Ito, Hori's Normal epidermis

nevi [1] Spindle-shaped dendritic melanocytes in the dermis
with abundant fine granules of melanin
Nevus spilus Lentiginous melanocytic hyperplasia

Papular foci represent junctional, compound, blue,
Spitz, and/or atypical nevi
Periorbital hyperpigmentation [5,6] Dermal melanocytosis and melanin in upper dermal

macrophages (melanophages)
Post-chikungunya pigmentation [7,8] Intact basal layer with diffuse hypermelanosis of the
entire epidermis
Postinflammatory hyperpigmentation Increased or normal amount of melanin at basal layer,

with or without melanin incontinence based on

etiology
Primary cutaneous amyloidosis [1] Macular amyloidosis with subtle amyloid globules in
the papillary dermis in areas of melanin incontinence
Lichen amyloidosis with small deposits of amyloid in
the dermal papillae
Riehl's melanosis [1] Lymphocytic perivascular or interface dermatitis with

melanin incontinence
Smoker's melanosis Mucosal surface with basal layer melanosis, with or

without melanin incontinence
Terra firma-forme dermatosis [9] Prominent lamellar hyperkeratosis with focal areas
having compact orthokeratosis in whorls
PAS: periodic acid-Schiff.
References:
1. Rapini RP. Practical Dermatopathology, 2nd ed, Saunders, Philadelphia 2012.

2. Cohen PR. Becker's nevus. Am Fam Physician 1988; 37:221.
3. Kim MG, Hong SJ, Son SJ, et al. Quantitative histopathologic findings of erythromelanosis follicularis faciei et colli. J
Cutan Pathol 2001; 28:160.
4. Kang WH, Yoon KH, Lee ES, et al. Melasma: histopathological characteristics in 56 Korean patients. Br J Dermatol
2002; 146:228.
5. Malakar S, Lahiri K, Banerjee U, et al. Periorbital melanosis is an extension of pigmentary demarcation line-F on
face. Indian J Dermatol Venereol Leprol 2007; 73:323.
6. Watanabe S, Nakai K, Ohnishi T. Condition known as "dark rings under the eyes" in the Japanese population is a
kind of dermal melanocytosis which can be successfully treated by Q-switched ruby laser. Dermatol Surg 2006;
32:785.
7. Khanna N, Rasool S. Facial melanoses: Indian perspective. Indian J Dermatol Venereol Leprol 2011; 77:552.
8. Inamadar AC, Palit A, Sampagavi VV, et al. Cutaneous manifestations of chikungunya fever: observations made
during a recent outbreak in south India. Int J Dermatol 2008; 47:154.
9. Browning J, Rosen T. Terra firma-forme dermatosis revisited. Dermatol Online J 2005; 11:15.

Ephelides (freckles)
Numerous ephelides on the face of a child with red hair. Note a tendency for confluence
in some areas.
Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved.

Disorders associated with multiple lentigines
Features of
Disorder Genetics Other manifestations
lentigines
Generalized
Noonan syndrome AD Onset in Electrocardiogram

with multiple PTPN11 infancy/early changes
lentigines (nonreceptor childhood Ocular hypertelorism
(LEOPARD protein tyrosine Generalized Pulmonary stenosis,
syndrome) phosphatase) Spare oral mucosa hypertrophic obstructive
RAF1 Also café-noir and cardiomyopathy
café-au-lait macules Abnormal genitalia
Retardation of growth and
intellectual disability
Deafness
Also triangular facies,
skeletal abnormalities
Carney complex AD Onset in early Atrial myxomas

(NAME/LAMB PRKAR1A (type 1- childhood, but the Mucocutaneous myxomas
syndrome) alpha regulatory full distribution is (often on eyelids, ears,
subunit of not seen until nipples)
protein kinase A) puberty Blue nevi (epithelioid
Generalized variant)
May involve eyelids, Pigmented nodular
conjunctiva, adrenocortical disease
vermilion border of Pituitary, thyroid, and
lips, genitals testicular (calcifying
Usually spare oral Sertoli cell) tumors
mucosa Myxoid mammary
fibroadenomas
Psammomatous
melanotic schwannomas
Arterial dissection AD versus AR Onset in childhood Dissection of aortic,

Generalized internal carotid, and
vertebral arteries
Localized
Peutz-Jeghers AD Onset in Multiple hamartomatous

syndrome STK11 infancy/early gastrointestinal polyps
(serine/threonine childhood (intussusception may
protein kinase Perioral (may fade), occur)
11) oral mucosa Increased incidence of
(persist), hands, gastrointestinal, ovarian,
feet testicular, cervical
Longitudinal (adenoma malignum),

melanonychia pancreatic, and breast
cancers
Laugier-Hunziker AD As in Peutz-Jeghers None

syndrome ? Also genital May see similar lesions in
melanosis patients receiving
zidovudine (AZT)
Cowden disease AD Onset in childhood Facial trichilemmomas

PTEN to young adulthood Oral mucosal
(phosphatase Periorificial and cobblestoning
and tensin acral lentigines Acral keratoses
homolog) (occasionally seen) Lipomas, sclerotic
Café-au-lait fibromas
macules Macrocephaly, adenoid
facies, mental retardation
Thyroid
adenomas/carcinoma
Breast
fibroadenomas/carcinoma
Gastrointestinal
hamartomas/carcinoma
Uterine
fibroids/carcinoma
Bannayan-Riley- AD Genital melanosis Capillary and/or venous

Ruvalcaba PTEN Café-au-lait malformations
syndrome (phosphatase macules Lipomas
and tensin Facial trichilemmomas
homolog) Acanthosis nigricans
Macrocephaly, mental
retardation
Gastrointestinal
hamartomas
Thyroid tumors
Centrofacial AD Onset in infancy; Neuropsychiatric

lentiginosis ? increase in number disorders
in childhood Osseous anomalies
Butterfly
distribution on
nose and cheeks >
forehead, eyelids,
upper lip
Inherited AD Central face, lips > None

patterned Black buttocks, elbows,
lentiginosis individuals with hands, feet

light brown skin Usually spare oral

mucosa
Partial unilateral ? Onset in childhood, May be associated with

lentiginosis ? with wavefront segmental
extension over time neurofibromatosis
Segmental A few reports of
distribution (no associated mental
background retardation and seizures
hyperpigmentation)
Often have café-au-
lait macules in
same area
Can have ocular
lesions
Xeroderma AR Favor (but not Photosensitivity

pigmentosum XP-A through G limited to) sun- Markedly increased
and variant exposed sites incidence of basal and
(abnormal (represent solar squamous cell carcinomas
nucleotide lentigines) and melanoma
excision repair) Also increased incidence
of internal malignancies
CNS degeneration in a
subset of patients
Neurofibromatosis AD "Freckling" (actually Cutaneous neurofibromas

type 1 NFI represents Lisch nodules (iris
(neurofibromin) lentigines) favors hamartomas)
flexural sites (neck, Optic glioma
axillae, groin), but
Distinct bone lesions (eg,
may be generalized
sphenoid dysplasia)
≥6 café-au-lait
Macrocephaly
macules (in 80 to
Learning disabilities
90% of patients)
Legius AD Intertriginous Lacks neurofibromas,

(neurofibromatosis SPRED1 (Sprouty- "freckling" (actually Lisch nodules, optic
type 1-like) related EVH1 lentigines) in gliomas, and typical
syndrome domain approximately half osseous lesions of
containing of patients neurofibromatosis type 1
protein 1) ≥6 café-au-lait Macrocephaly and
macules in >80% of learning disabilities are
patients common
Occasionally lipomas,
hypopigmented macules,
and vascular anomalies
LEOPARD: lentigines, electrocardiogram abnormalities, ocular hypertelorism, pulmonic stenosis,

abnormal genitalia, retardation of growth, and sensorineural deafness; AD: autosomal dominant;
NAME: nevi, atrial myxoma, ephelides; LAMB: lentigines, atrial myxoma, blue nevi; AR: autosomal
recessive; CNS: central nervous system.

Solar lentigines
Multiple irregular, light brown macules are present on the face of this
patient.

Solar lentigines
Clinical image of multiple solar lentigines on the forehead.

Solar lentigines presenting as brown macules on

the dorsum of the hand
Multiple brown macules are present on the dorsal hand.
Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights

reserved.

Solar lentigines
Numerous small solar lentigines on the photodamaged skin of the upper chest.

Solar lentigines
Solar lentigines typically present as small, well-circumscribed, brown macules on

sun-exposed areas.

Laugier-Hunziker syndrome
Hyperpigmented gingival maculae in a 38-year-old White female with Laugier-Hunziker syndrome.
Reproduced with permission from: Diepgen TL, Yihune G, et al. Dermatology Online Atlas. Published online at: www.dermis.net.
Copyright © 1996-2015 DermIS. All rights reserved.

Cronkhite-Canada syndrome
Onychodystrophy in the case patient.
Reprinted by permission from: Macmillan Publishers Ltd: Sweetser S, Alexander GL,

Boardman LA. A case of Cronkhite-Canada syndrome presenting with adenomatous
and inflammatory colon polyps. Nat Rev Gastroenterol Hepatol 2010; 7:460.
Copyright © 2010.

Labial melanotic macule
A brown hyperpigmented macule is visible on the lower lip of this patient.

Oral melanotic macule
A darkly pigmented macule is present on the gingival mucosa.
Image created by Carl Allen, DDS, MSD. Reproduced with permission from: www.visualdx.com.

Oral melanotic macule
Image created by Carl Allen, DDS, MSD. Reproduced with permission from: www.visualdx.com.

Becker's nevus (Becker's melanosis)
Becker's nevus presenting as a large, slightly hyperpigmented patch on the left shoulder
of a boy. Note the hyperpigmented "islands" at the periphery of the lesion.

Becker's nevus (Becker's melanosis)
Note the hypertrichosis and "islands" of hyperpigmentation.
Courtesy of Jean L Bolognia, MD, and Julie V Schaffer, MD.

Maturational dyschromia
Maturational dyschromia is an uneven, ill-defined

hyperpigmentation of the face most commonly seen in mature dark
skin.

Poikiloderma of Civatte
Chronic sun damage is associated with the development of

poikiloderma of Civatte, which typically presents as redness,
telangiectasias, and mottled hyperpigmentation on the lateral neck.

reserved.

Postinflammatory hyperpigmentation
In this patient, healing acne was the cause of the postinflammatory

hyperpigmented patch.
Reproduced with permission from: Goodheart HP. Goodheart's Photoguide of

Common Skin Disorders, 2nd ed. Lippincott Williams & Wilkins, Philadelphia 2003.
Copyright © 2003 Lippincott Williams & Wilkins.

Postinflammatory hyperpigmentation secondary to pseudofolliculitis barbae.

Postinflammatory hyperpigmentation secondary to burn.

Pigmented contact dermatitis (Riehl's melanosis)
Gray-brown, reticular facial pigmentation in a 33-year-old man with

Riehl's melanosis.
Reproduced with permission from: The Dermatology Online Atlas, www.dermis.net.

Copyright © 2013. All rights reserved.

Erythromelanosis follicularis faciei et colli
Erythematous patches with telangiectasias and follicular papules in a 19-year-old girl

with a history of redness and roughness of the cheeks since early childhood.
Reproduced with permission from: Augustine M, Jayaseelan E. Erythromelanosis follicularis faciei et colli:
Relationship with keratosis pilaris. Indian J Dermatol Venereol Leprol 2008: 74:47. Copyright © 2008
Medknow. All rights reserved.

Erythema dyschromicum perstans (ashy dermatosis)
Asymptomatic gray/blue macules on the trunk and proximal extremities are

characteristics of erythema dyschromicum perstans (ashy dermatosis), an
acquired hypermelanosis of unknown etiology.
Image created by Jeffrey Callen, MD. Reproduced with permission from: www.visualdx.com.
Copyright VisualDx. All rights reserved.

Erythema dyschromicum perstans (ashy

dermatosis)
Numerous light blue-gray, "ashy" macules on the arm of a patient

with erythema dyschromicum perstans.

Lichenoid drug eruption
A lichenoid drug eruption manifesting as violaceous and

hyperpigmented papules is present in this patient with dark skin.

reserved.

Atrophoderma of Pasini and Pierini
Multiple hyperpigmented, atrophic areas on the back.

Atrophoderma of Pasini and Pierini
Well-demarcated, depressed areas of the skin with subtle hyperpigmentation.

Fixed drug eruption
On darkly pigmented skin, fixed drug eruption presents as a dark brown/slate-gray patch.

Fixed drug eruption
Fixed drug eruptions (A) typically resolve with postinflammatory

hyperpigmentation (B).
Copyright © Chris Ha, MD, DermAtlas; http://www.dermatlas.org.

Multiple (generalized) fixed drug eruption
Generalized fixed drug eruption is an uncommon variant characterized by

multiple and disseminated brown macules or plaques involving the trunk
and extremities.

Exogenous ochronosis
Blue-gray discoloration of the skin with characteristic pinpoint, caviar-like papules on

the cheek of a patient with exogenous ochronosis associated with a prolonged use of
topical hydroquinone.

Some potential causes of phytophotodermatitis*
Plant family Common name(s)
Apiaceae (Umbelliferae) Angelica
Celery
Cow parsley, wild chervil
Cow parsnip, hogweed
Dill
Fennel
Giant hogweed
Parsley
Parsnip
Rutaceae Bergamot orange
Bitter orange
Burning bush, gas plant
Grapefruit
Lemon
Lime
Rue
Moraceae Fig
Fabaceae (Leguminosae) Bavachee, scurf-pea (Psoralea corylifolia)
Cruciferae Mustard
Ranunculaceae Buttercup
Hypericaceae St. John's wort (can cause systemic phytophotodermatitis)
* Other plants have also been implicated.

Phytophotodermatitis
Meadow grass-induced phytophotodermatitis. The bizarre, linear

hyperpigmented lesions on the lower leg correspond to the areas of
contact with the grass.

reserved.

Phytophotodermatitis
Linear, hyperpigmented lesions distributed in a bizarre pattern in a patient with phytophotodermatitis.

The lesions typically mark the skin areas that had come in contact with the offending substance.

Classes of drugs and chemicals associated with skin and mucous

membrane hyperpigmentation
Drug or
Class Clinical features
chemical
Chemotherapeutic Bleomycin Linear, flagellate bands

agents Hyperpigmentation over joints, striae, and/or
palmar creases
Busulfan, Diffuse hyperpigmentation of the skin and mucous

cyclophosphamide, membranes
procarbazine Pigment localized to the nails, palms/soles, or teeth
Cisplatin, Hyperpigmentation overlying the small joints of the

docetaxel, hands and involving the palmar creases,
doxorubicin, palms/soles, and oral mucosa including the tongue
idarubicin
Fluorouracil Hyperpigmentation in sun-exposed areas

Pigmentation along veins used for infusions*
Hydroxyurea Hyperpigmentation over pressure points and on the

back
Methotrexate Hyperpigmentation in sun-exposed areas and hair
Antimalarials Aminoquinolines Gray-blue pigmentation on pretibial surfaces and

also the face, hard palate, sclerae, and subungual
areas
Hormones Oral Hyperpigmentation of the nipples

contraceptives Increased pigmentation of nevi
Hyperpigmented patches of the face (melasma)
Heavy metals Arsenic Areas of bronze hyperpigmentation
Gold (chrysiasis) Permanent blue-gray pigmentation in sun-exposed

areas, especially periorbital
Iron Permanent brown pigment at injection or

application sites
Lead Pigmentation at gingival margin
Mercury Slate-gray discoloration, especially in skin folds
Silver (argyria) Generalized slate-gray discoloration, increased in

sun-exposed areas, nails, sclerae, oral mucosa, or
application sites

Prostaglandin Bimatoprost, Increased brown pigmentation of iris, eyelids,

agonists latanoprost, eyelashes, and periorbital skin
tafluprost,
travoprost,
unoprostone
Smoking Nicotine and other Brown hyperpigmented lesions of oral mucosa, lips,
substances in and gingiva (smoker's melanosis)
tobacco smoke
Miscellaneous Amiodarone Slate-gray discoloration in sun-exposed areas,

especially face
Clofazimine Diffuse red-brown discoloration of the skin

Blue-brown to violaceous discoloration in lesional
skin
Diltiazem Slate-gray-brown pigmentation of sun-exposed

areas, especially in darker skin types, may have
perifollicular accentuation and reticulated pattern
Ezogabine Blue-gray discoloration of skin, nails, conjunctivae,

and oral mucosa
Minocycline ¶ Generalized "muddy" brown discoloration

Blue-black discoloration in old acne scars or sites of
inflammation as well as lower extremities
Pigmentation may also involve the nails, sclerae, oral
mucosa, bones, thyroid, and teeth
Psoralens Increased skin pigmentation after exposure to

ultraviolet A light
Psychotropic drugs Slate-gray pigmentation in sun-exposed areas

(amitriptyline,
chlorpromazine,
desipramine,
imipramine,
thioridazine)
Tacrolimus, topical Brown pigmented macules at application sites
Zidovudine Mucocutaneous hyperpigmentation that can be

widespread/diffuse, acral, or on oral mucosa
Drug and chemical exposures associated with skin hyperpigmentation. Drug-associated skin
hyperpigmentation generally affects sun-exposed areas and may also involve mucous
membranes. Clinical features vary; pigmentation often fades slowly and incompletely following
withdrawal of the offending agent.

* Pigmentation along veins for infusion is also associated with vinorelbine, cisplatin, docetaxel,
and other chemotherapeutic infusions.
¶ Skin discoloration is described less frequently with use of tetracyclines other than minocycline;
this may be due to more frequent prolonged courses of treatment and higher cumulative doses in
use of minocycline (eg, in acne treatment) relative to the other tetracyclines.
Adapted from: Kang S, Lerner EA, Sober AJ, Levine N. Pigmentary disorders from exogenous causes. In: Pigmentation and
Pigmentary Disorders, Levine N (Ed), CRC Press, 1993. Updated with data from Krause W. Drug-induced
hyperpigmentation: A systematic review; J Dtsch Dermatol Ges 2013; 11:644.

Flagellate hyperpigmentation
Multiple linear, hyperpigmented streaks in a patient treated with bleomycin.

Erythema ab igne
A reticular, erythematous and hyperpigmented area on the back of a

patient who used to sit in close proximity of a heating radiator.
Reproduced with permission from: Wolters Kluwer Health. Copyright © 2011.

Erythema ab igne
Reticular hyperpigmentation on the back of a patient who used to sit with his back in
proximity of a heating source.

Erythema ab igne with residual hyperpigmentation
Reproduced with permission from: Berg D, Worzala K. Atlas of Adult Physical

Diagnosis. Philadelphia: Lippincott Williams & Wilkins, 2006. Copyright © 2006
Lippincott Williams & Wilkins.

Confluent and reticulated papillomatosis
Hyperpigmented, reticulated plaques with fine scale on the back.

Confluent and reticulated papillomatosis
Reticulated, hyperpigmented patches and thin plaques with mild

scale are present on the chest and inframammary areas.

reserved.

Hyperpigmentation in Addison disease
(A) A 57-year-old female presented with symptoms of primary adrenal insufficiency

secondary to autoimmune Addison disease. Diffuse skin hyperpigmentation had
developed during the last year, as illustrated by her facial appearance.
(B) The hands demonstrate increased pigmentation of the palmar creases and wrists
compared to a healthy female control (far right).
(C) With long-term glucocorticoid and mineralocorticoid therapy, her hyperpigmentation

resolved, as shown by the normal palmar skin pigmentation in the patient at age 83.
Of note, she wears a medical bracelet indicating her requirement for glucocorticoids in
case of severe illness.
Courtesy of André Lacroix, MD.

Black tongue in Addison disease

Hyperpigmentation of nails in primary adrenal

insufficiency
Fingers of a patient with Addison's disease beneath fingers of an

individual with similar baseline skin pigmentation without Addison's
disease. In the patient with Addison's disease, there is
hyperpigmentation of the skin and increased pigmentation of the
distal portion of the nails. The proximal portion of the nails are not
hyperpigmented, reflecting the reduction in corticotropin (ACTH)
secretion following the initiation of glucocorticoid therapy.
Courtesy of David N Orth, MD.

Diabetic dermopathy
Small brown spots on the shins of a patient with diabetes mellitus.

Acanthosis nigricans
A hyperpigmented, velvety plaque is present on the neck of this patient with acanthosis
nigricans.

Diffuse melanosis cutis and melanuria in a patient

with metastatic melanoma
Clinical and histologic findings in diffuse melanosis cutis. Patient #1

with blue-gray patches on his back (A), histologically confirmed as
diffuse melanosis cutis, and melanuria (B) manifesting after 2
infusions of pembrolizumab. Patient #2 demonstrated diffuse
melanosis cutis affecting his face and upper body (C) as well as
melanuria (D) after only 1 infusion of pembrolizumab. Histologic
examination (E) of dark gray patches on the neck of patient #2
showed characteristic changes of diffuse melanosis cutis with
perivascular and interstitial groups of histiocytes (melanophages)
with small-grained melanin below a regular epidermis (indicated by
black arrows; hematoxylin and eosin staining, magnification 200,
inlay 400).
From: Thiem A, Schummer P, Ueberschaar S, et al. Early onset of diffuse melanosis

cutis under pembrolizumab therapy illustrates the limitations of anti-PD-1
checkpoint inhibitors. Melanoma Res 2018; 28:465. DOI:
10.1097/CMR.0000000000000458. Copyright © 2018. Reproduced with permission
from Wolters Kluwer Health. Unauthorized reproduction of this material is
prohibited.

Histopathologic features of post-chikungunya fever hyperpigmentation
Increased basal pigmentation with melanophages and perivascular lymphocytic infiltrate in pigmented
macules (H&E, 40x).
H&E: hematoxylin and eosin.
Reproduced with permission from: Erkek E, Sahin S, Çetin ED, Sezer E. Terra firma-forme dermatosis. Indian J Dermatol Venereol Le
2012; 78:358. Copyright © 2012 Scientific Scholar.

Persistent facial hypermelanosis following chikungunya fever
This patient developed a reticular hypermelanosis of the facial skin soon after the rash associated
with chikungunya fever had resolved.
From: Bandyopadhyay D, Ghosh SK. Mucocutaneous manifestations of Chikungunya fever. Indian J Dermatol 2010; 55:64.
DOI: 10.4103/0019-5154.60356. Reproduced with permission from Wolters Kluwer - MedKnow. Copyright © 2010 Asian
Academy of Dermatology and Venereology. Unauthorized reproduction of this material is prohibited.

Facial hyperpigmentation associated with chikungunya fever
Persistent hyperpigmentation of the nose following chikungunya fever.
Reproduced with permission from: Erkek E, Sahin S, Çetin ED, Sezer E. Terra firma-forme dermatosis. Indian J
Dermatol Venereol Leprol 2012; 78:358. Copyright © 2012 Scientific Scholar.

Lichen planus pigmentosus
Multiple hyperpigmented macules on the back and abdomen of a patient with lichen planus pigmentosus
Reproduced with permission from: Diepgen TL, Yihune G, et al. Dermatology Online Atlas. Published online at: www.dermis.net.
Copyright © 1996-2015 DermIS. All rights reserved.

Macular amyloidosis
A characteristic rippled pattern of pigmentation in a patient with macular amyloidosis.

Macular amyloidosis
A characteristic rippled pattern of pigmentation on the leg of a patient with macular

amyloidosis.

Lichen amyloidosis
Hyperpigmented plaques on the extensor surfaces of the legs in a patient with lichen
amyloidosis. The plaques, which result from coalescing papules, are persistent and
intensely pruritic.

Lichen amyloidosis
Firm, hyperpigmented papules, some of which coalesce into plaques, on the buttocks of
a patient with lichen amyloidosis.
https://www.uptodate.com/contents/acquired-hyperpigmentation-disorders/print?search=Layers of skin&source=search_result&selectedTitle… 100/106

Cutaneous lichen amyloidosis in a patient with MEN2
The skin lesion is usually described as pruritic, scaly, papular,

pigmented, and located in the interscapular region or on the extensor
surfaces of the extremities. Amyloid deposition has been documented
histologically.
MEN2: multiple endocrine neoplasia type 2.
Courtesy of Cornelis J Lips, MD.

Cutaneous lichen amyloidosis in a patient with MEN2
The skin lesion is usually described as pruritic, scaly, papular,

pigmented, and located in the interscapular region or on the extensor
surfaces of the extremities. Amyloid deposition has been documented
histologically.
MEN2: multiple endocrine neoplasia type 2.
Courtesy of Cornelis J Lips, MD.

Amyloidosis cutis dyschromica
Multiple hypopigmented and depigmented macules are visible on

the upper back of a 26-year-old woman with amyloidosis cutis
dyschromica.
From: Kurian SS, Rai R, Madhukar ST. Amyloidosis cutis dyschromica. Indian
Dermatol Online J 2013; 4:344. DOI: 10.4103/2229-5178.120678. Reproduced with
permission from Wolters Kluwer - MedKnow. Copyright © 2013 Indian Association of
Dermatologists, Venereologists and Leprologists. Unauthorized reproduction of this
material is prohibited.

Terra firma-forme dermatosis
(A) Brown-gray, pigmented patches on the abdomen with islands of normal skin.
(B) Remarkable response to wiping of pigmented patches with a gauze pad saturated with isopropyl alcoh
2012 Scientific Scholar.

Terra firma-forme dermatosis
Thick, reticulated, brown plaques on the back of a 20-year-old man with terra firma-forme dermatosis. No
skin in the areas wiped with 70% ethyl alcohol.
2012 Scientific Scholar.

Contributor Disclosures
Neelam Vashi, MD Consultant/Advisory Boards: Janssen Pharmaceuticals [Cosmetics, discoloration,
hyperpigmentation]; Pfizer [Cosmetics, discoloration, hyperpigmentation]; Procter & Gamble
[Cosmetics, discoloration, hyperpigmentation]. All of the relevant financial relationships listed have
been mitigated. Roopal V Kundu, MD No relevant financial relationship(s) with ineligible companies to
disclose. Erik Stratman, MD No relevant financial relationship(s) with ineligible companies to
disclose. Rosamaria Corona, MD, DSc No relevant financial relationship(s) with ineligible companies to
disclose.
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these
are addressed by vetting through a multi-level review process, and through requirements for references
to be provided to support the content. Appropriately referenced content is required of all authors and
must conform to UpToDate standards of evidence.
Conflict of interest policy

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1/6/23, 16:56 Acquired hyperpigmentation disorders - UpToDate

Official reprint from UpToDate®

Literature review current through: May 2023.

Disorders of cutaneous discoloration comprise a large group of skin conditions characterized

Hyperpigmentation is a feature of a multitude of clinical conditions, ranging from normal

● (See "Melasma: Epidemiology, pathogenesis, clinical presentation, and diagnosis".)

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Melanin — Melanin is produced by melanocytes, specialized cells of neural crest origin that

Melanin synthesis is triggered by the hydroxylation of L-phenylalanine to L-tyrosine or

Hypermelanosis — Skin hyperpigmentation is, in most cases, caused by increased

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● Production of melanin by ectopic dermal melanocytes. Examples of dermal

● Binding of melanin to exogenous pigments deposited in the dermis.

Other pigments — Cutaneous hyperpigmentation can be caused by the deposition in the

PATIENT EVALUATION AND DIAGNOSIS

The diagnosis of hyperpigmentation disorders may be challenging. An algorithmic approach

● Is the disorder congenital or acquired?

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Skin examination — In all patients with hyperpigmentation disorders, a complete skin

● Extent of the pigmentary abnormality (localized versus diffuse)

● Epidermal hypermelanosis – Under natural light, epidermal hypermelanosis appears

● Dermal hypermelanosis – Under natural light, dermal hypermelanosis has a bluish or

● Mixed hypermelanosis – Mixed hypermelanosis appears light to dark brown under

Dermoscopy — Dermoscopy (dermatoscopy) refers to skin examination using

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Reflectance confocal microscopy — In vivo reflectance confocal microscopy is a technique

Ephelides — Ephelides, or freckles, are small, well-demarcated, hyperpigmented macules

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Other than for cosmetic purposes, treatment of lentigines is unnecessary. Therapeutic

Psoralen plus ultraviolet A lentigines — Psoralen plus ultraviolet A (PUVA) lentigines are

Partial unilateral lentiginosis — Partial unilateral lentiginosis (PUL) is a rare disorder

In a minority of cases, PUL may be a manifestation of segmental neurofibromatosis type 1

Laugier-Hunziker syndrome — Laugier-Hunziker syndrome is an acquired, benign disorder

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Cronkhite-Canada syndrome — Cronkhite-Canada syndrome is a rare, noninherited

Cronkhite-Canada syndrome is a progressive disease with variable course and poor

Oral melanotic macule — Oral melanotic macules are small, well-circumscribed, brown-to-

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Dermatosis papulosa nigra — Dermatosis papulosa nigra (DPN) is a common benign

Smoker's melanosis — Smoker's melanosis is characterized by irregular macular

melanoacanthoma, and mucosal melanoma. (See "Oral lesions", section on 'Pigmented

Becker's melanosis — Becker's melanosis, also called Becker's nevus, is a benign cutaneous

Maturational hyperpigmentation — Darkening of facial skin tone is frequently seen in

The etiopathogenesis of maturational hyperpigmentation remains unclear. Chronic sun

Maturational hyperpigmentation is a diagnosis of exclusion. It is most commonly confused

Treatment includes sun-protective measures and topical skin-lightening agents. (See

Periorbital hyperpigmentation — Periorbital hyperpigmentation, also called idiopathic

The cause of periorbital hyperpigmentation is multifactorial. Contributing factors include

There are no therapies of proven efficacy for periorbital hyperpigmentation. Treatment

Melasma — Melasma is an acquired hyperpigmentation of the skin that typically affects the

Poikiloderma of Civatte — Poikiloderma of Civatte (PC) is a common disorder characterized

Histologically, PC is characterized by thinning of the spinous layer, hydropic degeneration of

Nevus of Hori — Acquired bilateral nevus of Ota-like macules (ABNOM), or nevus of Hori, is a

Postinflammatory hyperpigmentation — Postinflammatory hyperpigmentation is a

The clinical presentation, diagnosis, and treatment of postinflammatory hyperpigmentation

Riehl's melanosis — Riehl's melanosis or pigmented contact dermatitis is a dermal

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Treatment involves complete avoidance of the suspected allergen. Sun-protective measures,

Erythrose péribuccale pigmentaire de Brocq — A rare form of facial hyperpigmentation

Histologic examination shows orthokeratotic hyperkeratosis, no specific inflammatory

Erythromelanosis follicularis faciei et colli — Erythromelanosis follicularis faciei et colli is a

There is no effective treatment for erythromelanosis follicularis faciei et colli. Topical

Erythema dyschromicum perstans — Erythema dyschromicum perstans (EDP), also called